Anti-CD19 chimeric antigen receptor T-cell therapy has less efficacy in Richter transformation than in de novo large B-cell lymphoma and transformed low-grade B-cell lymphoma.

The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.

Second hematopoietic stem cell transplantation as salvage therapy for relapsed acute myeloid leukemia/myelodysplastic syndromes after a first transplantation.

Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) relapsing after a first transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% confidence interval [95% CI]: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival rates were 25% (95% CI: 14-36%) and 7% (95% CI: 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate analysis identified female gender (hazard ratio [HR]=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (HR=13.4, P=0.001) or matched unrelated donor (HR=4.53, P=0.007) and relapse after HSCT1 in earlier years (HR=2.46, P=0.02) as factors predicting overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1.

The occurrence of thrombosis during intensive chemotherapy treatment for acute myeloid leukemia patients does not impact on long-term survival.

Venous thromboembolism (VTE) is frequently seen in acute myeloid leukemia (AML) patients and presents a significant clinical challenge. The association of VTE during intensive chemotherapy with risk models such as the Medical Research Council (MRC) cytogenetic-based assessment and the European LeukemiaNet (ELN) 2017 molecular risk model have not been rigorously evaluated. Additionally, there is a paucity of data pertaining to the long-term prognostic impact of VTE in AML patients. We performed an analysis of baseline parameters of AML patients diagnosed with VTE during intensive chemotherapy and compared them with patients without VTE. The analyzed cohort consisted of 335 newly diagnosed AML patients with a median age of 55 years. Thirty-five patients (11%) were classified as MRC favorable risk, 219 (66%) patients as intermediate risk, 58 patients (17%) as adverse risk. Per ELN 2017, 132 patients (40%) had favorable risk disease, 122 patients (36%) intermediate risk, and 80 patients (24%) had adverse risk. VTE was seen in 33 patients (9.9%), occurring mostly during induction (70%), and required catheter removal in 9 patients (28%). Baseline clinical, laboratory, molecular, and ELN 2017 parameters were not significantly different groups. However, MRC intermediate-risk group patients were significantly more likely to experience thrombosis compared to favorable risk and adverse risk patients (12.8% versus 5.7% and 1.7%, respectively; p = 0.049). Median overall survival was not significantly impacted by the diagnosis of thrombosis (3.7 years versus 2.2 years; p = 0.47). VTE is tightly associated with temporal and cytogenetic parameters in AML but does not significantly impact on long-term outcomes.

Defining Current Patterns of Blood Product Use during Intensive Induction Chemotherapy in Newly Diagnosed Acute Myeloid Leukemia Patients.

Introduction: Blood product transfusion retains a critical role in the supportive care of patients with acute myeloid leukemia (AML). Whereas previous studies have shown increased transfusion dependency to portend inferior outcome, predictive factors of an increased transfusion burden and the prognostic impact of transfusion support have not been assessed recently. Methods/Patients: We performed a retrospective analysis on a recent cohort of patients given intensive induction chemotherapy in 2014-2022. Results: The analysis comprised 180 patients with a median age of 57 years with 80% designated as de novo AML. Fifty-four patients (31%) were FLT3-ITD mutated, and 73 patients (42%) harbored NPM1. Favorable risk and intermediate risk ELN 2017 patients accounted for 43% and 34% of patients, respectively. The median number of red blood cell (RBC) and platelet units given during induction were 9 and 7 units, respectively. Seventeen patients (9%) received cryoprecipitate, and fresh frozen plasma (FFP) was given to 12 patients (7%). Lower initial hemoglobin and platelet levels were predictive of increased use of RBC (p < 0.0001) and platelet transfusions (p < 0.0001). FFP was significantly associated with induction related mortality (42% vs. 5%; p < 0.0001) and with FLT3-ITD (72% vs. 28%; p = 0.004). Blood group AB experienced improved mean overall survival compared to blood group O patients (4.1 years vs. 2.8 years; p = 0.025). In multivariate analysis, increased number of FFP (hazard ratio [HR], 4.23; 95% confidence interval [CI], 2.1-8.6; p < 0.001) and RBC units (HR, 1.8; 95% CI, 1.2-2.8; p = 0.008) given was associated with inferior survival. Conclusion: Transfusion needs during induction crucially impact the clinical trajectory of AML patients.

Immunogenicity and safety of the BNT162b2 mRNA COVID-19 vaccine in haematopoietic stem cell transplantation recipients.

