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Allogeneic hematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of mye-loproliferative neoplasm (BP-MPN). We report on a large, retrospective European Society for Blood and Marrow Transplantation registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005 and 2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year overall survival (OS) was 36% (95% confidence interval [CI], 32-36). Factors associated with lower OS were Karnofsky Performance Score (KPS) < 90 (hazard ratio [HR] 1.65, p < .001) and active disease at allo-HCT (HR 1.45, p < .001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p = .008). In a selected patient's population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS >= 90 was 60%. KPS < 90 (HR 1.4, p = .001) and active disease (HR 1.44, p = .0004) were associated with a lower progression-free survival (PFS). Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p = .008). Active dis-ease at allo-HCT (HR 1.34, p = .03) was associated with a higher cumulative inci-dence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p = .02) associated with a lower RI. Last, KPS < 90 (HR 1.91, p < .001), active disease (HR 1.74, p = .003) and allo-HCT from mismatched related donors were associated with a higher non-relapse mortality (HR 2.66, p = .003). In this large series of BPMPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS >= 90 and in CR at transplant had a better prognosis.

In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m2 (FluMel) and fludarabine/treosulfan 42 g/m2 (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

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Allogeneic haematopoietic cell transplant (allo-HCT) provides the only potential route to long-term remission in patients diagnosed with blast phase transformation of myeloproliferative neoplasm (BP-MPN). We report on a large, retrospective EBMT registry-based study of BP-MPN patients undergoing allo-HCT. BP-MPN patients undergoing first allo-HCT between 2005-2019 were included. A total of 663 patients were included. With a median follow-up of 62 months, the estimated 3-year OS was 36% (95% CI, 32-36). Factors associated with lower OS were Karnofsky Performance Status (KPS)90 (HR 1.65, p0.001) and active disease at allo-HCT (HR 1.45, p0.001), whereas patients undergoing allo-HCT more recently associated with a higher OS (HR 0.96, p=0.008). In a selected patients population, the 3-year OS of patients undergoing allo-HCT in complete response (CR) and with a KPS ≥90 was 60%. KPS90 (HR 1.4, p=0.001) and active disease (HR 1.44, p=0.0004) were associated with a lower PFS. Conversely, most recent allo-HCT associated with a higher PFS (HR 0.96, p=0.008). Active disease at allo-HCT (HR 1.34, p=0.03) was associated with a higher cumulative incidence of relapse (RI) and allo-HCT in earlier calendar years (HR 0.96, p=0.02) associated with a lower RI. Lastly, KPS90 (HR 1.91, p0.001), active disease (HR 1.74, p=0.003) and allo-HCT from mismatched related donors were associated with a higher NRM (HR 2.66, p=0.003). In this large series of BP-MPN patients, about one third were alive at 3 years after transplantation. Patients undergoing allo-HCT in the more recent era, with a KPS≥90 and in CR at transplant had a better prognosis. This article is protected by copyright. All rights reserved.

Decreased cytomegalovirus (CMV)-specific immunity after hematopoietic cell transplantation (HCT) is associated with late CMV reactivation and increased mortality. Whether letermovir prophylaxis-associated reduction in viral exposure influences CMV-specific immune reconstitution is unknown. In a prospective cohort of allogeneic HCT recipients who received letermovir, we compared polyfunctional CMV-specific T-cell responses to those of controls who received PCR-guided preemptive therapy before the introduction of letermovir. Thirteen-color flow cytometry was used to assess T-cell responses at 3 months after HCT following stimulation with CMV immediate early-1 (IE-1) antigen and phosphoprotein 65 (pp65) antigens. Polyfunctionality was characterized by combinatorial polyfunctionality analysis of antigen-specific T-cell subsets. Use of letermovir and reduction of viral exposure were assessed for their association with CMV-specific T-cell immunity. Polyfunctional T-cell responses to IE-1 and pp65 were decreased in letermovir recipients and remained diminished after adjustment for donor CMV serostatus, absolute lymphocyte count, and steroid use. Among letermovir recipients, greater peak CMV DNAemia and increased viral shedding were associated with stronger CD8+ responses to pp65, whereas the CMV shedding rate was associated with greater CD4+ responses to IE-1. In summary, our study provided initial evidence that letermovir may delay CMV-specific cellular reconstitution, possibly related to decreased CMV antigen exposure. Evaluating T-cell polyfunctionality may identify patients at risk for late CMV infection after HCT.

We analysed long-term outcome of patients receiving haematopoietic allogeneic stem cell transplantation (allo-HSCT) as a first transplant for high-risk Hodgkin lymphoma (HL). One hundred and ninety patients were included in this study, 63% of them had previously received brentuximab vedotin and/or checkpoint inhibitors. Seventy patients (37%) received an unrelated donor allo-HSCT, 99 (51%) had myeloablative conditioning (MAC) and 60% had in vivo T-cell/depleted grafts (TCD). The 100-day cumulative incidence (CI) of grade II-IV acute graft-versus-host disease (GVHD) was 25% and the 3-year CI of chronic GVHD was 38%. The 3-year CI of non-relapse mortality (NRM) and relapse rate were 21% and 38% respectively. After a median follow-up of 58 months, 3-year overall survival (OS) and progression-free survival (PFS) were 58% and 41% respectively. Multivariate analysis showed that, in comparison to reduced-intensity conditioning regimens with or without TCD, MAC using TCD had similar NRM and a lower risk of relapse leading to significantly better OS and PFS. MAC without TCD was associated with higher NRM and worse survival outcomes. These results suggest that in patients with high-risk HL and candidates of allo-HSCT, a MAC strategy with TCD might be the best option.

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Càncer hematològic; Malalties infeccioses Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Cáncer hematológico; Enfermedades infecciosas Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Haematological cancer; Infectious diseases COVID-19 is posing a significant threat to health in vulnerable patients, such as immunocompromised patients. For hematopoietic cell transplantation (HCT) recipients and patients with hematologic malignancies it is known that COVID-19 leads to severe morbidity and high mortality as compared to the general population [1–3]. For patients treated with Chimeric Antigen Receptor T-cell (CAR-T-cell) therapy for B-cell malignancies however, descriptions of the clinical course and outcome are still limited to small case series and case reports [4–8]. CAR-T-cell therapy recipients are believed to be at high risk of poor outcomes from COVID-19 due to their severely immunocompromised state, caused by prior lymphodepleting immunochemotherapy and CAR-T-cell therapy related side effects such as B-cell depletion, hypogammaglobulinemia, and cytopenias. In order to rapidly inform the medical field on the impact of COVID-19 on CAR-T-cell therapy recipients, the EBMT Infectious Diseases Working Party and the EHA Lymphoma Group joined forces and present the clinical course of COVID-19 in the largest European cohort to date.

