Allogeneic hematopoietic stem-cell transplantation for myelofibrosis

Introduction

Myelofibrosis (MF) is a Philadelphia chromosome (Ph)-negative myeloproliferative neoplasm, characterized by bone marrow fibrosis, leukoerythroblastosis in blood, extramedullary hematopoiesis, splenomegaly, constitutional symptoms, and an increased risk of transformation to acute myeloid leukemia (AML). The disease can arise de novo as primary MF (PMF) or evolve from polycythemia vera (post PV-MF), or essential thrombocythemia (post ET-MF). It primarily affects the elderly, with a median age at diagnosis of 67 years. ¹ Though Janus kinase (JAK) inhibitors have broadened the treatment options in MF, allogeneic hematopoietic stem-cell transplantation (AHSCT) remains the only known curative therapy. In this review, we describe the available data and summary current recommendations on transplantation for myelofibrosis.

Prognosis and risk stratification

The clinical course of MF is heterogeneous, ranging from an indolent course persisting for decades to rapidly progressive disease with a survival of a few months. Prognosis is currently assessed by the International Prognostic Scoring System (IPSS) at diagnosis, which incorporates the following five risk factors: age (>65 years), anemia (hemoglobin <10 g/dl), leukocyte count (>25 × 10⁹/l), circulating blasts (⩾1%), and constitutional symptoms. ² The presence of 0, 1, 2, and ⩾3 factors are categorized as low, intermediate-1, intermediate-2, and high-risk disease, with median survival of 135, 95, 48, and 27 months, respectively. The Dynamic International Prognostic Scoring System (DIPSS) uses the same risk factors as the IPSS, but more weight is assigned to anemia, and it allows for prognostic prediction at any time during the disease course. ³ DIPSS was later refined as DIPSS-plus with inclusion of three additional risk factors: transfusion dependence, platelet count <100 × 10⁹/l, and unfavorable karyotype. ⁴ For patients with post-PV/ET MF, the MF secondary to PV, and ET prognostic model (MYSEC-PM) has been defined and validated for risk stratification.^5–7 This new score assigns 2 points to hemoglobin level <11 g/dl, circulating blasts ⩾3% and CALR-unmutated genotype, 1 point to platelet count <150 × 10⁹/l and constitutional symptoms, and 0.15 points to any year of age. Patients are allocated into four risk categories with different survival: low (median survival not reached), intermediate-1 (9.3 years), intermediate-2 (4.4 years), and high (2 years) risk. Very recently, a large study confirmed that the MYSEC-PM allowed a more accurate prediction of survival after AHSCT than the DIPSS for post-PV/ET MF. ⁸

Molecular risk stratification

JAK2, CALR, and MPL are considered mutually exclusive driver mutations in MF. In general, CALR mutated patients are of younger age, with higher platelet counts and lower leukocyte counts, and have a favorable overall survival (OS).^9,10 MPL does not seem to be prognostically relevant. ¹¹ The prognosis impact of JAK2V617F in MF remains controversial. Some studies found JAK2 mutated patients had inferior survival ¹² and a higher risk of leukemic transformation (LT) ¹³ ; however, others did not observe such an impact.^14,15 Besides, about 10% of MF patients have JAK2/CALR/MPL triple-negative disease,^16,17 and usually have the worst prognosis.^9,10

In addition, several researchers found ASXL1, EZH2, SRSF2, or IDH1/2 mutations predicted poor outcomes.^18–21 In a study of 879 patients with PMF, Vannucchi and colleagues showed that ASXL1, SRSF2, and EZH2 mutations were associated with shorter OS, and mutations in IDH1 and SRSF2 with LT. ²¹ Moreover, the detrimental effects of these mutations were additive.^22,23 With incorporation of molecular mutations, the mutation-enhanced IPSS (MIPSS70) for transplant-age patients have been described, ²⁴ which highlights the importance of mutational profiling on refining patient risk.

