Hematological toxicity represents the most common adverse event following chimeric antigen receptor (CAR) T-cell therapy. Cytopenias can be profound, long-lasting, and can predispose for severe infectious complications. In a recent worldwide survey, we demonstrated that there remains considerable heterogeneity in regards to current practice patterns. Here, we sought to build consensus on the grading and management of Immune Effector Cell Associated Hemato-Toxicity (ICAHT) following CAR-T therapy. For this purpose, a joint effort between the European society for Blood and Marrow Transplantation (EBMT) and the European Hematology Association (EHA) involved an international panel of 36 CAR-T experts who met in a series of virtual conferences, culminating in a 2-day meeting in Lille, France. On the basis of these deliberations, best practice recommendations were developed. For the grading of ICAHT, a classification system based on depth and duration of neutropenia was developed for early (day 0-30) and late cytopenia (after day +30). Detailed recommendations on risk factors, available pre-infusion scoring systems (e.g. CAR-HEMATOTOX score), and diagnostic work-up are provided. A further section focuses on identifying hemophagocytosis in the context of severe hematotoxicity. Finally, we review current evidence and provide consensus recommendations for the management of ICAHT, including growth factor support, anti-infectious prophylaxis, transfusions, autologous hematopoietic cell boost, and allogeneic hematopoietic cell transplantation. In conclusion, we propose ICAHT as a novel toxicity category following immune effector cell therapy, provide a framework for its grading, review literature on risk factors, and outline expert recommendations for the diagnostic work-up and short- and long-term management.

The net impact of cytomegalovirus (CMV) DNAemia on overall mortality (OM) and nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. This was a retrospective, multicenter, noninterventional study finally including 749 patients. CMV DNA monitoring was conducted by real-time polymerase chain reaction (PCR) assays. Clinical outcomes of interest were OM and NRM through day 365 after allo-HSCT. The cumulative incidence of CMV DNAemia in this cohort was 52.6%. A total of 306 out of 382 patients with CMV DNAemia received preemptive antiviral therapy (PET). PET use for CMV DNAemia, but not the occurrence of CMV DNAemia, taken as a qualitative variable, was associated with increased OM and NRM in univariate but not in adjusted models. A subcohort analysis including patients monitored by the COBAS Ampliprep/ COBAS Taqman CMV Test showed that OM and NRM were comparable in patients in whom either low or high plasma CMV DNA threshold (<500 vs ≥500 IU/mL) was used for PET initiation. In conclusion, CMV DNAemia was not associated with increased OM and NRM in allo-HSCT recipients. The potential impact of PET use on mortality was not proven but merits further research.

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Introduction Brexucabtagene autoleucel (brexu-cel) is a second generation, CD19-targeted Chimeric Antigen Receptor (CAR) T-cell therapy approved for relapsed or refractory (R/R) mantle cell lymphoma (MCL). The pivotal phase 2 trial ZUMA-2 enrolled 74 patients and infused 68, with an overall response rate (ORR) of 85% (complete response rate, 59%) among all patients who underwent apheresis (intention-to-treat, ITT). Grade 3 or higher cytokine release syndrome (CRS) and neurologic events occurred in 15% and 31% of patients, respectively. However, very little is known regarding its safety and efficacy in the real-world setting. In our study, we report clinical outcomes of patients with R/R MCL treated with commercial brexu-cel. Methods Data were collected retrospectively from all consecutive patients with R/R MCL who underwent apheresis for brexu-cel at 7 European sites, in 3 different countries, from start of the Compassionate Use Program in Europe (February 2020) until June 2021. Evaluable patients included those who received a CAR-T infusion and had at least 1 month of follow-up. Adverse events after infusion were graded according to the ASTCT consensus and efficacy outcomes were assessed according to Lugano criteria. Efficacy outcomes were calculated in the patients who received a CAR T-cell infusion and in all patients who underwent apheresis for brexu-cel (ITT). Results During the study period 28 patients with R/R MCL underwent apheresis for brexu-cel. At data cutoff, 19 (68%) patients had received a CAR T-cell infusion whereas 9 (32%) had not due to progressive disease (n=4), pending manufacturing process (n=4) or achieving a complete response with bridging (n=1). Baseline characteristics of the whole cohort and