Follow-up of patients with R/R FLT3-mutation-positive AML treated with gilteritinib in the phase 3 ADMIRAL trial.

The phase 3 ADMIRAL (NCT02421939; Study ID: 2215-CL-0301) trial showed superior overall survival in patients with relapsed/refractory FLT3-mutation-positive acute myeloid leukemia (AML) randomized 2:1 to receive the oral FMS-like tyrosine kinase 3 inhibitor gilteritinib vs those randomized to receive salvage chemotherapy (SC). Here we provide a follow-up of the ADMIRAL trial 2 years after the primary analysis to clarify the long-term treatment effects and safety of gilteritinib in these patients with AML. At the time of this analysis, the median survival follow-up was 37.1 months, with deaths in 203 of 247 and 97 of 124 patients in the gilteritinib and SC arms, respectively; 16 gilteritinib-treated patients remained on treatment. The median overall survival for the gilteritinib and SC arms was 9.3 and 5.6 months, respectively (hazard ratio, 0.665; 95% confidence interval [CI], 0.518, 0.853; two-sided P = .0013); 2-year estimated survival rates were 20.6% (95% CI, 15.8, 26.0) and 14.2% (95% CI, 8.3, 21.6). The gilteritinib-arm 2-year cumulative incidence of relapse after composite complete remission was 75.7%, with few relapses occurring after 18 months. Overall, 49 of 247 patients in the gilteritinib arm and 14 of 124 patients in the SC arm were alive for ≥2 years. Twenty-six gilteritinib-treated patients remained alive for ≥2 years without relapse; 18 of these patients underwent transplantation (hematopoietic stem cell transplantation [HSCT]) and 16 restarted gilteritinib as post-HSCT maintenance therapy. The most common adverse events of interest during years 1 and 2 of gilteritinib therapy were increased liver transaminase levels; adverse event incidence decreased in year 2. Thus, continued and post-HSCT gilteritinib maintenance treatment sustained remission with a stable safety profile. These findings confirm that prolonged gilteritinib therapy is safe and is associated with superior survival vs SC. This trial was registered at www.clinicaltrials.gov as #NCT02421939.

Prognostic impact of 'multi-hit' versus 'single hit' TP53 alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases.

While there is clear evidence to suggest poorer outcome associated with multi-hit (MH) TP53 mutation compared to single-hit (SH) in lower-risk myelodysplastic syndrome (MDS), data are conflicting in both higher-risk MDS and acute myeloid leukemia (AML). We conducted an indepth analysis utilizing data from 10 US academic institutions to study differences in molecular characteristics and outcomes of SH (n= 139) versus MH (n= 243) TP53MTAML. Complex cytogenetics (CG) were more common in MH compared to SH TP53MT AML (p <0.001); whereas ASXL1 (p= <0.001), RAS (p<0.001), splicing factor (p= 0.003), IDH1/2 (p= 0.001), FLT3 ITD (p= <0.001) and NPM1 (p= 0.005) mutations significantly clustered with SH TP53MT AML. Survival after excluding patients who received best supportive care alone was dismal but not significantly different between SH and MH (event free survival [EFS]: 3.0 vs 2.20 months, p= 0.22/ overall survival [OS]: 8.50 vs 7.53 months, respectively, p= 0.13). In multivariable analysis, IDH1 mutation and allogeneic hematopoietic stem cell transplantation (allo-HCT) as a time-dependent covariate were associated with superior EFS (HR; 0.44, 95% CI: 0.19-1.01, p= 0.05/ HR; 0.34, 95% CI: 0.18-0.62, p<0.001) and OS (HR; 0.24, 95% CI: 0.08-0.71, p= 0.01/ HR; 0.28, 95% CI: 0.16-0.47, p<0.001). While complex CG (HR; 1.56, 95% CI: 1.01-2.40, p= 0.04) retained unfavorable significance for OS. Our analysis suggests that unlike in MDS, multihit TP53MT is less relevant in independently predicting outcomes in patients with AML.

