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• Patients with e13a2 transcripts have inferior outcomes with imatinib 400; e14a2 has favorable outcomes regardless of treatment modality.• Multivariate analysis showed that the expression of e14a2 or both e14a2 and e13a2 predicts optimal ELN responses and longer EFS and TFS.The most common breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2). The impact of the type of transcript on response and survival after initial treatment with different tyrosine kinase inhibitors is unknown. This study involved 481 patients with chronic phase CML expressing various BCR-ABL transcripts. Two hundred patients expressed e13a2 (42%), 196 (41%) expressed e14a2, and 85 (18%) expressed both transcripts. The proportion of patients with e13a2, e14a2, and both achieving complete cytogenetic response at 3 and 6 months was 59%, 67%, and 63% and 73%, 81%, and 82%, respectively, whereas major molecular response rates were 27%, 49%, and 50% at 3 months, 42%, 67%, and 70% at 6 months, and 55%, 83%, and 76% at 12 months, respectively. Median (international scale) levels of transcripts e13a2, e14a2, and both at 3 months were 0.2004, 0.056, and 0.0612 and at 6 months were 0.091, 0.0109, and 0.0130, respectively. In multivariate analysis, e14a2 and both predicted for optimal responses at 3, 6, and 12 months. The type of transcript also predicted for improved probability of event-free (P 5 .043; e14a2) and transformation-free survival (P 5 .04 for both). Compared to e13a2 transcripts, patients with e14a2 (alone or with coexpressed e13a2) achieved earlier and deeper responses, predicted for optimal European Leukemia Net (ELN) responses (at 3, 6, and 12 months) and predicted for longer event-free and transformation-free survival. (Blood. 2016;127(10):1269-1275

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Background The combination of chemotherapy with a tyrosine kinase inhibitor (TKI) is effective in the treatment of Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib is a more potent BCR-ABL1 inhibitor and selectively suppresses the resistant T315I clones. We examined the efficacy and safety of combining chemotherapy with ponatinib for patients with Ph+ ALL in this ongoing Phase II prospective trial. Methods Adult patients with newly diagnosed Ph+ ALL and good performance and organ status received 8 cycles of hyper-CVAD alternating with high dose methotrexate/cytarabine every 21 days. Ponatinib was given at 45 mg daily for the first 14 days of cycle 1 then continuously for the subsequent cycles. Patients in complete remission (CR) received maintenance with ponatinib 45 mg daily with vincristine/prednisone monthly for 2 years followed by ponatinib indefinitely. The primary endpoint for this study was the improvement of median event-free survival from 24 to 36 months. The trial was registered on clinicaltrials.gov with the identifier NCT01424982. Results Thirty-seven patients with a median age of 51 years were treated. The overall complete cytogenetic response, major molecular response, and complete molecular response rates were 32/32 (100%), 35/37 (95%), and 29/37 (78%), respectively. By multiparameter flow cytometry, 35 patients (95%) had no detectable minimal residual disease after a median of 3 weeks of therapy. Grade ≥ 3 toxicity included infections during induction (20 patients), increased liver functional tests (14 patients), thrombotic events (3 patients), myocardial infarction (3 patients), hypertension (6 patients), skin rash (8 patients), and pancreatitis (6 patients). Two potentially related deaths from myocardial infarction were observed. Nine patients underwent allogeneic stem cell transplantation. With a median follow up of 26 months, 29 patients (78%) remain alive and in CR. The 2-year event-free and overall survival rates are 81% and 80%, respectively. Conclusion The first results of this ongoing trial indicate that the combination of chemotherapy with ponatinib is highly effective in achieving early sustained remissions in patients with newly diagnosed Ph+ ALL. New strategies, including dosing titration of ponatinib and optimized control of vascular risk factors may further improve outcomes. ARIAD Pharmaceuticals Inc. provided free drug and financial support from the ARIAD Investigator Sponsored Trial program.

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• In patients with Ph 1 ALL, achievement of CMR at 3 months is independently associated with improved survival.• CMR at 3 months may identify patients with Ph 1 ALL who have excellent long-term outcomes without SCT in first CR.The impact of achieving complete molecular response (CMR) in Philadelphia chromosomepositive (Ph 1 ) acute lymphoblastic leukemia (ALL) remains undefined. We evaluated the impact of CMR on outcomes among 85 patients with Ph 1 ALL who received first-line hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine plus a tyrosine kinase inhibitor, had minimal residual disease (MRD) assessments for BCR-ABL1 by quantitative polymerase chain reaction at complete remission (CR) and at 3-month time points, and did not undergo allogeneic stem cell transplantation (SCT). MRD status at 3 months had better discrimination for overall survival (OS; P 5 .005) and relapse-free survival (RFS; P 5 .002) than did MRD status at CR (P 5 .11 and P 5 .04, respectively). At 3 months, achievement of CMR vs response less than CMR was associated with longer median OS (127 vs 38 months, respectively; P 5 .009) and RFS (126 vs 18 months, respectively; P 5 .007). By multivariate analysis, only CMR at 3 months was prognostic for OS (hazard ratio, 0.42; 95% confidence interval, 0.21-0.82; P 5 .01). Patients with Ph 1 ALL who achieve CMR at 3 months have superior survival compared with those with lesser molecular responses and have excellent long-term outcomes even without SCT. (Blood. 2016;128(4):504-507)

