European Journal of Haematology

REVIEW ARTICLE

How we manage JAK inhibition in allogeneic transplantation for myelofibrosis Tarah J. Ballinger1, Bipin N. Savani1,2, Vikas Gupta3, Nicolaus Kroger4,5, Mohamad Mohty6,7,8 1

Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; 2Department of Hematology/Oncology, Vanderbilt University Medical Center, Nashville, TN, USA; 3The Elizabeth and Tony Comper MPN Program, Princess Margaret Cancer Center, Toronto, ON, Canada; 4 Department of Stem Cell Transplantation, University Medical Center, Hamburg, Germany; 5Chronic Malignancies Working Party of EBMT, ^pital Saint-Antoine, AP-HP, Paris; EBMT study office, Paris, France; 6Service d’Hematologie Clinique et Therapie Cellulaire, Ho 7 University Pierre & Marie Curie, Paris; 8INSERM, UMRs 938, Paris, France

Abstract Hematopoietic stem cell transplantation (HCT) is currently the only curative treatment for myelofibrosis (MF), but this option is complicated by high incidences of associated morbidity and mortality. Ruxolitinib, a janus-activated kinase (JAK) 1/2 inhibitor, has proven to be beneficial in reduction of splenomegaly, improvement of constitutional symptoms, and possibly in overall survival. However, use of JAK inhibitors in the peritransplant period has been complicated by unpredictable response, return of MF symptoms or cytokine storm reaction upon discontinuation, and lack of long-term response data. This review considers the current limited available data on JAK inhibitor use prior to HCT, including common side effects and possible impact of severe adverse events on discontinuation of the drug. We provide our experience and recommendations regarding use of JAK inhibition in patients undergoing HCT. Additional studies are needed to determine the optimal schedule of JAK inhibitors in the transplant protocols and their impact on engraftment, graft-versus-host disease, and survival. Key words Myelofibrosis; transplantation; JAK inhibitors; complications Correspondence Bipin N. Savani, MD, Hematology and Stem Cell Transplantation Section, Vanderbilt University Medical Center and VAMC, 3927 Vanderbilt Clinic, Nashville, TN 37232-5505, USA. Tel: +1 615 343-5374; Fax: +1 615 936-1812; e-mail: bipin.savani@ vanderbilt.edu Accepted for publication 22 September 2014

Primary myelofibrosis (PMF) or postpolycythemia/essential thrombocythemia myelofibrosis (post-PV/ETMF) are chronic hematologic malignancies characterized by bone marrow fibrosis, leukoerythroblastosis, constitutional symptoms, and hepatosplenomegaly, with a median life expectancy less than 5 yr for patients with intermediate-2 or high-risk disease according to the recent prognostic scoring systems (1–4). The pathogenesis of the disease involves a clonal proliferation driven by the janus-activated kinase–signal transducer and activator of transcription (JAK-STAT) pathway and a cytokine-mediated inflammatory state that results in ineffective hematopoiesis. Allogeneic hematopoietic stem cell transplantation (HCT) is a curative option for MF; however, few transplants are performed for MF due to the rarity of the disease, concerns related to high mortality, and an older age of patients (5).

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

doi:10.1111/ejh.12455

Ruxolitinib (Jakifi, Incyte/Jakavi; Novartis) is a JAK1/2 inhibitor approved for disease-related symptoms and splenomegaly in intermediate- or high-risk MF in the USA, and irrespective of disease status in Europe. Its use has been proven to reduce spleen size, decrease constitutional symptoms, and have a potential positive impact on survival (6). These benefits are seen regardless of JAK2 mutational status, due to an anti-JAK1-mediated effect that reduces the pro-inflammatory state and cytokine dysregulation that are keys to the pathogenesis of MF (7). In terms of HCT for MF, splenomegaly has been shown to have a negative impact on engraftment and graft function, while constitutional symptoms are a source of morbidity and mortality that can reduce a patient’s chance to undergo transplantation (8, 9). In addition, downregulation of inflammatory cytokines (IL-6, IL-1ra, MIP-1b, TNF-a, and CRP) and modulation of T-cell

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How we manage JAK inhibition

response seen with JAK inhibition use may reduce the incidence of graft-versus-host disease (GVHD) after transplant, a significant cause of morbidity and mortality (10). For these reasons, it has been hypothesized that there may be additional benefits to pretransplant therapy with JAK1/2 inhibitors. However, the use of these inhibitors remains complicated by unpredictable response, return of MF-related symptoms upon their discontinuation, and lack of long-term data regarding their use. Some initial studies of ruxolitinib showed that the majority of patients experienced flares of acute symptoms and worsening splenomegaly on discontinuation of the drug, while 11% had severe side effects on withdrawal that required hospitalization (11). Complications

on withdrawal of ruxolitinib in the transplant setting included cardiogenic shock, tumor lysis syndrome, and severe GVHD, likely due to cytokine release reactions (12). Studies are ongoing to clarify the risks, benefits, and appropriate methods for use of ruxolitinib in the peritransplant setting. Therapeutic concern and management