A phase I study of pevonedistat, azacitidine, and venetoclax in patients with relapsed/refractory acute myeloid leukemia.

Azacitidine/venetoclax is an active regimen in patients with newly diagnosed AML. However, primary or secondary resistance to azacitidine/venetoclax is an area of unmet need and overexpression of MCL-1 is suggested to be a potential resistance mechanism. Pevonedistat inhibits MCL-1 through activation of NOXA, and pevonedistat/azacitidine has previously shown activity in AML. To assess the tolerability and efficacy of adding pevonedistat to azacitidine/venetoclax in relapsed/refractory AML, we conducted a phase I multicenter openlabel study in 16 adults with relapsed/refractory AML. Patients were treated with azacitidine, venetoclax along with pevonedistat intravenously on days 1, 3 and 5 of each 28-day cycle at 10, 15 or 20 mg/m2 in successive cohorts in the dose escalation phase. The impact of treatment on protein neddylation as well as expression of pro-apoptotic BCL2 family members was assessed. The recommended phase II dose of pevonedistat was 20 mg/m2. Grade 3 or higher adverse events included neutropenia (31%), thrombocytopenia (13%), febrile neutropenia (19%), anemia (19%), hypertension (19%) and sepsis (19%). The overall response rate was 46.7% for the whole cohort including complete remission (CR) in 5 of 7 (71.4%) patients who were naïve to the hypomethylating agent/venetoclax. No measurable residual disease (MRD) was detected in 80.0% of the patients who achieved CR. The median time to best response was 50 (range: 23 - 77) days. Four patients were bridged to allogeneic stem cell transplantation. The combination of azacitidine, venetoclax and pevonedistat is safe and shows encouraging preliminary activity in patients with relapsed/refractory AML. (NCT04172844).

Clinical outcomes of hypomethylating agents plus Venetoclax as frontline treatment in patients 75 years and older with acute myeloid leukemia: Real-world data from eight US academic centers.

Venetoclax (VEN) combined with hypomethylating agents (HMAs) is the standard of care for the treatment of patients with newly diagnosed acute myeloid leukemia (AML) unfit for intensive chemotherapy. To date, real-world data published on HMAs plus VEN have been either single-center studies or using community-based electronic databases with limited details on mutational landscape, tolerability, and treatment patterns in elderly patients. Therefore, we conducted a multicenter retrospective study to assess the real-world experience of 204 elderly patients (≥75 years) with newly diagnosed AML treated with HMAs plus VEN from eight academic centers in the United States. Overall, 64 patients achieved complete remission (CR; 38%) and 43 CR with incomplete count recovery (CRi; 26%) for a CR/CRi rate of 64%, with a median duration of response of 14.2 months (95% CI: 9.43, 22.1). Among responders, 63 patients relapsed (59%) with median overall survival (OS) after relapse of 3.4 months (95% CI, 2.4, 6.7). Median OS for the entire population was 9.5 months (95% CI, 7.85-13.5), with OS significantly worse among patients with TP53-mutated AML (2.5 months) and improved in patients harboring NPM1, IDH1, and IDH2 mutations (13.5, 18.3, and 21.1 months, respectively). The 30-day and 60-day mortality rates were 9% and 19%, respectively. In conclusion, HMAs plus VEN yielded high response rates in elderly patients with newly diagnosed AML. The median OS was inferior to that reported in the VIALE-A trial. Outcomes are dismal after failure of HMAs plus VEN, representing an area of urgent unmet clinical need.

Disparities in receiving disease-directed therapy, allogeneic stem cell transplantation in non-Hispanic Black patients with TP53-mutated acute myeloid leukemia.

