Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial.

This phase 1b trial (NCT02670044) evaluated venetoclax-idasanutlin in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) ineligible for cytotoxic chemotherapy. Two-dimensional dose escalation (DE, n = 50) was performed for venetoclax daily with idasanutlin on days 1 to 5 in 28-day cycles, followed by dosing schedule optimization (n = 6) to evaluate reduced venetoclax schedules (21-/14-day dosing). Common adverse events (occurring in ≥40% of patients) included diarrhea (87.3% of patients), nausea (74.5%), vomiting (52.7%), hypokalemia (50.9%), and febrile neutropenia (45.5%). During DE, across all doses, composite complete remission (CRc; CR + CR with incomplete blood count recovery + CR with incomplete platelet count recovery) rate was 26.0% and morphologic leukemia-free state (MLFS) rate was 12%. For anticipated recommended phase 2 doses (venetoclax 600 mg + idasanutlin 150 mg; venetoclax 600 mg + idasanutlin 200 mg), the combined CRc rate was 34.3% and the MLFS rate was 14.3%. Pretreatment IDH1/2 and RUNX1 mutations were associated with higher CRc rates (50.0% and 45.0%, respectively). CRc rate in patients with TP53 mutations was 20.0%, with responses noted among those with co-occurring IDH and RUNX1 mutations. In 12 out of 36 evaluable patients, 25 emergent TP53 mutations were observed; 22 were present at baseline with low TP53 variant allele frequency (median 0.0095% [range, 0.0006-0.4]). Venetoclax-idasanutlin showed manageable safety and encouraging efficacy in unfit patients with R/R AML. IDH1/2 and RUNX1 mutations were associated with venetoclax-idasanutlin sensitivity, even in some patients with co-occurring TP53 mutations; most emergent TP53 clones were preexisting. Our findings will aid ongoing/future trials of BCL-2/MDM2 inhibitor combinations. This trial was registered at www.clinicaltrials.gov as #NCT02670044.

High transferrin saturation predicts inferior clinical outcomes in patients with myelodysplastic syndromes.

Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.

A phase II open-label study of aprepitant as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) undergoing induction chemotherapy.

Despite the widespread use of 5-HT3 antagonists as anti-emetic prophylaxis in patients with acute myeloid leukemia (AML) receiving induction chemotherapy, nausea and vomiting persist in many cases. We performed a Phase II single-arm study evaluating the use of aprepitant on days 1-5, in combination with a 5-HT antagonist on days 1-3, in AML patients undergoing induction chemotherapy with daunorubicin on days 1-3 plus cytarabine, given as a continuous infusion, on days 1-7. This was compared to a retrospective cohort of AML patients that received the same chemotherapy regimen with a 5-HT antagonist but without aprepitant. The cumulative incidence of vomiting/retching by the end of day 5 was significantly lower in the aprepitant vs. the control group (26.3 vs. 52.8%, p = 0.013). The cumulative incidence of nausea by the end of day 5 was 61% in the aprepitant group vs. 75% in the control group. The total use of supplemental anti-emetics on days 2-5 was also significantly lower in the aprepitant group (p = 0.01). In contrast, the cumulative incidence of vomiting/retching by the end of day 8, the incidence of vomiting/retching on days 6-8, and the use of anti-emetics on days 6-8, were not significantly different between the two groups. The results suggest that the use of aprepitant may be associated with a lower rate of emesis during aprepitant dosing days, but not afterward. However, this requires confirmation in a randomized trial.

Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes for patients with relapsed or refractory acute myeloid leukemia (AML) are poor. Guadecitabine, a next-generation hypomethylating agent, could be useful in treating such patients. METHODS: In this multicenter, open-label, phase 2 dose-expansion study, AML patients from 10 North American medical centers were first randomized (1:1) to receive subcutaneous guadecitabine at 60 or 90 mg/m2 on 5 consecutive days in each 28-day cycle (5-day regimen). Subsequently, another cohort was treated for 10 days with 60 mg/m2 (10-day regimen). RESULTS: Between June 15, 2012, and August 19, 2013, 108 patients with previously treated AML consented to enroll in the study, and 103 of these patients were treated; 5 patients did not receive the study treatment. A total of 103 patients were included in the safety and efficacy analyses (24 and 26 patients who were randomly assigned to 60 and 90 mg/m2 /d, respectively [5-day regimen] and 53 patients who were assigned to 60 mg/m2 /d [10-day regimen]). The 90 mg/m2 dose showed no benefit in clinical outcomes in comparison with 60 mg/m2 in the randomized cohort. Composite complete response (CRc) and complete response (CR) rates were higher with the 10-day regimen versus the 5-day regimen (CRc, 30.2% vs 16.0%; P = .1061; CR, 18.9% vs 8%; P = .15). Adverse events (grade ≥ 3) were mainly hematologic, with a higher incidence on the 10-day regimen. Early all-cause mortality was low and similar between regimens. Twenty patients (8 on the 5-day regimen and 12 on the 10-day regimen) were bridged to hematopoietic cell transplantation. CONCLUSIONS: Guadecitabine has promising clinical activity and an acceptable safety profile and thus warrants further development in this population. Cancer 2018;124:325-34. © 2017 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.

Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

BACKGROUND: The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m2 guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. METHODS: We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m2 on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m2 in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock, 15 patients were still in follow-up for overall survival. This study is registered with ClinicalTrials.gov, number NCT01261312. FINDINGS: Between Aug 24, 2012, and Sept 15, 2014, 107 patients were enrolled: 54 on the 5-day schedule (26 randomly assigned to 60 mg/m2 and 28 to 90 mg/m2) and 53 were assigned to the 10-day schedule. Median age was 77 years (range 62-92), and median follow-up was 953 days (IQR 721-1040). All treated patients were assessable for a response. The number of patients who achieved a composite complete response did not differ between dose groups or schedules (13 [54%, 95% CI 32·8-74·4] with 60 mg/m2 on the 5-day schedule; 16 [59%; 38·8-77·6] with 90 mg/m2 on the 5-day schedule; and 26 [50%, 35·8-64·2] with 60 mg/m2 on the 10-day schedule). The most frequent grade 3 or worse adverse events, regardless of relationship to treatment, were febrile neutropenia (31 [61%] of 51 patients on the 5-day schedule vs 36 [69%] of 52 patients on the 10-day schedule), thrombocytopenia (25 [49%] vs 22 [42%]), neutropenia (20 [39%] vs 18 [35%]), pneumonia (15 [29%] vs 19 [37%]), anaemia (15 [29%] vs 12 [23%]), and sepsis (eight [16%] vs 14 [27%]). The most common serious adverse events, regardless of relationship to treatment, for the 5-day and 10-day schedules, respectively, were febrile neutropenia (27 [53%] vs 25 [48%]), pneumonia (14 [27%] vs 16 [31%]), and sepsis (eight [16%] vs 14 [27%]). 23 (22%) patients died because of adverse events (mainly from sepsis, eight [8%]; and pneumonia, five [5%]); four deaths were from adverse events deemed treatment-related (pneumonia, two [2%]; multiorgan failure, one [1%]; and sepsis, one [1%], all in the 10-day cohort). INTERPRETATION: More than half of older treatment-naive patients with acute myeloid leukaemia achieved a composite complete response with guadecitabine at all drug doses and schedules investigated, with tolerable toxicity. The recommended guadecitabine regimen for this population is 60 mg/m2 in a 5-day schedule. A phase 3 study in this patient population is ongoing (NCT02348489) to assess guadecitabine 60 mg/m2 in a 5-day schedule versus standard of care. FUNDING: Astex Pharmaceuticals and Stand Up To Cancer.

Overall survival in lower IPSS risk MDS by receipt of iron chelation therapy, adjusting for patient-related factors and measuring from time of first red blood cell transfusion dependence: an MDS-CAN analysis.

Analyses suggest iron overload in red blood cell (RBC) transfusion-dependent (TD) patients with myleodysplastic syndrome (MDS) portends inferior overall survival (OS) that is attenuated by iron chelation therapy (ICT) but may be biassed by unbalanced patient-related factors. The Canadian MDS Registry prospectively measures frailty, comorbidity and disability. We analysed OS by receipt of ICT, adjusting for these patient-related factors. TD International Prognostic Scoring System (IPSS) low and intermediate-1 risk MDS, at RBC TD, were included. Predictive factors for OS were determined. A matched pair analysis considering age, revised IPSS, TD severity, time from MDS diagnosis to TD, and receipt of disease-modifying agents was conducted. Of 239 patients, 83 received ICT; frailty, comorbidity and disability did not differ from non-ICT patients. Median OS from TD was superior in ICT patients (5·2 vs. 2·1 years; P < 0·0001). By multivariate analysis, not receiving ICT independently predicted inferior OS, (hazard ratio for death 2·0, P = 0·03). In matched pair analysis, OS remained superior for ICT patients (P = 0·02). In this prospective, non-randomized analysis, receiving ICT was associated with superior OS in lower IPSS risk MDS, adjusting for age, frailty, comorbidity, disability, revised IPSS, TD severity, time to TD and receiving disease-modifying agents. This provides additional evidence that ICT may confer clinical benefit.