PURPOSE Sixty percent of newly diagnosed patients with acute myeloid leukemia (ND-AML) receiving frontline therapy attain a complete response (CR), yet 30%-40% of patients relapse. Relapsed or refractory AML (R/R-AML) remains a particularly adverse population necessitating improved therapeutic options. This phase Ib/II study evaluated the safety and efficacy of fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin combined with the B-cell lymphoma-2 inhibitor venetoclax in ND-AML and R/R-AML. MATERIALS AND METHODS The phase IB portion (PIB) enrolled patients with R/R-AML using a 3 + 3 dose escalation and de-escalation algorithm for identification of maximum tolerated dose and dose-limiting toxicities. The phase II portion enrolled patients into two arms to evaluate response and time-to-event end points: phase IIA (PIIA): ND-AML and phase IIB (PIIB): R/R-AML. RESULTS Sixty-eight patients have enrolled to date (PIB, 16; PIIA, 29; PIIB, 23). Median age was 46 years (range, 20-73). Grade 3 and 4 adverse events occurring in ≥ 10% of patients included febrile neutropenia (50%), bacteremia (35%), pneumonia (28%), and sepsis (12%). The overall response rate for PIB, PIIA, and PIIB was 75%, 97%, and 70% with 75%, 90%, and 61%, respectively, achieving a composite CR. Measurable residual disease–negative composite CR was attained in 96% of ND-AML and 69% of R/R-AML patients. After a median follow-up of 12 months, median overall survival (OS) for both PII cohorts was not reached. Fifty-six percent of patients proceeded to allogeneic hematopoietic stem-cell transplantation (ND-AML, 69%; R/R-AML, 46%). In R/R-AML, allogeneic hematopoietic stem-cell transplantation resulted in a significant improvement in OS (median OS, NR; 1-year OS, 87%). One-year survival post-HSCT was 94% in ND-AML and 78% in R/R-AML. CONCLUSION Fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin + venetoclax represents an effective intensive treatment regimen in ND-AML and R/R-AML patients, associated with deep remissions and a high rate of transition to successful transplantation.

SummaryBackgroundTyrosine kinase inhibitors (TKIs) improved overall survival (OS) in patients with chronic myeloid leukemia in chronic phase (CML-CP). The purpose of this study was to compare OS in patients with newly diagnosed CML-CP to that of general population.MethodsResponse and survival data in six consecutive or parallel prospective clinical TKI trials were analyzed. Estimated OS rates in the general population matched by age, gender, ethnicity, and year at diagnosis were obtained from national vital statistics reports. Survival was also assessed by response and type of TKI.FindingsOf the 483 patients, 271 patients received imatinib, 105 nilotinib and 107 dasatinib. The age grouping was as follows: 15–44 years, 197 patients; 45–64 years, 222; 65–84 years, 64. Five-year OS in CML-CP decreased with increasing age: 15–44 years, 96% (95% confidence interval[CI], 93·2–99·2); 45–64 years, 94% (95%CI, 89·9–97·1); and 65–84 years, 80% (95%CI, 69·5–90·7). Five-year relative OS was only slightly lower compared to the matched general population: 15–44 years, 97% (95%CI, 94·0–100·0); 45–64 years, 97% (95%CI, 92·9–100·3); and 65–84 years, 92% (95%CI, 79·5–103·8). Five-year relative OS in all ages with complete cytogenetic response (CCyR) or better was similar to that in the general population.InterpretationWith TKI, the expected survival of patients diagnosed with CML-CP is only slightly lower to that of the general population, and for those patients who achieved CCyR or better it is similar to that of general population. Due to the relatively smaller number of patients followed for 10 years and the small number of older patients, the 10-year relative OS has a wider confidence interval and might vary with longer follow-up. However, 10-year relative OS derived from the imatinib cohort is favorable, and, considering the overall better results with dasatinib and nilotinib, it is reasonable to expect that the results will remain at least as favorable with additional follow-up observation with dasatinib or nilotinib. Thus with access to TKI, it is possible that most patients with CML can enjoy a near normal life expectancy.