sirolimus and Primary-Myelofibrosis

In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant.

Topics: Adult; Aged; Cyclin D1; Everolimus; Female; Humans; Janus Kinase 2; Male; Middle Aged; Mutation; Polycythemia Vera; Primary Myelofibrosis; Protein Kinase Inhibitors; Receptors, Thrombopoietin; RNA, Messenger; Signal Transduction; Sirolimus; Thrombocythemia, Essential; TOR Serine-Threonine Kinases; Treatment Outcome; WT1 Proteins

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX.

Topics: Adult; Aged; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Peripheral Blood Stem Cell Transplantation; Primary Myelofibrosis; Severity of Illness Index; Sirolimus; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome