Showing papers by "Elias Jabbour published in 2016"

TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes.

Abstract: BACKGROUND Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53–mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ≥60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ≤ .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484–3491. © 2016 American Cancer Society

Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: A propensity score analysis

Abstract: 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.

Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring.

Abstract: Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients’ comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease. Am. J. Hematol. 91:253–265, 2016. © 2015 Wiley Periodicals, Inc.

Rigosertib versus best supportive care for patients with high-risk myelodysplastic syndromes after failure of hypomethylating drugs (ONTIME): a randomised, controlled, phase 3 trial

Abstract: Summary Background Hypomethylating drugs are the standard treatment for patients with high-risk myelodysplastic syndromes. Survival is poor after failure of these drugs; there is no approved second-line therapy. We compared the overall survival of patients receiving rigosertib and best supportive care with that of patients receiving best supportive care only in patients with myelodysplastic syndromes with excess blasts after failure of azacitidine or decitabine treatment. Methods We did this randomised controlled trial at 74 hospitals and university medical centres in the USA and Europe. We enrolled patients with diagnosis of refractory anaemia with excess blasts (RAEB)-1, RAEB-2, RAEB-t, or chronic myelomonocytic leukaemia based on local site assessment, and treatment failure with a hypomethylating drug in the past 2 years. Patients were randomly assigned (2:1) to receive rigosertib 1800 mg per 24 h via 72-h continuous intravenous infusion administered every other week or best supportive care with or without low-dose cytarabine. Randomisation was stratified by pretreatment bone marrow blast percentage. Neither patients nor investigators were masked to treatment assignment. The primary outcome was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT01241500. Findings From Dec 13, 2010, to Aug 15, 2013, we enrolled 299 patients: 199 assigned to rigosertib, 100 assigned to best supportive care. Median follow-up was 19·5 months (IQR 11·9–27·3). As of Feb 1, 2014, median overall survival was 8·2 months (95% CI 6·1–10·1) in the rigosertib group and 5·9 months (4·1–9·3) in the best supportive care group (hazard ratio 0·87, 95% CI 0·67–1·14; p=0·33). The most common grade 3 or higher adverse events were anaemia (34 [18%] of 184 patients in the rigosertib group vs seven [8%] of 91 patients in the best supportive care group), thrombocytopenia (35 [19%] vs six [7%]), neutropenia (31 [17%] vs seven [8%]), febrile neutropenia (22 [12%] vs ten [11%]), and pneumonia (22 [12%] vs ten [11%]). 41 (22%) of 184 patients in the rigosertib group and 30 (33%) of 91 patients in the best supportive care group died due to adverse events and three deaths were attributed to rigosertib treatment. Interpretation Rigosertib did not significantly improve overall survival compared with best supportive care. A randomised phase 3 trial of rigosertib (NCT 02562443) is underway in specific subgroups of patients deemed to be at high risk, including patients with very high risk per the Revised International Prognostic Scoring System criteria. Funding Onconova Therapeutics, Leukemia & Lymphoma Society.

Activity of the oral mitogen-activated protein kinase kinase inhibitor trametinib in RAS-mutant relapsed or refractory myeloid malignancies

Abstract: BACKGROUND RAS/RAF/mitogen-activated protein kinase activation is common in myeloid malignancies. Trametinib, a mitogen-activated protein kinase kinase 1 (MEK1)/MEK2 inhibitor with activity against multiple myeloid cell lines at low nanomolar concentrations, was evaluated for safety and clinical activity in patients with relapsed/refractory leukemias. METHODS This phase 1/2 study accrued patients with any relapsed/refractory leukemia in phase 1. In phase 2, this study accrued patients with relapsed/refractory acute myeloid leukemia (AML) or high-risk myelodysplastic syndromes (MDS) with NRAS or KRAS mutations (cohort 1); patients with AML, MDS, or chronic myelomonocytic leukemia (CMML) with a RAS wild-type mutation or an unknown mutation status (cohort 2); and patients with CMML with an NRAS or KRAS mutation (cohorts 3). RESULTS The most commonly reported treatment-related adverse events were diarrhea, rash, nausea, and increased alanine aminotransferase levels. The phase 2 recommended dose for Trametinib was 2 mg orally daily. The overall response rates were 20%, 3%, and 27% for cohorts 1, 2, and 3, respectively, and this indicated preferential activity among RAS-mutated myeloid malignancies. Repeated cycles of trametinib were well tolerated with manageable or reversible toxicities; these results were similar to those of other trametinib studies. CONCLUSIONS The selective, single-agent activity of trametinib against RAS-mutated myeloid malignancies validates its therapeutic potential. Combination strategies based on a better understanding of the hierarchical role of mutations and signaling in myeloid malignancies are likely to improve the response rate and duration. Cancer 2016;122:1871–9. © 2016 American Cancer Society.

