For most patients with intermediate or high-risk diseases, allogeneic haematopoietic stem cell transplantation (SCT) is potentially the only curative treatment, although it is associated with a risk of transplant-related mortality (Kröger et al, 2015; Shantzer et al, 2017). Ruxolitinib, a potent JAK1/JAK2 inhibitor, is recommended for the relief of constitutional symptoms and splenomegaly in patients who are ineligible for allogeneic SCT (Marchetti et al, 2017). Ongoing studies further demonstrated improved allogeneic SCT outcomes in patients who were previously treated with ruxolitinib (Gupta et al, 2019). However, the role of ruxolitinib in post-SCT maintenance has not been illustrated. We report the data from a retrospective study that evaluated the feasibility and toxicity of ruxolitinib as both pre-SCT treatment and post-transplant maintenance regimens in allogeneic SCT for myelofibrosis.
The patients were grouped into 3 cohorts (A, B, C): 3 patients in Cohort A never received ruxolitinib, 9 Patients in Cohort B only received pre-SCT ruxolitinib and 4 patients in Cohort C received both pre-SCT and post-SCT ruxolitinib. All patients had constitutional symptoms and splenomegaly at diagnosis, except for 1 patient who had prior splenectomy. The median post-SCT follow-up time was 36.5 months (range: 18-72 months). Pre-SCT ruxolitinib doses were titrated from 10 to 20 mg twice daily and tapered off from 5 days before starting conditioning. The post-SCT dose was 5 mg twice daily, starting after the absolute neutrophil count (ANC) reached 0.5 × 109/l for 3 consecutive days. The median duration of ruxolitinib treatment pre-SCT was 8 months (range 5-20), whilst that of ruxolitinib maintenance post-SCT was 20 months (range 4-32).
Of 16 patients, 10 received SCT from a matched unrelated donor, 5 received SCT from a matched sibling donor and 1 received a haplo-identical SCT. Detailed conditioning regimen information is available in the Supplementary Appendix. Patient characteristics are summarized in Table I.
Table I.
Patient Characteristics
| Cohort | |||
|---|---|---|---|
| Baseline Characteristics | A (n = 3) | B (n = 9) | C (n = 4) |
| Mean age at SCT (years) | 54.3 | 63 | 57.8 |
| Gender (n) | |||
| Male | 3 | 5 | 3 |
| Female | 0 | 4 | 1 |
| ECOG PS at diagnosis (n) | |||
| 0 | 2 | 5 | 0 |
| 1 | 1 | 4 | 1 |
| 2 | 0 | 0 | 1 |
| 3 | 0 | 0 | 2 |
| Medical comorbidities (n) | |||
| 0 | 1 | 1 | 1 |
| 1-3 | 1 | 4 | 2 |
| >3 | 1 | 4 | 1 |
| Cytogenetic abnormalities (n) | |||
| Trisomy 8 | 0 | 0 | 1 |
| Del(12p) | 0 | 0 | 1 |
| Del(13q) | 0 | 1 | 0 |
| Trisomy 1q | 0 | 1 | 0 |
| Complex karyotype | 1 | 1 | 0 |
| JAK2 V617F mutated | 3 | 7 | 3 |
| Prior treatment (n) | |||
| Hydroxycarbamide | 0 | 2 | 0 |
| Lenalidomide + prednisone | 2 | 0 | 0 |
| Sirolimus | 0 | 0 | 1 |
| Eltrombopag | 0 | 0 | 1 |
| SCT conditioning regimen (n) | |||
| Flu/Bu | 2 | 8 | 4 |
| Flu/Bu/TBI | 0 | 1 | 0 |
| Bu/Cy | 1 | 0 | 0 |
Bu: busulfan; Cy: cyclophosphamide; ECOG PS: Eastern Cooperative Oncology Group performance status; Flu: fludarabine; n: number of patients; SCT: stem cell transplantation; TBI: total body irradiation
Molecular and cytogenetic mutation studies were performed on bone marrow aspiration samples of all patients via fluorescence insitu hybridisation (FISH) and/or polymerase chain reaction-based assay. The cohorts had a similar JAK2 V617F mutation occurrence incidence with 3/3 (A), 7/9 (B) and ¾ (C) respectively. One patient each in Cohorts A and B harboured an unfavourable complex karyotype; 2 patients in Cohort B harboured sole favourable karyotypes (13q- or +1); and 2 patients in Cohort C harboured sole unfavourable karyotypes (+8 or 12p-).
Both pre-SCT and post-SCT bone marrow specimens were stringently analysed, except for 3 patients who did not have bone marrow evaluation following transplant at the time of data analysis. Details of the specimen review are available in the Supplementary Appendix. Myelofibrosis grades were assigned based on World Health Organization Classification (Swerdlow et al, 2008). All patients had similar pre-SCT bone marrow myelofibrosis profiles (all patients graded 2 to 3, P=1.000). However, post-SCT bone marrow recovery from myelofibrosis in Cohort C (all 4 patients graded from 0 to 1) was significantly superior to Cohorts B (4 patients in grade 1, 2 in grade 2, and 1 in grade 3) and A (1 each in grade 2 and 3) (P=0.053).
The median times for achieving engraftment, splenomegaly reduction and transfusion independence are summarised in Table II.
Table II.
