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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]

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]

Summary: Belantamab mafodotin, an immuno‐conjugate targeting B‐cell maturation antigen, showed single‐agent activity in phase 1 and 2 studies, and was recently approved for heavily pretreated relapsed/refractory multiple myeloma (RRMM) patients. Real‐world data and long‐term follow‐up are scarce. We conducted a multisite retrospective study aimed to assess safety and efficacy of belantamab mafodotin monotherapy administered via the GSK expanded access compassionate care programme. One‐hundred and six RRMM patients were treated with belantamab mafodotin between July 2019 and March 2021. The median age was 69.4 years. Patients were heavily pretreated with a median of six (range 2–11) prior therapy lines. Major adverse effects included ocular toxicity (keratopathy 68.4%, grade ≥3: 40.5%; blurred vision 36.8%, grade ≥3: 6.3%), thrombocytopenia (27.4%, grade ≥3: 17.9%) and infections (11.3%, grade ≥3: 7.5%). Median follow‐up time was 11.9 [95% confidence interval (CI) 10.0–13.8] months. Overall response rate was 45.5%. Median progression‐free survival was 4.7 (95% CI 3.5–5.9) months in the entire cohort and 8.8 (95% CI 6.6–10.9) months among responders. Median overall survival was 14.5 (95% CI 9.5–19.6) months, and not reached for responders. To conclude, in a real‐world setting, belantamab mafodotin monotherapy showed efficacy comparable with the prospective clinical trials, with a tolerable toxicity profile. [ABSTRACT FROM AUTHOR]

Objectives: Midostaurin, a multikinase and FLT3 inhibitor, is the first non‐chemotherapy agent approved and widely adopted for the treatment of FLT3‐ITD acute myeloid leukemia (AML). Yet, its role in improving survival of patients referred to allogeneic stem cell transplantation (allo‐SCT) in first complete remission (CR1) needs to be defined. Methods: This multicenter study retrospectively evaluated the outcome of 119 FLT3‐ITD AML patients [59 (49.6%) males and 60 females] intensively treated between 2015 and 2019 at five Israeli centers. In our cohort, allo‐SCT in CR1 was widely implemented (47%) and patient stratification was based on the current allelic ratio (AR) cutoff of 0.5. Results: Ninety‐eight patients (82.3%) achieved CR1/CR with incomplete count recovery (CRi). Death during induction was reported in 7 (5.9%) patients. In multivariate analysis, midostaurin use and allo‐SCT in CR1 were the most significant factors affecting overall survival (OS). Midostaurin incorporation in chemotherapy regimens significantly improved CR + CRi rates (P =.002), reduced relapse rates (P =.02), and was remarkably advantageous for high‐AR patients (2‐year OS 82%). In low‐AR patients, the midostaurin effect was much less prominent. Conclusions: Our results demonstrate benefits of midostaurin incorporation in intensive chemotherapy regimens, particularly for high‐AR AML patients to whom it should be offered along with allo‐SCT in CR1. [ABSTRACT FROM AUTHOR]

Summary: Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37–144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five‐year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse. [ABSTRACT FROM AUTHOR]

Carfilzomib has been established in previous years as a treatment for patients with relapsed and/or refractory multiple myeloma (RR-MM). A retrospective multicentre study to evaluate the clinical use of carfilzomib for RR-MM outside of a clinical trial setting was conducted by our group. One hundred and thirty-five patients were included. All patients had been previously exposed to bortezomib and 93% had also been treated with lenalidomide. The vast majority of patients received carfilzomib as part of a two- or three-drug combination. The overall response rate was 47·2%. Multivariate analysis revealed bortezomib resistance, lenalidomide resistance and albumin <35 g/l to negatively impact the likelihood of achieving response. The median duration of response was 8·4 months, and was significantly higher in patients receiving three-drug combination and patients presenting without extramedullary disease. The median progression-free survival and overall survival for the entire cohort was 4·9 months (95% confidence interval [CI] 3·8-6·4) and 12·2 months (95% CI 9-not reached), respectively. Toxicity was manageable, although treatment-related death was seen in 5% of patients. In the setting of progressive multiple myeloma, carfilzomib in a combination regimens yields effective results with a manageable toxicity. [ABSTRACT FROM AUTHOR]

Very little is known about secondary acute lymphoblastic leukaemia (s- ALL). This retrospective analysis studied a cohort of s- ALL patients treated at a single centre between 1994 and 2013, while comparing therapy-associated ALL (t- ALL) and antecedent malignancy ALL (am- ALL) patients. Thirty-two patients with s- ALL were identified. The overall incidence was 9·4% among ALL adults while T-cell s- ALL was rare (12% of s- ALLs). The median time interval between two malignant diagnoses was 5·3 years (range: 0·1-28). In contrast to previous reports, most of the s- ALLs were CD10 + and without KMT2A ( MLL) abnormalities. The overall survival ( OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients ( n = 23, 72%) received prior chemo-/radio-therapy for their first malignancy (t- ALL) and only 9 (28%) did not (am- ALL). No significant difference was found in the incidence of B-/T- lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia-positive ALL, nor in the rates of complete remission ( P = 0·55) and OS ( P = 0·97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s- ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s- ALL. [ABSTRACT FROM AUTHOR]

Evaluation of early response during induction therapy for acute myeloid leukemia (AML) is used for prognostication and re-induction strategy, yet the optimal evaluation time point is unknown. Clearance of bone marrow (BM) blasts by day 14 of therapy does not ensure remission; thus, some patients requiring re-induction are neglected. This study aimed to examine the role of earlier BM evaluation during induction for predicting remission and overall survival. Results of BM testing on the 5th and 14th day of intensive induction were prospectively compared in 127 adult patients with AML. Re-induction was given, based on Day 14 results, to 25 patients. Reduction of the BM blast count to <5% as early as by the fifth day of induction was more specifically associated with the achievement of remission compared to Day 14 (88.2% vs. 60%, respectively). Rapid responders have a better 3-year overall survival (OS). Day 5 results are a stronger predictor of OS by multivariate analysis and better segregate long-term survivors than the Day 14th BM count (66% vs. 30%, P = 0.0001 and 48% vs. 37%, respectively, P = 0.04). The Day 5 evaluation of BM carries significant clinical information. The benefit of prescribing re-induction based on such early evaluation should be prospectively studied., (© 2015 Wiley Periodicals, Inc.)