Predictive value of molecular remissions postconsolidation chemotherapy in patients with Core Binding Factor Acute Myeloid Leukemia (CBF-AML) - a single center analysis.

We analyzed the outcome of 80 sequential patients with core binding factor acute myeloid leukemia and evaluated the influence of molecular monitoring by quantitative reverse transcriptase polymerase chain reaction. With a median follow-up of 5 years, the estimated 5-year relapse-free survival and overall survival were 58% and 66%, respectively. Patients who were in molecular remission at the completion of consolidation chemotherapy had a 21% risk of relapse, while the relapse risk for those in molecular remission at the end of 2 years was 5.5%. Our data indicate that postconsolidation molecular remission does not necessarily preclude disease relapse and further monitoring is required. In contrast, molecular negativity by quantitative reverse transcriptase polymerase chain reaction at the end of 2 years is associated with a low risk of relapse.

A predictive model of response to erythropoietin stimulating agents in myelodysplastic syndrome: from the Canadian MDS patient registry.

Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.

Patient-related factors independently impact overall survival in patients with myelodysplastic syndromes: an MDS-CAN prospective study.

UNLABELLED: Little is known about the effects of frailty, disability and physical functioning on the clinical outcomes for myelodysplastic syndromes (MDS). We investigated the predictive value of these factors on overall survival (OS) in 445 consecutive patients with MDS and chronic monomyelocytic leukaemia (CMML) enrolled in a multi-centre prospective national registry. Frailty, comorbidity, instrumental activities of daily living, disability, quality of life, fatigue and physical performance measures were evaluated at baseline and were added as covariates to conventional MDS-related factors as predictors of OS in Cox proportional hazards models. The median age was 73 years, and 79% had revised International Prognostic Scoring System (IPSS-R) risk scores of intermediate or lower. Frailty correlated only modestly with comorbidity. OS was significantly shorter for patients with higher frailty and comorbidity scores, any disability, impaired grip strength and timed chair stand tests. By multivariate analysis, the age-adjusted IPSS-R, frailty (Hazard ratio 2·7 (95% confidence interval [CI] 1·7-4·2), P < 0·0001) and Charlson comorbidity score (Hazard ratio 1·8 (95% CI 1·1-2·8), P = 0·01) were independently prognostic of OS. Incorporation of frailty and comorbidity scores improved risk stratification of the IPSS-R by 30% and 5%, respectively. These data demonstrate for the first time, the importance of considering frailty in prognostic models and a potential target for therapeutic intervention in optimizing clinical outcomes in older MDS patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02537990.

A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.

ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common non-hematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Dose-limiting toxicities (DLTs) consisted of grade 3 fatigue, grade 3 typhilitis, grade 3 syncope and grade 3 QTc prolongation). Of the 16 evaluable patients, one patient achieved a complete remission with incomplete count recovery (CRi), three experienced a morphologic leukemia-free state (MLFS) with a major hematologic improvement in platelets (HI-P), and 5 other patients had a reduction in marrow blast percentage (i.e. 11-65 %). The RP2D in this patient population is 225 mg orally once daily.

Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: 10-Color flow cytometry diagnosis and HyperCVAD therapy.

Few studies describe the comprehensive immunophenotypic pattern of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in the bone marrow and its treatment. This retrospective analysis evaluates the diagnostic flow cytometry (FCM) pattern and outcome of nine patients diagnosed with BPDCN. A four-tube 10-color FCM panel used for diagnosis of acute leukemia (AL), showed cells in the blast gate (CD45dim/low SSC) and were positive for CD4(bright), CD33(dim), CD56(heterogenous), CD123(bright), CD36, CD38, HLA-DR, CD71. Seven patients received front-line induction therapy with HyperCVAD with an overall response rate of 86%. Five of six responders underwent planned allogeneic hematopoietic cell transplantation (allo-HCT). For a median follow up of 13.3 months, the 1-year disease free survival and overall survival were 56 and 67%, respectively. An accurate diagnosis of BPDCN can be made by 10-color FCM using a four-tube AL panel demonstrating a characteristic pattern of antigen expression. Front-line induction chemotherapy with HyperCVAD can yield high remission rates, but allo-HCT is required for long-term durable remissions.

