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Venetoclax-azacitidine is the standard of treatment for unfit acute myeloid leukemia patients. In the VIALE-A study, treatment was given until progression but there are no data on its optimal duration for responding patients who do not tolerate indefinite therapy. We retrospectively analyzed the outcome of patients who discontinued venetoclax or venetoclax-azacitidine due to poor tolerance. Sixty-two newly diagnosed (ND) AML patients and 22 patients with morphological relapse or refractory AML were included. In the ND cohort (n = 62), 28 patients stopped venetoclax and azacitidine and 34 patients continued azacitidine monotherapy. With a median follow-up of 23 months (IQR, 20-32), median overall survival and treatment-free survival were 44 (IQR, 16-NR) and 16 (IQR, 8-27) months, respectively. Patients who stopped both treatments and those who continued azacitidine monotherapy had the same outcomes. Negative minimal residual disease was associated with a 2-year treatment-free survival of 80%. In the RR cohort (n = 22), median overall survival and treatment-free survival were 19 (IQR, 17-31) and 10 (IQR, 5-NR) months, respectively. Prior number of venetoclax-azacitidine cycles and IDH mutations were associated with increased overall survival. The only factor significantly impacting treatment-free survival was the number of prior cycles. This study suggests that patients who discontinued treatment in remission have favorable outcomes supporting the rationale for prospective controlled trials., (© 2024 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies., Patients and Methods: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle., Results: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway., Conclusion: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations., Competing Interests: Disclosure MYK is a consultant for AbbVie, Inc., Genentech, Inc., and F. Hoffmann La-Roche; is an advisory board member for F. Hoffmann La-Roche; holds shares from Reata Pharmaceuticals; has received honoraria from Amgen, AbbVie, Inc., and Genentech, Inc.; and has received research funding from AbbVie, Inc., Genentech, Inc., Eli Lilly, Cellectis, Calithera, Stemline, Threshold, Flexus Biosciences, Novartis, Ablynx, and Agios. MD, MO, JW, WH, DD, and HH are employees of Genentech, Inc. and may hold Roche stock or stock options. NGD has received research funding from Daiichi Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Inc., Astellas, Daiichi Sankyo, AbbVie, Inc., Hanmi, Trovagene, Fate Therapeutics, Amgen, Novimmune, GlycoMimetics, Trillium, Kite Pharma, Aptose, Shattuck Labs, KAHR, ArcellX, Sanofi, Sumitomo, and ImmunoGen; and has served in a consulting or advisory role for Daiichi Sankyo, Bristol-Myers Squibb, Arog Pharmaceuticals, Pfizer, Novartis, Jazz Pharmaceuticals, Celgene, AbbVie, Inc., Astellas, Genentech, Inc., Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck Labs, ArcellX, Kite Pharma, Sumitomo, Caribou Biosciences, Sanofi, Rigel, Aptose, KURA, GlycoMimetics, and Agios. JSG has received research funding (for trials) from AbbVie, Inc., Genentech, Inc., Pfizer, Prelude, and AstraZeneca; and has served on advisory boards for AbbVie, Inc., Astellas, Bristol-Myers Squibb and Servier. BAJ is a consultant/advisor for AbbVie, Inc., Bristol-Myers Squibb, Daiichi Sankyo, Genentech, Inc., Gilead, GlycoMimetics, Jazz Pharmaceuticals, Kymera, Pfizer, Rigel, Servier, and Takeda; protocol steering committee for GlycoMimetics; data monitoring committee for Gilead; travel reimbursement/support from Rigel; and research funding to his institution from AbbVie, Inc., Amgen, Arog Pharmaceuticals, Aptose, BMS, Celgene, Daiichi Sankyo, F. Hoffmann-La Roche, Forma Therapeutics, Forty-Seven, Genentech, Inc./Roche, Gilead, GlycoMimetics, Hanmi, Immune-Onc, Incyte, Jazz Pharmaceuticals, Loxo Oncology, Pfizer, Pharmacyclics, Sigma Tau, and Treadwell. KWLY is a consultant for Astex, Bristol-Myers Squibb/Celgene, F. Hoffmann-La Roche, Novartis, Otsuka, Paladin, Pfizer, Shattuck Labs, Taiho, and Takeda; has received honorarium from AbbVie, Inc. and Novartis; and has received research funding from Astex, Forma Therapeutics, F. Hoffmann-La Roche, Genentech, Inc., Geron, Janssen, Jazz Pharmaceuticals, MedImmune, Novartis, Onconova, and Tolero. KRK, NV, SP, AT, AP, PF, and GV declare no competing financial interests. SA reports non-financial support from Roche/Genentech, Inc. during the conduct of the study; and has received personal fees from Roche Canada, Pfizer, Bristol-Myers Squibb, Palladin, and Lundbeck outside of the submitted work. GJR consulted for AbbVie, Inc., Amgen, Argenx, AstraZeneca, Bluebird Bio, Blueprint Medicines, Bristol-Myers Squibb, Caribou Biosciences, Celgene, Daiichi Sankyo, Ellipses Pharma, GlaxoSmithKline, Janssen, Jasper Pharmaceuticals, Jazz Pharmaceuticals, Molecular Partners, Novartis, Pfizer, Roche, Syndax, Takeda (IRC Chair), and Telix Pharma; and has received research funding from Janssen. DAP has received research funding from AbbVie, Inc. and has served as a consultant or advisory board member for AbbVie, Inc. and Genentech, Inc. JMB consulted for AbbVie, Inc., Bristol-Myers Squibb, Astex, Pfizer, Astellas, Taiho, and Jazz Pharmaceuticals. BLP has received research funding from Ambit Biosciences, Genentech, Inc., F. Hoffmann-La Roche, Jazz Pharmaceuticals, Novartis, Pfizer, and Cornerstone Pharmaceuticals; and is a consultant for Cornerstone Pharmaceuticals. RLO has received research support for trials from Astellas, Pfizer, Genentech, Inc., Daiichi Sankyo, and Cellectis; and consulted for AbbVie, Inc., Astellas, and Actinium. GM is a consultant for AbbVie, Inc., Celgene, Roche, Janssen, Astellas, Pfizer, and Incyte. W-JH is a former employee of Genentech, Inc. and may hold Roche stock; and is a current employee of Prelude Therapeutics. MGO is an employee of F. Hoffmann-La Roche and may hold stock or stock options. MA consulted for Amgen, AstraZeneca, Daiichi Sankyo, Syndax, GlycoMimetics, Oncoceutics, and Aptose; has received research funding from F. Hoffmann-La Roche, AstraZeneca, Amgen, Daiichi Sankyo, Jazz Pharmaceuticals, GlycoMimetics; and holds stock from Reata, Oncoceutics/Chimerix and Aptose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In patients with isocitrate dehydrogenase (IDH)-mutated acute myeloid leukemia (AML) treated by intensive chemotherapy (IC), prognostic significance of co-occurring genetic alterations and allogeneic hematopoietic stem cell transplantation (HSCT) are of particular interest with the advent of IDH1/2 mutant inhibitors. We retrospectively analyzed 319 patients with newly diagnosed AML (127 with IDH1, 135 with IDH2R140, and 57 with IDH2R172 mutations) treated with IC in 3 Acute Leukemia French Association prospective trials. In each IDH subgroup, we analyzed the prognostic impact of clinical and genetic covariates, and the role of HSCT. In patients with IDH1 mutations, the presence of NPM1 mutations was the only variable predicting improved overall survival (OS) in multivariate analysis (P < .0001). In IDH2R140-mutated AML, normal karyotype (P = .008) and NPM1 mutations (P = .01) predicted better OS. NPM1 mutations were associated with better disease-free survival (DFS; P = .0009), whereas the presence of DNMT3A mutations was associated with shorter DFS (P = .0006). In IDH2R172-mutated AML, platelet count was the only variable retained in the multivariate model for OS (P = .002). Among nonfavorable European LeukemiaNet 2010-eligible patients, 71 (36%) underwent HSCT in first complete remission (CR1) and had longer OS (P = .03) and DFS (P = .02) than nontransplanted patients. Future clinical trials testing frontline IDH inhibitors combined with IC may consider stratification on NPM1 mutational status, the primary prognostic factor in IDH1- or IDH2R140-mutated AML. HSCT improve OS of nonfavorable IDH1/2-mutated AML and should be fully integrated into the treatment strategy., (© 2021 by The American Society of Hematology.)

