BCR-ABL Positive Chronic Myeloid Leukaemia (CML) with Del 11q22 and JAK 2 V617F Positive Chronic Myelomonocytic Leukaemia (CMML) in One Patient – a Rare Coincidence

Coincidence of BCR-ABL positive CML and JAK2 V617F positive CMML in one patient is a rare phenomenon.

We report on a 61 year old patient with a diagnosis of CML in August 2008. Peripheral blood count showed a WBC of 3.1 G/l and a mild thrombocytopenia with 139 G/l thrombocytes. Differential blood count revealed virtually all cells of the neutrophilic line with myelocytes, metamyelocytes and blasts, basophils were elevated with 3%. While bone marrow (BM) aspirate was not representative, histologic examination of the BM biopsy showed a hypercellular marrow with a pattern of cell maturation similar to peripheral blood. An increase in reticulin fibrosis and vascularity was demonstrated correlating with a diagnosis of CML. Cytogenetics confirmed diagnosis of CML with a t(9;22)(q34;q11) in 4 out of 21 metaphases, 11 metaphases showed a deletion 11q and 2 metaphases showed both, a del 11 q and a Philadelphia translocation. Four metaphases showed a normal karyotype. BCR-ABL and JAK2 V617F have been demonstrated on the molecular level.

Imatinib was started with a standard dose of 400 mg daily. The patient achieved a complete cytogenetic response (CCR) and a complete molecular response (CMR – BCR-ABL transcripts not detectable with quantitative and nested PCR) after 3 and 7 months of therapy, respectively. Despite having achieved an excellent response on cytogenetic and molecular level a complete haematological response was not obtained. At that time bone marrow examination revealed a marked hypercellular marrow with 10% blasts and 15% monocytic forms consistent with the diagnosis of CMML. Philadelphia chromosome was absent. The deletion 11q and JAK2 V617F were still detectable. Beause of comorbidities allogeneic stem cell transplantation was no treatment option for this patient. In July 2009 therapy with azacitidine, a hypomethylating agent licensed for the use in CMML was initiated. Imatinib was administered intermittently on azacitidine free days dependent on the current haematological situation. BCR-ABL transcript levels varied between one log up/down reflecting the intermittent imatinib administration. CMR and MMR were lost after 4 and 9 months, respectively. Subsequently, an additional deletion 7q was detected in 20% of metaphases with a deletion 11q (no Ph+ or normal metaphases were present). Azacitidine was stopped because of disease progression and hydroxyurea was commenced with no significant response. Cutaneous infiltrations resistant to systemic therapy reflected further disease progression. WBC increased to 334 G/l and the patient died 25 months after diagnosis due to progression of CMML to acute leukaemia.

Conventional karyotyping was done using Giemsa-Trysin banding. For FISH, BCR-ABL dual colour fusion probes and MLL dual colour break apart probes (both Abott Molecular) were used. JAK2V617F mutation was detected by melting curve analysis. BCR-ABL RNA monitoring was performed according to the Europe Against Cancer protocol (Gabert et al.).

Coincidence of two distinct myeloproliferative disorders in one patient is relatively rare. Both, conventional cytogenetics and molecular biology provided important information for diagnosis, course and treatment. This case vignette illustrates the importance of repeated cytogenetic and molecular analyses demonstrating an unexpected turn of an apparently predetermined course.

Burgstaller:AOP Orphan Pharmaceuticals AG: Research Funding. Thaler:AOP Orphan Pharmaceuticals AG: Research Funding.