PURPOSE Prognosis for adult B-cell acute lymphoblastic leukemia (B-ALL) is poor, and there are currently no licensed CD19 chimeric antigen receptor (CAR) therapeutics. We developed a novel second-generation CD19-CAR (CAT19-41BB-Z) with a fast off rate, designed for more physiologic T-cell activation to reduce toxicity and improve engraftment. We describe the multicenter phase I ALLCAR19 ( NCT02935257 ) study of autologous CAT19-41BB-Z CAR T cells (AUTO1) in relapsed or refractory (r/r) adult B-ALL. METHODS Patients age ≥ 16 years with r/r B-ALL were eligible. Primary outcomes were toxicity and manufacturing feasibility. Secondary outcomes were depth of response at 1 and 3 months, persistence of CAR-T, incidence and duration of hypogammaglobulinemia and B-cell aplasia, and event-free survival and overall survival at 1 and 2 years. RESULTS Twenty-five patients were leukapheresed, 24 products were manufactured, and 20 patients were infused with AUTO1. The median age was 41.5 years; 25% had prior blinatumomab, 50% prior inotuzumab ozogamicin, and 65% prior allogeneic stem-cell transplantation. At the time of preconditioning, 45% had ≥ 50% bone marrow blasts. No patients experienced ≥ grade 3 cytokine release syndrome; 3 of 20 (15%) experienced grade 3 neurotoxicity that resolved to ≤ grade 1 within 72 hours with steroids. Seventeen of 20 (85%) achieved minimal residual disease–negative complete response at month 1, and 3 of 17 underwent allogeneic stem-cell transplantation while in remission. The event-free survival at 6 and 12 months was 68.3% (42.4%-84.4%) and 48.3% (23.1%-69.7%), respectively. High-level expansion (Cmax 127,152 copies/µg genomic DNA) and durable CAR-T persistence were observed with B-cell aplasia ongoing in 15 of 20 patients at last follow-up. CONCLUSION AUTO1 demonstrates a tolerable safety profile, high remission rates, and excellent persistence in r/r adult B-ALL. Preliminary data support further development of AUTO1 as a stand-alone treatment for r/r adult B-ALL.

The therapeutic potential of donor-derived mesenchymal stromal cells (MSCs) has been investigated in diverse diseases1, including steroid-resistant acute graft versus host disease (SR-aGvHD)2. However, conventional manufacturing approaches are hampered by challenges with scalability and interdonor variability, and clinical trials have shown inconsistent outcomes3,4. Induced pluripotent stem cells (iPSCs) have the potential to overcome these challenges, due to their capacity for multilineage differentiation and indefinite proliferation5,6. Nonetheless, human clinical trials of iPSC-derived cells have not previously been completed. CYP-001 (iPSC-derived MSCs) is produced using an optimized, good manufacturing practice (GMP)-compliant manufacturing process. We conducted a phase 1, open-label clinical trial (no. NCT02923375) in subjects with SR-aGvHD. Sixteen subjects were screened and sequentially assigned to cohort A or cohort B (n = 8 per group). One subject in cohort B withdrew before receiving CYP-001 and was excluded from analysis. All other subjects received intravenous infusions of CYP-001 on days 0 and 7, at a dose level of either 1 × 106 cells per kg body weight, to a maximum of 1 × 108 cells per infusion (cohort A), or 2 × 106 cells per kg body weight, to a maximum dose of 2 × 108 cells per infusion (cohort B). The primary objective was to assess the safety and tolerability of CYP-001, while the secondary objectives were to evaluate efficacy based on the proportion of participants who showed a complete response (CR), overall response (OR) and overall survival (OS) by days 28/100. CYP-001 was safe and well tolerated. No serious adverse events were assessed as related to CYP-001. OR, CR and OS rates by day 100 were 86.7, 53.3 and 86.7%, respectively. The therapeutic application of iPSC-derived MSCs may now be explored in diverse inflammatory and immune-mediated diseases. A GMP-compliant process for generating human iPSC-derived mesenchymal stromal cells tested in a phase 1 trial is safe and well tolerated in subjects with acute steroid-resistant graft versus host disease.

Background: The success of unrelated haemopoietic cell transplantation (HCT) is limited by graft-versus-host disease (GVHD), which is the main post-transplantation challenge when HLA-matched donors are unavailable. A sequence dimorphism in exon 1 of HLA-B gives rise to leader peptides containing methionine (Met; M) or threonine (Thr; T), which differentially influence natural killer and T-cell alloresponses. The main aim of the study was to evaluate the role of the leader dimorphism in GVHD after HLA-B-mismatched unrelated HCT. Methods: We did a retrospective cohort study of 33 982 patients who received an unrelated HCT done in Australia, Europe, Japan, North America, and the UK between Jan 1, 1988, and Dec 31, 2016. Data were contributed by participants of the International Histocompatibility Working Group in Hematopoietic Cell Transplantation. All cases were included and there were no exclusion criteria. Multivariate regression models were used to assess risks associated with HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 mismatching. Among the 33 982 transplantations, the risks of GVHD associated with HLA-B M and T leaders were established in 17 100 (50·3%) HLA-matched and 1457 (4·3%) single HLA-B-mismatched transplantations using multivariate regression models. Leader frequencies were defined in 2 004 742 BeTheMatch US registry donors. Findings: Between Jan 20, 2017, and March 11, 2019, we assessed 33 982 HCTs using multivariate regression models for the role of HLA mismatching on outcome. Median follow-up was 1841 days (IQR 909–2963). Mortality and GVHD increased with increasing numbers of HLA mismatches. A single HLA-B mismatch increased grade 3–4 acute GVHD (odds ratio [OR] 1·89, 95% CI 1·53–2·33; p

We evaluated the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in transplant-naïve patients with relapsed/refractory Hodgkin lymphoma (HL) who failed to attain metabolic complete response (mCR) to 1 to 2 lines of salvage chemotherapyThose with residual but nonprogressive disease assessed by positron emission tomography/computed tomography scanning were eligible. An additional 1 to 2 cycles of salvage therapy were permissible in those with progressive disease or when required to bridge to allo-HSCT, with additional imaging at baseline before transplantation. Conditioning consisted of carmustine, etoposide, cytarabine, melphalan, and alemtuzumab. Donor lymphocyte infusions (DLI) were administered for mixed chimerism or residual or relapsed disease. Eleven patients had sibling donors, 13 had HLA-matched unrelated donors, and 7 had HLA-mismatched unrelated donors. There were no graft failures, and no episodes of grade 4 acute graft-versus-host disease (GVHD); only 19.4% of patients had grade 2 to 3 GVHD, and 22.2% had extensive chronic GVHD. The non-relapse mortality rate was 16.1% (95% confidence interval [CI], 7.1%-34.5%). Relapse incidence was 18.7% (95% CI, 8.2%-39.2%). The study met its primary objective, with a 3-year progression-free survival of 67.7% (95% CI, 48.4%-81.2%). Survival outcomes were equivalent in those with residual metabolically active disease immediately before transplantation (n = 24 [70.8%; 95% CI, 17.2%-83.7%]). Two of the 5 patients who relapsed received DLI and remained in mCR at latest follow-up, with a 3-year overall survival of 80.7% (95% CI, 61.9%-90.8%). We demonstrate encouraging results that establish a potential role for allo-HSCT in selected high-risk patients with HL. This trial was registered at www.clinicaltrials.gov as #NCT00908180.

