Despite taking hydroxyurea for months his leukocytosis splen
Despite taking hydroxyurea for 6 months, his leukocytosis, splenomegaly, and constitutional symptoms were poorly controlled and his performance status and overall function had declined even further. There was little clinical benefit to gain by increasing the hydroxyurea dose further especially in the setting of severe thrombocytopenia. Interferon therapy was considered contraindicated due to the potential for exacerbating his mood disturbances associated with Parkinson׳s disease. The patient was eventually prescribed ruxolitinib through his commercial insurance. Shortly before starting ruxolitinib but while still on hydroxyurea, his CBC showed WBC 56.0×10e3/microliter, ANC 48.7×10e3/microliter, Hgb 8.6g/dL, MCV 121fL, and platelet 28×10e3/microliter. His spleen volume was 4342cm3 and his total symptom score was 164 (total max of 270, MPN-symptom assessment form [MPN-SAF]) .
On December 2013 the patient was started on ruxolitinib 10mg twice a day (day 0). His dose was increased to 15mg twice a day on day +57 and to 20mg twice a day on day +84. He was tapered off hydroxyurea and was completely off on day +14. As shown in Fig. 1A, the WBC and MCV were reduced gradually over 3 months while his Hgb and AZD1208 cost steadily increased, indicating improved marrow function by targeting JAK1/JAK2 signaling and going off hydroxyurea. His peripheral blood showed reduced immature granulocytes while the neutrophils displayed increased cytoplasmic granularity/toxic granulation. His bone marrow had reduced granulocytic hyperplasia (myeloid:erythroid ratio 10:1) and fewer hypolobated megakaryocytes compared with the pre-ruxolitinib bone marrow evaluation. Peripheral and marrow blasts were less than 1%. In addition, his spleen volume was reduced by approximately 75% after approximately 3 months of ruxolitinib therapy as shown in Fig. 1B. Furthermore, his quality of life and total symptom score improved dramatically as shown in Fig. 1C. As a result of his excellent tolerance and response to ruxolitinib, his dose was increased further to the target dose of 20mg twice a day. After this adjustment, his platelets increased further as shown in Fig. 1A. He has gained weight and his performance status improved to ECOG of 1. As of this report, he continues to do well and remains on ruxolitnib 20 mg twice a day. Interestingly, his dramatic clinical response was not associated with a reduction in CSF3R-T618I allele frequency based on peripheral blood studies after approximately 4 months of ruxolitinib treatment. Single colony assays confirmed that the allele frequency was not significantly reduced.
Discussion Here we report a case of CSF3R-T618I-positive aCML with a robust clinical response to JAK1/2 inhibition with ruxolitinib. The clinical benefit in this case was not merely leukoreduction but also improved marrow function as evident by near normalization of Hgb, MCV, and platelet counts. In addition, the patient had a significant reduction in spleen volume and constitutional symptoms, which were refractory to hydroxyurea. In the report by Maxson et al.  a clinical case of CSF3R-T618I-positive CNL was described where the patient also had platelet and Hgb improvement with ruxolitinib. These clinical cases suggest interesting differences between myelofibrosis (primary, post-polycythemia vera, and post-essential thrombocytosis) and CNL/aCML. As noted in the Comfort I study, a randomized placebo-controlled phase III clinical trial with ruxolitinib in patients with myelofibrosis, (1) thrombocytopenia is a dose-limiting toxicity, (2) WBC is not substantially reduced in myelofibrosis patients, and (3) marrow function is not measureably improved with ruxolitinib despite clinical responses (spleen and symptom reduction). One similarity is that the allele burden of the oncogenic driver is not significantly reduced with ruxolitinib .
Acknowledgments KTD receives support from the OHSU Knight Cancer Institute and the National Institutes of Health, National Heart, Lung and Blood Institute (1K08HL111280). BJD is supported by the Howard Hughes Medical Institute. JWT is supported by Grants from the V Foundation for Cancer Research, the Leukemia and Lymphoma Society, the Gabrielle׳s Angel Foundation for Cancer Research, and the National Cancer Institute (5R00CA151457 and 1R01CA183974).