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de Castro III, Carlos Manuel

Overview:

Clinical research projects have focused on new and innovative treatments for myelodysplastic syndromes, paroxysmal nocturnal hemoglobinuria, adult leukemias, and lymphomas

Positions:

Professor of Medicine

Medicine, Hematologic Malignancies and Cellular Therapy
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1985

M.D. — University of Texas at Dallas

Resident, Medicine

University of Texas at Dallas

Fellow In Hematology Oncology, Medicine

Duke University

Grants:

EQAPOL - Years 2017 to 2024 - BASE

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Director
Start Date
September 30, 2017
End Date
September 29, 2024

RA101495-01-202

Administered By
Duke Cancer Institute
AwardedBy
Ra Pharmaceuticals, Inc
Role
Principal Investigator
Start Date
June 14, 2017
End Date
June 30, 2022

RA101495-01.203

Administered By
Duke Cancer Institute
AwardedBy
Ra Pharmaceuticals, Inc
Role
Principal Investigator
Start Date
June 14, 2017
End Date
June 30, 2022

GS US 339 1559

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
February 21, 2017
End Date
March 24, 2022

ALXN1210-PNH-301

Administered By
Duke Cancer Institute
AwardedBy
Alexion Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
March 24, 2017
End Date
March 23, 2022

Phase II study to evaluate safety of Azacitidine PLUS Durvalumab (medi4736) in MDS/AML

Administered By
Duke Cancer Institute
AwardedBy
Celgene Corporation
Role
Principal Investigator
Start Date
November 17, 2016
End Date
December 19, 2021

SGN33A-005 CASCADE

Administered By
Duke Cancer Institute
AwardedBy
Seattle Genetics, Inc
Role
Principal Investigator
Start Date
December 15, 2016
End Date
December 14, 2021

AC220-A-U302 QuANTUM-First

Administered By
Duke Cancer Institute
AwardedBy
Daiichi Sankyo Inc
Role
Principal Investigator
Start Date
August 22, 2016
End Date
August 21, 2021

Pevonedistat-2001

Administered By
Duke Cancer Institute
AwardedBy
Millennium Pharmaceuticals, Inc.
Role
Principal Investigator
Start Date
August 15, 2016
End Date
August 14, 2021

A Study to Evaluate Imetelstat (JNJ-63935937) in Transfusion-Dependent subjects with IPSS Low or Intermediate-1

Administered By
Duke Cancer Institute
AwardedBy
Janssen Research & Development, LLC
Role
Principal Investigator
Start Date
July 01, 2016
End Date
June 30, 2021

Phase III study of AG-221(CC-90007) with late AML harboring Isocitrate Dehydrogenase 2 mutation

Administered By
Duke Cancer Institute
AwardedBy
Celgene Corporation
Role
Principal Investigator
Start Date
May 01, 2016
End Date
April 30, 2021

An Open Label study to assess the safety of APL-2 as an Add-on to standard of care in subjects with PNH

Administered By
Duke Cancer Institute
AwardedBy
Apellis Pharmaceuticals, Inc
Role
Principal Investigator
Start Date
December 01, 2014
End Date
November 30, 2019

EQAPOL - 2016 to 2017 - Option 6 - BASE

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Director
Start Date
September 30, 2010
End Date
September 29, 2017

EQAPOL Option 5

Administered By
Duke Human Vaccine Institute
AwardedBy
National Institutes of Health
Role
Investigator
Start Date
September 30, 2010
End Date
September 29, 2017

Role Of C-Kit In Early Hematopoiesis

Administered By
Medicine, Medical Oncology
AwardedBy
National Institutes of Health
Role
Principal Investigator
Start Date
July 01, 1991
End Date
June 30, 1996
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Publications:

A multicenter, phase II study of maintenance azacitidine in older patients with acute myeloid leukemia in complete remission after induction chemotherapy.

Older patients with acute myeloid leukemia (AML) have poor outcomes, with median durations of complete remission lasting less than 1 year. Increased toxicity in older patients limits the delivery of standard consolidation therapies, such as allogeneic stem cell transplant or high-dose cytarabine. Azacitidine, a nucleoside analog/DNA methyltransferase inhibitor, has demonstrated significant activity and favorable tolerability in patients unable to tolerate intensive induction chemotherapy; however, the role of azacitidine in the maintenance setting has not been fully evaluated. We undertook a pilot study of low-dose subcutaneous azacitidine [50 mg/(m(2) day)] for 5 days every 4 weeks) in AML patients ≥60 years of age in first remission following standard induction therapy. The primary objective was to determine the 1-year disease-free survival (DFS); secondary objectives were to determine safety and tolerability. We enrolled 24 patients (median age 68, range 62-81 years), the majority of whom received anthracycline-cytarabine induction regimens. From the time of first complete remission, the estimated 1-year DFS was 50% and the median overall survival was 20.4 months. Thrombocytopenia and neutropenia were the most common grade 3/4 toxicities (50 and 58%, respectively). In our study population, maintenance therapy with subcutaneous azacitidine was safe and well tolerated.

Authors
Griffin, PT; Komrokji, RS; De Castro, CM; Rizzieri, DA; Melchert, M; List, AF; Lancet, JE
MLA Citation
Griffin, PT, Komrokji, RS, De Castro, CM, Rizzieri, DA, Melchert, M, List, AF, and Lancet, JE. "A multicenter, phase II study of maintenance azacitidine in older patients with acute myeloid leukemia in complete remission after induction chemotherapy." American journal of hematology 90.9 (September 2015): 796-799.
PMID
26089240
Source
epmc
Published In
American Journal of Hematology
Volume
90
Issue
9
Publish Date
2015
Start Page
796
End Page
799
DOI
10.1002/ajh.24087

Myelodysplastic syndromes, version 2.2015 featured updates to the NCCN guidelines

© JNCCN-Journal of the National Comprehensive Cancer Network. The NCCN Guidelines for Myelodysplastic Syndromes (MDS) comprise a heterogeneous group of myeloid disorders with a highly variable disease course that depends largely on risk factors. Risk evaluation is therefore a critical component of decision-making in the treatment of MDS. The development of newer treatments and the refinement of current treatment modalities are designed to improve patient outcomes and reduce side effects. These NCCN Guidelines Insights focus on the recent updates to the guidelines, which include the incorporation of a revised prognostic scoring system, addition of molecular abnormalities associated with MDS, and refinement of treatment options involving a discussion of cost of care.

Authors
Greenberg, PL; Stone, RM; Bejar, R; Bennett, JM; Bloomfield, CD; Borate, U; De Castro, CM; Deeg, HJ; DeZern, AE; Fathi, AT; Frankfurt, O; Gaensler, K; Garcia-Manero, G; Griffiths, EA; Head, D; Klimek, V; Komrokji, R; Kujawski, LA; Maness, LJ; O'Donnell, MR; Pollyea, DA; Scott, B; Shami, PJ; Stein, BL; Westervelt, P; Wheeler, B; Shead, DA; Smith, C
MLA Citation
Greenberg, PL, Stone, RM, Bejar, R, Bennett, JM, Bloomfield, CD, Borate, U, De Castro, CM, Deeg, HJ, DeZern, AE, Fathi, AT, Frankfurt, O, Gaensler, K, Garcia-Manero, G, Griffiths, EA, Head, D, Klimek, V, Komrokji, R, Kujawski, LA, Maness, LJ, O'Donnell, MR, Pollyea, DA, Scott, B, Shami, PJ, Stein, BL, Westervelt, P, Wheeler, B, Shead, DA, and Smith, C. "Myelodysplastic syndromes, version 2.2015 featured updates to the NCCN guidelines." JNCCN Journal of the National Comprehensive Cancer Network 13.3 (January 1, 2015): 261-272. (Review)
Source
scopus
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
13
Issue
3
Publish Date
2015
Start Page
261
End Page
272

Phase II open label study of the oral vascular endothelial growth factor-receptor inhibitor PTK787/ZK222584 (vatalanib) in adult patients with refractory or relapsed diffuse large B-cell lymphoma.

PTK787/ZK222584 (vatalanib), an orally active inhibitor of vascular endothelial growth factor receptors (VEGFRs), was evaluated in this phase II study of 20 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients received once-daily PTK787/ZK222584 at a target dose of 1250 mg. Eighteen patients were evaluable for response: one patient had a complete response (CR), six patients had stable disease but subsequently progressed, 10 patients had progressive disease by three cycles and one subject withdrew before response evaluation. The patient who attained a CR underwent autologous stem cell transplant and remains disease-free 76 months after study completion. There were no grade 4 toxicities. Grade 3 thrombocytopenia occurred in 20% and grade 3 hypertension occurred in 10%. There were no episodes of grade 3 proteinuria. In conclusion, PTK787/ZK222584 was well tolerated in a heavily pretreated population of patients with DLBCL, although its therapeutic potential as a single agent in DLBCL appears limited.

Authors
Brander, D; Rizzieri, D; Gockerman, J; Diehl, L; Shea, TC; Decastro, C; Moore, JO; Beaven, A
MLA Citation
Brander, D, Rizzieri, D, Gockerman, J, Diehl, L, Shea, TC, Decastro, C, Moore, JO, and Beaven, A. "Phase II open label study of the oral vascular endothelial growth factor-receptor inhibitor PTK787/ZK222584 (vatalanib) in adult patients with refractory or relapsed diffuse large B-cell lymphoma." Leuk Lymphoma 54.12 (December 2013): 2627-2630.
PMID
23488610
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
54
Issue
12
Publish Date
2013
Start Page
2627
End Page
2630
DOI
10.3109/10428194.2013.784969

Myelodysplastic syndromes: clinical practice guidelines in oncology.

The myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal hematopoietic disorders characterized by cytopenias, dysplasia in one or more myeloid lineages, and the potential for development of acute myeloid leukemia. These disorders primarily affect older adults. The NCCN Clinical Practice Guidelines in Oncology for MDS provide recommendations on the diagnostic evaluation and classification of MDS, risk evaluation according to established prognostic assessment tools (including the new revised International Prognostic Scoring System), treatment options according to risk categories, and management of related anemia.

Authors
Greenberg, PL; Attar, E; Bennett, JM; Bloomfield, CD; Borate, U; De Castro, CM; Deeg, HJ; Frankfurt, O; Gaensler, K; Garcia-Manero, G; Gore, SD; Head, D; Komrokji, R; Maness, LJ; Millenson, M; O'Donnell, MR; Shami, PJ; Stein, BL; Stone, RM; Thompson, JE; Westervelt, P; Wheeler, B; Shead, DA; Naganuma, M
MLA Citation
Greenberg, PL, Attar, E, Bennett, JM, Bloomfield, CD, Borate, U, De Castro, CM, Deeg, HJ, Frankfurt, O, Gaensler, K, Garcia-Manero, G, Gore, SD, Head, D, Komrokji, R, Maness, LJ, Millenson, M, O'Donnell, MR, Shami, PJ, Stein, BL, Stone, RM, Thompson, JE, Westervelt, P, Wheeler, B, Shead, DA, and Naganuma, M. "Myelodysplastic syndromes: clinical practice guidelines in oncology." J Natl Compr Canc Netw 11.7 (July 2013): 838-874.
PMID
23847220
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
11
Issue
7
Publish Date
2013
Start Page
838
End Page
874

A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma.

PURPOSE: This Phase I study assessed the feasibility of concomitant arsenic trioxide (ATO), ascorbic acid (AA), and bortezomib (Velcade™) (AAV) for patients with relapsed/refractory multiple myeloma. EXPERIMENTAL DESIGN: ATO (0.25 mg/kg) and AA (1 g) were given with an escalating dose of bortezomib (1 mg/m(2) or 1.3 mg/m(2) IV bolus on days 1 and 8 of a 21-day cycle). RESULTS: Ten patients (median age 62 years), with a median of 3 prior regimens, were enrolled. Four (40%) patients achieved clinical benefit, with one patient achieving a durable partial response. No formal DLTs were encountered. CONCLUSION: AAV combination was feasible and demonstrated some benefits in this heavily pretreated population.

Authors
Held, LA; Rizzieri, D; Long, GD; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Horwitz, ME; Chao, NJ; Gasparetto, C
MLA Citation
Held, LA, Rizzieri, D, Long, GD, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Horwitz, ME, Chao, NJ, and Gasparetto, C. "A Phase I study of arsenic trioxide (Trisenox), ascorbic acid, and bortezomib (Velcade) combination therapy in patients with relapsed/refractory multiple myeloma." Cancer Invest 31.3 (March 2013): 172-176.
PMID
23406188
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
31
Issue
3
Publish Date
2013
Start Page
172
End Page
176
DOI
10.3109/07357907.2012.756109

Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia.

PURPOSE: The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy. METHODS: Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone. RESULTS: Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient's (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD. CONCLUSIONS: A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.

Authors
Morris, TA; DeCastro, CM; Diehl, LF; Gockerman, JP; Lagoo, AS; Li, Z; Moore, JO; Rizzieri, DA; Rao, AV
MLA Citation
Morris, TA, DeCastro, CM, Diehl, LF, Gockerman, JP, Lagoo, AS, Li, Z, Moore, JO, Rizzieri, DA, and Rao, AV. "Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia." Leuk Res 37.1 (January 2013): 28-31.
PMID
23046833
Source
pubmed
Published In
Leukemia Research: clinical and laboratory studies
Volume
37
Issue
1
Publish Date
2013
Start Page
28
End Page
31
DOI
10.1016/j.leukres.2012.09.016

Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria

Summary: Paroxysmal nocturnal haemoglobinuria (PNH) is characterized by chronic, uncontrolled complement activation resulting in elevated intravascular haemolysis and morbidities, including fatigue, dyspnoea, abdominal pain, pulmonary hypertension, thrombotic events (TEs) and chronic kidney disease (CKD). The long-term safety and efficacy of eculizumab, a humanized monoclonal antibody that inhibits terminal complement activation, was investigated in 195 patients over 66 months. Four patient deaths were reported, all unrelated to treatment, resulting in a 3-year survival estimate of 97·6%. All patients showed a reduction in lactate dehydrogenase levels, which was sustained over the course of treatment (median reduction of 86·9% at 36 months), reflecting inhibition of chronic haemolysis. TEs decreased by 81·8%, with 96·4% of patients remaining free of TEs. Patients also showed a time-dependent improvement in renal function: 93·1% of patients exhibited improvement or stabilization in CKD score at 36 months. Transfusion independence increased by 90·0% from baseline, with the number of red blood cell units transfused decreasing by 54·7%. Eculizumab was well tolerated, with no evidence of cumulative toxicity and a decreasing occurrence of adverse events over time. Eculizumab has a substantial impact on the symptoms and complications of PNH and results a significant improvement in patient survival. © 2013 John Wiley & Sons Ltd.

