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The recommended starting dose of bosutinib is 500 mg/day for chronic-phase (CP) or accelerated-/blast-phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy. However, some patients may require dose reductions to manage the occurrences of adverse events (AEs). Bosutinib efficacy and safety were evaluated following dose reductions in a phase I/II study of Ph+ patients with CP CML resistant/intolerant to imatinib or imatinib plus dasatinib and/or nilotinib, and those with accelerated-/blast-phase CML or acute lymphoblastic leukemia after at least imatinib treatment. In all, 570 patients with ≥4 years' follow-up were included in this analysis. Among 144 patients who dose-reduced to bosutinib 400 mg/day (without reduction to 300 mg/day), 22 (15 %) had complete cytogenetic response (CCyR) before and after reduction, 40 (28 %) initially achieved CCyR after reduction, and 4 (3 %) only had CCyR before reduction. Among 95 patients who dose-reduced to bosutinib 300 mg/day, 23 (24 %) had CCyR before and after reduction, 13 (14 %) initially achieved CCyR after reduction, and 3 (3 %) only had CCyR before reduction. Results were similar to matched controls who remained on 500 mg/day, indicating dose reductions had not substantially affected efficacy. The incidence of treatment-emergent AEs was lower after dose reductions, particularly for gastrointestinal events. The incidence of hematologic toxicities generally was similar before and after dose reduction. The management of AEs with bosutinib through dose reduction can lead to improved/maintained efficacy and better tolerability; still, approximately half of patients on treatment at year 4 maintained a dose of ≥500 mg/day. ClinicalTrials.gov: NCT00261846., (Copyright © 2021. Published by Elsevier Ltd.)

Background: CXCR4 mediates the retention and survival of acute myelogenous leukemia blasts in bone marrow and contributes to their resistance to chemotherapy. The authors evaluated a combination of the high-affinity CXCR4 antagonist BL-8040 with high-dose cytarabine (HiDAC) chemotherapy in a phase 2a study of patients with relapsed and refractory AML., Methods: Forty-two patients received treatment with BL-8040 monotherapy for 2 days followed by a combination of BL-8040 with HiDAC for 5 days. Six escalating BL-8040 dose levels were investigated (0.5, 0.75, 1.0, 1.25, 1.5, and 2.0 mg/kg), and 1.5 mg/kg was selected as the dose for the expansion phase (n = 23)., Results: BL-8040 in combination with HiDAC was safe and well tolerated at all dose levels. Clinical response was observed with BL-8040 doses ≥1.0 mg/kg. The composite response rate (complete remissions plus complete remissions with incomplete hematologic recovery of platelets or neutrophils) was 29% (12 of 42) in all patients and 39% (9 of 23) in the 1.5-mg/kg phase. The median overall survival was 8.4 months for all patients, 10.8 months in the 1.5-mg/kg phase, and 21.8 months for responding patients in the 1.5-mg/kg cohort. Two days of BL-8040 monotherapy triggered the mobilization of blasts into peripheral blood, with significantly higher mean fold-changes in responders versus nonresponders. This was accompanied by a decrease in bone marrow blasts., Conclusions: The current results demonstrate the efficacy of CXCR4 targeting with BL-8040 and support continued clinical development in acute myelogenous leukemia., (© 2020 American Cancer Society.)

CPX-351 is a liposomal formulation of cytarabine/daunorubicin with a 5:1 fixed molar ratio. We investigated the safety and efficacy of escalating doses of CPX-351 in patients with acute myeloid leukemia (AML) at high risk of induction mortality with standard chemotherapy determined through assessment of leukemia and patient-related risk factors for intensive chemotherapy in an open-label, phase II trial. Patients were randomized to receive 50 or 75 units/m 2 on days 1, 3, and 5. Once safety was established, a 100 units/m 2 arm was opened. Fifty-six patients were enrolled, 16, 24, and 16 in the 50, 75, and 100 units/m 2 arms, respectively. The composite complete remission rate (complete remission + complete remission with incomplete blood count recovery) was lowest with 50 units/m 2 (19%) compared with 75 units/m 2 (38%) and 100 units/m 2 (44%) (P = 0.35). The 50 units/m 2 arm had a median OS of 4.3 months, compared with 8.6 and 6.2 months for the 75 and 100 units/m 2 respectively (P = 0.04). Nonhematologic grade 3/4 treatment-emergent adverse events included febrile neutropenia (34%), pneumonia (23%), and sepsis (16%). CPX-351 at 75 units/m 2 has favorable safety and efficacy for AML patients at high risk of induction mortality with some tolerating the standard dose of 100 units/m 2 .

Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting., (© 2020 Wiley Periodicals LLC.)

Purpose: Glasdegib, an oral inhibitor of the Hedgehog signaling pathway, is approved in the United States in combination with low-dose cytarabine (LDAC) to treat patients with newly diagnosed acute myeloid leukemia (AML) ineligible to receive intensive chemotherapy. This population pharmacokinetic/pharmacodynamic analysis characterized the time course of survival with glasdegib + LDAC relative to LDAC alone, and explored whether the differences in glasdegib exposure at the clinical dose of 100 mg once daily (QD) significantly affected overall survival (OS)., Methods: Data from the BRIGHT AML 1003 trial in patients with AML were included in treatment-response (glasdegib + LDAC, n = 78; LDAC alone, n = 38) and exposure-response (glasdegib + LDAC, n = 75) analyses., Results: The analyses demonstrate that patients treated with glasdegib + LDAC (vs LDAC alone) at any time point during the study period were 58% less likely to die, translating to prolonging of median OS by ~ 5 months (hazard ratio 0.42 [95% confidence interval 0.28-0.66]). Variability in glasdegib exposures did not impact the risk of death. Additionally, potential covariates such as patient demographics, prior treatment with a hypomethylating agent, baseline safety laboratory values, and disease characteristics, did not impact the probability of OS., Conclusion: Together these results confirm that glasdegib + LDAC treatment (vs. LDAC alone) is associated with a significant survival benefit in patients with newly diagnosed AML, and that variability in glasdegib doses (e.g., for dose reductions) and exposures do not compromise the survival benefit of glasdegib 100 mg QD., Clinical Trial Number: NCT01546038.