BACKGROUND: Although the clinical outcomes of patients with TP53-mutated acute myeloid leukemia (AML) are dismal, subsets of patients eligible for curative-intent therapies may fare better. Because racial disparities are known to affect outcome in hematologic malignancies, the authors sought to explore disparities among patients with TP53-mutated AML. METHODS: A multicenter, retrospective study was conducted in a cohort of 340 patients who had TP53-mutated AML (275 non-Hispanic White [NHW] and 65 non-Hispanic Black [NHB]) to analyze differences in treatment and outcome among NHW and NHB patients. RESULTS: The median patient age was comparable between NHW and NHB patients (p = .76). A higher proportion of NHB patients had therapy-related AML (31% vs. 20%; p = .08) and had co-mutations (74% vs. 61%; p = .06). A higher proportion of NHW patients received intensive chemotherapy compared with NHB patients (47% vs. 31%; p = .02). Conversely, a higher proportion of NHB patients received low-intensity chemotherapy (9% vs. 5.5%; p = .02) or best supportive care (22% vs. 7%; p < .001). The complete response rate (including complete responses with or without complete count recovery) was 31% versus 24.5% (p = .39) in NHW and NHB patients, respectively. Only 5% of NHB patients received allogeneic stem cell transplantation compared with 15.5% of NHW patients (p = .02). The proportion of patients who were event-free (18.5% vs. 8.5%; p = .49) or who remained alive (24.9% vs. 8.3%; p = .13) at 18 months was numerically higher in NHW versus NHB patients, respectively, but was not statistically significant. CONCLUSIONS: The current study highlights disparities between NHW and NHB patients with TP53-mutated AML. Efforts are warranted to eliminate treatment disparities in minority populations.

Proposals for Clinical Trials in Chronic Myelomonocytic Leukemia.

OPINION STATEMENT: Chronic myelomonocytic leukemia (CMML) is a clonal hematologic malignancy of mostly older individuals that exhibits both myelodysplastic and myeloproliferative features. CMML presentation and outcome are variable, reflecting genetic and clinical heterogeneity. Hypomethylating agents are the mainstay of therapy but induce complete remissions in less than 20% of patients and do not prolong survival compared to hydroxyurea. Allogeneic stem cell transplant (ASCT) is potentially curative, but few patients qualify due to advanced age and/or comorbidities. Work of the past several years has identified key molecular pathways that drive disease proliferation and transformation to acute leukemia, including JAK/STAT and MAPK signaling and epigenetic dysregulation. There is increasingly compelling evidence that inflammation is a major driver of CMML progression. Thus far however, this mechanistic knowledge has not yet been translated into improved outcomes, suggesting that fundamentally new approaches are required. In this review, we discuss the disease course, new classifications, and current treatment landscape of CMML. We review ongoing clinical studies and discuss options for rationally based future clinical trials.

Patient- and physician-reported pain after tyrosine kinase inhibitor discontinuation among patients with chronic myeloid leukemia.

For patients with optimally treated chronic myeloid leukemia (CML), discontinuation of tyrosine kinase inhibitor (TKI) therapy can lead to treatment-free remission. In previous trials, TKI discontinuation has been associated with increased musculoskeletal pain in some patients ("withdrawal syndrome"), based on physician-reported adverse events (AE). Patient-reported pain has not been described. The Life After Stopping TKI study was a 14-site prospective, non-randomized clinical trial of TKI discontinuation. We defined increased pain after discontinuation as: (i) a physician-reported pain AE, (ii) a 2-level increase in self-reported musculoskeletal pain (4-level single item), or (iii) initiation of a medication for pain. We plotted the trajectory of patient-reported pain over time using a piecewise mixed-effects ordinal logistic model. Within 3 months of discontinuation, 35 of 172 patients (20.3%) had a physician-reported pain AE, 22 of 172 (12.8%) had an increase in self-reported pain, and 18 of 154 (11.7%) initiated a pain medication. Agreement among these measures was limited; overall, 60 of 172 patients (34.9%) had increased pain. Three patients (1.7%) restarted a TKI because of pain. The modelpredicted trajectory showed an increase in pain in the first 3 months followed by a decrease, returning to baseline levels by 6 months and further decreasing after that. This trajectory was similar among patients who did and did not restart TKI, suggesting that resuming a TKI for withdrawal syndrome may be necessary for some, but other approaches to manage pain should be tried so that patients can remain in treatment-free remission when possible.