Patient selection and optimal timing of AHSCT

According to the IPSS, DIPSS, and DIPSS-plus scores, patients with intermediate-2 and high-risk disease have median survival of less than 5 years,^2–4 and should be considered potential candidates for AHSCT. ²⁵ A large retrospective study determined outcomes in 438 PMF patients who received AHSCT (n = 190) or conventional therapies (n = 248). ²⁶ The results showed that patients with intermediate-2 or high-risk, according to the DIPSS model, clearly benefited from AHSCT, with relative risk (RR) of death of 0.55 and 0.37, respectively. Patients at low risk benefited from nontransplant therapy (RR = 5.6), whereas individual counseling was indicated for those at intermediate-1 risk (RR = 1.6, p = 0.19). In a consensus publication by the European Blood and Marrow Transplantation group and the European LeukmiaNet (EBMT/ELN), ²⁵ patients with intermediate-1 risk disease up to age 65 years should also be considered candidates for AHSCT if they have either refractory, transfusion-dependent anemia, a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics (as defined by the DIPSS-plus classification). Besides, as mentioned above, JAK2/CALR/MPL triple-negative or ASXL1 mutation predicts poor outcomes, intermediate-1 risk patients with these molecular mutations are also suggested AHSCT if a suitable donor is available. ²⁵

The optimal timing of AHSCT for MF is controversial, especially in the era of JAK inhibitors. Though not curative, the first JAK1/2 inhibitor Ruxolitinib has shown clinical benefits in patients with intermediate-2 and high-risk MF, including spleen size reduction and improvement of constitutional symptoms and also survival benefit.^27–29 A major dilemma is when to proceed to AHSCT in a patient who responds well to JAK inhibitor. Early AHSCT may lead to significant morbidity and mortality, while delaying AHSCT may lead to a worse outcome due to advanced-stage disease, increasing age or LT. Some authors suggested that patients whose therapeutic goal was cure should still be referred for AHSCT, ³⁰ even if they are responding to JAK1/2 inhibitors. This approach is not contradictory because there is a sound rationale for combining JAK1/2 inhibitor therapy with AHSCT, which we will discuss later.

Pretransplant splenectomy

Splenomegaly reflects an expansion of the underlying malignant clone in MF, and many reports have shown poor transplant outcomes in patients with splenomegaly.^31,32 However, the role of splenectomy before AHSCT remains controversial. Some data observed faster engraftment in splenectomized patients.^33–36 A retrospective study included 26 patients with MF, of them 11 patients had undergone splenectomy and they had faster granulocyte recovery than nonsplenectomized patients (18 days versus 23 days, p = 0.04). ³³ In contrast, other researchers did not observe any difference in transplantation outcomes between patients who underwent splenectomy or not.^37,38 A study assessed the impact of spleen status on transplant outcome in 9683 patients with myeloid malignancy, including MF (472 splenectomy, 300 splenic irradiation; 1471 with splenomegaly). Despite the facilitation of engraftment after splenectomy, the OS was similar among groups. ³⁹ Kroger and colleagues even found that prior splenectomy was associated with an increased incidence of relapse. ⁴⁰ Taken together, the data of favorable outcome with splenectomy are not sufficient, and the procedure of splenectomy is associated with significant risk of perioperative complications (27.7%) and mortality (6.7%) ⁴¹ ; hence, routine pretransplant splenectomy is not recommended. Moreover, as JAK inhibitors have shown clinical benefit in reducing spleen size,^27–29 they may serve as an alternative to splenectomy in patients with significant splenomegaly.

Conditioning regimens

Many retrospective studies have demonstrated the curative potential of myeloablative conditioning (MAC) AHSCT in MF patients, with an OS of 30–60% and event-free survival (EFS) of 25–50%.^34,42–47 However, the transplant-related mortality (TRM) is rather high, ranging from 30% to 48% at 1 year, which limits its applicability to young patients with good performance status (PS). The introduction of reduced intensity conditioning (RIC) has expanded the scope of AHSCT to older patients, or patients with significant comorbid conditions. Over the past decades, many studies have reported encouraging results of RIC AHSCT in patients with MF.^42,48–53 In a prospective multicenter study, 103 patients received fludarabine/busulfan (FB)-based RIC regiment followed by AHSCT. The cumulative incidence of nonrelapse mortality (NRM) at 1 year was 16%, relapse at 3 years was 22%, and 5-year OS was 67%. ⁴⁰

Among many available RIC regimens, FB or fludarabine/melphalan (FM) are most commonly used for MF.^{31,40,44,49,51,54} One study compared FB and FM regimens, and a total of 160 MF patients (FB group, n = 105; FM group, n = 55) were included. Multivariable analyses revealed no significant differences in progression-free survival (PFS) between the two groups (52% versus 33%, p = 0.89); however, the relapse rate was significantly lower in the FM group (HR = 9.21; p = 0.008), and a trend toward reduced NRM was seen in the FB group (HR = 0.51; p = 0.068). ⁵² This study concluded that both regimens were efficient, the FM regimen appeared more toxic but with augmented control of disease. Recently, a retrospective study analyzed outcomes of 61 patients with MF who underwent AHSCT with the following three RIC regimens: FB, FM or Fludarabine Bischlorethyl-nitroso-urea/carmustine Melphalan (FBM). OS, acute graft-versus-host disease (GVHD) and relapse were not different in the three groups; however, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FM than FB. ⁵³