Data on outcome in older (≥70 years) patients with acute promyelocytic leukemia after treatment with arsenic trioxide (ATO) compared with standard chemotherapy (CTX) is scarce. We evaluated 433 patients (median age, 73.4 years) treated either with ATO+ all-trans retinoic acid (ATO/ATRA; n = 26), CTX/ATRA + ATO during consolidation (CTX/ATRA/ATO; n = 148), or with CTX/ATRA (n = 259). Median follow-up for overall survival (OS) was 4.8 years. Complete remissions (CR) were achieved in 92% with ATO/ATRA and 82% with CTX/ATRA; induction death rates were 8% and 18%, respectively. For analysis of postremission outcomes we combined the ATO/ATRA and CTX/ATRA/ATO groups (ATO/ATRA ± CTX). Cumulative incidence of relapse (CIR) was significantly lower after ATO/ATRA ± CTX compared with CTX/ATRA (P < 0.001). The same held true when restricting the analysis according to the treatment period after the year 2000. OS of patients in CR1 was not different between ATO/ATRA ± CTX compared with CTX/ATRA (P = 0.20). High (>10 × 10 9 /l) white blood cell (WBC) counts at diagnosis were associated with higher CIR (P < 0.001) compared with lower WBC in the CTX/ATRA group, but not in the ATO/ATRA ± CTX group (P = 0.48). ATO, when added to ATRA or CTX/ATRA is feasible and effective in elderly patients for remission induction and consolidation, particularly in patients with high WBC at diagnosis.