Limited reported data illustrate complications in the peritransplant period that may be attributable to discontinuation of ruxolitinib resulting in cytokine storm reaction and a dysregulated inflammatory response (Table 1) (12–16). Preliminary

Table 1 Summary of studies assessing the effects and outcomes of pretransplant ruxolitinib in MF patients Publication

Study design

Results

Conclusion

Robin et al. ASH abstract, 2013 (12)

22 Patients started on ruxolitinib and planned for HCST with the primary end point of DFS at 1 yr. Ruxolitinib was tapered and discontinued prior to conditioning

Shanavas et al. BMT, 2014 (17)

27 Patients received F, BU, and TBI conditioning prior to HSCT to assess engraftment and NRM. Six patients on ruxolitinib prior to HSCT were tapered up until conditioning

-10 Patients discontinued ruxolitinib -7 Developed SAEs (3, cardiogenic shock; 3, TLS) -2 Deaths due to severe GVHD -SAEs continued even with drug taper and prophylaxis -No patients with unexpected SAE -1/6 patients died post-transplant due to chronic GVHD -No increased incidence of GVHD -4/4 patients with CMV reactivated their disease

SAEs on ruxolitinib withdrawal prior to HSCT conditioning were unexpected and should inform future study design. Enrollment was closed, current trial design being modified and study is now again in recruitment (NCT01795677) Tapering ruxolitinib until conditioning did not result in any unexpected SAEs or increase in GVHD

Jaekel et al. BMT, 2014 (13)

14 Patients with prior exposure to ruxolitinib (median 6.5 months) undergo HSCT to assess ruxolitinib’s impact on HCST outcomes

-No patients with unexpected SAE -1/14 patients died of treatmentrelated sepsis -1 graft failure (7%) -2 patients with acute GVHD (14%)

Tapering ruxolitinib until conditioning did not result in any unexpected SAEs on drug withdrawal. Ruxolitinib prior to HSCT may have favorable impact on prognosis, engraftment, and GVHD

Stubig et al. Leukemia. 2014 (14)

22 Patients received ruxolitinib prior to HSCT to assess ruxolitinib impact on early post-transplant outcomes. Ruxolitinib was continued until conditioning in 82% of patients

Continuing ruxolitinib until conditioning without tapering did not result in any unexpected SAEs on drug withdrawal and may have a positive impact on graft survival. Survival was improved for patients who responded to ruxolitinib, compared with those who did not

Lebon et al., ASH abstract, 2013 (16)

11 Patients received ruxolitinib prior to HSCT, with different strategies for discontinuation (tapered n = 3, not tapered n = 4)

-4 Patients discontinued ruxolitinib early due to cytopenia or lack of response -No unexpected SAEs -No graft failures -4 Deaths (sAML, CMV, liver failure, and acute GVHD) -1-yr OS improved for patients who had good response to ruxolitinib (100% vs. 60%, P = 0.02) -No difference in T-cell counts at day 100 -8 Patients with spleen size reduction > 25% -No graft failures, all patients with neutrophil engraftment on median day + 17 -5 Patients developed acute GVHD, 1 patient died as a result

Ruxolitinib was well tolerated prior to HSCT, despite differing discontinuation strategies, and resulted in excellent engraftment rates

MF, myelofibrosis; SAE, severe adverse event; TLS, tumor lysis syndrome; GVHD, graft, versus, host disease; HSCT, hematopoietic stem cell transplantation; NRM, non, relapsed mortality; CMV, cytomegalovirus; sAML, secondary acute myeloid leukemia; OS, overall survival; TBI, total body irradiation.

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© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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reports from the JAK ALLO trial of ruxolitinib prior to HCT included ten patients who discontinued ruxolitinib, seven of whom developed life-threatening adverse events, and two who died within 21 d after drug withdrawal. These unexpected events included cardiogenic shock, tumor lysis syndrome, and rare cases of severe GVHD (limited data). The study protocol was amended to tapering ruxolitinib over a short period with the concomitant addition of steroids and tumor lysis prophylaxis, but these adverse events continued to be observed (12). In a study performed by Shanvanas et al. of fludarabine, busulfan, and low-dose TBI conditioning, six patients were taking a JAK1/2 inhibitor and underwent a tapering strategy over the 5–6 d prior to transplant, with the last dose received 24 h prior to initiation of the conditioning regimen. No adverse events or increase in the incidence of GVHD was observed on discontinuation of JAK inhibition (17). In a study by Jaekel et al. of 14 patients who received