Background: In a randomized study, glasdegib (a hedgehog inhibitor) plus low-dose cytarabine (LDAC) significantly prolonged survival in comparison with LDAC in patients with acute myeloid leukemia (AML). A quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) approach was used to evaluate comparative quality-adjusted survival., Methods: Overall survival was partitioned into the following: time with any treatment-emergent grade 3 or higher adverse events (TOX); time without symptoms of disease progression or toxicity (TWiST); and time after treatment discontinuation due to insufficient clinical response, relapse, or death time after progression (REL). Q-TWiST was calculated by multiplying the restricted mean time in each state by respective utilities and then summing up the utility-adjusted time., Results: At 20 months of follow-up, the survival probabilities for the glasdegib-LDAC arm and the LDAC arm were 28.2% and 7.9%, respectively. Glasdegib-LDAC patients (n = 78), in comparison with LDAC patients (n = 38), had significantly longer mean TWiST (+3.4 months; 95% confidence interval [CI], 1.8-5.2 months) and TOX (+0.8 months; 95% CI, 0.1-1.6 months) and longer but nonsignificant REL (+0.3 months; 95% CI, -1.9 to 2.3 months). Q-TWiST was 4.0 months (95% CI, 2.1-5.8 months) longer with glasdegib plus LDAC, and this translated into a 75% relative improvement in quality-adjusted survival with respect to LDAC. Results were robust to the length of follow-up (6-24 months) and remained significant when all adverse events, regardless of grade, were included., Conclusions: These results suggest that most of the survival benefit from glasdegib plus LDAC versus LDAC alone is TWiST, and this represents added time in relatively "good" health. These results support the clinical value of glasdegib plus LDAC as initial therapy for AML in patients for whom intensive chemotherapy is not an option., (© 2020 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: The phase 2 BRIGHT AML 1003 trial evaluated efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized patients to receive glasdegib + LDAC (n = 78) or LDAC alone (n = 38). The rate of complete remission (CR) was 19.2% in the glasdegib + LDAC arm versus 2.6% in the LDAC arm (P = 0.015)., Methods: This post hoc analysis determines whether the clinical benefits of glasdegib are restricted to patients who achieve CR, or if they extend to those who do not achieve CR., Results: In patients who did not achieve CR, the addition of glasdegib to LDAC improved overall survival (OS) versus LDAC alone (hazard ratio = 0.63 [95% confidence interval, 0.41-0.98]; P = 0.0182; median OS, 5.0 vs 4.1 months). Additionally, more patients receiving glasdegib + LDAC achieved durable recovery of absolute neutrophil count (≥ 1000/μl, 45.6% vs 35.5%), hemoglobin (≥ 9 g/dl, 54.4% vs 38.7%), and platelets (≥ 100,000/μl, 29.8% vs 9.7%). Transfusion independence was achieved by 15.0% and 2.9% of patients receiving glasdegib + LDAC and LDAC alone, respectively., Conclusions: Collectively, these data suggest that there are clinical benefits with glasdegib in the absence of CR., Trial Registration: ClinicalTrials.gov NCT01546038 (March 7, 2012).

Acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) is a heterogeneous disorder defined by multilineage dysplasia, myelodysplastic syndrome (MDS)-related karyotype, or history of prior MDS. We evaluated 415 patients with AML-MRC treated from 2013 to 2018 and analyzed their clinical outcomes based on the diagnostic criteria of AML-MRC, therapy type and mutation profile. Criteria for AML-MRC included: cytogenetic abnormalities (AML-MRC-C) in 243 (59%), prior history of MDS in 75 (18%) including 47 (11%) with previously untreated MDS (AML-MRC-H) and 28 (7%) with previously treated MDS (AML-MRC-TS), and 97 (23%) with multilineage dysplasia (AML-MRC-M). Median age was 70 years (range 18-94). Among 95 evaluable patients, a total of 37 (39%) had secondary-type (ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) mutations. Mutations in ASXL1, BCOR, SF3B1, SRSF2, and U2AF1 tended to appear in dominant clones. By multivariate analysis, AML-MRC subtype, age and serum LDH levels were independent predictors of outcome, with patients with AML-MRC-M (HR 0.56, CI 0.38-0.84, P = .004) and AML-MRC-H having better OS. Compared to a cohort of 468 patients with AML without MRC, patients with AML-MRC-M/AML-MRC-H had similar outcomes to those with intermediate risk AML by European LeukemiaNet criteria. Intensive therapy was associated with improved OS in patients with AML-MRC-M (HR 0.42, CI 0.19-0.94, P = .036) and with improved EFS in AML-MRC-M and AML-MRC-H (HR 0.26, CI 0.10-0.63, P = .003). This data suggests that not all diagnostic criteria for AML-MRC define high-risk patients and that specific subgroups may benefit from different therapeutic interventions., (© 2020 Wiley Periodicals, Inc.)

CPX-351 is a dual-drug liposomal encapsulation of cytarabine/daunorubicin. In a phase 3 study (ClinicalTrials.gov Identifier: NCT01696084), patients aged 60-75 years with newly diagnosed, high-risk/secondary AML received 1-2 induction cycles with CPX-351 or 7 + 3 chemotherapy; those achieving complete remission (including with incomplete platelet or neutrophil recovery) could receive up to 2 consolidation cycles with CPX-351 or 5 + 2 chemotherapy, respectively. In this exploratory analysis of the subgroup of patients who received consolidation, median overall survival was prolonged among patients receiving CPX-351 induction/consolidation versus 7 + 3/5 + 2 (25.43 vs. 8.53 months; HR = 0.44 [95% CI: 0.25-0.77]). The safety profile of CPX-351 consolidation was consistent with that of the overall study. Outpatient administration of CPX-351 consolidation occurred in 51%-61% of patients and did not diminish overall survival. These findings suggest consolidation with CPX-351 in this patient population contributed to the prolonged overall survival versus 7 + 3/5 + 2, building upon findings from the overall study population, and provide evidence that, with careful monitoring, some patients can successfully receive CPX-351 as outpatients.

Background: Philadelphia chromosome-positive (Ph+) advanced leukemias, including acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in myeloid blast phase (MBP), have poor outcomes. Venetoclax has shown synergism with BCR-ABL1 tyrosine kinase inhibitors (TKI) in preclinical studies. However, clinical activity of venetoclax and TKI-based regimens is unknown., Methods: We conducted a retrospective study on patients with Ph+ AML (n = 7) and CML-MBP (n = 9) who received venetoclax combined with TKI-based regimens at our institution., Results: Median patient age was 42 years, and the median number of prior therapy cycles was 5 (range 2-8). Nine patients received decitabine-based, and 7 received intensive chemotherapy-based regimens. Ten patients (63%) received ponatinib. The overall response rate (ORR) in 15 evaluable patients was 60% (1 complete remission [CR], 6 CR with incomplete hematologic recovery [CRi], 1 morphologic leukemia-free state, and 1 partial response). The ORR was 43% in Ph+ AML and 75% in CML-MBP. The median overall survival (OS) for all patients was 3.6 months, for AML OS was 2.0 months, and for CML-MBP OS was 10.9 months. The median relapse-free survival for AML and CML-MBP was 3.6 and 3.9 months, respectively. Compared to nonresponders, patients achieving CR/CRi had higher baseline Ph+ metaphases and BCR-ABL1 PCR., Conclusions: Combination therapy of venetoclax with TKI-based regimens shows encouraging activity in very heavily pretreated, advanced Ph+ leukemias, particularly CML-MBP., (© 2020 S. Karger AG, Basel.)

