Lenalidomide, rituximab (R2), and ixazomib for frontline treatment of high risk follicular and indolent non-Hodgkin lymphoma.

Lenalidomide and rituximab (R2) is an effective frontline treatment for patients with indolent B-cell non-Hodgkin lymphoma (iNHL). We investigated the safety and efficacy of addition of the proteasome inhibitor ixazomib to R2 for treatment of iNHL through a phase I/II clinical trial for high-risk patients. Twenty patients were enrolled, 18 were treated. The target dose of ixazomib 4 mg weekly was achieved during dose escalation. The most common treatment-related adverse events (AEs) were low grade gastrointestinal, rash, neuropathy, and myalgia/arthralgia. There were 33% grade 2 and 17% grade 3 infections. With median follow-up of 5.2 years, four patients discontinued treatment due to lymphoma progression. Best overall response rate (ORR) was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. Kaplan-Meier estimates of progression free and overall survival (OS) were 73% and 87% at 36 months, respectively. R2 can safely be combined with ixazomib for treatment-naïve iNHL patients.

Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies.

The 5-azacytidine (AZA) and decitabine (DEC) are noncytotoxic, differentiation-inducing therapies approved for treatment of myelodysplastic syndrome, acute myeloid leukemias (AML), and under evaluation as maintenance therapy for AML postallogeneic hematopoietic stem cell transplant and to treat hemoglobinapathies. Malignant cell cytoreduction is thought to occur by S-phase specific depletion of the key epigenetic regulator, DNA methyltransferase 1 (DNMT1) that, in the case of cancers, thereby releases terminal-differentiation programs. DNMT1-targeting can also elevate expression of immune function genes (HLA-DR, MICA, MICB) to stimulate graft versus leukemia effects. In vivo, there is a large inter-individual variability in DEC and 5-AZA activity because of pharmacogenetic factors, and an assay to quantify the molecular pharmacodynamic effect of DNMT1-depletion is a logical step toward individualized or personalized therapy. We developed and analytically validated a flow cytometric assay for DNMT1 epitope levels in blood and bone marrow cell subpopulations defined by immunophenotype and cell cycle state. Wild type (WT) and DNMT1 knock out (DKO) HC116 cells were used to select and optimize a highly specific DNMT1 monoclonal antibody. Methodologic validation of the assay consisted of cytometry and matching immunoblots of HC116-WT and -DKO cells and peripheral blood mononuclear cells; flow cytometry of H116-WT treated with DEC, and patient samples before and after treatment with 5-AZA. Analysis of patient samples demonstrated assay reproducibility, variation in patient DNMT1 levels prior to treatment, and DNMT1 depletion posttherapy. A flow-cytometry assay has been developed that in the research setting of clinical trials can inform studies of DEC or 5-AZA treatment to achieve targeted molecular pharmacodynamic effects and better understand treatment-resistance/failure.

A multicenter study of posttransplantation low-dose inotuzumab ozogamicin to prevent relapse of acute lymphoblastic leukemia.

ABSTRACT: The curative potential of allogeneic hematopoietic transplantation (allo-HCT) in patients with acute lymphoblastic leukemia (ALL) is hampered by relapse. Inotuzumab ozogamicin (INO) is an anti-CD22 monoclonal antibody bound to calicheamicin, which has significant activity against ALL. We hypothesized that low-dose INO would be safe and feasible after allo-HCT. Therefore, we conducted a phase 1 study to determine the dose and safety in this setting. Patients were eligible if they were aged 16 to 75 years, had undergone allo-HCT for CD22+ ALL, were in complete remission (CR) after allo-HCT, had high risk of recurrence, were between day 40 and 100 after allo-HCT with adequate graft function, and did not have a history of sinusoidal obstruction syndrome (SOS). The objectives of this trial were to define INO maximum tolerated dose (MTD), to determine post-allo-HCT INO safety, and to measure 1-year progression-free survival (PFS). The trial design followed a "3+3" model. The treatment consisted of INO given on day 1 of 28-day cycles. Dose levels were 0.3 mg/m2, 0.4 mg/m2, 0.5 mg/m2, and 0.6 mg/m2. Median age was 44 years (range, 17-66 years; n = 18). Disease status at transplantation was first CR (n = 14) or second CR or beyond (n = 4). Preparative regimen was of reduced intensity in 72% of patients who received transplantation. Most common toxicity was thrombocytopenia. There were no instances of SOS; the MTD was 0.6 mg/m2. One-year nonrelapse mortality was 5.6%. With a median follow-up of 18.1 months (range, 8.6-59 months) 1-year post-allo-HCT PFS and overall survival is 89% and 94%, respectively. Low-dose INO has a favorable safety profile and was associated with high rates of 1-year PFS. This trial was registered at www.clinicaltrials.gov as #NCT03104491.

