Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

Professional Challenges for United States Hematology/Oncology Trainees during COVID-19.

COVID-19 has been devastating for patients with cancer. In this commentary, we chronicle the pandemic's downstream impacts on United States hematology/oncology trainees in terms of professional development and career advancement. These include loss of access to clinical electives and protocol workshops, delays in research approval and execution, mentor shortages due to academic burnout, and obstacles with career transitions (most notably the post-fellowship job search). While certain silver linings from the pandemic have undoubtedly emerged, continued progress against COVID-19 will be essential to fully overcome the professional challenges it has created for the future hematology/oncology workforce.

A narrative review of red blood cell distribution width as a marker for pulmonary embolism.

Red blood cell distribution width (RDW) is a marker of variability in red blood cell size, and is routinely reported as part of a patient's complete blood count. RDW has been shown to be associated with the prediction, severity and prognosis of pulmonary embolism (PE) in recent studies. The underlying biomolecular mechanism of the relationship of RDW to PE is largely unknown, but is thought to be due to the relationship of RDW with acute inflammatory markers and variations in blood viscosity. This review substantiates that a high RDW level, defined using either an arbitrary number or according to receiver operator curve statistics, is associated with a higher risk of acute PE, increased severity (massive vs. submassive) of PE and increased mortality in patients with PE. Nevertheless, the comparison of current studies is limited due to the definition of high RDW (each study uses a different RDW cutoff level), the broad range of exclusion criteria and the inclusion of differing modalities used to diagnose a PE (computed tomography angiogram, ventilation-perfusion study, or clinical diagnosis). Despite the above limitations, these studies provide a promising future clinical use for RDW as a marker of PE.

Refractory type I cryoglobulinaemia requiring serial amputations.

We present a rare case of a man in his 40s who presented with bilateral lower extremity necrosis. After an extensive workup, he was diagnosed with type I cryoglobulinaemia (TIC) based on severe vaso-occlusive symptoms, presence of serum cryoglobins and tissue biopsy showing small-vessel vasculitis. Treatment was multimodal and targeted both his underlying lymphoproliferative disorder (monoclonal gammopathy of undetermined significance) and inflammatory state. Steroids, plasmapheresis and immunotherapy were administered with temporary remission of symptoms. After discharge, patient continued to repeatedly present with progressive bilateral lower extremity necrosis and new upper extremity digital necrosis necessitating further pharmacological treatment and surgical intervention-bilateral above the knee amputation and multiple digital hand amputations. This case illustrates a severe example of TIC where diagnosis was difficult due to atypical presentation, and disease was refractory to multimodal therapies necessitating surgical intervention to achieve temporary remission.

Bone Marrow Aplasia after CAR-T-Cell Therapy for Relapsed/Refractory Burkitt's Lymphoma.

Chimeric antigen receptor T-cells (CAR-T) are now a standard approach for treating relapsed/refractory B-cell lymphomas. Immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is a newly described entity that can manifest following CAR-T. Bone marrow (BM) aplasia is an uncommon manifestation of IEC-HS reported after CAR-T-cell therapy and is defined as the reduction or absence of hematopoietic progenitor cells resulting in severe pancytopenia. We describe the case of a 44-year-old female with relapsed/refractory Burkitt lymphoma (BL) who received treatment with lisocabtagene maraleucel with her post-CAR-T course complicated by cytokine release syndrome (CRS) and IEC-HS ultimately leading to persistent BM aplasia. She underwent a rescue allogeneic stem cell transplant but ultimately succumbed to progressive disease. IEC-HS is an increasingly recognized complication that occurs after CAR-T treatments that can result in aplasia, a dangerous complication with serious sequelae including infection, transfusion dependence, and high risk for hemorrhage. The underlying mechanism is poorly understood, and further studies are needed to understand how to treat it better.

Treatment of Mantle Cell Lymphoma in the Frontline Setting: Are We Ready for a Risk-Adapted Approach?

