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Brander, Danielle Marie

Positions:

Assistant 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. 2007

M.D. — Duke University School of Medicine

Resident, Internal Medicine

Duke University School of Medicine

Grants:

BGB-3111-304

Administered By
Duke Cancer Institute
AwardedBy
BeiGene, Ltd
Role
Principal Investigator
Start Date
April 26, 2018
End Date
May 09, 2023

D15-11094

Administered By
Duke Cancer Institute
AwardedBy
Zhejiang DTRM Biopharma Co.Ltd.
Role
Principal Investigator
Start Date
February 28, 2018
End Date
April 30, 2023

UTX-TGR-501

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
February 20, 2018
End Date
February 14, 2023

DFCI Obinutuzumab and Ibrutinib Protocol # 15-283

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
November 15, 2017
End Date
December 14, 2022

Ph 2 Study of TGR-1202 in Patients with CLL

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
September 01, 2016
End Date
September 01, 2021

Multi-Center, Open-Label Study of Ublituximab (TG-1101) in combination with TGR-1202

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2021

Ph 3 of Ublituximab in Combination with TGR-1202

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
September 01, 2016
End Date
August 31, 2021

Phase III study of ACP-196 vs Ibrutinib in High Risk CLL

Administered By
Duke Cancer Institute
AwardedBy
Acerta Pharma
Role
Principal Investigator
Start Date
June 01, 2016
End Date
May 31, 2021

A Phase II Study of Ibrutinib in combo with Fludarabine, Cyclophosphamide and Rituximab for young patients with CLL

Administered By
Duke Cancer Institute
AwardedBy
Dana Farber Cancer Institute
Role
Principal Investigator
Start Date
October 01, 2015
End Date
September 30, 2020

Phase 3 Study of Ublituximab in combination with Ibrutinib compared to Ibrutinib Alone in CLL pts.

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
March 01, 2015
End Date
February 29, 2020

Gilead GS-US 312 0133

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
November 10, 2014
End Date
November 09, 2019

Screening protocol to determine high risk cytogenetic features in previously treated CLL

Administered By
Duke Cancer Institute
AwardedBy
TG Therapeutics, Inc
Role
Principal Investigator
Start Date
July 01, 2016
End Date
October 19, 2017

A Phase II Study of PNT2258 in Patients with Richter's Transformation (RT).

Administered By
Duke Cancer Institute
AwardedBy
ProNAi Therapeutics, Inc.
Role
Principal Investigator
Start Date
January 01, 2016
End Date
October 11, 2017

MedImmune CD-ON-CAT-8015-1053

Administered By
Duke Cancer Institute
AwardedBy
MedImmune, Inc.
Role
Principal Investigator
Start Date
February 01, 2015
End Date
October 11, 2017

GS-US-312-0123

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
August 11, 2014
End Date
October 11, 2017

A Phase I Trial of a Bcl-2 inhibitor and a MEK inhibitor for patients with relapsed indolent B-NHL

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
AwardedBy
Lymphoma Research Foundation of America
Role
Principal Investigator
Start Date
January 15, 2014
End Date
May 15, 2016

Phase 2 GS-US-339-0103

Administered By
Duke Cancer Institute
AwardedBy
Gilead Sciences, Inc.
Role
Principal Investigator
Start Date
December 30, 2013
End Date
June 22, 2015
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Publications:

