Ask the Hematologist, September-October 2009

A 70-year-old gentleman presented with a two-month history of fatigue and bleeding gums. A recent CBC revealed a WBC of 38,600/μL, with a differential of 20,400 neutrophils/μL, 6,900 lymphocytes/μL, 400 monocytes/μL, 3,000 metamyelocytes/μL, 6,500 myelocytes/μL, 700 progranulocytes/μL, and 700 myleoblasts/μL. His hemoglobin was 9.4 g/dl, and his platelet count was 23,000/μL. A bone marrow biopsy revealed 80 percent to 90 percent cellularity with markedly decreased megakaryocytes with mono-lobate forms and decreased erythroid maturation with evidence of dyserythropoiesis. The M:E ratio was 23:1 and the differential was left-shifted, with 2 percent myeloblasts, 7 percent progranulocytes, 54 percent myelocytes, 15 percent metamyelocytes, 5 percent bands, and 8 percent segmented neutrophils. Moderate fibrosis was present. G-Banded chromosomal analysis was normal, 46 (X;Y). The BCR/ABL translocation was not detected by fluorescence in-situ hybridization (FISH) analysis; nor was the JAK2 (V617F) mutation identified. The final diagnosis by our pathologist was myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN)-u (unclassifiable). In the meantime, over a two-week period, the patient’s WBC has increased to 48,000/μL. What is your opinion on management?

The details of this patient’s history illustrate nicely how our ability to elegantly diagnose a rare bone marrow neoplasm (and exclude the diagnoses of other molecularly characterized abnormalities) exceeds the sophistication of the drugs we have available in our arsenal to treat it effectively. MDS/MPN overlap disorders come in many flavors: as a true overlap condition at initial presentation, with evidence of dysplasia of cellular elements and myeloproliferative components (such as fibrosis, hypercellularity, or organomegally); as MDS that takes on MPN features over time; or, conversely, as an MPN that develops progressive marrow dysplasia. These disorders include chronic myelomonocytic leukemia (CMML), atypical (BCR-ABL1 negative) chronic myeloid leukemia, juvenile myelomonocytic leukemia, and MDS/MPNu¹  as seen in this patient. Some MDS/MPN cases have JAK2 mutations (such as the provisional entity, refractory anemia with ring sideroblasts and thrombocytosis);²  the proliferative components of these disorders are related to abnormalities in the RAS/MAPK signaling pathways, and approximately 50 percent are associated with TET2 mutations.³  As should be done in any patient with clinical or pathologic aspects of an MPN, testing for the BCRABL1 mutation was done in this case to exclude the diagnosis of CML, a disease for which we have effective therapies. This patient did not have cytogenetic evidence of a PDGFRβ abnormality, which is usually associated with eosinophilia and which often responds to imatinib therapy; nor did he have a del (5q), for which lenalidomide has particular efficacy.

My treatment approach to patients with MDS/MPN is predicated on the presence of symptoms affecting quality of life (and thus, a need for therapy), the predominant clinical aspect of the disease at presentation (e.g., are they more proliferative or more dysplastic), and an estimate of prognosis. In one series, MDS/MPN-u represented only 2 percent of patients with MDS, with a median overall survival of 21 months (range 10-61).⁴  The international prognostic scoring system (IPSS) for MDS cannot be applied for many patients with this syndrome, as it excluded patients with a WBC >12,000/μL,⁵  but given the median survival of less than two years, I would consider this group of patients equivalent to the higher-risk IPSS groups and, thus, would initiate some sort of therapy now.

The patient described here appears to have a more proliferative disease, given the leukocytosis. My approach, then, would be cytoreduction, with blood and platelet support as needed. This can be accomplished with hydroxyurea, alkylating agents (such as busulfan), immunomodulatory drugs (thalidomide or lenalidomide), or cytarabine (all of which can be administered in the outpatient setting), and can be titrated to achieve a neutrophil count in the normal range or improvement of symptoms such as fatigue and splenomegaly. Treatment with a DNA methyltransferase inhibitor can also be considered an option. Although no therapeutic trials have been devoted to MDS/MPN-u patients exclusively, subgroup analyses of 31 patients with the overlap syndrome CMML treated on the decitabine registration study demonstrated overall responses (CR + PR) of 25 percent, which was comparable to responses seen in other patients with MDS included in the same trial.⁶  In a recently published European study, an overall survival advantage was seen in patients with CMML treated with azacitidine compared to those treated with conventional care, although this represented only 3 percent of the total study population.⁷  As with other patients with MDS or MPN, allogeneic hematopoietic stem cell transplantation represents the only potentially curative option; reduced-intensity conditioning regimens are options for particularly hardy septuagenarians, with one recent study of 148 patients with MDS, MPN, and MDS/ MPN (median age 59 years) showing a three-year survival rate of 27 percent.⁸ 

For this patient, if he is in otherwise good health, I would offer him the option of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning. If he is not a candidate for this, I would offer hydroxyurea initially, adjusting the dose based on the response of his WBC, platelet count, and symptoms, followed by an immunomodulatory drug with or without steroids.