Clinical features and survival of patients with indolent systemic mastocytosis defined by the updated WHO classification.

BACKGROUND: In indolent systemic mastocytosis (ISM), several risk factors of disease progression have been identified. Previous studies, performed with limited patient numbers, have also shown that the clinical course in ISM is stable and comparable to that of cutaneous mastocytosis (CM). The aim of this project was to compare the prognosis of patients with ISM with that of patients with CM. METHODS: We employed a dataset of 1993 patients from the registry of the European Competence Network on Mastocytosis (ECNM) to compare outcomes of ISM and CM. RESULTS: We found that overall survival (OS) is worse in ISM compared to CM. Moreover, in patients with typical ISM, bone marrow mastocytosis (BMM), and smoldering SM (SSM), 4.1% of disease progressions have been observed (4.9% of progressions in typical ISM group, 1.7% in BMM, and 9.4% in SSM). Progressions to advanced SM were observed in 2.9% of these patients. In contrast, six patients with CM (1.7%) converted to ISM and no definitive progression to advanced SM was found. No significant differences in OS and event-free survival (EFS) were found when comparing ISM, BMM, and SSM. Higher risk of both progression and death was significantly associated with male gender, worse performance status, and organomegaly. CONCLUSION: Our data confirm the clinical impact of the WHO classification that separates ISM from CM and from other SM variants.

Frontline nilotinib treatment in Turkish patients with Philadelphia chromosome-positive chronic Myeloid Leukemia in chronic phase: updated results with 2 years of follow-up.

OBJECTIVES: This report presents final results (24 months of follow-up) from the first prospective, national study of frontline nilotinib in chronic myeloid leukemia (CML) patients in Turkey. METHODS: Patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase (CML-CP; N = 112) received nilotinib 300 mg twice daily. The primary endpoint, which was the cumulative rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) by 12 months, was previously reported (66.1% [80% CI, 59.7%-72.0%]). ClinicalTrials.gov identifier NCT01274351 Results: By 24 months, 83.0% of patients achieved MMR, and 50.9% achieved MR4.5 (BCR-ABL1IS ≤0.0032%). Safety results at 24 months were consistent with those at 12 months. No additional deaths or disease progressions to accelerated phase/blast crisis were observed between 12 and 24 months. DISCUSSION: Treatment with nilotinib 300 mg twice daily for 2 years provided high MMR with a good safety/tolerability profile in newly diagnosed CML-CP patients in Turkey. Assessment of MMR across time points showed increasing rates through 18 months, after which as lower rate of increase was observed. The safety profile of nilotinib 300 mg twice daily with 24 months of follow-up was similar to that observed at 12 months, and no new safety concerns were identified. These efficacy and safety findings are consistent with the results from the 12-month analysis of this study and from previous nilotinib studies. These findings support nilotinib as an option for frontline treatment of CML-CP. CONCLUSION: Frontline nilotinib treatment provided sustained efficacy, with good tolerability, over 24 months in newly diagnosed CML-CP patients.

Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

OBJECTIVES: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1IS]) by 12 months. METHODS: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. This study is registered with ClinicalTrials.gov (NCT01274351). RESULTS: Of 112 patients enrolled, 66.1% (80% CI, 59.7-72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR4.5 (BCR-ABL1IS ≤0.0032%) by 12 months. During the first year of treatment, one patient progressed to blast crisis and two patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. CONCLUSION: These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP with low and intermediate risk.

Outcomes with frontline nilotinib treatment in Turkish patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

OBJECTIVE: Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor approved for the treatment of patients with chronic myeloid leukemia in chronic phase (CML-CP). This study was the first prospective evaluation of the efficacy and safety of nilotinib in Turkish patients with newly diagnosed CML-CP. The primary endpoint of the study was the rate of major molecular response (MMR; BCR-ABL1 ≤ 0.1% on the International Scale [BCR-ABL1(IS)]) by 12 months. METHODS: Patients with newly diagnosed CML-CP were treated with nilotinib 300 mg twice daily. This analysis was based on the first 12 months of follow-up in a 24-month study. RESULTS AND CONCLUSIONS: Of 112 patients enrolled, 66.1% (80% CI, 59.7-72.0%) achieved MMR and 22.3% achieved a deep molecular response of MR(4.5) (BCR-ABL1(IS) ≤ 0.0032%) by 12 months. During the first year of treatment, 1 patient progressed to blast crisis and 2 patients died. Safety results were consistent with previous studies. Most adverse events (AEs) were grade 1/2. Most frequently reported nonhematologic AEs of any grade were elevations in bilirubin, alanine aminotransferase, and triglycerides. These results support the use of nilotinib 300 mg twice daily as a standard-of-care treatment option for patients with newly diagnosed CML-CP.

Analysis of activation-induced cytidine deaminase mRNA levels in patients with chronic lymphocytic leukemia with different cytogenetic status.

Activation induced cytidine deaminase (AID) enzyme, which converts cytosine into uracil and is expressed only by activated B lymphocytes, plays a role in B cells in both the mechanisms of somatic hypermutation (SHM) and class switch recombination (CSR). There are studies showing that AID can cause numerous translocations in different lymphoproliferative diseases. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal B cells in bone marrow and peripheral blood. The predictability and clinical status of B-CLL are difficult to determine. About 30-50% of patients have chromosomal abnormalities. AID, which is thought to create fraction segments for translocations, might also cause deletions in DNA regions of 17p13, 11q22.3, 13q14 and 13q34 that are associated with prognostic implications in patients with CLL. In this study, the AID gene expression in patients with CLL with and without deletions was investigated. When compared to healthy subjects and patients without deletions, increased levels of AID expression in patients with deletions of 17p13, 11q22.3 or 13q14 were found, but not for the 13q34 region. Our results show that AID expression may be associated with deletions in patients with CLL.