Postremission treatment is crucial to prevent relapse in acute myeloid leukemia (AML). High-dose cytarabine delivered every 12 hours on days 1, 3, and 5 (HDAC-135) is the standard of care for younger adult patients with AML. Although this standard has been unsuccessfully challenged by other treatment regimens, including multiagent chemotherapy, the timing of HDAC administration has attracted little attention. Here, we retrospectively compared the safety, efficacy, and health care resource consumption associated with HDAC-135 and another standard, condensed HDAC-123 regimen, as consolidation treatment in younger AML patients in first complete response. This study included 221 patients (median age, 46.6 years; range, 18-60 years). HDAC-123 and HDAC-135 were used in 92 and 129 patients, respectively. Both regimens were associated with similar rates of relapse-free survival, cumulative incidence of relapse, nonrelapse mortality, and overall survival, including in core binding factor AML subgroup in which levels of minimal residual disease reduction were similar in both schedules. Hematological recovery times regarding neutrophils and platelets were significantly shorter in patients receiving HDAC-123, with an average difference of 3 to 4 days for each consolidation cycle. The total duration of hospitalization for the whole postremission program was shorter with HDAC-123 (32 days; interquartile ratio [IQR], 22.0,36.5) compared with HDAC-135 (41 days; IQR, 30.5, 50.0) (P < .0001). In conclusion, the condensed HDAC-123 regimen induced faster hematological recovery and therefore significantly reduced the length of hospital stay without affecting treatment response or outcome in younger AML patients., (© 2020 by The American Society of Hematology.)

In standard-risk acute promyelocytic leukemia, recent results have shown that all- trans retinoic acid plus arsenic trioxide combinations are at least as effective as classical all- trans retinoic acid plus anthracycline-based chemotherapy while being less myelosuppressive. However, the role of frontline arsenic trioxide is less clear in higher-risk acute promyelocytic leukemia, and access to arsenic remains limited for front-line treatment of standard-risk acute promyelocytic leukemia in many countries. In this randomized trial, we compared arsenic, all- trans retinoic acid and the "classical" cytarabine for consolidation treatment (after all- trans retinoic acid and chemotherapy induction treatment) in standard-risk acute promyelocytic leukemia, and evaluated the addition of arsenic during consolidation in higher-risk disease. Patients with newly diagnosed acute promyelocytic leukemia with a white blood cell count <10x10 9 /L, after an induction treatment consisting of all- trans retinoic acid plus idarubicin and cytarabine, received consolidation chemotherapy with idarubicin and cytarabine, arsenic or all- trans retinoic acid. Patients with a white blood cell count >10x10 9 /L received consolidation chemotherapy with or without arsenic. Overall, 795 patients with acute promyelocytic leukemia were enrolled in this trial. Among those with standard-risk acute promyelocytic leukemia (n=581), the 5-year event-free survival rates from randomization were 88.7%, 95.7% and 85.4% in the cytarabine, arsenic and all- trans retinoic acid consolidation groups, respectively ( P =0.0067), and the 5-year cumulative incidences of relapse were was 5.5%, 0% and 8.2%. ( P =0.001). Among those with higher-risk acute promyelocytic leukemia (n=214), the 5-year event-free survival rates were 85.5% and 92.1% ( P =0.38) in the chemotherapy and chemotherapy plus arsenic groups, respectively, and the corresponding 5-year cumulative incidences of relapse were 4.6% and 3.5% ( P =0.99). Given the prolonged myelosuppression that occurred in the chemotherapy plus arsenic arm, a protocol amendment excluded cytarabine during consolidation cycles in the chemotherapy plus arsenic group, resulting in no increase in relapse. Our results therefore advocate systematic introduction of arsenic in the first-line treatment of acute promyelocytic leukemia, but probably not concomitantly with intensive chemotherapy, a situation in which we found myelosuppression to be significant. ( ClinicalTrials.gov Identifier: NCT00378365 )., (Copyright© 2018 Ferrata Storti Foundation.)

Objectives: Anthracyclines and cytarabine are cornerstones for intensive chemotherapy in acute myeloid leukemia (AML). The goals of this study were to comprehensively assess deviations from theoretical doses and the impact of body-surface area (BSA) on patients' characteristics, physicians' strategy, dose adjustment, and clinical outcome., Methods: The GOELAMS 2001 phase III trial included 823 AML patients below 60 years of age. In the course of treatment, anthropomorphic parameters and chemotherapy doses were prospectively registered., Results: Very high BSA (≥2.15 m 2 ) was the factor most significantly associated with the physician's decision to reduce chemotherapy doses during induction and postremission therapy. Despite similar AML characteristics and therapeutic strategies, the very high BSA group exhibited a significantly worse survival (5-years OS of 27%) compared to the low (BSA≤1.5 m 2 ), intermediate (1.5 m 2 2 ), or high (2 m 2 2 ) BSA groups (46%, 47%, 56%, respectively) (P=.009). In the very high BSA group, dose capping was associated with worse overall survival, although not significantly (P=.09)., Conclusion: The presence of a very high BSA is the main reason prompting physicians to reduce chemotherapy doses in adult AML. Furthermore, these patients display a poor outcome and could benefit from full doses calculated on actual BSA., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.