Background: The addition of midostaurin to induction chemotherapy improves survival in younger patients with newly diagnosed, FLT3-mutated acute myeloid leukemia (AML). Sorafenib is a potent multikinase inhibitor with efficacy when given as monotherapy. The authors investigated whether the addition of sorafenib to intensive induction chemotherapy improves outcomes in patients with FLT3-internal tandem duplication (ITD)-mutated AML., Methods: In total, 183 patients who were newly diagnosed with FLT3-ITD-mutated AML between February 2001 and December 2017 were identified. Of these, 79 patients (43%) underwent intensive chemotherapy with the addition of sorafenib, and 104 (57%) received intensive chemotherapy alone. Propensity score matching identified 42 patients in each cohort., Results: The overall response rate was 98% in the sorafenib cohort and 83% in the intensive chemotherapy cohort (P = .057). The median follow-up was 54 months. The median event-free survival was 35 months in the sorafenib cohort and 8 months in the intensive chemotherapy cohort (P = .019), and the median overall survival was 42 and 13 months, respectively (P = .026). With censoring at the time of allogeneic stem cell transplantation, the median event-free survival was 31 and 8 months in the sorafenib and intensive therapy cohorts, respectively (P = .031), and the median overall survival was not reached and 10 months, respectively (P = .001). Multivariate Cox proportional hazards models confirmed that treatment with sorafenib was a favorable prognostic factor (P = .009; hazard ratio, 0.558; 95% CI, 0.360-0.865)., Conclusions: The addition of sorafenib improves survival in patients with FLT3-ITD-mutated AML regardless of whether they undergo allogeneic stem cell transplantation., (© 2019 American Cancer Society.)

Glasdegib, an oral Hedgehog pathway inhibitor, has been associated with significantly improved survival when combined with low-dose cytarabine in patients with untreated acute myeloid leukemia (AML) who were unsuitable for intensive chemotherapy, when compared with low-dose cytarabine alone. BRIGHT AML 1019 (NCT03416179) comprises two independently powered Phase III, randomized (1:1), double-blind global trials evaluating oral glasdegib 100 mg once daily or placebo plus one of two standard chemotherapy regimens in adults with untreated AML. The intensive trial combines glasdegib/placebo with cytarabine and daunorubicin (7 + 3), while the nonintensive trial combines glasdegib/placebo with azacitidine. The primary end point of both studies is overall survival. Secondary end points include response, time to and duration of response, event-free survival, safety, patient-reported outcomes and pharmacokinetics. Trial registration number: ClinicalTrials.gov identifier: NCT03416179.

Background: Outcomes for younger patients with acute myeloid leukaemia have moderately improved over the past two decades owing to better supportive care and recent introduction of novel targeted agents. Blocking PD-1 and its ligand's pathways enhances antileukaemia responses by enabling T cells in murine models. We aimed to assess the addition of nivolumab to frontline therapy with idarubicin and cytarabine in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome., Methods: This single-arm, phase 2 part of the phase 1-2 study of nivolumab in combination with idarubicin and cytarabine was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients were aged 18-60 years (or >60 years if suitable for intensive chemotherapy), and had newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome, and an Eastern Cooperative Oncology Group performance status of 0-2. Induction included cytarabine 1·5 g/m 2 by 24-h continuous infusion daily on days 1-4 (3 days in patients >60 years) and idarubicin 12 mg/m 2 daily on days 1-3. Nivolumab 3 mg/kg was started on day 24 (range 22-26) and continued every 2 weeks for up to a year in responders. Responders received either up to five consolidation cycles of attenuated doses of idarubicin and cytarabine, or allogeneic stem cell transplantation if eligible. The primary endpoint was event-free survival. Efficacy and safety analyses were done in all patients who received at least one dose of study treatment. Secondary endpoints were relapse-free survival and overall survival. This ongoing trial is registered with ClinicalTrials.gov, number NCT02464657., Findings: Between Aug 7, 2015, and June 2, 2018, 44 patients were enrolled of whom 22 (50%) had adverse genetic risk by European Leukaemia Network classification. All patients were evaluable for safety and efficacy. At a median follow-up of 17·25 months (IQR 0·50-30·40), median event-free survival was not reached (95% CI 7·93-NR). Median relapse-free survival of responders was 18·54 months (95% CI 8·20-23·22). The median overall survival was 18·54 months (95% CI 10·81-28·81). Six patients had seven grade 3-4 immune-related adverse events with two cases of rash, two of colitis, and one each of transaminitis, pancreatitis, and cholecystitis. 19 (43%) of 44 patients achieved a response and proceeded to allogeneic stem cell transplantation, with grade 3-4 graft-versus-host disease observed in five (26%). No treatment related deaths were attributed to nivolumab., Interpretation: Addition of nivolumab to induction chemotherapy with idarubicin and cytarabine is feasible in patients with newly diagnosed acute myeloid leukaemia or high-risk myelodysplastic syndrome. Post-transplant severe graft-versus-host disease could be improved, and earlier initiation of checkpoint inhibitor therapy is warranted in future studies., Funding: The MD Anderson Cancer Center Support Grant CA016672, and the MD Anderson Cancer Center Leukaemia SPORE CA100632 from the National Cancer Institute, Bristol Myers Squibb., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Preclinical studies have suggested a role for Bruton tyrosine kinase (BTK) as a potential therapeutic target in acute myeloid leukemia (AML), and anti-AML activity in vivo has been demonstrated with BTK inhibitors., Patients and Methods: In this open-label phase 2a study, patients with AML were treated with ibrutinib 560 mg per day alone (cohort 1; n = 7), or ibrutinib in combination with either cytarabine 20 mg administered subcutaneously twice daily for 10 days of a 28-day cycle (cohort 2; n = 21) or azacitidine 75 mg/m 2 administered intravenously once daily on days 1 to 7 of a 28-day cycle (cohort 3; n = 8). Best overall response (primary end point), overall survival, and safety were summarized., Results: A total of 36 patients were enrolled and received treatment; median duration of ibrutinib treatment was 5.4 weeks, and median time on study was 16 months. Of 24 patients evaluable for response, 1 partial remission (cohort 3) and 1 complete remission (cohort 2) were observed; the remaining responses were treatment failures. Median overall survival was 4.0 months in cohort 1, 2.2 months in cohort 2, 2.8 months in cohort 3, and 2.4 months for the overall population. No unexpected safety signals were identified. Grade 3 or higher adverse events that occurred in ≥ 10% of patients included AML progression, febrile neutropenia, pneumonia, anemia, thrombocytopenia, fatigue, asthenia, and respiratory failure., Conclusion: Ibrutinib alone or in combination with cytarabine or azacitidine demonstrated an acceptable safety profile. However, limited efficacy with ibrutinib was observed in patients with AML., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Preclinical models have shown that blocking PD-1/PD-L1 pathways enhances antileukemic responses. Azacitidine upregulates PD-1 and IFNγ signaling. We therefore conducted this single-arm trial, in which patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) were treated with azacitidine 75 mg/m 2 days 1 to 7 intravenously or subcutaneously with nivolumab 3 mg/kg intravenously on days 1 and 14, every 4 to 6 weeks. For the seventy patients who were treated, the median age was 70 years (range, 22-90) and the median number of prior therapies received was 2 (range, 1-7). The overall response rate (ORR) was 33%, including 15 (22%) complete remission/complete remission with insufficient recovery of counts, 1 partial response, and 7 patients with hematologic improvement maintained >6 months. Six patients (9%) had stable disease >6 months. The ORR was 58% and 22%, in hypomethylating agent (HMA)-naïve ( n = 25) and HMA-pretreated ( n = 45) patients, respectively. Grade 3 to 4 immune-related adverse events occurred in 8 (11%) patients. Pretherapy bone marrow and peripheral blood CD3 and CD8 were significantly predictive for response on flow cytometry. CTLA4 was significantly upregulated on CD4 + Teff in nonresponders after 2 and 4 doses of nivolumab. Azacitidine and nivolumab therapy produced an encouraging response rate and overall survival in patients with R/R AML, particularly in HMA-naïve and salvage 1 patients. Pretherapy bone marrow aspirate and peripheral blood CD3 percentage may be biomarkers for patient selection. SIGNIFICANCE: Azacitidine in combination with nivolumab appeared to be a safe and effective therapy in patients with AML who were salvage 1, prior hypomethylator-naïve, or had increased pretherapy CD3 + bone marrow infiltrate by flow cytometry or IHC. Bone marrow CD3 and CD8 are relatively simple assays that should be incorporated to select patients in future trials. This article is highlighted in the In This Issue feature, p. 305 ., (©2018 American Association for Cancer Research.)

