Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

BACKGROUND: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. METHODS: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). RESULTS: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017). CONCLUSIONS: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

WRN Mutation Update: Mutation Spectrum, Patient Registries, and Translational Prospects.

Werner syndrome (WS) is a rare autosomal recessive disorder characterized by a constellation of adult onset phenotypes consistent with an acceleration of intrinsic biological aging. It is caused by pathogenic variants in the WRN gene, which encodes a multifunctional nuclear protein with exonuclease and helicase activities. WRN protein is thought to be involved in optimization of various aspects of DNA metabolism, including DNA repair, recombination, replication, and transcription. In this update, we summarize a total of 83 different WRN mutations, including eight previously unpublished mutations identified by the International Registry of Werner Syndrome (Seattle, WA) and the Japanese Werner Consortium (Chiba, Japan), as well as 75 mutations already reported in the literature. The Seattle International Registry recruits patients from all over the world to investigate genetic causes of a wide variety of progeroid syndromes in order to contribute to the knowledge of basic mechanisms of human aging. Given the unusually high prevalence of WS patients and heterozygous carriers in Japan, the major goal of the Japanese Consortium is to develop effective therapies and to establish management guidelines for WS patients in Japan and elsewhere. This review will also discuss potential translational approaches to this disorder, including those currently under investigation.

Treatment of adults with acute lymphoblastic leukemia: do the specifics of the regimen matter?: Results from a prospective randomized trial.

BACKGROUND: Induction therapy for adults with acute lymphoblastic leukemia (ALL) is similar across essentially all regimens, comprised of vincristine, corticosteroids, and anthracyclines intensified with cyclophosphamide, asparaginase, or both. Given the lack of randomized data, to date, no regimen has emerged as standard. The authors previously evaluated cytarabine 3 g/m(2) daily for 5 days with mitoxantrone 80 mg/m(2) (the ALL-2 regimen) as a novel induction regimen. Compared with historic controls, the ALL-2 regimen was superior in terms of incidence of complete remission, failure with resistant disease, and activity in patients with Philadelphia chromosome (Ph)-positive ALL. METHODS: The authors conducted a multicenter, prospective, randomized trial of the ALL-2 regimen compared with a standard 4-drug induction (the L-20 regimen). Patients also received consolidation, maintenance therapy, and central nervous system prophylaxis. The trial accrued patients from August 1996 to October 2004. RESULTS: The median follow-up for survivors was 7 years, and the median patient age was 43 years. Responses were evaluated in 164 patients. The treatment arms were balanced in terms of pretreatment characteristics. The frequency of complete remission for the ALL-2 regimen versus the L-20 regimen was 83% versus 71% (P = .06). More patients on the L-20 arm failed with resistant disease (21% vs 8%; P = .02). Induction deaths were comparable at 9% (ALL-2) versus 7% (L-20). The median survival was similar; and, at 5 years, the survival rate was 33% alive on the ALL-2 arm versus 27% on the L-20. CONCLUSIONS: Despite superior results of induction therapy with the ALL-2 regimen, this treatment did not improve long-term outcomes. When coupled to the reported experience of other studies in adults with ALL, the results of this randomized trial raise the possibility that ultimate outcomes in adult ALL may be independent of the specific regimen chosen. Cancer 2013. © 2012 American Cancer Society.

Myelodysplasia: new approaches.

The myelodysplastic syndromes (MDS) are a group of clonal hematopoietic disorders characterized by bone marrow failure and a risk of progression to acute myelogenous leukemia (AML). A precise diagnosis is critical, because there is overlap between the clinical and laboratory findings of MDS and other malignant and nonmalignant hematologic disorders. Several prognostic scoring systems (IPSS, WPSS, LR-PSS, and IPSS-R) assess a patient's risk of progression to AML and overall survival. Many patients are elderly, so age and comorbidities are an important consideration. Patients with lower-risk disease are treated with growth factors (erythropoietin stimulating agents and/or G-CSF) and immunomodulatory agents (antithymocyte globulin and/or lenalidomide). Patients with higher-risk disease have a higher risk of progression to AML and are treated with hypomethylating agents (azacitidine or decitabine) and allogeneic stem cell transplantation if appropriate. Recent laboratory studies have increased our understanding of the pathophysiology of this disease. Mutations in genes effecting ribosomes, splicing of RNA and epigenetics have been discovered. It is likely that these breakthroughs will lead to newer classes of targeted therapies against this disease.