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Authors
Mato, AR; Thompson, M; Allan, JN; Brander, DM; Pagel, JM; Ujjani, CS; Hill, BT; Lamanna, N; Lansigan, F; Jacobs, R; Shadman, M; Skarbnik, AP; Pu, JJ; Barr, PM; Sehgal, AR; Cheson, BD; Zent, CS; Tuncer, HH; Schuster, SJ; Pickens, PV; Shah, NN; Goy, A; Winter, AM; Garcia, C; Kennard, K; Isaac, K; Dorsey, C; Gashonia, LM; Singavi, AK; Roeker, LE; Zelenetz, A; Williams, A; Howlett, C; Weissbrot, H; Ali, N; Khajavian, S; Sitlinger, A; Tranchito, E; Rhodes, J; Felsenfeld, J; Bailey, N; Patel, B; Burns, TF; Yacur, M; Malhotra, M; Svoboda, J; Furman, RR; Nabhan, C
MLA Citation
Mato, AR, Thompson, M, Allan, JN, Brander, DM, Pagel, JM, Ujjani, CS, Hill, BT, Lamanna, N, Lansigan, F, Jacobs, R, Shadman, M, Skarbnik, AP, Pu, JJ, Barr, PM, Sehgal, AR, Cheson, BD, Zent, CS, Tuncer, HH, Schuster, SJ, Pickens, PV, Shah, NN, Goy, A, Winter, AM, Garcia, C, Kennard, K, Isaac, K, Dorsey, C, Gashonia, LM, Singavi, AK, Roeker, LE, Zelenetz, A, Williams, A, Howlett, C, Weissbrot, H, Ali, N, Khajavian, S, Sitlinger, A, Tranchito, E, Rhodes, J, Felsenfeld, J, Bailey, N, Patel, B, Burns, TF, Yacur, M, Malhotra, M, Svoboda, J, Furman, RR, and Nabhan, C. "Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States." Haematologica 103.9 (September 2018): 1511-1517.
PMID
29880613
Source
epmc
Published In
Haematologica the Hematology Journal
Volume
103
Issue
9
Publish Date
2018
Start Page
1511
End Page
1517
DOI
10.3324/haematol.2018.193615

Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies

Authors
Mato, AR; Samp, JC; Gauthier, G; Terasawa, E; Brander, DM
MLA Citation
Mato, AR, Samp, JC, Gauthier, G, Terasawa, E, and Brander, DM. "Drivers of treatment patterns in patients with chronic lymphocytic leukemia stopping ibrutinib or idelalisib therapies." Cancer Biology & Therapy 19.7 (July 3, 2018): 636-643.
Source
crossref
Published In
Cancer Biology & Therapy
Volume
19
Issue
7
Publish Date
2018
Start Page
636
End Page
643
DOI
10.1080/15384047.2018.1449616

Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis.

Clinical trials that led to ibrutinib's approval for the treatment of chronic lymphocytic leukemia showed that its side effects differ from those of traditional chemotherapy. Reasons for discontinuation in clinical practice have not been adequately studied. We conducted a retrospective analysis of chronic lymphocytic leukemia patients treated with ibrutinib either commercially or on clinical trials. We aimed to compare the type and frequency of toxicities reported in either setting, assess discontinuation rates, and evaluate outcomes. This multicenter, retrospective analysis included ibrutinib-treated chronic lymphocytic leukemia patients at nine United States cancer centers or from the Connect® Chronic Lymphocytic Leukemia Registry. We examined demographics, dosing, discontinuation rates and reasons, toxicities, and outcomes. The primary endpoint was progression-free survival. Six hundred sixteen ibrutinib-treated patients were identified. A total of 546 (88%) patients were treated with the commercial drug. Clinical trial patients were younger (mean age 58 versus 61 years, P=0.01) and had a similar time from diagnosis to treatment with ibrutinib (mean 85 versus 87 months, P=0.8). With a median follow-up of 17 months, an estimated 41% of patients discontinued ibrutinib (median time to ibrutinib discontinuation was 7 months). Notably, ibrutinib toxicity was the most common reason for discontinuation in all settings. The median progression-free survival and overall survival for the entire cohort were 35 months and not reached (median follow-up 17 months), respectively. In the largest reported series on ibrutinib- treated chronic lymphocytic leukemia patients, we show that 41% of patients discontinued ibrutinib. Intolerance as opposed to chronic lymphocytic leukemia progression was the most common reason for discontinuation. Outcomes remain excellent and were not affected by line of therapy or whether patients were treated on clinical studies or commercially. These data strongly argue in favor of finding strategies to minimize ibrutinib intolerance so that efficacy can be further maximized. Future clinical trials should consider time-limited therapy approaches, particularly in patients achieving a complete response, in order to minimize ibrutinib exposure.