the infused patients are summarized in Table 1. Among infused patients, median age was 67 years (range 51-78) and 89% were male. Most of the patients had a high-risk simplified Mantle Cell Lymphoma International Prognostic Index score (63%), an advanced stage (84%) and 32% had received a prior autologous stem cell transplant. Median follow-up after CAR T-cell infusion was 5 months (range 1-10). Fifteen patients (79%) received bridging therapy after apheresis, including ibrutinib in 8/15 (53%) patients, immunochemotherapy in 7/15 (47%) and radiotherapy in 6/15 (40%). Half the patients (53%) had progressive disease as best response to bridging; 4 (27%) patients had stable disease, 2 (13%) partial response and 1 (7%) achieved a complete response. Median time from apheresis to brexu-cel delivery was 30 days (range 22-48) and median time from apheresis to infusion was 42 days (range 28-77). Among the infused patients, 17 (89%) and 12 (63%) developed any grade of CRS and neurotoxicity, respectively. Grade &gt;2 CRS and neurotoxicity events occurred in 1 (5%) and 5 (26%) patients, respectively. Tocilizumab was administered to 16 (84%) patients and steroids to 12 (63%) patients. Two (11%) patients required admission to the Intensive Care Unit for grade 4 neurotoxicity and septic shock, respectively. At data cutoff, all infused patients were alive except for 1 patient who died due to progressive disease. Other adverse events are summarized in table 2. Best response achieved among the infused patients included complete remission in 13 (68%) patients and partial remission in 4 (21%) patients, with an ORR of 89%. Stable disease and progressive disease were the best response in 1 (5%) patient each. Median progression-free survival (PFS) and overall survival (OS) for infused patients were not reached with the current follow-up (Figure 1); estimated 6-month OS was 91% (95%CI 50.8-98.6) and 6-month PFS was 83% (95%CI 55.4-94.2). Three (16%) patients progressed at days 14, 33 and 90 post-infusion. In the univariate analysis, the percentage of patients with complete response was consistent across key subgroups with high-risk features (including blastoid morphology and TP53 mutation). Response rate and survival analysis by ITT will be presented at the meeting when all products still undergoing manufacturing are complete. Conclusion This multicenter, international study confirms that treatment with brexu-cel in patients with R/R MCL in the real-world setting has very promising efficacy, including in high-risk patients. The early safety profile was manageable and similar to the pivotal trial. Longer follow-up is needed to better assess long-term efficacy and ITT analysis. Figure 1 Figure 1. Disclosures Iacoboni: BMS/Celgene, Gilead, Novartis, Janssen, Roche: Honoraria. Chiappella: Takeda: Other: advisory board; Clinigen: Other: lecture fee, advisory board; Novartis: Other: lecture fee; Gilead Sciences: Other: lecture fee, advisory board; Janssen: Other: lecture fee, advisory board; Roche: Other: lecture fee, advisory board; Servier: Other: lecture fee; Celgene Bristol Myers Squibb: Other: lecture fee, advisory board; Astrazeneca: Other: lecture fee; Incyte: Other: lecture fee. Corral: Gileqd: Honoraria; Gilead: Consultancy; Novartis: Consultancy. Bastos-Oreiro: BMS-Celgene: Honoraria, Speakers Bureau; Gilead: Honoraria; Janssen: Honoraria, Speakers Bureau; F. Hoffmann-La Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Kite: Speakers Bureau. Schmidt: Novartis: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Kite/Gilead: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Consultancy, Other: Travel, Accommodations, Expenses; Bayer Healthcare: Research Funding; Janssen: Other: Travel, Accommodations, Expenses. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Reguera: Janssen, Kite/Gilead, Novartis: Speakers Bureau; BMS-Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees. Kwon: Gilead: Honoraria. Martín García-Sancho: Janssen: Honoraria, Research Funding; Novartis: Consultancy; Gilead: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Zinzani: Beigene: Other, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; SANDOZ: Other: Advisory board; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Incyte: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Subklewe: Pfizer: Consultancy, Speakers Bureau; Janssen: Consultancy; Takeda: Speakers Bureau; Klinikum der Universität München: Current Employment; Gilead: Consultancy, Research Funding, Speakers Bureau; Miltenyi: Research Funding; MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Roche: Research Funding; Seattle Genetics: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau. Barba: Novartis: Honoraria; Pfizer: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria.

