Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group

Abstract

The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.

Introduction

Myelofibrosis, better termed myeloproliferative neoplasm-associated myelofibrosis (MPN-MF),1 is a BCR-ABL1-negative MPN that develops de novo (primary myelofibrosis; PMF) or from antecedent polycythemia vera (post PV-MF) or essential thrombocythemia (post ET-MF). MPN-MF is the most severe form of MPNs and is more commonly associated with bone marrow (BM) failure, malignant transformation and death. The median survival is estimated at 6 years, but it can range from months to many years.2

Therapy for MPN-MF is conventionally based on the patient risk category, age and presenting disease manifestations. For patients with advanced symptomatic disease, therapies are targeted to managing anemia, splenomegaly and improving quality of life.3

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a well-established treatment modality for MPN-MF and the only potentially curative treatment. Since the initial report of successful allo-SCT in MPN-MF,4 multiple publications have confirmed the curative potential of transplantation, and the adoption of reduced intensity conditioning (RIC) regimens has made allo-SCT applicable to a larger proportion of patients.5 However, there are no randomized controlled trials comparing allo-SCT with any drug therapy or supportive care; nor are there any randomized controlled trials comparing myeloablative conditioning (MAC) with RIC allo-SCT. Thus, the decision about allo-SCT is based on inductive reasoning and requires a high-degree of professional experience.

The European LeukemiaNet (ELN), in conjunction with the European Blood and Marrow Transplantation Group (EBMT), decided to review recent data regarding the results of allo-SCT in MPN-MF and to produce recommendations aimed at optimizing allo-SCT in MPN-MF. Owing to differences in biological characteristics, and prognostic classifications of PMF with respect to post PV and post ET-MF, recommendations were specifically addressed to PMF patients.

The consensus process

Two chairpersons (NK and GB) appointed an Expert Panel (hereafter referred to as the Panel) of 23 experts selected for their expertize in research and clinical practice of MPN-MF. A clinician with expertize in clinical epidemiology (GB) assured the methodological correctness of the process. During an initial meeting held in New Orleans, LO, USA, on December 2012, the areas of major concern in the performance of allo-SCT in PMF were selected through group discussion. The candidate key questions were ranked according to their priority votes, with the six that ranked highest forming the set of questions of the present guidelines.

MEDLINE, EMBASE and PubMed searches of English language literature (1999 to 31 January 2015) were performed. In addition, the proceedings of the latest annual meetings were searched for relevant unpublished evidence.

Four panelists drafted statements that addressed the identified key questions, and remaining panelists scored their agreement with those statements and provided suggestions for rephrasing. For exploiting this phase of the process, the Delphi questionnaire method was used.6 Finally, the Panel convened once again for a consensus conference held in San Francisco, CA, USA, on December 2014, where the nominal group technique7 was used for drafting the final recommendations.

Results

Patient selection

A number of prognostic scoring systems have been used to assess the allo-SCT candidacy. The Lille score, based on hemoglobin level and white blood cell count, has been used for many years.8 More recently, the International Prognostic Scoring System (IPSS) estimates the expected survival from the time of PMF diagnosis based on five risk factors: age, white blood cell count, hemoglobin, constitutional symptoms and blasts in peripheral blood (PB).9 A dynamic IPSS (DIPSS) score uses the same five risk factors but allows for prognostic prediction at any time during the disease course.10 The DIPSS has been further refined as DIPSS Plus, which adds three additional risk factors (transfusion dependence, unfavorable karyotype and platelet count <100 × 109/l).11 Unfavorable karyotype included complex karyotype or single or two abnormalities including +8, −7/7q-, i(17q), −5/5q-, 12p-, inv(3) or 11q23 rearrangement.

Patients candidacy for allo-SCT in PMF was mostly based upon the evidence that median overall survival (OS) for DIPSS intermediate-2- and high-risk patients after allo-SCT was superior to that after non-transplant management12, 13, 14, 15, 16 (Table 1). At variance, the median OS of low-risk patients was shorter after transplantation than with non-transplant management.