Glasdegib is a Hedgehog pathway inhibitor. This ongoing, open-label, phase 2 study (NCT01546038) evaluated glasdegib plus cytarabine/daunorubicin in patients with untreated acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS). Patients received glasdegib 100 mg orally, once daily in continuous 28-day cycles from day -3, with intravenous cytarabine 100 mg/m 2 on days 1-7 and daunorubicin 60 mg/m 2 on days 1-3. Patients in remission then received consolidation therapy (2-4 cycles of cytarabine 1 g/m 2 twice daily on days 1, 3, 5 of each cycle), followed by maintenance glasdegib (maximum 6 cycles). Primary endpoint was complete remission (CR) in patients aged ≥55 years. Secondary endpoints included overall survival (OS), safety and outcome by mutational status. Patients had a median (range) age of 64.0 (27-75) years, 60.0% were male, and 84.5% were white. In 69 evaluable patients, 46.4% (80% confidence interval [CI]: 38.7-54.1) achieved investigator-reported CR. Among patients ≥55 years old (n = 60), 40.0% (80% CI 31.9-48.1) achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4-19.3) months, with 12-month survival probability 66.6% (80% CI 58.5-73.4). The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea. There were no significant associations between mutational status (12 genes) and clinical response, suggesting potential benefit across diverse molecular profiles. Glasdegib plus cytarabine/daunorubicin was well tolerated and associated with clinical activity in patients with untreated AML or high-risk MDS. A randomized phase 3 trial of glasdegib in combination with chemotherapy (7 + 3 schedule) is ongoing., (© 2018 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.)

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m 2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m 2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487., (© 2018 by The American Society of Hematology.)

Purpose CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic 5:1 drug ratio into leukemia cells to a greater extent than normal bone marrow cells. Prior clinical studies demonstrated a sustained drug ratio and exposure in vivo and prolonged survival versus standard-of-care cytarabine plus daunorubicin chemotherapy (7+3 regimen) in older patients with newly diagnosed secondary acute myeloid leukemia (sAML). Patients and Methods In this open-label, randomized, phase III trial, 309 patients age 60 to 75 years with newly diagnosed high-risk/sAML received one to two induction cycles of CPX-351 or 7+3 followed by consolidation therapy with a similar regimen. The primary end point was overall survival. Results CPX-351 significantly improved median overall survival versus 7+3 (9.56 v 5.95 months; hazard ratio, 0.69; 95% CI, 0.52 to 0.90; one-sided P = .003). Overall remission rate was also significantly higher with CPX-351 versus 7+3 (47.7% v 33.3%; two-sided P = .016). Improved outcomes were observed across age-groups and AML subtypes. The incidences of nonhematologic adverse events were comparable between arms, despite a longer treatment phase and prolonged time to neutrophil and platelet count recovery with CPX-351. Early mortality rates with CPX-351 and 7+3 were 5.9% and 10.6% (two-sided P = .149) through day 30 and 13.7% and 21.2% (two-sided P = .097) through day 60. Conclusion CPX-351 treatment is associated with significantly longer survival compared with conventional 7+3 in older adults with newly diagnosed sAML. The safety profile of CPX-351 was similar to that of conventional 7+3 therapy.

Background: Indisulam possesses anticancer properties through down-regulation of various cell-cycle checkpoint molecules, thereby blocking the phosphorylation of retinoblastoma protein and inducing p53 and p21. Indisulam exhibits synergy with nucleoside analogs and topoisomerase inhibitors., Methods: The authors designed a phase 2 study of indisulam in combination with idarubicin and cytarabine in patients who had relapsed/refractory acute myeloid leukemia AML and high-risk myelodysplastic syndrome. In stage 1, patients received intravenous indisulam at 400 mg/m 2 on days 1 and 8 of a 28-day cycle. If they had no response, then patients received same dose schedule of indisulam followed by intravenous idarubicin 8 mg/m 2 daily for 3 days and cytarabine 1.0 g/m 2 over 24 hours daily on days 9 through 12 (for those aged < 60 years) or days 9 through 11 (for those aged > 60 years) of a 28-day cycle. Primary endpoints included the overall response rate, and secondary objectives included overall survival., Results: Forty patients were enrolled. Of the 37 evaluable patients, 31 received indisulam with chemotherapy. Of these, 11 (35%) responded for a median duration of 5.3 months. The estimated 1-year overall survival rate was 51% for responders compared with 8 % for nonresponders (P < .001). The most common grade ≥3 nonhematologic toxicities were electrolyte abnormalities (50%) and febrile neutropenia (28%)., Conclusions: The combination of indisulam with idarubicin and cytarabine yielded a 35% response rate in heavily pretreated patients with AML. With emerging data identifying the expression of DCAF15 (DDB1 and CUL4-associated factor 15) as a potential biomarker for activity, the combination of indisulam with idarubicin and cytarabine should be studied in a biomarker-driven trial or in patients who have splicing factor mutations. Cancer 2018;124:2758-65. © 2018 American Cancer Society. Cancer 2018;124:2758-2765. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry-based minimal residual disease revealed that patients with CMC had significantly better event-free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML.

