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We review knowledge on #socialgenomics in #oncology and discuss the opportunity for application in #AYA oncology research. #AYACSM [ABSTRACT FROM AUTHOR]

The anti-apoptotic protein myeloid cell leukemia-1 (Mcl-1) contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies (NCT03547115). Initially, voruciclib was administered daily continuously on a 28-day cycle (Group I). After two patients with prior allogeneic stem cell transplantation had a dose limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1-14 of a 28-day cycle (Group II). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in Group II was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%) and dyspnea (15%). In AML, one patient achieved a morphologic leukemia-free state and two had stable disease. Voruciclib treatment led to a decrease in MCL1 mRNA expression, downregulation of MYC and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase II. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax in patients with previously treated AML., (Copyright © 2024 American Society of Hematology.)

Abstract: Clonal cytopenia of undetermined significance (CCUS) represents a distinct disease entity characterized by myeloid-related somatic mutations with a variant allele fraction of ≥2% in individuals with unexplained cytopenia(s) but without a myeloid neoplasm (MN). Notably, CCUS carries a risk of progressing to MN, particularly in cases featuring high-risk mutations. Understanding CCUS requires dedicated studies to elucidate its risk factors and natural history. Our analysis of 357 patients with CCUS investigated the interplay between clonality, cytopenia, and prognosis. Multivariate analysis identified 3 key adverse prognostic factors: the presence of splicing mutation(s) (score = 2 points), platelet count of <100 × 109/L (score = 2.5), and ≥2 mutations (score = 3). Variable scores were based on the coefficients from the Cox proportional hazards model. This led to the development of the clonal cytopenia risk score (CCRS), which stratified patients into low- (score of <2.5 points), intermediate- (score of 2.5 to <5), and high-risk (score of ≥5) groups. The CCRS effectively predicted 2-year cumulative incidence of MN for low- (6.4%), intermediate- (14.1%), and high-risk (37.2%) groups, respectively, by the Gray test (P < .0001). We further validated the CCRS by applying it to an independent CCUS cohort of 104 patients, demonstrating a c-index of 0.64 (P = .005) in stratifying the cumulative incidence of MN. Our study underscores the importance of integrating clinical and molecular data to assess the risk of CCUS progression, making the CCRS a valuable tool that is practical and easily calculable. These findings are clinically relevant, shaping the management strategies for CCUS and informing future clinical trial designs., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Introduction: Relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) remains a therapeutic challenge. Preclinical data in both B- and T-ALL suggests synergy of venetoclax (VEN) with vincristine (VCR). We designed a phase I/II trial (EA9152) of the combination of L-VCR and VEN for patients with r/r B-or T-cell ALL or LL. Here, we report the safety and efficacy outcomes of the phase I portion of this trial (NCT03504644)., Methods: In a 3+3 dose escalation design, r/r ALL subjects were given single-agent VEN doses reaching 400, 600, or 800 mg for the three respective dose levels. Weekly L-VCR at 2.25 mg/m 2 IV was started on D15 of cycle 1. The primary phase I objective was to determine the maximum tolerated dose (MTD) of the combination., Results: Among the 18 patients in phase I, grade ≥ 3 treatment-related adverse events were reported in 89% of treated patients. Two patients (two of three) at dose level 3 experienced dose-limiting toxicities. Therefore, the MTD of the combination was determined to be dose level 2 (VEN 600 mg). Twenty-two percent of evaluable patients ( N  = 4) achieved a complete response, with two of them showing no evidence of measurable residual disease (MRD)., Conclusion: The combination of VEN and L-VCR was found to be safe for patients with r/r ALL and encouraging preliminary efficacy, including MRD negative responses. With the removal of L-VCR from the US market, the phase 2 portion of this trial is actively enrolling with vincristine sulfate., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Many older adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have a relapse despite having a measurable residual disease (MRD)-negative complete remission with combination chemotherapy. The addition of blinatumomab, a bispecific T-cell engager molecule that is approved for the treatment of relapsed, refractory, and MRD-positive BCP-ALL, may