PLAIN LANGUAGE SUMMARY What is the context? After haematopoletic stem cell transplantation, patlents have impaired immunity from conditioning chemotherapy regimens, often exacerbated by underlying diseases, putting them at high risk of developing herpes zoster. In this population, antiviral prophylaxis is the current standard of care to reduce herpes zoster risk. Vaccination provides an additional means to prevent herpes zoster. Live-attenuated vaccines are generally contraindicated in immuonocompromised patients. A non-live, adjuvanted recombinant zoster vaccine (RZV, Shingrix, GSK), has been approved for use in adults 250 years of age in the European Union, United States, Canada, Australia, Japan, and China. This vaccine is highly efficacious at preventing herpes zoster in adults over 50 years of age, as demonstrated in large, placebo-controlled randomised trials. Importantly, Shingrix use is not contraindicated in immunocompromised conditions, and was found to be highly efficacious in adults who had recently undergone autologous haematopoleticstem cell transplant. What is new? In autologous haematopoietic stem cell transplant recipients in whom Shingrix has demonstrated efficacy, two doseselicited high and persistent immune responses. Date presented here further support our understanding of the impact of specific factors such as age or underlying diseases on the vaccine's effect in the population studies, as well as the characteristics of the elicited cell-mediated immune responses. What is the impact? These results indicate that Shingrix, given shortly after haematopoletic stem cell transplant, can induce robust immune responses and reduce the risk of herpes zoster, even in individuals with immunosuppression due to underlying disease and/or use of immunosuppressive therapies, regardless of age or underlying disease. Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing >= 2 of four assessed activation markers) were similar between 18-49 and >= 50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response., GlaxoSmithKline Biologicals SA, This work was sponsored by GlaxoSmithKline Biologicals SA in all stages of the study conduct and analysis. GlaxoSmithKline Biologicals SA also took responsibility for all costs associated with the development and publishing of the present manuscript.

Aim: The objective of this study was to establish the maximum tolerated dose (MTD), safety, pharmacokinetics, and anti-leukemic activity of talazoparib. Patients & methods: This Phase I, two-cohort, dose-escalation trial evaluated talazoparib monotherapy in advanced hematologic malignancies (cohort 1: acute myeloid leukemia/myelodysplastic syndrome; cohort 2: chronic lymphocytic leukemia/mantle cell lymphoma). Results: Thirty-three (cohort 1: n = 25; cohort 2: n = 8) patients received talazoparib (0.1–2.0 mg once daily). The MTD was exceeded at 2.0 mg/day in cohort 1 and at 0.9 mg/day in cohort 2. Grade ≥3 adverse events were primarily hematologic. Eighteen (54.5%) patients reported stable disease. Conclusion: Talazoparib is relatively well tolerated in hematologic malignancies, with a similar MTD as in solid tumors, and shows preliminary anti leukemic activity. Clinical trial registration: NCT01399840 (ClinicalTrials.gov), Lay abstract The objective of this study was to define the highest dose of talazoparib that people with various types of leukemia (mainly various blood cancers) could tolerate. People were assigned into two cohorts based on their type of leukemia: cohort 1 included 25 people with acute myeloid leukemia or myelodysplastic syndrome; cohort 2 included 8 people with chronic lymphocytic leukemia or mantle cell lymphoma. Similar to what researchers observed for people with solid tumors, the highest tolerated dose was 1.35 mg per day in cohort 1, and it was estimated to be ∼0.9 mg per day in cohort 2. Side effects that occurred during the study were expected, given the types of leukemia being treated. Talazoparib also showed promising anti leukemic effects in some patients., Tweetable abstract In this Phase I talazoparib trial in hematologic malignancies (cohort 1: AML/MDS, n = 25; cohort 2: CLL/MCL, n = 8), the maximum tolerated dose was exceeded at 2.0 and 0.9 mg/day in cohorts 1 and 2, respectively. Stable disease and transfusion independence were also observed.

in press

The EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30–46%) at 2 years and 25% (17–32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24–46%); Others 9% (0–17%), p p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21–40%) vs. 10% (1–20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24–0.67), p

The reported influence of donor Killer-cell Immunoglobulin-like Receptor (KIR) genes on the outcomes of haematopoietic cell transplantation (HCT) are contradictory, in part due to diversity of disease, donor sources, era and conditioning regimens within and between different studies. Here, we describe the results of a retrospective clinical analysis establishing the effect of donor KIR motifs on the outcomes of 119 HLA-matched, unrelated donor HCT for adult acute myeloid leukaemia (AML) using myeloablative conditioning (MAC) in a predominantly T-cell deplete (TCD) cohort. We observed that HCT involving donors with at least one KIR B haplotype were more likely to result in non-relapse mortality (NRM) than HCT involving donors with two KIR A haplotypes (p = 0.019). Upon separation of KIR haplotypes into their centromeric (Cen) and telomeric (Tel) motif structures, we demonstrated that the Cen-B motif was largely responsible for this effect (p = 0.001). When the cause of NRM was investigated further, infection was the dominant cause of death (p = 0.006). No evidence correlating donor KIR B haplotype with relapse risk was observed. The results from this analysis confirm previous findings in the unrelated, TCD, MAC transplant setting and imply a protective role for donor-encoded Cen-A motifs against infection in allogeneic HCT recipients.

BACKGROUND: The treatment of patients with Hodgkin lymphoma (HL) who develop disease progression after undergoing allogeneic stem cell transplantation (allo‐SCT) remains challenging. METHODS: The authors assessed outcomes in 184 adult patients with HL who developed disease recurrence or progression after a matched related or unrelated allo‐SCT at European Society for Blood and Marrow Transplantation–participating centers between 2010 and 2014. RESULTS: Eighty patients who received brentuximab vedotin (BV) salvage therapy were compared with 104 patients who did not. Patients in the BV group were younger (median age of 30 years vs 34 years) and were more likely to receive pretransplant BV (65% vs 46%) or posttransplant donor lymphocyte infusion (66% vs 33%). The 2 groups otherwise were comparable. Patients in the BV group received a median of 6 doses of posttransplant BV, resulting in a complete remission rate of 29%, a partial response rate of 45%, and a stable disease rate of 26%. Response to BV after allo‐SCT did not appear to be affected by receipt of pretransplant BV. Despite a longer median follow‐up for surviving patients in the BV group (33 months vs 23 months; P