Background: The prognosis is poor for patients who have relapsed-refractory acute myelogenous leukemia (AML). Most published reports analyzed results from therapies in first-salvage AML or in studies that were conducted before 2000. Several novel agents and strategies are being tested for potential approval as treatment for patients with relapsed-refractory AML in second salvage. Therefore, it is important to establish the historic results of anti-AML therapies in this setting in the modern era. The objective of the current study was to analyze the results from second salvage therapies in patients with AML since 2000 with regard to response and survival., Methods: In total, 673 patients who received second salvage therapies for AML since 2000 were analyzed. Their median age was 60 years (range, 18-89 years). Salvage therapy consisted of cytarabine-based regimens in 267 patients, noncytarabine combinations in 37, hypomethylating agent-based regimens in 136, and phase 1 and 2 single agents in 233., Results: Eighty-six of the 673 patients (13%) achieved a complete response (CR) or a CR with low platelet count (CRp). The median duration of CR-CRp was 7.2 months. The median survival was 4.4 months (95% confidence interval, 4.0-4.8 months), and the 1-year survival rate was 16% (95% confidence interval, 14%-19%). Multivariate analysis identified the following as independent adverse factors for achievement of CR-CRp: platelets < 50 × 10 9 /L (P < .001), complex karyotype with ≥3 chromosomal abnormalities (P = .02), regimens that did not include cytarabine or hypomethylating agents (P = .014), and no prior CR lasting ≥12 months with frontline or salvage 1 therapies (P < .001). The independent adverse factors associated with worse survival were age ≥60 years (P = .01), platelets < 50 × 10 9 /L (P = .02), peripheral blasts ≥ 20% (P = .03), albumin ≤ 3 g/dL (P = .04), and complex karyotype (P = .003). The authors also applied and validated, in the current population, the 2 multivariate-derived prognostic models for CR and survival developed in their previous study of 594 patients who received treatment for second salvage AML from the previous 2 decades., Conclusions: This large-scale analysis establishes the modern historic results of second salvage therapy in AML and validates the prognostic models associated with outcome. These data could be used to analyze the differential benefits of current or future investigational strategies under evaluation in this setting and for the purpose of potential approval of new agents in the United States and the world. Cancer 2018;124:2534-40. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients ( N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A ( n = 23) and C ( n = 22) to confirm the recommended phase II dose (RP2D). Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting. Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294-303. ©2018 AACR ., (©2018 American Association for Cancer Research.)

The purine nucleoside analogues clofarabine and fludarabine are active in acute myeloid leukemia (AML). We conducted a phase I/II randomized study of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) for relapsed or refractory AML. Clofarabine 15 mg/m 2 was identified as the recommended phase II dose. Eighty-one patients were assigned using adaptive randomization to CIA (n = 48) or FIA (n = 33). The complete response (CR)/CR without platelet recovery rate did not differ between CIA and FIA (38% versus 30%, respectively; p = .50). In both arms, more than half of patients who had received only one prior line of therapy achieved remission. The median event-free survival for CIA and FIA was 2.0 and 1.9 months (p = .48), and the median overall survival was 6.3 and 4.7 months, respectively (p = .28). No significant differences in adverse events or early mortality rates were observed. Overall, CIA and FIA resulted in similar response rates and survival in patients with relapsed/refractory AML.

Background: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML)., Methods: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine., Results: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009])., Conclusions: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Chemoimmunotherapy regimens have been the standard first-line therapy for patients with chronic lymphocytic leukemia (CLL). For young, fit patients the standard of care is combination of fludarabine, cyclophosphamide, and rituximab (FCR). Based on the preclinical work demonstrating that bendamustine combined with fludarabine resulted in increased DNA damage, we designed a phase I-II clinical trial with fludarabine, bendamustine, and rituximab (FBR) for patients with relapsed/refractory CLL. Treatment consisted of fludarabine 20 mg/m2 daily x 3 days and rituximab 375-500 mg/m2 x 1 day. Phase I included bendamustine at increasing doses of 20, 30, 40, or 50 mg/m2 daily x 3 days; phase II was with FR, and B at the selected dose. DNA damage response (H2AX phosphorylation) was evaluated in a subset of patients. Fifty-one patients were enrolled. The median age was 62 years; median number of prior therapies was 2; 40% had del(11q); and 41 patients had received prior FCR-based therapies. Hematologic toxicity was more common in ≥40 mg/m2 dose cohorts. Maximum tolerated dose (MTD) was not identified. Bendamustine-elicited H2AX phosphorylation was not dose-dependent, but markedly increased after fludarabine. We identified bendamustine 30 mg/m2 as the safe dose for phase II. The overall response rate (ORR) was 67% with 36% complete response (CR) / CR with incomplete count recovery (CRi). Younger patients (<65 years) had significantly higher ORR (81% vs. 50%; p=0.038). The median progression-free survival was 19 months, and the median overall survival was 52.5 months. FBR is an effective and tolerable CIT regimen for patients with relapsed CLL.

In patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treated with chemotherapy plus a tyrosine kinase inhibitor (TKI), the prognostic impact of additional chromosomal abnormalities (ACAs) is not well-established. We evaluated the prognostic impact of individual ACAs in 152 patients with Ph+ ALL receiving first-line intensive chemotherapy plus either imatinib (n = 36), dasatinib (n = 74), or ponatinib (n = 42). ACAs were identified in 118 patients (78%). Compared to outcomes of patients without ACAs, ACAs were not associated with differences in either relapse-free survival (RFS; P = 0.42) or overall survival (OS; P = 0.51). When individual ACAs were evaluated, +der(22)t(9;22) and/or -9/9p in the absence of high hyperdiploidy (HeH) was present in 16% of patients and constituted a poor-risk ACA group. Patients with one or more poor-risk ACAs in the absence of HeH had significantly shorter RFS (5-year RFS rate 33% versus 59%, P = 0.01) and OS (5-year OS rate 24% versus 63%, P = 0.003). Poor-risk ACAs were prognostic in patients who received imatinib and dasatinib but not in those who received ponatinib. By multivariate analysis, this poor-risk ACA group was independently associated with worse RFS (HR 2.03 [95% CI 1.08-3.30], P = 0.03) and OS (HR 2.02 [95% CI 1.10-3.71], P = 0.02). Patients with Ph+ ALL who have +der(22)t(9;22) and/or -9/9p in the absence of HeH have relatively poor outcomes when treated with chemotherapy plus a TKI., (© 2016 Wiley Periodicals, Inc.)