Purpose Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, and innovative maintenance therapy could improve their outcomes. Androgens, used in the treatment of aplastic anemia, have been reported to block proliferation of and initiate differentiation in AML cells. We report the results of a multicenter, phase III, randomized open-label trial exploring the benefit of adding androgens to maintenance therapy in patients 60 years of age or older. Patients and Methods A total of 330 patients with AML de novo or secondary to chemotherapy or radiotherapy were enrolled in the study. Induction therapy included idarubicin 8 mg/m 2 on days 1 to 5, cytarabine 100 mg/m 2 on days 1 to 7, and lomustine 200 mg/m 2 on day 1. Patients in complete remission or partial remission received six reinduction courses, alternating idarubicin 8 mg/m 2 on day 1, cytarabine 100 mg/m 2 on days 1 to 5, and a regimen of methotrexate and mercaptopurine. Patients were randomly assigned to receive norethandrolone 10 or 20 mg/day, according to body weight, or no norethandrolone for a 2-year maintenance therapy regimen. The primary end point was disease-free survival by intention to treat. Secondary end points were event-free survival, overall survival, and safety. This trial was registered at www.ClinicalTrials.gov identifier NCT00700544. Results Random assignment allotted 165 patients to each arm; arm A received norethandrolone, and arm B did not receive norethandrolone. Complete remission or partial remission was achieved in 247 patients (76%). The Schoenfeld time-dependent model showed that norethandrolone significantly improved survival for patients still in remission at 1 year after induction. In arms A and B, respectively, 5-year disease-free survival was 31.2% and 16.2%, event-free survival was 21.5% and 12.9%, and overall survival was 26.3% and 17.2%. Norethandrolone improved outcomes irrelevant to all prognosis factors. Only patients with baseline leukocytes > 30 × 10 9 /L did not benefit from norethandrolone. Conclusion This study demonstrates that maintenance therapy with norethandrolone significantly improves survival in elderly patients with AML without increasing toxicity.

Background: Reports of patients with secondary acute promyelocytic leukemia (APL) have increased in recent years, particularly for those who received treatment with mitoxantrone, and retrospective studies have suggested that their characteristics and outcomes were similar to those of patients with de novo APL., Methods: The authors investigated patients with de novo and secondary APL who were included in the ongoing APL-2006 trial. Patients with secondary APL who were included in that trial also were compared with a previous retrospective cohort of patients with secondary APL., Results: In the APL-2006 trial, 42 of 280 patients (15%) had secondary APL. Compared with the retrospective cohort, patients with secondary APL in the APL-2006 trial had a lower incidence of prior breast carcinoma (35.7% vs 57%; P = .03) and a higher incidence of prior prostate carcinoma (26.2% vs 4.7%; P < .001). Treatment of the primary tumor in the APL-2006 trial less frequently included combined radiochemotherapy (28.6% vs 47.2%; P = .044) and no mitoxantrone (0% vs 46.7%; P = .016) but more frequently included anthracyclines (53.3% vs 38.3%; P = .015). In the APL-2006 trial, patients who had secondary APL, compared with those who had de novo APL, were older (mean, 60.2 years vs 48.7 years, respectively; P < .0001) but had a similar complete response rate (97.6% vs 90.3%, respectively), cumulative incidence of relapse (0% vs 1.8%, respectively), and overall survival (92.3% vs 90.9%, respectively) at 18 months., Conclusions: Although the incidence of secondary APL appears to be stable over time, evolving strategies for the treatment of primary cancers have reduced its occurrence among breast cancer patients but have increased its incidence among patients with prostate cancer. The current results confirm prospectively that patients with secondary APL have characteristics and outcomes similar to those of patients with de novo APL., (© 2015 American Cancer Society.)

Purpose: Secondary acute myeloid leukemia (sAML), defined as AML arising after a prior myelodysplastic syndrome or after antineoplastic therapy, responds poorly to current therapies. It is often associated with adverse karyotypic abnormalities and overexpression of proteins that mediate drug resistance. We performed a phase III trial to determine whether induction therapy with cytarabine and amonafide L-malate, a DNA intercalator and non-ATP-dependent topoisomerase II inhibitor that evades drug resistance mechanisms, yielded a superior complete remission rate than standard therapy with cytarabine and daunorubicin in sAML., Patients and Methods: Patients with previously untreated sAML were randomly assigned at a one-to-one ratio to cytarabine 200 mg/m(2) continuous intravenous (IV) infusion once per day on days 1 to 7 plus either amonafide 600 mg/m(2) IV over 4 hours on days 1 to 5 (A + C arm) or daunorubicin 45 mg/m(2) IV over 30 minutes once per day on days 1 to 3 (D + C arm)., Results: The complete remission (CR) rate was 46% (99 of 216 patients) in A + C arm and 45% (97 of 217 patients) in D + C arm (P = .81). The 30- and 60-day mortality rates were 19% and 28% in A + C arm and 13% and 21% in D + C arm, respectively., Conclusion: Induction treatment with A + C did not improve the CR rate compared with D + C in patients with sAML., (© 2015 by American Society of Clinical Oncology.)

