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In patients with primary and secondary myelofibrosis (MF), allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment, but it is associated with high rates of non-relapse mortality, early relapse, and primary graft failure (PGF).
Graft-versus-host disease (GvHD) represents one of the most common causes of death after allo-HSCT. Post-transplant cyclophosphamide (PTCy) has demonstrated to be effective for GvHD prevention in both haploidentical transplants and in matched unrelated transplants. For allo-HSCT in MF, peripheral blood stem cells represent the most appropriate stem cell source and PTCy is usually combined with a second agent, such as a calcineurin inhibitor or mycophenolate mofetil, which increase the rate of infections and reduce the graft-versus-leukemia effect.
Ruxolitinib is a Janus kinase (JAK) 1/2 inhibitor approved for both, the treatment of steroid-refractory acute GvHD (aGvHD) and MF. In addition, preclinical studies suggested that it may not impact on the graft-versus-leukemia effect.
In a study published in Acta Haematologica, Elena Vladislavovna Morozova and colleagues evaluated the combination of ruxolitinib and PTCy, as GvHD prophylactic regimen, in patients with primary or secondary MF who underwent allo-HSCT.1
Treatment
Methods
The primary endpoint of the study was the incidence of aGvHD Grade 2–4 and chronicmoderate and severe GvHD. Secondary endpoints were overall survival and event-free survival, incidence of relapse, PGF, and SPGF.
This prospective study (NCT02806375) enrolled 20 patients with primary MF, post-essential thrombocythemia, and post-polycythemia vera MF. Patient characteristics are reported in Table 1.
Table 1. Patient characteristics1
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; DIPSSplus, dynamic international prognostic scoring system plus; HCT-CI, Hematopoietic Cell Transplantation Co-morbidity Index; MF, myelofibrosis; PMF, primary myelofibrosis; Post-ET-MF, post-essential thrombocythemia MF; Post-PV-MF, post-polycythemia vera MF. |
|
Characteristics |
Patients (N = 20) |
---|---|
Age, years (range) |
51 (32–64) |
Diagnosis, n (%) PMF Post-PV-MF Post-ET-MF |
14 (70) 3 (15) 3 (15) |
Risk profile according to DIPSSplus, n (%) Intermediate-1 Intermediate-2 High Blast crisis |
2 (10) 14 (70) 4 (20) 0 |
Palpable spleen size at transplant, n (%) ≥ 10 cm < 10 cm Splenectomy |
6 (30) 7 (35) 7 (35) |
Median time between splenectomy and allo-HSCT, months (range) |
2.60 (0.17–4.50) |
Fibrosis grade before allo-HSCT, n (%) MF-2 MF-3 |
8 (40) 12 (60) |
Mutational status, n (%) JAK2 V617F-positive CALR-positive MPL Triple negative |
13 (65) 4 (20) 2 (10) 1 (5) |
Karyotype, n Normal t(6;11) (p25;q12) del(13q21) Trisomy 8 Unknown |
14 1 1 3 1 |
Median time of ruxolitinib therapy before allo-HSCT, months (range) |
7.4 (3.0–22.0) |
Response status at the moment of allo-HSCT, n (%) Clinical improvement Stable disease Progression |
7 (35) 12 (60) 1 (5) |
HCT-CI, n (%) 0 1 2 3 |
10 (50) 6 (30) 3 (15) 1 (5) |
СD34+ cells/kg × 106, median (range) |
6.9 (1.4–12.0) |
Donor, n (%) HLA-identical sibling Haploidentical
Unrelated HLA-matched HLA-mismatched 9/10 |
3 (15) 4 (20)
11 (55) 2 (10) |
Stem cell source, n (%) Bone marrow Peripheral blood |
1 (5) 19 (95) |
After a median follow-up of 27 months (1–51):
Toxicity
Observed toxicities are reported in Table 2.
Table 2. Toxicity1
Toxicity |
Patients, n (%) |
---|---|
Veno-occlusive disease None Mild |
19 (95) 1 (5) |
Sepsis |
7 (35) |
Invasive mycosis |
1 (5) |
Viral reactivation or infection |
9 (45) |
Viral hemorrhagic cystitis |
3 (15) |
Primary endpoint: Incidence of GvHD
The incidence of GvHD was the following:
Calcineurin inhibitors were used as a first-line therapy in six patients while two patients required systemic steroid therapy. GvHD-related mortality was reported in one case.
Secondary endpoints
This study showed that the combination of PTCy and ruxolitinib was well tolerated and provided a promising control of GvHD rates associated with stable ruxolitinib plasma concentration. However, the high incidence of SPGF and the relatively long median time to the leukocyte and platelet engraftment may require ruxolitinib dose adjustments. Relapse rates in this study were low, with no early relapses reported. In addition, there were no episodes of severe nephrotoxicity and a low rate of veno-occlusive disease was observed, which compares favorably with calcineurin inhibitors.
Despite the small sample size, these promising results prompted the initiation of a multicenter randomised phase II trial, which will compare PTCy + ruxolitinib with conventional PTCy + tacrolimus + mycophenolate mofetil prophylaxis in patients with acute leukemia undergoing unrelated and haploidentical transplantation.
References
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