Gilteritinib in Combination With Induction and Consolidation Chemotherapy and as Maintenance Therapy: A Phase IB Study in Patients With Newly Diagnosed AML.

PURPOSE: Gilteritinib is a type 1 FLT3 inhibitor active as monotherapy for relapsed or refractory FLT3-mutated AML. We investigated the safety, tolerability, and efficacy of gilteritinib incorporated into intensive induction and consolidation chemotherapy, and as maintenance therapy for adult patients with newly diagnosed, non-favorable-risk AML. METHODS: In this phase IB study (2215-CL-0103; ClinicalTrials.gov identifier: NCT02236013), 103 participants were screened and 80 were allocated to treatment. The study was divided into four parts: dose escalation, dose expansion, investigation of alternate anthracycline and gilteritinib schedule, and continuous gilteritinib during consolidation. RESULTS: After dose escalation, 120 mg gilteritinib once daily was chosen for further study. There were 58 participants evaluable for response at this dose, 36 of whom harbored FLT3 mutations. For participants with FLT3-mutated AML, the composite complete response (CRc) rate was 89% (83% were conventional complete responses), all achieved after a single induction cycle. The median overall survival time was 46.1 months. Gilteritinib was well-tolerated in this context although the median time to count recovery during induction was approximately 40 days. Longer time-to-count recovery was associated with higher trough levels of gilteritinib, which, in turn, were associated with azole use. The recommended regimen is gilteritinib at a dose of 120 mg once daily from days 4 to 17 or 8 to 21 of a 7 + 3 induction with either idarubicin or daunorubicin and from day 1 continuously with high-dose cytarabine consolidation. Maintenance therapy with gilteritinib was well-tolerated. CONCLUSION: These results demonstrated the safety and tolerability of gilteritinib incorporated into an induction and consolidation chemotherapy regimen, and as single-agent maintenance therapy for patients with newly diagnosed FLT3-mutant AML. The data herein provide an important framework for the design of randomized trials comparing gilteritinib with other FLT3 inhibitors.

Phase I study of intra-osseous co-transplantation of a single-unit cord blood and mesenchymal stromal cells with reduced intensity conditioning regimens.

Cord blood (CB) is a valuable graft source for patients undergoing allogeneic hematopoietic cell transplant (HCT) who lack human leukocyte antigen (HLA)-matched donors. However, single-unit CB-HCT is limited by the insufficient cell dose and slow engraftment. To overcome these limitations, we combined a single-unit CB with third-party healthy donors' bone marrow (BM) derived mesenchymal stromal cells (MSCs) to improve engraftment and injected intra-osseously (IO) to enhance homing. In this phase I clinical trial, six patients with high-risk hematologic malignancies were enrolled and received allogeneic HCT using reduced intensity conditioning regimens. The primary objective was to determine the engraftment rate at day 42. The median age of enrolled patients was 68 years, and only one patient was in complete remission at the time of HCT. The median CB total nucleated cell dose was 3.2x107/kg. No serious adverse events were reported. Two patients had early deaths due to persistent disease and multi-drug resistant bacterial infection, respectively. Of the remaining four evaluable patients, all had successful neutrophil engraftment in a median of 17.5 days. No grade 3 or higher acute graft-versus-host disease (GvHD) was observed, and only one patient developed moderate-extensive chronic GvHD. In conclusion, IO co-transplantation of a single-unit CB and MSCs was feasible and resulted in a reasonable engraftment rate in these very high-risk patients.

Risk factors for cardiovascular events and mortality in patients diagnosed with diffuse large B-cell lymphoma and treated with anthracyclines.