Authors
Hillmen, P; Muus, P; Röth, A; Elebute, MO; Risitano, AM; Schrezenmeier, H; Szer, J; Browne, P; Maciejewski, JP; Schubert, J; Urbano-Ispizua, A; Castro, CD; Socié, G; Brodsky, RA
MLA Citation
Hillmen, P, Muus, P, Röth, A, Elebute, MO, Risitano, AM, Schrezenmeier, H, Szer, J, Browne, P, Maciejewski, JP, Schubert, J, Urbano-Ispizua, A, Castro, CD, Socié, G, and Brodsky, RA. "Long-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria." British Journal of Haematology 162.1 (2013): 62-73.
Source
scival
Published In
British Journal of Haematology
Volume
162
Issue
1
Publish Date
2013
Start Page
62
End Page
73
DOI
10.1111/bjh.12347

Long-Term Safety of Sustained Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria

Authors
Szer, J; Muus, P; Roeth, A; Elebute, MO; Risitano, AM; Schrezenmeier, H; Maciejewski, JP; Urbano-Ispizua, A; III, DCCM; Socie, G; Brodsky, RA
MLA Citation
Szer, J, Muus, P, Roeth, A, Elebute, MO, Risitano, AM, Schrezenmeier, H, Maciejewski, JP, Urbano-Ispizua, A, III, DCCM, Socie, G, and Brodsky, RA. "Long-Term Safety of Sustained Eculizumab Treatment in Patients with Paroxysmal Nocturnal Hemoglobinuria." November 16, 2012.
PMID
23617322
Source
wos-lite
Published In
Blood
Volume
120
Issue
21
Publish Date
2012

Too many clots for comfort.

Authors
Mohanty, BD; De Castro, CM
MLA Citation
Mohanty, BD, and De Castro, CM. "Too many clots for comfort." Am J Med 125.3 (March 2012): 243-245.
PMID
22340919
Source
pubmed
Published In
American Journal of Medicine
Volume
125
Issue
3
Publish Date
2012
Start Page
243
End Page
245
DOI
10.1016/j.amjmed.2011.09.002

Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia.

Patients with chronic lymphocytic leukemia (CLL) with deletion or mutation of TP53 have exceedingly poor clinical outcomes. Cenersen, an oligonucleotide targeting TP53, has been shown to abrogate the activity of TP53 gain-of-function mutants and to increase sensitivity of lymphoma cells to cytotoxic chemotherapy in vitro. We combined cenersen with fludarabine, cyclophosphamide and rituximab (FCR) as treatment for patients with high-risk CLL. The purpose of this phase II study was to determine the overall response rate, response duration and toxicity of cenersen administered in combination with FCR. Twenty patients with relapsed or high-risk CLL were evaluated. Nineteen patients were previously treated. The complete response rate was 18%; the overall response rate was 53%. Median progression-free and overall survival was 5.3 and 10.6 months, respectively. The most common serious adverse events were neutropenia and thrombocytopenia. In this single arm phase II study, cenersen combined with FCR yielded clinical responses with acceptable toxicity in patients with high-risk CLL.

Authors
Lanasa, MC; Davis, PH; Datto, M; Li, Z; Gockerman, JP; Moore, JO; DeCastro, CM; Friedman, DR; Diehl, LF; Rehder, C; Cook, H; Daugherty, FJ; Matta, KMB; Weinberg, JB; Rizzieri, D
MLA Citation
Lanasa, MC, Davis, PH, Datto, M, Li, Z, Gockerman, JP, Moore, JO, DeCastro, CM, Friedman, DR, Diehl, LF, Rehder, C, Cook, H, Daugherty, FJ, Matta, KMB, Weinberg, JB, and Rizzieri, D. "Phase II study of cenersen, an antisense inhibitor of p53, in combination with fludarabine, cyclophosphamide and rituximab for high-risk chronic lymphocytic leukemia." Leuk Lymphoma 53.2 (February 2012): 218-224.
PMID
21827374
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
53
Issue
2
Publish Date
2012
Start Page
218
End Page
224
DOI
10.3109/10428194.2011.610012

Phase I study of dose dense induction and consolidation with gemtuzumab ozogamicin and high dose cytarabine in older adults with AML

Objective: Older adults with acute myeloid leukemia (AML) tend to have worse complete remission (CR) rates and overall survival compared to their younger counterparts. At least one reason for this is increased expression of the multidrug resistance gene (MDR1). Dose dense, high intensity chemotherapy may overcome the MDR1 effect, possibly when combined with anti-CD33 monoclonal antibody gemtuzumab ozogamicin (GO,Mylotarg™), which has been studied in older adults with relapsed AML. This phase I study was aimed at establishing safety by defining a maximum tolerated dose (MTD) by treating older AML patients with two cycles of dose-dense therapy with high dose cytarabine (HiDAC) combined with targeted therapy using GO. Materials and methods: Nine patients ≥60years with newly diagnosed, untreated CD33+ AML with adequate renal and hepatic function, and ECOG PS 0-2 were eligible. HiDAC was administered at two dose levels: 3000mg/m 2 every 12h for 6 doses (cohort 1), or 9 doses (cohort 2). GO was administered at 6mg/m 2 on days 1 and 8. Results: The MTD was HiDAC 3000mg/m 2 for six doses along with GO 6mg/m 2. All patients had grades 3-4 pancytopenia, and two patients developed reversible grade 2 neurotoxicity. There were no cases of veno-occlusive disease. Seven of nine patients had a complete response (CR or CRp). Conclusions: There was no difference in relapse-free survival in our patients when compared to historical data. However, despite high toxicity, two of nine patients treated in this dose-dense fashion remained in CR for > 60 months. © 2012 Elsevier Inc.

Authors
Rao, AV; Rizzieri, DA; DeCastro, CM; Diehl, LF; Lagoo, AS; Moore, JO; Gockerman, JP
MLA Citation
Rao, AV, Rizzieri, DA, DeCastro, CM, Diehl, LF, Lagoo, AS, Moore, JO, and Gockerman, JP. "Phase I study of dose dense induction and consolidation with gemtuzumab ozogamicin and high dose cytarabine in older adults with AML." Journal of Geriatric Oncology 3.3 (2012): 220-227.
Source
scival
Published In
Journal of Geriatric Oncology
Volume
3
Issue
3
Publish Date
2012
Start Page
220
End Page
227
DOI
10.1016/j.jgo.2012.02.002

SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target.

B-cell chronic lymphocytic leukemia (CLL), an incurable leukemia, is characterized by defective apoptosis. We found that the SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A) tumor suppressor, is overexpressed in primary CLL cells and B-cell non-Hodgkin lymphoma (NHL) cell line cells. In CLL, increased levels of SET correlated significantly with disease severity (shorter time to treatment and overall survival). We developed SET antagonist peptides that bound SET, increased cellular PP2A activity, decreased Mcl-1 expression, and displayed selective cytotoxicity for CLL and NHL cells in vitro. In addition, shRNA for SET was cytotoxic for NHL cells in vitro. The SET antagonist peptide COG449 inhibited growth of NHL tumor xenografts in mice. These data demonstrate that SET is a new treatment target in B-cell malignancies and that SET antagonists represent novel agents for treatment of CLL and NHL.

Authors
Christensen, DJ; Chen, Y; Oddo, J; Matta, KM; Neil, J; Davis, ED; Volkheimer, AD; Lanasa, MC; Friedman, DR; Goodman, BK; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Vitek, MP; Weinberg, JB
MLA Citation
Christensen, DJ, Chen, Y, Oddo, J, Matta, KM, Neil, J, Davis, ED, Volkheimer, AD, Lanasa, MC, Friedman, DR, Goodman, BK, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Vitek, MP, and Weinberg, JB. "SET oncoprotein overexpression in B-cell chronic lymphocytic leukemia and non-Hodgkin lymphoma: a predictor of aggressive disease and a new treatment target." Blood 118.15 (October 13, 2011): 4150-4158.
PMID
21844565
Source
pubmed
Published In
Blood
Volume
118
Issue
15
Publish Date
2011
Start Page
4150
End Page
4158
DOI
10.1182/blood-2011-04-351072

Myelodysplastic syndromes

These suggested practice guidelines are based on extensive evaluation of the reviewed risk-based data and indicate useful current approaches for managing patients with MDS. Four drugs have recently been approved by the FDA for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic abnormalities; azacytidine and decitabine for treating patients with higher-risk or nonresponsive MDS; and deferasirox for iron chelation of iron overloaded patients with MDS. However, because a substantial proportion of patient subsets with MDS lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, further determination of the effects of these therapeutic interventions on the patient's quality of life is important.116,119,120,128,129 Progress toward improving management of MDS has occurred over the past few years, and more advances are anticipated using these guidelines as a framework for coordination of comparative clinical trials. © JNCCN-Journal of the National Comprehensive Cancer Network.

Authors
Greenberg, PL; Attar, E; Bennett, JM; Bloomfield, CD; Castro, CMD; Deeg, HJ; Foran, JM; Gaensler, K; Garcia-Manero, G; Gore, SD; Head, D; Komrokji, R; Maness, LJ; Millenson, M; Nimer, SD; O'Donnell, MR; Schroeder, MA; Shami, PJ; Stone, RM; Thompson, JE; Westervelt, P
MLA Citation
Greenberg, PL, Attar, E, Bennett, JM, Bloomfield, CD, Castro, CMD, Deeg, HJ, Foran, JM, Gaensler, K, Garcia-Manero, G, Gore, SD, Head, D, Komrokji, R, Maness, LJ, Millenson, M, Nimer, SD, O'Donnell, MR, Schroeder, MA, Shami, PJ, Stone, RM, Thompson, JE, and Westervelt, P. "Myelodysplastic syndromes." JNCCN Journal of the National Comprehensive Cancer Network 9.1 (2011): 30-56.
PMID
21233243
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
9
Issue
1
Publish Date
2011
Start Page
30
End Page
56

A Phase II trial of gemcitabine and mitoxantrone for patients with acute myeloid leukemia in first relapse.

INTRODUCTION: We evaluated the complete remission (CR) rate in patients with acute myeloid leukemia (AML) in first relapse treated with fixed-dose-rate gemcitabine and mitoxantrone. In addition, we measured multidrug resistance (MDR) proteins on pretreatment bone marrows and correlated expression with outcome. PATIENTS AND METHODS: The study was performed in a 2-stage design. Pretreatment bone marrows were assayed for the MDR proteins (LRP, MDR1, MRP1, SLC28-29A1/A2, ABCC4/C5, and GSTP1) by immunohistochemistry and reverse-transcriptase polymerase chain reaction (RT-PCR). RESULTS: Only 5 of the first 24 patients (21%) achieved CR; therefore, the study was terminated. Eleven patients (46%) had poor-risk cytogenetics and the median duration of first CR was 7.3 months. Patients had significant expression of the various MDR genes, with 70% of patients expressing moderate to high levels of GSTP1 by immunohistochemistry. Higher sum total of ABCC4 and SLC29A2 expression measured by RT-PCR was associated with not achieving CR (20.6 vs. 12.1; P = .006). In addition, there was a trend for higher expression of the sum total of the 10 MDR genes (measured by RT-PCR) and not achieving CR (P = .06). CONCLUSION: The CR rate in this study was comparable to other regimens used in poor-risk patients. Of interest, ABCC4 and SLC29A2 expression were predictive of achieving CR. The high expression of GSTP1 suggests that this may be a therapeutic target for relapsed AML. Finally, the rapidity and ease of using RT-PCR to quantify MDR in this study may have clinical utility in future trials.

Authors
Advani, AS; Shadman, M; Ali-Osman, F; Barker, A; Rybicki, L; Kalaycio, M; Sekeres, MA; de Castro, CM; Diehl, LF; Moore, JO; Beaven, A; Copelan, E; Sobecks, R; Talea, P; Rizzieri, DA
MLA Citation
Advani, AS, Shadman, M, Ali-Osman, F, Barker, A, Rybicki, L, Kalaycio, M, Sekeres, MA, de Castro, CM, Diehl, LF, Moore, JO, Beaven, A, Copelan, E, Sobecks, R, Talea, P, and Rizzieri, DA. "A Phase II trial of gemcitabine and mitoxantrone for patients with acute myeloid leukemia in first relapse." Clin Lymphoma Myeloma Leuk 10.6 (December 2010): 473-476.
PMID
21156465
Source
pubmed
Published In
Clinical Lymphoma, Myeloma and Leukemia
Volume
10
Issue
6
Publish Date
2010
Start Page
473
End Page
476
DOI
10.3816/CLML.2010.n.082

The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function.

BACKGROUND: In patients with multiple myeloma, renal impairment (RI) at the time of diagnosis is associated with poor survival. To the authors' knowledge, the current retrospective analysis presented is the first to assess the impact of various degrees of renal dysfunction on safety and efficacy outcomes in a large cohort of patients with relapsed and/or refractory multiple myeloma who received treatment with lenalidomide plus dexamethasone. METHODS: Three hundred fifty-three patients from 2 large phase 3 trials were randomized to receive lenalidomide (25 mg) plus dexamethasone (40 mg). For the purpose of this analysis, RI was defined according to the calculated creatinine clearance (CLCr) level as follows: mild or no RI (CLCr>or=60 mL/minute), moderate RI (CLCr from >or=30 mL/minute to <60 mL/minute), and severe RI (CLCr<30 mL/minute). RESULTS: The RI subgroups did not differ significantly in terms of the overall response rate (range, 50%-64%) or response quality (very good partial response or better, 27%-37%). In all RI subgroups, the time to progression and progression-free survival did not differ significantly compared with the mild or no RI group. Patients with RI experienced an increased incidence of thrombocytopenia, required more frequent lenalidomide dose reduction or interruption, and had shorter overall survival than patients with mild or no RI (P=.006). Lenalidomide plus dexamethasone led to improvement in renal function in the majority of patients. CONCLUSIONS: The results from this study indicated that, with careful monitoring of the CLCr level and adverse events as well as appropriate dose adjustments, lenalidomide plus dexamethasone is an effective and well tolerated treatment option for patients with multiple myeloma who have RI.

Authors
Dimopoulos, M; Alegre, A; Stadtmauer, EA; Goldschmidt, H; Zonder, JA; de Castro, CM; Masliak, Z; Reece, D; Olesnyckyj, M; Yu, Z; Weber, DM
MLA Citation
Dimopoulos, M, Alegre, A, Stadtmauer, EA, Goldschmidt, H, Zonder, JA, de Castro, CM, Masliak, Z, Reece, D, Olesnyckyj, M, Yu, Z, and Weber, DM. "The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function." Cancer 116.16 (August 15, 2010): 3807-3814.
PMID
20564094
Source
pubmed
Published In
Cancer
Volume
116
Issue
16
Publish Date
2010
Start Page
3807
End Page
3814
DOI
10.1002/cncr.25139

Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy.

We present a study of the prevalence of genetic polymorphisms and expression of genes encoding the drug-resistance proteins glutathione S-transferases (GSTs) in order to gain insights into the pattern of failure evident in mantle cell lymphoma. We note a high preponderance of genetic alterations conferring resistance to standard chemotherapy in this illness. Concurrent with this investigation, we present a series of patients who were provided dose-dense and intense chemotherapy to circumvent these drug-resistance mechanisms. High responses were noted, though durable remissions were few, indicating non-traditional chemotherapy options are important to investigate in this illness.