Background The ongoing Coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is having an enormous impact on society worldwide and is especially posing a threat to health in vulnerable patients, such as patients with immune deficiencies. It is expected that patients who received Chimeric Antigen Receptor T-cell (CAR T-cell) therapy for hematologic malignancies are at risk for poor outcomes after COVID-19 due to their severely immunocompromised state caused by prior cumulative immunochemotherapy, on-target/off-tumor B-cell depletion, hypogammaglobulinemia and ongoing cytopenias. Current data are limited to small case series and case reports. This study describes the clinical characteristics and outcomes of CAR T-cell therapy recipients after developing COVID-19 in the largest cohort to date. Methods In response to the COVID-19 pandemic, the European Society for Blood and Marrow Transplantation (EBMT) developed a special COVID-19 report form to capture data from all patients with COVID-19 after treatment with CAR T-cell therapy for hematologic malignancies. Only PCR positive SARS-CoV-2 diagnosed patients before June 1 st, 2021 were included. The aim of this study was to describe the clinical course after COVID-19 diagnosis and evaluate overall survival. Overall survival probabilities were calculated using the Kaplan Meier method. Factors associated with mortality after COVID-19 diagnosis were examined using a Cox proportional hazard model. Results A total of 57 patients from 11 countries were reported to the EBMT. One patient with incomplete data at diagnosis and without any follow up information had to be excluded from the analysis. The median age of these 56 patients was 57.7 years (min-max 5.2 - 72.8) including 55 adults and one child. Of these patients, 32 were male. CAR T-cell therapy was given to 46 patients with B-cell-non-Hodgkin lymphoma, 7 patients with B-cell acute lymphoblastic leukemia, and 3 patients with multiple myeloma. The median time from CAR T-cell infusion to COVID-19 diagnosis was 7.4 months (min-max 0.03 - 25.3). At the time of COVID-19 diagnosis, 62.5% of patients were in complete remission, 12.5% of patients had a partial response and 25% of patients had relapsed/refractory disease. Forty-five patients (80%) were admitted to hospital (median 26,5 days, min-max 3-171) due to COVID-19. Of the admitted patients, 24 (53%) needed oxygen support. Twenty-two (49%) patients were admitted to the intensive care unit (median 14 days, min - max 2-65) and 16 (73%) of these patients received invasive ventilation. At the time of analysis, 25 of the 56 patients had died (44.6%), most (23/25) due to COVID-19, resulting in a COVID-19 attributable mortality rate of 41%. The Kaplan-Meier estimate of overall survival is shown in Figure 1. The median follow-up from COVID-19 diagnosis was 20.9 weeks. In 1 of the 32 alive patients there was no resolution of COVID-19 at the time of analysis. In multivariate analysis, older age (hazard ratio (HR) 1.50, 95% CI 1.11-2.03, p=0.009) and comorbidities (HR 2.56, 95% CI 1.05-6.23, p=0.001) had a negative impact on overall survival. Better performance status at time of admission (HR 0.72, 95% CI 0.59-0.88, p=0.038) had a positive impact on overall survival. Sex, time from CAR T-cell therapy to COVID-19 diagnosis, disease remission status and the occurrence of neurotoxicity or cytokine release syndrome after CAR T-cell infusion did not have a significant effect on overall survival in the multivariate analysis. Conclusion Patients with COVID-19 after B-cell-targeted CAR T-cell therapy have a very poor outcome. As it remains uncertain whether currently applied vaccination strategies against SARS-CoV-2 are effective after CAR T-cell therapy, vaccination of health-care personnel and family members in combination with protective measures against viral exposure are likely to play the most important role in protecting this vulnerable group of patients. Better treatment strategies are urgently needed. Figure 1 Figure 1. Disclosures Ljungman: OctaPharma: Other: DSMB; Enanta: Other: DSMB; Janssen: Other: Investigator; Takeda: Consultancy, Other: Endpoint committee, speaker; AiCuris: Consultancy; Merck: Other: Investigator, speaker. De La Camara: IQONE: Consultancy; Roche: Consultancy. Ortiz-Maldonado: Kite, Novartis, BMS, Janssen: Honoraria. Barba: Novartis: Honoraria; Gilead: Honoraria; BMS: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria. Sesques: Novartis: Honoraria; Chugai: Honoraria; Kite, a Gilead Company: Honoraria. Bachy: Kite, a Gilead Company: Honoraria; Novartis: Honoraria; Daiishi: Research Funding; Roche: Consultancy; Takeda: Consultancy; Incyte: Consultancy. Di Blasi: Kite, a Gilead Company: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Thieblemont: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Bristol Myers Squibb/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses , Research Funding; Gilead Sciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Kyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Cellectis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses ; Hospira: Research Funding; Bayer: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses . Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Nicholson: Kite, a Gilead Company: Other: Conference fees, Speakers Bureau; Novartis: Consultancy, Other: Conference fees; BMS/Celgene: Consultancy; Pfizer: Consultancy. Martínez-López: Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy; Roche, Novartis, Incyte, Astellas, BMS: Research Funding. Ribera: NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; AMGEN: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Sanderson: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Ayuk: Novartis: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Mallinckrodt/Therakos: Honoraria, Research Funding; Gilead: Honoraria; Miltenyi Biomedicine: Honoraria; Celgene/BMS: Honoraria. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Kersten: Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding. Mielke: DNA Prime SA: Speakers Bureau; Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau.

