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Razan Mohty,1 Mohamed A Kharfan-Dabaja,2 Julio C Chavez3 1Department of Blood and Marrow Transplantation and Cellular Therapy, Moffitt Cancer Center, Tampa, FL, USA; 2Division of Hematology-Oncology and Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, FL, USA; 3Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USACorrespondence: Julio C Chavez, Department of Malignant Hematology, Moffitt Cancer Center, 12902 Magnolia Drive FOB, Tampa, FL, 33612, USA, Email julio.c.chavez@moffitt.orgAbstract: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) that has shown efficacy in B-cell non-Hodgkin’s lymphoma. It has shown high efficacy in relapsed/refractory follicular lymphoma (FL) even in the presence of high risk features (early relapse, heavily pretreated patients and bulky disease). Treatment options for R/R follicular lymphoma do not offer long-term remissions, especially in the third-line setting. Axi-cel was studied in R/R FL in the ZUMA-5 study, which showed high response rates with durable remissions. Axi-cel was associated with anticipated but manageable toxicities. Long-term follow up may be able to inform the potential for cure of FL. Axi-cel should be part of the standard of care options for R/R FL beyond second line.Keywords: axicabtagene ciloleucel, follicular lymphoma, immunotherapy, cellular therapy

Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) mutations have uncertain prognostic implications in AML. We investigate the impact IDH1 and IDH2 mutations in AML patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) in first complete remission (CR1). In total, 1515 adult patients were included, 15.91% (n = 241) carried IDH1 mutation (mIDH1), and 26.27% (n = 398) IDH2 mutation (mIDH2) and 57.82% (n = 876) had no-IDH mutation. NPM1 was frequently encountered with IDH1 mutation (no-IDH group, n = 217, 24.8%, mIDH1, n = 103, 42.7%, mIDH2, n = 111, 27.9%, p < 0.0001). At day 180, the cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was significantly lower in mIDH1 and mIDH2 compared to no-IDH groups (Hazard ratio [HR] = 0.66 (95% CI 0.47-0.91), p = 0.011; HR = 0.73 (95% CI 0.56-0.96), p = 0.025, respectively). In the mIDH1 group, overall survival (OS) was improved compared to no-IDH (HR = 0.68 (95% CI 0.48-0.94), p = 0.021), whereas mIDH2 was associated with lower incidence of relapse (HR = 0.49 (95% CI 0.34-0.7), p < 0.001), improved leukemia free survival (LFS) (HR = 0.7 (95% CI 0.55-0.9), p = 0.004) and OS (HR = 0.74 (95% CI 0.56-0.97), p = 0.027). In the subgroup of NPM1 wild type, only IDH2 was associated with improved outcomes. In conclusion, our data suggest that IDH1 and IDH2 mutations are associated with improved outcomes in patients with AML undergoing allo-HCT in CR1., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

VEXAS syndrome is an X-linked monogenic disease with adult-onset inflammatory disease and myeloid dysplasia, with clinical presentation ensuing in the fifth decade of life or later. Inflammatory symptoms associated with VEXAS syndrome are treated with several lines of therapy, eventually requiring allogeneic hematopoietic cell transplantation (allo-HCT). No evidence from randomized controlled trials exists on allo-HCT versus other treatments in patients not responding to front-line therapy(ies). We show results of a systematic review/meta-analysis (SR/MA) following a search using EMBASE, PUBMED/MEDLINE and Web of Science on April 5, 2024. We extracted outcomes based on benefits (overall response rate (ORR), complete remission (CR), event-free survival (EFS) and overall survival (OS), and harms (non-relapse mortality (NRM) and acute and chronic graft-versus-host disease (GVHD)). The search identified 88 studies. Four studies (39 patients) met inclusion criteria. Median follow-up time after allo-HCT ranged from 8 to 18.5 months. Pooled EFS and OS rates were 56% and 86%, respectively. Pertaining to harms, pooled NRM rate was 14%. Pooled rates of acute and chronic GVHD were 42% and 13%, respectively. Allo-HCT is an effective treatment for VEXAS syndrome. We hope these results would increase awareness about this underdiagnosed and underreported disease., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a poor prognosis with conventional therapies. Diagnostic challenges and lack of standardized treatment protocols contribute to suboptimal outcomes. Additionally, while allogeneic hematopoietic cell transplantation (HCT) is frequently recommended in adults with Ph-like ALL given its high-risk nature, data supporting its role remains limited. We conducted a multicenter retrospective study evaluating outcomes of adult patients undergoing HCT in first complete remission (CR1) for Ph-like ALL compared to Philadelphia chromosome positive ALL (Ph-pos) and other B-cell Philadelphia negative (Ph-neg) ALL. Data was collected from five academic centers across the US, focusing on HCT outcomes for patients with ALL. Patients undergoing HCT in CR1 between 2006 and 2021 were included. Among 673 patients, 83 (12.3%) had Ph-like ALL, while 271 (40.3%) had Ph-pos and 319 (47.4%) had Ph-neg ALL. Outcomes following HCT in CR1 for Ph-like ALL were comparable to Ph-neg ALL, with no significant differences in 3-year overall survival (66% vs. 59%, P = .1), progression-free survival (59% and 54%, P = .1), or relapse rates (22% vs. 20%, P = .7). In contrast, Ph-pos ALL had superior outcomes; 3-year OS (75%, P < .001), PFS (70%, P = .001) and relapse (12%, P = .003), this is likely attributed to tyrosine kinase inhibitor therapy. Our study suggests that HCT, coupled with effective 2nd line therapies can possibly mitigate the poor prognosis associated with Ph-like ALL and offers promising outcomes for patients with Ph-like ALL., (Copyright © 2024. Published by Elsevier Inc.)

