• 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

disease (MRD) refers to neoplastic cells that cannot be detected by standard cytomorphologic analysis. In patients with acute myeloid leukemia (AML), determining the association of MRD with survival may improve prognostication and inform selection of efficient clinical trial end points.OBJECTIVE To examine the association between MRD status and disease-free survival (DFS) and overall survival (OS) in patients with AML using scientific literature.

BackgroundPatients with CML treated with TKI can have a life expectancy comparable to that of the general population. Due to the extended duration of TKI administration, treatment discontinuation has been increasingly sought.MethodsMedical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed.ResultsAfter a median follow-up of 30 months (range, 5–112 months) after discontinuation, 35% and 17% lost MR4.5 and major molecular response (MMR), respectively. Only six patients lost MMR 12 months or more after discontinuation. Loss of MR4.5 was observed in 29% and 7% of patients with sustained MR4.5 duration of more than 2 and 6 years before discontinuation, respectively. By univariate analysis, there was a higher risk of loss of MR4.5 for patients who were treated for less than 87 months, received second or subsequent line TKI, never received interferon, or those with sustained MR4.5 for less than 6 years. By multivariate analysis, sustained MR4.5 for 6 years or more was the only significant predictor for durable response. Overall, 30% of patients who discontinued while in MR4.5 were retreated with 93% regaining MR4.5 at a median of 5 months.ConclusionThese results demonstrate that under proper conditions, treatment discontinuation is feasible outside of clinical trial setting. MR4.5 duration of 6 years or more before discontinuation is associated with very low risk of loss of MR4.5.

Background Outcomes in blast phase CML (CML-BP) are historically dismal. We sought to analyse the characteristics, prognostic factors and survival outcomes in patients with CML-BP in the TKI era. Methods All patients with CML-BP (n=477) were treated with a TKI at some point during the course of their CML. Cox proportional hazard models identified characteristics which predicted for survival. Overall survival (OS) and failure free survival (FFS) were assessed. Optimal cut off points for specific parameters, were identified using CART (classification and regression tree). Results Median age was 53 years (range, 16 to 84); 64% were male. Eighty percent were initially diagnosed in chronic phase CML (CML-CP) median 41 months (0.7 to 298 months) before transformation to CML-BP. De-novo CML-BP occurred in 71 patients. Seventy two percent patients received TKI therapy prior to CML-BP. Initial therapy for CML-BP included, TKI alone (35%), TKI with chemotherapy (46%) and non-TKI therapies (19%). The median OS was 12 months and median FFS was 5 months. In multivariate analysis, myeloid immunophenotype, prior TKI, age ≥58 years, LDH ≥1227 IU/L, platelet count <102 K/μL, no stem cell transplantation (SCT), blast phase from CP/AP and presence of chromosome 15 aberrations predicted for a significantly increased risk of death. Achievement of major hematologic response and/or complete cytogenetic response to first line treatment predicted for better survival. Combination of TKI with intensive chemotherapy followed by stem cell transplant confer the best outcome. Conclusions Patients with CML-BP continue to pose a therapeutic challenge, have dismal outcomes and require newer treatment approaches.

The control of virulence regulator/sensor kinase (CovRS) two-component system is critical to the infectivity of group A streptococcus (GAS), and CovRS inactivating mutations are frequently observed in GAS strains causing severe human infections. CovS modulates the phosphorylation status and with it the regulatory effect of its cognate regulator CovR via its kinase and phosphatase activity. However, the contribution of each aspect of CovS function to GAS pathogenesis is unknown. We created isoallelic GAS strains that differ only by defined mutations which either abrogate CovR phosphorylation, CovS kinase or CovS phosphatase activity in order to test the contribution of CovR phosphorylation levels to GAS virulence, emergence of hypervirulent CovS-inactivated strains during infection, and GAS global gene expression. These sets of strains were created in both serotype M1 and M3 backgrounds, two prevalent GAS disease-causing serotypes, to ascertain whether our observations were serotype-specific. In both serotypes, GAS strains lacking CovS phosphatase activity (CovS-T284A) were profoundly impaired in their ability to cause skin infection or colonize the oropharynx in mice and to survive neutrophil killing in human blood. Further, response to the human cathelicidin LL-37 was abrogated. Hypervirulent GAS isolates harboring inactivating CovRS mutations were not recovered from mice infected with M1 strain M1-CovS-T284A and only sparsely recovered from mice infected with M3 strain M3-CovS-T284A late in the infection course. Consistent with our virulence data, transcriptome analyses revealed increased repression of a broad array of virulence genes in the CovS phosphatase deficient strains, including the genes encoding the key anti-phagocytic M protein and its positive regulator Mga, which are not typically part of the CovRS transcriptome. Taken together, these data establish a key role for CovS phosphatase activity in GAS pathogenesis and suggest that CovS phosphatase activity could be a promising therapeutic target in GAS without promoting emergence of hypervirulent CovS-inactivated strains.