Authors
Crout, CA; Koh, L-P; Gockerman, JP; Moore, JO; Decastro, C; Long, GD; Diehl, L; Gasparetto, C; Niedzwiecki, D; Edwards, J; Prosnitz, L; Horwitz, M; Chute, J; Morris, A; Davis, P; Beaven, A; Chao, NJ; Ali-Osman, F; Rizzieri, DA
MLA Citation
Crout, CA, Koh, L-P, Gockerman, JP, Moore, JO, Decastro, C, Long, GD, Diehl, L, Gasparetto, C, Niedzwiecki, D, Edwards, J, Prosnitz, L, Horwitz, M, Chute, J, Morris, A, Davis, P, Beaven, A, Chao, NJ, Ali-Osman, F, and Rizzieri, DA. "Overcoming drug resistance in mantle cell lymphoma using a combination of dose-dense and intense therapy." Cancer Invest 28.6 (July 2010): 654-660.
PMID
20521909
Source
pubmed
Published In
Cancer Investigation (Informa)
Volume
28
Issue
6
Publish Date
2010
Start Page
654
End Page
660
DOI
10.3109/07357901003631015

"Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma.

The purpose of this study was to evaluate the efficacy and safety of short-course bortezomib, melphalan, prednisone (VMP) in previously untreated multiple myeloma as frontline therapy for transplant-ineligible patients and induction prior to autologous stem cell transplantation (ASCT). Patients received up to 6 28-day cycles of bortezomib 1.3 mg/m(2), days 1, 4, 8, and 11, plus melphalan 6 mg/m(2) and prednisone 60 mg/m(2), days 1-7. After 2-6 cycles, eligible and consenting patients could proceed to ASCT. Responses were assessed by International Uniform Response Criteria. The primary endpoint was complete response (CR) rate with VMP. Forty-five patients were enrolled. Among 44 evaluable patients, response rate was 95%, including 18% >or=CR (9% stringent CR), 27% very good partial responses (VGPR), and 50% partial responses (PR). Twenty patients proceeded to ASCT. Stem cell collection was successful in all; median yield was 5.6 x 10(6) CD34(+) cells/kg. Posttransplant response rates were 30% >or=CR (10% stringent CR), 65% VGPR, and 5% PR. After median follow-up of 14.0/14.6 months, median time to progression and progression-free survival were both 19.8/27.9 months in non-ASCT/ASCT patients. Seven patients have died; 1-year survival rates were 82%/95% in non-ASCT/ASCT patients. The most common grade 3/4 toxicities were thrombocytopenia (20%), neutropenia (28%), and infection (9%). Peripheral neuropathy grade 2-4 was the most common nonhematopoietic side effect occurring 17 patients (38%), although it was typically reversible, and only 5 patients (11%) discontinued therapy as a result of it. Short-course VMP is highly effective and generally well tolerated, both as initial treatment in non-ASCT patients and induction prior to ASCT. VMP did not negatively affect stem cell collection. Longer follow-up and prospective phase III trials are required to validate these initial observations.

Authors
Gasparetto, C; Gockerman, JP; Diehl, LF; de Castro, CM; Moore, JO; Long, GD; Horwitz, ME; Keogh, G; Chute, JP; Sullivan, KM; Neuwirth, R; Davis, PH; Sutton, LM; Anderson, RD; Chao, NJ; Rizzieri, D
MLA Citation
Gasparetto, C, Gockerman, JP, Diehl, LF, de Castro, CM, Moore, JO, Long, GD, Horwitz, ME, Keogh, G, Chute, JP, Sullivan, KM, Neuwirth, R, Davis, PH, Sutton, LM, Anderson, RD, Chao, NJ, and Rizzieri, D. ""Short course" bortezomib plus melphalan and prednisone as induction prior to transplant or as frontline therapy for nontransplant candidates in patients with previously untreated multiple myeloma." Biol Blood Marrow Transplant 16.1 (January 2010): 70-77.
PMID
19733251
Source
pubmed
Published In
Biology of Blood and Marrow Transplantation
Volume
16
Issue
1
Publish Date
2010
Start Page
70
End Page
77
DOI
10.1016/j.bbmt.2009.08.017

A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia.

PURPOSE: Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a variable clinical course. Several parameters have prognostic capabilities but are associated with altered response to therapy in only a small subset of patients. EXPERIMENTAL DESIGN: We used gene expression profiling methods to generate predictors of therapy response and prognosis. Genomic signatures that reflect progressive disease and responses to chemotherapy or chemoimmunotherapy were created using cancer cell lines and patient leukemia cell samples. We validated and applied these three signatures to independent clinical data from four cohorts, representing a total of 301 CLL patients. RESULTS: A genomic signature of prognosis created from patient leukemic cell gene expression data coupled with clinical parameters significantly differentiated patients with stable disease from those with progressive disease in the training data set. The progression signature was validated in two independent data sets, showing a capacity to accurately identify patients at risk for progressive disease. In addition, genomic signatures that predict response to chlorambucil or pentostatin, cyclophosphamide, and rituximab were generated and could accurately distinguish responding and nonresponding CLL patients. CONCLUSIONS: Thus, microarray analysis of CLL lymphocytes can be used to refine prognosis and predict response to different therapies. These results have implications for standard and investigational therapeutics in CLL patients.

Authors
Friedman, DR; Weinberg, JB; Barry, WT; Goodman, BK; Volkheimer, AD; Bond, KM; Chen, Y; Jiang, N; Moore, JO; Gockerman, JP; Diehl, LF; Decastro, CM; Potti, A; Nevins, JR
MLA Citation
Friedman, DR, Weinberg, JB, Barry, WT, Goodman, BK, Volkheimer, AD, Bond, KM, Chen, Y, Jiang, N, Moore, JO, Gockerman, JP, Diehl, LF, Decastro, CM, Potti, A, and Nevins, JR. "A genomic approach to improve prognosis and predict therapeutic response in chronic lymphocytic leukemia." Clin Cancer Res 15.22 (November 15, 2009): 6947-6955.
PMID
19861443
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
15
Issue
22
Publish Date
2009
Start Page
6947
End Page
6955
DOI
10.1158/1078-0432.CCR-09-1132

Estimation of economic costs associated with transfusion dependence in adults with MDS.

OBJECTIVE: To examine the economic burden of myelodysplastic syndromes (MDS) and the incremental cost of transfusion dependence. RESEARCH DESIGN AND METHODS: Adults with evidence of MDS were identified between 05/01/2000 and 09/30/2003 from a longitudinal, retrospective claims database for a large, geographically diverse US health plan and their medical histories were followed for at least 6 months. Patients were classified as transfusion-dependent (MDS-TD) or transfusion-independent (MDS-TI). MAIN OUTCOME MEASURES: Variables were categorized as demographic, health status, utilization, or cost. Utilization (inpatient hospitalizations, outpatient facility visits, emergency department visits, and physician office visits) is reported as the mean and median numbers of each specified encounter per subject. Costs were measured as the sum of patient and plan liability. All variables were analyzed descriptively, and appropriate statistical tests were used to compare the MDS-TD and MDS-TI cohorts. Pharmacy, medical, and total health care costs, adjusted for demographics and comorbidity, were estimated using gamma regression with a log link. RESULTS: The MDS-TI cohort consisted of 2864 patients, and the MDS-TD cohort comprised 336 patients. Mean age for the entire study sample was 70.2 years. The MDS-TI cohort tended to receive most of its medical care at physicians' offices, whereas the MDS-TD cohort received nearly as much medical care at outpatient facilities (e.g., infusion clinics, hospital outpatient clinics) as it did in physicians' offices. The MDS-TD cohort had significantly higher mean annual costs: pharmacy, $4457 vs. $2926; medical, $50,663 vs. $17,469; total, $51,066 vs. $19,811 (p < 0.001 for all comparisons). Thus, transfusion dependence was associated with an incremental cost of $31,255 per patient per year. Some limitations inherent to using claims data and diagnosis codes for research apply to this study. CONCLUSIONS: This study demonstrated that an important consequence of transfusion dependence for MDS patients was markedly greater use of, and consequently higher costs associated with, inpatient and outpatient services. Continued research and efforts to develop biologic and pharmaceutical therapies may help more patients achieve transfusion independence, thereby reducing the financial burden of MDS.

Authors
Frytak, JR; Henk, HJ; De Castro, CM; Halpern, R; Nelson, M
MLA Citation
Frytak, JR, Henk, HJ, De Castro, CM, Halpern, R, and Nelson, M. "Estimation of economic costs associated with transfusion dependence in adults with MDS." Curr Med Res Opin 25.8 (August 2009): 1941-1951.
PMID
19552620
Source
pubmed
Published In
Current Medical Research and Opinion
Volume
25
Issue
8
Publish Date
2009
Start Page
1941
End Page
1951
DOI
10.1185/03007990903076699

Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia.

BACKGROUND: Response and survival in 96 patients with secondary acute myeloid leukemia (sAML) who received aggressive induction chemotherapy was reviewed. METHODS: The median follow-up of survivors was 2.3 years. A total of 70 (73%) patients achieved a morphologic complete remission (CR) confirmed by absence of leukemic blasts by flow cytometry. RESULTS: For all 96 patients, the median event-free survival (EFS) was 8 months, and overall survival (OS) was 13.6 months (range, 1-119 months). Eight patients died shortly after induction therapy because of disease or side effects, and 13 are currently in continuous first remission. The median disease-free survival (DFS) for all 70 patients who achieved a morphologic CR was 9 months (range, 1-51 months), with a 64% chance of surviving 1 year. Patients with AML after previous chemotherapy or radiation therapy had a higher morphologic remission rate compared with those arising from myelodysplastic syndrome or myeloproliferative disease (82% vs 62%; P = .027). However, among the patients from the 2 groups who attained a morphologic remission, there was no difference in terms of CR rate (P = .94), DFS, EFS, or OS (P = .55, .83, and .71, respectively). This is a similar DFS to the group of 7 patients who went directly to ablative allogeneic transplant rather than having induction therapy first. In this population of patients who received aggressive chemotherapy, Charlson comorbidity index or a higher number of factors recognized as high risk in leukemia patients did not affect the chance of OS, DFS, and EFS, although having more recognized leukemia risk factors was related to a lower chance of surviving 1 year. However, it is important to note that those with higher comorbidity indexes were underrepresented in this aggressively treated cohort. CONCLUSIONS: The data from the current study demonstrate that many patients with sAML can tolerate aggressive induction therapy and attain remission, but duration of response and the chance of long-term survival remain poor.

Authors
Rizzieri, DA; O'Brien, JA; Broadwater, G; Decastro, CM; Dev, P; Diehl, L; Beaven, A; Lagoo, A; Gockerman, JP; Chao, NJ; Moore, JO
MLA Citation
Rizzieri, DA, O'Brien, JA, Broadwater, G, Decastro, CM, Dev, P, Diehl, L, Beaven, A, Lagoo, A, Gockerman, JP, Chao, NJ, and Moore, JO. "Outcomes of patients who undergo aggressive induction therapy for secondary acute myeloid leukemia." Cancer 115.13 (July 1, 2009): 2922-2929.
PMID
19452542
Source
pubmed
Published In
Cancer
Volume
115
Issue
13
Publish Date
2009
Start Page
2922
End Page
2929
DOI
10.1002/cncr.24379

P134 A phase II pilot study of sorafenib in patients with myelodysplastic syndromes

Authors
Castro, CD; Adams, D; Rizzieri, D; Moore, J; Gockerman, J; Diehl, L; Horwitz, M; Edmonds, E; Warzecho, J
MLA Citation
Castro, CD, Adams, D, Rizzieri, D, Moore, J, Gockerman, J, Diehl, L, Horwitz, M, Edmonds, E, and Warzecho, J. "P134 A phase II pilot study of sorafenib in patients with myelodysplastic syndromes." Leukemia Research 33.SUPPL. 1 (2009): S137-.
Source
scival
Published In
Leukemia Research
Volume
33
Issue
SUPPL. 1
Publish Date
2009
Start Page
S137
DOI
10.1016/S0145-2126(09)70215-2

P129 A pilot study of decitabine in combination with arsenic trioxide for patients with myelodysplastic syndromes

Authors
Castro, CD; Adams, D; Rizzieri, D; Moore, J; Gockerman, J; Diehl, L; Horwitz, M; Edmonds, E; Warzecho, J
MLA Citation
Castro, CD, Adams, D, Rizzieri, D, Moore, J, Gockerman, J, Diehl, L, Horwitz, M, Edmonds, E, and Warzecho, J. "P129 A pilot study of decitabine in combination with arsenic trioxide for patients with myelodysplastic syndromes." Leukemia Research 33.SUPPL. 1 (2009): S134-.
Source
scival
Published In
Leukemia Research
Volume
33
Issue
SUPPL. 1
Publish Date
2009
Start Page
S134
DOI
10.1016/S0145-2126(09)70210-3

Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan: A randomized phase 2 trial by the Cancer and Leukemia Group B (CALGB 19803)

BACKGROUND: The Cancer and Leukemia Group B evaluated oral topotecan administered at 2 schedules and doses for myelodysplastic syndrome (MDS). METHODS: Patients with previously untreated primary or therapy-related MDS were eligible. Patients with refractory anemia (RA), RA with ringed sideroblasts, or refractory cytopenia with multilineage dysplasia (RCMD) were eligible only if they were dependent on erythrocyte transfusion, had a platelet count <50,000/μL, or had an absolute neutrophil count <1000/μL with a recent infection that required antibiotics. Patients were randomized to receive oral topotecan either at a dose of 1.2 mg/m2 twice daily for 5 days (Arm A) or once daily for 10 days (Arm B) repeated every 21 days for at least 2 cycles. Responding patients continued until they developed disease progression or unacceptable toxicity or until they had received 2 cycles beyond a complete response. RESULTS: Ninety patients received treatment, including 46 patients on Arm A and 44 patients on Arm B. Partial responses with improvement in all 3 cell lines occurred in 6 patients (7%), and hematologic improvement (in 1 or 2 cell lines) was observed in 21 patients (23%), for an overall response rate of 30%. Response duration was longer on Arm A (23 months vs 14 months; P = .02). Seven of 14 patients with chronic myelomonocytic leukemia responded. There were 8 treatment-related deaths from infection (6 deaths) and bleeding (2 deaths). Diarrhea was the most frequent nonhematologic toxicity (grade 3, 11%; grade 4, 2%; grading determined according to the National Cancer Institute Comman Toxicity Criteria v.2.0). CONCLUSIONS: Oral topotecan in the dose and schedules evaluated in this trial demonstrated only a modest response rate with a troublesome toxicity profile in the treatment of MDS. © 2008 American Cancer Society.

