• 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

Background TP53 gene mutations predict for poor prognosis in acute myeloid leukemia (AML). Methods Peripheral blood or bone marrow samples from 293 newly diagnosed AML patients were analysed with targeted amplicon-based next-generation sequencing based mutation analysis. Results We found TP53 mutations in 53 (18%; 45 were missense mutations; the most common pattern of amino acid substitution, in 13 of the 53 patients, was a substitution of arginine to histidine on different codons). The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML -TP53-mutated (n=53) vs. TP53-wildtype (n=240) were compared. TP53-mutations were significantly more likely in patients with complex karyotype, abnormalities of chromosome 5, 7, and 17, and therapy-related AML. TP53-mutated AMLs have significantly lower incidence of mutations in FLT3, RAS, and NPM1 and higher incidence of coexisting MPL mutations compared to wild type. Distribution of TP53-mutations was equal in both age groups(<60 years vs ≥ 60 years). TP53 mutated AML was associated with a lower response rate(CR 41% vs. 57%; p=0.04), significantly inferior complete remission duration (CRD) (at 2 yrs 30% vs. 55%; p=0.001) and overall survival (OS) (at 2 yrs 9% vs. 24%; p= <0.0001) irrespective of the age or the type of treatment used - high vs low intensity chemotherapies. Conclusions The type of treatment did not improve the outcome in younger or older patients with TP53 mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with TP53 mutations.

Unprecedented advances in our understanding of the pathobiology, prognostication, and therapeutic options in mantle cell lymphoma (MCL) have taken place in the last few years. Heterogeneity in the clinical course of MCL—indolent vs aggressive—is further delineated by a correlation with the mutational status of the variable region of immunoglobulin heavy chain, methylation status, and SOX‐11 expression. Cyclin‐D1 negative MCL, in situ MCL neoplasia, and impact of the karyotype on prognosis are distinguished. Apart from Ki‐67% and morphology pattern (classic vs blastoid/pleomorphic), the proliferation gene signature has helped to further refine prognostication. Studies focusing on mutational dynamics and clonal evolution on Bruton's tyrosine kinase (BTK) inhibitors (ibrutinib, acalabrutinib) and/or Bcl2 antagonists (venetoclax) have further clarified the prognostic impact of somatic mutations in TP53, BIRC3, CDKN2A, MAP3K14, NOTCH2, NSD2, and SMARCA4 genes. In therapy, long‐term follow‐up on chemo‐immunotherapy studies has demonstrated durable remissions in some patients; however, long‐term toxicities, especially from second cancers, are a serious concern with chemotherapy. The therapeutic options in MCL are constantly evolving, with dramatic responses from nonchemotherapeutic agents (ibrutinib, acalabrutinib, and venetoclax). Chimeric antigen receptor therapy and combinations of nonchemotherapeutic agents are actively being studied and our focus is shifting toward making the treatment of MCL chemotherapy‐free. Still, MCL remains incurable. The following aspects of MCL continue to pose a challenge: disease transformation, role of the cytokine‐microenvironmental milieu, incorporation of positron emission tomography‐computerized tomography imaging, minimal residual disease in the prognosis, circulating tumor DNA testing for clonal evolution, predicting resistance to BTK inhibitors, and optimal management of patients who progress on BTK/Bcl2 inhibitors. Next‐generation clinical trials should incorporate nonchemotherapeutic agents and personalize the treatment based upon the genomic profile of individual patient. Recent advances in the field of MCL are reviewed.

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.

No abstract