have efficacy in patients with MRD-negative remission., Methods: In a phase 3 trial, we randomly assigned patients 30 to 70 years of age with BCR::ABL1 -negative BCP-ALL (with :: indicating fusion) who had MRD-negative remission (defined as <0.01% leukemic cells in bone marrow as assessed on flow cytometry) after induction and intensification chemotherapy to receive four cycles of blinatumomab in addition to four cycles of consolidation chemotherapy or to receive four cycles of consolidation chemotherapy alone. The primary end point was overall survival, and relapse-free survival was a secondary end point., Results: The data and safety monitoring committee reviewed the results from the third efficacy interim analysis and recommended that they be reported. Complete remission with or without full count recovery was observed in 395 of 488 enrolled patients (81%). Of the 224 patients with MRD-negative status, 112 were assigned to each group. The characteristics of the patients were balanced between the groups. At a median follow-up of 43 months, an advantage was observed in the blinatumomab group as compared with the chemotherapy-only group with regard to overall survival (at 3 years: 85% vs. 68%; hazard ratio for death, 0.41; 95% confidence interval [CI], 0.23 to 0.73; P = 0.002), and the 3-year relapse-free survival was 80% with blinatumomab and 64% with chemotherapy alone (hazard ratio for relapse or death, 0.53; 95% CI, 0.32 to 0.87). A higher incidence of neuropsychiatric events was reported in the blinatumomab group than in the chemotherapy-only group., Conclusions: The addition of blinatumomab to consolidation chemotherapy in adult patients in MRD-negative remission from BCP-ALL significantly improved overall survival. (Funded by the National Institutes of Health and others; E1910 ClinicalTrials.gov number, NCT02003222.)., (Copyright © 2024 Massachusetts Medical Society.)

There have been major paradigm shifts in the treatment of Philadelphia chromosome negative (Ph-) acute lymphoblastic leukemia (ALL) in the last decade with the introduction of new immunotherapies and targeted agents, adoption of pediatric-type chemotherapy protocols in younger adults as well as chemotherapy light approaches in older adults and the incorporation of measurable residual disease (MRD) testing to inform clinical decision making. With this, treatment outcomes in adult Ph- ALL have improved across all age groups. However, a subset of patients will still develop relapsed disease, which can be challenging to treat and associated with poor outcomes. Here we review the treatment of Ph- ALL in both younger and older adults, including the latest advancements and future directions., Competing Interests: Declaration of competing interest Shira Dinner has the following conflicts of interest to disclose: Pfizer, Kite, Novartis, BMS, and Rigel. Madelyn Burkart has no conflicts of interest to disclose related to this manuscript., (Copyright © 2023. Published by Elsevier Ltd.)

Abstract: A041202 (NCT01886872) is a phase 3 study comparing bendamustine plus rituximab (BR) with ibrutinib and the combination of ibrutinib plus rituximab (IR) in previously untreated older patients with chronic lymphocytic leukemia (CLL). The initial results showed that ibrutinib-containing regimens had superior progression-free survival (PFS) and rituximab did not add additional benefits. Here we present an updated analysis. With a median follow-up of 55 months, the median PFS was 44 months (95% confidence interval [CI], 38-54) for BR and not yet reached in either ibrutinib-containing arm. The 48-month PFS estimates were 47%, 76%, and 76% for BR, ibrutinib, and IR, respectively. The benefit of ibrutinib regimens over chemoimmunotherapy was consistent across subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and immunoglobulin heavy chain variable region (IGHV). No significant interaction effects were observed between the treatment arm and del(11q), the complex karyotype, or IGHV. However, a greater difference in PFS was observed among the patients with TP53 abnormalities. There was no difference in the overall survival. Notable adverse events with ibrutinib included atrial fibrillation (afib) and hypertension. Afib was observed in 11 patients (pts) on BR (3%) and 67 pts on ibrutinib (18%). All-grade hypertension was observed in 95 pts on BR (27%) and 263 pts on ibrutinib (55%). These data show that ibrutinib regimens prolong PFS compared with BR for older patients with treatment-naïve CLL. These benefits were observed across subgroups, including high-risk groups. Strikingly, within the ibrutinib arms, there was no inferior PFS for patients with abnormalities in TP53, the highest risk feature observed in CLL. These data continue to demonstrate the efficacy of ibrutinib in treatment-naïve CLL.