Authors
Grinblatt, DL; Yu, D; Hars, V; Vardiman, JW; Powell, BL; Nattam, S; Silverman, LR; III, CDC; Stone, RM; Bloomfield, CD; Larson, RA
MLA Citation
Grinblatt, DL, Yu, D, Hars, V, Vardiman, JW, Powell, BL, Nattam, S, Silverman, LR, III, CDC, Stone, RM, Bloomfield, CD, and Larson, RA. "Treatment of myelodysplastic syndrome with 2 schedules and doses of oral topotecan: A randomized phase 2 trial by the Cancer and Leukemia Group B (CALGB 19803)." Cancer 115.1 (2009): 84-93.
PMID
19025972
Source
scival
Published In
Cancer
Volume
115
Issue
1
Publish Date
2009
Start Page
84
End Page
93
DOI
10.1002/cncr.23995

Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia.

Survival of chronic lymphocytic leukemia (CLL) cells requires sustained activation of the antiapoptotic PI-3-K/Akt pathway, and many therapies for CLL cause leukemia cell death by triggering apoptosis. Blood lipoprotein particles are either pro- or antiapoptotic. High-density lipoprotein particles are antiapoptotic through sphingosine-1-phosphate receptor 3-mediated activation of the PI-3-K/Akt pathway. Apolipoprotein E4 (apoE4)-very low density lipoproteins (VLDL) increase apoptosis, but the apoE2-VLDL and apoE3-VLDL isoforms do not. As increased B-cell apoptosis favors longer survival of CLL patients, we hypothesized that APOE4 genotype would beneficially influence the clinical course of CLL. We report here that women (but not men) with an APOE4 genotype had markedly longer survival than non-APOE4 patients. VLDL is metabolized to low-density lipoprotein through lipoprotein lipase. Higher levels of lipoprotein lipase mRNA in these CLL patients correlated with shorter survival. The beneficial effect of APOE4 in CLL survival is likely mediated through APOE4 allele-specific regulation of leukemia cell apoptosis. The APOE allele and genotype distribution in these CLL patients is the same as in unaffected control populations, suggesting that although APOE genotype influences CLL outcome and response to therapy, it does not alter susceptibility to developing this disease.

Authors
Weinberg, JB; Volkheimer, AD; Mihovilovic, M; Jiang, N; Chen, Y; Bond, K; Moore, JO; Gockerman, JP; Diehl, LF; de Castro, CM; Rizzieri, DA; Levesque, MC; Dekroon, R; Strittmatter, WJ
MLA Citation
Weinberg, JB, Volkheimer, AD, Mihovilovic, M, Jiang, N, Chen, Y, Bond, K, Moore, JO, Gockerman, JP, Diehl, LF, de Castro, CM, Rizzieri, DA, Levesque, MC, Dekroon, R, and Strittmatter, WJ. "Apolipoprotein E genotype as a determinant of survival in chronic lymphocytic leukemia." Leukemia 22.12 (December 2008): 2184-2192.
PMID
18784741
Source
pubmed
Published In
Leukemia
Volume
22
Issue
12
Publish Date
2008
Start Page
2184
End Page
2192
DOI
10.1038/leu.2008.241

Phase I evaluation of gemcitabine, mitoxantrone, and their effect on plasma disposition of fludarabine in patients with relapsed or refractory acute myeloid leukemia.

Our aim was to estimate the duration of maximum tolerated dose (MTD) duration for gemcitabine given as a continuous infusion in combination with fludarabine and mitoxantrone and to evaluate potential pharmacokinetic (PK) interactions in 17 patients with refractory or relapsed acute myeloid leukaemia (AML). Gemcitabine was administered at 10 mg/m(2)/min for 3-15 h, fludarabine at 25 mg/m(2) daily for days 1-5 and mitoxantrone at 10 mg/m(2) daily on days 1-3. PK studies revealed that fludarabine clearance was not affected by gemcitabine but mean terminal half-life and volume of distribution of fludarabine were slightly increased. The duration of MTD for gemcitabine was 12 h. Our previous in vitro work has demonstrated the binary combination of gemcitabine + fludarabine is most synergistic at a molar ratio around 0.002. However, with MTD dosing this drug ratio is not optimal to produce synergy and future studies using ratiometric dosing are required to confirm these findings.

Authors
Rao, AV; Younis, IR; Sand, GJ; Spasojevic, I; Adams, DJ; Decastro, CM; Gockerman, JP; Peterson, BL; Petros, WP; Moore, JO; Rizzieri, DA
MLA Citation
Rao, AV, Younis, IR, Sand, GJ, Spasojevic, I, Adams, DJ, Decastro, CM, Gockerman, JP, Peterson, BL, Petros, WP, Moore, JO, and Rizzieri, DA. "Phase I evaluation of gemcitabine, mitoxantrone, and their effect on plasma disposition of fludarabine in patients with relapsed or refractory acute myeloid leukemia." Leuk Lymphoma 49.8 (August 2008): 1523-1529.
PMID
18766965
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
49
Issue
8
Publish Date
2008
Start Page
1523
End Page
1529
DOI
10.1080/10428190802210700

Myelodysplastic syndromes

These suggested practice guidelines are based on extensive evaluation of reviewed risk-based data and indicate useful current approaches for managing patients with MDS. The FDA recently approved 4 drugs for treating specific subtypes of MDS: lenalidomide for MDS patients with del(5q) cytogenetic, abnormalities; azacytidine and decitabine for treating higher-risk or nonresponsive MDS patients; and deferasirox for iron chelation of MDS patients with iron overload. However, because a substantial proportion of MDS patient subsets lack effective treatment for their cytopenias or for altering disease natural history, clinical trials with these and other novel therapeutic agents along with supportive care remain the hallmark of management for this disease. The role of thrombopoietic cytokines in managing thrombocytopenia in MDS requires fiirther evaluation. In addition, further determination of the effects of these therapeutic interventions on patient QOL is important.97,100,101,109,110 Progress toward improving management of MDS has occurred over the past few years and more advances are anticipated using these guidelines as a framework for coordinating comparative clinical trials. © Journal of the National Comprehensive Cancer Network.

Authors
Greenberg, PL; Attar, E; Battiwalla, M; Bennett, JM; Bloomfield, CD; DeCastro, CM; Deeg, J; Erba, HP; Foran, JM; Garcia-Manero, G; Gore, SD; Head, D; Maness, LJ; Millenson, M; Nimer, SD; O'Donnell, MR; Saba, HI; Shami, PJ; Spiers, K; Stone, RM; Tallman, MS; Westervelt, P
MLA Citation
Greenberg, PL, Attar, E, Battiwalla, M, Bennett, JM, Bloomfield, CD, DeCastro, CM, Deeg, J, Erba, HP, Foran, JM, Garcia-Manero, G, Gore, SD, Head, D, Maness, LJ, Millenson, M, Nimer, SD, O'Donnell, MR, Saba, HI, Shami, PJ, Spiers, K, Stone, RM, Tallman, MS, and Westervelt, P. "Myelodysplastic syndromes." JNCCN Journal of the National Comprehensive Cancer Network 6.9 (2008): 902-925.
PMID
18926100
Source
scival
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
6
Issue
9
Publish Date
2008
Start Page
902
End Page
925

Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria

The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, non-placebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 ± 2 days for 4 weeks; 900 mg 7 ± 2 days later; followed by 900 mg every 14 ± 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 ± 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at http://clinicaltrials.gov as NCT00130000. © 2008 by The American Society of Hematology.

Authors
Brodsky, RA; Young, NS; Antonioli, E; Risitano, AM; Schrezenmeier, H; Schubert, J; Gaya, A; Coyle, L; Castro, CD; Fu, C-L; Maciejewski, JP; Bessler, M; Kroon, H-A; Rother, RP; Hillmen, P
MLA Citation
Brodsky, RA, Young, NS, Antonioli, E, Risitano, AM, Schrezenmeier, H, Schubert, J, Gaya, A, Coyle, L, Castro, CD, Fu, C-L, Maciejewski, JP, Bessler, M, Kroon, H-A, Rother, RP, and Hillmen, P. "Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria." Blood 111.4 (2008): 1840-1847.
PMID
18055865
Source
scival
Published In
Blood
Volume
111
Issue
4
Publish Date
2008
Start Page
1840
End Page
1847
DOI
10.1182/blood-2007-06-094136

Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia.

Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV(H)) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV(H)) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV(H), and those with higher Zap-70 tended to have shorter survival. IgV(H)4-34 or IgV(H)1-69 was the most common IgV(H) genes used (16 and 12%, respectively). Of those with IgV(H)1-69, 86% had unmutated IgV(H) and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV(H). We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers.

Authors
Weinberg, JB; Volkheimer, AD; Chen, Y; Beasley, BE; Jiang, N; Lanasa, MC; Friedman, D; Vaccaro, G; Rehder, CW; Decastro, CM; Rizzieri, DA; Diehl, LF; Gockerman, JP; Moore, JO; Goodman, BK; Levesque, MC
MLA Citation
Weinberg, JB, Volkheimer, AD, Chen, Y, Beasley, BE, Jiang, N, Lanasa, MC, Friedman, D, Vaccaro, G, Rehder, CW, Decastro, CM, Rizzieri, DA, Diehl, LF, Gockerman, JP, Moore, JO, Goodman, BK, and Levesque, MC. "Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia." Am J Hematol 82.12 (December 2007): 1063-1070.
PMID
17654680
Source
pubmed
Published In
American Journal of Hematology
Volume
82
Issue
12
Publish Date
2007
Start Page
1063
End Page
1070
DOI
10.1002/ajh.20987

Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution.

PURPOSE: Allogeneic transplantation is typically limited to younger patients having a matched donor. To allow a donor to be found for nearly all patients, we have used a nonmyeloablative conditioning regimen in conjunction with stem cells from a related donor with one fully mismatched HLA haplotype. PATIENTS AND METHODS: Fludarabine, cyclophosphamide, and alemtuzumab were used as the preparatory regimen. Additional graft-versus-host disease (GVHD) prophylaxis included mycophenolate with or without cyclosporine. Patients with persistence of disease had a donor lymphocyte boost planned. Toxicities, engraftment, response, survival, and immune recovery are reported. RESULTS: Forty-nine patients with hematologic malignancies or marrow failure and no other available donors were enrolled. Ninety-four percent of patients had successful engraftment, and 8% had secondary graft failure. The treatment-related mortality rate was 10.2%, and 8% of patients had severe GVHD. Encouraging evidence of quantitative lymphocyte recovery through expansion of transplanted T cells was noted by 3 to 6 months. Seventy-five percent of patients attained a complete remission, and 1-year survival rate was 31% (95% CI, 18% to 44%). A standard-risk group of 19 patients with aplasia or in remission at transplantation demonstrated a 63% 1-year survival rate (95% CI, 38% to 80%) and 2.9-year median overall survival time (95% CI, 6.2 to 48 months). CONCLUSION: Nonmyeloablative therapy using haploidentical family member donors is feasible because the main obstacles of GVHD and graft rejection are manageable, allowing readily available stem-cell donors to be found for nearly all patients. Further qualitative and quantitative improvement in immune recovery is needed to address the high rate of relapse and risk of severe infections.

Authors
Rizzieri, DA; Koh, LP; Long, GD; Gasparetto, C; Sullivan, KM; Horwitz, M; Chute, J; Smith, C; Gong, JZ; Lagoo, A; Niedzwiecki, D; Dowell, JM; Waters-Pick, B; Liu, C; Marshall, D; Vredenburgh, JJ; Gockerman, J; Decastro, C; Moore, J; Chao, NJ
MLA Citation
Rizzieri, DA, Koh, LP, Long, GD, Gasparetto, C, Sullivan, KM, Horwitz, M, Chute, J, Smith, C, Gong, JZ, Lagoo, A, Niedzwiecki, D, Dowell, JM, Waters-Pick, B, Liu, C, Marshall, D, Vredenburgh, JJ, Gockerman, J, Decastro, C, Moore, J, and Chao, NJ. "Partially matched, nonmyeloablative allogeneic transplantation: clinical outcomes and immune reconstitution." J Clin Oncol 25.6 (February 20, 2007): 690-697.
PMID
17228020
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
25
Issue
6
Publish Date
2007
Start Page
690
End Page
697
DOI
10.1200/JCO.2006.07.0953

Multiple myeloma. Clinical practice guidelines in oncology.

Authors
Anderson, KC; Alsina, M; Bensinger, W; Biermann, JS; Chanan-Khan, A; Comenzo, RL; De Castro, CM; Djulbegovic, B; Farag, S; Huff, CA; Meredith, R; Schriber, J; Shrieve, D; Singhal, S; Smith, MR; Stockerl-Goldstein, K; Vose, JM; Weber, D; Yahalom, J; Yunus, F; National Comprehensive Cancer Network (NCCN),
MLA Citation
Anderson, KC, Alsina, M, Bensinger, W, Biermann, JS, Chanan-Khan, A, Comenzo, RL, De Castro, CM, Djulbegovic, B, Farag, S, Huff, CA, Meredith, R, Schriber, J, Shrieve, D, Singhal, S, Smith, MR, Stockerl-Goldstein, K, Vose, JM, Weber, D, Yahalom, J, Yunus, F, and National Comprehensive Cancer Network (NCCN), . "Multiple myeloma. Clinical practice guidelines in oncology." J Natl Compr Canc Netw 5.2 (February 2007): 118-147.
PMID
17335683
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
5
Issue
2
Publish Date
2007
Start Page
118
End Page
147

Safety, tolerability and satisfaction with tegaserod therapy in Asia-Pacific patients with irritable bowel syndrome with constipation

Background and Aim: The 5-HT4 receptor agonist tegaserod (6 mg b.i.d.) provides significantly better overall multiple symptom relief compared with placebo in patients with irritable bowel syndrome with constipation (IBS-C). The clinical benefit and safety of tegaserod in IBS-C patients has been demonstrated worldwide in several studies. The aim of this study was to obtain further safety and tolerability data in patients with IBS in the Asia-Pacific region, and to assess patients' satisfaction and compliance with treatment and willingness to re-use tegaserod in a post-marketing setting. Methods: A multicenter, single-arm, open-label trial was conducted at 869 outpatient centers in 10 countries. Men and women with IBS, whose predominant bowel symptom was not diarrhea (non-D-IBS), received tegaserod for 4-12 weeks. Safety and tolerability were assessed by recording adverse events (AE). Patients were questioned about compliance, satisfaction with treatment and willingness to use tegaserod in future. Results: Data were available from 14 537 patients (18% men, 82% women). Four percent of patients reported at least one AE. The most common AE were diarrhea (2%) and abdominal pain (1%), and most treatment-related AE occurred in the first week of treatment. Serious AE (SAE) were observed in eight patients, and no deaths were reported. Most patients (79%) reported to be satisfied or very satisfied with treatment, and 76% stated they would use tegaserod in the future. Compliance was 97%. Conclusions: Tegaserod has a favorable safety and tolerability profile for treating non-D-IBS and IBS-C in men and women in the Asia-Pacific region. Satisfaction with tegaserod treatment can be expected in the majority of patients. © 2007 The Authors.

