Treatment with a 5-day versus a 10-day schedule of decitabine in older patients with newly diagnosed acute myeloid leukaemia: a randomised phase 2 trial.

BACKGROUND: Hypomethylating agents, such as decitabine, are the standard of care for older patients with newly diagnosed acute myeloid leukaemia. Single-arm studies have suggested that a 10-day schedule of decitabine cycles leads to better outcomes than the usual 5-day schedule. We compared the efficacy and safety of these two schedules. METHODS: Eligible patients were aged 60 years or older with acute myeloid leukaemia but unsuitable for intensive chemotherapy (or <60 years if unsuitable for intensive chemotherapy with an anthracycline plus cytarabine). The first 40 patients were allocated equally to the two treatment groups by computer-generated block randomisation (block size 40), after which a response-adaptive randomisation algorithm used all previous patients' treatment and response data to decide the allocation of each following patient favouring the group with superior response. Patients were assigned to receive 20 mg/m2 decitabine intravenously for 5 or 10 consecutive days as induction therapy, every 4-8 weeks for up to three cycles. Responding patients received decitabine as consolidation therapy on a 5-day schedule for up to 24 cycles. We assessed a composite primary endpoint of complete remission, complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete haematological recovery (CRi) achieved at any time and assessed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01786343. FINDINGS: Between Feb 28, 2013, and April 12, 2018, 71 patients were enrolled. 28 received decitabine for 5 days and 43 for 10 days, and all were assessable for efficacy and safety. The primary endpoint was achieved in similar proportions of patients in the two treatment groups (12 [43%] of 28 in the 5-day schedule group, 95% credible interval 26-60, and 17 [40%] of 43 in the 10-day schedule group, 26-54, p=0·78; difference 3%, -21 to 27). Total follow-up was 38·2 months, during which the median duration of overall survival was 5·5 months (IQR 2·1-11·7) in the 5-day group and 6·0 months (1·9-11·7) in the 10-day group. 1-year overall survival was 25% in both groups. Complete remission, CRp, CRi, and overall survival did not differ between groups when stratified by cytogenetics, de-novo versus secondary or therapy-related acute myeloid leukaemia, or TP53mut status. The most common grade 3-4 adverse events were neutropenic fever (seven patients [25%] in the 5-day group and 14 [33%] in the 10-day group) and infection (five [18%] and 16 [37%], respectively). One patient (4%) died from sepsis in the context of neutropenic fever, infection, and haemorrhage in the 5-day group, and in the 10-day group six patients (14%) died from infection. Early mortality was similar in the two groups. INTERPRETATION: In older patients with newly diagnosed acute myeloid leukaemia, efficacy and safety did not differ by the 5-day or the 10-day decitabine schedule. FUNDING: University of Texas MD Anderson Cancer Center and National Cancer Institute Specialized Programs of Research Excellence.

Sorafenib Combined with 5-azacytidine in Older Patients with Untreated FLT3-ITD Mutated Acute Myeloid Leukemia.

Based on our previous study of the combination of sorafenib with 5-azacytidine (AZA) in relapsed/refractory patients with FLT3 mutated acute myeloid leukemia (AML), we hypothesized that the combination would be efficacious and well tolerated in untreated patients with FLT3 mutated AML who are unsuitable for standard chemotherapy due to advanced age or lack of fitness. Newly diagnosed patients with untreated FLT3 mutated AML who underwent frontline therapy on 2 separate protocols of AZA plus sorafenib were analyzed. The clinical trials were registered at clinicaltrials.gov (NCT02196857 and NCT01254890). Overall, 27 patients with untreated FLT3 mutated AML (median age of 74 years, range, 61-86) were enrolled. The overall response rate was 78% (7 [26%] CR, 12 [44%] CRi/CRp, and 2 [7%] PR). Patients received a median of 3 treatment cycles (1-35). The median duration of CR/CRp/CRi is 14.5 months (1.1-28.7 months). Three (11%) responding patients (1 CR, 2 CRi) proceeded to allogeneic stem cell transplant. The median follow-up for surviving patients was 4.1 months (3.0-17.3 months). The median overall survival for the entire group was 8.3 months, and 9.2 months in the 19 responders. The regimen was well tolerated in elderly patients with untreated FLT3 mutated AML with no early deaths.

