Zhiguo Li

Overview:

survival analysis, dynamic treatment regimes, clinical trials

Positions:

Associate Professor of Biostatistics & Bioinformatics

Biostatistics & Bioinformatics
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2008

University of Michigan, Ann Arbor

Grants:

Effects of PPAR agonists on response to immunomodulatory agents in patients with multiple myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Effects of PPAR agonists on response to immunomodulatory agents in patients with multiple myeloma

Administered By
Medicine, Hematologic Malignancies and Cellular Therapy
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Publications:

Phase II Study of Single-Agent and Combination Everolimus and Panobinostat in Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

Novel therapeutics are needed for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Everolimus is an mTOR pathway inhibitor with synergistic anti-tumor activity when combined with histone deacetylase inhibitors, such as panobinostat, in preclinical lymphoma models. In this Phase II study, we evaluated overall response rate to single and combination everolimus and panobinostat in R/R DLBCL. Fifteen patients were enrolled to single-agent and 18 to combination. One patient responded to everolimus, while none responded to panobinostat. Though 25% of patients responded to combination therapy, responses were not durable with significant toxicity. We demonstrated minimal single-agent activity and prohibitive toxicity with combination therapy.
Authors
Islam, P; Rizzieri, D; Lin, C; de Castro, C; Diehl, L; Li, Z; Moore, J; Morris, T; Beaven, A
MLA Citation
Islam, Prioty, et al. “Phase II Study of Single-Agent and Combination Everolimus and Panobinostat in Relapsed or Refractory Diffuse Large B-Cell Lymphoma.Cancer Invest, vol. 39, no. 10, Nov. 2021, pp. 871–79. Pubmed, doi:10.1080/07357907.2021.1983584.
URI
https://scholars.duke.edu/individual/pub1499230
PMID
34643126
Source
pubmed
Published In
Cancer Invest
Volume
39
Published Date
Start Page
871
End Page
879
DOI
10.1080/07357907.2021.1983584

Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.

Authors
Pabon, CM; Li, Z; Hennig, T; de Castro, C; Neff, JL; Horwitz, ME; LeBlanc, TW; Long, GD; Lopez, RD; Sung, AD; Chao, N; Gasparetto, C; Sarantopoulos, S; Adams, DB; Erba, H; Rizzieri, DA
MLA Citation
Pabon, Cindy M., et al. “Morphologic leukemia-free state in acute myeloid leukemia is sufficient for successful allogeneic hematopoietic stem cell transplant.Blood Cancer J, vol. 11, no. 5, May 2021, p. 92. Pubmed, doi:10.1038/s41408-021-00481-9.
URI
https://scholars.duke.edu/individual/pub1482850
PMID
33994546
Source
pubmed
Published In
Blood Cancer Journal
Volume
11
Published Date
Start Page
92
DOI
10.1038/s41408-021-00481-9

Evaluation of the Oral SYK Inhibitor Fostamatinib in Patients after Allogeneic Transplantation for Chronic Graft-Versus-Host Disease