Oral sapacitabine for the treatment of acute myeloid leukaemia in elderly patients: a randomised phase 2 study.

BACKGROUND: Available treatments for acute myeloid leukaemia (AML) have limited durable activity and unsatisfactory safety profiles in most elderly patients. We assessed the efficacy and toxicity of sapacitabine, a novel oral cytosine nucleoside analogue, in elderly patients with AML. METHODS: In this randomised, phase 2 study, we recruited patients with AML who were either treatment naive or at first relapse and who were aged 70 years or older from 12 centres in the USA. We used a computer-generated randomisation sequence to randomly allocate eligible patients to receive one of three schedules of oral sapacitabine (1:1:1; stratified by a history of AML treatment): 200 mg twice a day for 7 days (group A); 300 mg twice a day for 7 days (group B); and 400 mg twice a day for 3 days each week for 2 weeks (group C). All schedules were given in 28 day cycles. To confirm the safety and tolerability of dosing schedules, after 20 patients had been treated in a group we enrolled an expanded cohort of 20-25 patients to that group if at least four patients had achieved complete remission or complete remission with incomplete blood count recovery, and if the 30 day death rate was 20% or less. Our primary endpoint was 1-year overall survival, analysed by intention-to-treat (ie, patients who have received at least one dose of sapacitabine) in those patients who had been randomly allocated to treatment. This trial is registered with ClinicalTrials.gov, number NCT00590187. RESULTS: Between Dec 27, 2007, and April 21, 2009, we enrolled 105 patients: 86 patients were previously untreated and 19 were at first relapse. Of the 60 patients randomly allocated to treatment, 1-year overall survival was 35% (95% CI 16-59) in group A, 10% (2-33) in group B, and 30% (13-54) in group C. 14 (13%) of 105 patients died within 30 days and 27 (26%) died within 60 days. The most common grade 3-4 adverse events were anaemia (eight of 40 patients in group A, 12 of 20 patients in group B, and 15 of 45 patients in group C), neutropenia (14 in group A, 10 in group B, 11 in group C), thrombocytopenia (24 in group A, 12 in group B, and 22 in group C), febrile neutropenia (16 in group A, nine in group B, and 22 in group C), and pneumonia (seven in group A, five in group B, and 10 in group C). The most common grade 5 events were pneumonia (two in group A, one in group B, and three in group C) and sepsis (six in group A, three in group B, and one in group C). Seven deaths were thought to be probably or possibly related to sapacitabine treatment. INTERPRETATION: Sapacitabine seems active and tolerable in elderly patients with AML. The 400 mg dose schedule had the best efficacy profile. Future investigations should aim to combine sapacitabine with other low-intensity therapies in elderly patients with AML. FUNDING: Cyclacel Limited.

Olutasidenib alone or with azacitidine in IDH1-mutated acute myeloid leukaemia and myelodysplastic syndrome: phase 1 results of a phase 1/2 trial.

