Tyrosine kinase inhibitors-induced myelosuppression - case report

W pracy przedstawiono opis leczenia chorej na przewlekłą białaczkę szpikową (CML) w fazie przewlekłej dostępnymi obecnie inhibitorami kinazy tyrozynowej (TKI), w tym imatynibem, dazatynibem oraz nilotynibem. Leczenie to było powikłane głęboką cytopenią, co powodowało konieczność przerywania terapii i zmniejszania dawek leków. Konsekwencją powtarzających się epizodów mielosupresji i zmniejszania dawek kolejnych TKI było niepowodzenie terapii CML. Opisany przypadek ilustruje trudności terapeutyczne związane z mielosupresją zależną od TKI w trakcie leczenia przewlekłej fazy CML. Hematologia 2010; 1, 3: 249-253This paper presents a patient with chronic myeloid leukemia (CML) in chronic phase and profound myelosuppression induced by tyrosine kinase inhibitors (TKI), included imatinib, dasatinib and nilotinib. Therapy with each of TKI was complicated by severe cytopenia, which resulted in interruptions and daily dose reduction of the drugs. Finally, myelosuppression and reduced dense-dosage of each TKI resulted in CML treatment failure. This case illustrates the therapeutic difficulties related to TKI-induced myelosuppresion in the chronic phase of CML. Hematologia 2010; 1, 3: 249-25

Plasma cell myeloma with predominant symptoms of bone disease-effective first-line treatment interrupted by low-energy pubic bone fracture — therapy complications management

W przebiegu nowotworów z komórek plazmatycznych wskazania do rozpoczęcia leczenia bywają dyskusyjne z punktu widzenia zarówno pacjenta, jak i lekarza prowadzącego. Postawienie diagnozy szpiczaka bezobjawowego powoduje obawy o zbyt późne wdrożenie postępowania ze skutkiem w postaci gorszego rokowania i obniżenia jakości życia chorego, u którego w dalszym przebiegu wystąpiły uszkodzenia tkankowe i narządowe. Wyrazem tych wątpliwości jest określenie w kryteriach International Myeloma Working Group (IMWG) zdarzeń definiujących szpiczaka. W niniejszej pracy przedstawiono przypadek 75-letniej chorej na szpiczaka plazmocytowego, którą pierwotnie zdyskwalifikowano z leczenia, a chemioterapię według schematu VMP (winkrystyna, melfalan, prednizon) wdrożono u niej w momencie wystąpienia powikłań kostnych, w tym złamań, które znacznie utrudniły prowadzenie właściwej terapii. Chora uzyskała bardzo dobrą częściową odpowiedź na leczenie i obecnie pozostaje pod obserwacją.In the course of plasma cell malignancies, indications to start of treatment are often controversial from patient and guiding physician point of view. Diagnosis of smouldering myeloma, causes concerns about the late implementation of the proceedings with the effect of a worse prognosis and reduced quality of life of patient who developed tissue and organ damage in the further course of the disease. Myeloma defining events in the new International Myeloma Working Group (IMWG) criteria are the expression of those concerns. A case of 75 year old female patient with plasma cell myeloma, which was originally disqualified from treatment. Chemotherapy according to the VMP (vincristine, melphalan, prednisone) has been introduced when the bone complications, including fractures, appeared, which caused difficulties to proceed with the appropriate treatment. Patient with very good partial response is a subject to periodic follow-up

Primary myelofibrosis with normal karyotype and cryptic aberrations detected by FISH: case report