Background: One major limitation for broader applicability of allogeneic hematopoietic cell transplantation (allo-HCT) in the past was the lack of HLA-matched histocompatible donors. Preclinical mouse studies using T-cell depleted haploidentical grafts led to an increased interest in the use of ex vivo T-cell depleted (TCD) haploidentical allo-HCT. TCD grafts through negative (T-cell depletion) or positive (CD34+ cell selection) techniques have been investigated to reduce the risk of graft-versus-host disease (GVHD) given the known implications of alloreactive T cells. A more practical approach to deplete alloreactive T cells in vivo using high doses of cyclophosphamide after allografting has proved to be feasible in overcoming the HLA barrier. Such approach has extended allo-HCT feasibility to patients for whom donors could not be found in the past. Nowadays, haploidentical donors represent a common donor source for patients in need of an allo-HCT. The broad application of haploidentical donors became possible by understanding the importance of depleting alloreactive donor T cells to facilitate engraftment and reduce incidence and severity of GVHD. These techniques involve ex vivo graft manipulation or in vivo utilization of pharmacologic agents, notably post-transplant cyclophosphamide (PTCy)., Discussion: While acknowledging that no randomized controlled prospective studies have been yet conducted comparing TCD versus PTCy in haploidentical allo-HCT recipients, there are two advantages that would favor the PTCy, namely ease of application and lower cost. However, emerging data on adverse events associated with PTCy including, but not limited to cardiac associated toxicities or increased incidence of post-allograft infections, and others, are important to recognize.

Introduction: Chronic inflammatory dermatoses (CIDs) can significantly affect patients' lives. The Observatory of Chronic Inflammatory Skin Diseases (OMCCI) cohort was initiated to quantify the impact and disease evolution of four CID over 4 years' follow-up; at least 1,000 patients per CID are planned to be enrolled. The objective of this study was to present baseline characteristics of patients included in the OMCCI cohort between December 2020 and September 2022., Methods: This French, prospective, multicenter registry included adult patients treated in daily practice for moderate-to-severe psoriasis (PS), atopic dermatitis (AD), hidradenitis suppurativa (HS), or chronic urticaria (CU) starting or modifying a systemic treatment. At the inclusion visit and then every 6 months during 4 years, patient-reported outcomes and data on these diseases and their treatments are recorded., Results: A total of 2,058 patients from 24 centers were included: 1,137 PS, 413 AD, 301 HS, and 207 CU. Of these, 1,950 patients started or changed systemic treatment, and 108 reduced the dose of existing systemic treatment. Disease impact was qualified as debilitating by 80.1% (PS), 90.5% (AD), 90.5% (HS), and 89.4% (CU), affecting daily, family, and professional life. According to the SF-12 Survey, the impact of all four diseases was borderline pathological for physical health and severe for mental health. At inclusion, 20.4% of patients were receiving a conventional systemic or biologic treatment. After the first visit, this percentage raised to 83.3%. During the 6 months preceding study inclusion, 17.7% (PS), 27.9% (AD), 43.1% (HS), and 43.6% (CU) of patients missed work due to their illness, and 26.3% of patients with HS had been admitted to hospital (vs. 8.1%, 5.8%, and 13% of patients with PS, AD, or CU, respectively)., Conclusion: These CIDs (especially HS) had a major impact on all aspects of patients' quality of life. The low baseline use of systemic drugs and the high burden of these CIDs suggest that these agents are underused. Long-term and dynamic evaluation of the changes brought by the initiation or optimization of these treatments on the evolution of patients' lives will be studied prospectively during the 4-year follow-up of the OMCCI., (© 2024 S. Karger AG, Basel.)

Chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment landscape for hematologic malignancies, notably B-cell non-Hodgkin lymphoma (B-NHL) and B-cell acute lymphoblastic leukemia (B-ALL). While autologous CAR T products have shown remarkable efficacy, their complex logistics, lengthy manufacturing process, and high costs impede widespread accessibility and pose therapeutic challenge especially for patients in rapid need for therapy. "Off-the-shelf" allogeneic CAR T-cell therapy (alloCAR T) has emerged as a promising alternative therapy, albeit experimental to date. AlloCARTs are derived from healthy donors, manufactured by batches and stored, making them available off-the-shelf which lowers financial burden. Various gene editing techniques have been employed to mitigate graft-versus-host disease (GVHD) and host-versus-graft (HvG) to enhance alloCAR T persistence. In this review, we summarize available manufacturing techniques, current evidence, and discuss challenges faced with the use of alloCAR Ts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mohty and Lazaryan.)