There is no prospective randomized trial comparing MAC with RIC, and all results were based on retrospective comparisons. Most studies found that patients who performed with RIC had similar outcomes to patients with MAC though they were older or with poor PS.^{36,45,54–56} However, a very large long-term study by Robin and colleagues observed poor results in patients with RIC AHSCT. ⁵⁷ The study analyzed outcome in 1055 patients with MF undergoing transplant between 1995 and 2014, of which 645 patients received a RIC regimen. The 10-year OS, disease free survival (DFS), and relapse for 2-year survivors were 74%, 64%, and 21%, respectively. RIC was associated significantly with lower DFS and higher relapse. The consensus of the EBMT/ELN is that patients with older age or comorbidities should select a lower intensity regimen, while for patients with advanced disease and good PS a more intensive regimen is more appropriate. ²⁵

Factors affecting AHSCT outcomes

Leukemic transformation

LT is observed in approximately 20% of patients with MF and the prognosis is dismal, with a median survival of less than 3 months.^73,74 Risk factors for LT were unfavorable karyotype, thrombocytopenia, and increased circulating blasts.^75,76 Molecular abnormalities such as IDH-1/2, SRSF2, EZH2, or ASXL1 also predicted higher risk of LT. ⁷⁷ Patients with LT may achieve long-term remission after induction chemotherapy and AHSCT. Alchalby and colleagues conducted a study of 46 patients who received AHSCT for AML evolving from MF. Before AHSCT, 42 patients received induction chemotherapy, while only 9 achieved complete remission (CR), 10 achieved a minor or partial remission, and 19 were refractory or had progressive disease at the time of AHSCT. The 3-year PFS, OS, and relapse rates were 26%, 33%, and 47%, respectively, and the only significant factor for survival was CR before transplantation. ⁷⁷ Hence, AHSCT after chemotherapy is associated with a potential survival benefit, especially for patients with CR before transplantation.

Role of JAK inhibitors

Ruxolitinib is the first JAK inhibitor approved by the US Food and Drug Administration for patients with intermediate- or high-risk MF and in Europe for symptomatic MF patients with splenomegaly, irrespective of disease status. The results of COMFORT-I and COMFORT-II showed that ruxolitinib rapidly reduced splenomegaly and improved MF-related symptoms and quality of life.^27,28 Several studies^78–83 suggested pretreatment with ruxolitinib was well tolerated and might improve outcome after AHSCT (Table 1). Besides, two studies found patients who responded well to ruxolitinib had better transplant results.^79,80 In one study, 100 patients with MF were stratified into five groups based on clinical status and response to JAK1/2 inhibitors at the time of AHSCT. OS at 2 years was 61%, and this was 91% for those who experienced clinical improvement, while only 32% for those who developed LT on JAK1/2 inhibitors. ⁷⁹

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Table 1.

Major studies of ruxolitinib therapy prior to AHSCT for myelofibrosis.

