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Internal tandem duplication mutations in FLT3 are common in acute myeloid leukaemia and are associated with rapid relapse and short overall survival. The clinical benefit of FLT3 inhibitors in patients with acute myeloid leukaemia has been limited by rapid generation of resistance mutations, particularly in codon Asp835 (D835). We aimed to assess the highly selective oral FLT3 inhibitor gilteritinib in patients with relapsed or refractory acute myeloid leukaemia. In this phase 1–2 trial, we enrolled patients aged 18 years or older with acute myeloid leukaemia who either were refractory to induction therapy or had relapsed after achieving remission with previous treatment. Patients were enrolled into one of seven dose-escalation or dose-expansion cohorts assigned to receive once-daily doses of oral gilteritinib (20 mg, 40 mg, 80 mg, 120 mg, 200 mg, 300 mg, or 450 mg). Cohort expansion was based on safety and tolerability, FLT3 inhibition in correlative assays, and antileukaemic activity. Although the presence of an FLT3 mutation was not an inclusion criterion, we required ten or more patients with locally confirmed FLT3 mutations (FLT3mut+) to be enrolled in expansion cohorts at each dose level. On the basis of emerging findings, we further expanded the 120 mg and 200 mg dose cohorts to include FLT3mut+ patients only. The primary endpoints were the safety, tolerability, and pharmacokinetics of gilteritinib. Safety and tolerability were assessed in the safety analysis set (all patients who received at least one dose of gilteritinib). Responses were assessed in the full analysis set (all patients who received at least one dose of study drug and who had at least one datapoint post-treatment). Pharmacokinetics were assessed in a subset of the safety analysis set for which sufficient data for concentrations of gilteritinib in plasma were available to enable derivation of one or more pharmacokinetic variables. This study is registered with ClinicalTrials.gov, number NCT02014558, and is ongoing. Between Oct 15, 2013, and Aug 27, 2015, 252 adults with relapsed or refractory acute myeloid leukaemia received oral gilteritinib once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated; the maximum tolerated dose was established as 300 mg/day when two of three patients enrolled in the 450 mg dose-escalation cohort had two dose-limiting toxicities (grade 3 diarrhoea and grade 3 elevated aspartate aminotransferase). The most common grade 3–4 adverse events irrespective of relation to treatment were febrile neutropenia (97 [39%] of 252), anaemia (61 [24%]), thrombocytopenia (33 [13%]), sepsis (28 [11%]), and pneumonia (27 [11%]). Commonly reported treatment-related adverse events were diarrhoea (41 [16%] of 252]), fatigue (37 [15%]), elevated aspartate aminotransferase (33 [13%]), and elevated alanine aminotransferase (24 [10%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (78 [31%] of 252; five related to treatment), progressive disease (43 [17%]), sepsis (36 [14%]; two related to treatment), pneumonia (27 [11%]), acute renal failure (25 [10%]; five related to treatment), pyrexia (21 [8%]; three related to treatment), bacteraemia (14 [6%]; one related to treatment), and respiratory failure (14 [6%]). 95 people died in the safety analysis set, of which seven deaths were judged possibly or probably related to treatment (pulmonary embolism [200 mg/day], respiratory failure [120 mg/day], haemoptysis [80 mg/day], intracranial haemorrhage [20 mg/day], ventricular fibrillation [120 mg/day], septic shock [80 mg/day], and neutropenia [120 mg/day]). An exposure-related increase in inhibition of FLT3 phosphorylation was noted with increasing concentrations in plasma of gilteritinib. In-vivo inhibition of FLT3 phosphorylation occurred at all dose levels. At least 90% of FLT3 phosphorylation inhibition was seen by day 8 in most patients receiving a daily dose of 80 mg or higher. 100 (40%) of 249 patients in the full analysis set achieved a response, with 19 (8%) achieving complete remission, ten (4%) complete remission with incomplete platelet recovery, 46 (18%) complete remission with incomplete haematological recovery, and 25 (10%) partial remission. Gilteritinib had a favourable safety profile and showed consistent FLT3 inhibition in patients with relapsed or refractory acute myeloid leukaemia. These findings confirm that FLT3 is a high-value target for treatment of relapsed or refractory acute myeloid leukaemia; based on activity data, gilteritinib at 120 mg/day is being tested in phase 3 trials. Astellas Pharma, National Cancer Institute (Leukemia Specialized Program of Research Excellence grant), Associazione Italiana Ricerca sul Cancro.

Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. Ambit Biosciences/Daiichi Sankyo.

Tiacci, Falini, and colleagues discovered BRAF mutations in nearly all patients with hairy-cell leukemia. Now, their group, along with U.S. investigators, has found response rates of 90% or higher among patients treated with the BRAF inhibitor vemurafenib. Hairy-cell leukemia is a chronic mature B-cell cancer with unique clinicopathologic and biologic features. 1 – 4 Purine analogues (cladribine and pentostatin) induce durable complete responses in approximately 80% of patients with this cancer. 5 , 6 However, in 30 to 50% of patients, the disease relapses and there is a progressively worse response to purine analogues, 7 , 8 which can also cause cumulative myelotoxic effects and immune suppression. Thus, new therapeutic approaches are needed. Tiacci and colleagues found that the V600E mutation of BRAF, a kinase commonly mutated in solid tumors, 9 was the key genetic lesion of hairy-cell leukemia, 10 , 11 and Chung et al. . . .