Background: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone (D-RVd) in the GRIFFIN study improved the stringent complete response rate by the end of consolidation in transplantation-eligible patients with newly diagnosed multiple myeloma. Here, we report the findings of the predefined final analysis., Methods: GRIFFIN was an open-label, randomised, active-controlled, phase 2 trial done in 35 research centres in the USA. Patients had newly diagnosed multiple myeloma with measurable disease by M protein or free light chain, were aged 18-70 years, had an ECOG performance score of 0-2, and were eligible for autologous haematopoietic stem-cell transplantation (HSCT). Patients were randomly assigned (1:1) to four D-RVd or RVd induction cycles, autologous HSCT, two D-RVd or RVd consolidation cycles, and lenalidomide with or without daratumumab maintenance therapy for 2 years. Patients received 21-day cycles of oral lenalidomide (25 mg on days 1-14), subcutaneous bortezomib (1·3 mg/m 2 on days 1, 4, 8, and 11), oral dexamethasone (40 mg weekly) with or without intravenous daratumumab (16 mg/kg weekly, cycles 1-4; day 1, cycles 5-6). Maintenance therapy (28-day cycles) was oral lenalidomide (10 mg on days 1-21) with or without daratumumab (16 mg/kg intravenously every 4 or 8 weeks, or 1800 mg subcutaneously monthly). Patients could continue lenalidomide maintenance after study treatment completion. The primary endpoint was stringent complete response rate by the end of consolidation in the response-evaluable population, and has already been reported. Here we report updated stringent complete response rates and secondary outcomes including progression-free survival and overall survival. The trial is registered with ClinicalTrials.gov (NCT02874742) and ended on April 8, 2022., Findings: Between Dec 20, 2016, and April 10, 2018, 104 patients were randomly assigned to the D-RVd group and 103 were randomly assigned to the RVd group; most patients were White (85 [82%] in the D-RVd group and 76 [74%] in the RVd group) and male (58 [56%] in the D-RVd group and 60 [58%] in the RVd group). At a median follow-up of 49·6 months (IQR 47·4-52·1), D-RVd improved rates of stringent complete response (67 [67%] of 100] vs 47 [48%] of 98]; odds ratio 2·18 [95% CI 1·22-3·89], p=0·0079), and 4-year progression-free survival was 87·2% (95% CI 77·9-92·8) for D-RVd versus 70·0% (95% CI 55·9-80·3) for RVd, with a hazard ratio (HR) of 0·45 (95% CI 0·21-0·95, p=0·032) for risk of disease progression or death with D-RVd. Median overall survival was not reached for either group (HR 0·90 [95% CI 0·31-2·56], p=0·84). The most common grade 3-4 treatment-emergent adverse events in the D-RVd versus RVd groups were neutropenia (46 [46%] of 99 vs 23 [23%] of 102), lymphopenia (23 [23%] vs 23 [23%]), leukopenia (17 [17%] vs eight [8%]), thrombocytopenia (16 [16%] vs nine [9%]), pneumonia (12 [12%] vs 14 [14%]), and hypophosphataemia (ten [10%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 46 (46%) of 99 patients in the D-RVd group and in 53 (52%) of 102 patients in the RVd group. One patient in each treatment group reported a treatment-emergent adverse event that resulted in death (bronchopneumonia in the D-RVd group; cause unknown in the RVd group); neither was related to study treatment. No new safety concerns occurred with maintenance therapy., Interpretation: Addition of daratumumab to RVd improved the depth of response and progression-free survival in transplantation-eligible patients with newly diagnosed multiple myeloma. These results justify further evaluation in phase 3 studies., Funding: Janssen Oncology., Competing Interests: Declaration of interests PMV served as a consultant for, served on an advisory board for, and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Novartis, Oncopeptides, Pfizer, Sanofi, and Secura Bio. DWS served as a consultant or in an advisory role for GlaxoSmithKline, AbbVie, Sanofi, Bristol Myers Squibb, Janssen, and Pfizer. JLK served as a consultant for AbbVie, Bristol Myers Squibb, Janssen, Roche/Genentech, and Tecnopharma; received research funding from AbbVie, Amgen, Bristol Myers Squibb, Fortis Therapeutics, Heidelberg Pharma, Janssen, Novartis, Roche/Genentech, Sutro Biopharma, and Takeda; received honoraria from AbbVie, Janssen, Roche/Genentech, and Tecnopharma; and served on an advisory board for Incyte and TG Therapeutics. BR received