Hesham Mohamed

Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION)

This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 DASatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247.

Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study.

We present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474.

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.

Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia: Effects on response and toxicity.

The proliferation of clonal cytotoxic T‐cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML).

Lymphocytosis after treatment with dasatinib in chronic myeloid leukemia

The proliferation of clonal cytotoxic T‐cells or natural killer cells has been observed after dasatinib treatment in small studies of patients with chronic myeloid leukemia (CML).

A phase 2 safety study of accelerated elotuzumab infusion, over less than 1 h, in combination with lenalidomide and dexamethasone, in patients with multiple myeloma

Elotuzumab, an immunostimulatory SLAMF7‐targeting monoclonal antibody, induces myeloma cell death with minimal effects on normal tissue. In a previous phase 3 study in patients with relapsed/refractory multiple myeloma (RRMM), elotuzumab (10 mg/kg, ∼3‐h infusion), combined with lenalidomide and dexamethasone, demonstrated durable efficacy and acceptable safety; 10% (33/321) of patients had infusion reactions (IRs; Grade 1/2: 29; Grade 3: 4). This phase 2 study (NCT02159365) investigated an accelerated infusion schedule in 70 patients with newly diagnosed multiple myeloma or RRMM. The primary endpoint was cumulative incidence of Grade 3/4 IRs by completion of treatment Cycle 2. Dosing comprised elotuzumab 10 mg/kg intravenously (weekly, Cycles 1‐2; biweekly, Cycles 3+), lenalidomide 25 mg (daily, Days 1‐21), and dexamethasone (28 mg orally and 8 mg intravenously, weekly, Cycles 1‐2; 40 mg orally, weekly, Cycles 3+), in 28‐day cycles. Premedication with diphenhydramine, acetaminophen, and ranitidine (or their equivalents) was given as in previous studies. If no IRs occurred, infusion rate was increased in Cycle 1 from 0.5 to 2 mL/min during dose 1 (∼2 h 50 min duration) to 5 mL/min for the entire infusion by dose 3 and also during all subsequent infusions (∼1‐h duration). Median number of treatment cycles was six. No Grade 3/4 IRs occurred; only one Grade 1 and one Grade 2 IR occurred, both during the first infusion. These data support the safety of a faster infusion of elotuzumab administered over ∼1 h by the third dose, providing a more convenient alternative dosing option for patients.

Cross-Intolerance With Dasatinib Among Imatinib-Intolerant Patients With Chronic Phase Chronic Myeloid Leukemia

BACKGROUND BCR-ABL inhibitors have improved the prognosis of patients with chronic myeloid leukemia (CML). However, imatinib, the first approved BCR-ABL inhibitor, must be discontinued in many patients because of resistance or intolerance. PATIENTS AND METHODS The present retrospective, pooled analysis of phase II and III data explored the extent of cross-intolerance between imatinib and dasatinib, a second-generation BCR-ABL inhibitor, in 271 CML imatinib-intolerant patients. RESULTS Overall, 47 patients (17%) had cross-intolerance to dasatinib, determined by recurrence of grade 3 or 4 adverse events (AEs). Of the 228 patients who discontinued imatinib because of nonhematologic intolerance, 10 (4%) experienced the same severe nonhematologic AEs with dasatinib, with 4 of these patients (2%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients who discontinued imatinib because of hematologic intolerance, 37 (86%) experienced a recurrence of grade 3 or 4 hematologic AEs with dasatinib, with 8 patients (19%) discontinuing dasatinib because of cross-intolerance. Of the 43 patients taking dasatinib at the optimized dose of 100 mg/d, 1 (2%) discontinued therapy because of recurrence of nonhematologic AEs and 3 (7%) because of recurrence of hematologic AEs. With a median treatment duration of 22 months, the estimated rates of progression-free survival and overall survival at 2 years were greater for patients with nonhematologic versus hematologic intolerance to imatinib who switched to dasatinib (progression-free survival, 94% vs. 68%, respectively; overall survival, 98% vs. 88%, respectively). CONCLUSION Dasatinib could be an appropriate treatment option for imatinib-intolerant patients with CML, with cross-intolerance resulting in discontinuation in a few patients.

