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Objectives: Dysregulation of BCL‐2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3‐dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven‐chemotherapy or ven‐navitoclax combinations, to assess efficacy and safety. Methods: Seventeen patients were included in the analysis, median age was 32 years, with 6 B‐ALL and 11 T‐ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines. Results: ORR was 55% and 46% among the ven‐chemotherapy and the ven‐navitoclax‐chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven‐navitoclax combination were infectious complications and hepatotoxicity. Conclusions: Our data demonstrated the possible efficacy of ven‐chemotherapy and ven‐navitoclax in r/r ALL with moderate toxicity. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: The use of haploidentical hematopoietic cell transplantation (haplo‐HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL). METHODS: The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo‐HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018. RESULTS: The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2‐year leukemia‐free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100‐day incidence of grade 2 through 4 acute graft‐vs‐host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia‐free survival (64.9% vs 47.3%; P =.019) and OS (75.5% vs 53.5%; P =.006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P =.047). The incidence of relapse, GVHD‐free/relapse‐free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22‐0.89; P =.022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26‐0.86; P =.014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes. CONCLUSIONS: The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2‐year OS of 75% and, most recently, an NRM rate of only 17%. In patients with acute lymphocytic leukemia who undergo haploidentical transplantation with posttransplantation cyclophosphamide prophylaxis, significant improvements in leukemia‐free survival and survival are observed in more recently transplanted patients. A nonrelapse mortality rate of 17% is reported in recently transplanted patients with acute lymphocytic leukemia who receive posttransplantation cyclophosphamide prophylaxis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Patients with acute myeloid leukemia (AML) are surviving longer. There are no data on changes in myocardial mechanics from standard of care low‐dose anthracycline‐based induction chemotherapy in older patients with AML. The aim of this study was to demonstrate the potential utility of strain imaging in detecting early changes in left ventricular function in this patient population after induction chemotherapy. Methods: Thirty two patients enrolled in the ECOG‐ACRIN E2906 study (cytarabine and daunorubicin vs clofarabine [Genzyme/Sanofi]) from 2011 to 2014 were evaluated retrospectively. Two‐dimensional transthoracic echocardiography (TTE) imaging with Doppler and two‐dimensional speckle‐tracking echocardiography (2DSTE) using EchoInsight software (Epsilon imaging) were performed before and after induction chemotherapy. Results: Eighteen patients received cytarabine and daunorubicin (7 + 3) and 14 received clofarabine. The clofarabine group was older than the 7 + 3 cohort (67.8 ± 4.0 vs 63.7 ± 3.8, P = .007). There were no other significant differences in cardiac risk factors between groups. The 7 + 3 group had a decrease in average peak systolic global longitudinal (−19.1 ± 2.8 to −17.2 ± 3.0, P = .01) and circumferential strain (−29.4 ± 6.3 to −23.9 ± 4.3, P = .011). These changes were not demonstrated in the clofarabine group and were not associated with a decline in left ventricular ejection fraction (LVEF). Conclusions: In older AML patients, standard cytarabine and daunorubicin chemotherapy causes early changes in global longitudinal and circumferential strain not seen with clofarabine therapy. These findings demonstrate subclinical left ventricular dysfunction after exposure to low cumulative doses of anthracycline‐based induction chemotherapy and may help us better identify those patients at risk for adverse long‐term cardiovascular outcomes. [ABSTRACT FROM AUTHOR]

Summary: Assessment of minimal residual disease (MRD) is being routinely used to assess response in patients with acute myeloid leukaemia (AML). While it is well established that pre‐transplant positive MRD studies predict for relapse in patients transplanted either from matched sibling donors or matched unrelated donors, it is currently unknown whether MRD has comparable prognostic value in haploidentical stem cell transplantation (haplo‐SCT). To this end we performed a retrospective analysis using the Acute Leukaemia Working Party/European Society of Blood and Marrow Transplantation multicentre registry. All adult AML patients with known MRD status at transplant who underwent a first T‐cell replete haplo‐SCT while in remission between 2006 and 2016 were included. Two hundred and sixty‐five MRD‐negative and 128 MRD‐positive patients were assessed. In multivariate analysis, MRD‐negative patients experienced lower relapse incidence and better leukaemia‐free survival (LFS) compared to MRD‐positive patients. Subset analysis for MRD‐positive patients revealed that patients with donors positive for cytomegalovirus experienced decreased relapse rates as well as increased survival. A 6‐month landmark analysis suggests that the clinical benefit of pre‐transplant MRD negativity in terms of relapse, overall survival and LFS is realized at this time point. Pre‐transplant MRD status is potentially a pivotal prognosticator of outcome in AML patients undergoing T‐cell replete haplo‐SCT. [ABSTRACT FROM AUTHOR]

