Results
After the first 3 months of ruxolitinib therapy the spleen volume decreased in 9 out of the 10 cases by 9.1 – 67.5% (M = 35.4%) compared to the initial size (р = 0.003). The difference in size was 180 сm3 (SD +/- 146 сm3) on average. In the interval from 3 to 6 months after therapy start the spleen volume was reduced in 7 out of the 10 patients by 2.5 – 44.9% (M = 17.6%, р = 0.811). In 2 cases (Pt 2 and 3) the spleen volume increased by 43.9% and 18.3% respectively after reducing the dose of ruxolitinib due to infection. In patient 4 ruxolitinib was discontinued 5 months after therapy start and the spleen volume increased by 90% in one month virtually returning to the initial size. Therefore, the maximum effect in the spleen volume reduction was achieved after the first 3 months of ruxolitinib therapy. Differences in the spleen volume at the interval from 0 to 3 months and from 3 to 6 months after therapy start are shown on Fig. 1.
The sTfR concentration decreased in 9 out of the 10 patients by 15.6 – 77.7% (М = 49%, р = 0.011) after the first 3 months of ruxolitinib therapy and continued to decrease thereafter in between 3 to 6 months of therapy start in 6 of them by 3.9 – 68.9% (М = 37.3%, р = 0.411) reflecting IE suppression (Fig. 2).
The RBC transfusion volume (ml/kg) required to maintain Hb at 110 - 120 g/L compared to baseline decreased in line with reduction of the spleen volume. After first 3 months of ruxolitinib therapy the RBC transfusion volume was reduced by 16.7 – 54.8% (M=37.5%) compared to the initial volume (р = < 0.001), and 3 months later it decreased in 9 out of the 10 patients by 8.3 – 36.0 % (M = 20.4%, р = 0.025) (Fig. 3).
Before ruxolitinib therapy start the relative erythrocyte progenitor count in bone marrow was on average 4.7-fold higher for proerythroblasts and 1.6-fold higher for erythroblasts compared to normal. The erythrocyte progenitor count tended to decline after the first 3 months of taking ruxolitinib, which was consistent with the reduction of the spleen volume and the sTfR concentration. More specifically the proerythroblast (CD45-/CD71+/CD117+) count was reduced in 5 out of the 9 cases by 17.5 – 67.5% (M = 40.6%, р = 0.910) and the erythroblast (CD45-/CD71+/CD235+) count was reduced in 7 out of the 9 cases by 13.1 – 56.8% (М = 26,4%, р=0.313) (Fig. 4).
AE probably related to ruxolitinib were observed in 9 out of the 10 patients, mainly grade II - III in severity. Stomatitis, herpes labialis, respiratory tract infections or furunculosis were present in the 7 cases; thrombocytopenia (the minimum platelet count was 75 x 109/L) – in one case; one patient had a headache. All AE resolved after ruxolitinib dose reduction by 30-50%.
At the time of analysis eight patients have undergone HSCT from allogeneic donors. Primary engraftment occurred in 7 out of the 8 cases. One patient (3) experienced primary graft failure, then rejected second graft from another 9/10 HLA-compatible MUD, and achieved engraftment after third transplant from an HLA-haploidentical parent. In one patient (Pt 7), long-lasting thrombocytopenia occurred and was successfully managed with romiplostim.
One patient (Pt 5) developed moderately severe veno-occlusive disease of liver, which resolved with defibrotide treatment, one patient (Pt 9) had acute graft-versus-host disease (GVHD) stage IV (gastrointestinal tract and liver - grade IV, skin – grade II). Details of transplant procedure and outcomes are reported in Table 1.
All patients are currently alive. Two out of the 10 patients (Pt 2 and 4), who have not received HSCT due to the lack of a compatible donor, discontinued ruxolitinib therapy after 6 and 5 months, respectively, and the clinical features of IE almost returned to baseline.