There is an increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Little is known about risk factors of CHF, other cardiovascular events (CVE), and CVE effect on outcomes. We conducted a retrospective review of 463 newly diagnosed DLBCL patients treated between 2002 and 2016 with anthracycline containing regimens. At a median follow up of 71.3 months, 10.4% patients developed new CHF, 4.97% had new atrial fibrillation and 3.2% had new coronary artery disease. Age over 65, advanced stage DLBCL and diabetes were associated with increased cumulative incidence of CVE. Patients with prior diabetes had decreased progression-free survival and overall survival in comparison to non-diabetics. Patients who had a CVE in the first year had significant worse OS then patients who did not have a CVE (Hazard Ratio 10.0, 95% CI, 7.24-13.88). A risk score incorporating age at DLBCL diagnosis, baseline lymphocyte count, disease stage and diabetes stratified into groups with low, intermediate and high risk for CVE, with 1-year cumulative incidence of CVE of 5.3%, 7.9% and 13.4%. Diffuse large B-cell lymphoma patients treated with anthracycline containing regimens have high incidence of CVE, which are not limited to CHF. Clinical variables at the time of diagnosis can identify the group of DLBCL patients at highest risk of CVE, for whom preventive interventions should be considered.

Targeted Marrow Irradiation Intensification of Reduced-Intensity Fludarabine/Busulfan Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation.

Reduced-intensity conditioning (RIC) regimens frequently provide insufficient disease control in patients with high-risk hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated intensification of fludarabine/busulfan (Flu/Bu) RIC with targeted marrow irradiation (TMI) in a dose escalation with expansion phase I clinical trial. TMI doses were delivered at 1.5 Gy in twice daily fractions on days -10 through -7 (dose levels: 3 Gy, 4.5 Gy, and 6 Gy), Flu (30 mg/m2 for 5 days) and Bu (area under the curve, 4800 µM*minute for 2 days). Eligible patients were age ≥18 years with high-risk hematologic malignancy and compromised organ function ineligible for myeloablative transplantation (n = 26). The median patient age was 64 years (range, 25 to 76 years). Nineteen patients (73%) had active or measurable residual disease at transplantation. One-year disease-free survival and overall survival were 55% (95% confidence interval [CI], 34% to 76%) and 65% (95% CI, 46% to 85%), respectively. Day +100 and 1 year transplantation-related mortality were 4% (95% CI, 0.6% to 27%) and 8.5% (95% CI, 2% to 32%), respectively. The 1-year cumulative incidence of relapse was 43% (95% CI, 27% to 69%). Rates of grade II-IV and III-IV acute GVHD rates were 57% (95% CI, 39% to 84%) and 22% (95% CI, 9% to 53%), respectively. Whole blood immune profiling demonstrated enrichment of central/transitional memory-like T cells with higher TMI doses, which correlated with improved survival compared with control samples from patients undergoing allogeneic HSCT. Intensification of a Flu/Bu RIC regimen with TMI is feasible with a low incidence of transplantation-related mortality in medically frail patients with advanced malignancies. The recommended phase 2 TMI dose is 6 Gy.

A Phase I Study to Determine the Maximum Tolerated Dose of ex Vivo Expanded Natural Killer Cells Derived from Unrelated, HLA-Disparate Adult Donors.

