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.

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.

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.

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.

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.

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.

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.

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.

Successful treatment of ibrutinib-associated central nervous system hemorrhage with platelet transfusion support.

Ibrutinib is a novel targeted therapy for B-cell malignancies. Hemorrhagic events were reported in the original trials, however the mechanism of bleeding is just being elucidated. Recent studies have demonstrated platelet dysfunction as a mechanism of bleeding. Currently we report two patients who developed life-threatening central nervous system hemorrhage while receiving ibrutinib for chronic lymphoid leukemia (CLL) and mantle cell lymphoma, respectively. Both patients improved rapidly after platelet transfusions even though their platelet counts were normal or only mildly reduced at the time of hemorrhage. We suggest that platelet transfusions can ameliorate the platelet dysfunction defect of ibrutinib and can support the patient through the critical period until new platelet production occurs.

CD34(+) therapy-related acute promyelocytic leukemia in a patient previously treated for breast cancer.

Therapy-related acute myeloid leukemia (AML) is a long term complication of chemotherapy for a variety of cancers. In most cases, the marrow demonstrates high risk cytogenetics and the prognosis is poor. In a minority of patients "good risk" cytogenetics, including t(15;17)(q22;q12), are seen and the patient's prognosis is similar to those who have de novo disease. Currently we present a patient who developed therapy-related acute promyelocytic leukemia (APL) after chemoradiotherapy for breast cancer. This case was especially atypical because the leukemic cells were CD34(+), which is an unusual immunophenotype for APL. Recognition that this patient had APL, rather than the more common therapy-related MDS or AML, was imperative to initiate chemotherapy in a timely manner.

Acute promyelocytic leukemia co-existing with JAK2 V617F positive myeloproliferative neoplasm: a case report.

The V617F mutation of Janus-associated kinase 2 (JAK2) is commonly seen in myeloproliferative neoplasms (MPN). Transformation of JAK2 positive MPNs to acute leukemia has been reported. We here report a case of acute promyelocytic leukemia which was later confirmed to have a co-existing JAK2 V617F positive MPN. In addition, the patient was found to have FLT3-TKD mutation, which, together with PML/RARa, could play a role in the MPN transformation to APL.

CLAG-based induction therapy in previously untreated high risk acute myeloid leukemia patients.

The CLAG regimen is highly active in patients with relapsed and/or refractory acute myeloid leukemia (AML). We administered CLAG-based chemotherapy to 20 previously untreated AML patients who were poor candidates for standard induction therapy. Responding patients received further CLAG as post-remission therapy followed by additional therapy that was tailored to their AML subtype. Patients were considered poor candidates for standard therapy due to either cardiac disease, prior chemotherapy for another malignancy, prior myeloproliferative disease, or myelodysplastic syndrome that had progressed after hypomethylator therapy. Overall, thirteen patients had a complete response (CR) to the first cycle of therapy (65%), one patient had a CR without platelet recovery, and 3 patients had a partial response (PR). Two of the patients with PR converted to CR after further therapy. The median duration of response has not been reached; the mean duration of response is 36.8 months (95% CI 28.8-44.8 months). Median overall survival (including deaths from all causes) is 29.0 months (95% CI 18.0-46.0 months). Patients with de novo AML had a CR rate of 90.9% and a median overall survival of 38.5 months. CLAG-based therapy is a well-tolerated, efficacious induction strategy in previously-untreated patients with high risk AML. CLAG-based regimens should be studied in a broader group of newly diagnosed AML patients.

Obinutuzumab treatment in the elderly patient with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults in Western countries. Fludarabine-based regimens demonstrate higher response rates in younger patients but have a significant risk of infection and are thus poorly tolerated by older, frail patients. Anti-CD20 monoclonal antibodies have added to the efficacy of chemotherapy in CLL. Obinutuzumab is a potent Type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular toxicity and direct cell death compared with rituximab. In Phase I studies, infusion reactions and neutropenia were the predominant toxicities. Phase II studies demonstrated efficacy both as a single agent and in combination with chemotherapy in patients with CLL. The CLL11 trial was a Phase III randomized trial of chlorambucil alone or with either obinutuzumab or rituximab in elderly, unfit patients. Progression-free survival (the primary end point) was 26.7 months for patients receiving obinutuzumab plus chlorambucil versus 16.3 months for those receiving rituximab plus chlorambucil and 11.1 months for those receiving chlorambucil alone (P<0.001). Overall survival was improved for patients receiving obinutuzumab plus chlorambucil versus chlorambucil alone (P=0.002). This trial led to the US Food and Drug Administration (FDA) approval of obinutuzumab in this patient population.