Authors
Mato, AR; Nabhan, C; Thompson, MC; Lamanna, N; Brander, DM; Hill, B; Howlett, C; Skarbnik, A; Cheson, BD; Zent, C; Pu, J; Kiselev, P; Goy, A; Claxton, D; Isaac, K; Kennard, KH; Timlin, C; Landsburg, D; Winter, A; Nasta, SD; Bachow, SH; Schuster, SJ; Dorsey, C; Svoboda, J; Barr, P; Ujjani, CS
MLA Citation
Mato, AR, Nabhan, C, Thompson, MC, Lamanna, N, Brander, DM, Hill, B, Howlett, C, Skarbnik, A, Cheson, BD, Zent, C, Pu, J, Kiselev, P, Goy, A, Claxton, D, Isaac, K, Kennard, KH, Timlin, C, Landsburg, D, Winter, A, Nasta, SD, Bachow, SH, Schuster, SJ, Dorsey, C, Svoboda, J, Barr, P, and Ujjani, CS. "Toxicities and outcomes of 616 ibrutinib-treated patients in the United States: a real-world analysis." Haematologica 103.5 (May 2018): 874-879.
PMID
29419429
Source
epmc
Published In
Haematologica the Hematology Journal
Volume
103
Issue
5
Publish Date
2018
Start Page
874
End Page
879
DOI
10.3324/haematol.2017.182907

Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study.

Umbralisib (TGR-1202) is a novel next-generation inhibitor of phosphatidylinositol 3-kinase (PI3K) isoform p110δ (PI3Kδ), which is structurally distinct from other PI3Kδ inhibitors and shows improved isoform selectivity. Umbralisib also uniquely inhibits casein kinase-1ε, a major regulator of protein translation. The aim of this first-in-human phase 1 study was to establish the safety and preliminary activity profile of umbralisib in patients with haematological malignancies.We did an open-label, phase 1, dose-escalation study at seven clinics in the USA. We recruited patients aged at least 18 years with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, B-cell and T-cell non-Hodgkin lymphoma, or Hodgkin's lymphoma, who had received one or more previous lines of therapy, with measurable and assessable disease, and adequate organ system function. Patients self-administered an umbralisib oral tablet once per day in 28-day cycles, with dose escalation done in a traditional 3 + 3 design to establish safety and determine the maximum tolerated dose. In initial cohorts, patients took umbralisib in a fasting state at a starting dose of 50 mg, increasing to 100, 200, 400, 800, 1200, and 1800 mg until the maximum tolerated dose was reached, or the maximal dose cohort was accrued without a dose-limiting toxicity. Subsequent cohorts self-administered a micronised formulation of umbralisib tablet in a fed state at an initial dose of 200 mg, increased in increments to 400, 800, 1200, and 1800 mg until the maximum tolerated dose or the maximal dose level was accrued. In August, 2014, all patients still on study were transitioned to 800 mg of the micronised formulation and dosing of the initial formulation was discontinued. The primary endpoints of the study were investigator-assessed safety in all treated patients (the safety population), the maximum tolerated dose, and the pharmacokinetics of umbralisib. Secondary endpoints included preliminary assessments of anti-cancer activity (objective responses and duration of response). Follow-up stopped for a patient once they discontinued therapy. This study has been completed and is registered with ClinicalTrials.gov, number NCT01767766.Between Jan 17, 2013, and Jan 14, 2016, we enrolled and treated 90 patients with umbralisib. The median duration of treatment and follow-up was 4·7 cycles (IQR 2·0-14·0) or 133 days (IQR 55-335). The most common treatment-emergent adverse events irrespective of causality were diarrhoea (in 39 [43%] of 90 patients), nausea (38 [42%]), and fatigue (28 [31%]). The most common grade 3 or 4 adverse events were neutropenia (in 12 [13%] patients), anaemia (eight [9%]) and thrombocytopenia (six [7%]). Serious adverse events considered at least possibly related to umbralisib occurred in seven patients: pneumonia in three (3%) patients, lung infection in one (1%), febrile neutropenia in one (1%), and colitis in two (2%), one of whom also had febrile neutropenia. The maximum tolerated dose was 1200 mg of the micronised formulation, with 800 mg of this formulation selected as the recommended phase 2 dose. Both cases of colitis occurred at above the recommended phase 2 dose. 33 (37%) of the 90 patients enrolled had an objective response to treatment with umbralisib.Umbralisib was well tolerated and showed preliminary signs of activity in patients with relapsed or refractory haematological malignancies. The safety profile of umbralisib in this phase 1 study was distinct from that of other PI3Kδ inhibitors, with fewer occurrences of autoimmune-like toxicities such as colitis. These findings warrant further evaluation of this agent in this setting.TG Therapeutics.

