Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.

Introduction Accurate detection of GATA1 mutation is highly significant in patients with acute myeloid leukemia (AML) and trisomy 21 as it allows optimization of clinical protocol. This study was aimed at (a) enhanced search for GATA1 mutations; and (b) characterization of molecular landscapes for such conditions. Methods The DNA samples from 44 patients with newly diagnosed de novo AML with trisomy 21 were examined by fragment analysis and Sanger sequencing of the GATA1 exon 2, complemented by targeted high‐throughput sequencing (HTS). Results Acquired GATA1 mutations were identified in 43 cases (98%). Additional mutations in the genes of JAK/STAT signaling, cohesin complex, and RAS pathway activation were revealed by HTS in 48%, 36%, and 16% of the cases, respectively. Conclusions The GATA1 mutations were reliably determined by fragment analysis and/or Sanger sequencing in a single PCR amplicon manner. For patients with extremely low blast counts and/or rare variants, the rapid screening with simple molecular approaches must be complemented with HTS. The JAK/STAT and RAS pathway‐activating mutations may represent an extra option of targeted therapy with kinase inhibitors.

Introduction Translocations involving the KMT2A gene (also known as MLL) are frequently diagnosed in pediatric acute leukemia cases with either lymphoblastic or myeloid origin. KMT2A is translocated to multiple partner genes, including MLLT10/AF10 localizing at chromosomal band 10p12. KMT2A‐MLLT10 is one of the common chimeric genes diagnosed in acute leukemia with KMT2A rearrangement (8%), especially in acute myeloid leukemia (AML; 18%). MLLT10 is localized in very close proximity to two other KMT2A partner genes at 10p11‐12—NEBL and ABI1, so they could not be distinguished by conventional cytogenetics. Methods In this work, we present a cohort of 28 patients enrolled into Russian Pediatric AML registration study carrying rearrangements between chromosomal regions 11q23.3 and 10p11‐12. G‐banding, FISH, reverse transcription PCR, and long‐distance inverse PCR were used to characterize the KMT2A gene rearrangements in these patients. Results We demonstrate that 25 patients harbor the KMT2A‐MLLT10 rearrangement, while three patients show the rare KMT2A rearrangements (2× KMT2A‐NEBL; 1× KMT2A‐ABI1). Conclusions Therefore, the combination of cytogenetic and molecular genetic methods is of high importance in diagnosing cases with t(10;11)(p11‐12;q23.3).

Objectives: to study the long-term results of surgical treatment of patients with medullary thyroid carcinoma and evaluate the significance of prognostic factors. Materials and methods: the continuous retrospective study included 169 patients with histologically confirmed medullary cancer who were initially operated at the Northwestern Center for Endocrinology and Endocrine Surgery of the SPbSU University Clinic from 2010 to 2016. They were divided into prognostic groups according to the level and dynamics of postoperative calcitonin and clinical manifestations of the disease. Results: The study allowed to assess the effect of predictive factors on the risks of progression and recurrence in medullary thyroid cancer. Size of the primary tumor more than 2 cm significantly increases the risk of disease progression (OR=6,56 (0.52-17.96) p=0,00001495). Invasion of the thyroid capsule and metastases to regional lymph nodes are even more important prognostic value as OR=49,08 (10.72-224.89), p=0,00000011 и OR=30,63 (9,75-96,27), p<0.0000001 respectively. Regional MTC metastases are a significant threat to the life of the patient. This fact is a fundamental difference with differentiated thyroid carcinoma were regional metastases do not affect the prognosis. This study failed to link the prognosis to the patient's age. As expected the level of basal calcitonin >600 pg/ml affects the prognosis (OR=6,65 (2,53-17,59) p=0.01055). Its prognostic value is comparable to the size of the primary tumor and significantly less than the presence of regional and distant metastases. Conclusions: Unfavorable prognosis in 21 (12.4%) observed patients is associated not only with the presence of distant metastases, but also and independently with regional ones.

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