Clofarabine, a second-generation purine analog displaying potent inhibition of DNA synthesis and favorable pharmacologic profile, is approved for the treatment of acute lymphoblastic leukemia (ALL) after failure of at least two previous regimens in patients up to 21 years of age at diagnosis. Good neurologic tolerance, synergy with alkylating agents, management guidelines defined through pediatric ALL and adult acute myeloid leukemia, have also prompted its administration in more than 100 adults with Philadelphia chromosome-positive and negative B lineage and T lineage ALL, as single agent (40 mg/m(2)/ day for 5 days), or in combination. In a Group for Research on Adult Acute Lympho- blastic Leukemia (GRAALL) retrospective study of two regimens (clofarabine ± cyclophosphamide + / - etoposide (ENDEVOL) ± mitoxantrone ± asparaginase ± dexamethasone (VANDEVOL)), remission was achieved in 50% of 55 relapsed/refractory patients, and 17-35% could proceed to allogeneic stem cell. Clofarabine warrants further exploration in advanced ALL treatment and bridge-to-transplant.

Background: CPX-351 is a liposome-encapsulated fixed-molar-ratio formulation of cytarabine and daunorubicin that exploits molar ratio-dependent drug-drug synergy to enhance antileukemic efficacy., Methods: This phase II study randomized 125 patients 2:1 to CPX-351 or investigators' choice of first salvage chemotherapy. Patients with acute myeloid leukemia (AML) in first relapse after initial Complete Remission (CR) lasting ≥1 month were stratified per the European Prognostic Index (EPI) into favorable, intermediate, and poor-risk groups based on duration of first CR, cytogenetics, age, and transplant history. Control salvage treatment was usually based on cytarabine and anthracycline, often with 1 or more additional agents. Survival at 1 year was the primary efficacy end point., Results: Patient characteristics were well balanced between the 2 study arms. Improvements in efficacy outcomes were observed following CPX-351, but did not meet prospectively defined statistical criteria for 1-year survival improvement in the overall population. Subset analyses of the EPI-defined poor-risk strata demonstrated higher response rates (39.3% vs 27.6%) and improvements in event-free survival (HR, 0.63; P = .08) and overall survival (HR, 0.55; P = .02). Also, 60-day mortality was lower in the CPX-351 study arm for poor-risk patients (16.1% vs 24.1%)., Conclusions: Taken together, the data suggest possible improved outcomes in CPX-351-treated first relapse AML patients with EPI-defined poor-risk disease., (© 2014 American Cancer Society.)

Early response to chemotherapy has a major prognostic impact in acute myeloid leukemia patients treated with a double induction strategy. Less is known about patients treated with standard-dose cytarabine and anthracycline. We designed a risk-adapted remission induction regimen in which a second course of intermediate-dose cytarabine was delivered after standard "7+3" only if patients had 5% or more bone marrow blasts 15 days after chemotherapy initiation (d15-blasts). Of 823 included patients, 795 (96.6%) were evaluable. Five hundred and forty-five patients (68.6%) had less than 5% d15-blasts. Predictive factors for high d15-blasts were white blood cell count (P<0.0001) and cytogenetic risk (P<0.0001). Patients with fewer than 5% d15-blasts had a higher complete response rate (91.7% vs. 69.2%; P<0.0001) and a lower induction death rate (1.8% vs. 6.8%; P=0.001). Five-year event-free (48.4% vs. 25%; P<0.0001), relapse-free (52.7% vs. 36.9%; P=0.0016) and overall survival (55.3% vs. 36.5%; P<0.0001) were significantly higher in patients with d15-blasts lower than 5%. Multivariate analyses identified d15-blasts and cytogenetic risk as independent prognostic factors for the three end points. Failure to achieve early blast clearance remains a poor prognostic factor even after early salvage. By contrast, early responding patients have a favorable outcome without any additional induction course. (ClinicalTrials.gov identifier NCT01015196).

All-trans retinoic acid (ATRA) combined to anthracycline-based chemotherapy is the reference treatment of acute promyelocytic leukemia (APL). Whereas, in high-risk patients, cytarabine (AraC) is often considered useful in combination with anthracycline to prevent relapse, its usefulness in standard-risk APL is uncertain. In APL 2000 trial, patients with standard-risk APL [i.e., with baseline white blood cell (WBC) count <10,000/mm(3) ] were randomized between treatment with ATRA with Daunorubicin (DNR) and AraC (AraC group) and ATRA with DNR but without AraC (no AraC group). All patients subsequently received combined maintenance treatment. The trial had been prematurely terminated due to significantly more relapses in the no AraC group (J Clin Oncol, (24) 2006, 5703-10), but follow-up was still relatively short. With long-term follow-up (median 103 months), the 7-year cumulative incidence of relapses was 28.6% in the no AraC group, compared to 12.9% in the AraC group (P = 0.0065). In standard-risk APL, at least when the anthracycline used is DNR, avoiding AraC may lead to an increased risk of relapse suggesting that the need for AraC is regimen-dependent., (Copyright © 2013 Wiley Periodicals, Inc.)

