ALBERT

Description: Treatment outcome in patients with AML is determined by a variety of prognostic factors such as WBC, LDH, age, presence of chromosomal aberration. Recently, two acquired genetic alterations, internal tandem duplications (ITD) and Asp835 codon mutations of the fms-like tyrosine kinase 3 (FLT3) gene were reported in AML as prognostic factors. 66 consecutive adult patients (39 females and 27 males) were treated with newly diagnosed AML in our institute between January 2002 and June 2004. The median age of onset was 49±15 (range 17–83) years. The gender distribution was 1.44 (female/male). We analyzed FLT3 ITD and Asp835 mutations at the time point of diagnosis by fluorescent PCR and PCR-RFLP methods. ITD was present in 22.7% (15/66) of the patients and Asp835 mutations were detected in 7.6 % (5/66). Two patients carried both mutations. 13 of 15 ITD-positive patients had myelomonocytic or monocytic leukemia (M4 and M5 in the FAB classification system). There was no difference between the numbers of ITD-positive and negative patients in complete remission (10/15 [66.7%] vs. 31/51 [60.8%]). In the ITD-positive patient group, the relapse rate was increased (5/15 [33.3%] vs. 7/51 [13.7%]) however, this difference was statistically not significant. The age of onset was greater than 40 years in all Asp835 mutation-positive patients and in this group, no relapse occurred within the follow-up time. The remission rate (4/5) of this group was high in spite of the old age of onset. The single Asp835-positive patient also carried the ITD mutation and showed primary resistance. Our results are in agreement and confirm earlier observations for the ITD mutation in a different patient population. In our relatively small patient group the Asp835 mutation seemed to have a beneficial effect.

Description: Chronic myeloproliferative diseases (CMPD) are clonal disorders of pluripotent hematopoietic stem cells. Acquired JAK2 V617F point mutation has recently been identified as disease causing activating genetic abnormality in classic BCR-ABL negative CMPD (80% of polycythemia vera, 35% of essential thrombocythemia and 50% of chronic idiopathic myelofibrosis cases). JAK2 V617F is rare in other myeloid stem cell disorders like acute myeloid leukemia, chronic myelomonocyter leukemia or myelodysplasia with reported frequency of 3–8%. Between January 2001 and December 2005 155 consecutive adult patients [87 females and 68 males, median age of onset was 49±14 (range 18–83) years] were diagnosed with AML in our institute. Peripheral blood or bone marrow samples drawn at the time point of diagnosis were analyzed for the presence of JAK2 V617F by allele-specific PCR. JAK2 V617F mutation was present in 5 patients (3 males and 2 females; 3.2%). 3 of the 5 patients had prior history of CMPD, while 2 patients were diagnosed with de novo AML. The clinical characteristics and laboratory features of JAK2 V617F positive patients are shown in Table 1. FLT3 internal tandem duplication, FLT3 tyrosine kinase domain mutations, AML1-ETO, CBFB-MYH, PML-RARA rearrangements or nucleophosmin mutations were not present at the time point of AML diagnosis. In the case of patient 1, thrombocytosis was present prior the diagnosis of AML, and bone marrow biopsy revealed grade 3 fibrosis at diagnosis of AML, suggesting the presence of an atypical CMPD with the coexistence of del(5q) MDS. Patient 2 had no remarkable disease in his previous medical history. Induction therapy resulted in complete hematological and cytogenetic remission with persistent JAK2 V617F positivity. 10 month later clinical features of CMPD (elevated white blood cell count, left shifted peripheral blood smear, hepatosplenomegaly) appeared. In conclusion, these two cases suggest that acute myeloid leukemia with JAK-2 V617F mutation in fact corresponds to the blastic transformation of a clinically atipical chronic myeloproliferative disorders. Clinical characteristics and laboratory features of JAK2 V617F positive patients Case Sex AML subtype Age of onset (years) FAB subtype Cytogenetic abnormality Therapy Overall Survival (months) 1 F de novo 52 M1 del(5q) DNR+ara-C, HDara-C 23 2 M de novo 65 M4 t(13;17) DNR+ara-C, HDara-C 12 3 F CMPD blastic transformation 65 M4 trisomy (1q) Supportive 18 4 M CMPD blastic transformation 70 M4 not available Supportive 3 5 M CMPD blastic transformation 71 M4 not available Supportive 6