Sequencing of novel agents in relapsed/refractory B-cell acute lymphoblastic leukemia: Blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia.

BACKGROUND: The availability of novel agents (NAs), including blinatumomab and inotuzumab ozogamicin (InO), has improved the outcomes of patients with relapsed/refractory (RR) B-cell acute lymphoblastic leukemia (ALL). Because of the relative effectiveness, it is often a challenge for clinicians to determine how to best sequence these NAs with respect to efficacy and toxicity. METHODS: In this multicenter, retrospective study of patients with RR ALL treated with blinatumomab, InO, or both, their efficacy as a first or second NA was compared. RESULTS: Among 276 patients, 221 and 55 received blinatumomab and InO, respectively, as a first NA therapy. The complete remission (CR)/complete remission with incomplete count recovery (CRi) rate was 65% and 67% for the blinatumomab and InO groups, respectively (P = .73). The rate of treatment discontinuation due to adverse events was 4% and 7% in the blinatumomab and InO groups, respectively. Ninety-two patients (43%) in the blinatumomab group and 13 patients (29%) in the InO group proceeded with allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) was 15 and 11.6 months in the blinatumomab and InO groups, respectively. A subset analysis was performed for 61 patients who received both NAs (blinatumomab and then InO [n = 40] or InO and then blinatumomab [n = 21]). The CR/CRi rate was 58% for patients who received InO as the second NA and 52% for patients who received blinatumomab as the second NA. The median OS was 10.5 for patients who received InO as the second NA and 5.9 months for patients who received blinatumomab as the second NA (P = .09). CONCLUSIONS: Although the limited power of this study to detect a significant difference between subgroups is acknowledged, the data suggest that blinatumomab and InO may have comparable efficacy as a first or second NA therapy in RR ALL.

Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: when and for whom?

Treatment discontinuation is considered one of the main goals of therapy for patients with chronic myeloid leukemia. Several criteria are felt to be necessary to consider discontinuation, while others may predict a better chance of achieving treatment-free remission. Criteria for discontinuation include patients in chronic phase chronic myeloid leukemia, a minimum duration of tyrosine kinase inhibitor therapy of 3 years, sustained deep molecular response for at least 2 years and a molecular response of at least MR4. In addition, proper education of the patient on the need for more frequent monitoring, possible side effects related to stopping and having a reliable real-time quantitative polymerase chain reaction laboratory are paramount to the safety and success of treatment-free remission. Realistically though, a maximum of only 20-30% of newly diagnosed patients will be able to achieve a successful treatment-free remission. In this article we will review for whom and when a trial of discontinuation should be considered.

Improving Outcomes of Acute Promyelocytic Leukemia in the Current Era: Analysis of the SEER Database.