No series have reported the results of the use of the therapeutic anti-CD20 monoclonal antibody (Rituximab) in the setting of adult refractory/relapsed B-ALL. We report here the outcomes of such nine patients treated at two french institutions by a combination of Rituximab+chemotherapy. We showed that four patients could achieve complete response while four other patients were documented with blast clearance superior to 50% from the baseline in bone marrow. We conclude that our results suggested some efficacy for the use of Rituximab in combination with chemotherapy in the setting of refractory/relapsed adult B-ALL. Larger series within prospective trials are needed to confirm these results., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The economic profile of acute myeloid leukaemia (AML) is badly known. The few studies published on this disease are now relatively old and include small numbers of patients. The purpose of this retrospective study was to evaluate the induction-related cost of 500 patients included in the AML 2001 trial, and to determine the explanatory factors of cost., Setting: "Induction" patient's hospital stay from admission for "induction" to discharge after induction., Method: The study was performed from the French Public Health insurance perspective, restrictive to hospital institution costs. The average management of a hospital stay for "induction" was evaluated according to the analytical accounting of Besançon University Teaching Hospital and the French public Diagnosis-Related Group database. Multiple linear regression was used to search for explanatory factors., Main Outcome Measure: Only direct medical costs were included: treatment and hospitalisation., Results: Mean induction-related direct medical cost was estimated at €41,852 ± 6,037, with a mean length of hospital stay estimated at 36.2 ± 10.7 days. After adjustment for age, sex and performance status, only two explanatory factors were found: an additional induction course and salvage course increased induction-related cost by 38% (± 4) and 15% (± 1) respectively, in comparison to one induction. These explanatory factors were associated with a significant increase in the mean length of hospital stay: 45.8 ± 11.6 days for 2 inductions and 38.5 ± 15.5 if the patient had a salvage course, in comparison to 32.9 ± 7.7 for one induction (P < 10⁻⁴). This result is robust and was confirmed by sensitivity analysis., Conclusion: Consideration of economic constraints in health care is now a reality. Only the control of length of hospital stay may lead to a decrease in induction-related cost for patients with AML.

Purpose: No significant improvement in treatment outcome has been seen in elderly patients with acute myeloid leukemia (AML) over the past 20 years. This retrospective analysis investigated the prognostic factors for complete remission (CR) and survival in older patients with AML., Patients and Methods: The study involved 847 patients older than 60 years enrolled onto three trials carried out in France between 1995 and 2005. Induction therapy consisted of idarubicin (8 mg/m(2), days 1 through 5) and cytarabine (100 mg/m(2), days 1 through 7; group I, 339 patients) or the same drugs plus lomustine (200 mg/m(2) orally on day 1; group II, 508 patients). Consolidation therapy consisted of anthracycline and cytarabine courses at lower doses, preceded or not by a first course of intermediate-dose cytarabine., Results: The rate of CR was significantly higher in patients in group II compared with group I (68% v 58%; P = .002). The rate of toxic death was similar in the two groups. In multivariate analysis, two prognostic factors were linked to CR: nonadverse cytogenetic (P < .003) and addition of lomustine to induction chemotherapy (P = .002). Median overall survival was significantly improved in patients treated with lomustine (median and SE, 12.7 +/- 2.2 months v 8.7 +/- 2.7 months; P = .004). In multivariate analysis, five prognostic factors positively affected overall survival: addition of lomustine (P = .002), age < or = 69 years (P < .001), Eastern Cooperative Oncology Group performance status lower than 2 (P = .002), French-American-British subgroup 1/2 (P = .02), and nonadverse cytogenetic (P < .001)., Conclusion: Lomustine improves the rate of CR and survival in elderly patients with de novo AML when added to standard induction therapy.