Authors
Burris, HA; Flinn, IW; Patel, MR; Fenske, TS; Deng, C; Brander, DM; Gutierrez, M; Essell, JH; Kuhn, JG; Miskin, HP; Sportelli, P; Weiss, MS; Vakkalanka, S; Savona, MR; O'Connor, OA
MLA Citation
Burris, HA, Flinn, IW, Patel, MR, Fenske, TS, Deng, C, Brander, DM, Gutierrez, M, Essell, JH, Kuhn, JG, Miskin, HP, Sportelli, P, Weiss, MS, Vakkalanka, S, Savona, MR, and O'Connor, OA. "Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study." The Lancet. Oncology 19.4 (April 2018): 486-496.
PMID
29475723
Source
epmc
Published In
The Lancet. Oncology
Volume
19
Issue
4
Publish Date
2018
Start Page
486
End Page
496
DOI
10.1016/s1470-2045(18)30082-2

Minimal Residual Disease in Chronic Lymphocytic Leukemia in the Era of Novel Agents

Authors
Thompson, M; Brander, D; Nabhan, C; Mato, A
MLA Citation
Thompson, M, Brander, D, Nabhan, C, and Mato, A. "Minimal Residual Disease in Chronic Lymphocytic Leukemia in the Era of Novel Agents." Jama Oncology 4.3 (March 1, 2018): 394-394.
Source
crossref
Published In
Jama Oncology
Volume
4
Issue
3
Publish Date
2018
Start Page
394
End Page
394
DOI
10.1001/jamaoncol.2017.2009

Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology.

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.

Authors
Wierda, WG; Byrd, JC; Abramson, JS; Bhat, S; Bociek, G; Brander, D; Brown, J; Chanan-Khan, A; Coutre, SE; Davis, RS; Fletcher, CD; Hill, B; Kahl, BS; Kamdar, M; Kaplan, LD; Khan, N; Kipps, TJ; Lancet, J; Ma, S; Malek, S; Mosse, C; Shadman, M; Siddiqi, T; Stephens, D; Wagner, N; Zelenetz, AD; Dwyer, MA; Sundar, H
MLA Citation
Wierda, WG, Byrd, JC, Abramson, JS, Bhat, S, Bociek, G, Brander, D, Brown, J, Chanan-Khan, A, Coutre, SE, Davis, RS, Fletcher, CD, Hill, B, Kahl, BS, Kamdar, M, Kaplan, LD, Khan, N, Kipps, TJ, Lancet, J, Ma, S, Malek, S, Mosse, C, Shadman, M, Siddiqi, T, Stephens, D, Wagner, N, Zelenetz, AD, Dwyer, MA, and Sundar, H. "Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology." Journal of the National Comprehensive Cancer Network : Jnccn 15.11 (November 2017): 1414-1427.
PMID
29118233
Source
epmc
Published In
Jnccn Journal of the National Comprehensive Cancer Network
Volume
15
Issue
11
Publish Date
2017
Start Page
1414
End Page
1427
DOI
10.6004/jnccn.2017.0165

Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients.

Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P < 0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Authors
Mato, AR; Hill, BT; Lamanna, N; Barr, PM; Ujjani, CS; Brander, DM; Howlett, C; Skarbnik, AP; Cheson, BD; Zent, CS; Pu, JJ; Kiselev, P; Foon, K; Lenhart, J; Henick Bachow, S; Winter, AM; Cruz, A-L; Claxton, DF; Goy, A; Daniel, C; Isaac, K; Kennard, KH; Timlin, C; Fanning, M; Gashonia, L; Yacur, M; Svoboda, J; Schuster, SJ; Nabhan, C
MLA Citation
Mato, AR, Hill, BT, Lamanna, N, Barr, PM, Ujjani, CS, Brander, DM, Howlett, C, Skarbnik, AP, Cheson, BD, Zent, CS, Pu, JJ, Kiselev, P, Foon, K, Lenhart, J, Henick Bachow, S, Winter, AM, Cruz, A-L, Claxton, DF, Goy, A, Daniel, C, Isaac, K, Kennard, KH, Timlin, C, Fanning, M, Gashonia, L, Yacur, M, Svoboda, J, Schuster, SJ, and Nabhan, C. "Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients." Annals of Oncology : Official Journal of the European Society for Medical Oncology 28.5 (May 2017): 1050-1056.
PMID
28453705
Source
epmc
Published In
Annals of Oncology
Volume
28
Issue
5
Publish Date
2017
Start Page
1050
End Page
1056
DOI
10.1093/annonc/mdx031

Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.

Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.AbbVie Inc and Genentech Inc.

Authors
Seymour, JF; Ma, S; Brander, DM; Choi, MY; Barrientos, J; Davids, MS; Anderson, MA; Beaven, AW; Rosen, ST; Tam, CS; Prine, B; Agarwal, SK; Munasinghe, W; Zhu, M; Lash, LL; Desai, M; Cerri, E; Verdugo, M; Kim, SY; Humerickhouse, RA; Gordon, GB; Kipps, TJ; Roberts, AW
MLA Citation
Seymour, JF, Ma, S, Brander, DM, Choi, MY, Barrientos, J, Davids, MS, Anderson, MA, Beaven, AW, Rosen, ST, Tam, CS, Prine, B, Agarwal, SK, Munasinghe, W, Zhu, M, Lash, LL, Desai, M, Cerri, E, Verdugo, M, Kim, SY, Humerickhouse, RA, Gordon, GB, Kipps, TJ, and Roberts, AW. "Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study." The Lancet. Oncology 18.2 (February 2017): 230-240.
PMID
28089635
Source
epmc
Published In
The Lancet. Oncology
Volume
18
Issue
2
Publish Date
2017
Start Page
230
End Page
240
DOI
10.1016/S1470-2045(17)30012-8

Rationale for combinatory chronic lymphocytic leukaemia treatment paradigms in the era of the B-cell receptor pathway and anti-apoptotic inhibitors: how do we mix, match, and move forward?

Authors
Brander, DM
MLA Citation
Brander, DM. "Rationale for combinatory chronic lymphocytic leukaemia treatment paradigms in the era of the B-cell receptor pathway and anti-apoptotic inhibitors: how do we mix, match, and move forward?." British journal of haematology 176.3 (February 2017): 337-340.
PMID
27984636
Source
epmc
Published In
British Journal of Haematology
Volume
176
Issue
3
Publish Date
2017
Start Page
337
End Page
340
DOI
10.1111/bjh.14446

Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial.

Although several consolidation strategies to prolong treatment-free survival (TFS) in chronic lymphocytic leukaemia have been investigated, most have proven either ineffective or toxic. Ofatumumab is a human type I anti-CD20 antibody approved by the US Food and Drug Administration as maintenance treatment of patients with recurrent or progressive chronic lymphocytic leukaemia who are in complete or partial response after at least two lines of treatment; higher efficacy might be observed if used as consolidation strategy than without consolidation in previously untreated patients.We recruited patients with previously untreated progressive chronic lymphocytic leukaemia who had an Eastern Cooperative Oncology Group performance status of 0-2 and adequate renal and hepatic function from centres in the USA. Patients with recent myocardial infarction; class III or IV heart failure; uncontrolled, HIV, or active hepatitis B or C infection; or active haemolytic anaemia were excluded. In the first arm of this study, which has been previously reported, patients were treated with six cycles of induction with pentostatin (2 mg/m(2) on day 1), cyclophosphamide (600 mg/m(2) on day 1), and ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg/m(2) on day 2; cycles 2-6: 1000 mg/m(2) on day 1) given intravenously every 21 days. Here were report the second arm, where patients received the same regimen as the first arm, with the addition of six cycles of consolidation with ofatumumab (1000 mg once every 4 weeks), also given intravenously. The primary endpoint was TFS at 18 months, assessed in those who began consolidation. We estimated the distribution of TFS using the Kaplan-Meier method, assessing between-group differences with log-rank statistics. The phase 2 trial, which is completed, is registered at ClinicalTrials.gov, number NCT01024010.Between Sept 21, 2011, and Nov 7, 2012, 34 patients were recruited to this second arm of the trial. Among the 31 (91%) patients who completed induction treatment and started consolidation, 26 (84%) completed the planned six cycles of ofatumumab consolidation. TFS at 18 months was 94·1% (95% CI 78·5-98·5). Grade 3 or worse adverse events deemed at least possibly related to treatment were neutropenia (14 [41%] patients), infection (2 [6%]), and one (3%) each with anaemia, haemolysis, fatigue, and a neurological, metabolic, respiratory, and vascular complication.Ofatumumab-based consolidation appears to be a well tolerated and effective consolidation strategy in patients with chronic lymphocytic leukaemia, which could improve survival.GlaxoSmithKline.