honoraria from Incyte, Bristol Myers Squibb, and PharmaEssentia. CR served as a consultant and on a speakers bureau for Janssen, Takeda, Bristol Myers Squibb, Amgen, and Karyopharm Therapeutics. ACh served as a consultant or in an advisory role for Amgen, Janssen Oncology, Seattle Genetics, Karyopharm Therapeutics, Genzyme, Oncopeptides, Takeda, Antengene, GlaxoSmithKline, Secura Bio, Shattuck Labs, Genentech, AbbVie, and Bristol Myers Squibb/Celgene; and received research funding from Celgene, Janssen, Amgen, Seattle Genetics, Takeda, and Pharmacyclics. RS served as a consultant or in an advisory role for Sanofi/Aventis, Janssen Oncology, and Oncopeptides; and received research funding from Sanofi. LJC served as a consultant or in an advisory role for AbbVie, Amgen, Celgene, Karyopharm Therapeutics, and Sanofi; served on a speakers bureau for Amgen and Sanofi; received honoraria from Amgen, Celgene, Janssen, Karyopharm Therapeutics, and Sanofi; and received research funding from Amgen and Janssen. LDA served as a consultant or in an advisory role for and received honoraria from GlaxoSmithKline, Bristol Myers Squibb, Celgene, Janssen, Amgen, Oncopeptides, Karyopharm Therapeutics, AbbVie, BeiGene, Cellectar, and Sanofi. NS served as a consultant for Amgen, CareDx, CSL Behring, GlaxoSmithKline, Indapta Therapeutics, Karyopharm Therapeutics, Kite, Oncopeptides, and Sanofi; and received research funding from bluebird bio, Bristol Myers Squibb/Celgene, Janssen, Nektar, Poseida, Precision BioSciences, Sutro Biopharma, and TeneoBio. NB received honoraria from OncLive; and served as a consultant or in an advisory role and on a speakers bureau for Janssen, Sanofi Genzyme, and Oncopeptides. YAE received research funding, received honoraria, and served on a speakers bureau for Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Pfizer, Sanofi, and Bristol Myers Squibb. SAH served as a consultant for Bristol Myers Squibb/Celgene, Janssen, Takeda, Oncopeptides, GlaxoSmithKline, Secura Bio, and Sanofi; and received research funding from Oncopeptides. CC received honoraria from Takeda, Bristol Myers Squibb, Pfizer, and Janssen. AJ served as a consultant or in an advisory role for and received honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Karyopharm Therapeutics, and Sanofi. TMW served as a consultant for Janssen, Carevive, and Sanofi. RZO holds stock and other ownership interests in Asylia Therapeutics; received honoraria from and served as a consultant or in an advisory role for AbbVie, Biotheryx, Bristol Myers Squibb, GlaxoSmithKline, Karyopharm Therapeutics, Meridian Therapeutics, Monte Rosa Therapeutics, Neoleukin Corporation, Oncopeptides, Regeneron, Sanofi, and Takeda; received research funding from Asylia Therapeutics, Biotheryx, and Heidelberg Pharma; and holds patents, royalties, or other intellectual property for Asylia Therapeutics. KHS served on an advisory board for AbbVie, Amgen, Bristol Myers Squibb, GlaxoSmithKline, and Janssen; received research funding from AbbVie and Karyopharm Therapeutics; served on a speakers bureau for Adaptive Biotechnologies Corporation, Amgen, Bristol Myers Squibb, Janssen, and Sanofi Genzyme; served as a consultant for Adaptive Biotechnologies Corporation, Novartis, and Sanofi Genzyme; and received honoraria from Karyopharm Therapeutics. AJC served as a consultant for Janssen, Bristol Myers Squibb, EUSA Pharma, AbbVie, Sanofi, Cellectar, GlaxoSmithKline, and Secura Bio; and received research funding from Janssen, AbbVie, Sanofi, Harpoon, Bristol Myers Squibb, Adaptive Biotechnologies, and Nektar. SD is the Executive Officer for Alliance Foundation Trials for Clinical Trials. HP, ACo, and SP are employees of and hold stock and other ownership in Janssen. TSL is an employee of Janssen. SZU served as a consultant or in an advisory role for Celgene, Amgen, Janssen Oncology, Seattle Genetics, Takeda, GlaxoSmithKline, Karyopharm Therapeutics, AbbVie, SkylineDx, Merck, Oncopeptides, Genentech, Gilead Sciences, and Bristol Myers Squibb/Celgene; served on a speakers bureau for Takeda, Amgen, Janssen Oncology, Sanofi, and Bristol Myers Squibb/Celgene; and received research funding from Celgene and Array BioPharma. PGR received research funding from Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, and Karyopharm Therapeutics; and served on an advisory committee for Oncopeptides, Celgene/Bristol Myers Squibb, Takeda, Karyopharm Therapeutics, Janssen, Sanofi, Secura Bio, GlaxoSmithKline, Regeneron, AstraZeneca, and Protocol Intelligence. JL and NN declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