Minimal residual disease assessed by multi-parameter flow cytometry is highly prognostic in adult patients with acute lymphoblastic leukaemia.

Abstract: 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.

Final results of a single institution experience with a pediatric-based regimen, the augmented Berlin–Frankfurt–Münster, in adolescents and young adults with acute lymphoblastic leukemia, and comparison to the hyper-CVAD regimen

Abstract: 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-Munster (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.

Crenolanib besylate, a type I pan-FLT3 inhibitor, to demonstrate clinical activity in multiply relapsed FLT3-ITD and D835 AML.

Abstract: 7008Background: We investigated the clinical activity, PK, safety and resistance mechanisms to single-agent crenolanib patients (pts) with refractory/relapsed acute myeloid leukemia (R/R AML) with FLT3 ITD. Methods: From Aug 2012 to May 2015, 69 pts (65 evaluable) with R/R FLT3+ AML (29 ITD, 11 D835, 29 ITD+D835) were treated with crenolanib 100 mg TID (42) or 200 mg/m2/d in 3 divided doses (27). Results: Crenolanib therapy resulted in a 39% CRi and 11% PR amongst the 18 pts (6 D835, 9 ITD, 3 ITD+D835) with R/R FLT3 AML who had not received prior FLT3 inhibitors (Cohort A). OS was 234d (238d in pts with ≤ 2 prior therapies and 133d in ≥ 3 prior therapies). Activity was seen in FLT3 ITD (OS 238d), TKD (OS 185d), and TKD+ITD (128d). Pts < 60 had a higher survival (OS 234d) than those ≥ 60 (OS 185d). 36 pts received crenolanib after progressing on prior TKIs (Cohort B), sorafenib (28), quizartinib (11), midostaurin (3), pexidartinib (4), gilteritinib (2) and FLX-925 (1). 10 pts had received ≥ 2 prior TKIs. F...

IDH1 and IDH2 mutations in myelodysplastic syndromes and role in disease progression.

Abstract: Recurrent pathogenic mutations in IDH1 and IDH2 at the conserved amino acid sites IDH1-R132, IDH2-R140 and IDH2-R172 occur in ~20% of patients with acute myeloid leukemia (AML).1 A recent analysis of AML patients at our institution identified IDH1/2 mutations in 20% (n=167) of 826 AML patients, with IDH1/2 mutations occurring most frequently in the setting of diploid karyotype or other intermediate-risk cytogenetics, particularly trisomy 8 (77 vs 53%, P<0.0005). AML patients with IDH1/2 mutations were overall less likely to have a diagnosis of therapy-related AML (8 vs 17%, P=0.003).2

Clinical implications of TP53 mutations in myelodysplastic syndromes treated with hypomethylating agents.

Abstract: // Koichi Takahashi 1, 3, 4 , Keyur Patel 2 , Carlos Bueso-Ramos 2 , Jianhua Zhang 3 , Curtis Gumbs 3 , Elias Jabbour 1 , Tapan Kadia 1 , Michael Andreff 1 , Marina Konopleva 1 , Courtney DiNardo 1 , Naval Daver 1 , Jorge Cortes 1 , Zeev Estrov 1 , Andrew Futreal 3 , Hagop Kantarjian 1 , Guillermo Garcia-Manero 1 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Correspondence to: Guillermo Garcia-Manero, e-mail: ggarciam@mdanderson.org Keywords: TP53, myelodysplastic syndromes, hypomethylating agents Received: October 17, 2015 Accepted: January 09, 2016 Published: February 9, 2016 ABSTRACT We screened TP53 mutations in 168 MDS patients who were treated with HMA and evaluated predictive and prognostic value of TP53 mutations. Overall response to HMA was not different based on TP53 mutation status (45% vs. 32% in TP53 -mutated and wild type [WT], respectively, P = 0.13). However, response duration was significantly shorter in TP53 -mutated patients compared to WT patients (5.7 months vs. 28.5 months, P = 0.003). Longitudinal analysis of TP53 mutations after HMA showed that TP53 mutations almost always persisted at times of disease progression. TP53 -mutated patients showed significantly worse overall survival (OS) compared to WT patients (9.4 months vs. 20.7 months, P <0.001). Further, TP53 mutations distinguished prognosis in the subgroup of patients with complex karyotype and Revised International Prognostic Scoring System (IPSS-R) defined very high-risk disease. Multivariate analysis showed that TP53 mutation status is significantly prognostic for OS after adjusting prognostic effect from other factors. The current study provides evidence that TP53 mutations are independently prognostic in MDS patients treated with HMA. While TP53 -mutated MDS patients initially respond well to HMA, their duration of response is significantly shorter than WT patients. Novel strategies to improve duration of response in TP53- mutated MDS are urgently needed.