Authors
Fock, KM; Wagner, A; Ahad, MA; Ahmed, DS; Ahmed, F; Ahmed, MM; Ali, MS; Bhuiyan, MR; Chowdhury, D; Hasan, M; Ishaqe, SM; Kabir, A; Khan, MR; Masud, H; Masud, MA; Sarkar, MAR; Mia, MAR; Rahman, MH; Raihan, ASMA; Rowsan, AHM; Roy, PK; Saha, SK; Bai, WY; Cai, JT; Cao, B; Chang, XM; Chen, JF; Chen, JX; Chen, JY; Chen, LD; Chen, LJ; Chen, MX; Chen, WC; Chen, WX; Chen, XM; Chen, Y; Chen, YL; Chen, YS; Cheng, JX; Cui, XY; Deng, MM; Ding, YJ; Dong, JD; Dong, L; Dong, SX; Du, GP; Duan, LP; Fan, DM et al.
MLA Citation
Fock, KM, Wagner, A, Ahad, MA, Ahmed, DS, Ahmed, F, Ahmed, MM, Ali, MS, Bhuiyan, MR, Chowdhury, D, Hasan, M, Ishaqe, SM, Kabir, A, Khan, MR, Masud, H, Masud, MA, Sarkar, MAR, Mia, MAR, Rahman, MH, Raihan, ASMA, Rowsan, AHM, Roy, PK, Saha, SK, Bai, WY, Cai, JT, Cao, B, Chang, XM, Chen, JF, Chen, JX, Chen, JY, Chen, LD, Chen, LJ, Chen, MX, Chen, WC, Chen, WX, Chen, XM, Chen, Y, Chen, YL, Chen, YS, Cheng, JX, Cui, XY, Deng, MM, Ding, YJ, Dong, JD, Dong, L, Dong, SX, Du, GP, Duan, LP, and Fan, DM et al. "Safety, tolerability and satisfaction with tegaserod therapy in Asia-Pacific patients with irritable bowel syndrome with constipation." Journal of Gastroenterology and Hepatology (Australia) 22.8 (2007): 1190-1198.
Source
scival
Published In
Journal of Gastroenterology and Hepatology
Volume
22
Issue
8
Publish Date
2007
Start Page
1190
End Page
1198
DOI
10.1111/j.1440-1746.2007.04955.x

Myelodysplastic syndromes clinical practice guidelines in oncology.

Authors
Greenberg, PL; Baer, MR; Bennett, JM; Bloomfield, CD; De Castro, CM; Deeg, HJ; Devetten, MP; Emanuel, PD; Erba, HP; Estey, E; Foran, J; Gore, SD; Millenson, M; Navarro, WH; Nimer, SD; O'Donnell, MR; Saba, HI; Spiers, K; Stone, RM; Tallman, MS
MLA Citation
Greenberg, PL, Baer, MR, Bennett, JM, Bloomfield, CD, De Castro, CM, Deeg, HJ, Devetten, MP, Emanuel, PD, Erba, HP, Estey, E, Foran, J, Gore, SD, Millenson, M, Navarro, WH, Nimer, SD, O'Donnell, MR, Saba, HI, Spiers, K, Stone, RM, and Tallman, MS. "Myelodysplastic syndromes clinical practice guidelines in oncology." J Natl Compr Canc Netw 4.1 (January 2006): 58-77.
PMID
16403405
Source
pubmed
Published In
Journal of the National Comprehensive Cancer Network : JNCCN
Volume
4
Issue
1
Publish Date
2006
Start Page
58
End Page
77

Hairy cell leukemia: An elusive but treatable disease

Hairy cell leukemia (HCL) is a unique chronic lymphoproliferative disorder that can mimic or coexist with other clonal hematologic disorders and has been associated with autoimmune disorders. It should be entertained as an alternative diagnosis in patients with cytopenias being assigned the diagnosis of aplastic anemia, hypoplastic myelodysplastic syndrome, atypical chronic lymphocytic leukemia, B-prolymphocytic leukemia, or idiopathic myelofibrosis. Causative etiology or molecular defects remain unclear, although nonspecific chromosomal and molecular changes have been described. The typical presentation is that of a middle-aged man with an incidental finding of pancytopenia, splenomegaly, and inaspirable bone marrow. Treatment with a purine analogue, cladribine or pentostatin, results in extremely high, durable, overall, and complete response rates, although resistance and relapses do occur. A variant subtype exists and is frequently associated with a poor response. Because of its simplified dosing schedule, cladribine is commonly used as the initial therapy. Treatment of relapsed HCL is dictated by the duration of the preceding remission. Relapsed disease after a prolonged remission can often be successfully retreated with the same initial agent. Resistance in typical HCL is treated with the alternate purine analogue. New agents, such as rituximab and BL22, are actively being evaluated and show promising results in both HCL subtypes. This article uses two patients diagnosed with aplastic anemia and recently seen in consultation at our institution as a springboard to discuss the biology, pathogenesis, clinical presentation, diagnostic evaluation, and treatment options of HCL. ©AlphaMed Press.

Authors
Wanko, SO; Castro, CD
MLA Citation
Wanko, SO, and Castro, CD. "Hairy cell leukemia: An elusive but treatable disease." Oncologist 11.7 (2006): 780-789.
PMID
16880237
Source
scival
Published In
The oncologist
Volume
11
Issue
7
Publish Date
2006
Start Page
780
End Page
789
DOI
10.1634/theoncologist.11-7-780

Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study

BACKGROUND. Aberrant DNA methylation, which results in leukemogenesis, is frequent in patients with myelodysplastic syndromes (MDS) and is a potential target for pharmacologic therapy. Decitabine indirectly depletes methylcytosine and causes hypomethylation of target gene promoters. METHODS. A total of 170 patients with MDS were randomized to receive either decitabine at a dose of 15 mg/m2 given intravenously over 3 hours every 8 hours for 3 days (at a dose of 135 mg/m2 per course) and repeated every 6 weeks, or best supportive care. Response was assessed using the International Working Group criteria and required that response criteria be met for at least 8 weeks. RESULTS. Patients who were treated with decitabine achieved a significantly higher overall response rate (17%), including 9% complete responses, compared with supportive care (0%) (P < .001). An additional 12 patients who were treated with decitabine (13%) achieved hematologic improvement. Responses were durable (median, 10.3 mos) and were associated with transfusion independence. Patients treated with decitabine had a trend toward a longer median time to acute myelogenous leukemia (AML) progression or death compared with patients who received supportive care alone (all patients, 12.1 mos vs. 7.8 mos [P= 0.16]; those with International Prognostic Scoring System intermediate-2/high-risk disease, 12.0 mos vs. 6.8 mos [P = 0.03]; those with de novo disease, 12.6 mos vs. 9.4 mos [P = 0.04]; and treatment-naive patients, 12.3 mos vs. 7.3 mos [P = 0.08]). CONCLUSIONS. Decitabine was found to be clinically effective in the treatment of patients with MDS, provided durable responses, and improved time to AML transformation or death. The duration of decitabine therapy may improve these results further. © 2006 American Cancer Society.

Authors
Kantarjlan, H; Issa, J-PJ; Rosenfeld, CS; Bennett, JM; Albitar, M; DiPersio, J; Klimek, V; Slack, J; Castro, CD; Ravandi, F; III, RH; Shen, L; Nimer, SD; Leavitt, R; Raza, A; Saba, H
MLA Citation
Kantarjlan, H, Issa, J-PJ, Rosenfeld, CS, Bennett, JM, Albitar, M, DiPersio, J, Klimek, V, Slack, J, Castro, CD, Ravandi, F, III, RH, Shen, L, Nimer, SD, Leavitt, R, Raza, A, and Saba, H. "Decitabine improves patient outcomes in myelodysplastic syndromes: Results of a phase III randomized study." Cancer 106.8 (2006): 1794-1803.
PMID
16532500
Source
scival
Published In
Cancer
Volume
106
Issue
8
Publish Date
2006
Start Page
1794
End Page
1803
DOI
10.1002/cncr.21792

Dose-intense cyclophosphamide and etoposide for patients with refractory or high-risk non-Hodgkin's lymphoma.

A retrospective review was performed on the toxicity and response to one cycle of dose-intense cyclophosphamide/etoposide, followed by consolidation in patients with refractory or previously untreated, high-risk non-Hodgkin's lymphoma (NHL). Fifty-five patients with refractory NHL and 13 with untreated, high-risk NHL were administered one cycle of daily cyclophosphamide 1.5 g/m2 intravenously on days 1-4 and etoposide 300 mg/m2 intravenously every 12 hours on days 1-3. Responders then received other consolidated regimens. Twenty-seven percent of patients with refractory disease had moderate or severe stomatitis, and 44% had moderate or severe infections with 6 (11%) dying of this complication. Similar complication rates were noted in the previously untreated, high-risk group, but there was no treatment-related mortality. The overall response rate to this one cycle of therapy was 31% in the refractory group, with 18% complete response and 13% partial response. The overall response rate in the previously untreated, high-risk group was 69%, with 54% complete and 15% partial responses. In responders, the 2-year event-free survival was 27% in the refractory group and 56% in high-risk group. Dose-intense cyclophosphamide/etoposide has promising efficacy; however, nonhematologic toxicity can be considerable. The better tolerance, high response rate, and encouraging 2-year survival of this regimen in combination with further dose-dense consolidation in patients with high-risk NHL are encouraging.

Authors
Talbot, J; Ibom, VK; Rizzieri, DA; Barrier, R; Niedzwieki, D; DeCastro, CM; Moore, JO; Buckley, P; Laney, R; Stevenson, D; Rumbaugh, H; Gockerman, JP
MLA Citation
Talbot, J, Ibom, VK, Rizzieri, DA, Barrier, R, Niedzwieki, D, DeCastro, CM, Moore, JO, Buckley, P, Laney, R, Stevenson, D, Rumbaugh, H, and Gockerman, JP. "Dose-intense cyclophosphamide and etoposide for patients with refractory or high-risk non-Hodgkin's lymphoma." Clin Lymphoma 5.2 (September 2004): 116-122.
PMID
15453927
Source
pubmed
Published In
Clinical lymphoma
Volume
5
Issue
2
Publish Date
2004
Start Page
116
End Page
122

Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma.

We report a phase 1 study of pharmacokinetics, dosimetry, toxicity, and response of (131)I anti-tenascin chimeric 81C6 for the treatment of lymphoma. Nine patients received a dosimetric dose of 370 MBq (10 mCi). Three patients received an administered activity of 1480 MBq (40 mCi), and 2 developed hematologic toxicity that required stem cell infusion. Six patients received an administered activity of 1110 MBq (30 mCi), and 2 developed toxicity that required stem cell infusion. The clearance of whole-body activity was monoexponential with a mean effective half-life of 110 hours (range, 90-136 hours) and a mean effective whole-body residence time of 159 hours (range, 130-196 hours). There was rapid uptake within the viscera; however, tumor uptake was slower. Activity in normal viscera decreased proportional to the whole body; however, tumor sites presented a slow clearance (T(1/2), 86-191 hours). The mean absorbed dose to whole-body was 67 cGy (range, 51-89 hours), whereas the dose to tumor sites was 963 cGy (range, 363-1517 cGy). Despite lack of a "blocking" antibody, 1 of 9 patients attained a complete remission and 1 a partial remission. These data demonstrate this radiopharmaceutical to be an encouraging agent for the treatment of lymphoma particularly if methods to protect the normal viscera are developed.

Authors
Rizzieri, DA; Akabani, G; Zalutsky, MR; Coleman, RE; Metzler, SD; Bowsher, JE; Toaso, B; Anderson, E; Lagoo, A; Clayton, S; Pegram, CN; Moore, JO; Gockerman, JP; DeCastro, C; Gasparetto, C; Chao, NJ; Bigner, DD
MLA Citation
Rizzieri, DA, Akabani, G, Zalutsky, MR, Coleman, RE, Metzler, SD, Bowsher, JE, Toaso, B, Anderson, E, Lagoo, A, Clayton, S, Pegram, CN, Moore, JO, Gockerman, JP, DeCastro, C, Gasparetto, C, Chao, NJ, and Bigner, DD. "Phase 1 trial study of 131I-labeled chimeric 81C6 monoclonal antibody for the treatment of patients with non-Hodgkin lymphoma." Blood 104.3 (August 1, 2004): 642-648.
PMID
15100153
Source
pubmed
Published In
Blood
Volume
104
Issue
3
Publish Date
2004
Start Page
642
End Page
648
DOI
10.1182/blood-2003-12-4264

Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma.

BACKGROUND: Many patients with recurrent, intermediate or high-grade non-Hodgkin lymphoma (NHL) may not respond to or are not candidates for aggressive salvage chemotherapy. Effective, less toxic regimens are needed. Although high-dose taxanes have not been reported to be very effective for the treatment of lymphoma, different delivery rates may allow for different mechanisms of action to be manifest and result in a different toxicity profile and response rate. The current study tested this hypothesis by using low-dose, weekly paclitaxel in patients with recurrent or refractory NHL. METHODS: Adults age > 18 years with refractory or recurrent, aggressive NHL who were not considered curable with standard high-dose therapy received paclitaxel at a dose of 80 mg/m2 weekly for 5 weeks for 2 cycles. RESULTS: Thirty-four patients with refractory NHL and 4 patients with recurrent disease were treated. Approximately 45% of the patients had achieved a prior disease remission. The median number of prior regimens received was 3, 74% of the patients had an International Prognostic Index of > or = 3 at the time of study entry, and 29% had failed high-dose therapy with autologous hematopoietic support. Only one patient encountered severe toxicity (sepsis). Myelosuppression was reported to occur in approximately 20% of patients. A total of 10 patients (26%) achieved a complete disease response and 4 patients (11%) achieved a partial response. CONCLUSIONS: In the current study, low-dose, weekly paclitaxel therapy was found to provide a well tolerated and less toxic approach to the treatment of refractory NHL, with encouraging responses noted in heavily pretreated patients. However, evaluation in patients with an earlier stage of disease is warranted.

Authors
Rizzieri, DA; Sand, GJ; McGaughey, D; Moore, JO; DeCastro, C; Chao, NJ; Vredenburgh, JJ; Gasparetto, C; Long, GD; Anderson, E; Foster, T; Toaso, B; Adams, D; Niedzwiecki, D; Gockerman, JP
MLA Citation
Rizzieri, DA, Sand, GJ, McGaughey, D, Moore, JO, DeCastro, C, Chao, NJ, Vredenburgh, JJ, Gasparetto, C, Long, GD, Anderson, E, Foster, T, Toaso, B, Adams, D, Niedzwiecki, D, and Gockerman, JP. "Low-dose weekly paclitaxel for recurrent or refractory aggressive non-Hodgkin lymphoma." Cancer 100.11 (June 1, 2004): 2408-2414.
PMID
15160345
Source
pubmed
Published In
Cancer
Volume
100
Issue
11
Publish Date
2004
Start Page
2408
End Page
2414
DOI
10.1002/cncr.20245

Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan.

: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH.

