By Mikkael A. Sekeres, MD, MS
Dr. Sekeres is Director, Myelodysplastic
Syndromes Program, Department of Hematologic Oncology and Blood Disorders,
Cleveland Clinic Taussig Cancer Institute.
Note: This question was submitted through the Consult-a-Colleague
Program. Dr. Sekeres was asked to respond.)
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
- Vardiman J, Thiele J, Arber DA, et al. The 2008 Revisions of the WHO classification
of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009. [Epub ahead of print]
- Szpurka H, Tiu
R, Murugesan G, et al. Refractory anemia with ringed sideroblasts
associated with marked thrombocytosis (RARS-T), another myeloproliferative
condition characterized by JAK2 V617F mutation. Blood. 2006;108:2173-81.
- Jankowska AM,
Szpurka H, Tiu RV, et al. Loss of heterozygosity 4q24 and TET2
mutations associated with myelodysplastic/myeloproliferative neoplasms. Blood. 2009;113:6403-10.
- Cannella L, Breccia M, Latagliata R, Frustaci A, Alimena
G. Clinical and prognostic features of patients with
myelodysplastic/myeloproliferative syndrome categorized as unclassified
(MDS/MPD-U) by WHO classification. Leuk
- Greenberg P,
Cox C, LeBeau MM, et al. International
scoring system for evaluating prognosis in myelodysplastic syndromes.
- Wijermans PW,
Rüter B, Baer MR, et al. Efficacy
of decitabine in the treatment of patients with chronic myelomonocytic leukemia
(CMML). Leuk Res. 2008;32:587-91.
- Fenaux P,
Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that
of conventional care regimens in the treatment of higher-risk myelodysplastic
syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10:223-32.
GG, Sandmaier BM, Storer BE, et al. Reduced-intensity
conditioning followed by allogeneic hematopoietic cell transplantation for
adult patients with myelodysplastic syndrome and myeloproliferative disorders.
Biol Blood Marrow Transplant. 2008;14:246-55.
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