Background and Objective Gilteritinib is a novel, highly selective tyrosine kinase inhibitor approved in the USA, Canada, Europe, Brazil, Korea, and Japan for the treatment of FLT3 mutation-positive acute myeloid leukemia. This article describes the clinical pharmacokinetic profile of gilteritinib. Methods The pharmacokinetic profile of gilteritinib was assessed from five clinical studies. Results Dose-proportional pharmacokinetics was observed following once-daily gilteritinib administration (dose range 20–450 mg). Median maximum concentration was reached 2–6 h following single and repeat dosing of gilteritinib; mean elimination half-life was 113 h. Elimination was primarily via feces. Exposure to gilteritinib was comparable under fasted and fed conditions. Gilteritinib is primarily metabolized via cytochrome P450 (CYP) 3A4; coadministration of gilteritinib with itraconazole (a strong P-glycoprotein inhibitor and CYP3A4 inhibitor) or rifampicin (a strong P-glycoprotein inducer and CYP3A inducer) significantly affected the gilteritinib pharmacokinetic profile. No clinically relevant interactions were observed when gilteritinib was coadministered with midazolam (a CYP3A4 substrate) or cephalexin (a multidrug and toxin extrusion 1 substrate). Unbound gilteritinib exposure was similar between subjects with hepatic impairment and normal hepatic function. Conclusions Gilteritinib exhibits a dose-proportional pharmacokinetic profile in healthy subjects and in patients with relapsed/refractory acute myeloid leukemia. Gilteritinib exposure is not significantly affected by food. Moderate-to-strong CYP3A inhibitors demonstrated a significant effect on gilteritinib exposure. Coadministration of gilteritinib with CYP3A4 or multidrug and toxin extrusion 1 substrates did not impact substrate concentrations. Unbound gilteritinib was comparable between subjects with hepatic impairment and normal hepatic function; dose adjustment is not warranted for patients with hepatic impairment. Clinical Trial Registration NCT02014558, NCT02456883, NCT02571816.

Ziftomenib (KO-539) is an oral selective menin inhibitor with known preclinical activity in menin-dependent acute myeloid leukaemia models. The primary objective of this study was to determine the recommended phase 2 dose in patients with relapsed or refractory acute myeloid leukaemia based on safety, pharmacokinetics, pharmacodynamics, and preliminary activity. KOMET-001 is a multicentre, open-label, multi-cohort, phase 1/2 clinical trial of ziftomenib in adults with relapsed or refractory acute myeloid leukaemia. Results of the phase 1 study, conducted at 22 hospitals in France, Italy, Spain, and the USA, are presented here and comprise the dose-escalation (phase 1a) and dose-validation and expansion (phase 1b) phases. Eligible patients were aged 18 years or older, had relapsed or refractory acute myeloid leukaemia, and had an Eastern Cooperative Oncology Group performance status of 2 or less. For phase 1a, patients (all molecular subtypes) received ziftomenib (50–1000 mg) orally once daily in 28-day cycles. For phase 1b, patients with NPM1 mutations or with KMT2A rearrangements were randomly assigned (1:1) using third-party interactive response technology to two parallel dose cohorts (200 mg and 600 mg ziftomenib). Primary endpoints were maximum tolerated dose or recommended phase 2 dose in phase 1a, and safety, remission rates, and pharmacokinetics supporting recommended phase 2 dose determination in phase 1b. Analyses were performed in all patients who received at least one dose of ziftomenib (modified intention-to-treat population). Phase 1a/1b is complete. This trial is registered with ClinicalTrials.gov, NCT04067336, and the EU Clinical Trials register, EudraCT 2019-001545-41. From Sept 12, 2019, to Aug 19, 2022, 83 patients received 50–1000 mg ziftomenib (39 [47%] were male and 44 [53%] were female). Median follow-up was 22·3 months (IQR 15·4–30·2). Of 83 patients, the most common grade 3 or worse treatment-emergent adverse events were anaemia (20 [24%]), febrile neutropenia (18 [22%]), pneumonia (16 [19%]), differentiation syndrome (12 [15%]), thrombocytopenia (11 [13%]), and sepsis (ten [12%]). Overall, 68 of 83 patients had serious adverse events, with two reported treatment-related deaths (one differentiation syndrome and one cardiac arrest). Differentiation syndrome rate and severity influenced the decision to halt enrolment of patients with KMT2A rearrangements. In Phase 1b, no responses were reported in patients treated at the 200 mg dose level. At the recommended phase 2 dose of 600 mg, nine (25%) of 36 patients with KMT2A rearrangement or NPM1 mutation had complete remission or complete remission with partial haematologic recovery. Seven (35%) of 20 patients with NPM1 mutation treated at the recommended phase 2 dose had a complete remission. Ziftomenib showed promising clinical activity with manageable toxicity in heavily pretreated patients with relapsed or refractory acute myeloid leukaemia. Phase 2 assessment of ziftomenib combination therapy in the upfront and relapsed or refractory setting is ongoing. Kura Oncology.