Introduction. Myeloproliferative neoplasms (MPNs) are the result of clonal haematopoietic stem cell disorders. The most common cytogenetic aberrations are: partial trisomy 1q, 13q–, 20q–, trisomy 8 and abnormalities of chromosomes 1, 7 and 9. Conventional karyotyping is a routinely used method. Fluorescent in situ hybridisation (FISH) analysis however may also be an integral component of the diagnostic evaluation, especially when the abnormality is cryptic. Subject and methods. A 70-year-old woman was admitted to the Department of Haematology in September 2013 with suspected acute myeloid leukemia (AML). The final diagnosis was primary myelofibrosis and NYHA class III heart failure. Bone marrow (BM) was used for karyotyping and FISH. Peripheral blood (PB) was used for PCR. Results. Cytogenetic GTG analysis revealed normal female karyotype — 46,XX [22]. The result of analysis of JAK2 V617F mutation was negative. Analysis using LSI BCR/ABL Dual Fusion Probe, JAK2 Break Probe and RB1 Deletion Probe showed abnormal cells, of which the numbers were beyond the normal cutoffs. FISH examinations using p53 Deletion Probe and LSI CDKN2A/CEP 9 showed normal cells. Conclusion. The diagnosis of primary myelofibrosis may pose a problem. We still do not know the specific abnormalities (i.e. genomic and chromosomal aberrations or gene mutations), the occurrence of which may help to diagnose and assess a probable time of survival of patients with PMF. Further examinations are needed (e.g. using aCGH) to find out more about myeloproliferative neoplasms

Retrospective analysis of nilotinib and dasatinib efficacy in second line treatment of chronic myeloid leukemia in Polish hematological centers

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p=0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p=0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p=0.89) or overall survival (p=0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient

A risk of essential thrombocythemia in carriers of constitutional CHEK2 gene mutations

Germline mutations of the CHEK2 gene have been reported in some myeloid and lymphoid malignancies, but their impact on development of essential thrombocythemia has not been studied. In 16 out of 106 (15.1%) consecutive patients, newly diagnosed with essential thrombocythemia, we found one of four analyzed CHEK2 mutations: I157T, 1100delC, IVS2+1G>A or del5395. They were associated with the increased risk of disease (OR=3.8; P=0.002). The median age at ET diagnosis among CHEK2+/JAK2V617F+ patients was seven years lower than that among CHEK2−/JAK2V617F+ (52 vs. 59 years; P=0.04), whereas there was no difference in the medians of hematologic parameters between these groups. The results obtained suggest that CHEK2 mutations could potentially contribute to the susceptibility to essential thrombocythemia. The germline inactivation of CHEK2, as it seems, has no direct impact on the development of disease, but it could cause disruption of cell cycle checkpoints and initiate or support the cancerogenic process of essential thrombocythemia at a younger age

Cereblon (CRBN) gene polymorphisms predict clinical response and progression-free survival in relapsed/refractory multiple myeloma patients treated with lenalidomide: a pharmacogenetic study from the IMMEnSE consortium

Cereblon (CRBN) is crucial for antiproliferative and immunomodulatory properties of immunomodulatory drugs. The objective of this study was to verify whether germline single nucleotide polymorphisms (SNPs) in the CRBN gene may influence response to lenalidomide in multiple myeloma (MM). Fourteen tagging SNPs covering the genetic variability in the CRBN gene region were genotyped in 167 Polish patients with refractory/relapsed MM treated with lenalidomide-based regimens. We found that carriers of minor alleles of two studied CRBN SNPs rs1714327G > C (OR = 0.26; 95% CI = 0.1-0.67; p = .0055, Bonferroni corrected p = .033) and rs1705814T > C (OR = 0.22; 95% CI = 0.07-0.65; p = .0063, Bonferroni corrected p = .037) were significantly associated with lower probability of achievement at least partial remission while treated with lenalidomide-based regimens, using the dominant inheritance model. Moreover, one of these SNPs, namely rs1705814T > C, was correlated with shorter progression-free survival (HR = 2.49; 95%CI = 1.31-4.74, p = .0054, Bonferroni corrected p = .033). It is suggested that selected germline CRBN allelic variants (rs1714327G > C and rs1705814T > C) affect lenalidomide efficacy in patients with relapsed/refractory MM