Authors
Nishimura, J-I; Kanakura, Y; Ware, RE; Shichishima, T; Nakakuma, H; Ninomiya, H; Decastro, CM; Hall, S; Kanamaru, A; Sullivan, KM; Mizoguchi, H; Omine, M; Kinoshita, T; Rosse, WF
MLA Citation
Nishimura, J-I, Kanakura, Y, Ware, RE, Shichishima, T, Nakakuma, H, Ninomiya, H, Decastro, CM, Hall, S, Kanamaru, A, Sullivan, KM, Mizoguchi, H, Omine, M, Kinoshita, T, and Rosse, WF. "Clinical course and flow cytometric analysis of paroxysmal nocturnal hemoglobinuria in the United States and Japan." Medicine (Baltimore) 83.3 (May 2004): 193-207.
PMID
15118546
Source
pubmed
Published In
Medicine
Volume
83
Issue
3
Publish Date
2004
Start Page
193
End Page
207

Rituximab in lymphocyte predominance Hodgkin's disease: a case series.

Rituximab in combination with chlorambucil or radiation therapy may be an effective and less-toxic therapeutic alternative for patients with lymphocyte predominance Hodgkin's disease (LPHD). We treated 6 patients with LPHD with weekly rituximab at 375 mg/m2 for 4 weeks, followed by either radiation therapy or chlorambucil. Four patients had previously untreated disease and 2 had relapsed LPHD. All patients had no evidence of disease progression at a median follow-up time of 12.5 months after receiving rituximab therapy (range, 6-39 months) and a median follow-up time of 6.5 months after completion of chlorambucil or radiation therapy (range, 3-25 months). Further follow-up is warranted to evaluate response duration and late toxicity of this novel treatment strategy

Authors
Ibom, VK; Prosnitz, RG; Gong, JZ; Moore, JO; DeCastro, CM; Prosnitz, LR; Rizzieri, DA; Gockerman, JP
MLA Citation
Ibom, VK, Prosnitz, RG, Gong, JZ, Moore, JO, DeCastro, CM, Prosnitz, LR, Rizzieri, DA, and Gockerman, JP. "Rituximab in lymphocyte predominance Hodgkin's disease: a case series." Clin Lymphoma 4.2 (September 2003): 115-118.
PMID
14556684
Source
pubmed
Published In
Clinical lymphoma
Volume
4
Issue
2
Publish Date
2003
Start Page
115
End Page
118

High-dose cyclophosphamide and etoposide for patients with refractory acute myeloid leukemia: a case series.

Authors
Talbot, J; Rizzieri, DA; DeCastro, CM; Moore, JO; Buckley, P; Laney, R; Stevenson, D; Brumbaugh, H; Gockerman, JP
MLA Citation
Talbot, J, Rizzieri, DA, DeCastro, CM, Moore, JO, Buckley, P, Laney, R, Stevenson, D, Brumbaugh, H, and Gockerman, JP. "High-dose cyclophosphamide and etoposide for patients with refractory acute myeloid leukemia: a case series." Am J Hematol 73.4 (August 2003): 295-296. (Letter)
PMID
12879438
Source
pubmed
Published In
American Journal of Hematology
Volume
73
Issue
4
Publish Date
2003
Start Page
295
End Page
296
DOI
10.1002/ajh.10362

Increased expression of anti-apoptosis genes in peripheral blood cells from patients with paroxysmal nocturnal hemoglobinuria.

Resistance to apoptosis has been described in neutrophils from patients with PNH and related hematologic disorders (aplastic anemia, myelodysplastic syndrome), but its molecular basis is not understood. Using gene expression analysis, PNH granulocytes had relative overexpression of four anti-apoptosis genes (human A1, hHR23B, Mcl-1, and RhoA) compared to normal controls. These findings were confirmed by RT-PCR analysis and observed in both peripheral blood granulocytes and mononuclear cells of patients with PNH. Anti-apoptosis gene upregulation may confer resistance to apoptosis in PNH and related disorders, and provide a common compensatory mechanism after bone marrow injury that allows survival and growth of remaining hematopoietic stem cells.

Authors
Heeney, MM; Ormsbee, SM; Moody, MA; Howard, TA; DeCastro, CM; Ware, RE
MLA Citation
Heeney, MM, Ormsbee, SM, Moody, MA, Howard, TA, DeCastro, CM, and Ware, RE. "Increased expression of anti-apoptosis genes in peripheral blood cells from patients with paroxysmal nocturnal hemoglobinuria." Mol Genet Metab 78.4 (April 2003): 291-294.
PMID
12706380
Source
pubmed
Published In
Molecular Genetics and Metabolism
Volume
78
Issue
4
Publish Date
2003
Start Page
291
End Page
294

Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia.

PURPOSE: The purpose of this study was to determine the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with fludarabine at 25 mg/m(2) daily for 5 days in the treatment of relapsed or refractory acute myelogenous leukemia. EXPERIMENTAL DESIGN: Eighteen patients with relapsed or refractory acute myelogenous leukemia were enrolled. The median age was 54.5 years (range, 21-80 years). Patients received a 30-min infusion of fludarabine at 25 mg/m(2) daily for 5 days. i.v. gemcitabine was given as a single infusion at 10 mg/m(2)/min with the duration adjusted following a modified continuous reassessment method. RESULTS: After 18 patients, the maximum recommended duration of infusion of gemcitabine in combination with fludarabine was selected as a 15-h infusion given at 10 mg/m(2)/min (9,000 mg/m(2)). Severe stomatitis or esophagitis was the most common nonhematological dose-limiting toxicity. Myelosuppression was universal. Febrile neutropenia was common, and 3 of 18 (17%) patients developed bacteremia. Occasional nausea, vomiting, or diarrhea was also reported. There were three complete responses and two partial responses for an overall response rate of 28%. CONCLUSIONS: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 15 h with 25 mg/m(2)/day fludarabine for 5 days is a tolerable induction regimen for relapsed or refractory leukemia. Stomatitis, esophagitis, febrile neutropenia, and myelosuppression should be anticipated; however, this regimen may be beneficial in patients with relapsed or refractory leukemia.

Authors
Rizzieri, DA; Ibom, VK; Moore, JO; DeCastro, CM; Rosner, GL; Adams, DJ; Foster, T; Payne, N; Thompson, M; Vredenburgh, JJ; Gasparetto, C; Long, GD; Chao, NJ; Gockerman, JP
MLA Citation
Rizzieri, DA, Ibom, VK, Moore, JO, DeCastro, CM, Rosner, GL, Adams, DJ, Foster, T, Payne, N, Thompson, M, Vredenburgh, JJ, Gasparetto, C, Long, GD, Chao, NJ, and Gockerman, JP. "Phase I evaluation of prolonged-infusion gemcitabine with fludarabine for relapsed or refractory acute myelogenous leukemia." Clin Cancer Res 9.2 (February 2003): 663-668.
PMID
12576433
Source
pubmed
Published In
Clinical cancer research : an official journal of the American Association for Cancer Research
Volume
9
Issue
2
Publish Date
2003
Start Page
663
End Page
668

Commentary: targeting myelodysplastic syndromes.

Authors
de Castro, CM
MLA Citation
de Castro, CM. "Commentary: targeting myelodysplastic syndromes." Leuk Res 26.8 (August 2002): 703-.
PMID
12191563
Source
pubmed
Published In
Leukemia Research
Volume
26
Issue
8
Publish Date
2002
Start Page
703

Phase I evaluation of prolonged-infusion gemcitabine with irinotecan for relapsed or refractory leukemia or lymphoma.

PURPOSE: To estimate the maximum-tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with irinotecan at 40 mg/m(2) daily for 3 days in the treatment of relapsed or refractory acute leukemia or lymphoma. PATIENTS AND METHODS: Patients with leukemia or lymphoma were escalated in separate strata. Stratum I consisted of 11 patients, median age of 47 years (range, 18 to 68 years), with relapsed or refractory leukemia. Stratum II contained nine patients, median age of 48 years (range, 39 to 68 years), who had refractory non-Hodgkin's lymphoma. Patients received irinotecan at 40 mg/m(2) daily for 3 days, beginning just before the first dose of gemcitabine. Gemcitabine was given at 10 mg/m(2)/min, with the total duration adjusted following a modified continuous reassessment model. RESULTS: Severe myelosuppression and stomatitis/esophagitis were the most serious hematologic and nonhematologic toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours delivered at 10 mg/m(2)/min (7,200 mg/m(2)). The overall response rate for one cycle of this therapy in this phase I trial for patients with leukemia was 18% (95% confidence interval, 8% to 45%), and for those with lymphoma, 33% (95% confidence interval, 17% to 66%). CONCLUSION: A prolonged infusion of gemcitabine at 10 mg/m(2)/min for 12 hours with 3 days of irinotecan at 40 mg/m(2)/d is a tolerable induction regimen for patients with acute leukemia or lymphoma. Stomatitis/esophagitis should be anticipated; however, this regimen may induce responses in patients with difficult-to-treat hematologic malignancies.

Authors
Bass, AJ; Gockerman, JP; Hammett, E; DeCastro, CM; Adams, DJ; Rosner, GL; Payne, N; Davis, P; Foster, T; Moore, JO; Rizzieri, DA
MLA Citation
Bass, AJ, Gockerman, JP, Hammett, E, DeCastro, CM, Adams, DJ, Rosner, GL, Payne, N, Davis, P, Foster, T, Moore, JO, and Rizzieri, DA. "Phase I evaluation of prolonged-infusion gemcitabine with irinotecan for relapsed or refractory leukemia or lymphoma." J Clin Oncol 20.13 (July 1, 2002): 2995-3000.
PMID
12089230
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
13
Publish Date
2002
Start Page
2995
End Page
3000
DOI
10.1200/JCO.2002.08.166

Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B.

PURPOSE: Patients with high-risk myelodysplastic syndrome (MDS) have high mortality from bone marrow failure or transformation to acute leukemia. Supportive care is standard therapy. We previously reported that azacitidine (Aza C) was active in patients with high-risk MDS. PATIENTS AND METHODS: A randomized controlled trial was undertaken in 191 patients with MDS to compare Aza C (75 mg/m(2)/d subcutaneously for 7 days every 28 days) with supportive care. MDS was defined by French-American-British criteria. New rigorous response criteria were applied. Both arms received transfusions and antibiotics as required. Patients in the supportive care arm whose disease worsened were permitted to cross over to Aza C. RESULTS: Responses occurred in 60% of patients on the Aza C arm (7% complete response, 16% partial response, 37% improved) compared with 5% (improved) receiving supportive care (P <.001). Median time to leukemic transformation or death was 21 months for Aza C versus 13 months for supportive care (P =.007). Transformation to acute myelogenous leukemia occurred as the first event in 15% of patients on the Aza C arm and in 38% receiving supportive care (P =.001). Eliminating the confounding effect of early cross-over to Aza C, a landmark analysis after 6 months showed median survival of an additional 18 months for Aza C and 11 months for supportive care (P =.03). Quality-of-life assessment found significant major advantages in physical function, symptoms, and psychological state for patients initially randomized to Aza C. CONCLUSION: Aza C treatment results in significantly higher response rates, improved quality of life, reduced risk of leukemic transformation, and improved survival compared with supportive care. Aza C provides a new treatment option that is superior to supportive care for patients with the MDS subtypes and specific entry criteria treated in this study.

Authors
Silverman, LR; Demakos, EP; Peterson, BL; Kornblith, AB; Holland, JC; Odchimar-Reissig, R; Stone, RM; Nelson, D; Powell, BL; DeCastro, CM; Ellerton, J; Larson, RA; Schiffer, CA; Holland, JF
MLA Citation
Silverman, LR, Demakos, EP, Peterson, BL, Kornblith, AB, Holland, JC, Odchimar-Reissig, R, Stone, RM, Nelson, D, Powell, BL, DeCastro, CM, Ellerton, J, Larson, RA, Schiffer, CA, and Holland, JF. "Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B." J Clin Oncol 20.10 (May 15, 2002): 2429-2440.
PMID
12011120
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
10
Publish Date
2002
Start Page
2429
End Page
2440
DOI
10.1200/JCO.2002.04.117

Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study.

PURPOSE: The impact of azacytidine (Aza C) on the quality of life of 191 patients with myelodysplastic syndrome was assessed in a phase III Cancer and Leukemia Group B trial (9221). PATIENTS AND METHODS: One hundred ninety-one patients (mean age, 67.5 years; 69% male) were randomized to receive either Aza C (75 mg/m(2) subcutaneous for 7 days every 4 weeks) or supportive care, with supportive care patients crossing over to Aza C upon disease progression. Quality of life was assessed by centrally conducted telephone interviews at baseline and days 50, 106, and 182. Overall quality of life, psychological state, and social functioning were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 and the Mental Health Inventory (MHI). RESULTS: Patients on the Aza C arm experienced significantly greater improvement in fatigue (EORTC, P =.001), dyspnea (EORTC, P =.0014), physical functioning (EORTC, P =.0002), positive affect (MHI, P =.0077), and psychological distress (MHI, P =.015) over the course of the study period than those in the supportive care arm. Particularly striking were improvements in fatigue and psychological state (MHI) in patients treated with Aza C compared with those receiving supportive care for patients who remained on study through at least day 106, corresponding to four cycles of Aza C. Significant differences between the two groups in quality of life were maintained even after controlling for the number of RBC transfusions. CONCLUSION: Improved quality of life for patients treated with Aza C coupled with significantly greater treatment response and delayed time to transformation to acute myeloid leukemia or death compared with patients on supportive care (P <.001) establishes Aza C as an important treatment option for myelodysplastic syndrome.

Authors
Kornblith, AB; Herndon, JE; Silverman, LR; Demakos, EP; Odchimar-Reissig, R; Holland, JF; Powell, BL; DeCastro, C; Ellerton, J; Larson, RA; Schiffer, CA; Holland, JC
MLA Citation
Kornblith, AB, Herndon, JE, Silverman, LR, Demakos, EP, Odchimar-Reissig, R, Holland, JF, Powell, BL, DeCastro, C, Ellerton, J, Larson, RA, Schiffer, CA, and Holland, JC. "Impact of azacytidine on the quality of life of patients with myelodysplastic syndrome treated in a randomized phase III trial: a Cancer and Leukemia Group B study." J Clin Oncol 20.10 (May 15, 2002): 2441-2452.
PMID
12011121
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
10
Publish Date
2002
Start Page
2441
End Page
2452
DOI
10.1200/JCO.2002.04.044

Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia.

Twenty-three adult patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or prolymphocytic leukemia (PLL) were treated for up to 12 weeks with the anti-CD52 monoclonal antibody alemtuzumab. Patients were a median of six years from diagnosis and had been treated with a median of four chemotherapy regimens (median of 24 total cycles) prior to enrollment. Fourteen patients (61%) had received prior monoclonal antibody therapy with rituximab. Adverse symptoms were primarily mild to moderate fever, rigor/chills, nausea/vomiting, or fatigue/malaise in up to 86% of patients. Patients with low blood counts at the initiation of alemtuzumab tolerated therapy well. A total of 17 patients were evaluable for disease response. Nine patients (53%) responded with complete remissions in the peripheral blood. Of these nine, five were evaluated by bone marrow biopsy with four complete responses (CR) and one partial response. Six of the nine presented with nodal disease at the start of alemtuzumab therapy with three CRs and three partial responses. Alemtuzumab is a monoclonal antibody that offers effective treatment for chemotherapy refractory CLL and PLL and is generally well tolerated in the outpatient setting.