A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome

Abstract: Decitabine may open the chromatin structure of leukemia cells making them accessible to the calicheamicin epitope of gemtuzumab ozogamicin (GO). A total of 110 patients (median age 70 years; range 27-89 years) were treated with decitabine and GO in a trial designed on model-based futility to accommodate subject heterogeneity: group 1: relapsed/refractory acute myeloid leukemia (AML) with complete remission duration (CRD) <1 year (N=28, 25%); group 2: relapsed/refractory AML with CRD ⩾1 year (N=5, 5%); group 3: untreated AML unfit for intensive chemotherapy or untreated myelodysplastic syndrome (MDS) or untreated myelofibrosis (MF; N=57, 52%); and group 4: AML evolving from MDS or relapsed/refractory MDS or MF (N=20, 18%). Treatment consisted of decitabine 20 mg/m(2) daily for 5 days and GO 3 mg/m(2) on day 5. Post-induction therapy included five cycles of decitabine+GO followed by decitabine alone. Complete remission (CR)/CR with incomplete count recovery was achieved in 39 (35%) patients; group 1= 5/28 (17%), group 2=3/5 (60%), group 3=24/57 (42%) and group 4=7/20 (35%). The 8-week mortality in groups 3 and 4 was 16% and 10%, respectively. Common drug-related adverse events included nausea, mucositis and hemorrhage. Decitabine and GO improved the response rate but not overall survival compared with historical outcomes in untreated AML ⩾60 years.

A Phase II Study of Coltuximab Ravtansine (SAR3419) Monotherapy in Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia

Abstract: Background Long-term disease-free survival in adult patients with acute lymphoblastic leukemia (ALL) remains unsatisfactory, and treatment options are limited for those patients who relapse or fail to respond following initial therapy. We conducted a dose-escalation/expansion phase 2, multicenter, single-arm study to determine the optimal dose of coltuximab ravtansine (SAR3419), an anti-CD19 antibody-drug conjugate, in this setting. Patients and Methods The dose-escalation part of the study determined the selected dose of coltuximab ravtansine for evaluation of efficacy and safety in the dose-expansion phase. Patients received coltuximab ravtansine induction therapy (up to 8 weekly doses); responding patients were eligible for maintenance therapy (biweekly administrations for up to 24 weeks). Three dose levels of coltuximab ravtansine were examined: 55, 70, and 90 mg/m2. The primary endpoint was objective response rate (ORR). Secondary endpoints included duration of response (DOR) and safety. Results A total of 36 patients were treated: 19 during dose escalation; 17 during dose expansion. One dose-limiting toxicity was observed at 90 mg/m2 (grade 3 peripheral motor neuropathy), and therefore 70 mg/m2 was selected for the dose-expansion phase. Five patients discontinued therapy due to adverse events (AEs). The most common AEs were pyrexia, diarrhea, and nausea. Of 17 evaluable patients treated at the selected dose, 4 responded (estimated ORR using Bayesian methodology: 25.47% [80% confidence interval: 14.18-39.6%]); DOR was 1.94 (range: 1-5.6) months. Based on these results, the study was prematurely discontinued. Conclusions Coltuximab ravtansine is well tolerated but is associated with a low clinical response rate in patients with relapsed/refractory ALL