BACKGROUND: Outcomes of acute promyelocytic leukemia (APL) have significantly improved with the availability of targeted agents. It remains unclear whether the population-level outcomes of APL have improved over time. METHODS: Using the SEER database, we identified patients aged ≥20 years with pathologically confirmed APL diagnosed in 2000 through 2014 and who were actively followed. Patients were stratified by diagnosis period into 3 groups (2000-2004, 2005-2009, and 2010-2014) to assess the temporal trends in overall survival (OS), cause-specific survival (CSS), and other outcomes. RESULTS: A total of 2,962 patients with a median age of 48 years (range, 20-96 years) were included. Hispanic patients constituted 21.5% of the cohort and the largest proportion (47.9%) of uninsured patients. The incidence of APL was 0.33 cases per 100,000 population per year. Incidence varied significantly by age, sex, race/ethnicity, and diagnosis period. Survival was significantly higher for patients diagnosed in 2010 through 2014 compared with those diagnosed in 2005 through 2009 and in 2000 through 2004 (4-year OS, 73.4% vs 65.6% vs 57.3%, respectively; 4-year CSS, 78.3% vs 70.8% vs 60.8%, respectively). Early mortality improved significantly over time (2000-2004, 25.3%; 2005-2009, 20.6%; 2010-2014, 17.1%) and was higher in men and Hispanic patients. According to multivariate analysis, diagnosis before 2010 and unmarried status were associated with a higher mortality risk. Uninsured patients had a significantly higher early mortality without a significant difference in post-30-day CSS. No significant changes were noted in risk of secondary malignancies. CONCLUSIONS: Population-level outcomes of APL have continued to improve over time. However, significant discrepancies in disease outcomes continue to exist, highlighting the need for more research.

Exploring Patient Decision Making Regarding Discontinuation of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia.

BACKGROUND: The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Multiple clinical trials have demonstrated that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now offered to select patients in routine clinical care. In order to better support patient decision making, we explored patients' views on TKI discontinuation and the factors patients consider when making this decision. MATERIALS AND METHODS: Patients were recruited from three U.S. academic cancer centers. Qualitative interviews were recorded, transcribed, and content analyzed. RESULTS: We interviewed 22 patients, half of whom wanted to try TKI discontinuation. Eleven factors relevant to the decision emerged, and patients weighed these factors differently. Commonly mentioned factors included perceived risk of relapse, TKI side effects, financial considerations, polypharmacy, and willingness to change something that was working (status quo). There were notable differences in patients' understanding of the likelihood of achieving a treatment-free remission, with patients who did not want to stop TKIs more accurately reporting the risk of relapse than patients who wanted to stop. CONCLUSION: This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for patient education and decision support so that patients and providers can make shared decisions that are informed and values based. IMPLICATIONS FOR PRACTICE: The standard treatment for chronic phase chronic myeloid leukemia (CML) is lifelong oral tyrosine kinase inhibitor (TKI) therapy. Clinical trials have shown that some patients with a sustained deep molecular response to TKI therapy can safely stop therapy and remain in a treatment-free remission. TKI discontinuation is now being offered to patients outside of clinical trials. This study explored factors that patients who are eligible to try TKI discontinuation considered when making this decision. Factors relevant to the decision included risk of relapse, side effects, financial considerations, polypharmacy, and willingness to change something that was working. This is a novel decision that will become more common as the prevalence of patients with well-controlled CML continues to increase. These results highlight the need for decision support and outline the factors that should be included so that patients and providers can make shared decisions that are informed and values based.

Implementation and evaluation of high-dose methotrexate administration guidelines.

BACKGROUND: High-dose methotrexate is used to treat a variety of malignancies. Methotrexate-associated supportive care and the threshold methotrexate level for the discontinuation of supportive care are not consistent among studies. We evaluated the implementation of high-dose methotrexate administration guidelines, which raised the standard threshold methotrexate level for the discontinuation of supportive care from <0.05 to <0.1 µmol. METHODS: A single-center, observational analysis of patients receiving high-dose methotrexate from 1 January 2015 to 31 May 2017 was conducted. The primary endpoint was time from the start of the methotrexate infusion until the discontinuation of the sodium bicarbonate infusion, before and after guideline implementation. RESULTS: Fifty-two patients met the inclusion criteria, which comprised of a total of 136 individual methotrexate doses and were included in the retrospective analysis. Twenty-four patients were included in the prospective analysis, which comprised a total of 46 individual methotrexate doses. The primary endpoint, time until discontinuation of the sodium bicarbonate infusion, was a median of 97.7 h in the retrospective group versus 73.2 h in the prospective group (p = 0.098). Secondary endpoints also favored patients in the prospective group, including hours of hospitalization, number of methotrexate levels checked, weight gained during admission, and adherence to the guideline. CONCLUSION: Among patients who received high-dose methotrexate, implementation of a guideline using a methotrexate threshold of <0.1 µmol was able to significantly decrease the time to discontinuation of supportive care and subsequently may lead to early hospital discharge given that we did not show a statistical significance.