Authors
McCune, SL; Gockerman, JP; Moore, JO; Decastro, CM; Bass, AJ; Chao, NJ; Long, GD; Vredenburgh, JJ; Gasparetto, C; Adams, D; Payne, N; Rizzieri, DA
MLA Citation
McCune, SL, Gockerman, JP, Moore, JO, Decastro, CM, Bass, AJ, Chao, NJ, Long, GD, Vredenburgh, JJ, Gasparetto, C, Adams, D, Payne, N, and Rizzieri, DA. "Alemtuzumab in relapsed or refractory chronic lymphocytic leukemia and prolymphocytic leukemia." Leuk Lymphoma 43.5 (May 2002): 1007-1011.
PMID
12148879
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
43
Issue
5
Publish Date
2002
Start Page
1007
End Page
1011
DOI
10.1080/10428190290021597

Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia.

PURPOSE: To ascertain the maximum tolerated duration of infusion of gemcitabine at 10 mg/m(2)/min in combination with mitoxantrone at 12 mg/m(2) daily for 3 days in the treatment of acute leukemia. PATIENTS AND METHODS: Thirty-four patients were enrolled. Stratum I consisted of 26 patients, median age 50 years (range, 25 to 71 years), with relapsed or refractory leukemia. Stratum II contained eight patients, median age 62.5 years (range, 38 to 83 years), who had received fewer than three cycles of myelotoxic therapy for chronic myeloid leukemia or myelodysplasia that had evolved into leukemia. Patients received mitoxantrone at 12 mg/m(2) daily for 3 days. After the first mitoxantrone dose, gemcitabine was provided intravenously at 10 mg/m(2)/min with the duration adjusted by following a continuous reassessment model. RESULTS: Severe myelosuppression, and stomatitis or esophagitis were the most common hematologic and nonhematologic dose-limiting toxicities. Several patients developed febrile neutropenia, nausea, or vomiting. In both strata, the maximum recommended duration of infusion of gemcitabine was 12 hours (7,200 mg/m(2)). The mean steady-state concentration of gemcitabine was 24.72 micromol/L and varied over a fivefold range among patients. Overall response rates in this phase I trial for strata I and II were 42% and 63%, respectively. CONCLUSION: Prolonged-infusion gemcitabine at a fixed dose rate of 10 mg/m(2)/min for 12 hours with 12 mg/m(2)/d mitoxantrone for 3 days is a tolerable induction regimen and achieves plasma concentrations sufficient for maximal intracellular activation. Stomatitis or esophagitis should be anticipated; however, this regimen may induce significant responses in patients with difficult-to-treat leukemias.

Authors
Rizzieri, DA; Bass, AJ; Rosner, GL; Gockerman, JP; DeCastro, CM; Petros, WP; Adams, DJ; Laughlin, MJ; Davis, P; Foster, T; Jacobson, R; Hurwitz, H; Moore, JO
MLA Citation
Rizzieri, DA, Bass, AJ, Rosner, GL, Gockerman, JP, DeCastro, CM, Petros, WP, Adams, DJ, Laughlin, MJ, Davis, P, Foster, T, Jacobson, R, Hurwitz, H, and Moore, JO. "Phase I evaluation of prolonged-infusion gemcitabine with mitoxantrone for relapsed or refractory acute leukemia." J Clin Oncol 20.3 (February 1, 2002): 674-679.
PMID
11821447
Source
pubmed
Published In
Journal of Clinical Oncology
Volume
20
Issue
3
Publish Date
2002
Start Page
674
End Page
679
DOI
10.1200/JCO.2002.20.3.674

Phase i trial of continuously infused gemcitabine with cpt-11 for refractory hematologic malignancies

In vitro modeling suggests additive efficacy of the nucleoside analogue gemcitabine with the topoisomerease inhibitor CPT-11. We are performing a phase I trial for patients with refractory leukemia or lymphoma using 1 cycle of variable durations of infusion of gemcitabine delivered at a rate of 10 mg/sq m/min in combination with CPT-11 40 mg/sq m infused over 90 minutes daily for 3 days, followed by growth factor support. Duration of gemcitabine infusion is varied according to a modified continuous reassessment model with the MTD being the duration at which we estimate 1/3 of patients will experience a DLT. In the NHL strata, a DLT is neutropenia for > 10 days, non-heme grade 4 toxicity for >1 day or grade 3 for > 4 days. In the leukemia strata, a DLT is neutropenia for > 4 weeks (not due to disease), non-heme grade 4 toxicity for >2 days or grade 3 for > 6 days. 12 patients aged 19-69 yo have been treated to date. 3-6 days of myelosuppression is anticipated in the NHL group and 2-4 weeks in the leukemia cohort. Average # 9 hours gem/ 12 hours gem/ 15 hours gem/ Responses prior regimens toxicity toxicity toxicity NHL 4(2-8) 0 3; 1 with grade 2; 1 DLT stomatitis 1PR;3SD;1NR 3 stomatitis x 2d Leukemia 3 (2-6) 2; no DLT 4; 1 with grade 1; no DLT 1PR;2SD 5 tumor lysis, 1 fungal pn Patients in the NHL cohort had low grade or transformed disease. Two had a significant PR, 3 have SD lasting for 1 -2 months after therapy. In the Leukemia cohort, 3/6 évaluable cleared all blasts from the marrow at nadir and at recovery 1 had a PR and 2 had SD. These data suggest the combination is feasible with toxicities similar to other aggressive regimens. The few preliminary responses noted in this refractory group encourage continued investigation with this regimen.

Authors
Rizzieri, DA; Gockerman, JP; Decastro, CM; Lilly, S; Foster, T
MLA Citation
Rizzieri, DA, Gockerman, JP, Decastro, CM, Lilly, S, and Foster, T. "Phase i trial of continuously infused gemcitabine with cpt-11 for refractory hematologic malignancies." Blood 96.11 PART II (2001): 216b-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART II
Publish Date
2001
Start Page
216b

Circulating PIG-A mutant T lymphocytes in healthy adults and patients with bone marrow failure syndromes

ObjectiveParoxysmal nocturnal hemoglobinuria (PNH) is a clonal hematological disorder with acquired PIG-A gene mutations and absent surface expression of proteins utilizing glycosylphosphatidylinositol (GPI) anchors. PNH often follows aplastic anemia, suggesting PIG-A mutant cells have relative dominance over normal hematopoietic cells. Somatic PIG-A mutations could arise after aplasia, or healthy persons could have rare PIG-A mutant cells that expand under selection pressure.MethodsWe developed an in vitro negative selection method to isolate GPI-deficient T lymphocytes using aerolysin, an Aeromonas toxin that binds GPI anchors and induces cell lysis. Peripheral blood mononuclear cells (PBMC) from normal adults and patients with PNH or other bone marrow failure syndromes were analyzed.ResultsFrom healthy adults, 166 T lymphocyte clones with deficient GPI-linked surface protein expression (CD55, CD59) were isolated. The mean mutant frequency (Mf) of aerolysin-resistant clones was 17.8 ± 13.8 per 106 PBMC, range 5.0-59.6 per 106 cells. Clones had a Class A complementation defect and distinct PIG-A mutations. Patients with PNH had elevated aerolysin-resistant Mf values averaging 19 × 10-2, a 10,000-fold difference. Two patients with Fanconi anemia and two others with mild aplastic anemia had Mf values less than 15 × 10-6, but two with recovering aplastic anemia had Mf values of 20 × 10-4, representing an intermediate value between normal persons and PNH patients.ConclusionIdentification of PIG-A mutant T lymphocytes in healthy adults suggests PNH could develop following intense negative selection of hematopoiesis, with clonal outgrowth of naturally occurring PIG-A mutant stem cells. Copyright © 2001 International Society for Experimental Hematology.

Authors
Ware, RE; Pickens, CV; DeCastro, CM; Howard, TA
MLA Citation
Ware, RE, Pickens, CV, DeCastro, CM, and Howard, TA. "Circulating PIG-A mutant T lymphocytes in healthy adults and patients with bone marrow failure syndromes." Experimental Hematology 29.12 (2001): 1403-1409.
PMID
11750098
Source
scival
Published In
Experimental Hematology
Volume
29
Issue
12
Publish Date
2001
Start Page
1403
End Page
1409
DOI
10.1016/S0301-472X(01)00746-9

Circulating pig-a mutant t lymphocytes in healthy adults and patients with bone marrow failure syndromes including pnh

Paroxysmal nocturnal hemoglobinuria (PNH) is a stem cell disorder characterized by one or more hematopoietic clones with an acquired PIG-A gene mutation, which leads to reduced or absent surface expression of proteins that utilize glycosylphosphatidylinositol (GPI) anchors. The clinical observation of PNH frequently developing after aplastic anemia suggests that rare naturally occurring PIG-A mutant hematopoietic stem cells could expand under selection pressure. To date, however, these primitive PIG-A mutant cells have not been identified in normal persons. We have developed an in vitro negative selection method to isolate and grow GPI-deficient and PIG-A mutant cells using aerolysin, a toxin that binds GPI anchors and causes cell lysis. From peripheral blood mononuclear cells (PBMC), the mutant frequency (Mf) of aerolysin-resistant T lymphocytes in 16 healthy adults was 18 ±4 per 10' PBMC. In contrast, the aerolysin-resistant Mf for 11 patients with PNH was 19 ±12 per 102 PBMC, a 10,000-fold difference. Two pédiatrie patients with Fanconi Anemia and 2 with mild untreated aplastic anemia had low Mf values below 10 per 106 PBMC, but 2 others with recovering aplastic anemia had elevated Mf values of 20 per 104 PBMC, representing an intermediate value 100 times greater than normal adults but 100 less than patients with PNH. Neither of these latter 2 patients currently has clinical or laboratory evidence of PNH, but we speculate that their elevated aerolysin-resistant Mf may portend the development of clinically apparent PNH. Aerolysin negative selection allows the analysis of PIG-A mutant cells and may provide an efficient strategy to identify rare PIG-A mutant hematopoietic stem cells in normal persons. Identification of PIG-A mutant T lymphocytes in healthy adults suggests PNH could develop following intense negative selection of hematopoiesis, with clonal outgrowth of naturally occurring PIG-A mutant stem cells.

Authors
Ware, RE; Pickens, CV; Decastro, CM; Howard, TA
MLA Citation
Ware, RE, Pickens, CV, Decastro, CM, and Howard, TA. "Circulating pig-a mutant t lymphocytes in healthy adults and patients with bone marrow failure syndromes including pnh." Blood 96.11 PART I (2000): 231a-.
Source
scival
Published In
Blood
Volume
96
Issue
11 PART I
Publish Date
2000
Start Page
231a

Genomic structure and chromosomal localization of the novel ETS factor, PE-2 (ERF).

The members of the ETS family of transcription factors are grouped because they share a highly conserved DNA binding domain. These factors are involved in growth factor pathways and regulate both proliferation and differentiation. To identify ETS factors that may be involved in early hematopoietic progenitor regulation, we isolated a novel member of the ETS family by reverse transcriptase-PCR of the conserved DNA binding domain using degenerate oligonucleotides. This gene directs the synthesis of a 2704-nucleotide transcript whose largest open reading frame encodes a 548-amino-acid protein. Northern blot analysis reveals ubiquitous expression in all human tissues and cell lines tested, with highest levels in the testis, ovary, pancreas, and heart. Comparison of this gene with the available databases reveals very significant homology to the ETS factor PE-1 and probable near-identity with the recently cloned factor ERF. The PE-2 gene is composed of four exons spanning over 9 kb of genomic DNA. Sequence analysis of the promoter region reveals a GC-rich sequence without a TATA motif and with putative binding motifs for CREB, c-myb, and AP-1 factors. Using mouse-human somatic hybrids and FISH analysis, the PE-2 gene is localized to human chromosome 19q13.2, a region involved in translocations and deletions in leukemias and several solid tumors, suggesting that this novel ETS factor may play a role in carcinogenesis.

Authors
de Castro, CM; Rabe, SM; Langdon, SD; Fleenor, DE; Slentz-Kesler, K; Ahmed, MN; Qumsiyeh, MB; Kaufman, RE
MLA Citation
de Castro, CM, Rabe, SM, Langdon, SD, Fleenor, DE, Slentz-Kesler, K, Ahmed, MN, Qumsiyeh, MB, and Kaufman, RE. "Genomic structure and chromosomal localization of the novel ETS factor, PE-2 (ERF)." Genomics 42.2 (June 1, 1997): 227-235.
PMID
9192842
Source
pubmed
Published In
Genomics
Volume
42
Issue
2
Publish Date
1997
Start Page
227
End Page
235
DOI
10.1006/geno.1997.4730

Neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia and myelodysplastic and myeloproliferative syndromes.

The CD56 antigen is normally expressed on natural-killer cells but has additionally been shown to be present on a variety of hematologic malignancies, including a subset of acute myelogenous leukemia (AML). There is disagreement, however, about its prognostic significance and its association with specific cytogenetic abnormalities. All clinical samples from June 1994, through September 1995, with increased myeloblasts were analyzed by multiparameter flow cytometry for anomalous expression of CD56. Patients with CD56+ blast cells were selected, and morphologic review was performed. Clinical information was obtained, and cytogenetic data were reviewed. Southern blot analysis to detect rearrangement of the mixed lineage leukemia (MLL) gene was performed when possible. The samples from 23 of 114 patients studied demonstrated anomalous expression of CD56 on myeloblasts, including patients with AML, myelodysplastic syndromes (MDS), and chronic myelogenous leukemia in blast crisis. The samples from 10 of 15 patients with CD56+ AML demonstrated at least partial monocytic differentiation. Dysplastic features were displayed in the samples of 12 patients. Correlation with specific cytogenetic abnormalities was not found. The MLL gene was rearranged in five of 18 patients. Seventeen patients have died, with a median survival of 4.6 months for patients with AML. Three have sustained a complete remission. One has findings of high-grade myelodysplastic syndrome. Two were unavailable for follow-up. Expression of CD56 was found in 20% of patients with increased myeloblasts, including patients with high-grade MDS, chronic myelogenous leukemia in blast crisis, and AML. This phenotype was associated with dysplasia, monocytic differentiation, and rearrangement of the MLL gene.