Introduction Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment option in patients with advanced Chronic Myeloid Leukemia (CML) who have disease resistant to tyrosine kinase inhibitors (TKI) or who cannot tolerate these agents. In the absence of a matched sibling donor (MSD), the use of an unrelated donor (UD) is recommended; however, this approach is associated with a higher incidence of both graft-versus-host disease (GvHD) and non-relapse mortality (NRM). Post-transplant cyclophosphamide (PTCy) has been found to result in similar rates of GvHD-free, relapse-free survival (GRFS) in allo-HCT using UD, haploidentical donors (HD) and MSD across a range of haematological malignancies. However, the role of PTCy in allo-HCT using UD and HD in CML is unknown. We here report an observational, retrospective, comparative study on the role of PTCy in UD and HD in CML patients undergoing allo-HCT. Methods Inclusion criteria were age ≥ 18 years, diagnosis of CML, first AlloHCT from 2012 to 2019, and UD and HD. The main endpoints of the study were to compare the one-year GRFS of allo-HCT using UD with standard GvHD prophylaxis (SP), PTCy UD and PTCy HD. Secondary endpoints were 3-year OS, 3-year PFS, 3-year NRM, 3-year RI, Day +100 acute GvHD (aGvHD) and one-year chronic GvHD (cGvHD). The Kaplan-Meier estimator and log-rank test were used for GRFS, OS and PFS, and the crude cumulative incidence estimator and Gray's test were used for competing events (RI/NRM, aGvHD/death before aGvHD and cGvHD/death before cGvHD). Cox proportional hazard regression was used in multivariable analyses (MVA) using patients with complete data with cause-specific models for competing risk outcomes. Results A total of 1,341 CML patients treated in EBMT centers were included. 1,094 patients received allo-HCT from SP UD, 113 from PTCy UD and 134 from PTCy HD. 61% and 54% of patients received an allo-HCT from matched UD in the SP UD and PTCy UD cohort, respectively. SP UD GvHD prophylaxis was calcineurin inhibitor-based in 88% of patients; some form of T-cell depletion was used in 82%, 19% and 9% in the SP UD, PTCy UD, and PTCy HD cohorts, respectively. Further transplant and patient details can be found in Table 1. The median follow-up was 34.9 (IQR 13.2-61.2) months. One-year GRFS was comparable in the three cohorts: 56%, 53% and 48% in SP UD, PTCy UD, and PTCy HD, respectively (log-rank p=0.30). There was no significant difference in the cumulative incidence of aGvHD at D+100 (Gray's test p=0.10) and one-year cGvHD (p=0.40) among cohorts. Conversely, the 3-year relapse incidence (RI) was significantly lower in the SP UD cohort (26%), compared to the PTCy UD (35%) and PTCy HD (34%) cohorts (Gray's test p=0.03) and the 3-year progression-free survival (PFS) was 53% vs 47% vs 45% in the SP UD, PTCy UD and PTCy HD cohorts, respectively (log-rank p=0.05). 3-year NRM was similar among cohorts 20% vs 18% vs 21% in SP UD, PTCy UD and PTCy HD, respectively (Gray's test p=0.80) and the three cohorts had a similar 3-year OS (64%, 60% and 59% in SP UD, PTCy UD and PTCy UD, respectively) (p=0.50). In total 902 patients (68%) had complete data. In MVA, higher age (HR per 10 year increase in age 1.24, 95% CI 1.06-1.45, p=0.007) and high HCT-CI (HR high vs. low 2.43, 1.59-3.71, p Conclusion Based on our results, PTCy resulted in comparable outcomes in UD and HD allo-HCT, when compared to SP UD allo-HCT, as GRFS, PFS, NRM and OS were similar. However, there was a trend to a lower RI and higher PFS in SP UD allo-HCT which may have reached significance in a larger cohort. Furthermore, the findings of this study confirm that PTCy HD allo-HCT in CML is a valid option for patients lacking a MSD or UD. In addition, disease stage pre-transplant remains a major prognostic factor with CP1 patients having better outcomes when compared to those with more advanced phases and ≥CP1 CML. Overall, our results provide information on the efficacy of PTCy in allo-HCT for CML, and show that PTCy UD and PTCy HD are feasible allo-HCT platforms for patients diagnosed with CML. Figure 1 Figure 1. Disclosures Ortí: BMS, Novartis, Incyte, Pfizer: Honoraria, Speakers Bureau. Kulagin: X4 Pharmaceuticals, Alexion, Apellis, Biocad: Research Funding; Novartis, Generium, Sanofi, Roche, Johnson & Johnson, Pfizer: Speakers Bureau. Apperley: Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau; Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau. Kröger: Novartis: Research Funding; Riemser: Honoraria, Research Funding; Sanofi: Honoraria; Neovii: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Gilead/Kite: Honoraria; Celgene: Honoraria, Research Funding; AOP Pharma: Honoraria. Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria. Angelucci: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene BSM: Honoraria, Other: DMC; Blue Bird Bio: Honoraria, Membership on an entity's Board of Directors or advisory committees; Menarini-Stemline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: steering commitee, Speakers Bureau; Vertex Pharmaceuticals: Honoraria, Other: DMC; Crispr therapeutics: Honoraria, Other: DMC; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. Lopez Corral: Gilead, Novartis: Consultancy, Honoraria. Anagnostopoulos: Abbvie: Other: clinical trials; Sanofi: Other: clinical trials ; Ocopeptides: Other: clinical trials ; GSK: Other: clinical trials; Incyte: Other: clinical trials ; Takeda: Other: clinical trials ; Amgen: Other: clinical trials ; Janssen: Other: clinical trials; novartis: Other: clinical trials; Celgene: Other: clinical trials; Roche: Other: clinical trials; Astellas: Other: clinical trials . Wrobel: Janssen: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; BeiGene: Honoraria, Speakers Bureau. Rigacci: Merck: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Menarini: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Introduction: Ibrutinib (Ibr) is the first approved irreversible BTK inhibitor. Cardiovascular (CV) adverse events, include hypertension (HT) and atrial fibrillation (AF). Ventricular tachyarrhythmias and sudden death have been reported possibly due to off target kinase inhibition. Several randomised Phase III trials have reported low numbers of cardiac deaths, sudden/unexplained deaths, and/or ventricular arrhythmias with Ibr including 9 deaths in RESONATE-2 Trial, 11 unexplained or unwitnessed deaths in Alliance Trial A041202 (med age 71; Ibr (n=7 [4%]), Ibr+ritux (IR; 4 [2%]), one death in the IR arm of ECOG1912 Trial (mean age 56.7) and 3 unexplained plus 5 cardiac deaths with BR + Ibr in the HELIOS trial (med age 64). Methods: FLAIR, a phase III, multicentre, randomised, controlled, open, trial recruiting 771 pts with untreated CLL requiring therapy. Pts were ≤75 years, considered fit for FCR and were randomized to IR or FCR. Pts with inadequately controlled symptomatic cardiac failure or unstable angina were excluded. We conducted ad hoc evaluations of the potential association of sudden or cardiac deaths with prior medical history or therapies for cardiac disorders (AF, Ischaemic heart disease, MI or angina) and HT via univariate analyses. We used Fisher's Exact test and estimated relative risk (RR) and associated confidence intervals under a normal approximation. Results: In FLAIR, 384 and 378 pts were treated with IR and FCR, respectively, median 52.7 months FU and treatment durations of 47.2 and 4.7 months. Median age 62. 84/384 (22%) IR pts had pre-existing HT and 17/384 (4%) a prior history of a cardiac disorder. 74/378 (20%) FCR pts had HT and 18/378 (5%) a cardiac disorder. To date 10 pts had a sudden or cardiac death: 2 (0.5%) FCR and 8 (2%) IR - median 33 mo (range: 13-48) from initiating IR to death. 9/10 pts were male aged 54 to 73 years at randomisation. 7/ 8 IR pts experiencing a sudden or cardiac death, had a prior history of HT and/or cardiac disorder (RR 23.6 vs pts with no HT/CV history, 95%CI [2.9-195]; Fisher's Exact P=0.0003; Table 1). Hypertensive cardiomyopathy and/or coronary artery disease was found at post mortem of all 3 IR pts having a PM. The risk of sudden or cardiac death with IR was 0.3% (1/291) in pts without pre-existing risk. The number of pts taking anti-hypertensives at trial entry (some taking more than one class) was: ACE inhibitors (ACEi) 47 IR, 37 FCR; Angiotensin II receptor blockers (ARB's) 15 IR, 17 FCR; Ca channel blockers 30 IR, 34 FCR; B-blockers 24 IR, 20 FCR; Diuretics 13 IR, 16 FCR; and alpha blockers 7 IR, 5 FCR. Overall, 291/384 (76%) IR and 296/378 (78%) FCR were taking no HT or cardiac medications at trial entry. The use of ACEi at study entry was associated with an increased risk of sudden or cardiac death with IR: 7/47 (15%) pts on ACEi at trial entry had a sudden or cardiac death compared to 1/336 (0.3%) not taking ACEi (RR 50.2, 95%CI [6.3-399]; P < 0.0001; Table 1). 2/7 pts had discontinued ACEi and switched to ARB's due to cough sometime prior to death. In contrast 0/37 FCR pts with a history of HTN/CV taking ACEi experienced a sudden or cardiac death. In the IR arm, none of the 46 pts receiving cardiac medication but not ACEi had a sudden or cardiac death suggesting that the risk was not simply a prior history of HT or cardiac disorder. 3/11 (27%) IR pts taking an ACEi plus a beta blocker at study entry had a sudden or cardiac death vs 4/32 (12.5%) pts on ACEi without a beta blocker. Factors potentially confounding the interpretation: 1) analyses did not take into account severity of underlying HT/CV risk, as it is possible that pts on ACEi had more severe underlying CV disease than others; and 2) analyses did not adjust for changes in HT/CV medications during the course of the study. However, the lack of any such signal in pts with a prior cardiovascular/HT history on therapies other than ACEi suggests a potential association with the medication itself. Conclusion: Sudden or cardiac deaths seen on IR in FLAIR were observed predominantly among male pts with a prior history of HT or cardiac disease. The prior use of ACEi was correlated with the risk of sudden or cardiac death in IR pts. In contrast, pts treated with IR who were not on ACEi (regardless of medical history) had a very low rate of cardiac or sudden death. Whilst these findings need confirming in other Ibr trials we believe that caution should be taken when concurrently administering ibrutinib and ACE inhibitors in pts with a medical history of HT or CV disease. Figure 1 Figure 1. Disclosures Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support; AbbVie; Takeda: Other: Conference support; Janssen: Honoraria; Kite: Honoraria. Cwynarski: Atara: Consultancy; BMS/Celgene: Other; Celgene: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Other; Kite, a Gilead Company: Consultancy, Speakers Bureau; Roche: Consultancy, Other, Speakers Bureau; Takeda: Consultancy, Other, Speakers Bureau. Gatto: Roche: Consultancy. Paneesha: AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Howard: Roche: Current Employment. Cairns: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; JANSSEN: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding. Hillmen: BeiGene: Honoraria; SOBI: Honoraria; AstraZeneca: Honoraria; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding.

Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,; attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del; with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR; HR: 0.44; p Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. Figure 1 Figure 1. Disclosures Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; SOBI: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria; Janssen: Honoraria; AbbVie; Takeda: Other: Conference support; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ROCHE: Research Funding; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria.

Introduction: Recent developments in management of patients with myeloma have resulted in longer survival. Availability of newer class of agents for treatment has prolonged survival, improved quality of life and achieved better disease control. Use of SCT, either autologous (AutoSCT) and to a lesser extent allogeneic (AlloSCT) still forms an important aspect of myeloma treatment pathway. Improved survivorship mandates evaluation of long term consequences and risk of SMN is one of the most important long-term consequences affecting overall outcome. Aim: Estimate the risk of SMN post SCT in patients with Myeloma. Methods and Materials: Analysis includes 779 patients who received SCT for myeloma from January 2002 to December 2019. Data was collected using case records, electronic patient records, transplant database and information from referring hospitals. Follow-up was updated to June 2020. Results: Analysis includes 779 patients with myeloma (M: 488, F:291; median age:59yr, range: 26-75) receiving AutoSCT (n=716) or AlloSCT (n=63). Conditioning for AutoSCT was high dose melphalan in majority (n=714, 99.7%). AlloSCT conditioning was RIC (n=40/63, 63.5%) or MAC (n=23/63, 36.5%). TBI was part of conditioning in 51/779 (6.5%). There was no difference in demographics between two groups. Results: Median follow-up was 46 mo (range: 0.2-220). Second malignancy was identified in 48 of 779 cases (6.0%). SMN developed in 6/63 (10%) AlloSCT and 42/716 (6%) AutoSCT patents (p=0.25). SMN types were haematological (n=21), lymphoma (n=6) and solid tumours (n=21). MDS was the only haematological SMN in this series. Secondary MDS developed in 20/21 of AutoSCT as compared to 1/63 in AlloSCT (p=0.01). Non-haematological SMN were breast (n=3), upper GI (n=3), lower GI (n=2), hepato-billiary (n=2), prostate (n=3), skin (n=5), and unknown primary (n=1). SMN incidence was higher with increasing follow-up (2002-2014, 8%; 2015-2017, 2.8%, 2018-2019, 0%, p=0.002). There was no association with development of SMN and gender, age at transplant, type of stem cell source or transplant conditioning. Incidence of SMN was significantly higher for all sites as compared to general population. Cumulative incidence of SMN was 5% at 5 yr, and 15% at 10 yr for AutoSCT patients. Conclusion: Myeloma patients are at increased risk of SMN and need monitoring for long term side effects. Development of MDS post AutoSCT is the commonest SMN post AutoSCT but there is increased incidence of solid tumours as well. Impact of new modalities of treatment needs long term monitoring. Disclosures Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria.

Use of Cryopreserved Allogeneic PBSC Results in Delayed Engraftment And Increased Incidence of Poor Graft Function Introduction: During COVID Pandemic, national and international transplant centres agreed to use cryopreserve the donor PBSC as a safer option to deliver allogeneic transplants. Published data suggests that use of cryopreserved allogeneic PBSC is safe and comparable to use of fresh PBSC but cryopreservation of stem cells may lead to cell loss and hence efficacy. During COVID pandemic, use of cryopreserved allogeneic PBSC was adopted as policy on 01/06/2020. This look back analysis evaluates the impact of change in policy. Aims: Evaluate Engraftment time, compare with historical data, blood component support, and use of growth factors Methods and Materials: Data was collected from health records (paper and electronic) and laboratory records. Transplant features and engraftment kinetics were analysed. Results: Group A June 2020 to November 2020, 19 patients [M: 13; F: 6; median age: 50yr (range: 23-69)] who received cryopreserved allogeneic PBSC were compared to 35 patients [M:24; F:11; median age: 59yr (range: 21-71)] receiving fresh allogeneic PBSC for engraftment kinetics. There were no differences between two groups regarding underlying diagnosis (p=0.31), sex mismatch, CMV mismatch, blood group mismatch, reduced intensity conditioning [RIC](p=0.28), type of donor (p=0.98) or use of Alemtuzumab (p=0.88). Median infused Cell dose in group A was 5.3 (3.4-7.16) and in group B 4.9 (1.03-6.85), [p=0.11]. Neutrophil engraftment was significantly faster with fresh PBSC as compared to cryopreserved PBSC (16d vs. 25d, p=0.0025) predominantly with MUD (18d vs. 27d, p=0.009) and RIC (16d vs. 25d, p=0.009). Platelet engraftment to 25 was faster with fresh PBSC (13d vs. 20d, p=0.021) with delayed engraftment in MUD (20d vs. 13d, p=0.006) and RIC (23d vs. 13d, p=0.039). Day to engraftment per unit CD34 was shorter with fresh PBSC for neutrophils (median: 3.2, range: 2.0-7.7 vs. 5.3, range: 2.5-16.7; p=0.006) and platelets (median: 2.4, range: 1.7-25 vs. 3.8, range: 2.2-25; p=0.001) but only for MUD. This suggests 35-40% less efficiency with use of cryopreserved PBSC. There was no difference in the need for transfusion support [RBCs (6 units vs. 3 units, p=0.32); platelets (5 pools vs. 7 pools, p=0.33)]. G-CSF use was higher with cryopreserved PBSC in RIC (54% vs. 20%, p=0.031). Two patients experienced TRM before day 90 (3.7%). At day 90, 17/52 (32.7%) had cytopenia in one lineage and 8/52 (16%) had cytopenia in more than one lineage. Delayed engraftment was observed in 10 of 33 patients (30.3%) transplanted in 2020 and the only significant association was use of cryopreserved PBSC (0% vs. 53%, p=0.001). There was no difference in the incidence of aGVHD, hepatic VOD, microangiopathy and bacterial infections. Numbers are not sufficient to make disease specific comparisons. Conclusion: Cryopreserved PBSC result in delayed neutrophil and platelet engraftment predominantly with MUDS and RIC. Incidence of delayed engraftment and poor graft function is higher. Per unit CD34 dose, cryopreserved PBSC are 30-40% less efficient to achieve engraftment. Delayed engraftment with cryopreserved PBSC especially in MUD raises the possibility that time from harvest to cryopreservation contributes to reduced efficacy. Based on these findings it was decided to infuse higher CD34 dose (6-7x10^6/kg as compared to usual 4-5x10^6/kg) for cryopreserved MUD PBSC. Disclosures Bloor: Kite, a Gilead Company: Honoraria; Novartis: Honoraria.

Whilst autologous stem cell transplantation (auto-SCT) is considered standard of care for relapsed/refractory classical Hodgkin lymphoma, the role of auto-SCT in nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined due to limited data. We report the first study on auto-SCT for NLPHL with a larger cohort. Eligible for this retrospective registry study were patients reported to the EBMT between 2003 and 2013, aged 18 or older with relapsed/refractory NLPHL who underwent first auto-SCT with disease chemosensitive to salvage therapy. NLPHL transformed to diffuse large B cell lymphoma were excluded. Sixty patients (83% male; median age 40 years) met the eligibility criteria. The median time between diagnosis and transplant was 21 months (IQR 13-58), and the median number of prior treatment lines was 2 (range 1-5), including rituximab in 63% of the patients. At auto-SCT, 62% of the patients were in complete remission (CR) and 38% in partial remission. Seventy-two percent of the patients received BEAM as high-dose therapy. With a median follow-up of 56 months (range 3-105), 5-year progression-free and overall survival (OS) were 66% and 87%, respectively. Univariate comparisons considering age, time from diagnosis to transplant, prior chemotherapy lines, and prior rituximab use failed to identify significant predictors for any survival endpoint except for being in CR at the time of auto-SCT (vs PR, P = .049) for OS. Auto-SCT in patients with relapsed/refractory NLPHL who are sensitive to salvage therapy gives excellent disease control and long-term survival independent of the time interval between diagnosis and transplant.