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

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.

A Phase I/II Study of the mTOR Inhibitor Everolimus in Combination with HyperCVAD Chemotherapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

PURPOSE: Previous studies suggest a potential therapeutic role for mTOR inhibition in lymphoid malignancies. This single-center phase I/II study was designed to test the safety and efficacy of the mTOR inhibitor everolimus in combination with HyperCVAD chemotherapy in relapsed/refractory acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: Twenty-four patients were treated; 15 received everolimus 5 mg/day and 9 received 10 mg/day with HyperCVAD. RESULTS: The median age of patients was 25 years (range, 11-64) and median number of prior treatments was 2 (range, 1-7). Grade 3 mucositis was the dose-limiting toxicity and the maximum tolerated everolimus dose was 5 mg/day. Responses included complete remission (CR) in 6 patients (25%), CR without platelet recovery (CRp) in 1 (4%), and CR without recovery of counts (CRi) in 1 (4%), for an overall response rate of 33%. In addition, partial response (PR) was noted in 2 patients (8%). Seven of 11 patients treated in first salvage achieved CR/CRp (64%). The median OS was 29 weeks for patients in first salvage versus 15 weeks for patients in second salvage and beyond (P ≤ 0.001). A response was noted in 5 of 10 (50%) heavily pretreated T-ALL patients (median of 4 prior salvage regimens). Everolimus significantly inhibited phosphorylation of S6RP, but this did not correlate with response. No significant decreases in p4EBP1 and pAkt levels were noted. Responders had higher everolimus dose-adjusted area under the curve (P = 0.025) and lower clearance (P = 0.025) than nonresponders. CONCLUSIONS: The combination of HyperCVAD and everolimus is well tolerated and moderately effective in relapsed ALL, specifically T-ALL.

Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation.

Patients received 5-azacytidine (AZA) 75 mg/m(2) intravenously daily for 7 days and sorafenib 400 mg orally twice daily continuously; cycles were repeated at ~1-month intervals. Forty-three acute myeloid leukemia (AML) patients with a median age of 64 years (range, 24-87 years) were enrolled; 37 were evaluable for response. FMS-like tyrosine kinase-3 (FLT3)-internal tandem duplication (ITD) mutation was detected in 40 (93%) patients, with a median allelic ratio of 0.32 (range, 0.009-0.93). They had received a median of 2 prior treatment regimens (range, 0-7); 9 had failed prior therapy with a FLT3 kinase inhibitor. The response rate was 46%, including 10 (27%) complete response with incomplete count recovery (CRi), 6 (16%) complete responses (CR), and 1 (3%) partial response. The median time to achieve CR/CRi was 2 cycles (range, 1-4), and the median duration of CR/CRi was 2.3 months (range, 1-14.3 months). Sixty-four percent of patients achieved adequate (defined as >85%) FLT3 inhibition during their first cycle of therapy. The degree of FLT3 inhibition correlated with plasma sorafenib concentrations. FLT3 ligand levels did not rise to levels seen in prior studies of patients receiving cytotoxic chemotherapy. The combination of AZA and sorafenib is effective for patients with relapsed AML and FLT-3-ITD. This trial was registered at clinicaltrials.gov as #NCT01254890.

Experience with everolimus (RAD001), an oral mammalian target of rapamycin inhibitor, in patients with systemic mastocytosis.