A retrospective observational study of leucoreductive strategies to manage patients with acute myeloid leukaemia presenting with hyperleucocytosis.

Acute myeloid leukaemia (AML) patients with hyperleucocytosis have higher early mortality, lower complete remission (CR) and overall survival (OS). Whether different pre-induction leucoreduction strategies can improve outcome is unknown. A single centre retrospective cohort study was conducted on AML patients with a white blood cell count (WBC) >100 × 10(9) /l between 1987 and 1997, and on all AML patients between 1998 and 2006, to determine (a) the effect of four different leucoreductive strategies (leukapheresis, hydroxycarbamide, leukapheresis and hydroxycarbamide or no pre-induction leucoreduction) on early (day 28) mortality, CR, and OS; and (b) whether a high presenting WBC remains a negative predictor of OS in patients surviving induction (first 28 d). In the 1998-2006 cohort (n = 702), higher WBC was associated with higher early mortality and lower OS but its effects were greatly diminished in patients who survived the first 28 d (Hazard Ratio 1·094 vs. 1·002). A WBC of 34·1 × 10(9) /l had the highest sensitivity (75·6%) and specificity (67·4%) for early mortality. None of the four leucoreduction strategies differed significantly in early mortality, CR, or OS in patients with WBC>100 × 10(9) /l (n = 166). The number of leucostatic signs was a significant predictor of early mortality (P < 0·0001) and OS (P = 0·0007). The results suggest that AML patients with hyperleucocytosis should be induced, if eligible, without pre-induction leucoreduction.

A phase I and pharmacodynamic study of the histone deacetylase inhibitor belinostat plus azacitidine in advanced myeloid neoplasia.

Background We hypothesized that targeting two mechanisms of epigenetic silencing would be additive or synergistic with regard to expression of specific target genes. The primary objective of the study was to establish the maximum tolerated dose (MTD) of belinostat in combination with a fixed dose of azacitidine (AZA). Methods In Part A of the study, patients received a fixed dose of AZA, with escalating doses of belinostat given on the same days 1-5, in a 28 day cycle. Part B was designed to evaluate the relative contribution of belinostat to the combination based on analysis of pharmacodynamic markers, and incorporated a design in which patients were randomized during cycle 1 to AZA alone, or the combination, at the maximally tolerated dose of belinostat. Results 56 patients with myeloid neoplasia were enrolled. Dose escalation was feasible in part A, up to 1000 mg/m(2) dose level of belinostat. In Part B, 18 patients were assessable for quantitative analysis of specific target genes. At day 5 of therapy, MDR1 was significantly up-regulated in the belinostat/AZA arm compared with AZA alone arm (p = 0.0023). There were 18 responses among the 56 patients. Conclusions The combination of belinostat and AZA is feasible and associated with clinical activity. The recommended phase II dose is 1000 mg/m(2) of belinostat plus 75 mg/m(2) of AZA on days 1-5, every 28 days. Upregulation in MDR1 was observed in the combination arm at day 5 compared with the AZA alone arm, suggesting a relative biologic contribution of belinostat to the combination.

Oral ciclopirox olamine displays biological activity in a phase I study in patients with advanced hematologic malignancies.

The antimycotic ciclopirox olamine is an intracellular iron chelator that has anticancer activity in vitro and in vivo. We developed an oral formulation of ciclopirox olamine and conducted the first-in-human phase I study of this drug in patients with relapsed or refractory hematologic malignancies (Trial registration ID: NCT00990587). Patients were treated with 5-80 mg/m² oral ciclopirox olamine once daily for five days in 21-day treatment cycles. Pharmacokinetic and pharmacodynamic companion studies were performed in a subset of patients. Following definition of the half-life of ciclopirox olamine, an additional cohort was enrolled and treated with 80 mg/m² ciclopirox olamine four times daily. Adverse events and clinical response were monitored throughout the trial. Twenty-three patients received study treatment. Ciclopirox was rapidly absorbed and cleared with a short half-life. Plasma concentrations of an inactive ciclopirox glucuronide metabolite were greater than those of ciclopirox. Repression of survivin expression was observed in peripheral blood cells isolated from patients treated once daily with ciclopirox olamine at doses greater than 10 mg/m², demonstrating biological activity of the drug. Dose-limiting gastrointestinal toxicities were observed in patients receiving 80 mg/m² four times daily, and no dose limiting toxicity was observed at 40 mg/m² once daily. Hematologic improvement was observed in two patients. Once-daily dosing of oral ciclopirox olamine was well tolerated in patients with relapsed or refractory hematologic malignancies, and further optimization of dosing regimens is warranted in this patient population.