Authors
Strati, P; Lanasa, M; Call, TG; Leis, JF; Brander, DM; LaPlant, BR; Pettinger, AM; Ding, W; Parikh, SA; Hanson, CA; Chanan-Khan, AA; Bowen, DA; Conte, M; Kay, NE; Shanafelt, TD
MLA Citation
Strati, P, Lanasa, M, Call, TG, Leis, JF, Brander, DM, LaPlant, BR, Pettinger, AM, Ding, W, Parikh, SA, Hanson, CA, Chanan-Khan, AA, Bowen, DA, Conte, M, Kay, NE, and Shanafelt, TD. "Ofatumumab monotherapy as a consolidation strategy in patients with previously untreated chronic lymphocytic leukaemia: a phase 2 trial." The Lancet. Haematology 3.9 (September 2016): e407-e414.
PMID
27570087
Source
epmc
Published In
The Lancet Haematology
Volume
3
Issue
9
Publish Date
2016
Start Page
e407
End Page
e414
DOI
10.1016/s2352-3026(16)30064-3

Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies.

Abstract Because of the importance of the phosphoinositide 3-kinase (PI3K)/AKT pathway in chronic lymphocytic leukemia (CLL), we evaluated in vitro cytotoxicity induced by perifosine, an AKT inhibitor, in CLL lymphocytes and found that the mean 50% effective dose (ED50) was 313 nM. We then performed a phase II trial of perifosine in patients with relapsed/refractory CLL to assess response, outcomes, toxicity and ex vivo correlative measures. After 3 months of treatment, six of eight patients showed stable disease, one achieved a partial response and one had progressive disease. Median event-free survival and overall survival in all patients treated were 3.9 and 9.7 months. Adverse events included hematologic, infectious/fever, pain, gastrointestinal and constitutional toxicities. Unexpectedly, AKT phosphorylation in CLL lymphocytes from treated patients was not correlated with response. Additionally, perifosine did not inhibit AKT phosphorylation in cultured CLL lymphocytes. Perifosine is cytotoxic to CLL cells in vitro, and largely induces stabilized disease in vivo, with an AKT-independent mechanism.

Authors
Friedman, DR; Lanasa, MC; Davis, PH; Allgood, SD; Matta, KM; Brander, DM; Chen, Y; Davis, ED; Volkheimer, AD; Moore, JO; Gockerman, JP; Sportelli, P; Weinberg, JB
MLA Citation
Friedman, DR, Lanasa, MC, Davis, PH, Allgood, SD, Matta, KM, Brander, DM, Chen, Y, Davis, ED, Volkheimer, AD, Moore, JO, Gockerman, JP, Sportelli, P, and Weinberg, JB. "Perifosine treatment in chronic lymphocytic leukemia: results of a phase II clinical trial and in vitro studies." Leuk Lymphoma 55.5 (May 2014): 1067-1075.
PMID
23863122
Source
pubmed
Published In
Leukemia & Lymphoma (Informa)
Volume
55
Issue
5
Publish Date
2014
Start Page
1067
End Page
1075
DOI
10.3109/10428194.2013.824080

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." Leukemia & lymphoma 54.12 (December 2013): 2627-2630.
PMID
23488610
Source
epmc
Published In
Leukemia & Lymphoma
Volume
54
Issue
12
Publish Date
2013
Start Page
2627
End Page
2630
DOI
10.3109/10428194.2013.784969

Update on treatment of follicular non-Hodgkin's lymphoma: focus on potential of bortezomib.

Follicular lymphoma is predominantly managed as a chronic disease, with intermittent chemo/immunotherapy reserved for symptomatic progression. It is considered incurable with conventional treatments, and current therapeutic options are associated with significant toxicities that are especially limiting in older patients. Bortezomib (PS-341; Velcade(®)), a first-in-class drug targeting the proteolytic core subunit of the 26S proteasome, has emerged as a therapeutic alternative in follicular lymphoma, with promising preclinical data and efficacy in patients with other hematological malignancies. Several clinical trials were conducted with bortezomib for the treatment of non-Hodgkin's lymphoma. As a single agent, overall responses in follicular lymphoma varied greatly (16%-41%), with weekly bortezomib showing less neurotoxicity than twice-weekly regimens, but with concern about decreased responses. Combination with rituximab was projected to improve the efficacy of bortezomib, but this resulted in increased toxicities and questionable added benefit. Although the largest Phase III study in follicular lymphoma of bortezomib plus rituximab versus rituximab alone demonstrated a significant progression-free survival difference, the absolute difference was small (12.8 months versus 11 months). Combining bortezomib with established regimens, such as rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP), or rituximab-bendamustine also did not show definite benefit, and many of these studies did not meet their primary endpoint when bortezomib failed to improve responses or survival to the degree anticipated. In a disease where the goal of treatment is palliative and affected patients often have other medical and treatment-related comorbidities, decisions regarding therapies which carry risks of additional toxicities must be considered carefully. Conclusive evidence of the ability of bortezomib to improve patient outcomes meaningfully and to justify the added toxicity is lacking, but limitations in cross-trial comparisons are recognized. Large randomized trials and investigations of combinations with promising novel targeted agents will aid in determining the role of bortezomib, if any, in the future treatment of follicular lymphoma.