Introduction: Recent studies have shown that young to middle-aged adults who receive a pediatric-inspired chemotherapy regimen for treatment of Ph-neg ALL do not appear to require an alloHSCT if they achieve good response on MRD testing after induction therapy. Patients (pts) who are not good MRD responders achieve better outcomes with alloHSCT than their counterparts who do not receive alloHSCT. However, it is not clear if this approach can be translated to adult ALL pts with HR features at baseline. The aim of the prospective ALL-HR-11 trial from the Spanish PETHEMA Group was to evaluate the response to a differentiated post-induction therapy (chemotherapy or alloHSCT) according to MRD levels (assessed by 8-color, centrally-performed flow cytometry at the end of induction-week 5- and consolidation therapy-week 17-) in HR Ph-neg adult ALL patients. Patients and methods: HR ALL included one or more of the following parameters at baseline: age 30-60 yr, WBC count >30x109/L for B-cell precursor ALL or >100x109/L for thymic T-ALL, pro-B, early or mature T-ALL, 11q23 or MLL rearrangements or complex karyotype. Induction therapy included vincristine, prednisone, daunorubicin and asparaginase (E coli native or PEG according to center availability) for 4 weeks (Induction-1). FLAG-Ida was administered as intensified induction (Induction-2) in pts not achieving CR or those in CR with MRD≥0.1% at the end of induction. For pts in CR and MRD<0.1% early consolidation therapy included 3 cycles with rotating cytotoxic drugs with high-dose methotrexate, high-dose ARA-C and high-dose asparaginase (E coli native or PEG). These pts continued with delayed consolidation (identical to that of early consolidation) followed by maintenance therapy up to 2 yr. in CR if MRD levels after consolidation were <0.01%, otherwise they were assigned to alloHSCT. Pts in CR after Induction-2 received one consolidation cycle and were assigned to alloHSCT. Results: On June 2015, 115 HR ALL pts were evaluable [mean (SD) age 38(13) yr, 67 males, 80/114 precursor B-ALL, 34/114 T-ALL, WBC count 56(96) x109/L]. Results of Induction-1: therapy-related death: 4(4%), resistance: 11 (10%), CR: 95(86%). MRD<0.1% at the end of induction was observed in 75% of CR patients. Induction-2 was administered to 33 patients (no CR: 11, CR and MRD≥0.1%: 22). No differences in the CR rate or in the rate of MRD clearance after induction were observed according to the type of asparaginase administered, although significantly increased hepatic toxicity in consolidation was observed in patients treated with PEG-asparaginase. The 2-yr DFS and OS probabilities for whole series were 51%±18% and 62%±13%. By intention-to treat after Induction-1 36 pts were assigned to alloHSCT and 68 to delayed consolidation and maintenance. The 2-yr DFS and OS probabilities were 54%±25% and 49%±20%, respectively, for pts assigned to alloHSCT, and 50%±22% and 73%±17%, respectively, for those assigned to chemotherapy (P=0.002 for OS comparison). Patients with MRD<0.1% at the end of induction and <0.01% at the end of consolidation (n=51) showed a 2-yr DFS and OS of 55%±25% and 81%±18%, respectively. Conclusions: The preliminary results of this trial, in which the post-induction therapy decision is only based on MRD results, suggest that in HR, Ph-neg adult ALL pts with adequate MRD response after induction and after consolidation the results of therapy are not hampered by avoiding alloHSCT. Supported by grants RD12/0036/0029 (RTICC, FEDER), PI14/01971 FIS, Instituto Carlos III, and SGR225 (GRE), Spain Disclosures No relevant conflicts of interest to declare.