Purpose: Acute promyelocytic leukemia (APL) with pretreatment WBC counts greater than 10,000/microL is still considered to carry a poorer prognosis than APL with WBC lower than 10,000/mL. We evaluated outcome improvement in such patients in recent years., Patients and Methods: Nine hundred two patients with APL, including 204 patients and 68 patients with WBC counts more than 10,000/microL and more than 50,000/microL, respectively, were enrolled between 1993 and 2005 in two successive randomized trials of the European APL group (APL 93 and APL 2000) that tested, in particular, the modalities of combination of all-trans retinoic acid (ATRA) and chemotherapy, maintenance treatment, escalating doses of cytarabine, early administration of dexamethasone, and CNS prophylaxis., Results: Between the APL 93 and 2000 trials, the complete response (CR) rate increased from 89.6% to 93%, and the 5-year cumulative incidence of relapse (CIR) decreased from 40% to 9.5% in patients with WBC counts of 10,000 to 50,000/microL. In patients with WBC counts more than 50,000/microL, the CR rate increased from 82% to 91%, and 5-year CIR decreased from 59% to 24%. Whereas in the APL 93 trial, increased WBC counts were significantly associated with higher CIR and shorter survival, this was not the case in the APL 2000 trial. In patients with increased WBC counts, enrollment onto the APL 2000 trial (v APL 93) and combined maintenance with ATRA and chemotherapy were associated with significantly lower CIR and better survival., Conclusion: Outcome of APL with high WBC count has markedly improved over the years as a result of fewer early deaths and fewer relapses. Better initial supportive care and combined maintenance treatment have contributed to this improvement.

Objective: Triptolide has shown antitumor activity in a broad range of solid tumors and on leukemic cells in vitro., Materials and Methods: The THP1 cell line and primary acute myeloid leukemia (AML) cells were cultured with triptolide alone or in association with AraC or idarubicin in increasing concentrations. Apoptosis was measured by flow cytometry using DiOC6(3) for the cell line and fluorescein isothiocyanateAnnexin-V and CD45 labeling for fresh blast cells. Protein expression was measured by Western blot. Cell cycle distribution of apoptotic cells was measured by flow cytometry., Results: A synergistic effect was observed when triptolide was added to idarubicin or to AraC to induce apoptosis of THP-1 leukemic cells. The triptolide/AraC association was also investigated in vitro on primary blast cells from 25 AML patients. This combination induced significantly higher percentages of apoptosis vs treatment with each drug separately (p<0.005). The IkappaB and X-linked inhibitor of apoptosis protein contents, which were altered by triptolide in idarubicin-treated cells, were not modified in AraC-treated cells. The association of AraC with triptolide increased the number of cells blocked in the S phase and most underwent apoptosis., Conclusion: These results suggest that, by modifying the cell cycle kinetics, AraC sensitizes AML cells to apoptosis induced by low concentration triptolide. The in vitro proapoptotic effect of triptolide associated with the antiproliferative activity of AraC warrants further clinical investigation for treatment of AML patients, especially elderly patients for whom low-dose AraC treatment could be improved by the addition of triptolide.

Purpose: To determine the antitumor activity and safety of a combination of gemtuzumab ozogamicin (GO), intermediate-dose cytarabine, and mitoxantrone (MIDAM) in patients with refractory or relapsed CD33(+) acute myeloid leukemia (AML)., Patients and Methods: We treated 62 patients with refractory (n = 18) or relapsed (n = 44) CD33(+) AML. Median age was 55.5 years. Salvage regimen consisted of GO 9 mg/m(2) on day 4, cytarabine 1 g/m(2) every 12 hours on days 1 through 5, and mitoxantrone 12 mg/m(2)/d on days 1 through 3. Median follow-up time was 26.5 months., Results: Thirty-one patients (50%) achieved complete remission (CR), and eight patients (13%) had CR with delayed platelet recovery (CRp); the overall response (OR; CR + CRp) rate was 63%. A significantly higher OR rate was achieved in patients who had relapsed versus refractory AML (73% v 39%, respectively; P = .007) and patients with CD33 expression more than 98% of the blast population versus less than 98% (79% v 52.3%, respectively; P = .03). The overall, event-free, and disease-free survival rates were 41%, 33%, and 53% at 2 years, respectively. Leukocytosis more than 20,000/microL at MIDAM therapy, high-risk cytogenetics, and absence of postremission therapy were adverse prognostic factors. Age, disease status, and/or CD33 expression did not influence survival parameters. Four early toxic deaths occurred; a grade 3 to 4 hyperbilirubinemia rate of 16% was observed, and two patients had veno-occlusive disease (3%)., Conclusion: The MIDAM regimen seems to be an effective salvage regimen for refractory/relapsed CD33(+) AML patients. These encouraging results support the need for a randomized phase III trial before considering this combination of GO and chemotherapy as superior or the standard of care treatment for refractory/relapsed CD33(+) AML patients.

The combination of imatinib with chemotherapy has been recently reported as very promising in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). During 2004 and 2005, 45 patients with newly diagnosed Ph+ ALL were treated in the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAAPH) 2003 study, in which imatinib was started with HAM (mitoxantrone with intermediate-dose cytarabine) consolidation in good early responders (corticosensitive and chemosensitive ALL) or earlier during the induction course in combination with dexamethasone and vincristine in poor early responders (corticoresistant and/or chemoresistant ALL). Imatinib was then continuously administered until stem cell transplantation (SCT). Overall, complete remission (CR) and BCR-ABL real-time quantitative polymerase chain reaction (RQ-PCR) negativity rates were 96% and 29%, respectively. All of the 22 CR patients (100%) with a donor actually received allogeneic SCT in first CR. At 18 months, the estimated cumulative incidence of relapse, disease-free survival, and overall survival were 30%, 51%, and 65%, respectively. These 3 end points compared very favorably with results obtained in the pre-imatinib LALA-94 trial. This study confirms the value of the combined approach and encourages prospective trials to define the optimal chemotherapy that has to be combined with imatinib and to carefully reevaluate the place of allogeneic SCT in this new context.

