Mark Brandt

Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia

Adult Burkitt‐type lymphoma (BL) and acute lymphoblastic leukemia (B‐ALL) are rare entities composing 1% to 5% of non‐Hodgkin lymphomas NHL) or ALL. Prognosis of BL and B‐ALL has been poor with conventional NHL or ALL regimens, but has improved with dose‐intensive regimens.

Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia

PURPOSE To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. PATIENTS AND METHODS In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m(2) by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m(2) IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. RESULTS Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional FLT3-WT patients had CRp). FLT3-mutated patients were more likely to achieve a CR than FLT3-WT patients (P = .033). With a median follow-up of 54 weeks (range, 8 to 87 weeks), the probability of survival at 1 year is 74%. Among the FLT3-mutated patients, 10 have relapsed and five remain in CR with a median follow-up of 62 weeks (range, 10 to 76 weeks). Plasma inhibitory assay demonstrated an on-target effect on FLT3 kinase activity. CONCLUSION Sorafenib can be safely combined with chemotherapy, produces a high CR rate in FLT3-mutated patients, and inhibits FLT3 signaling.

Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia

We reviewed the outcome of 671 patients 65 years of age or older with newly diagnosed acute myeloid leukemia (AML) treated at our institution between 2000 and 2010 with intensive chemotherapy (n = 557) or azacitidine- or decitabine-based therapy (n = 114). Both groups were balanced according to cytogenetics and performance status. The complete response rates with chemotherapy and epigenetic therapy were 42% and 28%, respectively (P = .001), and the 8-week mortality 18% and 11%, respectively (P = .075). Two-year relapse-free survival rates (28% vs 39%, P = .843) and median survival (6.7 vs 6.5 months, P = .413) were similar in the 2 groups. Multivariate analysis identified older age, adverse cytogenetics, poor performance status, elevated creatinine, peripheral blood and BM blasts, and hemoglobin, but not type of AML therapy, as independent prognostic factors for survival. No outcome differences were observed according to cytogenetics, FLT3 mutational status, age, or performance status by therapy type. Decitabine was associated with improved median overall survival compared with azacitidine (5.5 vs 8.8 months, respectively, P = .03). Survival after failure of intensive chemotherapy, azacitidine, or decitabine was more favorable in patients who had previously received decitabine (1.1 vs 0.9 vs 3.1 months, respectively, P = .109). The results of the present study show that epigenetic therapy is associated with similar survival rates as intensive chemotherapy in older patients with newly diagnosed AML. The studies reviewed are registered at www.clinicaltrials.gov as 2009-0172 (NCT00926731) and 2009-0217 (NCT00952588).

Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

PURPOSE To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). PATIENTS AND METHODS Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m(2) intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m(2) IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. RESULTS After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. CONCLUSION The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

Myeloid Sarcoma Is Associated with Superior Event-Free Survival and Overall Survival Compared with Acute Myeloid Leukemia

It is unknown whether patients with nonleukemic myeloid sarcoma (MS) and those with acute myeloid leukemia (AML) have similar responses to anti‐AML treatment. In the current study, the authors addressed this question by matching MS patients with analogous AML patients and comparing their clinical outcomes.

Characteristics and outcome of patients with acute myeloid leukemia refractory to 1 cycle of high-dose cytarabine-based induction chemotherapy

Pretreatment characteristics and outcome of patients treated with induction regimens containing high-dose ara-C (HiDAC) at M. D. Anderson Cancer Center refractory to 1 cycle of induction were compared with similar patients achieving a complete response (CR). Among 1597 patients treated with HiDAC-based induction from 1995 to 2009, 285 were refractory to 1 cycle. Median age was 59 years (range, 18-85 years). Induction regimens included HiDAC with anthracyclines (n = 181; 64%) or HiDAC with nonanthracycline chemotherapy (n = 104; 36%). Refractory patients were older (median age, 59 vs 56 years; P < .001), more likely with unfavorable cytogenetics (P < .001) and antecedent hematologic disorder (P < .001), and had a higher presentation white blood cell count (P = .04), but not a higher incidence of FLT3 mutations (P = .85), than those achieving CR. Forty-three patients (22%) responded to salvage (35 CR and 8 CR without platelet recovery). With a median follow-up of 72 months (range, 27-118 months) in responders, 11 are alive. Nineteen patients (7%) were alive and in CR for at least 6 months, including 9 who underwent allogeneic stem cell transplantation. On multivariate analysis, severe thrombocytopenia, leukocytosis, increasing marrow blast percentage, unfavorable cytogenetics, and salvage not including allogeneic stem cell transplantation were associated with a worse survival. Alternative strategies are needed for these patients.

Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia

Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single‐arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results.

Characteristics, clinical outcome, and prognostic significance of IDH mutations in AML

The pathophysiology of IDH mutations in tumorigenesis is increasingly described, yet the prognostic significance of IDH1 and IDH2 mutations in AML remains controversial. The primary objective of this study was to define the natural history and prognosis of patients with AML and IDH1 or IDH2 mutations and provide historical survival expectations. A total of 826 patients treated from 2010 to 2014 at a single institution were evaluated, including 167 patients (20%) with AML and IDH1 or IDH2 mutations. Median age was 62 years (range 18–92). There were 59 IDH1‐R132, 83 IDH2‐R140, and 23 IDH2‐R172 mutations. Clinicopathologic characteristics associated with IDH‐mutations included older age, less frequent therapy‐related status, and increased incidence of intermediate‐risk cytogenetics, FLT3‐ITD mutations, and NPM1 mutations. Remission rates (CR/CRi) by AML treatment status were: induction, 68%; Salvage‐1 (S1), 42%; and Salvage‐2 and beyond (S2+), 27%. No difference in response was identified by IDH mutation status. Similarly, overall survival (OS) was not dependent on IDH status within any cohort. The median OS was 15.4 months in induction, 8.7 months in S1, and 4.8 months in S2+. This analysis defines the clinical outcome associated with IDH‐mutations in both the front‐line and salvage AML treatment settings, and confirms that response rate and OS for both IDH‐mutated and IDH wild‐type AML patients is comparable. This provides contemporary data to be used for comparison with results of novel investigational (e.g., selective IDH inhibitor) strategies. Am. J. Hematol. 90:732–736, 2015.

Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia

We conducted this study to determine the feasibility and safety of cladribine followed by rituximab in patients with hairy cell leukemia including the vari-ant form (HCLv). Cladribine 5.6 mg/m² given IV over 2 hours daily for 5 days was followed ∼ 1 month later with rituximab 375 mg/m² IV weekly for 8 weeks. Responses were recorded and BM minimal residual disease (MRD) was evaluated after the completion of rituximab. Thirty-six patients have been treated including 5 with HCLv. Median age was 57 years (range, 37-89). All patients (100%) have achieved complete response (CR), defined as presence of no hairy cells in BM and blood with normalization of counts (absolute neutrophil count [ANC]> 1.5 × 10⁹/L, hemoglobin [Hgb] > 12.0 g/dL, platelets [PLT] > 100 × 10⁹/L), as well as resolution of splenomegaly. There were no grade 3 or 4 nonhematologic adverse events directly related to the treatment. Only 1 patient (with HCLv) has relapsed; median CR duration has not been reached (range,1+-63+ months). Three patients with HCLv died including 1 with relapsed disease and 2 from unrelated malignancies. Median survival duration has not been reached (range, 2+-64+ months). Treatment with cladribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594.

Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse

Mutations of Fms-like tyrosine kinase-3 (FLT3) have been described in about 30% of patients with acute myeloid leukemia (AML) and are associated with a shorter disease-free and overall survival after initial therapy. We sought to examine whether the presence of these mutations in relapsed disease was also associated with a poor response to salvage chemotherapy by comparing the outcome of 34 patients with diploid cytogenetics and mutated FLT3 (internal tandem duplication mutation, ITD) to 69 patients with normal karyotype and wild-type FLT3 (FLT3-WT) in first relapse. On univariate analysis, patients with mutated FLT3 were less likely to achieve a CR to first salvage compared to FLT3-WT patients (24% vs. 41%; P=0.09). Furthermore, survival was longer for the FLT3-WT patients achieving a second CR after salvage compared to FLT3-mutated patients (P=0.017). Overall, patients with mutated FLT3 had a shorter survival from the time of relapse compared to those with FLT3-WT (P<0.001). The adverse prognostic impact of FLT3 mutations appears to persist beyond the initial treatment.