Chronic myeloid leukemia: First-line drug of choice

Abstract: The advent of tyrosine kinase inhibitors (TKIs) has drastically changed the treatment outcome of chronic myeloid leukemia (CML). Imatinib was the first TKI approved, and has been considered the standard of care for more than a decade. Second generation compounds, namely dasatinib and nilotinib, are highly effective in newly diagnosed patients as well as those who fail imatinib. Second generation TKIs have been demonstrated to induce deeper and faster responses compared to imatinib, however no survival advantage has been observed so far. Today, the expected survival of CML patients, if properly managed, is likely to be similar to the general population. Clinicians are faced the challenge of making decision for which TKI to choose upfront. Comorbidities of the patient, the side effect profile, and the cost of the TKI of interest should be an important consideration in decision making. Whatever TKI is chosen as frontline, noncompliance or treatment failure should be recognized early as a prompt intervention increases the chance of achieving best possible response. Herein, we review the frontline options for the management of patients with CML and how to best choose these agents.

Interactions and relevance of blast percentage and treatment strategy among younger and older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS).

Abstract: Acute myeloid leukemia (AML) is defined as ≥20% myeloblasts, representing a change from original guidelines where ≤30% blasts were considered as myelodysplastic syndromes (MDS), and 20-29% blasts classified as refractory anemia with excess blasts in transformation (RAEB-T). Whether the diagnostic bone marrow blast percentage has current value with regards to patient prognostication or identification of optimal treatment strategies is unclear. We retrospectively studied 1652 treatment-naive adults with MDS or AML and ≥10% blasts from January 2000 to April 2014. Patients with 20-29% blasts were more similar to MDS patients in terms of advanced age, increased frequency of poor-risk cytogenetics, lower WBC count, and less frequent NPM1 and FLT3-ITD mutations. Median overall survival of MDS and RAEB-T were similar, 16.0 and 16.0 months, compared to 13.5 months for AML with ≥30% blasts (P = 0.045). Multivariate analysis showed inferior survival with increased age (HR 1.81 age 60-69, HR 2.68 age ≥70, P < 0.0005); poor-risk cytogenetics (HR 2.25, P < 0.0005); therapy-related disease (HR 1.44, P < 0.0005); and markers of proliferative disease including WBC ≥25 × 10(9) /L (HR 1.35, P = 0.0003), elevated LDH count (HR 1.24, P = 0.0015), and peripheral blasts (HR 1.25, P = 0.004). Among younger patients (≤60 years), intensive AML-type therapy resulted in similar outcomes regardless of blast percentage, suggesting this to be optimal therapy in this context. Among older patients (≥70 years), patients with 20-29% blasts had similar outcomes to patients with <20% blasts, and better than those with ≥30% blasts. In addition, among older patients, epigenetic therapy provided at least equivalent outcome to intensive chemotherapy.

The efficacy of current prognostic models in predicting outcome of patients with myelodysplastic syndromes at the time of hypomethylating agent failure

Abstract: Several prognostic scoring systems have been developed to risk stratify patients with myelodysplastic syndromes (MDS) in order to serve as clinical decision tools. Such models include: the International Prognostic Scoring System (IPSS),[1][1] the World Health Organization (WHO) classification-based

Phase I study of evofosfamide, an investigational hypoxia-activated prodrug, in patients with advanced leukemia.

Abstract: Tumor hypoxia causes resistance to radiation and chemotherapy Evofosfamide (TH-302) has exhibited specific hypoxia-dependent cytotoxicity against primary acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) samples in vitro Based on these findings, a Phase I study of evofosfamide was designed for patients with relapsed/refractory leukemia (NCT01149915) In this open-label study, patients were treated with evofosfamide as a 30-60 min/day infusion on Days 1-5 of a 21-day cycle (Arm A, n = 38) or as a continuous infusion over 120 hr over Days 1-5 of a 21-day cycle (Arm B, n = 11) Forty-nine patients were treated including 39 (80%) with AML and 9 (18%) with ALL Patients had received a median of five prior therapies In Arm A, the dose-limiting toxicities (DLTs) were grade 3 esophagitis, observed at a dose of 550 mg/m(2) The maximum tolerated dose (MTD) was a daily dose of 460 mg/m(2) In Arm B, the DLTs were grade 3 stomatitis and hyperbilirubinemia, observed at a daily dose of 460 mg/m(2) The continuous infusion MTD was a daily dose of 330 mg/m(2) Hypoxia markers HIF-1α and CAIX were highly expressed in leukemic bone marrow and were significantly reduced after evofosfamide therapy The combined overall response rate in Arms A and B was 6% (2 CR/CRi and 1 PR), with all responses seen in Arm A Evofosfamide has shown limited activity in heavily pretreated leukemia patients Further evaluation investigating evofosfamide in combination with cytotoxic or demethylating agents is warranted Am J Hematol 91:800-805, 2016 © 2016 Wiley Periodicals, Inc