Preclinical characterization and clinical trial of CFI-400945, a polo-like kinase 4 inhibitor, in patients with relapsed/refractory acute myeloid leukemia and higher-risk myelodysplastic neoplasms.

CFI-400945 is a selective oral polo-like kinase 4 (PLK4) inhibitor that regulates centriole duplication. PLK4 is aberrantly expressed in patients with acute myeloid leukemia (AML). Preclinical studies indicate that CFI-400945 has potent in vivo efficacy in hematological malignancies and xenograft models, with activity in cells harboring TP53 mutations. In this phase 1 study in very high-risk patients with relapsed/refractory AML and myelodysplastic syndrome (MDS) (NCT03187288), 13 patients were treated with CFI-400945 continuously in dose escalation from 64 mg/day to 128 mg/day. Three of the 9 efficacy evaluable AML patients achieved complete remission (CR). Two of 4 AML patients (50%) with TP53 mutations and complex monosomal karyotype achieved a CR with 1 patient proceeding to allogenic stem cell transplant. A third patient with TP53 mutated AML had a significant reduction in marrow blasts by > 50% with an improvement in neutrophil and platelet counts. Responses were observed after 1 cycle of therapy. Dose-limiting toxicity was enteritis/colitis. A monotherapy and combination therapy study with a newer crystal form of CFI-400945 in patients with AML, MDS and chronic myelomonocytic leukemia (CMML) is ongoing (NCT04730258).

Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

Treatment of elderly patients with acute lymphoblastic leukaemia using a paediatric-based protocol.

All newly diagnosed patients aged 60-79 years with acute lymphoblastic leukaemia (ALL) receiving induction chemotherapy with a modified paediatric-based regimen over a 7-year period were retrospectively analysed (n = 51, median age 65 years). The treatment regimen consisted of induction, central nervous system prophylaxis, seven cycles of intensification and 24 cycles of maintenance. BCR-ABL1 negative patients received weekly asparaginase during intensification, while BCR-ABL1+ patients received daily imatinib. Post-remission therapy was given in an outpatient setting. The complete response rate was 75%, with an induction mortality of 20%; 6% of patients had resistant disease. 37% of patients who achieved a complete remission relapsed. The estimated 5-year overall survival was 40% for BCR-ABL1 negative and 47% for BCR-ABL1+ patients (P = not significant); the 5-year disease-free survival was 57% and 39%, respectively (P = NS). The post-induction phase was generally well tolerated, with 81% able to complete the intensification phase and proceed to maintenance. In conclusion, administration of this modified paediatric-based protocol is feasible and active for elderly patients with ALL. Survival is superior to most previously reported series in this age group, but remains worse compared to younger patients. Further improvement of the toxicity profile, particularly during induction, is required to improve outcomes.

Management of Patients with Lower-Risk Myelodysplastic Neoplasms (MDS).

Myelodysplastic neoplasms (MDS) are a heterogenous group of clonal hematologic disorders characterized by morphologic dysplasia, ineffective hematopoiesis, and cytopenia. In the past year, the classification of MDS has been updated in the 5th edition of the World Health Organization (WHO) Classification of Haematolymphoid Tumours and the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemia with incorporation of morphologic, clinical, and genomic data. Furthermore, the more comprehensive International Prognostic Scoring System-Molecular (IPSS-M) allows for improved risk stratification and prognostication. These three developments allow for more tailored therapeutic decision-making in view of the expanding treatment options in MDS. For patients with lower risk MDS, treatment is aimed at improving cytopenias, usually anemia. The recent approval of luspatercept and decitabine/cedazuridine have added on to the current armamentarium of erythropoietic stimulating agents and lenalidomide (for MDS with isolated deletion 5q). Several newer agents are being evaluated in phase 3 clinical trials for this group of patients, such as imetelstat and oral azacitidine. This review provides a summary of the classification systems, the prognostic scores and clinical management of patients with lower risk MDS.