Predictors of performing response monitoring in patients with chronic-phase chronic myeloid leukemia (CP-CML) in a prospective observational study (SIMPLICITY).

116 Background: Previous SIMPLICITY data (ASCO 2014) have shown, in CP-CML patients (pts) with at least 12 months (mths) follow-up, monitoring for cytogenetic response (CyR) and molecular response (MR) differs from NCCN/ ELN recommendations and shows regional and practice-type variation. Few data describe predictors of monitoring. METHODS SIMPLICITY is an ongoing observational study of CP-CML pts receiving first-line (1L) imatinib (IM), dasatinib (DAS) or nilotinib (NIL) in the United States (US) and Europe (Eu); its primary objective is to understand tyrosine kinase inhibitor (TKI) management patterns in clinical practice (NCT01244750). Frequency of testing for CyR, by FISH or karyotype, and MR, by PCR, were analyzed in 3, 6 and 12 mth increments from TKI start. Stepwise multivariable logistic regression was performed to assess predictors of monitoring (including: age, sex at birth, region, practice type, 1L TKI, ECOG performance status, still on 1L TKI). RESULTS 1,083 pts (US: 66%; Eu: 34%) were enrolled prospectively through 1Apr2014, receiving IM (n=415), DAS (n=343) or NIL (n=325). 1,050, 985 and 862 pts were followed for at least 3, 6 and 12 mths, respectively. Of these, 15%, 34% and 49% were tested for CyR, and 27%, 65% and 83% were tested for MR, between 0-3 mths, 0-6 mths and 0-12 mths. By 3 mths, 33% had either CyR and/or MR testing and 88% of pts underwent testing by 12 mths. None of the candidate predictors distinguished between pts who were monitored vs. those that were not by 3 mths after start of 1L TKI. Pts <65 years (yrs) at start of 1L TKI (odds ratio [OR]=1.41) and those in Eu vs. US (OR=1.45) were more likely to be monitored by 6 mths. By 12 mths, pts <65 yrs (OR=2.27), those no longer on 1L TKI (OR=1.96), and those seen in academic centers (OR=1.59) were more likely to be monitored (all p<.05). A comparison of monitoring patterns with ELN/NCCN recommendations will also be presented. CONCLUSIONS Two-thirds of pts were not monitored for CyR or MR within 3 mths of TKI start.Although there were no predictors of monitoring for CyR or MR by 3 mths, age <65 yrs at initiation of 1L TKI was a consistent predictor of monitoring by 6 and 12 mths. CLINICAL TRIAL INFORMATION NCT01244750.

Cell-type-specific transcriptional regulation of PIGM underpins the divergent hematologic phenotype in inherited GPl deficiency.

A rare point mutation in the core promoter -270GC-rich box of PIGM, a housekeeping gene, disrupts binding of the generic transcription factor (TF) Sp1 and causes inherited glycosylphosphatidylinositol (GPI) deficiency (IGD). We show that whereas PIGM messenger RNA levels and surface GPI expression in IGD B cells are low, GPI expression is near normal in IGD erythroid cells. This divergent phenotype results from differential promoter chromatin accessibility and binding of Sp1. Specifically, whereas PIGM transcription in B cells is dependent on Sp1 binding to the -270GC-rich box and is associated with lower promoter accessibility, in erythroid cells, Sp1 activates PIGM transcription by binding upstream of (but not to) the -270GC-rich box. These findings explain intact PIGM transcription in IGD erythroid cells and the lack of clinically significant intravascular hemolysis in patients with IGD. Furthermore, they provide novel insights into tissue-specific transcriptional control of a housekeeping gene by a generic TF.