How we manage JAK inhibition

HCT following treatment with ruxolitinib, the drug was tapered over approximately 2 wk and continued up until initiation of conditioning. Only one patient died as a result of treatment-related septic shock, and no unexpected adverse events were observed. There is typically a high graft failure rate among MF patients, but in this study, only one graft failure occurred. This improvement may be due to the low sample size of 14 patients, but can likely be explained by the downregulation of cytokines seen with ruxolitinib therapy. In a study by Stubig et al., 22 patients with intermediate- or high-risk MF being treated with ruxolitinib underwent HCT. Four of these patients discontinued ruxolitinib greater than 28 d prior to transplant, but interestingly no adverse events were seen. The remainder of patients continued the drug until conditioning and no withdrawal effect was reported. Engraftment was seen at an average of 15 d after transplant, and GVHD was seen in 36% of patients. Numbers in this study

Table 2 Potential beneficial and detrimental effects of JAK1/2 inhibitors in the transplant setting Potentially beneficial effects

Potentially detrimental effects

Improvement in performance status JAK1/2 inhibitor therapy has potential to improve the pre-HCT performance status by effective control of MF-related symptom burden (6, 22) Several transplant studies have shown a relationship of better performance status with improved survival after transplant (24)

Withdrawal effect If stopped suddenly prior to HCT, it can cause rapid return of MFrelated symptoms. Therefore, the drug should be continued until initiation of conditioning. Thus far, it is not clear whether abrupt discontinuation upon start of conditioning vs. gentle tapering is preferred

Reduced splenomegaly Reduced spleen size may help in faster hematological recovery (17)

May delay hematopoietic recovery Myelosuppressive properties of JAK inhibitors may have impact of hematological recovery after HCT and may also limit the use of JAK inhibitor therapy in the post-HCT setting May increase risk of infections Increase in infection has been shown in the non-transplant setting, but a higher risk of infection after HCT has not been reported so far Increased risk of urinary tract infections and zoster infection with JAK1/2 inhibitor therapy in comparison with placebo or other available treatments (6, 22) Anecdotal case reports of opportunistic infections such as reactivation of hepatitis, mycobacterial infections, and invasive fungal infections have raised concerns of opportunistic infections with JAK inhibitor therapy (20) May decrease GVL effect Impaired function of NK cells and dendritic cells (18) Drug–drug interactions Due to CYP3A4 inhibition, potential of significant drug interactions with routine transplant medications such as calcineurin inhibitors and antifungal medications However, the elimination half-life of ruxolitinib is 2.8–3 h (4–5 h in hepatic impairment). Therefore, if ruxolitinib is stopped about 7 d prior to transplant effect of calcineurin inhibitors, drug interaction is unlikely Potential of tumor lysis syndrome Cases of tumor lysis syndrome reported in a recent prospective study (11), not clear whether ruxolitinib may cause chemo-sensitization to drugs used in conditioning therapy. Therefore, TLS prophylaxis is suggested with conditioning therapy

Potential decrease in GVHD JAK1/2 inhibitor therapy has recently been shown to be effective in reducing the risk of GVHD in a mouse model by inhibiting donor T-cell expansion and inflammatory cytokine production (10) Beneficial effect also demonstrated on 6 patients with steroid refractory GVHD (10)

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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were small, but it was suggested that patients had improved survival when a better response to ruxolitinib was seen in terms of spleen size prior to transplant (14). Ruxolitinib is not a specific inhibitor of JAK2 and also inhibits JAK1, phosphatidylinositol-3 kinase, and other kinases, which may cause additional side effects. The cytokines inhibited by ruxolitinib are necessary for the pathogenesis of MF and therefore make the drug effective, but these cytokines are also necessary for the development and function of important immune cells. A study by Schonberg et al. showed a significant and dose-dependent effect on natural killer (NK) cell activation. This may have clinical implications given the impact of NK cells on the pathogenesis of GVHD (18). In addition, ruxolitinib has been shown to inhibit in vitro and in vivo dendritic cell activation, migration, and antigen-specific T-cell response, in a dose-dependent fashion (19, 20). Dendritic cells function as antigen-presenting cells and prime T cells for an immune response; therefore, their inhibition may result in an increased propensity for infection, particularly viruses. Notably, in the study by Shanvanas et al., four patients who were cytomegalovirus (CMV)-positive developed reactivation of their disease on discontinuation of ruxolitinib (17). Stubig et al. found a decrease in regulatory T cells in patients taking ruxolitinib prior to transplant, but did not note a difference in the number of CD3+, CD4+, or CD8+ T-cell reconstitution after transplant, compared with those who did not receive ruxolitinib (19). Due to this non-selective inhibition, studies are ongoing to determine the efficacy of selective JAK2 inhibitors that may carry less adverse side effects (15, 21). The major side effect of ruxolitinib is a worsening of thrombocytopenia and anemia; therefore, the dose is typically based on platelet counts as follows: 20 milligrams (mg) twice daily if platelets are >200 000/mm3, 15 mg twice daily if platelets are between 100 000 and 200 000/mm3, and 10 mg twice daily if platelets are

How we manage JAK inhibition in allogeneic transplantation for myelofibrosis.

Hematopoietic stem cell transplantation (HCT) is currently the only curative treatment for myelofibrosis (MF), but this option is complicated by high ...
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