Jorge Milone

Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

Intermittent Target Inhibition With Dasatinib 100 mg Once Daily Preserves Efficacy and Improves Tolerability in Imatinib-Resistant and -Intolerant Chronic-Phase Chronic Myeloid Leukemia

PURPOSE Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. PATIENTS AND METHODS In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. RESULTS With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). CONCLUSION Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034

Dasatinib was approved at 100 mg once daily for imatinib‐resistant or ‐intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180‐034 (NCT00123474) study. Here we present the final 7‐year analysis of this pivotal study, the longest follow‐up to date of any second‐generation BCR–ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib‐resistant or ‐intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven‐year rates for major molecular response (MMR), progression‐free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR–ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug‐related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug‐related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long‐term efficacy and well‐established safety profile of dasatinib for patients with imatinib‐resistant or ‐intolerant CML in chronic phase. Am. J. Hematol. 91:869–874, 2016.

Clinical outcome of chronic myeloid leukemia imatinib-resistant patients: do BCR–ABL kinase domain mutations affect patient survival? First multicenter Argentinean study

In imatinib-treated patients with chronic myeloid leukemia (CML), BCR–ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.

Molecular Monitoring of Imatinib in Chronic Myeloid Leukemia Patients in Complete Cytogenetic Remission: Does Achievement of a Stable Major Molecular Response at any Time Point Identify a Privileged Group of Patients? A Multicenter Experience in Argentina and Uruguay

BACKGROUND Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival. PATIENTS AND METHODS The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals. RESULTS MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment. CONCLUSIONS A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world.

Allogeneic hematopoietic stem cell transplantation in adults with myelodysplastic syndrome: Experience of the Argentinean Group of Bone Marrow Transplantation (GATMO)

Introduction: Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative approach for patients with myelodysplastic syndrome (MDS). Methods: In this multicenter retrospective study, we analyzed the outcome of adult patients with MDS who underwent AHSCT in Argentina and evaluated the prognostic factors associated with progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of relapse, and non-relapse mortality (NRM). Results: We analyzed data from 87 adults (median age: 43 years, range 18–66) who underwent SCT after myeloablative (n = 60) or non-myeloablative conditioning (n = 27), and from related (n = 62) or unrelated (n = 25) donors. For all patients, unadjusted 4-year PFS and OS were 37% and 38%, respectively; no significant differences were found between recipients of related or unrelated donors. One-year CI of relapse and NRM were 21% and 20%, respectively. In the multivariate analysis, intermediate disease risk index (DRI) and acute graft versus host disease AGVHD of all grades (I–IV) were independent variables associated with better PFS and lower relapse CI; only intermediate DRI was associated with better OS. Conclusions: AHSCT is a feasible procedure in Argentina, with more than 30% of the patients achieving long-term survival. Recipients with unrelated donors had at least similar outcome than those with related donors. DRI may be useful to identify patients at higher risk of relapse after transplantation.

Acute Lymphoblastic Leukemia (ALL) Philadelphia Positive (Ph1) (Incidence Classifications, Prognostic Factor in ALL Principles of ALL Therapy)

In the last years much progress has been made in understanding the biology of acute lymphoblastic leukemia which is now recognized as an expanding group of heterogene‐ ous entities. Recognition of distinct gene expression patterns may identify patient sub‐ group with unique response to therapy and prognosis. Accurate definition of prognostic subgroups based on cytogenetic molecular marker has allowed institution of risk orient‐ ed therapies. [2] The Philadelphia (Ph1+) chromosome was first described in 1960 in a patient with chronic myeloid leukemia (CML). This is the product of the fusion of chromosomes 9 and 22, t (9;22), which results in a BCR-ABL hybrid gene. [2]