The administration of allogeneic natural killer (NK) cells following a lymphodepleting chemotherapy regimen is emerging as a well-tolerated therapeutic approach in the management of various malignancies. Contrary to the expected complications of allogeneic T cell therapy, there remains no evidence of graft-versus-host disease (GVHD) mediated by NK cells in numerous clinical trials. On the contrary, preclinical and clinical studies suggest that NK cells do not induce GVHD and in fact may prevent its development following allogeneic hematopoietic cell transplantation (HCT). In this study, we sought to determine the maximum tolerated dose of non-HLA-matched donor NK cells derived from peripheral blood and ex vivo expanded using a novel feeder cell platform. In a single-center Phase I clinical trial using a 3 × 3 design, 9 subjects each received 2 infusions of NK cells 2 weeks apart following a preparative regimen of cyclophosphamide (60 mg/kg i.v.) and fludarabine (25 mg/m2/day i.v for 5 days). No exogenous cytokines were administered. NK cells were administered at 3 dose levels: 1 × 107/kg, 2.5 × 107/kg, and 5 × 107/kg. Three subjects had myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML), and the other 6 subjects had colorectal carcinoma. Recipients were monitored over a 4-week period for GVHD as well as other adverse events and for persistence of donor NK cells in systemic circulation. Disease assessment was started at 28 days following the first NK cell infusion and continued until postinfusion day 100 or disease progression. In all 9 study subjects, there was no occurrence of GVHD and no dose-limiting toxicities that would warrant cohort expansion at any of the 3 planned cell dose levels. Low-level donor NK cell persistence was observed up to 4 weeks after the first NK cell infusion at all dose levels. The best observed response was a complete response with incomplete platelet recovery in a MDS subject who experienced disease relapse after prior allogeneic HCT. Other responses were stable disease in 1 subject with MDS and 2 subjects with colorectal cancer up to postinfusion day 100. This off-the-shelf, third-party NK cell product can be administered safely without inducing GVHD and exhibits in vivo persistence promoted by preparative lymphodepletion alone. The observed clinical responses could be enhanced by administration of exogenous cytokine support, as well as complementary approaches that promote NK cell function in the tumor microenvironment.

Tipifarnib as maintenance therapy did not improve disease-free survival in patients with acute myelogenous leukemia at high risk of relapse: Results of the phase III randomized E2902 trial.

PURPOSE: Despite the achievement of complete remission with chemotherapy in patients with acute myeloid leukemia (AML), relapse is common and the majority of patients will die of their disease. Patients who achieve a remission after refractory or relapsed disease as well as elderly patients have a very high rate of relapse even if they achieve a complete remission. A phase 3 randomized ECOG-ACRIN-led intergroup study was conducted to determine whether post-remission therapy with the farnesyl transferase inhibitor, tipifarnib (R115777), improved the disease-free survival (DFS) of adult patients with AML in complete remission (CR), at high risk for relapse. PATIENTS AND METHODS: Adult patients with AML in remission after salvage therapy and/or over age 60 in first remission were enrolled in this study. They were randomly assigned to treatment with tipifarnib or observation (control). The primary objective was to compare the disease-free survival (DFS) between the two arms based on intention to treat, which includes all randomized patients. RESULTS: One hundred and forty-four patients were enrolled on the study. Median DFS was 8.9 vs 5.3 months, for tipifarnib vs observation (one-sided p = 0.026) and did not cross the pre-specified boundary to call the study positive. For the 134 eligible patients, median DFS was 10.8 vs 5.3 months for those randomized to tipifarnib vs observation (one-sided p = 0.008). Moreover in an ad hoc evaluation of all women (n = 71) median DFS was 12.1 vs 3.9 months for tipifarnib vs observation (one-sided p = 0.0004) while median OS was 26.5 vs 8.4 months respectively (one-sided p = 0.001). CONCLUSION: This study was not able to demonstrate a benefit to tipifarnib as maintenance therapy in patients with AML in remission. While subsets of patients may indeed benefit, additional studies would be needed to elucidate that benefit which is unlikely given that other seemingly better options have since become available.

Diffuse Large B Cell Lymphoma in Patients 80 Years and Older: Worse Survival After Treatment Without Increased Relapse Rates.

BACKGROUND: Age is an adverse prognostic factor in diffuse large B cell lymphoma (DLBCL), but there are limited data on the outcomes of patients' ≥80 years, including those treated with dose reduced chemoimmunotherapy. PATIENTS AND METHODS: We conducted a retrospective analysis of 542 patients, 85 (16%) were ≥80 years of age. RESULTS: Although the very elderly group had more frequent comorbidities and decreased performance status, 89% received therapy. Four-year PFS was 42% vs. 61% (P < .001) in patients ≥80 years vs. younger patients, while 4-year OS was 42% vs. 72% (P < .0001), respectively. In patients treated with anthracycline-containing regimens (n = 416) 4-year cumulative incidence of relapse with death as competing risk was not different between age groups. Median survival for DLBCL patients ≥80 years treated with R-CHOP or R-miniCHOP was 4.5 years. Survival after first relapse was significantly different between age groups: 5 vs. 19 months (P = .002), respectively. CONCLUSION: Very elderly DLBCL patients have worse OS and PFS compared with younger patients but can achieve long term disease control and potentially be cured with chemoimmunotherapy. Older DLBCL patients treated with effective regimens do not have increased rates of relapse, but outcomes after relapse remain poor.