Summary Patients with FLT3‐mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard‐of‐care for patients with R/R FLT3‐mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt‐ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt‐ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt‐ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem‐cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt‐ven (12‐month OS 58.8% [95% CI 39.5%–87.6%]) versus gilteritinib (42.1% [95% CI 24.9%–71.3%] for gilteritinib). Early salvage with gilt‐ven versus any other gilteritinib‐based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt‐ven did not improve remissions or HSCT‐realization rates in patients with R/R FLT3‐mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt‐ven and a survival benefit was shown for gilt‐ven approach when sequenced early for salvage. [ABSTRACT FROM AUTHOR]

Introduction Baseline karyotype at diagnosis remains the pivotal determinant of outcome in patients with acute myeloid leukemia (AML). The Medical Research Council (MRC) prognostic model is currently the benchmark for risk assessment in this patient population. However, the prognostic role of the complete spectrum of chromosomal abnormalities in AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-SCT) is currently unknown. Furthermore, their significance in conjunction with FLT3-ITD status has not been addressed thus far. Methods Using the Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation multicenter database a retrospective analysis was performed to assess the clinical outcomes of AML patients undergoing allo-SCT with respect to specific recurring cytogenetic abnormalities complemented with FLT3-ITD status. We analyzed a cohort consisting of 8558 adult AML patients who underwent allo-SCT in first remission from either a matched sibling or a matched unrelated donor in 2006-2016. Results Patients with inv(3)(q21q26)/t(3;3)(q21;q26), del(5q), monosomy 7, chromosome 17p abnormalities, t(10;11)(p11-14;q13-23), t(6;11)(q27;q23), as well as those patients with a monosomal or complex karyotype experienced significantly inferior leukemia-free survival (LFS) compared to patients with a normal karyotype. Del (9q), trisomy 14, and loss of chromosome X were associated with improved LFS rates. A novel prognostic model delineating 5 distinct groups incorporating cytogenetic complexity and FLT3-ITD status was constructed with significant prognostic implications. Conclusion Our analysis endorses the prognostic significance of the MRC predictive model in patients undergoing allo-SCT in CR1 with some specific modifications. Furthermore, consideration of FLT3-ITD and karyotypic complexity improved the projective capacity of the MRC model in transplanted patients. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented regarding the case of rearrangement of 11q23/mixed-lineage leukemia (MLL) in acute myeloid leukemia (AML) after the application of fludarabine, cyclophosphamide, and rituximab (FCR).

Although having promising anti-myeloma properties, the pan-histone deacetylase inhibitor (HDACi) panobinostat lacks therapeutic activity as a single agent. The aim of the current study was to elucidate the mechanisms underlying multiple myeloma (MM) resistance to panobinostat monotherapy and to define strategies to overcome it. Sensitivity of MM cell lines and primary CD138+ cells from MM patients to panobinostat correlated with reduced expression of the chemokine receptor CXCR4, whereas overexpression of CXCR4 in MM cell lines increased their resistance to panobinostat. Decreased sensitivity to HDACi was associated with reversible G0/G1 cell growth arrest while response was characterized by apoptotic cell death. Analysis of intra-cellular signaling mediators revealed the pro-survival mTOR pathway to be regulated by CXCR4 overexpression. Combining panobinostat with mTOR inhibitor everolimus abrogated the resistance to HDACi and induced synergistic cell death. The combination of panobinostat/everolimus resulted in sustained DNA damage and irreversible suppression of proliferation accompanied by robust apoptosis. Gene expression analysis revealed distinct genetic profiles of single versus combined agent exposure. Whereas panobinostat increased the expression of the cell cycle inhibitor p21, co-treatment with everolimus abrogated the increase in p21 and synergistically downregulated the expression of DNA repair genes and mitotic checkpoint regulators. Importantly, the combination of panobinostat with everolimus effectively targeted CXCR4-expressing resistant MM cells in vivo in the BM niche. In summary, our results uncover the mechanism responsible for the strong synergistic anti-MM activity of dual HDAC and mTOR inhibition and provide the rationale for a novel potential therapeutic approach to treat MM. [ABSTRACT FROM AUTHOR]