Muhammad Husnain

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Scholarly Contributions

Chapters

• Husnain, M., Zhang, Y., & Rosenblatt, J. (2021). The Role of Breg Cells in Modulating the Antitumor Immune Response. In Cancer Immunotherapy Principles and Practice, Second Edition. New York: NY: Demos Medical Publishing.

Journals/Publications

• Barker, K., Koza, S., Katsanis, E., & Husnain, M. (2023). Hypophosphatemia and pre-infusion thrombocytopenia as biomarkers for CRS and ICANS after CAR T therapy. Bone marrow transplantation, 58(11), 1267-1269.
• Ghafoor, B., Masthan, S. S., Hameed, M., Akhtar, H. H., Khalid, A., Ghafoor, S., Allah, H. M., Arshad, M. M., Iqbal, I., Iftikhar, A., Husnain, M., & Anwer, F. (2023). Waldenström macroglobulinemia: a review of pathogenesis, current treatment, and future prospects. Annals of hematology.
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  Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.
• Mian, A., Naqvi, S. A., Ayaz, A., Husnain, M., Aljama, M. A., Mohyuddin, G. R., Koehn, K., Mohan, M., Bin Riaz, I., & Chakraborty, R. (2023). Incidence of second primary malignancies in patients with multiple myeloma receiving anti-CD38 monoclonal antibodies: A systematic review and meta-analysis. Leukemia research, 131, 107324.
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  Anti-CD38 monoclonal antibodies (mAbs) are commonly used for treating newly diagnosed and relapsed/refractory (r/r) multiple myeloma (MM). However, concerns have been raised about the occurrence of second primary malignancies (SPMs) in patients receiving anti-CD38 mAbs. Assessing the safety data for rare adverse events like SPMs is challenging because individual clinical trials are typically focused on the primary endpoint. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) published between January 2005 and April 2022, including patients with newly diagnosed or r/r MM. Our aim was to compare SPM rate with the use of anti-CD38 mAb-based regimens with other anti-myeloma regimens. After a median follow-up of 35.3 months (range: 8.2-56.2), we found that exposure to anti-CD38 mAbs was associated with an increased risk of developing SPMs compared to the control group (6.8% vs. 5.2%; Peto odds ratio [OR]: 1.53 [95% confidence interval (CI): 1.20-1.95]; I= 0%, p-value for heterogeneity= 0.44). This increased risk was primarily driven by non-melanoma cutaneous cancers (92 vs. 47; Peto OR: 1.77 [95% CI: 1.25-2.51]; I = 0%, p-value for heterogeneity = 0.54). However, there was no significant difference in the incidence of solid tumors (including malignant melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) or hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27]). In conclusion, the use of anti-CD38 mAb-based combination regimens is associated with a higher risk of non-invasive cutaneous SPMs, but not solid tumors or hematologic SPMs. The increased occurrence of non-invasive cutaneous SPMs may be due to enhanced monitoring resulting from longer treatment duration with anti-CD38 mAbs.
• Wu, C., Manchen, P., Edelman, A., Husnain, M., Katsanis, E., Fuchs, D., Stephens, L., & Khurana, S. (2023). Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab. Journal of hematology, 12(6), 277-282.
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  Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.
• Chakraborty, R., Siddiqi, R., Willson, G., Gupta, S., Asghar, N., Husnain, M., Aljama, M. A., Behera, T. R., Anwer, F., Perrot, A., & Riaz, I. B. (2022). Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials. Cancer, 128(12), 2288-2297.
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  Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk.
• Katsanis, E., Stea, B., Kovacs, K., Truscott, L., Husnain, M., Khurana, S., Roe, D. J., & Simpson, R. J. (2022). Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation. Transplantation and cellular therapy, 28(7), 390.e1-390.e10.
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  Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.
• Hashmi, H., Husnain, M., Khan, A., & Usmani, S. Z. (2021). CD38-Directed Therapies for Management of Multiple Myeloma. ImmunoTargets and therapy, 10, 201-211.
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  The survival outcomes for multiple myeloma have improved several-fold in the past two decades, primarily due to the introduction of therapies with novel mechanisms of action including immunomodulatory agents, proteasome inhibitors, stem cell transplant and monoclonal antibodies in the schema of therapy. Antibody-based therapies targeting the surface marker CD38, namely daratumumab and isatuximab, have emerged as being highly effective as single agents as well as in combination regimens for both newly diagnosed and relapsed settings. Herein, the authors summarize the most recent data with both the current and emerging CD38-directed therapies in multiple myeloma.
• Riaz, I. B., He, H., Ryu, A. J., Siddiqi, R., Naqvi, S. A., Yao, Y., Husnain, M., Narasimhulu, D. M., Mathew, J., Sipra, Q. U., Vandvik, P. O., Joseph, R. W., Liu, H., Wang, Z., Herasevich, V., Singh, P., Hussain, S. A., Ho, T. H., Bryce, A. H., , Pagliaro, L. C., et al. (2021). A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma. European urology, 80(6), 712-723.
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  Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations.

Poster Presentations

• Husnain, M. (2021, December). Non-Relapse Mortality in TP53-Mutated MDS/AML - a Multi-Center Collaborative Study. American Society of Hematology. Atlanta, GA.

Reviews

• Filioglou, D., Husnain, M., Khurana, S., Simpson, R. J., & Katsanis, E. (2023. Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?(p. 1329850).
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  The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.