Background: The clinical efficacy of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) plus ponatinib has not been compared with that of HCVAD plus dasatinib in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in a randomized clinical trial., Methods: The authors analyzed 110 patients with newly diagnosed Ph+ ALL who were enrolled in 2 consecutive, prospective, phase 2 clinical trials of frontline HCVAD with either dasatinib (63 patients) or ponatinib (47 patients). Propensity score analysis with 1:1 matching with the nearest neighbor matching method and inverse probability of treatment weighting (IPTW) analysis based on the propensity scores were performed to assess response rates, event-free survival (EFS), and overall survival (OS) between the cohorts., Results: Propensity score matching identified 41 patients in each cohort. With propensity score matching, the 3-year EFS rates for patients treated with HCVAD plus ponatinib and HCVAD plus dasatinib were 69% and 46%, respectively (P =.04), and the 3-year OS rates were 83% and 56%, respectively (P =.03). IPTW analysis using prematching cohorts demonstrated that patients treated with HCVAD plus ponatinib had significantly higher rates of minimal residual disease negativity by flow cytometry on day 21, complete cytogenetic response at complete response, major molecular response at complete response and at 3 months, and complete molecular response at 3 months. IPTW confirmed that treatment with HCVAD plus ponatinib was associated with longer EFS (P =.003) and OS (P =.001) compared with treatment with HCVAD plus dasatinib., Conclusions: The clinical outcome of patients treated with HCVAD plus ponatinib appears to be superior to that of patients treated with HCVAD plus dasatinib among individuals with Ph+ ALL. Cancer 2016;122:3650-6. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Both dasatinib and nilotinib are approved frontline therapy for chronic myeloid leukemia in chronic phase (CML-CP) based on randomized trials compared with imatinib. However, no head-to-head comparison of dasatinib and nilotinib has been conducted in patients with newly diagnosed CML-CP., Methods: The authors conducted a propensity score (PS) matched comparison of patients with CML-CP who received frontline therapy with either dasatinib (N = 102) or nilotinib (N = 104) under the respective phase 2 trials conducted in parallel., Results: PS matching resulted in 87 patients from each trial being matched for pretreatment characteristics. The 3-month BCR-ABL1/ABL1 ratio <10% rate was 93% with dasatinib and 94% with nilotinib (P = .25); the rates of major molecular response at 12 months were 77% and 85%, respectively (P = .13); and the rates of molecular response with 4.5-log reduction in the ratio at 36 months were 66% and 64%, respectively (P = .96). All other clinically relevant responses were similar between the 2 treatment cohorts. The 3-year probability of event-free survival was 89% among the patients who received dasatinib and 87% among those who received nilotinib (P = .99), and the corresponding 3-year overall survival probabilities were 99% and 93%, respectively (P = .95). No statistical difference was observed between the dasatinib and nilotinib groups in any of the other survival endpoints. The treatment discontinuation rate also was similar between the 2 cohorts (dasatinib group, 18%; nilotinib group, 19%; P = .82)., Conclusions: In a PS-matched cohort of patients with newly diagnosed CML-CP, dasatinib and nilotinib offer similar response and survival outcomes. Both drugs can be considered reasonable standard-of-care options as first-line therapy for patients with CML-CP. Cancer 2016;122:3336-3343. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Several studies reported improved outcomes of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated with pediatric-based ALL regimens. This prompted the prospective investigation of a pediatric Augmented Berlin-Frankfurt-Münster (ABFM) regimen, and its comparison with hyper-fractionated cyclophosphamide, vincristine, Adriamycin, and dexamethasone (hyper-CVAD) in AYA patients. One hundred and six AYA patients (median age 22 years) with Philadelphia chromosome- (Ph) negative ALL received ABFM from October 2006 through March 2014. Their outcome was compared to 102 AYA patients (median age 27 years), treated with hyper-CVAD at our institution. The complete remission (CR) rate was 93% with ABFM and 98% with hyper-CVAD. The 5-year complete remission duration (CRD) were 53 and 55%, respectively (P = 0.98). The 5-year overall survival (OS) rates were 60 and 60%, respectively. The MRD status on Day 29 and Day 84 of therapy was predictive of long-term outcomes on both ABFM and hyper-CVAD. Severe regimen toxicities with ABFM included hepatotoxicity in 41%, pancreatitis in 11%, osteonecrosis in 9%, and thrombosis in 19%. Myelosuppression-associated complications were most significant with hyper-CVAD. In summary, ABFM and hyper-CVAD resulted in similar efficacy outcomes, but were associated with different toxicity profiles, asparaginase-related with ABFM and myelosuppression-related with hyper-CVAD. Am. J. Hematol. 91:819-823, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The impact of achieving complete molecular response (CMR) in Philadelphia chromosome-positive (Ph(+)) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph(+) ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P = .005) and relapse-free survival (RFS; P = .002) than did MRD status at CR (P = .11 and P = .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P = .009) and RFS (126 vs 18 months, respectively; P = .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P = .01). Patients with Ph(+) ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT., (© 2016 by The American Society of Hematology.)

The prognostic value of minimal residual disease (MRD) assessed by multi-parameter flow cytometry (MFC) was investigated among 340 adult patients with B-cell acute lymphoblastic leukaemia (B-ALL) treated between 2004 and 2014 using regimens including the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine) backbone. Among them, 323 (95%) achieved complete remission (CR) and were included in this study. Median age was 52 years (range, 15-84). Median white blood cell count (WBC) was 9·35 × 10(9) /l (range, 0·4-658·1 ×1 0(9) /l). MRD by MFC was initially assessed with a sensitivity of 0·01%, using a 15-marker, 4-colour panel and subsequently a 6-colour panel on bone marrow specimens obtained at CR achievement and at approximately 3 month intervals thereafter. MRD negative status at CR was associated with improved disease-free survival (DFS) and overall survival (OS) (P = 0·004 and P = 0·03, respectively). Similarly, achieving MRD negative status at approximately 3 and 6 months was associated with improved DFS (P = 0·004 and P < 0·0001, respectively) and OS (P = 0·004 and P < 0·0001, respectively). Multivariate analysis including age, WBC at presentation, cytogenetics (standard versus high risk) and MRD status at CR, 3 and 6 months, indicated that MRD negative status at CR was an independent predictor of DFS (P < 0·05). Achievement of an MRD negative state assessed by MFC is an important predictor of DFS and OS in adult patients with ALL., (© 2015 John Wiley & Sons Ltd.)