Patient outcomes
| Cohort | P - value | |||
|---|---|---|---|---|
| A (n = 3) | B (n = 9) | C (n = 4) | ||
| MF Grade (WHO) Pre-SCT (n) | ||||
| 3 | 2 | 5 | 2 | 1.000 |
| 2 | 1 | 4 | 2 | |
| 1 | 0 | 0 | 0 | |
| 0 | 0 | 0 | 0 | |
| MF Grade (WHO) Post-SCT (n) | ||||
| 3 | 1 | 1 | 0 | 0.053 |
| 2 | 1 | 2 | 0 | |
| 1 | 0 | 4 | 1 | |
| 0 | 0 | 0 | 3 | |
| Incidence of GVHD (n) | ||||
| Acute | 3 Grades I-III | 4 Grades I-II | 0 | 0.0365 |
| Chronic | 1 Grade III | 4 Grades I-II | 4 Grades I-II | 0.1692 |
| Incidence of transplant related infection (n) | ||||
| Bacterial | 2 | 4 | 1 | 0.8017 |
| Viral | 3 | 3 | 2 | 0.2559 |
| Fungal | 0 | 3 | 0 | 0.3571 |
| Reduction in spleen size post –SCT (%) | 17 (12-24) | 11 (16-40) | 32 (20-38) | 0.3737 |
| Time to ANC > 0.5 × 109/l (days) | 17 (13-18) | 15 (12-19) | 12.5 (12-16) | 0.2308 |
| Time to platelet count > 100 × 109/l (days) | 150 (118-198) | 152 (109-243) | 106 (94-138) | 0.5988 |
| Time to transfusion independence (days) | 148 (118-540) | 120 (110-510) | 165 (108-270) | 0.5599 |
| Degree of response at time of last follow-up (n) | ||||
| Overall Response | 0 | 4 | 4 | 0.0378 |
| Complete Response | 0 | 2 | 4 | 0.0087 |
| Partial Response | 0 | 2 | 0 | 1.00 |
| Stable Disease | 2 | 5 | 0 | 0.1692 |
| Progressive Disease | 1 | 0 | 0 | 0.1875 |
Values shown are median (range) or number of patients.
ANC: absolute neutrophil count; GVHD: graft-versus-host disease; MF: myelofibrosis; n: number of patients; SCT: stem cell transplantation; WHO: World Health Organization.
All 3 Cohort A patients experienced viral infections before day 100, including disseminated herpes zoster, cytomegalovirus (CMV) and Epstein–Barr virus viraemia; 2 experienced vancomycin-resistant Enterococcus bacteraemia, and none of them developed a fungal infection. In Cohort B, 3 experienced viral as well as fungal infections including aspergillus pneumonia, CMV colitis and BK cystitis. There were 4 patients who experienced bacterial infections including Clostridium difficile colitis, methicillin-susceptible Staphylococcus aureus bacteraemia, and Klebsiella bacteraemia. Among patients in Cohort C, 2 experienced viral infections with herpes zoster and CMV viraemia, and 1 experienced C. diff colitis. There were no fungal infections observed in cohort C.
Most incidences of acute graft-versus-host disease (GVHD) involved the skin, followed by gut and liver. Most incidences of chronic GVHD involved the skin, followed by eyes, liver and gut.
Patient response criteria were adopted from the revised International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report (Tefferi et al, 2013). All patients were still alive at last data collection. Two of the 3 patients in Cohort A were in stable condition, while 1 had disease progression. In Cohort B, 2 achieved a complete response, 2 a partial response and 5 had stable disease. All 4 patients in Cohort C achieved a complete response at a median of 11.5 months.
Mounting evidence indicated ruxolitinib could shorten the neutrophil engraftment time and reduce GVHD burden via regulation of T cells and cytokine signal transduction pathway (Kröger et al, 2018; Spoerl et al, 2014). However, ruxolitinib-induced cytopenia and CMV reactivation appeared to be a problem (Zeiser et al, 2015). In the present study, Cohort C showed a superior acute GVHD profile (0/4) in comparison to Cohorts A (3/3) or B (4/9) (P=0.0365) without significant side effects. Therefore, our ruxolitinib management schedule could be a novel approach for GVHD prophylaxis.
This study demonstrated that continuation of ruxolitinib as a maintenance therapy following SCT is a safe and tolerable approach with no significant toxicity. With respect to the measured outcomes, Cohort C achieved a greater spleen size reduction, better fibrosis resolution and rapid engraftment in comparison to Cohorts A and B. The significant spleen size reduction might, to some extent, explain the better platelet count recovery observed in Cohort C. According to the revised IWG-MRT response criteria (Tefferi et al, 2013), the patients in Cohort C achieved a superior treatment response than the other two cohorts though it took slightly longer time to achieve transfusion independence, which might be caused by ruxolitinib-induced bone marrow suppression.
This study is the first investigation comparing different ruxolitinib management approaches in patients undergoing allogeneic SCT. Our data demonstrate improved outcomes in patients receiving ruxolitinib both pre- and post-SCT. This study postulates that ruxolitinib maintenance post-SCT is safe and improves SCT outcomes. A large-scale prospective study is needed to determine whether this approach can be implemented in daily practice.
Supplementary Material
Acknowledgements
This study is supported by: NIDA/FDA research grant to JJP (P50 DA036107), AA and MDSIF research grant to JJP (146818), American Cancer Society research grant to JJP (124171-IRG-13-043-02), Paige’s Cancer Researcher Fund to JJP (Pu33860), and a SUNY Upstate Medical University research grant to JJP.
Footnotes
Conflict-of-interest disclosure: JJP was a faculty member of Incyte Speaker Bureau; the other authors declare no competing financial interests.
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