Synergy between FLT3 and Pim kinase inhibition in acute myeloid leukemia with FLT3-ITD mutation.

The combination of carmustine, etoposide, aracytin, and melphalan(BEAM) conditioning regimen in autologous stem-cell transplantation (ASCT) is widely used in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma. It is also an option in patients with very-high risk aggressive NHL in first complete remission (CR). Recently, a phase Ib-II feasibility study using bendamustine replacing carmustine (BCNU) was reported. We report herein a safety and efficacy analysis of bendamustine-EAM (BeEAM) with a control BEAM counterpart paired cohort (1/2). One hundred and two patients were analyzed. Overall survival (OS) and progression-free survival (PFS) were not reached and seemed to be comparable between both groups. However, grade III or greater diarrhea was significantly higher in BeEAM patients (44 vs. 15%, p = .002). The median number of days with fever >38 °C was significantly higher in BeEAM group (5.5 vs. 2, p < .001). This case-control study suggests that BeEAM followed by ASCT using bendamustine at 100 mg/m/d is effective but has a different toxicity profile than the BEAM regimen.

Mantle cell lymphoma (MCL) is usually an aggressive disease. However, a few patients do have an "indolent" evolution (iMCL) defined by a long survival time without intensive therapy. Many studies highlight the prognostic role of additional genetic abnormalities, but these abnormalities are not routinely tested for and do not yet influence the treatment decision. We aimed to evaluate the prognostic impact of these additional abnormalities detected by conventional cytogenetic testing, as well as their relationships with the clinical characteristics and their value in identifying iMCL. All consecutive MCL cases diagnosed between 1995 and 2011 at four institutions were retrospectively selected on the basis of an informative karyotype with a t(11;14) translocation at the time of diagnosis. A total of 125 patients were included and followed for an actual median time of 35 months. The median overall survival (OS) and survival without treatment (TFS) were 73.7 and 1.3 months, respectively. In multivariable Cox models, a high mantle cell lymphoma international prognostic index score, a complex karyotype, and blastoid morphology were independently associated with a shortened OS. Spleen enlargement, nodal presentation, extra-hematological involvement, and complex karyotypes were associated with shorter TFS. A score based on these factors allowed for the identification of "indolent" patients (median TFS 107 months) from other patients (median TFS: 1 month). In conclusion, in this multicentric cohort of MCL patients, a complex karyotype was associated with a shorter survival time and allowed for the identification of iMCL at the time of diagnosis.

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N  =  61) or MRD (N  =  90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR  =  2.95, P < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR  =  1.74, P  =  0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR  =  0.52, P  =  0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.

© F e r r a t a S t o r t i F o u n d a t i o nknown, 12-16 but few groups 6,7,17,18 have studied its effect in octogenarian AML patients and conclusions have been mixed. This may stem from the differences in classification systems among studies, treatments, inadequate numbers of patients or all of the above. We, therefore, evaluated whether the European LeukemiaNet (ELN) classification, 19 a modified ELN classification (i.e., a classification based only on karyotype, without molecular markers), and the ELN-associated molecular alterations FLT3-ITD and NPM1 mutations have prognostic significance in octogenarian AML patients receiving intensive induction treatment. Methods Patients, treatment, cytogenetic and molecular analysesWe analyzed octogenarian AML patients treated with intensive induction [cytarabine and anthracycline (7+3) or similar regimens] for whom pretreatment karyotyping information was available. The patients were drawn from the German-Austrian AML Study Group [AMLSG; 5 (0.5%) Pretreatment karyotype analyses were performed by the Cooperative Groups' institutional cytogenetic laboratories with the results confirmed by central karyotype review, or were performed centrally. The diagnosis of cytogenetically normal AML (CN-AML) was based on the analysis of ≥20 metaphase cells in bone marrow specimens subjected to short-term culture. 31 We used both a modified, karyotype only, ELN-based classification [including t(8;21) Statistical analysesEstimated probabilities of relapse-free survival and overall survival were calculated using the Kaplan-Meier method, and the logrank test evaluated differences between survival distributions. Associations for baseline demographic, clinical, and molecular features were compared using the Fisher exact and Wilcoxon rank sum tests for categorical and continuous variables, respectively. All analyses were two-sided, with a P-value <0.05 considered statistically significant.Response criteria are described in the Online Supplementary Material. ResultsThe 138 patients had a median age of 82 years (range, 80-89 years); 81 (59%) were male. One-hundred fifteen patients had de novo AML, 13 had secondary AML following an antecedent hematologic disorder (s-AML), nine had therapy-related AML (t-AML) and one had both s-AML and t-AML. Because there was no difference in complete response, relapse-free survival and overall survival rates between patients with de novo AML and s-AML/t-AML, all patients were considered together for outcome analyses. Thirteen (11%) patients had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 71 (58%) had a PS of 1, 31 (25%) had a PS of 2, six (5%) had a PS of 3 and one (1%) patient had a PS of 4; information on PS was not available for 16 of the patients. Normal karyotype was the most common cytogenetic finding (47.1%), followed by complex karyotype (14.5%) and sole +8 (9.4%). We first categorized patients according to the modified ELN classification into favorable (n=2), intermediate-I (n=65), intermediate-II (n=42) ...

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Fractionated gemtuzumab ozogamicin and standard dose cytarabine produced prolonged second remissions in patients over the age of 55 years with acute myeloid leukemia in late first relapse Gemtuzumab ozogamicin (fGO), a humanized anti-CD33 monoclonal antibody linked to calicheamicin in combination with intensive chemotherapy gives high response rates in adult acute myeloid leukemia (AML) patients in relapse. However, reduced intensity chemotherapy in combination with fractionated GO has not been tested in aged relapsing patients. Patients from our institution with CD331 AML aged 55 years or more in first late relapse ( 6 months) were proposed participation in a GO compassionate use program. Induction therapy consisted in fractionated GO (fGO; 3 mg/m 2 , days 1, 4, 7) with standard-dose cytarabine (200 mg/m 2 /day, 7 days). Patients were consolidated with two courses of GO and intermediate dose cytarabine. Twenty-four patients (median age 68 years) received fGO with cytarabine. Median follow-up was 42 months. The response rate was 75%, including complete remission (CR) in 16 patients and CR with incomplete platelet recovery (CRp) in two patients. Two-year overall survival (OS) was 51% (95% CI: 28-69) and 2 years relapse-free survival (RFS) was 51% (95%CI: 25-72). Duration of second CR (CR2) was longer than first CR (CR1) in 9 out of 18 patients. Minimal residual disease (MRD) was negative in evaluable patients in CR2, particularly in NPM1 mutated cases. Toxicity was in line with that of the same fractionated single agent GO schedule. Fractionated GO with low intensity chemotherapy produced high response rates and prolonged CR2 in aged AML patients in first late relapse.

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