Myelodysplastic syndromes (MDS) are age-related myeloid neoplasms with Increased risk of progression to acute myeloid leukemia (AML). The mechanisms of transformation of MDS to AML are poorly understood, especially in relation to the aging microenvironment. We previously established an mDia1/miR-146a double knockout (DKO) mouse model phenocopying MDS. These mice develop age-related pancytopenia with oversecretion of proinflammatory cytokines. Here, we found that most of the DKO mice underwent leukemic transformation at 12-14 months of age. These mice showed myeloblast replacement of fibrotic bone marrow and widespread leukemic infiltration. Strikingly, depletion of IL-6 in these mice largely rescued the leukemic transformation and markedly extended survival. Single-cell RNA sequencing analyses revealed that DKO leukemic mice had increased monocytic blasts that were reduced with IL-6 knockout. We further revealed that the levels of surface and soluble IL-6 receptor (IL-6R) in the bone marrow were significantly increased in high-risk MDS patients. Similarly, IL-6R was also highly expressed in older DKO mice. Blocking of IL-6 signaling significantly ameliorated AML progression in the DKO model and clonogenicity of CD34-positive cells from MDS patients. Our study establishes a mouse model of progression of age-related MDS to AML and indicates the clinical significance of targeting IL-6 signaling in treating high-risk MDS.

mTOR-generated signals play critical roles in growth of leukemic cells by controlling mRNA translation of genes that promote mitogenic responses. Despite extensive work on the functional relevance of rapamycin-sensitive mTORC1 complexes, much less is known on the roles of rapamycin-insensitive (RI) complexes, including mTORC2 and RI-mTORC1, in BCR-ABL-leukemogenesis. We provide evidence for the presence of mTORC2 complexes in BCR-ABL-transformed cells and identify phosphorylation of 4E-BP1 on Thr37/46 and Ser65 as RI-mTORC1 signals in primary chronic myelogenous leukemia (CML) cells. Our studies establish that a unique dual mTORC2/mTORC1 inhibitor, OSI-027, induces potent suppressive effects on primitive leukemic progenitors from CML patients and generates antileukemic responses in cells expressing the T315I-BCR-ABL mutation, which is refractory to all BCR-ABL kinase inhibitors currently in clinical use. Induction of apoptosis by OSI-027 appears to negatively correlate with induction of autophagy in some types of BCR-ABL transformed cells, as shown by the induction of autophagy during OSI-027-treatment and the potentiation of apoptosis by concomitant inhibition of such autophagy. Altogether, our studies establish critical roles for mTORC2 and RI-mTORC1 complexes in survival and growth of BCR-ABL cells and suggest that dual therapeutic targeting of such complexes may provide an approach to overcome leukemic cell resistance in CML and Ph+ ALL.

The fms-like tyrosine kinase 3 (FLT3) inhibitor gilteritinib is indicated for relapsed or refractory (R/R) FLT3-mutated acute myeloid leukemia (AML), based on its observed superior response and survival outcomes compared with salvage chemotherapy (SC). Frontline use of FLT3 tyrosine kinase inhibitors (TKIs) midostaurin and sorafenib may contribute to cross-resistance to single-agent gilteritinib in the R/R AML setting but has not been well characterized. To clarify the potential clinical impact of prior TKI use, we retrospectively compared clinical outcomes in patients with R/R FLT3-mutated AML in the CHRYSALIS and ADMIRAL trials who received prior midostaurin or sorafenib against those without prior FLT3 TKI exposure. Similarly high rates of composite complete remission (CRc) were observed in patients who received a FLT3 TKI before gilteritinib (CHRYSALIS, 42%; ADMIRAL, 52%) and those without prior FLT3 TKI therapy (CHRYSALIS, 43%; ADMIRAL, 55%). Among patients who received a prior FLT3 TKI in ADMIRAL, a higher CRc rate (52%) and trend toward longer median overall survival was observed in the gilteritinib arm versus the SC arm (CRc = 20%; overall survival, 5.1 months; HR = 0.602; 95% CI: 0.299, 1.210). Remission duration was shorter with prior FLT3 TKI exposure. These findings support gilteritinib for FLT3-mutated R/R AML after prior sorafenib or midostaurin.

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and cytopenia-related toxicities, which can affect treatment tolerability and quality of life. In this review, we summarize the available evidence for triplet therapy in AML and offer our recommendations on the practical application of triplets in clinical practice, with particular focus on adjustments to dosing schedules in induction and continuation cycles. We also outline drug-specific adverse effects and interactions based on emerging clinical data to help guide the clinician, given the increasing use of novel combination therapies.