Dasatinib dose management for the treatment of chronic myeloid leukemia.

Chronic myeloid leukemia (CML) has evolved into a chronic disease that is managed with tyrosine kinase inhibitor therapy. Now that long-term survival has been achieved in patients with CML, the focus of treatment has shifted to dose optimization, with the goal of maintaining response while improving quality of life. In this review, the authors discuss optimizing the dose of the second-generation tyrosine kinase inhibitor dasatinib. Once-daily dosing regimens for dasatinib in the first and later lines of treatment were established through long-term (5-year and 7-year) trials. Recently published data have indicated that further dose optimization may maintain efficacy while minimizing adverse events. Results obtained from dose optimization and discontinuation trials currently in progress will help practitioners determine the best dose and duration of dasatinib for patients with CML, because treatment decisions will be made through continued discussions between physicians and patients. Cancer 2018;124:1660-72. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia.

BACKGROUND: Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health-related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. METHODS: The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non-randomized, prospective, single-group longitudinal study of 173 patients. The co-primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABLIS) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient-reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system. DISCUSSION: Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation. TRIAL REGISTRATION: This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267 .

Recipient Immune Modulation with Atorvastatin for Acute Graft-versus-Host Disease Prophylaxis after Allogeneic Transplantation.

Atorvastatin administration to both the donors and recipients of matched related donor (MRD) allogeneic hematopoietic cell transplantation (allo-HCT) as acute graft-versus-host disease (GVHD) prophylaxis has been shown to be safe and effective. However, its efficacy as acute GVHD prophylaxis when given only to allo-HCT recipients is unknown. We conducted a phase II study to evaluate the safety and efficacy of atorvastatin-based acute GVHD prophylaxis given only to the recipients of MRD (n = 30) or matched unrelated donor (MUD) (n = 39) allo-HCT, enrolled in 2 separate cohorts. Atorvastatin (40 mg/day) was administered along with standard GVHD prophylaxis consisting of tacrolimus and methotrexate. All patients were evaluable for acute GVHD. The cumulative incidences of grade II to IV acute GVHD at day +100 in the MRD and MUD cohorts were 9.9% (95% confidence interval [CI], 0 to 20%) and 29.6% (95% CI,15.6% to 43.6%), respectively. The cumulative incidences of grade III and IV acute GVHD at day +100 in the MRD and MUD cohorts were 3.4% (95% CI, 0 to 9.7%) and 18.3% (95% CI, 6.3% to 30.4%), respectively. The corresponding rates of moderate/severe chronic GVHD at 1 year were 28.1% (95% CI, 11% to 45.2%) and 38.9% (95% CI, 20.9% to 57%), respectively. In the MRD cohort, the 1-year nonrelapse mortality, relapse rate, progression-free survival, and overall survival were 6.7% (95% CI, 0 to 15.4%), 43.3% (95% CI, 24.9% to 61.7%), 50% (95% CI, 32.1% to 67.9%), and 66.7% (95% CI, 49.8% to 83.6%), respectively. The respective figures for the MUD cohort were 10.3% (95% CI, 8% to 19.7%), 20.5% (95% CI, 7.9% to 33.1%), 69.2% (95% CI, 54.7% to 83.7%), and 79.5% (95% CI, 66.8% to 92.2%), respectively. No grade 4 toxicities attributable to atorvastatin were seen. In conclusion, the addition of atorvastatin to standard GVHD prophylaxis in only the recipients of MRD and MUD allo-HCT appears to be feasible and safe. The preliminary efficacy seen here warrants confirmation in randomized trials.

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

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.