Mantle cell lymphoma (MCL), a type of B-cell non-Hodgkin lymphoma characterized by the t(11;14)(q13q32) translocation, is a clinically heterogenous disease which can range from indolent to highly aggressive. Numerous prognostic factors have been identified, including blastoid histology, the Mantle Cell Lymphoma International Prognostic Index (MIPI) score, high proliferation index, p53 deletions and/or mutations, complex karyotype, minimal residual disease, and several others. However, using these prognostic factors to guide treatment selection has largely remained elusive. Given the heterogeneous behavior of this disease and varying patient characteristics, we suggest that the time has come for a more risk-adapted approach to this disease. In this article, we review the numerous prognostic factors that have been described for MCL, both at the time of diagnosis and following first-line treatment. We then propose a risk-adapted approach to first-line therapy for MCL, which would reserve intensive therapy for the highest risk patients and spare others excessive toxicity.

Ozaki procedure complicated by postpericardiotomy syndrome and cardiac tamponade.

Aortic valve replacement has long been the standard of care for many aortic valve diseases. Neo sinus reconstruction and aortic valve reconstruction with native pericardium, known as the Ozaki procedure, is a relatively new technique with early studies showing good mid-term durability and hemodynamics without the need for life-long anticoagulation. We present the case of a 56-year-old male presenting with aortic valve endocarditis and severe aortic insufficiency who underwent successful aortic valve reconstruction via the Ozaki procedure complicated by postpericardiotomy syndrome and cardiac tamponade. Although the Ozaki procedure is a promising alternative to conventional aortic valve replacement, further study is needed to determine long-term re-operation rates, stability and mortality.

Neoadjuvant Tyrosine Kinase Inhibition in Locally-advanced Non-small Cell Lung Cancer: Two Cases and a Brief Literature Review.

BACKGROUND: Despite their remarkable efficacy in metastatic non-small cell lung cancer (NSCLC), EGFR- and ALK-targeted therapies have not been shown to confer any survival benefit in stage III disease, even in subsets of patients with driver mutations. CASE STUDIES: Here, two patients with unresectable stage III NSCLC carrying mutations in the ALK (case 1) and EGFR (case 2) genes are presented. Treatment of the patient carrying an ALK mutation with an ALK inhibitor and the patient carrying an EGFR mutation with an EGFR inhibitor resulted in dramatic and durable responses. CONCLUSION: These cases demonstrated that ALK or EGFR mutation-positive stage III NSCLC patients can be treated with the corresponding inhibitors. They also highlight the urgent need for prospective data to assess their potential efficacy in order to improve patient outcomes.

Presence of fluorescent in situ hybridization abnormalities is associated with plasma cell burden in light chain amyloidosis.

OBJECTIVE/BACKGROUND: To assess abnormalities found on CD138-enriched fluorescent in situ hybridization (FISH) studies on pre-treatment bone marrow in systemic amyloid light-chain amyloidosis (AL) and correlate findings between these abnormalities with organ involvement and 1-year survival. METHODS: We reviewed 107 patients with systemic AL to identify the impact of a diagnostic FISH study done on plasma cell-enriched bone marrow in our institution between January 2010 and January 2015; 77 had pre-treatment testing performed. RESULTS: A total of 77 (61%) patients had abnormal FISH including: hyperdiploidy (29%), t(11;14), (20%), hypodiploidy (16%), t(4;14), (1%), del17p (5%), and+1q21 (5%). Abnormal FISH studies were more likely in those patients with plasma cell involvement≥10% (p=.002). FISH abnormalities were not shown to correlate with stage, cardiac involvement, or survival at 1year. One-year survival was significantly affected by stage at diagnosis and presence of cardiac and hepatic amyloid involvement. CONCLUSION: We conclude that in AL, FISH abnormalities are associated with clonal burden. We found no impact of these markers on the type of organ involvement or 1-year survival.

Kinetics of Humoral Immunodeficiency With Bispecific Antibody Therapy in Relapsed Refractory Multiple Myeloma.

This case series describes the kinetics of humoral deficiency in patients with relapsed refractory multiple myeloma treated with bispecific antibodies, the infectious complications, and response to COVID-19 immunization.