Short-course use of recombinant factor VIIa in a haemophilia patient with inhibitor undergoing cataract surgeries.

A 36 year-old patient with severe haemophilia A and high-titre inhibitor underwent cataract surgery under topical anaesthesia. Recombinant factor VIIa was used only three times, once before and twice following surgery. Tranexamic acid was given concomitantly. One month after the first successful procedure on the right eye, a second operation was performed on the left eye in the same manner. Both procedures were uneventful. Neither bleeding complications nor any other side effects occurred.

Analysis of the lineage relationship between mast cells and basophils using the c-kit D816V mutation as a biologic signature.

BACKGROUND: Mast cells and basophils share similar morphologic and functional properties; however, it is not known whether they are derived from a bilineage (basophil/mast cell)-restricted progenitor. OBJECTIVE: To assess whether basophils and mast cells are derived from common committed progenitors using the c-kit D816V mutation as a biologic signature. METHODS: The D816V c-kit mutation found in mast cells of patients with systemic mastocytosis is used as a trackable genetic marker to assess the lineage relationship between mast cells and basophils. Blood and bone marrow aspirates were collected from 33 consecutive patients with mastocytosis with different disease severity. Peripheral blood basophils, monocytes and neutrophils were sorted by immunomagnetic beads. Presence of the D816V c-kit mutation was analyzed by restriction fragment length polymorphism in the genomic DNA and mRNA from sorted cells in all patients and in the genomic DNA of individual basophils of 1 patient. RESULTS: The c-kit D816V mutation was detectable in basophils of 5 patients (15%). All 5 patients had the c-kit mutation also detectable in monocytes and thus had multilineage involvement. Single cell analysis of the genomic DNA in 1 patient showed a similar degree of clonal expansion in basophils, monocytes, and neutrophils. Mutated c-kit was expressed at the mRNA level in all 5 patients. There was no difference in surface Kit expression levels in basophils. CONCLUSION: Basophils carrying the D816V c-kit mutation in mastocytosis were detected only in the context of a multilineage involvement. These results argue against the presence of a bilineage-restricted committed progenitor for mast cells and basophils.

A novel form of mastocytosis associated with a transmembrane c-kit mutation and response to imatinib.

Mutational analysis of the c-kit gene in a patient with a previously undescribed variant of mast cell disease revealed a germline mutation, Phe522Cys, within the transmembrane portion of the Kit receptor protein. Transfection experiments revealed that the mutation caused ligand-independent autophosphorylation of Kit, which was inhibited by the tyrosine kinase inhibitor imatinib mesylate. The patient's bone marrow biopsy and aspirate displayed unique pathologic features with the presence of excessive numbers of mature-appearing mast cells and absence of aberrant mast cell surface expression of CD2, CD25, and CD35. Therapy with imatinib mesylate resulted in a dramatic improvement in mast cell burden and clinical symptoms. These results highlight the significance of the transmembrane region of Kit in activation of the molecule and its importance in mast cell development and suggest a role for screening for transmembrane c-kit mutations in patients with mastocytosis in association with the decision to use imatinib mesylate.

Different patterns of bcl-6 and p53 gene mutations in tonsillar B cells indicate separate mutational mechanisms.

Mutations within the 5'-non-coding region of the bcl-6 gene can occur in lymphomas that originate from germinal centers (GCs), as well as in normal memory and GC B cells. Mutations in the p53 gene occur in 50% of human cancers. Since both bcl-6 and p53 can be mutated in certain circumstances, we investigated the accumulation of mutations in these genes in individual tonsillar B and T cells to determine whether the mutations exhibited a pattern anticipated from the B-cell hypermutation machinery. In tonsillar GC B cells, the overall mutational frequencies in the 5'-non-coding region of the bcl-6 gene was 0.85 x 10(-3)/bp. In contrast, there were no mutations in a region 2.8 kb downstream of the promoter. RGYW (purine, guanine, pyrimidine, A/T) targeting and a significantly lower mutational frequency in nai;ve B and GC founder B cells compared with GC B cells suggested that a similar mutator mechanism was active on Ig genes and this non-Ig gene. The mutational frequency in the exon-7-region of p53 was similar in the GC, memory and nai;ve B-cell subsets (1.02 x 10(-3) to 1.25 x 10(-3)/bp). RGYW/WRCY motifs were not targeted preferentially in the p53 gene. Moreover, a comparable mutational frequency of p53 was noted in tonsillar B and T cells. Hence, mutations in p53 do not appear to be the result of the B-cell hypermutational mechanism.

The role of polymerase eta in somatic hypermutation determined by analysis of mutations in a patient with xeroderma pigmentosum variant.

To determine the possible role of polymerase eta (pol eta) in somatic hypermutation of B cells, a mutational analysis of 24 nonproductive rearrangements from a patient with xeroderma pigmentosum variant with a defect in pol eta was conducted. Although the mutational frequency of A and T bases decreased in WA (A/T, A) motifs, regardless of their RGYW (purine, G; pyrimidine, A/T) context, the overall mutational frequency of A or T bases was not affected. Moreover, the overall mutational frequency of the sequences examined was not decreased. There was an apparent increase in the number of insertions and deletions. The results are consistent with the conclusion that pol eta specifically targets WA motifs. However, its overall contribution to the somatic hypermutational process does not appear to be indispensable and in its absence other mechanisms maintain mutational activity.