BACKGROUND: Olutasidenib (FT-2102) is a potent, selective, oral, small-molecule inhibitor of mutant isocitrate dehydrogenase 1 (IDH1). The aims for phase 1 of this phase 1/2 study were to assess the safety, pharmacokinetics, pharmacodynamics, and clinical activity of olutasidenib, as monotherapy or in combination with azacitidine, in patients with acute myeloid leukaemia or myelodysplastic syndrome, harbouring mutant IDH1. METHODS: In this phase 1/2, multicentre, open-label clinical trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia or intermediate, high, or very high risk myelodysplastic syndrome harbouring mutant IDH1 at 18 study sites in the USA, Australia, France, and Spain. Other key eligibility criteria included Eastern Cooperative Oncology Group performance status 0-2 with adequate liver and renal function. The primary outcomes were dose-limiting toxicities and the maximum tolerated dose, maximum evaluated dose, and the recommended phase 2 dose of olutasidenib. Olutasidenib was administered orally in doses of 150 mg once daily, 150 mg twice per day, and 300 mg once daily. Azacitidine (75 mg/m2) was administered subcutaneously or intravenously daily for 7 days on, 21 days off. The study was ongoing at the data cutoff (Oct 2, 2019) and is registered with ClinicalTrials.gov, NCT02719574. FINDINGS: Patients were enrolled between Aug 8, 2016, and Nov 14, 2018. 78 patients received olutasidenib as monotherapy (n=32) or in combination with azacitidine (n=46). The median follow-up was 8·3 months (IQR 3·1-13·3) for monotherapy and 10·1 months (4·2-15·3) for combination therapy. 16 (50%) of 32 patients in the monotherapy group and 24 (52%) of 46 patients in the combination therapy group were women. Most patients were White (26 [81%] for monotherapy and 31 [67%] for combination therapy). No dose-limiting toxicities were reported in the dose-escalation cohorts and 150 mg twice per day was declared the recommended phase 2 dose on the basis of safety, pharmacokinetics and pharmacodynamics, and clinical activity. The most common (≥20%) grade 3-4 treatment-emergent adverse events with monotherapy were thrombocytopenia (nine [28%] of 32 patients), febrile neutropenia (seven [22%] of 32), and anaemia (seven [22%] of 32); and with combination therapy were thrombocytopenia (19 [41%] of 46), febrile neutropenia (13 [28%] of 46), neutropenia (13 [28%] of 46), and anaemia (nine [20%] of 46). 11 (34%) of 32 patients in the monotherapy group and nine (20%) of 46 patients in the combination therapy group died (most commonly from disease progression [three (9%) of 32 and four (9%) of 46]). No deaths were considered study-drug related. For patients with relapsed or refractory acute myeloid leukaemia, 41% (95% CI 21-64; nine of 22) receiving monotherapy and 46% (27-67; 12 of 26) receiving combination therapy had an overall response. For treatment-naive patients with acute myeloid leukaemia, 25% (1-81; one of four) receiving monotherapy and 77% (46-95; ten of 13) receiving combination therapy had an overall response. INTERPRETATION: Olutasidenib, with or without azacitidine, was well tolerated and showed meaningful clinical activity in patients with IDH1-mutated acute myeloid leukaemia. The results of this phase 1 study provide rationale for the continued evaluation of olutasidenib in multiple patient populations with myeloid malignancies. FUNDING: Forma Therapeutics.

Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse.

Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m(2) per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m(2) (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.

Murine double minute 2 inhibition alone or with cytarabine in acute myeloid leukemia: Results from an idasanutlin phase 1/1b study⋆.

The prognosis remains poor for patients with relapsed or refractory (r/r) acute myeloid leukemia; thus, novel therapies are needed. We evaluated idasanutlin-a new, potent murine double minute 2 antagonist-alone or with cytarabine in patients with r/r acute myeloid leukemia, de novo untreated acute myeloid leukemia unsuitable for standard treatment or with adverse features, or secondary acute myeloid leukemia in a multicenter, open-label, phase 1/1b trial. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended dose for expansion (RDE) and characterize the safety profile of idasanutlin monotherapy and combination therapy. Clinical activity and pharmacokinetics were secondary objectives. Two idasanutlin formulations were investigated: a microprecipitate bulk powder (MBP) and optimized spray-dried powder (SDP). Following dose escalation, patients (N = 122) received idasanutlin at the RDE in the extension cohorts. No formal MTD was identified. Idasanutlin was tolerable alone and in combination with cytarabine. The RDE was determined as 600 mg twice a day for the MBP formulation and 300 mg twice a day for the SDP formulation. Adverse events were mostly grade 1/2 (76.2 %). The most common any-grade adverse events were gastrointestinal (including diarrhea [90.2 %]). The early death rate across all patients was 14.8 %. Plasma idasanutlin exposure was dose related. In TP53 wild-type patients, composite complete remission rates were 18.9 % with monotherapy and 35.6 % with combination therapy. Based on these results, idasanutlin development continued with further investigation in the treatment of acute myeloid leukemia. ClinicalTrials.gov: NCT01773408.

t(3;9;22) 3-way chromosome translocation in chronic myeloid leukemia is associated with poor prognosis.