We conducted a multi-center study to analyze factors predicting survival among patients with TP53-mutated (m) AML receiving allogeneic hematopoietic stem cell transplant (allo-HSCT) in the recent era. Out of 370 TP53m AML patients, 68 (18%) patients were bridged to allo-HSCT. The median age of the patients was 63 years (range, 33-75), 82% of patients had complex cytogenetics and 66% of patients had multi-hit TP53m. Forty three percent received myeloablative conditioning and 57% received reduced intensity conditioning. The incidence of acute graft versus host disease (GVHD) was 37% and chronic GVHD was 44%. The median event-free survival (EFS) from the time of allo-HSCT was 12.4 months (95% CI: 6.24-18.55) and median overall survival (OS) was 24.5 months (95% CI: 21.80-27.25). In multivariate analysis utilizing variables that showed significance in univariate analysis, complete remission at day 100 post allo-HSCT retained significance for EFS (HR: 0.24, 95% CI: 0.10-0.57, p = 0.001) and OS (HR: 0.22, 95% CI: 0.10-0.50, p ≤ 0.001). Similarly, occurrence of chronic GVHD retained significance for EFS (HR: 0.21, 95% CI: 0.09-0.46, p ≤ 0.001) and OS (HR: 0.34, 95% CI: 0.15-0.75, p = 0.007). Our report suggests that allo-HSCT offers the best opportunity to improve long-term outcome among patients with TP53m AML., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1., Methods: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m 2 ) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574., Findings: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response., Interpretation: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies., Funding: Forma Therapeutics., Competing Interests: Declaration of interests JMW has received research funding from and was a board/advisory committee member for Takeda; has received research funding from Immune System Key Ltd and Takeda; and was a board/advisory committee member for Genentech, Rafael Pharma, Reven Pharma, and Celgene/Bristol-Myers Squib (BMS). MRB has received research funding for her institution from AbbVie, Forma Therapeutics, Kite, Kura, and Takeda. JY has received research funding from Seattle Genetics, Janssen, AROG, Loxo Oncology, and Agios. TP is a consultant to Curios and Daiichi; and has received research funding, is a consultant to, and has recently become an employee of BMS. SL is a consultant to AstraZeneca, BMS, Helsinn, Innate Pharma, and PIN Pharma, and has recently become an employee of Janssen Research and Development. GJS has received research funding, honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for Agios, Gamida, Gilead, and Incyte; has received research funding, honoraria, is on the speakers’ bureau for, holds stock in, and is a board/advisory committee member for Amgen and BMS; has received research funding, honoraria, and is a board/advisory committee member for Novartis, Ono Pharma, and AVM Biotech; has received honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for GlaxoSmithKline (GSK); has received research funding and holds stock in Janssen/Johnson & Johnson; has received research funding and is on the speakers’ bureau for AbbVie, Astellas, Celgene, Karyopharm, and Stemline; has received honoraria and is a board/advisory committee member for AstraZeneca; and has received research funding from Actinium, Actuate, Ambit, Cellectis, Cyclacel, Constellation, Daiichi-Sankyo, Deciphera, DeltaFly, Forma Therapeutics, FujiFilm, Genentech/Roche, Geron, Glycomimetics, Kura Oncology, Mateon, Medimmune, Millennium; Onconova, Pfizer, PrECOG, RegImmune, Sangamo, Samus, Sellas, Tolero, and Trovagene. SND has no conflicts to disclose. AP has received honoraria from and is a consultant to AbbVie; is a consultant to Gilead; and has received honoraria from Astellas, Agios, Pfizer, and Jazz Pharmaceuticals. PM has received research funding from, is a consultant to, and is on the speakers’ bureau for BMS; and is a consultant to Forma Therapeutics, Syndax, and Kura Oncology. ESW is a consultant to and a board/advisory committee member for AbbVie and Gilead; is a consultant to, and is on the speakers’ bureau for Astellas, Pfizer, and Stemline; is a board/advisory committee member for Rafael