Study	No. of patients	Median age (range), year	Median exposure to ruxolitinib (range), months	Ruxolitinib tapering schedule	Response to ruxolitinib	Adverse events	Results	Conclusions
Jaekel 78	14	67 (33–80)	6.5 (2–12)	14 days prior to conditioning	Ameliorate MF-related symptoms: 71.4% Reduce splenomegaly: 64%	No unexpected adverse events	Engraftment: 13 patients OS 78.6%, EFS 64%, TRM 7% (9-month follow-up).	Ruxolitinib might improve AHSCT outcome
Stubig 80	22	59 (42–74)	3.2 (0.7–10.5)	No tapering schedule	Improvement of constitutional symptoms: 86% Spleen size reduction > 50%: 41%; <50%: 14%; No response or loss of response: 45%	No unexpected adverse events	Graft failure: none 1-year OS 81%, DFS 76%, NRM 14% OS was superior in patients who responded to ruxolitinib	Patients who responded to ruxolitinib prior to AHSCT might have favorable transplant results
Hanif 83	10	56 (47–60)	5.7 (1.9–9)	6 days prior to conditioning	Spleen size reduction in 5 of 9 patients	No unexpected adverse events	After a median follow-up of 14.5 months, all 10 patients were alive	This study supported the safety of ruxolitinib therapy prior to AHSCT, provided a taper was used
Shanavas 79	100	59 (32–72)	5 (1–56)	66 patients underwent different tapering schedule	Group-A: clinical improvement Group-B: stable disease Group-C: new cytopenia or increasing blasts Group-D: progressive disease: splenomegaly Group-E: progressive disease: leukemic transformation	2 SAEs; 1 pulmonary infiltrate and rebound splenomegaly; 1 hypoxic respiratory failure Adverse events were more common in patients who stopped ruxolitinib ⩾6 days prior to conditioning	4 patients each experienced primary and second graft failure Grade II-IV, III-IV aGVHD were 37% and 16% 1-year OS was 61%, and was 91%, 54%, 54%, 60%, 32% in group-A, B, C, D, E, respectively	Patients responded well to JAK1/2 inhibitors had better AHSCT outcomes JAK1/2 inhibitors should be continued near to the start of conditioning to minimize the risk of withdrawal symptoms
Shahnaz Syed Abd Kadir 81	159	59 (28–74)	4.9 (0.4–39.1)	No tapering schedule	Splenic size response in 18 of 42 (42.9%) patients	No unexpected adverse events	Engraftment, aGVHD, NRM and OS did not differ between the ruxolitinib group (n = 46) and non-ruxolitinib group (n = 113) CMV reactivation rate was higher in the ruxolitinib group	Ruxolitinib pretreatment did not negatively influence outcome after AHSCT
Salit 82	28	56 (43–68)	7 (2–36)	Form the start of conditioning to Day -4		No unexpectedadverse events	Graft failure: none2-year OS: 86%	Pre-AHSCT ruxolitinib was well tolerated and might improve post-transplant outcomeOverlap of ruxolitinib with conditioning did notresult in unexpected adverse events

aGVHD, acute graft-versus-host disease; AHSCT, allogeneic hematopoietic stem-cell transplantation; DFS, disease free survival; EFS, event free survival; NRM, nonrelapse mortality; OS, overall survival; SAEs, serious adverse events; TRM, transplant-related mortality.

Adverse events associated with ruxolitinib in pretransplant setting including ruxolitinib withdrawal syndrome and increased risk for infections. Preliminary results of a prospective research from France reported unusual serious adverse effects such as tumor lysis syndrome, cardiogenic shock, and sepsis. ⁸⁴ Of note, a large retrospective study observed two serious adverse events in MF patients who stopped JAK inhibitor ⩾6 days prior to conditioning therapy. ⁷⁹ Rates of adverse symptoms were very low in patients who continued JAK inhibitor near to transplant conditioning therapy. Hanif and colleagues reported 10 patients who underwent AHSCT for MF and all patients were pretreated with ruxolitinib. ⁸³ The steady state dose of ruxolitinib was 20 mg BID, and a standard tape schedule was employed starting 6 days prior to conditioning. At 6 days, 96 h, 72 h, 48 h, and 24 h prior to conditioning, ruxolitinib was reduced to 15 mg BID, 10 mg BID, 5 mg BID, 5 mg Daily, and None, respectively. No unexpected adverse events were observed upon ruxolitinib withdrawal. Therefore, it is recommended that the drug be initiated at least 2 months before transplant, and weaning start 5–7 days prior to conditioning, with the drug stopping the day before conditioning. ²⁵ Ruxolitinib has been shown to inhibit in vitro and in vivo dendritic cell activation, migration, and antigen-specific T-cell response,^85,86 resulting in an increased risk for infection, particularly viruses. In a small study of 12 patients with MF who were treated with ruxolitinib and underwent AHSCT, ruxolitinib was continued until stable engraftment. The authors demonstrated a higher incidence (41%) of cytomegalovirus reactivation and the onset was earlier compared with a historical group. ⁸⁷ In summary, careful attention should be paid to these adverse events when received ruxolitinib prior to AHSCT.

There is little indication for JAK1/2 inhibitors after AHSCT for MF. However, they could be considered in patients who relapse to decrease the symptom burden. They may be also effective in the treatment of steroid-refractory GVHD by suppressing the production of pro-inflammatory cytokines, which needs prospective trials to validate it.

Post-transplant management

Conclusion

AHSCT remains the only curative therapy for patients with MF. The optimal conditioning regimen has not been defined and should be based on patient age, comorbidity, and PS. MSD and MUD are preferred, mismatched related donor provides an attractive alternative donor source. JAK inhibitors have proved clinical benefits for MF patients, and further researches are needed to explore the safety and effectiveness of pretransplant therapy with ruxolitinib. Molecular mutations not only have prognostic value but also serve as MRD markers to predict early relapse. For patients with relapse, reduction of immune-suppressive drugs, DLIs, or a second AHSCT are effective treatment choices.