Background: Ibrutinib (IBR) inhibits CLL proliferation and effects prolonged remission without eradicating disease. Obinutuzumab (OBI) is an anti-CD20 monoclonal antibody that can effect depletion of measurable residual disease (MRD) below 0.01%. In the IcICLLe study (ISRCTN12695354), 20 treatment-naïve (TN) CLL patients & 20 with relapsed/refractory (R/R) CLL received IBR until complete remission with Aim: To assess the long-term MRD response status for patients treated with IBR as a sole agent or in combination with OBI. Patients: Patients received continuous IBR (420mg OD) with the addition of 6 cycles of OBI given over 6 months in the extension study. 20 TN patients received IBR monotherapy; 20 R/R patients (median 2 prior treatments, range 1-7) initiated IBR monotherapy of which 10/20 enrolled in the Extension study receiving OBI after >1year of IBR monotherapy; and 30 IBR-naïve R/R (median 1 prior treatment, range 1-3) started OBI 24 hours after first IBR dose. MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5. Results: IBR monotherapy in TN patients was well tolerated with 18/20 patients alive and 13/20 remaining on IBR after median 4.9 years follow-up (range 0-5.9). IBR was stopped due to toxicity (3), progression/relapse (2) or other causes (2). IBR-monotherapy resulted in median 0.65 log depletion per year in years 1-2, followed by relatively stable disease levels (median 0.2 log depletion per year) in the subsequent 3 years in 13/20 evaluable patients. Only 1 patient showed >0.3log increase in PB MRD level and this preceded clinical progression. No patients achieved an IWCLL CR/CRi and MRD was >0.01% in PB/BM in all patients at all time points. In the R/R group initially receiving IBR-monotherapy, 11/20 patients remain alive and 3/20 remain on IBR after a median 3.9 years follow-up (range 0.3-5.3). In this heavily pre-treated group, 10 did not enrol on the OBI Extension study (1 died, 1 progression/relapse, 4 ineligible/other causes, 4 patient preference) with 10/20 receiving OBI at median 16.2 months (range 13-19) after starting IBR-monotherapy of which 7/10 had resolved any lymphadenopathy pre-OBI. 2/10 achieved MRD-negative remission and stopped treatment, while 6/10 have since stopped IBR due to death (2), progression/relapse (3) or other causes (1). 30 R/R patients with no prior IBR exposure (most in first relapse) started IBR & OBI at the same time: 26/30 remain alive and 18/30 remain on IBR after median 3.0 years follow-up (range 0.8-4.2). IBR was stopped in 2/30 patients achieving MRD-negative remission while 10 stopped IBR due to death (2), disease progression/transformation (3), toxicity (4), or patient decision (1). There were no Grade 5 adverse events related to OBI. 3 months post-OBI, patients with >1 year prior IBR-monotherapy achieved a higher response rate (CR/CRi 50% vs. 30%), MRD response ( The deepest PB MRD responses were observed 6-12 months after the last OBI infusion. MRD levels showed little change in the following year to month 24 (median 0 log depletion, range 1.3 log depletion to 2.5 log increase). After 2 years of IBR exposure, the MRD levels shows a similar pattern to TN patients on IBR monotherapy, being generally very stable (0.3log increase at two sequential timepoints of which 4/7 have shown clinical disease progression and 3/7 still have low ( Conclusions: The addition of OBI to IBR may substantially improve depletion of CLL cells from the PB and BM. A greater impact in MRD response rate and depth was seen when OBI was introduced after >1 year of IBR treatment and tumour bulk was low. One fifth of patients maintain Figure 1 Disclosures Rawstron: Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding. Hillmen:AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company; Eli Lilly: Other: Consulting and speaker fees; Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Pettitt:Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; Celgene: Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding; Napp: Research Funding; Roche: Honoraria, Other: Hospitality, Research Funding. Fox:Abbvie: Honoraria, Research Funding; Adienne: Honoraria, Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; Sunesis: Research Funding; Atarabio: Research Funding; Roche: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Hillmen:Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Alexion: Consultancy, Research Funding, Speakers Bureau.

Background: The Blood Cancer UK TAP CLARITY trial for relapsed or refractory CLL combined IBR with VEN in order to eradicate detectable disease with a plan to stop therapy early if measurable residual disease (MRD) Aims: To provide long term follow up data for the combination of IBR and VEN for R/R CLL patients. IWCLL response status and MRD responses status at the 38 month time point are now presented in this abstract. Methods: CLARITY is a Phase II trial combining IBR with VEN in 50 patients with R/R CLL. After 2 months of IBR, VEN was added initially at a daily dose of 10mg or 20mg/day escalating weekly to a final daily dose of 400mg/day. CLL MRD was quantified using >6 colour ERIC-standard flow cytometry (detection limit 10-5/0.001%). Paired PB & BM samples were assessed at months 8, 14, 26 and longitudinal PB samples were taken at multiple time points. Fifty-four patients were recruited from May 2016 to November 2017. The median number of prior therapies was 1 (range: 1-6). 20% patients had del(17p); 25% del(11q); 75% had unmutated IGVH. Four patients that discontinued treatment due to ibrutinib-related adverse events in the first 8 weeks before starting VEN were replaced so that, in total, 50 patients received the combination of IBR and VEN. The interruption of therapy was indicated following confirmation of a CR according to the iwCLL2008 criteria and MRD reduction Results: Of the 50 evaluable patients recruited to the study, 23 patients stopped both treatments at or before M38; the majority due to achieving MRD4 (17/23). 27/50 patients were still receiving at least one trial treatment at this time point, with M38 response data pending for 11 patients. Of the 27 evaluable patients on treatment, the overall response rate (ORR), comprising of 10 patients with CR and 3 with CRi, was 81% compared to an ORR of 91% in the 36 patients receiving at least one trial treatment at M26 respectively. One additional patient discontinued treatment due to MRD negativity after M38. Of the 18 patients stopping due to MRD negativity, 14/18 continue to have Overall, MRD responses continued to improve after the first year of combination treatment with 24/50 (48%) patients achieving MRD4 in the BM at month 26 compared to 20/50 (40%) at month 14. After 4 months of combination, the median log CLL depletion was 2.9 (range 0.2-4.8) for patients achieving There was only one case of biochemical TLS. Other side-effects were mild and/or manageable, most commonly neutropenia (3/37 grade 2, 34/37 grade 3/4). Two Suspected Unexpected Serious Adverse Reactions (SUSARs) were reported (abdominal pain and pemphigus), 44 Serious Adverse Events (SAEs), and 1153 Adverse Events (AEs) (of which 141 were grade 3 or 4) were reported. Summary/Conclusion: After 38 months, the response to IBR+VEN is sustained despite planned discontinuation of therapy in MRD negative patients. The initial rate of disease depletion (during the first two months of combined IBR+VEN exposure) is highly predictive of longer-term response to combination IBR+VEN treatment in relapsed/refractory CLL. Patients who do not show rapid disease clearance and have persistent MRD after 12 months of combination IBR+VEN usually have stable or slowly decreasing disease levels akin to that seen in IBR monotherapy. These data will be updated at ASH 2020. Disclosures Hillmen: AbbVie: Speakers Bureau; Janssen: Speakers Bureau; Gilead: Speakers Bureau; Pharmacyclics: Other: Financial or Material spport; Morphosys: Other: Consulting fees; Sunesis: Other: Consulting fees. Brock:Invex: Other: Consulting and speaker fees; Merck: Other: Reimbursement of costs; Eli Lilly: Other: Consulting and speaker fees; AstraZeneca: Current equity holder in publicly-traded company; GlaxoSmithKline: Current equity holder in publicly-traded company. Schuh:Illumina: Other: Consulting fees; Abbvie: Other: Consulting fees; Gilead: Other: Consulting fees; Roche: Other: Consulting fees. Pettitt:Roche: Honoraria, Other: Hospitality, Research Funding; Napp: Research Funding; Celgene: Other: Hospitality, Research Funding; Chugai: Research Funding; Gilead: Honoraria, Other: Hospitality, Research Funding; Kite: Honoraria, Other: Hospitality, Research Funding; GSK: Research Funding; Novartis: Research Funding. Gribben:Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria; Celgene: Research Funding. Patten:Roche: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bloor:Abbvie: Consultancy, Honoraria, Other: Conference Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Conference Funding , Speakers Bureau. Fox:Celgene: Current equity holder in publicly-traded company; Sunesis: Current equity holder in publicly-traded company; Atarabio: Current equity holder in publicly-traded company; Abbvie: Current equity holder in private company, Current equity holder in publicly-traded company; Gilead: Current equity holder in private company, Current equity holder in publicly-traded company; Adienne: Current equity holder in private company, Current equity holder in publicly-traded company; Roche: Current equity holder in private company, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Takeda: Current equity holder in private company, Current equity holder in publicly-traded company. Forconi:Roche: Honoraria; Janssen: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; AbbVie: Honoraria, Other: Fees for cosulting or advisory role, received travel and expenses, Speakers Bureau; Gilead: Research Funding; Astra Zeneca: Other: Fees for cosulting or advisory role; Menarini: Other: Fees for cosulting or advisory role; Novartis: Honoraria. Rawstron:BD Biosciences (Intrasure): Patents & Royalties. Hillmen:Alexion: Consultancy, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Acerta: Other: Financial or material support; Roche: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; AbbVie: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Pharmacyclics: Other: Financial or material support, Research Funding; Janssen: Consultancy, Other: Financial or material support, Research Funding, Speakers Bureau; Apellis: Consultancy, Research Funding, Speakers Bureau; Gilead: Other: Financial or material support, Research Funding.