Conditional survival in patients with chronic myeloid leukemia in chronic phase in the era of tyrosine kinase inhibitors.

Abstract: BACKGROUND Tyrosine kinase inhibitors (TKIs) significantly improve survival in patients with chronic myeloid leukemia in chronic phase (CML-CP). Conditional probability provides survival information in patients who have already survived for a specific period of time after treatment. METHODS Cumulative response and survival data from 6 consecutive frontline TKI clinical trials were analyzed. Conditional probability was calculated for failure-free survival (FFS), transformation-free survival (TFS), event-free survival (EFS), and overall survival (OS) according to depth of response within 1 year of the initiation of TKIs, including complete cytogenetic response, major molecular response, and molecular response with a 4-log or 4.5-log reduction. RESULTS A total of 483 patients with a median follow-up of 99.4 months from the initiation of treatment with TKIs were analyzed. Conditional probabilities of FFS, TFS, EFS, and OS for 1 additional year for patients alive after 12 months of therapy ranged from 92.0% to 99.1%, 98.5% to 100%, 96.2% to 99.6%, and 96.8% to 99.7%, respectively. Conditional FFS for 1 additional year did not improve with a deeper response each year. Conditional probabilities of TFS, EFS, and OS for 1 additional year were maintained at >95% during the period. CONCLUSIONS In the era of TKIs, patients with chronic myeloid leukemia in chronic phase who survived for a certain number of years maintained excellent clinical outcomes in each age group. Cancer 2016;122:238–248. © 2015 American Cancer Society.

Unraveling Myelodysplastic Syndromes: Current Knowledge and Future Directions

Abstract: Myelodysplastic syndromes (MDS) affect more than 30,000 patients in the USA per year, most of whom are elderly, and these diseases are associated with dismal prognoses. The main features of MDS are ineffective hematopoiesis and aberrant myeloid differentiation. Furthermore, MDS are heterogeneous, both clinically and molecularly. This heterogeneity and the frequent occurrence of age-related comorbidities make the management of these diseases challenging. In fact, there have been no new drug approvals for MDS in the USA in the last 9 years, and few currently available investigational drugs are likely to be approved in the near future. Novel targeted treatment based on better understanding of the pathogenesis of MDS is needed to maximize patient outcomes. Here, we discuss new insights into diagnostic accuracy, prognostic assessment, pathogenic mechanisms, and effective treatments for MDS.

Clofarabine Plus Low-Dose Cytarabine Is as Effective as and Less Toxic Than Intensive Chemotherapy in Elderly AML Patients

Abstract: Introduction Most patients with acute myeloid leukemia (AML) age ≥ 60 years are not offered intensive induction because of high mortality. Phase 2 studies of clofarabine plus low-dose cytarabine (CLDA) as frontline therapy for elderly AML patients demonstrated high response and acceptable toxicity. Patients and Methods We hypothesized that induction therapy with CLDA provides equivalent outcomes to but is less toxic than intensive induction in these patients. To test this hypothesis, we conducted a propensity score-matched comparison of AML patients age ≥ 60 years given induction CLDA versus idarubicin and cytarabine (IA). Ninety-five patients in both groups were matched according to their propensity score. Results We did not observe statistically significant differences in response, overall survival, or mortality rate between the two induction regimens. However, CLDA produced significantly fewer grade 3 or worse toxicities (46% for CLDA vs. 62% for IA; P = .03). Furthermore, among responders, the median response duration was significantly longer with CLDA when we censored patients who underwent stem cell transplantation (15.9 months for CLDA vs. 7.0 months for IA; P = .033). Conclusion Compared with intensive induction, CLDA offers equivalent responses and survival but less toxicity in clinically well-matched cohorts of elderly AML patients. Prospective randomized trials to confirm these findings are warranted.