Despite therapeutic advances for acute promyelocytic leukemia (APL) with the emergence of all-trans retinoic acid, arsenic trioxide, and gemtuzumab-ozogamycin, approximately 10% of patients still experience disease relapse, typically occurring within 24 to 36 months following completion of front-line treatment. Traditionally, both allogeneic (allo) and autologous (auto) hematopoietic cell transplantation (HCT) have been considered reasonable treatment options for relapsed APL; however, no randomized controlled studies have been conducted comparing allo-HCT and auto-HCT in patients with relapsed APL. We performed a systematic review/meta-analysis to assess the totality of evidence pertaining to allo-HCT or auto-HCT in relapsed APL. Our search identified 1158 references, of which 23 met our inclusion criteria. While acknowledging the limitations of comparing these 2 treatment modalities indirectly, based on results from separate meta-analyses, it appears that pooled rates of event-free survival (71% versus 54%), progression-free survival (63% versus 43%), and overall survival (82% versus 58%) are higher after auto-HCT. This difference can be explained in part by the higher risk of pooled nonrelapse mortality (NRM) in patients undergoing allo-HCT (29% versus 5%), owing to inherent risks associated with this modality. In the absence of a randomized prospective clinical trial comparing allo-HCT and auto-HCT, our results show that both modalities are acceptable in patients with relapsed APL. The higher pooled NRM rate with allo-HCT is an important consideration when choosing this option. Additionally, the comparable pooled relapse rate for auto-HCT and allo-HCT (24% versus 23%) provides a rationale for evaluating post-HCT consolidative strategies to mitigate this risk., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Abstract: Cytopenias represent the most common side effect of CAR T-cell therapy (CAR-T) and can predispose for severe infectious complications. Current grading systems, such as the Common Terminology Criteria for Adverse Events (CTCAE), neither reflect the unique quality of post-CAR-T neutrophil recovery, nor do they reflect the inherent risk of infections due to protracted neutropenia. For this reason, a novel EHA/EBMT consensus grading was recently developed for Immune Effector Cell-Associated HematoToxicity (ICAHT). In this multicenter, observational study, we applied the grading system to a large real-world cohort of 549 patients treated with BCMA- or CD19-directed CAR-T for refractory B-cell malignancies (112 multiple myeloma [MM], 334 large B-cell lymphoma [LBCL], 103 mantle cell lymphoma [MCL]) and examined the clinical sequelae of severe (≥3°) ICAHT. The ICAHT grading was strongly associated with the cumulative duration of severe neutropenia (r = 0.92, P < .0001), the presence of multilineage cytopenias, and the use of platelet and red blood cell transfusions. We noted an increased rate of severe ICAHT in patients with MCL vs those with LBCL and MM (28% vs 23% vs 15%). Severe ICAHT was associated with a higher rate of severe infections (49% vs 13%, P < .0001), increased nonrelapse mortality (14% vs 4%, P < .0001), and inferior survival outcomes (1-year progression-free survival: 35% vs 51%, 1-year overall survival: 52% vs 73%, both P < .0001). Importantly, the ICAHT grading demonstrated superior capacity to predict severe infections compared with the CTCAE grading (c-index 0.73 vs 0.55, P < .0001 vs nonsignificant). Taken together, these data highlight the clinical relevance of the novel grading system and support the reporting of ICAHT severity in clinical trials evaluating CAR-T therapies., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

In recent years, chimeric antigen receptor T-cell therapy (CAR T) has revolutionized the treatment landscape for large B cell lymphoma (LBCL), demonstrating remarkable efficacy and ushering a new era of therapeutic possibilities. However, a subset of patients may not achieve the desired response with CAR T. This review examines strategies aimed at optimizing outcomes for patients who relapse or progress after CAR T. Available data on utilization of CD19-directed monoclonal antibodies and antibody drug conjugates have shown limited efficacy in this setting. Moreover, bispecific antibodies have also emerged as an alternative therapy in relapsed and or refractory LBCL, but long-term follow up treated cases post-CAR T failure are lacking. Several observational studies have shown efficacy of allogeneic hematopoietic cell transplantation, but attainment of a complete remission prior to allografting is a prerequisite to achieve durable remissions. As we navigate the intricate landscape of treatment of post CAR T failure, it becomes evident that this represents a therapeutic challenge which necessitates a multifaceted approach., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

While acknowledging that newer therapies have improved survival rates in chronic lymphocytic leukemia (CLL), patients with high-risk disease features are at an increased risk of treatment failure. Allogeneic hematopoietic cell transplantation (allo-HCT) was traditionally offered as front-line consolidation in high-risk CLL; however, with the emergence of targeted therapies like Bruton tyrosine kinase (BTK) and B-cell lymphoma 2 (BCL-2) inhibitors, the role of allo-HCT has been relegated to later stages of the disease. Patients with relapsed/refractory (R/R) CLL who have failed both BTK and BCL-2 inhibitors represent a therapeutic challenge owing to a poor prognosis. Chimeric antigen receptor T-cell (CAR T) therapies targeting CD19 have improved response rates and overall survival in various types of R/R B-cell non-Hodgkin lymphomas. For CLL, no approved CAR T-cell therapies are yet available. Emerging data appear to show a therapeutic benefit of CAR T-cell therapy in patients with R/R CLL, even after failing an allo-HCT., Competing Interests: R.M., S.A., M.G., Y.L., R.P., and H.Q.: No COI M.A.K-D: research/grant support to institutions from Novartis and Bristol Myers Squibb