Chronic myelogenous leukemia (CML) is genetically characterized by the reciprocal translocation of chromosome 9 and 22. Around 5-8% of CML develop complex variant Ph translocations involving one or more chromosomal regions besides 9 and 22. Chromosome 3 is not frequently involved in complex translocations in CML. We report in this study a case of CML displaying a t(3;9;22) 3-way translocation. A review of the literature appears to indicate that CML patients with this translocation tend to have an aggressive course and poor outcome. Additional 3-way chromosome translocations associated with CML are also reviewed.

Lineage switch from T-cell lymphoblastic leukemia/lymphoma to acute myeloid leukemia and back to T-cell lymphoblastic leukemia/lymphoma in a patient diagnosed during pregnancy.

Although relapse of acute leukemia is common, a change of immunophenotype at relapse only occurs rarely. Some of these cases have been labeled "lineage switch". In most cases, B-cell lymphoblastic leukemia/lymphoma (B-ALL) relapses as acute myeloid leukemia (AML). We report a rare case of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) relapsing as AML and then returning as T-ALL again in a patient who began her therapy during the third trimester of pregnancy. The patient retained the same cytogenetic and next generation molecular findings in both leukemias. This case provides further evidence of the plasticity of the leukemic stem cell.

High-dose chemotherapy with autologous stem cell rescue in stage IIIB inflammatory breast cancer.

BACKGROUND: Despite the advances in breast cancer care, inflammatory breast cancer (IBC) has a poor prognosis. The purpose of this study was to determine the efficacy of high-dose chemotherapy (HDCT) with thiotepa, mitoxantrone and carboplatin (TMJ regimen) in women with TNM stage IIIB IBC. PATIENTS AND METHODS: Between 1991 and 1998, twenty-eight patients with stage IIIB IBC underwent an autologous stem cell transplant after undergoing chemotherapy, surgery and/or radiation. Stem cells were collected from the bone marrow and periphery after mobilization with growth factors. Patients received thiotepa 250 mg/m2 once daily i.v. for 3 days, mitoxantrone 40 mg/m2 for 1 day and carboplatin 333 mg/m2 once daily i.v. for 3 days as the conditioning regimen for the HDCT. Radiation therapy and tamoxifen was offered to patients post HDCT if appropriate. Progression-free survival and overall survival was assessed over a 15-year period. RESULTS: At the time of last follow-up in May, 2007, sixteen patients had relapsed. The median overall survival was 49.5 months. The median progression free survival was 40 months. There were no transplant-related deaths. Mucositis and infections were the major side-effects. These results show that HDCT with the TMJ regimen is safe and effective in patients with stage IIIB IBC.

Acute myeloid leukemia in a father and son with a germline mutation of ASXL1.

BACKGROUND: Myelodysplastic syndromes and acute myeloid leukemia usually occur sporadically in older adults. More recently cases of familial acute myeloid leukemia and/or myelodysplastic syndrome have been reported. CASE PRESENTATION: Currently we report a father and son who both developed myelodysplastic syndrome that progressed to acute myeloid leukemia. Both patients were found to have the identical mutation of ASXL1 on nextgen sequencing of both hematologic and nonhematologic tissues. CONCLUSIONS: These cases support the diagnosis of a germline mutation of ASXL1.

Burden of Infections Among Chronic Myeloid Leukemia Patients Receiving Dasatinib or Nilotinib: A Real-World Retrospective Healthcare Claims Study in the United States.

