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We conclude that IKZF1 deletions are likely to be a genomic alteration that significantly affects the prognosis of Ph-positive ALL in adults.

Despite recent advancements, approximately 50% of patients with acute myeloid leukemia (AML) do not respond to induction therapy (primary induction failure, PIF) or relapse after <6 months (early relapse, ER). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART® antibody-based molecule to CD3ε and CD123. This study reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in adults with relapsed/refractory AML. Eighty-eight AML patients were enrolled, 42 in dose-finding and 46 at the recommended phase 2 dose (RP2D) of 500ng/kg/day. Consistent with flotetuzumab's mode of action, the most frequent adverse events were infusion-related reactions (IRR)/cytokine release syndrome (CRS), the majority as grade 1-2. Stepwise dosing during week 1, pre-treatment dexamethasone, prompt use of tocilizumab and temporary dose reductions/interruptions successfully prevented severe IRR/CRS, resulting in acceptable tolerability. Clinical benefit accrued to PIF/ER AML patients, who showed an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the CR/CRh rate was 26.7%, with an overall response rate (CR/CRh/CRi) of 30.0%. In PIF/ER patients who achieved CR/CRh, median OS was 10.2 months (range 1.87-27.27), with 6- and 12-month survival rates of 75% (95%CI, 0.450-1.05) and 50% (95%CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted complete responses to flotetuzumab (AUROC=0.904 versus 0.672 for the ELN risk classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER AML patients. Trial registration number: NCT02152956.

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The BCR-ABL1 fusion gene defines the subgroup of acute lymphoblastic leukemia (ALL) with the worst clinical prognosis. To identify oncogenic lesions that combine with BCR-ABL1 to cause ALL, we used Affymetrix Genome-Wide Human SNP arrays (250K NspI and SNP 6.0), fluorescence in situ hybridization, and genomic polymerase chain reaction to study 106 cases of adult BCR-ABL1-positive ALL. The most frequent somatic copy number alteration was a focal deletion on 7p12 of IKZF1, which encodes the transcription factor Ikaros and was identified in 80 (75%) of 106 patients. Different patterns of deletions occurred, but the most frequent were those characterized by a loss of exons 4 through 7 (⌬4-7) and by removal of exons 2 through 7 (⌬2-7). A variable number of nucleotides (patient specific) were inserted at the conjunction and maintained with fidelity at the time of relapse. The extent of the ⌬4-7 deletion correlated with the expression of a dominant-negative isoform with cytoplasmic localization and oncogenic activity, whereas the ⌬2-7 deletion resulted in a transcript lacking the translation start site. The IKZF1 deletion also was identified in the progression of chronic myeloid leukemia to lymphoid blast crisis (66%) but never in myeloid blast crisis or chronicphase chronic myeloid leukemia or in patients with acute myeloid leukemia. Known DNA sequences and structural features were mapped along the breakpoint cluster regions, including heptamer recombination signal sequences recognized by RAG enzymes during V(D)J recombination, suggesting that IKZF1 deletions could arise from aberrant RAGmediated recombination. (Blood. 2009;

Clofarabine is active and generally well tolerated in this patient group. It is worthy of further evaluation in comparative trials and might be of particular use in patients with adverse cytogenetics.

T he striking efficacy of imatinib mesylate in chronic myeloid leukemia (CML) 1,2 has established this therapy as the new standard of care for the disease. However, resistance is an emerging problem which has prompted the design of several second-generation Bcr-Abl inhibitors. One of these, dasatinib , is now in advanced clinical development. 4 In vitro assays 5,6 and crystallographic studies 7 have suggested that the less stringent conformational requirements for Bcr-Abl binding are likely to render dasatinib active against many of the kinase domain mutants responsible for imatinib resistance. One remarkable exception appears to be the T315I, which has been shown to disrupt a hydrogen bond critical for dasatinib binding and to create steric hindrance which interferes with the entrance of the inhibitor into the ATP-binding site. In order to assess which pre-existent or emerging mutations are associated with decreased clinical efficacy of dasatinib, we analyzed BCR-ABL kinase domain sequences before and during treatment in Philadelphia chromosome-positive (Ph + ) leukemia patients who failed to respond to or relapsed during dasatinib therapy. Design and MethodsIn a phase II program (sponsored by Bristol-Myers Squibb) we treated with dasatinib 70 mg twice daily a total of 45 patients with either CML (n=35) or Ph + acute lymphoblastic leukemia (ALL) (n=10) who were resistant to or intolerant of imatinib. Their median age was 50 years (range, 18-74), the median duration since the diagnosis of CML was 32 months (range, 4-158); and the median duration of imatinib treatment was 17 months (2-57). At the time of writing, with a median follow-up of 12 months (range, 1-19), 21 patients have shown evidence of either primary or acquired resistance, defined as a failure to achieve a hematologic response or loss of hematologic response during treatment, respectively. All the patients provided written informed consent to their participation in this study. Hematologic response was assessed according to the criteria already described for the phase I study.4 Cytogenetic ABSTRACT Brief ReportThe emergence of resistance to the Bcr-Abl inhibitor imatinib mesylate in patients with Philadelphia chromosome-positive (Ph + ) leukemia has prompted the development of second-generation compounds active against several imatinib-insensitive mutant forms of Bcr-Abl, including dasatinib (BMS-354825; Bristol-Myers Squibb). In order to assess which pre-existent or emerging kinase domain mutations are associated with decreased clinical efficacy of desatinib, we analyzed BCR-ABL kinase sequences before and during treatment in 21 Ph + patients who failed to respond to or relapsed during dasatinib therapy. In all patients but one, resistance to dasatinib was invariably found to be associated with mutations at residue 315 and/or at residue 317. Hematology and Medical Oncology "L. e A. Seràgnoli", S. OrsolaMalpighi Hospital, Massarenti 9, 40138 Bologna, Resistance to dasatinib in Philadelphia-positive leukemia patients and the presence or the selec...