Authors
Mann, KP; DeCastro, CM; Liu, J; Moore, JO; Bigner, SH; Traweek, ST
MLA Citation
Mann, KP, DeCastro, CM, Liu, J, Moore, JO, Bigner, SH, and Traweek, ST. "Neural cell adhesion molecule (CD56)-positive acute myelogenous leukemia and myelodysplastic and myeloproliferative syndromes." Am J Clin Pathol 107.6 (June 1997): 653-660.
PMID
9169661
Source
pubmed
Published In
American Journal of Clinical Pathology
Volume
107
Issue
6
Publish Date
1997
Start Page
653
End Page
660

Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene

HIV-1 infection of the central nervous system (CNS) frequently causes dementia and other neurological disorders. The mechanisms of CNS injury in HIV-1 infection are poorly understood. Apoptosis of neurons and astrocytes is induced by HIV-1 infection in vitro and in brain tissue from AIDS patients, but the apoptotic stimuli have not been identified. We report herein that HIV-1 infection of primary brain cultures induces the receptor tyrosine kinase protooncogene c-kit and that high levels of c-Kit expression are associated with astrocyte apoptosis. Overexpression of c-Kit in an astrocyte- derived cell line in the absence of HIV-1 induces rapid apoptotic death. The apoptotic mechanism requires the c-Kit tyrosine kinase domain. The mechanism of c-kit induction by HIV-1 involves transactivation of the c-kit promoter by the HIV-1 Nef protein. These studies demonstrate that c-Kit can induce astrocyte apoptosis and suggest that this mechanism may play a role in CNS injury caused by HIV-1 infection. We propose that c-Kit can serve dual functions as a growth factor receptor or apoptosis inducer.

Authors
He, J; Decastro, CM; Vandenbark, GR; Busciglio, J; Gabuzda, D
MLA Citation
He, J, Decastro, CM, Vandenbark, GR, Busciglio, J, and Gabuzda, D. "Astrocyte apoptosis induced by HIV-1 transactivation of the c-kit protooncogene." Proceedings of the National Academy of Sciences of the United States of America 94.8 (1997): 3954-3959.
PMID
9108086
Source
scival
Published In
Proceedings of the National Academy of Sciences of USA
Volume
94
Issue
8
Publish Date
1997
Start Page
3954
End Page
3959
DOI
10.1073/pnas.94.8.3954

Cloning, sequencing, and recombinant expression of the porcine inhibitor of carbonic anhydrase: A novel member of the transferrin family

The plasma from many vertebrates contains a component that specifically binds and inhibits carbonic anhydrase II with nanomolar affinity. Amino- terminal sequencing of pICA, the previously identified 79-kDa carbonic anhydrase inhibitor isolated from porcine plasma [Roush, E. D., and Fierke, C. A. (1992) Biochemistry 31, 12536-12542], and sequencing of four proteolytic fragments of pICA revealed that each of the partial sequences has 40-80% sequence identity with members of the transferrin protein family. We describe here the isolation of a full-length cDNA clone of pICA from a λgt11 porcine liver cDNA library. Heterologous expression of this cDNA clone in a Pichia pastoris expression system led to the secretion into the medium of 5 mg/L of a 79-kDa protein that specifically reacts with anti-pICA antibodies and binds tightly to a carbonic anhydrase-Sepharose affinity column. Pairwise sequential alignment of pICA with various transferrins reveals an amino acid identity as high as 64% and predicts that 16 transferrin disulfide bonds are conserved. However, despite these structural similarities, the properties of pICA are distinct from the properties of transferrin. pICA exhibits a significantly decreased affinity for iron that can be attributed to the loss of one of the eight amino acids that coordinate iron in the transferrins as well as both of the arginine residues responsible for anion binding. In addition, the antigenic determinants of pICA and the transferrins are not identical. These data imply that pICA, along with saxiphilin, is a member of a diverse superfamily of transferrin-like proteins with functions other than iron binding.

Authors
Wuebbens, MW; Roush, ED; Decastro, CM; Fierke, CA
MLA Citation
Wuebbens, MW, Roush, ED, Decastro, CM, and Fierke, CA. "Cloning, sequencing, and recombinant expression of the porcine inhibitor of carbonic anhydrase: A novel member of the transferrin family." Biochemistry 36.14 (1997): 4327-4336.
PMID
9100029
Source
scival
Published In
Biochemistry
Volume
36
Issue
14
Publish Date
1997
Start Page
4327
End Page
4336
DOI
10.1021/bi9627424

Comparison of human and Xenopus GATA-2 promoters.

GATA proteins comprise a family of transcription factors that are required for appropriate development of hematopoietic lineages. In order to understand the transcriptional regulation of GATA genes, we have cloned the human GATA-2 gene and identified and characterized its promoter. Comparison with the Xenopus GATA-2 promoter demonstrates highly conserved CCAAT box elements, which are essential for appropriate Xenopus expression. Unlike the Xenopus gene, the human GATA-2 gene lacks GATA binding motifs within the first 800 bp of 5' flanking sequence. In addition, the human GATA-2 promoter has two highly conserved ets sites that resemble the binding site for a recently described ets repressor factor, ERF. These conserved DNA sequence motifs provide strong candidate regions for the regulation of GATA-2.

Authors
Fleenor, DE; Langdon, SD; deCastro, CM; Kaufman, RE
MLA Citation
Fleenor, DE, Langdon, SD, deCastro, CM, and Kaufman, RE. "Comparison of human and Xenopus GATA-2 promoters." Gene 179.2 (November 14, 1996): 219-223.
PMID
8972903
Source
pubmed
Published In
Gene
Volume
179
Issue
2
Publish Date
1996
Start Page
219
End Page
223

Complex regulation of human c-kit transcription by promoter repressors, activators, and specific myb elements

The c-kit proto-oncogene is expressed in several tissues during development. To understand the mechanisms controlling the expression of this gene, we characterized the human c-kit promoter. Expression is controlled transcriptionally. The 5'-flanking DNA was used to make promoter deletion- reporter constructs that were tested in cells that were either positive or negative for endogenous c-Kit. The results demonstrate that DNA, to at least position -4100, directs transcription well in both positive and negative cells. Addition of DNA from position -4100 to -5500 causes a reduction in expression to near-basal levels in c-Kit-negative cells but has little effect in c-Kit-positive cells. The DNA from -4100 to -5500 was tested for repressor function. It inhibits transcription from some heterologous promoters in c- Kit-negative cells. Likewise, this segment inhibits transcription from the homologous proximal promoter in a cell-specific manner, but the entire promoter is necessary for complete repression in c-Kit-negative cells. Two Myb binding motifs were also identified, and their role in regulating transcription was examined by mutation and functional testing. One, MYB1, acts as a partial repressor, whereas the other, MYB2, is a positive element that appears essential for expression. Binding proteins to both sites were characterized by several methods. MYB1 binds and responds functionally to c- Myb, but MYB2 does not. The results of these studies indicate that the regulation of c-kit transcription is complex, involving interactions among several activators and repressors.

Authors
Vandenbark, GR; Chen, Y; Friday, E; Pavlik, K; Anthony, B; DeCastro, C; Kaufman, RE
MLA Citation
Vandenbark, GR, Chen, Y, Friday, E, Pavlik, K, Anthony, B, DeCastro, C, and Kaufman, RE. "Complex regulation of human c-kit transcription by promoter repressors, activators, and specific myb elements." Cell Growth and Differentiation 7.10 (1996): 1383-1392.
PMID
8891342
Source
scival
Published In
Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research
Volume
7
Issue
10
Publish Date
1996
Start Page
1383
End Page
1392

The c-kit proto-oncogene receptor is expressed on a subset of human CD3-CD4-CD8- (triple-negative) thymocytes.

The c-kit receptor is a tyrosine-kinase transmembrane receptor first identified as an oncogene in the HZ4-feline leukemia virus and later found to be important in hematopoiesis in mice. The ligand for this receptor (Steel factor) can stimulate hematopoiesis both in vitro and in vivo. To study the pattern of c-kit receptor expression in normal human hematopoietic progenitor cells, we prepared a monoclonal antibody (9B9) against human c-kit receptor by using a synthetic peptide (amino acids 476-501) from the extracellular domain of c-kit receptor to immunize Balb/c mice. Monoclonal antibody 9B9 bound to recombinant c-kit protein, the erythroleukemic line HEL, the megakaryocytic line MEG-01, and the murine mast cell line P815. Monoclonal antibody 9B9 also bound to the surface of the CD7+CD3-CD4-CD8- T cell lymphoid cell lines DU.528 and HSB2T, and also to 1 to 4% of normal bone-marrow cells. The majority (67 +/- 6%) of CD34+ bone-marrow progenitor cells coexpressed c-kit receptor. Flow-cytometry analysis of immature CD3-CD4-CD8- (triple-negative) thymocytes indicated 30 +/- 9.5% expressed the c-kit receptor, and thymidine incorporation assay revealed that the receptor is functional. Indirect fluorescent microscopy of human thymic tissue, using a monoclonal antibody against Steel factor, revealed its presence on scattered mononuclear cells within the intralobular septae and the subcapsular cortex, which are regions where the triple-negative thymocytes are also localized. These data provide evidence that the c-kit receptor is present on human hematopoietic bone marrow and intrathymic T cell progenitor cells, and that it likely plays a role in early T cell lymphopoiesis.

Authors
deCastro, CM; Denning, SM; Langdon, S; Vandenbark, GR; Kurtzberg, J; Scearce, R; Haynes, BF; Kaufman, RE
MLA Citation
deCastro, CM, Denning, SM, Langdon, S, Vandenbark, GR, Kurtzberg, J, Scearce, R, Haynes, BF, and Kaufman, RE. "The c-kit proto-oncogene receptor is expressed on a subset of human CD3-CD4-CD8- (triple-negative) thymocytes." Exp Hematol 22.10 (September 1994): 1025-1033.
PMID
7522182
Source
pubmed
Published In
Experimental Hematology
Volume
22
Issue
10
Publish Date
1994
Start Page
1025
End Page
1033

A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype.

Mutations within exon 3 of the beta-globin gene are relatively uncommon, and many of these mutations produce a dominant thalassemia-like phenotype. We describe a novel thalassemic hemoglobinopathy caused by a single nucleotide substitution (CTG-->CCG) at codon 114 resulting in a leucine to proline substitution and designate it beta Durham-NC [beta 114 Leu-->Pro]. The mutation producing this thalassemic hemoglobinopathy is located near to the beta Showa-Yakushiji mutation (beta 110 Leu-->Pro). Both of these hemoglobinopathies share similar phenotypic features with moderately severe microcytic anemia. Using computer imaging of the hemoglobin molecule, we examined several reported point mutations within exon 3 of the beta-globin gene. These point mutations cause a single amino acid substitution in the G helix, and result in a thalassemic and/or hemolytic phenotype. Computer imaging of nine separate examples suggests that amino acid substitutions affecting side chains that project into the heme pocket may destabilize the heme moiety within the beta-globin chain, resulting in a thalassemic phenotype. Hemolytic phenotypes may be the result of decreased alpha 1 beta 1 interactions. The beta Durham-NC mutation further characterizes a novel group of thalassemias/hemoglobinopathies that are clinically difficult to identify and require accessory laboratory testing.

Authors
de Castro, CM; Devlin, B; Fleenor, DE; Lee, ME; Kaufman, RE
MLA Citation
de Castro, CM, Devlin, B, Fleenor, DE, Lee, ME, and Kaufman, RE. "A novel beta-globin mutation, beta Durham-NC [beta 114 Leu-->Pro], produces a dominant thalassemia-like phenotype." Blood 83.4 (February 15, 1994): 1109-1116.
PMID
8111050
Source
pubmed
Published In
Blood
Volume
83
Issue
4
Publish Date
1994
Start Page
1109
End Page
1116

Two new polymorphisms but no mutations of the KIT gene in patients with myelodysplasia at positions corresponding to human FMS and murine W locus mutational hot spots

The KIT proto-oncogene encodes a tyrosine kinase receptor which plays a critical role in haemopoiesis. We have screened genomic DNA from bone marrow mononuclear cells of 46 patients with myelodysplasia (MDS) for mutations/deletions of exons 6, 13, 17, and 21 of the KIT gene (stem cell factor receptor) using polymerase chain reaction (PCR), polyacrylamide gel electrophoresis, and autoradiography to detect single-stranded conformational polymorphisms (SSCP). These exons include positions analogous to those mutated in the FMS gene (colony-stimulating factor-1 receptor) in myelodysplastic syndrome (MDS) and mutated/ deleted in the Dominant White Spotting mouse (W locus) which results in macrocytic anaemia. Two different gel running conditions were used for each exon. Polymorphisms were identified only at 4°C in exon 17 (three out of 44 MDS samples and two of 21 DNA samples from normal subjects), and in the non-coding region of exon 21 (five out of 34 MDS samples and seven out of 19 normals). Direct sequencing identified a G to A base change at nucleotide 3169 within exon 21, and a C to T change at position 2415 in exon 17. No conformational changes suggestive of mutations or deletions have been found to date, although we cannot rule out low frequency clonal abnormalities undetectable by our method, which has a sensitivity in our hands of approximately 5%. Polymorphisms occur frequently in the KIT gene. Together with this study, a total of five have been described.

Authors
Bowen, DT; Padua, RA; Burnett, AK; DeCastro, CM; Kaufman, RE
MLA Citation
Bowen, DT, Padua, RA, Burnett, AK, DeCastro, CM, and Kaufman, RE. "Two new polymorphisms but no mutations of the KIT gene in patients with myelodysplasia at positions corresponding to human FMS and murine W locus mutational hot spots." Leukemia 7.11 (November 1, 1993): 1883-1885.
Source
scopus
Published In
Leukemia
Volume
7
Issue
11
Publish Date
1993
Start Page
1883
End Page
1885

Cloning and structural analysis of the human c-kit gene.

The recent identification of the mouse White spotting and Steel loci as genes encoding the c-kit receptor and its ligand, respectively, has shed light on the importance of this ligand and receptor in embryogenesis, melanogenesis and hematopoiesis. In order to determine if the c-kit proto-oncogene is involved in human disease, we isolated seven overlapping lambda recombinants, using a fetal brain cDNA, and characterized the normal human gene (KIT). The longest mapped transcript is 5230 bp, is alternatively spliced and includes 21 exons that span more than 70 kb of DNA. From the exon-intron structure, we have localized an alternative splice site to the 3' end of exon 9. The overall c-kit gene structure closely resembles that found in the CSF-1R gene (c-fms). This similarity includes a large first intron, the same number of exons containing translated sequence and very similar exon-intron boundaries. Using pulsed-field gel electrophoresis, we have linked KIT to the platelet-derived growth factor receptor A gene, with both residing on a 700-kb BssHI fragment. These data will allow investigation into the control of KIT expression and the potential to identify mutations or altered expression of this gene in human disease.

Authors
Vandenbark, GR; deCastro, CM; Taylor, H; Dew-Knight, S; Kaufman, RE
MLA Citation
Vandenbark, GR, deCastro, CM, Taylor, H, Dew-Knight, S, and Kaufman, RE. "Cloning and structural analysis of the human c-kit gene." Oncogene 7.7 (July 1992): 1259-1266.
PMID
1377810
Source
pubmed
Published In
Oncogene: Including Oncogene Reviews
Volume
7
Issue
7
Publish Date
1992
Start Page
1259
End Page
1266
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