CD19-directed CAR T-cell therapy with brexucabtagene autoleucel (brexu-cel) has substantially improved treatment outcomes for patients with relapsed/refractory mantle cell lymphoma (r/r MCL). Prolonged cytopenias and infections represent common and clinically relevant side effects. In this multicenter observational study, we describe cytopenias and infections in 103 r/r MCL patients receiving brexu-cel. Furthermore, we report associations between the baseline CAR-HEMATOTOX (HT) score and toxicity events, non-relapse mortality (NRM), and progression-free/overall survival (PFS/OS). At lymphodepletion, 56 patients were HT low (score 0-1) while 47 patients were HT high (score ≥2). The HT high cohort exhibited prolonged neutropenia (median 14 vs. 6 days, p < .001) and an increased rate of severe infections (30% vs. 5%, p = .001). Overall, 1-year NRM was 10.4%, primarily attributed to infections, and differed by baseline HT score (high vs. low: 17% vs. 4.6%, p = .04). HT high patients experienced inferior 90-day complete response rate (68% vs. 93%, p = .002), PFS (median 9 months vs. not-reached, p < .0001), and OS (median 26 months vs. not-reached, p < .0001). Multivariable analyses showed that high HT scores were independently associated with severe hematotoxicity, infections, and poor PFS/OS. In conclusion, infections and hematotoxicity are common after brexu-cel and contribute to NRM. The baseline HT score identified patients at increased risk of poor treatment outcomes., (© 2023 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Multiple myeloma (MM) is the second most common hematologic malignancy, with 34,470 estimated new cases in 2022. High-dose therapy followed by autologous hematopoietic cell transplantation (auto-HCT) remains a standard treatment for MM even in the era of novel therapies. This is usually performed in hospital-based settings, either in the inpatient or outpatient units. Advanced Care at Home (ACH) represents a virtual hybrid hospital-at-home program that combines a virtual provider-staffed command center with a vendor-mediated supply chain capable of delivering high-acuity care in the comfort of the patients' own homes. In our program, we used the existing ACH platform to deliver post-HCT care for recipients of auto-HCT., Patients and Methods: Four patients (female = 2, 50%) with MM, with a median age of 60 (range, 40-74) years, were admitted to the inpatient Blood and Marrow Transplant (BMT) unit. The conditioning regimen consisted of melphalan 200 mg/m 2 , administered on day -2. All patients received stem cell infusion (day 0) in the inpatient setting, with a median dose of 3.64 (range, 2.92-8.22) × 10 6 /kg CD34 cells., Results: Patients were discharged to their homes after completing the infusion on day 0 or day +1 at the latest. Post-infusion care was provided by the ACH team in coordination with the BMT team. The median time intervals to absolute neutrophil count and platelet engraftment were 12 (range, 11-13) and 11 (range, 9-16) days, respectively. All patients were successfully discharged from the ACH program at a median of day +14 (range, day +14 to day +15)., Conclusions: Our results highlight the feasibility of delivering post-HCT care for auto-HCT recipients in the home setting and confirm the generalizability of this approach.

Introduction: Chimeric antigen receptor T (CAR T) cell therapy epitomizes the success of T cell engineering. Today, it is an integral component of the treatment algorithm for various types of B-cell non-Hodgkin lymphoma (NHL). Large B-cell lymphoma (LBCL) is the most common subtype of NHL accounting for 30-35% of cases. A lack of response to second-line therapy portends a poor prognosis as only 7-15% of patients attain complete remission (CR) with subsequent conventional chemoimmunotherapy., Areas Covered: Lisocabtagene maraleucel (liso-cel) is an autologous CD-19 directed CAR T-cell product with a 4-1BB co-stimulatory domain administered as a sequential infusion of 2 separately manufactured components: CD8 + and CD4 + CAR T-cells in equal doses. Liso-cel showed an impressive objective response rate of 73% (CR = 53%) in patients who had received a median of 3 prior therapies. Median time-to-first CR or partial response (PR) was 1 month., Expert Opinion: When evaluated in the second line setting in LBCL, liso-cel demonstrated superior event-free survival (EFS) versus standard of care. While acknowledging that choice of a particular CAR T-cell is based chiefly on familiarity of the treating physician with a specific product, liso-cel definitely represents an important addition to the treatment armamentarium of R/R LBCL whether in the second-line setting or beyond.

