The impact of additional cytogenetic abnormalities at diagnosis and during therapy with tyrosine kinase inhibitors in Chronic Myeloid Leukaemia.

BACKGROUND: Chronic Myeloid Leukemia's (CML) treatment was optimized since the development of tyrosine kinase inhibitors (TKI) and an increased overall survival during TKI was noticed. During the TKI era, protocols for assessing response and resistance to treatment were developed. Additional chromosomal abnormalities (ACAs) are strongly associated with disease progression but their prognostic impact and influence on treatment response are yet to be defined. The aim of this study was to analyze the impact of ACAs on time to achieve complete cytogenetic response (CCyR), treatment and overall survival. MATERIALS AND METHODS: Since 2005 until 2013, the data from the Hematology and Bone Marrow Transplantation Department of Fundeni Clinical Institute was collected. In this observational retrospective single centre study, 28 CML patients with ACAs at diagnosis and during TKI treatment were included. RESULTS: From ACAs at diagnosis group, the most frequent major route ACAs were trisomy 8, trisomy 19 and second Philadelphia (Ph) chromosome and the most frequent minor route ACAs were monosomies and structural abnormalities (inversions and translocations). From the ACAs during the TKI group, the most frequent major route cytogenetic abnormalities in Ph positive and negative cells were trisomy 8, trisomy 19 and second Ph chromosome and the most frequent minor route cytogenetic abnormalities in Ph positive and negative cells were marker chromosomes and structural abnormalities (inversions, translocations and dicentric chromosomes). CONCLUSIONS: In both groups, the time to CCyR was longer and long-term results were inferior in comparison with standard patients but the differences were not significant and in accordance to published data. The 12 months follow-up after the study's end showed that 26 patients were alive and in long-term CCyR and 2 deaths were reported. ABBREVIATIONS: CML = Chronic Myeloid Leukemia, BCR-ABL1 = Break Cluster Region - Abelson gene, TKI = tyrosine kinase inhibitor treatment, ACAs = additional cytogenetic abnormalities, CCyR = complete cytogenetic response, PCyR = partial cytogenetic response, mCyR = minor cytogenetic response, MMR = major molecular response, HSCT = hematopoietic stem cell transplant, HLA = human leukocyte antigens, CP = chronic phase, AP = accelerated phase, BP = blast phase, OS = overall survival, CBA = chromosome banding analysis, +8 = trisomy 8, i(17q) = isochromosome (17q), +Ph = second Philadelphia chromosome, -7 = monosomy 7, -17 = monosomy 17, +17 = trisomy 17, -21 = monosomy 21, +21 = trisomy 21, -Y = loss of Y chromosome, ELN = European LeukemiaNet, IMA600 = Imatinib 600 mg daily, IMA400 = Imatinib 400 mg daily, NILO600 = Nilotinib 600 mg daily, DASA100 = Dasatinib 100mg daily, DASA140 = Dasatinib 140 mg daily.

The simultaneous occurrence of multiple myeloma and JAK2 positive myeloproliferative neoplasms - Report on two cases.

Multiple myeloma and JAK2 positive chronic myeloproliferative neoplasms are hematologic malignancies with a completely different cellular origin. Two cases of simultaneous occurrence of multiple myeloma, one with primary myelofibrosis and another one with essential thrombocythemia are reported in this article. In such cases, an accurate diagnosis requires a molecular testing, including gene sequencing and differential diagnosis of pancytosis associated with splenic amyloidosis. In general, in such cases, of two coexisting malignant hematologic diseases, the treatment of the most aggressive one is recommended. For our two cases, it was decided to start a Velcade based therapy. The main concern was the medullar toxicity, especially when a multiple myeloma was associated with a primary myelofibrosis.

The concomitant occurrence of JAK2V617F mutation and BCR/ABL transcript with phenotypic expression - an overlapping myeloproliferative disorder or two distinct diseases? - case report.

The concomitant occurrence of JAK2617F mutation and BCR/ABL translocation is a rare event. It is unclear if this is a result of the clonal evolution or a separately emergence of two clones and if it could lead to the progression to a more aggressive phase of the disease. We present the case of a 61-year-old man diagnosed and treated for polycythaemia vera for 7 years, which evolved into chronic myeloid leukemia BCR/ABL positive and with JAK2617F mutated clone, that became dominant after an effective treatment with Imatinib.

Importance of assessing cytogenetic and molecular risk factors in acute myeloid leukemia therapy.

Acute myeloid leukemia (AML) is a heterogeneous disease in clinical presentation, outcome and therapeutic response. Cytogenetic and molecular characteristics are important prognostic indicators allowing the identification of distinct subtypes of AML, prognostic stratification and risk-adapted treatment. We present our experience during 5 years, in which we treated 245 patients with AML, of which we could genetically characterize 48 cases (26 females, 22 males) with a median age of 52 years. Cytogenetic analysis was performed by GTG banding on cultures of marrow cells treated with colcemid. Molecular analysis used RT-PCR performed on ABI 9700 platform in order to identify the following fusion genes: E2A-PBX1, TEL-AML1, AML1-ETO, PML-RARα, MLL-AF4, CBFC-MYH11, BCR-ABL, SIL-TAL, and MLL-AF9as well as mutations in Flt3, NPM1, WT1 genes. Fourteen patients were older than 60 years. In 12 we performed cytogenetic analysis showing 5 cases with complex karyotype, 2 normal karyotypes, 1 case of del(21), del (9), 11q- and t(3;15) respectively as well as 2 unevaluable karyotypes. These anomalies were associated with a high incidence of secondary AMLs (10/14) and with a low remission (CR) rate (5/14). Out of the 35 patients younger than 60 years, 25 were evaluated by cytogenetics showing a high incidence of favorable cytogenetic changes: 6 anomalies of chromosome 16 (5 inv (16) and 1 t (16; 16)), 3 t (15; 17), 3 cases of t (8; 21) of which 2 with additional abnormalities, 7 normal karyotypes and 1 case of 7q-, -y,-3 and respectively -8 associated with +18. In 25 cases molecular analysis was performed showing alterations in 21 patients: 6 cases with AML/ETO, 3 PML/RAR, 7 Flt3 mutations (2 associated with NPM1 mutation) as well as 1 case of isolated mutation of NPM1 and respectively WT1. CR rate was of 28/35. All cases with t (15; 17) and PML/RAR as well all cases with t (8; 21) and/or AML/ETO achieved CR. Out of the 7 cases with Flt3 mutations only 4 achieved CR including the 2 cases with associated NPM1 mutations. In our experience, genetic characteristics correlate with other prognostic markers such as age and secondary leukemia; "favorable" genetic anomalies were associated with a high CR rate; association of t (8; 21) with additional abnormalities did not influence CR rate.