The immunogenicity and safety of Pfizer-BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT recipients who were at least six months following transplantation and with no active acute graft-versus-host disease (GVHD). Blood samples were taken 2-4 weeks after the second vaccination and analyzed for receptor-binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 [95% CI (confidence interval), 2·16-3·16]. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70-6·28), P < 0·0001. The GMT of NA in HSCT recipients and controls was 116·0 (95% CI 76·5-175·9), and 427·9 (95% CI 354·3-516·7) respectively (P < 0001). Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls. In conclusion; the BNT162b2 mRNA vaccination is safe and effective in HSCT recipients, especially those who are immunosuppression-free. A significant fraction developed protecting NA.

ELN 2017 classification significantly impacts the risk of early death in acute myeloid leukemia patients receiving intensive induction chemotherapy.

Early mortality remains a challenging therapeutic facet of the initial induction phase of intensive chemotherapy in patients with acute myeloid leukemia (AML). The impact of standard molecular evaluation and risk category of the European LeukemiaNet (ELN) 2017 classification model on early mortality has not been rigorously evaluated thus far. We reviewed the medical records of 320 consecutive adult patients with newly diagnosed AML treated with intensive induction chemotherapy in our center from 2007 to 2021. The median age was 56 years; 33 patients (10%) died during induction. Patient age, white blood cell count, hemoglobin level, platelet level, creatinine, uric acid, lactate dehydrogenase serum levels, and FLT3-ITD and CEBPA mutational status did not significantly impact early mortality. NPM1mut patients had a lower likelihood of early death compared to NPM1wt (5% versus 13%; p = 0.023) whereas patients with high-risk cytogenetic studies experienced higher rates of induction mortality compared with intermediate and favorable risk patients (20% versus 8 and 7%, respectively; p = 0.049). Adverse risk ELN 2017 was significantly more likely to die during induction compared with intermediate and favorable risk patients (20% versus 10 and 4%, respectively; p = 0.001). Patients treated in 2007-2011 experienced a significantly higher rate of induction death compared with patients in 2012-2021 (17% versus 8%; p = 0.039). Multivariate analysis confirmed adverse ELN 2017 [odds ratio (OR), 6.7; 95% confidence interval (CI), 1.74-25.3; p = 0.006) and treatment timeframe (OR, 0.35; 95% CI, 0.14-0.85; p = 0.019) as pivotal predictors of early mortality. ELN 2017 is a robust prognosticator of early mortality in intensively treated AML patients.

Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in first complete remission after 5-azacitidine and venetoclax: a multicenter retrospective study.

The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for curative-intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (n = 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.

Evaluating outcomes of adult patients with acute lymphoblastic leukemia and lymphoblastic lymphoma treated on the GMALL 07/2003 protocol.

Chemotherapy-based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established protocol for ALL. In this study, we assessed our recent experience with the GMALL 07/2003 protocol reviewing all adult ALL patients who were treated with GMALL in three major centers in Israel during 2007-2020. The analysis comprised 127 patients with a median age of 41 years (range 17-83). Sixty-two were B-ALL (49%), 20 (16%) patients were Philadelphia chromosome positive ALL, and 45 (35%) were T-ALL. The 2-year and 5-year overall survival rates were 71% and 57%, respectively. The 2-year relapse rate was 30% with 2-year and 5-year leukemia-free survival rates of 59% and 50%, respectively. Adolescents and young adults experienced significantly longer overall survival (84 months versus 51 months; p=0.047) as well as leukemia-free survival compared with older patients (66 months versus 54 months, p=0.003; hazard ratio=0.39, 95% confidence interval, 0.19-0.79; p=0.009). T-ALL patients had longer survival compared to B-ALL patients while survival was comparable among Philadelphia chromosome positive patients and Philadelphia chromosome negative patients. An increased number of cytogenetic clones at diagnosis were tightly associated with adverse prognosis (15-month survival for ≥2 clones versus 81 months for normal karyotype; p=0.003). Positive measurable residual disease studies following consolidation were predictive for increased risk of relapse (64% versus 22%; p=0.003) and shorter leukemia-free survival (11 months versus 42 months; p=0.0003). While GMALL is an effective adult regimen, a substantial patient segment still experiences relapse.

Contemporary evaluation of acute myeloid leukemia patients with long-term survival exceeding 5 years.