Participation of women and early-career faculty in hematology and medical oncology board review lecture series has not been studied previously. We aimed to evaluate gender and early-career faculty disparities in hematology and medical oncology board review lecture series. Speakers at major hematology and/or oncology board review lecture series meetings in the United States were analyzed in this cross-sectional study during a 5-year period from the years 2017 through 2021. Data about the lecture topic, field, speaker's gender, years of experience, and the frequency at which the lecture was given by the speaker were collected. Of 386 speakers participating, 315 (81.6%) were ABIM (American Board of Internal Medicine)-certified. A total of 1,224 board review lectures were given in the studied period, of which 1,016 (83%) were given by an ABIM-certified speaker. Women constituted 37.7% of all speakers, with less than 50% representation in five out of six courses. Lectures discussing malignant hematology topics had the lowest proportion of women presenters (24.8%), followed by solid tumors (38.9%) and benign hematology lectures (44.1%). Faculty with more than 15 years since initial certification presented more than 50% of lectures. The median time from initial hematology or medical oncology certification to lecture presentation was 12.5 years and 14 years, respectively. A positive trend in the participation of women was found at all board review conferences across the studied period. Our data suggest that women and early-career faculty participation in hematology and oncology board review series is inadequate., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Patients with relapsed and/or refractory (R/R) follicular lymphoma (FL) and mantle cell lymphoma (MCL) have a poor prognosis with anticipated short progression-free and overall survivals. Two CD19-directed chimeric antigen receptor T-cell (CAR T) therapies are approved in the United States for R/R FL, namely, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. The results of ZUMA-5 and ELARA studies led to the approval of axi-cel and tisagenlecleucel, respectively, after demonstrating high overall (ORR) and complete response (CR) rates in this high-risk population of FL patients who had received a median of 3 (range = 2-4) and 4 (range = 2-13) prior lines of therapies, respectively. For instance, the ORR for ZUMA-5 was 94% (CR = 79%), and for ELARA, it was 86% (CR = 69.1%). Pertaining to MCL, brexucabtagene autoleucel is approved for R/R MCL based on results of the ZUMA-2 study. In the latter study, despite the fact that all R/R MCL patients had been exposed to prior Bruton's tyrosine kinase inhibitors, the reported ORR was 91%, with 68% achieving a CR. These results undoubtedly demonstrate a strong efficacy of CAR T therapy in both R/R FL and MCL; yet, one must acknowledge the relatively short follow-up time of all aforementioned studies. Thus, longer follow-up showing durability of responses and long-term safety is definitely needed., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Chimeric antigen receptors (CARs) are synthetic engineered receptors with an antigen recognition domain derived from a high-specificity monoclonal antibody that can target surface molecules on tumor cells. T cells are genetically engineered to express CARs, thereby harnessing the antigen-recognition ability of antibodies and effector function of T cells. Target surface molecule selection is crucial for manufacturing CARs. Ideally, a target surface molecule should be restricted to tumor cells and minimally expressed or absent on normal tissues. Different CD19-targeted CAR-T cell therapies have been approved for the treatment of B-cell lymphoid malignancies that are refractory to other therapies, including indolent and aggressive B-cell non-Hodgkin lymphomas (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). Despite impressive results, many patients with aggressive and refractory B-cell malignancies do not respond to or relapse after CD19 CAR-T cell therapies. Thus, several additional strategies are currently being evaluated to overcome these limitations. This review discusses studies on other promising CAR-T cell targets, including CD20, CD22, BAFF-R, ROR1, CD70, BCR complex, kappa/lambda light chains, multitargeted CAR-T cells, and combinations of CAR-T cell therapy with different drugs.

Chimeric antigen receptor T-cell (CAR T) therapy has been proven effective in the third-line (and beyond) setting in patients with large B-cell lymphoma (LBCL). Until recently, high-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) was considered the standard of care in the second-line setting in patients demonstrating an objective response before the procedure. The ZUMA-7 and TRANSFORM studies showed the benefit of axicabtagene ciloleucel and lisocabtagene maraleucel, respectively, in patients refractory to or relapsing within 12 months of first-line anthracycline-based chemoimmunotherapy. However, a third trial (BELINDA study) using tisagenlecleucel failed to show a benefit in the same setting compared to standard salvage chemoimmunotherapy followed by auto-HCT. Several differences exist between these trials, including trial designs, patient population, crossover permissibility, bridging therapy, and end-point definitions. In this review, we summarize the current evidence for the treatment of patients with LBCL in the third line and beyond and standard treatment in the second line before CAR T therapy approval and interpret outcomes of the three trials examining the role of CAR T therapy in the second line and their impact in reshaping future practice.

Chimeric antigen receptor (CAR) T cell therapy represents a significant advancement in the treatment of patients with relapsed/refractory B cell lymphoid malignancies. Cytokine release syndrome and immune effector cell-associated neurotoxicity represent the most acute serious adverse events post CAR T cell therapy but the occurrence and persistence of cytopenias post CAR T cell therapy represent a significant adverse event and a management challenge. While most patients typically recover blood counts by 30 days, a significant subset of patients have persistent or late cytopenias beyond 30 days. Patients receiving CAR T cell are heavily pre-treated and the impact of prior therapies on late cytopenias is not well understood. In this study, we found an association between increased number of rituximab infusions and/or cumulative rituximab dose received prior to CAR T cell infusion and persistent anemia and thrombocytopenia at 90 and 180 days afterwards. An overall increased number of prior lines of therapy was also associated with persistent lymphopenia and anemia at 90 days while receiving a prior autologous hematopoietic cell transplant was associated with a greater risk of neutropenia and lymphopenia., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Myelodysplastic syndromes (MDS) are a heterogeneous clonal disease of myeloid neoplasms characterized by ineffective hematopoiesis, variable degree of cytopenias, and an increased risk of progression to acute myeloid leukemia (AML). Molecular and genetic characterization of MDS has led to a better understanding of the disease pathophysiology and is leading to the development of novel therapies. Targeted and immune therapies have shown promising results in different hematologic malignancies. However, their potential use in MDS is yet to be fully defined. Here, we review the most recent advances in therapeutic approaches in MDS, focusing on higher-risk disease. Allogeneic hematopoietic cell transplantation is beyond the scope of this article., (© 2022. The Author(s).)