Authors
Brander, DM; Beaven, AW
MLA Citation
Brander, DM, and Beaven, AW. "Update on treatment of follicular non-Hodgkin's lymphoma: focus on potential of bortezomib." Patient preference and adherence 6 (January 2012): 239-251.
PMID
22536060
Source
epmc
Published In
Patient Preference and Adherence
Volume
6
Publish Date
2012
Start Page
239
End Page
251
DOI
10.2147/ppa.s23241

Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF.

PURPOSE: p16(INK4a) has been appreciated as a key regulator of cell cycle progression and senescence. Cultured human mammary epithelial cells that lack p16(INK4a) activity have been shown to exhibit premalignant phenotypes, such as telomeric dysfunction, centrosomal dysfunction, a sustained stress response, and, most recently, a dysregulation of chromatin remodeling and DNA methylation. These data suggest that cells that lack p16(INK4a) activity would be at high risk for breast cancer development and may exhibit an increased frequency of DNA methylation events in early cancer. EXPERIMENTAL DESIGN: To test this hypothesis, the frequencies of INK4a/ARF promoter hypermethylation, as well as four additional selected loci, were tested in the initial random periareolar fine needle aspiration samples from 86 asymptomatic women at high risk for development of breast cancer, stratified using the Masood cytology index. RESULTS: INK4a/ARF promoter hypermethylation was observed throughout all early stages of intraepithelial neoplasia and, importantly, in morphologically normal-appearing mammary epithelial cells; 29 of 86 subjects showed INK4a/ARF promoter hypermethylation in at least one breast. Importantly, INK4a/ARF promoter hypermethylation was not associated with atypia, and the frequency of hypermethylation did not increase with increasing Masood cytology score. The frequency of INK4a/ARF promoter hypermethylation was associated with the combined frequency of promoter hypermethylation of retinoic acid receptor-beta2, estrogen receptor-alpha, and breast cancer-associated 1 genes (P = 0.001). CONCLUSIONS: Because INK4a/ARF promoter hypermethylation does not increase with age but increases with the frequency of other methylation events, we predict that INK4a/ARF promoter hypermethylation may serve as a marker of global methylation dysregulation.

Authors
Bean, GR; Bryson, AD; Pilie, PG; Goldenberg, V; Baker, JC; Ibarra, C; Brander, DMU; Paisie, C; Case, NR; Gauthier, M; Reynolds, PA; Dietze, E; Ostrander, J; Scott, V; Wilke, LG; Yee, L; Kimler, BF; Fabian, CJ; Zalles, CM; Broadwater, G; Tlsty, TD; Seewaldt, VL
MLA Citation
Bean, GR, Bryson, AD, Pilie, PG, Goldenberg, V, Baker, JC, Ibarra, C, Brander, DMU, Paisie, C, Case, NR, Gauthier, M, Reynolds, PA, Dietze, E, Ostrander, J, Scott, V, Wilke, LG, Yee, L, Kimler, BF, Fabian, CJ, Zalles, CM, Broadwater, G, Tlsty, TD, and Seewaldt, VL. "Morphologically normal-appearing mammary epithelial cells obtained from high-risk women exhibit methylation silencing of INK4a/ARF." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research 13.22 Pt 1 (November 2007): 6834-6841.
PMID
18006786
Source
epmc
Published In
Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Volume
13
Issue
22 Pt 1
Publish Date
2007
Start Page
6834
End Page
6841
DOI
10.1158/1078-0432.ccr-07-0407
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