PURPOSE The treatment of chronic lymphocytic leukemia (CLL) has been revolutionized by targeted therapies that either inhibit proliferation (ibrutinib) or reactivate apoptosis (venetoclax). Both significantly improve survival in CLL and replace chemoimmunotherapy for many patients. However, individually, they rarely lead to eradication of measurable residual disease (MRD) and usually are taken indefinitely or until progression. We present the CLARITY trial that combined ibrutinib with venetoclax to eradicate detectable CLL with the intention of stopping therapy. PATIENTS AND METHODS CLARITY is a phase II trial that combined ibrutinib with venetoclax in patients with relapsed or refractory CLL. The primary end point was eradication of MRD after 12 months of combined therapy. Key secondary end points were response by International Workshop on CLL criteria, safety, and progression-free and overall survival. RESULTS In 53 patients after 12 months of ibrutinib plus venetoclax, MRD negativity (fewer than one CLL cell in 10,000 leukocytes) was achieved in the blood of 28 (53%) and the marrow of 19 (36%). Forty-seven patients (89%) responded, and 27 (51%) achieved a complete remission. After a median follow-up of 21.1 months, one patient progressed, and all patients were alive. A single case of biochemical tumor lysis syndrome was observed. Other adverse effects were mild and/or manageable and most commonly were neutropenia or GI events. CONCLUSION The combination of ibrutinib plus venetoclax was well tolerated in patients with relapsed or refractory CLL. There was a high rate of MRD eradication that led to the cessation of therapy in some patients. The progression-free and overall survival rates are encouraging for relapsed and refractory CLL.

HLA matching at an allelic-level resolution for volunteer unrelated donor (VUD) hematopoietic cell transplantation (HCT) results in improved survival and fewer post-transplant complications. Limitations in typing technologies used for the hyperpolymorphic HLA genes have meant that variations outside of the antigen recognition domain (ARD) have not been previously characterized in HCT. Our aim was to explore the extent of diversity outside of the ARD and determine the impact of this diversity on transplant outcome. Eight hundred ninety-one VUD-HCT donors and their recipients transplanted for a hematologic malignancy in the United Kingdom were retrospectively HLA typed at an ultra-high resolution (UHR) for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 using next-generation sequencing technology. Matching was determined at full gene level for HLA class I and at a coding DNA sequence level for HLA class II genes. The HLA matching status changed in 29.1% of pairs after UHR HLA typing. The 12/12 UHR HLA matched patients had significantly improved 5-year overall survival when compared with those believed to be 12/12 HLA matches based on their original HLA typing but were found to be mismatched after UHR HLA typing (54.8% versus 30.1%, P = .022). Survival was also significantly better in 12/12 UHR HLA-matched patients when compared with those with any degree of mismatch at this level of resolution (55.1% versus 40.1%, P = .005). This study shows that better HLA matching, found when typing is done at UHR that includes exons outside of the ARD, introns, and untranslated regions, can significantly improve outcomes for recipients of a VUD-HCT for a hematologic malignancy and should be prospectively performed at donor selection.

BACKGROUND: Patients with primary refractory acute lymphoblastic leukemia (PREF ALL) who fail to achieve a complete remission (CR) after >= 2 courses of chemotherapy have a dismal prognosis without undergoing allogeneic hematopoietic cell transplantation (HCT). To the authors' knowledge, there currently are no data regarding factors influencing transplantation outcomes. METHODS: The authors retrospectively studied outcomes of transplantation for cases of PREF ALL reported to European Society for Blood and Marrow Transplantation registry. Eligibility criteria for the current analysis included adult patients who underwent their first HCT for PREF ALL between 2000 and 2012. PREF disease was defined as the failure to achieve a morphological CR after >= 2 courses of induction chemotherapy. RESULTS: Data regarding 86 adult patients were analyzed. With a median follow-up of 106 months, the probability of survival was 36% at 2 years and 23% at 5 years. The probability of leukemia-free survival was 28% and 17%, respectively, and the probability of nonrecurrence mortality was 20% and 29%, respectively, at 2 years and 5 years. For 66 patients who achieved a CR (77%), the survival at 2 years and 5 years was 36% and 29%, respectively. In multivariate analysis, use of total body irradiation was found to be associated with improved survival. Total body irradiation and infusion of female hematopoietic cells into male recipients was associated with improved leukemia-free survival. These findings were incorporated into a scoring system that identified 3 groups (those with 2, 1, or no prognostic factors) with survival rates of 57%, 22%, and 8%, respectively. CONCLUSIONS: Although overall these patients would clearly benefit from the introduction of novel antileukemic therapies, the data from the current study support the use of allogeneic HCT in selected patients with PREF ALL. (C) 2017 American Cancer Society.