Development of murine model of allogeneic bone marrow transplantation and graft versus host diseaseModeling of allogeneic bone marrow transplantation and graft versus host disease (GVHD) plays a crucial role in the improvement of transplantation procedures and testing novel immunosuppressive drugs. In this study we evaluated the feasi bility of busulfan and cyclophosphamide conditioning with post transplantation cyclophosphamide (150 mg/kg) in donor recipient pairs C57Bl/6 Balb/с and Balb/с C57Bl/6. We ob served that Balb/с mice as opposed to C57Bl/6 mice can't be the recipients because of the unacceptably high acute mortality from acute toxicity of chemotherapeutic drug. Histological studies in the C57Bl/6 recipients revealed acute GVHD in 93 % of animals. All animals had only grade I-II severity of GVHD. This model has the potential for future studies in the field of transplantology, nonetheless a decrease in the intensity of prophylaxis is required to augment the manifestations of GVHD.

Aim. To comparatively analyze myelofibrosis treatment outcomes with the use of ruxolitinib versus ruxolitinib with subsequent allogeneic hematopoietic stem cell transplantation (allo-HSCT) as well as to assess the efficacy of ruxolitinib in pre- and post-transplantation periods. Materials & Methods. The study enrolled 78 myelofibrosis patients who were referred to the RM Gorbacheva Scientific Research Institute to determine the indications for allo-HSCT. Allo-HSCT was performed in 33 patients, among them 32 patients with ruxolitinib pre-conditioning (ruxolitinib + allo-HSCT group). They received reduced intensity conditioning (fludarabine 180 mg/m² and busulfan 10 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclophosphamide 50 mg/kg on Day +3 and Day +4, ruxolitinib 10 mg per day from Day +5 to Day +100 (n = 31), rabbit antithymocyte globulin, tacrolimus, and mycophenolate mofetil (n = 2). Ruxolitinib without allo-HSCT was administered to 45 patients (ruxolitinib group). Between the groups there were no significant differences with respect to gender, age, diagnosis, and molecular genetic variant. Results. Median therapy duration in ruxolitinib group was 16 months (range 2-78 months). In 2 (4 %) patients partial response was achieved, 8 (20 %) patients showed clinical improvement, in 16 (39 %) patients stable disease (SD) was reported, in 15 (37 %) patients disease progression (DP) was detected. The treatment succeeded in reducing the spleen size in 8 (20 %) patients and in relieving disease symptoms in 16 (39 %) patients. Cumulative incidence of progression within 3 years was 44 % (95% confidence interval [95% CI] 27-60 %). In ruxolitinib + allo-HSCT group median ruxolitinib therapy duration was 7 months (range 3-22 months). As a result, clinical improvement in 9 (28 %) cases, SD in 17 cases (53 %), and DP in 6 (19 %) cases were observed. In 5 (20 %) patients acute GVHD of grade 2-4, in 3 (12 %) patients acute GVHD of grade 3-4, and in 6 (24 %) patients chronic medium severity GVHD were identified. Within 1 year nonrelapse mortality was 28 % (95% CI 14-44 %). The 3-year cumulative incidence of relapse was 12 % (95% CI 3-28 %) in ruxolitinib + allo-HSCT group. According to the landmark analysis performed throughout 6 months from the first visit to the center, the 3-year overall survival in the group with allo-HSCT was 80 %, whereas in ruxolitinib group it was 41 % (p = 0.022), 12-month landmark analysis resulted in 77 % and 43 % (p = 0.028), and 18-month landmark analysis showed 86 % and 46 % (p = 0.015) in two groups, respectively. Conclusion. Despite the efficacy of JAK1/2 inhibitor ruxolitinib, the risk of myelofibrosis progression is not to be underestimated. Therefore, in DIPSS intermediate-2 and high-risk patients the issue about performing allo-HSCT should be promptly clarified.

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