Pharmaceuticals; is a consultant to Amgen, BMS, GSK, Janssen, Jazz Pharmaceuticals, Kite, Mana Therapeutics, Novartis, PharmaEssentia; and is on the speakers’ bureau for Kura Oncology and Dava Oncology. KPS has received research funding and honoraria from, is a consultant to, and is on the speakers’ bureau of Jazz Pharmaceuticals; has received honoraria from, is a consultant to, and is on the speakers’ bureau for Novartis; has received honoraria from and is on the speakers’ bureau for Incyte; and has received research funding from Rafael, Glycomimetics, and Celgene. AHW has received research funding, honoraria, is a consultant to, is on the speakers’ bureau for, and is a board/advisory committee member for Astellas; has received research funding, honoraria, is on the speakers’ bureau for, and is a board/advisory committee member for AbbVie/Genentech, Amgen, Celgene/BMS, and Novartis; has received research funding, honoraria, is a consultant to, is a board/advisory committee member for Servier and Syndax; has received honoraria, is a consultant to, and is a board/advisory committee member for Janssen and Gilead; has received honoraria, and is a board/advisory committee member for MacroGenetics and Pfizer; has received research funding and honoraria from, and is a board/advisory committee member for AstraZeneca; has received research funding from Astex; and is an employee of the Walter and Eliza Hall Institute and is eligible for a fraction of the royalty stream related to venetoclax. SDB has received honoraria and research funding from Forma Therapeutics, has received honoraria, research funding, and is a consultant to Agios; has received honoraria, is a consultant to, and is on the speakers’ bureau for Celgene; has received honoraria and is a consult to Astellas, Daiichi Sankyo, Syros, AbbVie, Bayer, and Janssen; has received honoraria from Seattle Genetics; and is a consultant to Pierre Fabre, Novartis, Pfizer, and Servier. MA is a consultant to and a board/advisory committee member for BMS-Celgene and Novartis; and is a consultant to Astellas, Jazz Pharmaceuticals, and Pfizer. WD is a consultant to Janssen, BMS, and BeiGene. APS has received honoraria from AbbVie, Novartis, and Amgen; and is a board/advisory committee member for Pfizer. CR has received research funding from MaaT Pharma; has received honoraria from Incyte and Janssen; has received honoraria and has membership on an entity's board of directors or advisory committee for MacroGenics, Pfizer, and Takeda; has received honoraria, research funding, and has membership on an entity's board of directors or advisory committee for Amgen, Astellas, BMS/Celgene and Roche; and has received honoraria, research funding, is a consultant to, and has membership on an entity's board of directors or advisory committee for AbbVie, Daiichi Sankyo, Jazz Pharmaceuticals, and Novartis. BAJ has received research funding to his institution, is a consultant to, and is a board/advisory committee member for AbbVie, BMS, Genentech/Roche, Jazz Pharmaceuticals, Pfizer, and Treadwell; has received research funding to his institution, is a consultant to, and is a data monitoring committee member for Gilead; has received research funding to his institution, is a consultant to, and is a protocol steering committee member for GlycoMimetics; is a consultant to and a board/advisory committee member for Servier, Takeda, and Tolero; has received travel reimbursement from AbbVie; has received research funding to his institution from 47, Accelerated Medical Diagnostics, Amgen, AROG, Celgene, Daiichi Sankyo, F. Hoffman-La-Roche, Forma Therapeutics, Hanmi, Immune-Onc, Incyte, Loxo Oncology, LP Therapeutics, Pharmacyclics, and Sigma Tau. PBF has received research funding from Forma Therapeutics, Astex Pharmaceuticals, and Incyte. CM has received honoraria from Astellas, BMS, and Celgene. PK, JS, SF, SMG, and JB are employees of and hold stock in Forma Therapeutic. PH was an employee of and holds stock in Forma Therapeutics; and is an employee of and holds stock in Kymera Therapeutics. HM was an employee of and holds stock in Forma Therapeutics. JEC has received research funding for his institution from, and is a consultant to BMS, Novartis, Pfizer, Takeda, Daiichi, Jazz Pharmaceuticals, Merus, and Forma Therapeutics; has received research funding for his institution from Astellas and Amphivena; and is a consultant to BiolineRx and