OBJECTIVES: Define clinical and laboratory attributes of acute myeloid leukemia (AML) patients with long-term survival exceeding five years and compare them with AML patients succumbing to disease within 2 years of diagnosis. METHODS: A retrospective analysis of AML patients alive at least five years from the time of initial diagnosis. Baseline clinical data were compared with patients who died within 2 years of diagnosis. RESULTS: The long-term cohort consisted of 93 patients treated in 2007-2016 with a median follow-up duration of 7.7 years (range 5-13.6 years). European LeukemiaNet (ELN) 2017 favorable risk patients accounted for 60% of the cohort. All long-term survivors achieved remission following induction chemotherapy. Multivariate analysis showed that compared with 132 patients experiencing death within 2 years of diagnosis, long-term survivors were more likely to be of younger age [odds ratio (OR), 0.92; 95% confidence interval (CI), 0.9-0.95; p < 0.001], have a lower initial WBC count (OR, 0.58; 95% CI, 0.43-0.79; p = 0.0004), undergo an allogeneic stem cell transplantation (OR, 7.95; 95% CI, 3.07-20.59; p < 0.0001), and harbor favorable risk cytogenetics (OR, 0.03; 95% CI, 0.006-0.23; p = 0.0004). CONCLUSIONS: Long-term survival of AML is seen in a distinct demographic and biologic patient subset.

BL-8040 CXCR4 antagonist is safe and demonstrates antileukemic activity in combination with cytarabine for the treatment of relapsed/refractory acute myelogenous leukemia: An open-label safety and efficacy phase 2a study.

BACKGROUND: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML. METHODS: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23). RESULTS: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts. CONCLUSIONS: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia.

Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome using treosulfan based compared to other reduced-intensity or myeloablative conditioning regimens. A report of the chronic malignancies working party of the EBMT.

Allogeneic haematopoietic-cell transplantation (allo-HCT) is a potentially curative therapy for high-risk myelodysplastic syndrome (MDS). Reduced-intensity conditioning (RIC) is usually associated with lower non-relapse mortality (NRM), higher relapse rate and similar overall-survival (OS) as myeloablative-conditioning (MAC). Fludarabine/treosulfan (FT) is a reduced-toxicity regimen with intense anti-leukaemia activity and a favourable toxicity profile. We investigated post-transplant outcomes in 1722 MDS patients following allo-HCT with FT (n = 367), RIC (n = 687) or MAC (n = 668). FT and RIC recipients were older than MAC recipients, median age 59, 59 and 51 years, respectively (P < 0·001) but other disease characteristics were similar. The median follow-up was 64 months (1-171). Five-year relapse rates were 25% (21-30), 38% (34-42) and 25% (22-29), after FT, RIC and MAC, respectively, (P < 0·001). NRM was 30% (25-35), 27% (23-30) and 34% (31-38, P = 0·008), respectively. Five-year OS was 50% (44-55), 43% (38-47), and 43% (39-47), respectively (P = 0·03). In multivariate analysis, FT was associated with a lower risk of relapse (HR 0·55, P < 0·001) and better OS (HR 0·72, P = 0·01). MAC was associated with higher NRM (HR 1·44, P = 0·001). In conclusion, FT is associated with similar low relapse rates as MAC and similar low NRM as RIC, resulting in improved OS. FT may be the preferred regimen for allo-HCT in MDS.

A phase II study of bisantrene in patients with relapsed/refractory acute myeloid leukemia.

OBJECTIVES: To determine the current role of bisantrene, an anthracene with anthracycline-like activity which was shown in earlier studies to be effective therapy in relapsed/refractory acute myeloid leukemia with no discernible cardiotoxicity, in the treatment of patients with R/R AML. METHODS: This phase 2, single-center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Disease assessment included routine blood work and bone marrow studies. RESULTS: In all, 10 patients were enrolled with a median of 3 lines of prior therapy including seven patients who had relapsed following allogeneic stem cell transplantation. The most frequently reported grade ≥3 treatment-attributed hematologic AE was thrombocytopenia, whereas the most frequently reported grade ≥3 treatment-attributed non-hematologic AE was mucositis. Of the 10 patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40%. Next-generation sequencing of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification. CONCLUSIONS: In view of the observed low toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned.

Complete Remission with Incomplete Blood Count Recovery Is a Strong Predictor of Nonrelapse Mortality in Acute Myeloid Leukemia Patients Undergoing Allogeneic Stem Cell Transplantation.