Background: Mantle cell lymphoma is the rarest subtype of non-Hodgkin's lymphoma. It can exhibit diverse extranodal manifestations. However, renal involvement is uncommon, and if it occurs, it usually only gets detected postmortem. There are several mechanisms by which mantle cell lymphoma can damage the kidneys. Renal failure is a potential complication, and prompt evaluation and diagnosis are critical steps to prevent long-term complications., Case Presentation: We present the case of a 75-year-old non-Hispanic White male with past medical history significant for hypertension and dyslipidemia, presenting with fever, weight loss, and night sweats. Work-up showed markedly elevated white blood cells, multiple enlarged lymph nodes, and a kidney mass. The patient was diagnosed with mantle cell lymphoma with kidney involvement confirmed with a kidney biopsy. His disease was positive for cyclin D1 overexpression despite t(11; 14) absence. The patient received six cycles of alternating vincristine, rituximab, cyclophosphamide, doxorubicin, and prednisone then dexamethasone, high-dose cytarabine, and oxaliplatin, after which he was maintained on ibrutinib and rituximab, with resolution of symptoms and disease regression., Conclusion: We present a case of a rare presentation of Mantle cell lymphoma while describing the clinical presentation and diagnostic and treatment approaches. This case report can assist physicians in the clinical work-up and treatment of patients with similar diagnosis or presentation., (© 2022. The Author(s).)

Methemoglobinemia is a rare disorder associated with oxidization of divalent ferro-iron of hemoglobin (Hb) to ferri-iron of methemoglobin (MetHb). Methemoglobinemia can result from either inherited or acquired processes. Acquired forms are the most common, mainly due to the exposure to substances that cause oxidation of the Hb both directly or indirectly. Inherited forms are due either to autosomal recessive variants in the CYB5R3 gene or to autosomal dominant variants in the globin genes, collectively known as HbM disease. Our recommendations are based on a systematic literature search. A series of questions regarding the key signs and symptoms, the methods for diagnosis, the clinical management in neonatal/childhood/adulthood period, and the therapeutic approach of methemoglobinemia were formulated and the relative recommendations were produced. An agreement was obtained using a Delphi-like approach and the experts panel reached a final consensus >75% of agreement for all the questions., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Myelofibrosis (MF) is a clonal stem cell neoplasm with heterogeneous clinical phenotypes and well-established molecular drivers. Allogeneic haematopoietic stem cell transplantation (HSCT) offers an important curative treatment option for primary MF and post-essential thrombocythaemia/polycythaemia vera MF or secondary MF. With a disease course that varies from indolent to highly progressive, we are now able to stratify risk of mortality through various tools including patient-related clinical characteristics as well as molecular genetic profile. Owing to the high risk of mortality and morbidity associated with HSCT for patients with myelofibrosis, it is important to improve patient selection for transplant. Our primary goal is to comprehensively define our understanding of current practices including the role of Janus Kinase (JAK) inhibitors, to present the data behind transplantation before and after leukaemic transformation, and to introduce novel personalization of MF treatment with a proposed clinical-molecular prognostic model to help elucidate a timepoint optimal for consideration of HSCT., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

CD19-targeted chimeric antigen receptor (CAR) T cell therapy has shown high efficacy in patients with refractory B-cell malignancies such as non-Hodgkin lymphoma and acute lymphoblastic leukemia. Despite promising results, responses are not durable in most patients. In addition, patients receiving CD19 CAR T cell therapy are at risk of developing severe, potentially life-threatening, adverse events including cytokine release syndrome and immune effector-cell associated neurotoxicity syndrome. Many combinatorial approaches are currently being investigated to improve CAR T cell in vivo function, antitumor effects, and mitigate toxicities. In this review, we discuss the use of ibrutinib and immune checkpoint inhibitors in combination with CAR T cell therapy in patients with lymphoid B-cell malignancies., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for patients with EGFR-mutated non-small cell lung cancer (NSCLC) has been shown to have superior outcomes when compared to chemotherapy. First-generation EGFR TKI, including gefitinib and erlotinib, and second-generation EGFR TKI, including afatinib and dacomitinib, proved to be effective in patients with NSCLC harboring EGFR-sensitizing mutation. Later, resistance mutations were identified. Consequently, osimertinib, a third-generation EGFR TKI, was studied and demonstrated activity against EGFR-sensitizing and resistant mutations. Osimertinib moved recently to the first-line setting with the positive results of the FLAURA (AZD9291 Versus Gefitinib or Erlotinib in Patients With Locally Advanced or Metastatic Non-small Cell Lung Cancer) trial. The use of these drugs is limited by their cost and availability mainly in middle- to low-income countries.

Patients receiving allogeneic hematopoietic cell transplantation (alloHCT) were previously shown to display a bacterial gut dysbiosis; however, limited data are available regarding the role of fungal microbiota in these patients. We evaluated the bacterial and fungal composition of the fecal microbiota at day 0 of alloHCT. Higher bacterial diversity was associated with an improved overall survival (OS) and disease-free survival (DFS). While fungal diversity had no impact on patient outcomes, we observed that high versus low relative abundance of Candida albicans in alloHCT patients at day 0 was associated with a significantly lower OS, DFS and graft-versus-host-free, relapse-free survival (GRFS) (p = 0.0008, p = 0.0064 and p = 0.026, respectively). While these results are limited by low patient numbers and low fungal read counts in some samples, they suggest a potentially important role for C albicans in alloHCT., (© 2021. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

The first 'advanced course on biomarkers in molecular and immuno-oncology' in the Middle East took place in Beirut, Lebanon, as a hybrid meeting on 11 December 2020. The aim of this seminar was to discuss biomarker development, implications and detection modalities and to highlight advances in molecular technologies as well as the clinical applicability of biomarkers in oncology. The seminar consisted of five sessions, each discussing a special topic in the biomarker field. It also included a competition in the form of a quiz following each session. This was followed by a plenary session presented by well-known national and international speakers, highlighting various aspects of biomarkers in immuno-oncology.