Purpose: Several phase II studies have suggested that cytarabine (AraC) was not required in the treatment of newly diagnosed acute promyelocytic leukemia (APL) patients receiving all-trans-retinoic acid (ATRA), an anthracycline, and maintenance therapy, and we aimed at confirming this finding in a randomized trial., Patients and Methods: Newly diagnosed APL patients younger than age 60 years with a WBC count of less than 10,000/microL were randomly assigned to receive either ATRA combined with and followed by three daunorubicin (DNR) plus AraC courses and a 2-year maintenance regimen (AraC group) or the same treatment but without AraC (no AraC group). Patients older than age 60 years and patients with initial WBC count of more than 10,000/microL were not randomly assigned but received risk-adapted treatment, with higher dose of AraC and CNS prophylaxis in patients with WBC counts more than 10,000/microL., Results: Overall, 328 (96.5%) of 340 patients achieved complete remission (CR). In the AraC and the no AraC groups, the CR rates were 99% and 94% (P = .12), the 2-year cumulative incidence of relapse (CIR) rates were 4.7% and 15.9% (P = .011), the event-free survival (EFS) rates were 93.3% and 77.2% (P = .0021), and survival rates were 97.9% and 89.6% (P = .0066), respectively. In patients younger than age 60 years with WBC counts more than 10,000/microL, the CR, 2-year CIR, EFS, and survival rates were 97.3%, 2.9%, 89%, and 91.9%, respectively., Conclusion: These results support a role for AraC in addition to ATRA and anthracyclines in the treatment of newly diagnosed APL, at least using DNR at the cumulative dose we used and with the consolidation and maintenance regimens we used.

Background: Thirty-three patients (median age 52; range 26-60) with acute myeloblastic leukemia (AML) were included in a pilot study of allogeneic stem cell transplantation (Allo-SCT) following a reduced-intensity conditioning (RIC)., Methods: Patients achieving first complete remission (CR1) were selected for their high-risk clinical and/or leukemic features. All patients received two courses of consolidation chemotherapy including one high-dose cytarabine course. Among them, 13 patients in addition received a high-dose melphalan course followed by autologous SCT. Then, all patients received an RIC Allo-SCT combining fludarabine, busulfan, and antithymocyte globulin., Results: All patients engrafted had cumulative incidences of Gluksberg System Grade 2 acute and chronic graft-versus-host-disease (GVHD) of 24 (9-39%) and 64 (48-80%), respectively. Three patients died from nonrelapse causes (NRD) (cumulative incidence: 9%, 95% confidence interval (CI): 0-19) and 6 relapsed (cumulative incidence: 18%, 95% CI: 5-31). With a median follow-up of 18 months (range 7-52) after Allo-SCT, 26 patients are alive, of whom 24 remained in CR1 for a 2-year overall survival and leukemia-free survival (LFS) probabilities of 79 (range 61-90%) and 76 (range 59-87%), respectively. In a 'landmark' analysis starting on Day 100, the occurrence of chronic GVHD was associated with a lower relapse rate (0% vs. 44%: P = 0.007) and improved outcome (LFS; 95% vs. 53%, P = 0.007; overall survival, 95% vs. 61%, P = 0.05)., Conclusions: We conclude that the sequential combination of intensive chemotherapy and allogeneic immunotherapy might offer relatively low NRD and leukemia relapse rates even in high-risk patients., ((c) 2005 American Cancer Society.)

We report on a randomized trial aimed to determine the impact of a second consolidative high-dose cytarabine-based chemotherapy (HiDAC) in patients with acute myeloid leukaemia prior to an autologous stem cell transplantation (ASCT). Patients aged 18-60 years, in complete remission (CR) received a first consolidation with daunorubicin and cytarabine at reduced dose. Patients not allocated to allogeneic transplantation received one course of HiDAC and then were randomized to receive an ASCT immediately (HiDAC 1 group) or after one more course of HiDAC (HiDAC 2 group). Out of the 437 initial patients, 351 achieved CR (80%), of those 277 (79%) were eligible for first HiDAC, and 128 (36%) were randomized (HiDAC 1:65, HiDAC 2:63). Overall survival, leukaemia-free survival and cumulative incidence of relapse and non-relapse deaths were 41% and 53% (P = 0.14), 39% and 48% (P = 0.12), 57% and 47% (P = 0.11), 8% and 8% (P = 0.95) for HiDAC 1 and HiDAC 2 groups, respectively. Further studies are warranted with a larger number of patients to test the place of a second course of HiDAC in this setting.

BackgroundSafe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia.MethodsThis phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801.FindingsBetween Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p