Physical Activity and Sleep Measures Using a Fitness Tracking Device during Hematopoietic Cell Transplantation: A Pilot Study.

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices.

Efficacy and cost-benefit of filgrastim administered after early assessment bone marrow biopsy during induction therapy for acute myeloid leukemia.

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days, p < .01), absolute neutrophil count recovery days (median 23 vs 25 days, p = .03), and intravenous antibiotics days (mean 18.5 vs 21.4 days, p = .01) in patients with eGCSF comparing with no-eGCSF. There was no significant difference regarding complete response rates; however, for those failed to achieve remission, eGCSF was associated with higher blast count. There was no significant difference regarding overall survival or progression-free survival. The use of eGCSF was associated with cost savings of $5199 per patient over no-eGCSF.

A Phase II Trial of Imatinib Mesylate as Maintenance Therapy for Patients With Newly Diagnosed C-kit-positive Acute Myeloid Leukemia.

INTRODUCTION: Adults with acute myeloid leukemia (AML) have a high rate of remission; however, more than 50% relapse. C-kit is expressed in approximately 60% of patients with de novo AML and represents a potential therapeutic target. MATERIALS AND METHODS: Patients with newly diagnosed AML received 12 months of imatinib mesylate as maintenance therapy after the completion of post-remission therapy. The primary objective was to determine whether this approach improved progression-free survival (defined as no relapse and no death) compared with historical controls. RESULTS: The median progression-free survival of patients < 60 years of age was 52.1 months (historical control, 13 months) and for patients ≥ 60 years of age was 10.7 months (historical control, 8 months). The median level of AF1q expression was high (9.59), and 84% of patients had moderate or high levels of drug-resistance factors. CONCLUSIONS: Imatinib maintenance therapy may improve the outcome of newly diagnosed patients with AML who are < 60 years of age.

History of drug use in allogeneic hematopoietic cell transplant recipients.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use. The medical charts of 232 patients were reviewed. Recipients of matched unrelated donor (MUD) or matched related donor (MRD) transplants were included. Drug use was defined by either metabolic evidence or provider documentation prior to transplant. Transplants were MUD (n = 148) or MRD (n = 84). Median follow-up duration was 15.5 months. There were 35 (15%) patients in the drug use group and 197 (85%) patients in the control group; 49% and 60.4% were in remission at the time of transplant, respectively. In univariate analysis, drug use was associated with a 3-year cumulative incidence of NRM of 43% vs 29% for the control group (p = 0.048), and an HR of 1.75, (95% CI: 1.02-2.99). After controlling for age, sex, disease status, and graft type, drug use was associated with a hazard ratio (HR) of 1.6 (95% CI: 0.95-2.92) for NRM, and an HR 1.2 (95% CI: 0.74-1.94) for OS. Larger cohorts may be needed to further evaluate this association.

Aggressive lymphoma subtype is a risk factor for venous thrombosis. Development of lymphoma - specific venous thrombosis prediction models.

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score. A group of 790 patients were diagnosed from 2002 to 2014 (DLBCL = 542, FL = 248). Median follow- up was 49 months. We observed 106 VTE, with higher incidence in DLBCL (5-year cumulative incidence = 16.3% vs 3.8% in FL patients). Five-year OS for patients with VTE was 51.4% vs 73.1% in patients without VTE (P < .001). Baseline VTE risk factors identified in the training cohort included lymphoma subtype, previous VTE, ECOG performance status ≥2, decreased albumin, increased calcium, elevated WBC, absolute lymphocyte count or monocyte count, and presence of bulky disease. Addition of new variables to the Khorana score improved its performance measured by Akaike information criterion and Concordance index. A new risk model including lymphoma subtype, albumin, WBC count, and bulky disease was validated in time-based ROC analyses. These findings were confirmed in the validation cohort. Lymphoma subtypes have different VTE risk. The effect of lymphoma subtype was independent from disease burden and the use of systemic therapy. The Khorana risk-score was validated in time to event analyses, and a more robust lymphoma-specific VTE risk score is proposed. These findings suggest lymphoma patients with highest VTE risk can be identified with baseline parameters.