KIT D816V mutation has been observed in more than 90% of patients with systemic mastocytosis (SM). This mutation constitutively activates the mammalian target of rapamycin (mTOR) signaling pathway. We tested the efficacy of everolimus (RAD001), a novel oral mTOR inhibitor, at a dose of 10 mg daily in an open label, non-comparative Phase II trial for patients with SM. Ten patients were enrolled from April 2007 to October 2008. Median age was 55 years, four were males, seven had indolent and three aggressive SM, and six were previously treated with other agents. Median duration of therapy was 4 months (range 0.2-18). No objective responses were noted. Four patients had a short-lasting subjective improvement in symptoms for a median duration of 3 months (range 3-15). Grade 1-3 diarrhea, mucositis, and neutropenia were the most common adverse effects. No Grade 4 toxicity was noted. In conclusion, everolimus does not result in appreciable clinical activity in patients with SM.

Pegylated interferon alfa-2a yields high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera.

PURPOSE: We conducted a phase II study of pegylated interferon alfa-2a (PEG-IFN-alpha-2a) in patients with essential thrombocythemia (ET) and polycythemia vera (PV). PATIENTS AND METHODS: Seventy-nine patients (40 with PV and 39 with ET) have been treated. Median time from diagnosis to PEG-IFN-alpha-2a was 54 months in patients with PV and 33 months in patients with ET. Eighty-one percent of patients had received prior therapy. The first three patients received PEG-IFN-alpha-2a at 450 microg weekly. As a result of poor tolerance, this dose was decreased in a stepwise manner to a current starting dose of 90 microg weekly. Seventy-seven patients are evaluable and have been observed for a median of 21 months. RESULTS: The overall hematologic response rate was 80% in PV and 81% in ET (complete in 70% and 76% of patients, respectively). The JAK2(V617F) mutation was detected in 18 patients with ET and 38 patients with PV; sequential measurements by a pyrosequencing assay were available in 16 patients with ET and 35 patients with PV. The molecular response rate was 38% in ET and 54% in PV, being complete (undetectable JAK2(V617F)) in 6% and 14%, respectively. The JAK2(V617F) mutant allele burden continued to decrease with no clear evidence for a plateau. The tolerability of PEG-IFN-alpha-2a at 90 microg weekly was excellent. CONCLUSION: PEG-IFN-alpha-2a resulted in remarkable clinical activity, high rates of molecular response, and acceptable toxicity in patients with advanced ET or PV. The ability of PEG-IFN-alpha-2a to induce complete molecular responses suggests selective targeting of the malignant clone.

PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: final result of a phase 2 study.

BACKGROUND: Interferon-alpha (IFN-alpha) has shown significant activity in the treatment of BCR-ABL-negative myeloproliferative disorders (MPDs), particularly essential thrombocythemia (ET) and polycythemia vera (PV). PEG-IFN-alpha-2b is a pegylated IFN-alpha-2b with a significant advantage over nonpegylated form in that it is administered once a week. METHODS: Thirty-eight patients with BCR-ABL-negative MPDs were treated with PEG-IFN-alpha-2b, given subcutaneously weekly, at the starting dose of 3 microg/kg/wk for the first 14 patients and then 2 microg/kg/wk for the next 24 patients, with intent to treat patients as long as they benefited from the therapy. RESULTS: Median age was 54 years. Patient diagnoses were: 13 (34%) ET; 11 (29%) primary myelofibrosis (PMF); 5 (13%) BCR-ABL-negative chronic myeloid leukemia (CML); 4 (10.5%) hypereosinophilic syndrome (HES); 4 (10.5%) PV; and 1 (3%) unclassified myeloproliferative disease (uMPD). Recorded grade 3-4 toxicities were related to fatigue, myelosuppression, and musculoskeletal pain. Ten (26%) patients stopped treatment because of toxicity. Thirteen (34%) patients achieved a complete remission, and 4 (11%) achieved a partial response. Only 1 patient with PMF responded. Median time to response was 5 months. Median duration of response was 20 months. Three patients had a sustained response for >24 months. CONCLUSIONS: PEG-IFN-alpha-2b, with proper dose modifications, is effective in controlling disease in a significant proportion of BCR-ABL-negative MPD patients, particularly ET and PV. However, toxicities encountered with PEG-IFN-alpha-2b therapy are similar to those obtained with conventional IFN-alpha, thus limiting the duration of therapy.