INTRODUCTION: Achievement of an initial complete remission (CR) following induction chemotherapy is tightly correlated with survival in acute myeloid leukemia (AML) patients, yet patients in CR with incomplete hematologic recovery (CRi) still experience improved outcomes compared with nonresponding patients. Whether CRi predicts prognosis in patients referred to an allogeneic stem cell transplantation (allo-SCT) is incompletely defined. In this analysis, we evaluated whether clinical outcomes of transplanted AML patients in CR and CRi were significantly different. METHODS: A retrospective single-center analysis of all de novo AML patients who underwent an allo-SCT between 2001 and 2015. The cohort included all adult patients with AML who underwent a first allo-SCT either in first or second CR or CRi at the time of transplantation. RESULTS: The study cohort included 186 CR patients and 44 CRi patients. In univariate analysis, CRi was associated with inferior 3-year survival and 3-year nonrelapse mortality (NRM) compared to CR (41 vs. 62%; p = 0.022 and 27 vs. 10%; p = 0.006, respectively). In multivariate analysis, CRi was associated with decreased rates of survival (hazard ratio [HR] 2.01; 95% CI, 1.24-3.25; p = 0.005) and NRM (HR, 3.5; 95% CI, 1.6-7.8; p = 0.002). CONCLUSION: CRi in transplanted AML patients is potentially a potent predictor of increased NRM and survival.

Comprehensive single institute experience with melanoma TIL: Long term clinical results, toxicity profile, and prognostic factors of response.

Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) mediates objective responses in 30% to 50% of patients with metastatic melanoma according to multiple, small phase 2 trials. Here we report the long-term clinical results, intent-to-treat analysis, predictors of response and toxicity profile in a large patient cohort. A total of 179 refractory melanoma patients were enrolled in the ACT trial. TIL were administered in combination with high-dose bolus interleukin-2 following preconditioning with cyclophosphamide and fludarabine. Patients were followed-up for a median of 7.2 years. A total of 107 (60%) of 179 enrolled patients were treated. The main reason for the drop out of the study was clinical deterioration. Of 103 evaluated patients, 29 patients (28%) achieved an objective response (OR), including complete remission (8%) or partial response (20%). Sixteen pateints exhibited stable disease. Predictors of response were performance status, time of TIL in culture and CD8 frequency in the infusion product. The absolute lymphocyte count 1 and 2 weeks after TIL infusion was the most predictive parameter of response. With a medium follow-up time of 7.2 years, OR patients reached a median overall survival (OS) of 58.45 months and a median progression-free survival (PFS) of 15.43 months, as compared with nonresponders, with 6.73 months OS and 2.60 months PFS. By 6 years, 50% of OR patients were alive and 43% had no documented progression. TIL ACT can yield durable objective responses, even as salvage therapy in highly advanced metastatic melanoma patients.

Comparable Long-Term Outcome after Allogeneic Stem Cell Transplantation from Sibling and Matched Unrelated Donors in Patients with Acute Myeloid Leukemia Older Than 50 Years: A Report on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Allogeneic stem cell transplantation (SCT) is potentially curative therapy in acute myeloid leukemia (AML). Marked improvement has been achieved with SCT from matched unrelated donors (MUDs) in recent years. However, there are limited data comparing the long-term outcomes (beyond 10 years) after SCT from sibling donors and MUDs in older patients with AML. We analyzed these outcomes in a large cohort of patients with AML (n = 1134), age ≥50 years, who were alive and leukemia-free 2 years after SCT from matched siblings (n = 848) or MUDs (n = 286), with a median follow-up of 8.9 years. The median age was 56 and 58 years after SCT from siblings and MUDs, respectively (P = .005). In the sibling group, 77%, 12%, and 11% were in first complete remission (CR1), second complete remission (CR2), and active leukemia at SCT compared with 50%, 25%, and 25% in the MUD group, respectively (P < .001). Sixty-one percent of siblings and 62% of MUDs had reduced-intensity conditioning (P = .78). The 10-year leukemia-free survival (LFS) of patients surviving leukemia-free 2 years after SCT was 72% and 62%, respectively (P = .30). Multivariate analysis identified active leukemia at SCT (hazard ratio [HR], 1.86; P = .0001) or CR2 (HR, 1.51; P = .02) compared with CR1, female recipients (HR, 0.71; P = .006), adverse cytogenetics (HR, 2.52; P = .01), and prior graft-versus-host disease (HR, 1.31; P = .04) as independent factors predicting LFS. Donor and conditioning type were not significant. The cumulative incidence was 15% and 17% (P = .97) for late relapse mortality and 13% and 21% for late nonrelapse mortality, respectively (P = .15). In conclusion, long-term LFS is similar, and patients who are leukemia-free 2 years after SCT can expect favorable outcomes with both donor types.