Phase I Trial of Lithium and Tretinoin for Treatment of Relapsed and Refractory Non-promyelocytic Acute Myeloid Leukemia.

Glycogen synthase kinase-3 (GSK3) inhibitors induce differentiation and growth inhibition of acute myeloid leukemia (AML) cells. Our pre-clinical studies showed GSK3 inhibition leads to sensitization of AML cells to tretinoin-mediated differentiation. We conducted a phase I trial of lithium, a GSK3 inhibitor, plus tretinoin for relapsed, refractory non-promyelocytic AML. Nine patients with median (range) age 65 (42-82) years were enrolled. All subjects had relapsed leukemia after prior therapy, with a median (range) of 3 (1-3) prior therapies. Oral lithium carbonate 300 mg was given 2-3 times daily and adjusted to meet target serum concentration (0.6 to 1.0 mmol/L); tretinoin 22.5 or 45 mg/m2/day (two equally divided doses) was administered orally on days 1-7 and 15-21 of a 28-day cycle. Four patients attained disease stability with no increase in circulating blasts for ≥4 weeks. Median (range) survival was 106 days (60-502). Target serum lithium concentration was achieved in all patients and correlated with GSK3 inhibition in leukemic cells. Immunophenotypic changes associated with myeloid differentiation were observed in five patients. The combination treatment led to a reduction in the CD34+ CD38- AML stem cell population both in vivo and in vitro. The combination of lithium and tretinoin is well-tolerated, induces differentiation of leukemic cells, and may target AML stem cells, but has limited clinical activity in the absence of other antileukemic agents. The results of this clinical trial suggest GSK3 inhibition can result in AML cell differentiation and may be a novel therapeutic strategy in this disease, particularly in combination with other antileukemic agents. Lithium is a weak GSK3 inhibitor and future strategies in AML treatment will probably require more potent agents targeting this pathway or combinations with other antileukemic agents. This trial is registered at ClinicalTrials.gov NCT01820624.

A Phase II Study of Midostaurin and 5-Azacitidine for Untreated Elderly and Unfit Patients With FLT3 Wild-type Acute Myelogenous Leukemia.

BACKGROUND: Midostaurin, a multikinase inhibitor, is approved for treatment of FLT3-mutant acute myeloid leukemia (AML). A phase I study established that midostaurin 75 mg orally twice daily for 14 days with standard dose azacitidine was safe and tolerable in elderly patients with AML. Herein, we report the phase II expansion cohort of previously untreated elderly or unfit patients with AML. PATIENTS AND METHODS: Primary objectives were to further describe the toxicity profile and determine the response rate in untreated patients with AML. Patients received midostaurin 75 mg orally twice daily on days 8 to 21 in combination with intravenous azacitidine at 75 mg/m2 on days 1 to 7. Plasma inhibitory activity assay for FLT3 was performed pretreatment and on day 8 and day 15 of each cycle. RESULTS: Twenty-six patients (median age, 74 years; range, 59-85 years) with FLT3 wild-type AML were accrued. Patients received a median of 2 cycles of therapy (range, 1-10 cycles). Seven (29%) of 24 evaluable patients achieved a clinical response (4 complete response; 1 complete response with incomplete count recovery; and 2 partial response). The median overall survival was 244 days (95% confidence interval, 203-467 days). Hematologic, infectious, and gastrointestinal toxicities were comparable to similar studies. Peripheral blood FLT3 wild-type phosphorylation declined to 8% to 55% of pretreatment by day 15 of cycle 1 (7 patients) and declined with subsequent cycles (< 10% baseline) in 2 patients who were analyzed after cycle 3. CONCLUSION: Multiple cycles of azacitidine and midostaurin were not well-tolerated, but persistent inhibition of FLT3 wild-type phosphorylation suggest intermittent dosing of midostaurin should be considered in future low-intensity regimens for FLT3-mutant AML.