1Division of Hematology-Oncology, Department of Medicine, Chung-Ang University, Seoul, Korea.
2Department of Laboratory Medicine, Chung-Ang University, Seoul, Korea.
The 68-year-old man had visited our clinic with hematologic test abnormalities; that is, 28,710/µL for white blood cell (WBC) counts, 10.4 g/dL for hemoglobin, and 244,000/µL for platelet counts. A peripheral blood smear examination demonstrated an excess of myelocytes and metamyelocytes. Elevation of the serum lactate dehydrogenase (LD) level was also noted. His abdominal computed tomography (CT) scan demonstrated marked splenomegaly (22.7 cm).
Suspecting an MPN of mostly CML, a bone marrow examination was done. The cellularity was almost 100% and prominent granulopoiesis was noted. The megakaryocytes were high in number, and some of them showed atypia, such as decreased cytoplasm, cloud-like nuclei, and dense cluster formation (Fig. 1). A grade I-II fibrosis was observed. Regarding the cytogenetics, a
In the bone marrow examination done at 3 months, atypical megakaryocytes were still noted as well as grade II fibrosis. A CT scan revealed the spleen size to be 20.9 cm. Suspecting treatment failure, the dasatinib was increased to 140 mg once daily. Five days later, a complete cytogenetic response test reported none of the 14 cells by chromosomal analysis and none of the 400 cells by FISH had the
We assumed that both CML and PMF clones existed, and suppressing the CML clones may have stimulated the PMF clone, which resulted in leukocytosis and aggravation of the constitutional symptoms. Thus, on December 9, 2016, the patient started to take ruxolitinib 20 mg twice daily concurrently with dasatinib. At this time, his MPN10 score was 62, and the international prognostic scoring system (IPSS) group was high-risk owing to his age, symptoms, and leukocytosis. The leukocytosis resolved after 2 weeks, and so did the constitutional symptoms. In March 2017, after 3 months of ruxolitinib treatment, the MPN10 score improved to 26 and the spleen size decreased to 16.7 cm. The IPSS grouping was intermediate-1, owing to his age. After 12 months of dasatinib treatment, a bone marrow examination carried out in May 2017 demonstrated still-noted hypercellularity, atypical megakaryocytes, and grade III myelofibrosis. Continuing complete cytogenetic and molecular responses were observed.
The patient continued to take dasatinib and ruxolitinib until April 2017. He then stopped taking ruxolitinib because of an insurance issue, whereupon the constitutional symptoms and leukocytosis recurred. He resumed the concurrent treatment in July 2017 and the dose of ruxolitinib was decreased to 15 mg twice daily because of anemia and thrombocytopenia. He has been taking both drugs for 18 months while maintaining the major molecular response and improvement in MPN10 score of over 50%. In May 2018, 2-year follow-up studies were performed. The transcript level determined by RQ-PCR was 0.06% IS, and the spleen size had decreased to 16.2 cm. The IPSS grouping was intermediate-1. Bone marrow examination showed grade III myelofibrosis with increased fibroblasts. The clinicolaboratory course is described in Fig. 2.
We have described the case of a patient who initially presented the features of both CML and PMF. After taking dasatinib, he promptly achieved cytogenetic and molecular responses but not a hematologic response. Moreover, increasing the dose of dasatinib induced aggravated leukocytosis and constitutional symptoms. Despite the sustained molecular response, the persistent leukocytosis and constitutional symptoms bothered the patient, but these resolved after he started taking ruxolitinib. He has been faring well for 18 months with the concurrent treatment.
According to the WHO classification, the diagnosis of CML and that of other
In our case, the patient was definitively diagnosed with CML as he presented with granulocytosis, an excess of precursors, and the presence of
Ruxolitinib is a potent JAK inhibitor, and its major role in PMF is for symptom control. Thus, its incorporation into
Our experience provides several clinical implications. First, CML and other types of MPNs may coexist, even though the incidence may be very rare. Second, physicians should consider hidden MPNs when there are discrepancies in the molecular response and clinical response in CML. Third, although dasatinib and ruxolitinib can be safely combined, hematologic adverse events may be a concern. This is one of the few case reports of a patient who initially had features of both CML and PMF, and to the best of our knowledge, the first case report of treating such a patient with dasatinib and ruxolitinib.
Bone marrow biopsy specimens at the time of diagnosis (hematoxylin and eosin stain, ×400). Atypical megakaryocytes showing cloud-like nuclei with a high nucleusto-cytoplasm ratio
Clinicolaboratory course of the patient. a)Number of Ph+ cells/number of analyzed cells by chromosome analysis; b)Number of Ph+ cells/number of analyzed cells by fluorescence