Second allogeneic stem cell transplantation in patients with acute lymphoblastic leukaemia: a study on behalf of the Acute Leukaemia Working Party of the European Society for Blood and Marrow Transplantation.

Although second allogeneic haematopoietic cell transplantation (allo-HCT2) is a therapeutic option for patients relapsing after first HCT (allo-HCT1), there is limited data on allo-HCT2 in patients with acute lymphoblastic leukaemia (ALL). We retrospectively studied 245 patients receiving allo-HCT2 as a salvage treatment for relapse following allo-HCT1 between the 2000 and 2017. The median age at allo-HCT2 was 34·6 years (range: 18-74). One hundred and one patients (41%) received sibling donor and 144 (59%) unrelated donor allo-HCT2. Acute graft-versus-host disease (GVHD) grade II-IV and III-IV occurred in 33% and 17% of the patients, respectively. The incidence of 2-year total and extensive chronic GVHD was 38% and 19%, respectively. The 2- and 5-year cumulative incidence of non-relapse mortality, relapse incidence, leukaemia-free survival, overall survival and GVHD-free, relapse-free survival (GRFS) were 24% and 26%, 56% and 62%, 20% and 12%, 30% and 14% and 12% & 7%, respectively. In multivariate analysis, factors associated with overall survival were age, time from allo-HCT1 to relapse, conditioning for allo-HCT1, Karnofsky score at allo-HCT2 and donor type for allo-HCT2. In conclusion, outcomes of allo-HCT2 in ALL patients were poor, with only 14% overall survival and 7% GRFS at 5 years with very high relapse incidence.

Risk factors and implications of oral mucositis in recipients of allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Oral mucositis (OM) is a common toxicity of stem cell transplantation (SCT). We sought to evaluate OM burden, risk factors, and implications in a cohort of allogeneic-SCT recipients. METHODS: This was a single-center study including 115 adult allogeneic-SCT transplanted between 2016 and 2018 for various hematological conditions. Conditioning intensity was categorized as myeloablative (MAC, 39%), reduced intensity (34%), or reduced toxicity (RTC, 27%) in patients conditioned with fludarabine-treosulfan. OM was prospectively graded using the Common Terminology Criteria for Adverse Events (v.4.0) system. RESULTS: Moderate-to-severe OM (grade 2-4) was experienced by 60% of patients. In a univariate analysis, younger age (P = .023), lower body mass index (P = .01), recent smoking (P = .08), recent antibiotics exposure (P = .018), MAC (P < .001), and methotrexate (P = .009) were associated with moderate-to-severe OM. In a multivariable logistic regression model, conditioning and graft-versus-host disease prophylaxis remained significant. OM risk was lowest with RTC (RTC vs MAC: odd ratio [OR] 0.05, P < .001), and recent antibiotic exposure trended toward increased risk (OR 1.88, P = .168). OM was associated with longer hospitalization, delayed neutrophil engraftment, and gastrointestinal-related infections. CONCLUSION: Oral mucositis remains a leading SCT complication. Treosulfan-based conditioning has low mucosal toxicity and is appealing given previous reports on its high efficacy.

A simplified method for detection of N-terminal valine adducts in patients receiving treosulfan.

RATIONALE: Treosulfan is a substance that is being studied as part of the conditioning regimen given prior to allogeneic stem cell transplantation in patients with hematological malignancies. It is known to decompose into 1,2:3,4-diepoxybutane (DEB) under physiologic conditions. In this study, we investigate whether N-terminal valine adducts can be utilized to monitor differences in DEB formation of patients receiving treosulfan as part of the conditioning regimen for transplantation. METHODS: Blood samples were collected from a group of 14 transplant recipients and analyzed for N,N-(2,3-dihydroxy-1,4-butadiyl)valine (pyr-Val) and 2,3,4-trihydroxybutylvaline (THB-Val) adducts as biomarkers for drug uptake and metabolism before treosulfan treatment and 6 days after treatment. RESULTS: A new direct injection liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated prior to clinical analysis. The assay precision was determined by 3 replicate analyses on 3 individual days using control globin spiked with known amounts of pyr-Val and THB-Val. The intra- and inter-day precision coefficients of variance (CVs) and accuracy were < 10% and 15%, respectively. In clinical specimens, the means ± SD of pyr-Val and THB-Val background were 0.29 ± 0.10 pmol/g HB and 5.17 ± 1.7 pmol/g HB, respectively. CONCLUSIONS: These values are similar to those found previously. Treosulfan treatment leads to a significant increase in pyr-Val and THB-Val adducts in each patient (Student's t-test p <0.0001). The mean ± SD amounts of adduct formed were 245.3 ± 89.6 and 210 ± 78.5 pmol/g globin for pyr-Val and THB-Val, respectively. Importantly, these results show that this direct injection method can quantitate both background and treosulfan-induced pyr-Val and THB-Val N-terminal valine globin adducts in humans.