<jats:p>Our group previously showed that B cells signal aberrantly through the B cell receptor (BCR) in allogeneic hematopoietic stem cell transplant (HCT) patients with active chronic graft-versus-host disease (cGVHD). Preclinical mouse studies have demonstrated the importance of the proximal BCR molecule, spleen tyrosine kinase (SYK), in cGVHD development. Hypothesizing that the oral small molecule SYK inhibitor, fostamatinib, would safely target aberrant BCR-activated B cells in HCT patients, we are conducting a single-center, investigator-initiated phase 1 trial (NCT02611063). Our primary objective is to evaluate the safety and tolerability of fostamatinib in patients early after HCT and in those with refractory active cGVHD. Secondary objectives include assessment of cGVHD manifestations, B cell activation, and immune recovery.</jats:p> <jats:p>Methods: All patients receive HCT treatment per program standards at Duke University. Prophylaxis (P-cGVHD) subjects enroll 80-150 days after HCT and have no evidence of cGVHD. P-cGVHD subjects receive drug for up to 1 year post-transplant (215-285 fostamatinib days). Steroid-refractory cGVHD (SR-cGVHD) subjects enroll with active cGVHD that persists despite systemic high-dose steroids. SR-cGVHD subjects receive drug for up to 365 days total. For all enrollees, modified continual reassessment criteria are used to determine starting dose (100mg daily, 150mg daily, or 100mg twice BID) and any needed dose modifications. We monitor for drug-limiting toxicities (DLTs), adverse events (AEs), and cGVHD manifestations using NIH cGVHD consensus criteria at up to 12 follow-up visits.</jats:p> <jats:p>Results: 15 of a planned 18 total patients have enrolled. In the P-cGVHD group (n=5), of the 4 patients who completed treatment (mean 239 fostamatinib days), 1 patient developed cGVHD while enrolled and 2 patients subsequently developed cGVHD, 4 and 6 weeks after study completion. The fifth P-cGVHD subject discontinued therapy on study day 155 (provider decision to initiate donor lymphocyte infusion for low CD3+ chimerism). In the SR-cGVHD group (n=10), 2 patients completed treatment (mean 365 fostamatinib days); 3 patients withdrew (mean 132 fostamatinib days), for non-cardiac chest pain, progression of cGVHD, and moved away; and 5 patients are actively enrolled (mean 207 fostamatinib days). Both SR-cGVHD patients who completed the study clinically improved while on fostamatinib and requested continuation of drug. A total of 2, 9, and 4 patients have been initiated on 100mg daily, 150mg daily, and 100mg BID, respectively. At the 100mg daily dose, no DLTs were noted. At the 150mg daily dose, 1 patient developed liver function test (LFT) elevation. At the 100mg BID dose, 2 patients developed LFT elevation and 1 patient developed non-cardiac chest pain. One patient required dose adjustment: 100mg BID to 150mg daily, for LFT elevation. Two serious AEs possibly related to fostamatinib occurred: 1 patient developed non-cardiac chest pain and 1 patient developed a deep venous thrombosis. No probably- or definitely-related serious AEs occurred.</jats:p> <jats:p>To assess whether fostamatinib effectively targets aberrantly activated B cells, we examined subjects' whole blood using flow cytometry. When comparing CD19+ B cells on study day 1 versus study day 60 in the SR-cGVHD group (n=7), we found the relative proportion of CD19+CD38+IgDlow plasmablast-like cells was decreased (p=0.03, Fig 1A-B), suggesting fostamatinib 'hit target.' Importantly, in the P-cGVHD group, total lymphocyte and B cell counts did not decrease during day 1 to day 225 (Fig 1C-D), suggesting fostamatinib did not affect immune recovery when given early after HCT. Further investigations with functional assays are underway.</jats:p> <jats:p>Conclusions: This study demonstrates for the first time that fostamatinib is safe and tolerated in HCT recipients both early after transplant and in those with active cGVHD. Importantly, fostamatinib does not appear to hinder lymphocyte or B cell recovery when initiated between days 80-150 after HCT. Additionally, fostamatinib may effectively target aberrantly activated B cells in patients with active SR-cGVHD. Fostamatinib, now FDA-approved for treatment of immune thrombocytopenia, merits a phase 2, randomized controlled trial to assess efficacy as a prophylactic agent against cGVHD.</jats:p> <jats:p>This work was supported by a National Institutes of Health grant, NIH (NHLBI) R01 HL 129061. Fostamatinib was supplied by Rigel.</jats:p> <jats:p /> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Horwitz: Abbvie Inc: Membership on an entity's Board of Directors or advisory committees. Gasparetto:BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Sung:Novartis: Research Funding; Merck: Research Funding; Seres: Research Funding. Rizzieri:Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding.</jats:p> </jats:sec>
Authors
McManigle, WC; DiCioccio, RA; Anand, S; Li, Z; Poe, JC; Nichols, KR; Suthers, AN; Jia, W; Corbet, K; Covington, M; Lloyd-Cowden, J; Lopez, RD; Long, GD; Horwitz, ME; Gasparetto, C; Sung, AD; Chao, NJ; Rizzieri, DA; Sarantopoulos, S
MLA Citation
McManigle, William C., et al. “Evaluation of the Oral SYK Inhibitor Fostamatinib in Patients after Allogeneic Transplantation for Chronic Graft-Versus-Host Disease.” Blood, vol. 134, no. Supplement_1, American Society of Hematology, 2019, pp. 4521–4521. Crossref, doi:10.1182/blood-2019-130742.
URI
https://scholars.duke.edu/individual/pub1469325
Source
crossref
Published In
Blood
Volume
134
Published Date
Start Page
4521
End Page
4521
DOI
10.1182/blood-2019-130742

Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis

<jats:p>Introduction/Background:</jats:p> <jats:p>Standard therapy for both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) is myelosuppressive, and patients are expected to be neutropenic for a prolonged period. Due to the high risk of infection, antimicrobial prophylaxis is warranted and should be continued throughout neutropenia. The incidence of documented invasive fungal infections ranges from 12 to 24% in patients with AML and approximately 6.5% in patients with ALL. Guidelines currently include posaconazole as a category 1 recommendation for antifungal prophylaxis, with echinocandins and other azole antifungals as category 2B. However, posaconazole can be subject to drug-drug interactions and can increase the risk of hepatotoxicity, both of which can be problematic in acute leukemia patients undergoing chemotherapy. For patients unable to receive posaconazole or another second-generation azole antifungal, micafungin is utilized.</jats:p> <jats:p>To our knowledge, there are no studies comparing second-generation azole antifungals to micafungin as prophylaxis in both AML and ALL during initial or relapsed/refractory induction therapy. The aim of this retrospective study is to compare the incidence of invasive fungal infections in patients with acute leukemia in the setting of micafungin or second-generation azole antifungal prophylaxis during initial and/or relapsed/refractory induction therapy at an academic medical center.</jats:p> <jats:p>Methods:</jats:p> <jats:p>Retrospective, single-center study from June 22, 2013 to June 22, 2018. Detailed chart reviews were performed by hand.</jats:p> <jats:p>Results:</jats:p> <jats:p>The incidence of invasive fungal infections within 100 days of chemotherapy was 11.2% in patients who received a second-generation azole and 2.7% in patients who received micafungin (P=0.7618). The incidence of invasive fungal infections within 100 days in patients who received a high intensity AML regimen was 11.2%, low intensity AML regimen 0.9%, and ALL regimen 1.8% (P=0.5378). The incidence of invasive fungal infections within 30 days of chemotherapy was 4.5% in patients who received a second-generation azole and 2.2% in patients who received micafungin (P=0.2447). The most common reason for micafungin prophylaxis was drug-drug interactions with standard ALL regimens that utilize vincristine. Of those with a documented fungal infection, 14 patients (6.3%) had a proven invasive fungal infection, and 17 patients (7.6%) had a probable/possible invasive fungal infection. The most common site of infection was in the chest (9.8%), followed by fungemia (2.2%). Other sites of infection include the brain, sinuses, liver/spleen, and skin. Beta-D-glucan was collected in 17 patients, and galactomannan antigen was collected in 26 patients. Three patients had a positive beta-D-glucan, and 1 patient had an indeterminate beta-D-glucan. Two patients had a positive galactomannan antigen. Fusarium species accounted for 4 positive cultures in patients. For those patients who did experience an invasive fungal infection, 23 out of the 31 patients (74.2%) were on posaconazole, 6 patients on micafungin (19.4%), and 2 on voriconazole (6.5%). Ten out of the 14 proven fungal infections (71.4%) occurred while on posaconazole prophylaxis, and 3 of these patients had posaconazole levels &lt;0.7 mcg/mL. Twenty-one patients (67.7%) with documented infections had a neutrophil nadir &lt; 0.1x109/L. The majority (93.5%) of those with breakthrough infections while on antifungal prophylaxis were switched to another antifungal.</jats:p> <jats:p>Conclusions:</jats:p> <jats:p>Micafungin is a reasonable alternative therapy for use in patients who are unable to receive second-generation azoles as antifungal prophylaxis during induction therapy for acute leukemia. Some invasive fungal infections occurred while patients had sub-therapeutic posaconazole levels, however others had breakthrough fungal infections with therapeutic levels. Our conclusions are limited by the small sample size and non-randomized, retrospective nature of this analysis.</jats:p> <jats:sec> <jats:title>Disclosures</jats:title> <jats:p>Erba: Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding; Celgene, Incyte, Novartis: Speakers Bureau; Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy. LeBlanc:Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NINR/NIH: Research Funding; Jazz Pharmaceuticals: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; CareVive: Consultancy; American Cancer Society: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Medtronic: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; Heron: Membership on an entity's Board of Directors or advisory committees; Duke University: Research Funding; Celgene: Honoraria; Flatiron: Consultancy. Rizzieri:AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Stemline: Research Funding; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board.</jats:p> </jats:sec>
Authors
Morris, H; Moorman, MT; Mackey, MC; Erba, HP; LeBlanc, TW; Rizzieri, DA; Barak, I; Li, Z; Zapolskaya, T
MLA Citation
Morris, Heather, et al. “Incidence of Invasive Fungal Infections in Acute Leukemia Patients Utilizing Micafungin Prophylaxis Compared to Second-Generation Azole Prophylaxis.” Blood, vol. 134, no. Supplement_1, American Society of Hematology, 2019, pp. 5105–5105. Crossref, doi:10.1182/blood-2019-132197.
URI
https://scholars.duke.edu/individual/pub1469326
Source
crossref
Published In
Blood
Volume
134
Published Date
Start Page
5105
End Page
5105
DOI
10.1182/blood-2019-132197

BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation.

Patients with chronic graft-versus-host disease (cGVHD) have increased B cell-activating factor (BAFF) levels, but whether BAFF promotes disease after allogeneic bone marrow transplantation (allo-BMT) remains unknown. In a major histocompatibility complex-mismatched model with cGVHD-like manifestations, we first examined B-lymphopenic μMT allo-BMT recipients and found that increased BAFF levels in cGVHD mice were not merely a reflection of B-cell number. Mice that later developed cGVHD had significantly increased numbers of recipient fibroblastic reticular cells with higher BAFF transcript levels. Increased BAFF production by donor cells also likely contributed to cGVHD, because BAFF transcript in CD4+ T cells from diseased mice and patients was increased. cGVHD manifestations in mice were associated with high BAFF/B-cell ratios and persistence of B-cell receptor (BCR)-activated B cells in peripheral blood and lesional tissue. By employing BAFF transgenic (Tg) mice donor cells, we addressed whether high BAFF contributed to BCR activation in cGVHD. BAFF increased NOTCH2 expression on B cells, augmenting BCR responsiveness to surrogate antigen and NOTCH ligand. BAFF Tg B cells had significantly increased protein levels of the proximal BCR signaling molecule SYK, and high SYK protein was maintained by BAFF after in vitro BCR activation or when alloantigen was present in vivo. Using T cell-depleted (BM only) BAFF Tg donors, we found that BAFF promoted cGVHD manifestations, circulating GL7+ B cells, and alloantibody production. We demonstrate that pathologic production of BAFF promotes an altered B-cell compartment and augments BCR responsiveness. Our findings compel studies of therapeutic targeting of BAFF and BCR pathways in patients with cGVHD.
Authors
Jia, W; Poe, JC; Su, H; Anand, S; Matsushima, GK; Rathmell, JC; Maillard, I; Radojcic, V; Imai, K; Reyes, NJ; Cardona, DM; Li, Z; Suthers, AN; Curry-Chisolm, IM; DiCioccio, RA; Saban, DR; Chen, BJ; Chao, NJ; Sarantopoulos, S
MLA Citation
Jia, Wei, et al. “BAFF promotes heightened BCR responsiveness and manifestations of chronic GVHD after allogeneic stem cell transplantation.Blood, vol. 137, no. 18, May 2021, pp. 2544–57. Pubmed, doi:10.1182/blood.2020008040.
URI
https://scholars.duke.edu/individual/pub1473570
PMID
33534893
Source
pubmed
Published In
Blood
Volume
137
Published Date
Start Page
2544
End Page
2557
DOI
10.1182/blood.2020008040