Background: The long-term efficacy of a combination of chemotherapy and dasatinib in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is not well established., Methods: Patients received dasatinib with 8 cycles of alternating hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and high-dose cytarabine and methotrexate. Patients in complete remission (CR) continued maintenance dasatinib, vincristine, and prednisone for 2 years, which was followed by dasatinib indefinitely. Patients eligible for allogeneic stem cell transplantation (SCT) received it during their first CR., Results: Seventy-two patients with a median age of 55 years (range, 21-80 years) were treated; 69 (96%) achieved CR. Among them, 57 (83%) achieved cytogenetic CR after 1 cycle, and 64 (93%) achieved a major molecular response at a median of 4 weeks (range, 2-38 weeks). Sixty-five patients (94%) were negative for minimal residual disease assessed by flow cytometry at a median of 3 weeks (range, 2-37 weeks). Dasatinib-related grade 3 and 4 adverse events included bleeding, pleural/pericardial effusions, and elevated transaminases. With a median follow-up of 67 months (range, 33-97 months), 33 patients (46%) were alive, and 30 (43%) were in CR; 12 underwent allogeneic SCT. Thirty-nine patients died (3 at induction, 19 after relapse, 7 after SCT performed during first CR, and 10 during CR). The median disease-free survival and overall survival were 31 (range, 0.3-97 months) and 47 months (range, 0.2-97 months), respectively. Seven relapsed patients had BCR-ABL kinase domain mutations, including 4 with T315I., Conclusions: A combination of chemotherapy with dasatinib is effective in achieving long-term remission for patients with newly diagnosed Ph + ALL., (© 2015 American Cancer Society.)

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.)

Background: Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen., Methods: Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes., Results: The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively., Conclusions: ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD., (© 2014 American Cancer Society.)

Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of gemtuzumab ozogamicin in frontline regimens for CBF AML., (© 2014 Wiley Periodicals, Inc.)

CPX-351 is a liposomal formulation of cytarabine:daunorubicin designed to deliver synergistic drug ratios to leukemia cells. In this phase 2 study, newly diagnosed older acute myeloid leukemia (AML) patients were randomized 2:1 to first-line CPX-351 or 7+3 treatment. The goal was to determine efficacy and identify patient subgroups that may benefit from CPX-351 treatment. Response rate (complete remission + incomplete remission) was the primary end point, with event-free survival (EFS) and overall survival (OS) as secondary end points. The 126 patients entered were balanced for disease and patient-specific risk factors. Overall, CPX-351 produced higher response rates (66.7% vs 51.2%, P = .07), meeting predefined criteria for success (P < .1). Differences in EFS and OS were not statistically significant. A planned analysis of the secondary AML subgroup demonstrated an improved response rate (57.6% vs 31.6%, P = .06), and prolongation of EFS (hazard ratio [HR] = 0.59, P = .08) and OS (HR = 0.46, P = .01). Recovery from cytopenias was slower after CPX-351 (median days to absolute neutrophil count ≥1000: 36 vs 32; platelets >100 000: 37 vs 28) with more grade 3-4 infections but without increase in infection-related deaths (3.5% vs 7.3%) or 60-day mortality (4.7% vs 14.6%), indicating acceptable safety. These results suggest a clinical benefit with CPX-351, particularly among patients with secondary AML, and provide the rationale for a phase 3 trial currently underway in newly diagnosed secondary AML patients. This study is registered at Clinicaltrials.gov as #NCT00788892., (© 2014 by The American Society of Hematology.)

From 2001 to 2011, 122 patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia were treated with chemotherapy + imatinib (n = 54) or + dasatinib (n = 68). One hundred fifteen (94%) achieved complete remission (CR) including 101 patients who achieved it with only 1 induction course and had at least 1 minimal residual disease (MRD) assessment; 25 patients underwent an allogeneic stem cell transplant in first CR and were excluded, leaving 76 patients as the subject of this report. MRD monitoring by multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (PCR) was performed at the end of induction and at ~3-month intervals thereafter. Median age was 54 years (range, 21-84 years). There was no difference in survival by achievement of at least a major molecular response (MMR; BCR-ABL/ABL < 0.1%) at CR (P = .22). Patients achieving MMR at 3, 6, 9, and 12 months had a better survival (P = .02, .04, .05, and .01, respectively). Negative MFC at CR did not predict for improved survival (P = .2). At 3 and 12 months, negative MRD by MFC was associated with improved survival (P = .04 and .001). MRD monitoring by PCR and MFC identifies patients who benefit from treatment intensification in first CR.

Purpose: To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS)., Patients and Methods: Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely., Results: After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival., Conclusion: The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier-estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

Background: From 20% to 30% of patients with acute promyelocytic leukemia (APL) who are treated with all-trans retinoic acid (ATRA) develop recurrent disease. Arsenic trioxide (ATO) is an effective agent for the salvage of patients with recurrent APL, and gemtuzumab ozogamicin (GO) has shown activity in patients with APL., Methods: The authors investigated the efficacy of a combination of ATO, ATRA, and GO in 8 patients with APL in first recurrence (7 patients with hematologic recurrences and 1 patient with a molecular recurrence). All patients had received previous treatment with ATRA either alone or in combination with other agents. Patients received ATO 0.15 mg/kg intravenously until they achieved a bone marrow complete remission (CR). Once in CR, patients received consolidation with ATO, ATRA, and GO for 10 months. Patients then received maintenance with idarubicin, ATRA, 6-marcaptopurine, and oral methotrexate for 11 months., Results: All 7 patients who had hematologic recurrences achieved CR after a median of 39 days (range, 21-56 days). After a median follow-up of >/=36 months (range, 4-55 months), 6 patients remained alive in CR, and 2 patients died in CR. Six of 8 patients remained in second CR that was longer than their first CR. All 7 evaluable patients achieved molecular remission. There were no grade 3 or 4 extramedullary toxicities. Two patients died, 1 secondary to a complication of metastatic lung adenocarcinoma, and the other of sepsis., Conclusions: The combination of ATO, ATRA, and GO was effective and may achieve durable remissions in patients with APL in first recurrence. It should be considered as an effective alternative to allogeneic or autologous transplantation., ((c) 2007 American Cancer Society.)