Intravenous Busulfan Compared with Treosulfan-Based Conditioning for Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of European Society for Blood and Marrow Transplantation.

Dose intensity of the conditioning regimen has significant impact on the outcomes after stem cell transplantation (SCT) for acute myeloid leukemia. Most studies have shown more relapse, less nonrelapse mortality (NRM), and similar overall survival after reduced-intensity and myeloablative conditioning. There are limited data on the dose equivalence and expected outcomes of treosulfan-based compared with busulfan-based conditioning. We compared SCT outcomes after fludarabine with either intravenous busulfan at a myeloablative dose (FB4, 12.8 mg/kg, n = 1265) or a reduced dose (FB2, 6.4 mg/kg, n = 1456) or treosulfan at 42 g/m2 (FT14, n = 403) or 36 g/m2 (FT12, n = 168). Median patient age was 48, 60, 57, and 60 years in the FB4, FB2, FT14, and FT12 groups, respectively (P < .0001). Two-year overall survival was 58%, 53%, 53%, and 51%, respectively (P = .25). Multivariate analysis identified advanced age, advanced disease status, and secondary leukemia to be associated with worse survival. Relapse rate was 30%, 35%, 34%, and 40%, respectively. Relapse was more common after FB2, advanced age and disease status, secondary leukemia, and sibling donors. NRM was 17%, 18%, 21%, and 16%, respectively. NRM was least common after FT12 and more common with advanced age and disease status and unrelated donors. Treosulfan-based regimens were associated with lower rates of graft-versus-host disease. There was no difference in any outcome among patients in first complete remission at transplantation. However, there was better survival with treosulfan-based conditioning in advanced leukemia. In conclusion, survival is determined mostly by disease biology and is similar after various regimens. Treosulfan-based conditioning is more similar to myeloablative than to reduced-intensity conditioning but can be administered safely in older patients, with lower rates of graft-versus-host disease and possibly better outcomes in patients with active leukemia.

Baseline Renal Function and Albumin are Powerful Predictors for Allogeneic Transplantation-Related Mortality.

Biomarkers measured in blood chemistry before allogeneic hematopoietic stem cell transplantation (HSCT) may reflect patients' physiological status. We hypothesized that selected markers are predictive for nonrelapse mortality (NRM) following transplantation and could contribute to risk assessment. We investigated the value of pre-HSCT albumin, estimated glomerular filtration rate (eGFR), and alkaline phosphatase (AlkP) in predicting NRM. We retrospectively analyzed clinical and laboratory data from 1217 patients receiving a first HSCT in 2 European centers between 2003 and 2015. Transplantation indications and conditioning regimens were diverse. Patients had a median age of 55 years and hematopoietic cell transplantation comorbidity index (HCT-CI) scores of 0 (24%), 1 to 2 (39%), and ≥3 (37%). Cutoffs of eGFR <60 mL/min, albumin <3.5 g/dL, and AlkP >180 IU/L corresponded with 8.8%, 8.3%, and 6.5% of the patients, respectively. eGFR and albumin were associated with increased risk and higher cumulative incidence of day-100, 1-year, and 2-year NRM, both as continuous or categorized variables. A similar pattern was observed for AlkP, except for day-100 NRM. In multivariable analyses, eGFR and albumin were consistently among the top risk factors for early and late-term NRM, abrogating the role of age. Prediction models for day-100, 1-year, and 2-year NRM based only on HCT-CI resulted in c-statistics of .565, .575, and .577, respectively. Addition of both biomarkers increased c-statistics for day-100, 1-year, and 2-year NRM to .651, .633, and .624, respectively. Albumin and eGFR are prognostic biomarkers for NRM after HSCT and improve the discriminative power of the HCT-CI.