Hodgkin lymphoma is a highly curable disease. Although most patients achieve complete response following frontline therapy, key unmet clinical needs remain including relapsed/refractory disease, treatment-related morbidity, impaired quality of life and poor outcome in patients older than 60 years. The incorporation of novel therapies, including check point inhibitors and antibody-drug conjugates, into the frontline setting, sequential approaches, and further individualized treatment intensity may address these needs. We summarize the current treatment options for patients with classical Hodgkin lymphoma from frontline therapy to allogeneic hematopoietic stem cell transplantation and describe novel trials in the field., (© 2021. The Author(s).)

Background: Post-transplant cyclophosphamide (PT-Cy) has become a standard of care in haploidentical hematopoietic stem cell transplantation (HSCT) to reduce the risk of graft-versus-host disease. However, data on cardiac events associated with PT-Cy are scarce., Objectives: This study sought to assess the incidence and clinical features of cardiac events associated with PT-Cy., Methods: The study compared clinical outcomes between patients who received PT-Cy (n = 136) and patients who did not (n = 195), with a focus on early cardiac events (ECE) occurring within the first 100 days after HSCT. All patients had the same systematic cardiac monitoring., Results: The cumulative incidence of ECE was 19% in the PT-Cy group and 6% in the no-PT-Cy group (p < 0.001). The main ECE occurring after PT-Cy were left ventricular systolic dysfunction (13%), acute pulmonary edema (7%), pericarditis (4%), arrhythmia (3%), and acute coronary syndrome (2%). Cardiovascular risk factors were not associated with ECE. In multivariable analysis, the use of PT-Cy was associated with ECE (hazard ratio: 2.7; 95% confidence interval: 1.4 to 4.9; p = 0.002]. Older age, sequential conditioning regimen, and Cy exposure before HSCT were also associated with a higher incidence of ECE. Finally, a history of cardiac events before HSCT and ECE had a detrimental impact on overall survival., Conclusions: PT-Cy is associated with a higher incidence of ECE occurring within the first 100 days after HSCT. Patients who have a cardiac event after HSCT have lower overall survival. These results may help to improve the selection of patients who are eligible to undergo HSCT with PT-Cy, especially older adult patients and patients with previous exposure to Cy., Competing Interests: This study was supported by the Association for Training, Education and Research in Hematology, Immunology, and Transplantation (ATERHIT). Drs. Duléry, Mohty, and Malard have received honoraria for lectures from Keocyt and Sanofi, whose drugs were included in this study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2021 The Authors.)

This perspective article discusses the various practices classified as complementary and alternative medicine (CAM) and reviews the benefits and uncertainties with respect to nutritional supplements in patients with hematological disease. It considers the high prevalence of CAM use especially among cancer survivors, particularly patients with hematologic malignancies and allogeneic stem cell transplant survivors, many of whom believe (because of extensive advertising) that supplements are anticancer/antitoxic agents, despite the paucity of evidence to support any benefit and the enormous cost to the individual. CAM constitutes various practices and nutritional behaviors including prayers, relaxation, spiritual healing, nutritional supplements, meditation, religious counseling, massage, and support groups. We highlighted the current literature regarding CAM practices and focused our discussion on the omnipresent nutritional supplements in particular to further expound on their benefits and adverse effects. As the number of survivors after HSCT increases over the next several years along with prevalence of CAM use, it becomes imperative to ascertain any beneficial potential, as well as toxicities associated with CAM use in this population., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Introduction: Despite advances in the treatment of acute myeloid leukemia (AML), cytotoxic chemotherapy remains the standard induction regimen., Patients and Methods: In this single center retrospective study, we assessed outcomes of 99 consecutive adult AML patients treated with a risk-adapted strategy with a median follow-up of 35.5 months., Results: We identified 24 (24 %), 55 (56 %) and 20 (20 %) patients classified as favorable-, intermediate-, and adverse- risk group respectively, according to the European LeukemiaNet (ELN) 2017 classification. Patients either received idarubicin and cytarabine induction chemotherapy with or without FLT3 inhibitors or hypomethylating agents based on age and comorbidity. The complete response (CR) rate was 76 % (82 % and 61 % in patients aged < 60 and ≥ 60, respectively). For the whole cohort, the 3-year overall survival (OS) was 53 %, being 62 % and 30 % in patients aged < 60 and ≥ 60, respectively. The 3-year leukemia-free survival (LFS) was 54 %, with 56 % and 45 % in patients aged < 60 and ≥ 60, respectively. The 3-year LFS were 58 %, 62 % and 25 % for patients within ELN favorable-, intermediate-, and adverse-risk groups respectively. Twenty-seven (36 %) out of 75 patients with intermediate- and adverse-risk disease underwent allogeneic hematopoietic cell transplantation (allo-HCT) in first CR with 92 % of them receiving post-transplant maintenance consisting of azacitidine in 19 (76 %) patients or sorafenib in 6 (24 %) patients. Of these patients younger than 60 years, the 3-year OS and LFS were 85 % and 69 %, respectively., Conclusion: These results indicate an improved OS for AML patients especially in intermediate-risk category who were treated with a total therapy consisting of induction chemotherapy followed by allo-HCT and post-transplant maintenance., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: CYP3A5 and ABCB1 are highly implicated in the pharmacokinetics and pharmacodynamics of immunosuppressive agents, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. The polymorphisms of their coding genes play important roles in the interindividual and intraindividual differences of bioavailability of these drugs. In this study, our objective was to investigate, in a Lebanese population,the frequency of ABCB1C3435T (rs1045642) and CYP3A5*3 (rs776746) polymorphisms and to compare the results to preexisting data from other populations., Materials and Methods: We determined the frequencies of the allelic variants of interest for 1824 Lebanese participants, and we compared these results with those from other major ethnic groups., Results: The allelic frequencies were 91.4% (C) and 8.6% (T) for CYP3A5*3 and 50.8% (T) and 49.2% (C) for ABCB1 C3435T. Our results were significantly different from most other world populations, except the European population., Conclusions: The frequencies of gene variants of interest in our Lebanese population were similar to those found in European populations. Most of our study population were CYP3A5*3 carriers, and more than half may have a lower P-glycoprotein efflux pump. These characteristics might render Lebanese transplant recipients more prone to the development of drug toxicity and in need of lower drug doses.