Bioptah. All authors had access to and had the opportunity to review the study data and are responsible for data analysis and interpretation. All authors participated in writing of the report (including original draft, review, and editing). All authors attest to study completeness, and accuracy of the data and data analysis. JMW and JEC participated in analysis of the data, and directly accessed and verified the underlying data reported in the manuscript. JMW had final responsibility for the decision to submit for publication., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36-59%) and 58% (95% CI: 45-69%), respectively. The cumulative incidence of GIII-IV aGVHD at 3 months was 9.9% (95% CI: 5.0-16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7-45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5-89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8-75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the "real-world" setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD-). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD- at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest "real-world" experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study., (© 2020 by The American Society of Hematology.)

Moxetumomab pasudotox (MP) is an immunotoxin that recently received US Food and Drug Administration (FDA) approval for the treatment of hairy cell leukemia (HCL) that has failed at least 2 prior lines of therapy, including a purine analog. MP is a recombinant immunotoxin that consists of an anti-CD22 immunoglobulin variable domain genetically joined to Pseudomonas exotoxin (PE38). Unlike most antibody-drug conjugates, which use a chemical linker, recombinant DNA techniques are used to produce MP. MP and its predecessor, BL22, were initially developed to treat non-Hodgkin lymphoma, acute lymphoblastic leukemia, and HCL. However, MP was found to be particularly effective in HCL due to the high level of CD22 cell-surface expression. The recent pivotal phase 3 trial of MP in relapsed/refractory HCL demonstrated a durable complete remission rate of 30%, and 85% of complete responders achieved minimal residual disease negativity, which is associated with improved disease-free survival outcomes in HCL. In addition to an exceptional depth of response, MP appears to be less immunosuppressive than purine analogs. MP is generally well tolerated but has unique toxicities, including capillary leak syndrome and hemolytic uremic syndrome, which are poorly understood. This review will encompass the preclinical and clinical development of MP, with particular attention to its current indication in HCL., (© 2019 by The American Society of Hematology.)

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

Immunoglobulin light chain amyloidosis remains incurable despite recent therapeutic advances, and is particularly difficult to treat in patients with amyloid cardiomyopathy. Based on evidence of activity in multiple myeloma, we designed a pilot study of an oral regimen of lenalidomide in combination with dexamethasone and low-dose melphalan in order to evaluate its safety and efficacy in patients with amyloidosis, including those with advanced cardiac involvement. Twenty-five patients were enrolled. Ninety-two percent of patients had cardiac involvement by amyloidosis, and 36% of patients met the criteria for Mayo Clinic cardiac stage III disease. Patients received up to nine cycles of treatment, consisting of lenalidomide 10 mg/day orally on days 1 - 21 (28-day cycle); melphalan 0.18 mg/kg orally on days 1-4; and dexamethasone 40 mg orally on days 1, 8, 15, and 22. High rates (33%) of cardiac arrhythmias and low rates of treatment completion (12.5%) were observed. Ten patients died during the study, all within the first several months of treatment due to acute cardiac events. The overall hematologic response rate was 58%, however organ responses were seen in only 8% of patients. The overall survival rate at 1 year was 58%. While we confirmed the hematologic response rates observed with similar regimens, front-line treatment with melphalan, lenalidomide and dexamethasone was toxic, ineffective, and did not alter survival outcomes for patients with high-risk cardiac disease. Our data highlight the importance of developing novel treatment approaches for amyloid cardiomyopathy. This trial was registered at www.clinicaltrials.gov (NCT00890552).