Immune anaemias (IA) [auto-immune haemolytic anaemia (AIHA) and pure red cell aplasia (PRCA)] are complications of chronic lymphocytic leukaemia (CLL). Fludarabine has been associated with AIHA, whereas both rituximab and cyclophosphamide have been used to treat this condition. Combining these agents with fludarabine may reduce the likelihood of AIHA. We report on the incidence, outcome and pretreatment predictors of IA in 300 patients treated with fludarabine, cyclophosphamide and rituximab (FCR). Nineteen patients (6.5%) developed IA [AIHA (5.8%), PRCA (0.7%)] on or after treatment with FCR. Most patients (82.4%) with AIHA had a negative direct antiglobulin test (DAT). Additional markers of haemolysis (indirect hyperbilirubinaemia, reticulocytosis, low haptoglobin and elevated lactate dehydrogenase levels) confirmed the presence of AIHA in these patients. The majority of patients responded to therapies including steroids, ciclosporin, i.v. immunoglobulin, etc. High pretreatment levels of beta-2 microglobulin predicted for development of IA. No haemolytic crisis was observed during FCR therapy in eight patients with AIHA prior to FCR. Thus, the incidence of IA among CLL patients treated with FCR was comparable with historical rates. The diagnosis of AIHA can be considered even if the DAT is negative. Pre-existing AIHA need not preclude front-line FCR therapy.

A higher complete remission (CR) rate was observed in patients with acute myeloid leukemia (AML) who, on a prior randomized study of induction therapy, received gemtuzumab ozogamicin (GO) plus interleukin-11 (IL-11) rather than GO alone. An adaptive randomized phase III study of the addition of IL-11 to idarubicin and cytarabine (IA) induction in 100 patients >/=50 years of age with AML or high-risk myelodysplastic syndrome (MDS) was conducted. Median patient age was 67 years (range 50-82). Twenty-four of the 45 (53%) patients randomized to IA plus IL-11 achieved CR. Eight (33%) subsequently relapsed, 4 (17%) died in CR; median time to treatment failure (TTF) was 37 weeks. Twenty-nine of the 55 (53%) patients treated without IL-11 achieved CR. Eight (28%) subsequently relapsed, 2 (7%) died in CR; median TTF was 46 weeks. Median overall survivals were 21 and 59 weeks for the IA plus IL-11 and IA cohorts, respectively (p=0.271, log rank test; 0.435, Gehan-Breslow test). Ten episodes of the following grade 3 or 4 cardiopulmonary toxicities were observed in patients receiving IA plus IL-11, 12 such episodes in those receiving IA alone: atrial fibrillation, pleural effusions, myocardial infarction, bradycardia or hypotension. Two patients in each arm experienced grade 3 peripheral edema. There was no significant difference in incidence of any grade 3 or 4 adverse event, including thrombocytopenia, between treatment arms. There was no significant impact on CR rates, TTF, survival, or toxicity of adding an IL-11 regimen to IA induction in patients >/=50 years of age with AML.

As fludarabine, topotecan and cytarabine (ara-C) are effective in acute myeloid leukemia (AML), a pilot study of these three agents combined (FTA) was conducted. FTA consisted of topotecan 1.25 mg/m2 by CIV days 1-5, fludarabine 15 mg/m2 and ara-C 0.5 g/m2 IV, BID, on days 2-6. Seventeen patients (6 primary resistant, 11 relapsed) with AML received 33 courses of FTA. Six patients (35%) achieved complete remission. Seven patients (41%) developed grade 3 or 4 diarrhea. FTA was effective and warrants further study in patients with refractory AML.

Purpose: Mylotarg, a humanized anti-CD33 antibody linked to an antitumor antibiotic, is approved for the treatment of patients with relapsed acute myeloid leukemia (AML). Its role as a component of post-remission therapy in AML has not been established. The Mylotarg, fludarabine, cytarabine, and cyclosporine (MFAC) regimen was evaluated in patients in complete remission following Mylotarg-containing regimens., Methods: The MFAC regimen comprised: Mylotarg 4.5 mg/m2 intravenously (i.v.) over 2 h after a loading dose of cyclosporine A (CSA) on day 1; fludarabine 15 mg/m2 i.v. over 30 min every 12 h for six doses on days 2 through 4; ara-C 0.5 g/m2 over 2 h every 12 h for six doses on days 2 through 4, 4 h after fludarabine started; CSA 6 mg/kg over 2 h, followed by 16 mg/kg continuous i.v. infusion on days 1 and 2. Patients in complete remission (CR) commenced idarubicin and ara-C (IA) alternating with MFAC or vice versa for 9 months from the date of CR. Idarubicin was administered at 8 mg/m2 on days 1 and 2 and ara-C at 1.5 g/m2 on days 1 and 2., Results: A total of 22 patients received 76 courses of MFAC (35 courses) alternating with IA (41 courses) or vice versa. The interval between courses, and degrees of myelosuppression, were equivalent in the alternating regimens. Failure-free and 12-month survival rates of were 32% and 55%, respectively. Grade 3/4 toxicities, including sepsis, neutropenic fever, and nausea/vomiting, were equivalent with MFAC and IA., Conclusions: Post-remission therapy with MFAC is feasible and well tolerated in patients with AML.

Purpose: Amifostine is an organic thiophosphate that may selectively protect normal tissues from the toxicities of chemotherapy. The combination of fludarabine and cyclophosphamide (FC) is highly active in patients with chronic lymphocytic leukemia (CLL). Infection is a serious toxicity of the FC regimen., Methods: Amifostine was added to the FC regimen in a phase II study of 46 patients with CLL. Patients received FCA (fludarabine 30 mg/m(2) i.v. daily for 3 days, cyclophosphamide 300 mg/m(2) i.v. daily for 3 days, and amifostine 500 mg i.v. over 15 min daily for 3 days starting 30 min before cyclophosphamide) at intervals of 4-6 weeks for a maximum of six courses., Results: Patients receiving FCA had equivalent rates of sepsis, early death, objective response and survival to those observed in a prior series of 78 patients treated with FC. Amifostine-associated toxicities included nausea, vomiting, and hypotension., Conclusion: The study amifostine regimen did not reduce the toxicity or activity of the FC regimen in patients with CLL.

Purpose: Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin. A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy., Patients and Methods: Patients were randomized to receive idarubicin and ara-C (IA) versus troxacitabine and ara-C (TA) versus troxacitabine and idarubicin (TI). A Bayesian design was used to adaptively randomly assign patients to treatment. Thus, although there was initially an equal chance for randomization to IA, TA, or TI, treatment arms with a higher success rate progressively received a greater proportion of patients., Results: Thirty-four patients were treated. Randomization to TI stopped after five patients and randomization to TA stopped after 11 patients. Defining success as complete remission (CR) that occurred within 49 days of starting treatment, success rates were 55% (10 of 18 patients) with IA, 27% (three of 11 patients) with TA, and 0% (zero of five patients) with TI. Because three CRs occurred after day 49, final CR rates were 55% (10 of 18 patients) with IA, 45% (five of 11 patients) with TA, and 20% (one of five patients) with TI. The probability that TA was inferior to IA was 70%, with a 5% probability that TA would have a 20% higher CR rate than IA. Survival was equivalent with all three regimens., Conclusion: Neither troxacitabine combination was superior to IA in elderly patients with previously untreated adverse karyotype AML.