Background: Graft-versus-host disease (GVHD) is a major cause of mortality after allogeneic stem-cell transplantation. Posttransplantation cyclophosphamide (PT/CY) has become standard prophylaxis of GVHD in T-replete haploidentical transplantation. The question is whether adding antithymocyte globulin (ATG) to PT/CY may further reduce the incidence of GVHD compared to PT/CY only., Patients and Methods: We retrospectively studied 268 patients undergoing myeloablative haploidentical transplantation with thiotepa, busulfan, and fludarabine (TBF) conditioning. Sixty-nine patients (26%) received ATG., Results: In the ATG group, 3% died due to GVHD versus 8% in the no ATG group. The 100-day and 1-year nonrelapse mortality (NRM) was 0% and 19%, respectively, in the whole cohort. On univariate analysis, the 1-year NRM was 8% versus 23% in patients receiving ATG and no ATG, respectively (P = .005). The no ATG group had a higher incidence of acute GVHD at 12 months compared to the ATG group (22% vs. 12%, respectively, P = .029). The ATG group had better overall survival at 12 months compared to the no ATG group (79% vs. 69%, P = .029). On multivariate analysis, adding ATG to PT/CY had no significant impact on any of the outcomes. A low disease risk index was associated with better overall survival and lower NRM, while Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥ 3 was associated with higher NRM., Conclusion: ATG can be safely used as part of the pretransplantation conditioning and does not increase the incidence of relapse or complications after transplantation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

We report results of a thiotepa-based conditioning in haploidentical stem cell transplantation (haplo-SCT) with posttransplant cyclophosphamide (PT-CY) and antithymocyte globulin (ATG), for unmanipulated peripheral blood stem cell (PBSC) transplants, in 80 patients with hematological malignancies. Patients in complete remission (CR) received a thiotepa-busulfan-fludarabine (TBF) regimen, while patients with relapsed/refractory (R/R) malignancies received a sequential regimen consisting of thiotepa-etoposide-cyclophosphamide (TEC) and reduced-intensity conditioning (RIC). The median age was 52 (range, 17-72) years, 44% patients had R/R disease at transplant, and the median follow-up was 417 (range, 180-1595) days. The median days to neutrophil engraftment was 17 (range, 12-34). The cumulative incidences (CI) of acute graft-versus-host disease (GVHD) grade III to IV, severe chronic GVHD, nonrelapse mortality (NRM), and relapse were 16%, 16%, 26, and 26%, respectively. The 2-year overall survival (OS) and disease-free survival (DFS) were 53% and 47%, respectively. There were no significant differences between the patients in CR and R/R patients in terms of engraftment, GVHD, NRM, relapse, OS, or DFS. We conclude that thiotepa-based regimen with PT-CY can be modified with PBSC and ATG, still providing low toxicity, protection against GVHD, and low relapse incidence. Particularly encouraging are the results with the modification to sequential regimen in R/R patients.

We developed an electronic records methodology to programmatically estimate the date of first appearance of coccidioidomycosis symptoms in patients. We compared the diagnostic delay with overall healthcare utilization charges. Many patients (46%) had delays in diagnosis of >1 month. Billed healthcare charges before diagnosis increased with length of delay.

Objectives: This retrospective study analyzed the impact of early cyclosporine A (CsA) initiation (day -3) on the risk of acute graft-vs-host disease (aGvHD) after haploidentical hematopoietic cell transplantation (Haplo-HCT) using post-transplant cyclophosphamide., Methods: Sixty-one consecutives patients who underwent Haplo-HCT were analyzed., Results: At day +180, the cumulative incidences of grade II-IV and grade III-IV aGvHD were 39% and 18%, respectively. Patients having a lowest CsA concentration (<301 ng/mL; the cutoff value used to segregate the patients between low and high CsA concentrations) in the first week after Haplo-HCT had a significantly higher risk of grade II-IV aGvHD (P = 0.02), severe grade III-IV aGvHD (P = 0.03), cGvHD (P = 0.02), and extensive cGvHD (P = 0.04). In multivariate analysis, a higher CsA concentration (≥301 ng/mL) during the first week following Haplo-HCT was the only parameter significantly associated with a reduced risk of grade II-IV and grade III-IV aGvHD (RR = 0.21; P = 0.049 and RR < 0.001; P < 0.0001, respectively). We find no correlation between CsA concentration and relapse, non-relapse mortality, progression-free survival, GvHD-free and progression-free survival, or overall survival., Conclusions: CsA could be initiated early before Haplo-HCT with achievement of high CsA concentration to reduce the risk of aGvHD without any detrimental effect on relapse., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)