INTRODUCTION: Tyrosine kinase inhibitors (TKI) have been demonstrated to prolong survival in patients with chronic myeloid leukemia (CML). However, TKIs may be associated with an increased risk of infections. This study compared healthcare resource utilization (HRU) and costs among patients with CML receiving dasatinib or nilotinib, with a focus on infection-related economic outcomes. METHODS: Two large administrative databases were used to identify adult patients newly diagnosed with CML who initiated dasatinib or nilotinib as first- (1L) or second-line (2L) therapy and were classified into the following 1L (dasatinib 1L/nilotinib 1L cohorts) or 2L (dasatinib 2L/nilotinib 2L) cohorts based on the initiated 1L/2L TKI therapy. Infection-related HRU and healthcare costs were compared between cohorts, separately for 1L and 2L. RESULTS: Cohorts included 1156 patients in the dasatinib 1L and 677 patients in the nilotinib 1L cohorts, 322 patients in the dasatinib 2L, and 207 in the nilotinib 2L cohorts. In 1L and 2L, infection-related HRU was higher for dasatinib than nilotinib cohorts. Infection-related inpatient (IP) days constituted a larger proportion of all-cause IP days in the 1L/2L dasatinib than 1L/2L nilotinib cohorts (dasatinib 1L/2L: 53%/58%; nilotinib 1L/2L: 50%/46%). Compared to the nilotinib cohort, the dasatinib cohort had higher all-cause total costs per patient per year by US$17,901 in 1L and $28,625 in 2L. Of the total cost difference, infection-related were $6048 (34%) in 1L and $28,192 (99%) in 2L, largely driven by IP cost differences (1L/2L: 96%/98%). CONCLUSIONS: Dasatinib was associated with higher HRU and healthcare costs compared to nilotinib, particularly related to infections. FUNDING: Novartis Pharmaceutical Corporation.

t(8;14;18): a 3-way chromosome translocation in two patients with Burkitt's lymphoma/leukemia.

Burkitt's lymphoma (BL) is a heterogeneous group of highly aggressive mature B-cell malignancies. It is characterized by a high rate of turnover of malignant cells and deregulation of the c-myc gene. It is typically associated with a t(8;14) translocation. Dual translocation of t(8;14) (c-myc) and t(14;18) (bcl-2) was reported to be associated with extremely poor prognosis. This study reports a novel t(8;14;18) triple translocation in two patients with Burkitt's lymphoma.

Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies.

Triapine, a potent inhibitor of ribonucleotide reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1-5 and 15-19 or 1-5 and 8-12 of a 4-week cycle. When administered twice a day on days 1-5 and 8-12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2-5.5 microM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.

Acute myeloid leukemia and fatal Scedosporium prolificans sepsis after eculizumab treatment for paroxysmal nocturnal hemoglobinuria: a case report.

Eculizumab has become the standard of care for patients with paroxysmal nocturnal hemoglobinuria (PNH). As more patients are treated, the long-term outcomes of these patients will become apparent. We recently treated a patient who developed PNH in the setting of aplastic anemia. The patient developed acute myeloid leukemia less than three years after initiating eculizumab. The patient also died suddenly from Scedosporium sepsis during induction therapy. This patient's course seemed more aggressive than would be expected. The possible effect of complement blockade is discussed.

A Phase II study of Bcl-2 antisense (oblimersen sodium) combined with gemtuzumab ozogamicin in older patients with acute myeloid leukemia in first relapse.

Oblimersen selectively targets Bcl-2 mRNA and has been shown to enhance the apoptotic activity of various antileukemic agents, including gemtuzumab ozogamicin (GO), in preclinical studies. We evaluated the efficacy and safety of oblimersen combined with GO in patients > or =60 years of age in first relapse with CD33+ acute myeloid leukemia. Oblimersen 7 mg/kg/day was given as a continuous intravenous infusion on days 1-7 and 15-21. GO 9 mg/m2 was given intravenously on days 4 and 18. Twelve of 48 patients (25%) achieved a major response (five, complete response and seven, complete response without platelet recovery). Ten of the 12 patients who achieved a major response survived >6 months compared with six of 36 non-responders. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone. Oblimersen can be safely combined with GO. Assessment of incremental benefit will require a randomized trial.