Table 1 Outcome after allo-SCT according to DIPSS prognostic system in studies with MPN-MF published after 2012

A larger retrospective comparison between allo-SCT and conventional therapy indicates that PMF patients of 65 years of age or younger at diagnosis with intermediate-2- or high-risk disease are likely to benefit from allo-SCT, while for patients with low-risk disease a non-transplant approach is more appropriate.17

The Panel highlighted the unmet need of identifying the category of patients with DIPSS intermediate-1 disease in whom transplant is indicated. The prognostic factors for blood transplant identified by Tefferi et al.18 were considered relevant for this issue.

ASXL1, SRSF2, IDH1/2 and EZH2 mutations were independently associated with poor survival.19, 20 Recently, mutations involving the calreticulin (CALR) gene have been described in patients with PMF and ET,21, 22 documenting that patients with PMF who harbor a CALR mutation have superior survival compared with those with a JAK2 mutation. Tefferi et al. suggested that OS was the longest in CALR(+)/ASXL1(−) (median 10.4 years) and shortest in CALR(−)/ASXL1(+) patients (median, 2.3 years).23 The CALR/ASXL1 mutations-based prognostic model was DIPSS+ independent (P<0.0001) and was effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median, 20 years) survival.

Benefits of allo-SCT in patients with blood transplant were analyzed by reviewing five reports.24, 25, 26, 27, 28 Overall, induction followed by allo-SCT in responders achieved long-term disease control in a proportion of patients, providing a 47–53% of 2-year OS. The significant factor for survival was complete remission before transplantation.

The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) assigns weighted scores to particular medical conditions that affect non-relapse mortality (NRM) and survival.29 Although a formal validation in PMF patients is pending, two recent analyses in patients with MPN-MF showed an inverse correlation of HCT-CI scores and transplantation success.12, 13

As portal hypertension could be related to hepatic intrasinusoidal hematopoiesis, this represents a risk factor for transplant outcome in PMF due to liver toxicity.30

Two patient-specific prognostic systems were also considered for transplant eligibility. In a total of 46 patients with PMF (median age 51 years) who underwent allo-SCT after a thiotepa-based RIC regimen, Bacigalupo et al.31 discovered that independent unfavorable factors for survival were red blood cell transfusions >20, a spleen size >22 cm and use of an alternative donor. The actuarial survival of low-risk (0–1 unfavorable factors) and high-risk (2 or more negative factors) patients was 77% and 8%, respectively. In multivariate Cox analysis, the score maintained its predictive value.

In 150 uniformly treated patients with RIC allo-SCT, Alchalby and coworkers14 developed a risk score for OS in which only JAK2 V617F wild-type, age 57 years and constitutional symptoms were independent predictors.

Recommendations

All patients with intermediate-2 or high-risk disease according to IPSS, DIPSS or DIPSS+, and age <70 years, should be considered potential candidates for allo-SCT.

Patients with intermediate-1-risk disease and age <65 years should be considered candidates for allo-SCT if they present with either refractory, transfusion-dependent anemia or a percentage of blasts in PB >2%, or adverse cytogenetics (as defined by the DIPSS+ classification).

Patients with low-risk disease should not undergo allo-SCT. They should be monitored and evaluated for transplantation when disease progression occurs.

Patients in blast transformation (blasts in PB or in BM or both equal to or >20%) are not good candidates for allo-SCT. They should receive debulking therapy and be reconsidered for transplant after achieving a partial or complete remission of leukemia.

Although the use of molecular risk classification for the identification of candidates for allo-SCT among intermediate-1-risk patients deserves further clinical validation, patients in this risk category who are triple negative (that is, JAKV617F, CALR and MPL negative) or ASXL1 positive, or both, should be considered for allo-SCT.

Individual transplant-specific prognostic factors should be considered in every patient candidate for allo-SCT to arrive at an individualized decision. Transplant-specific high risk factors include: spleen extending more than 22 cm, having been transfused with more than 20 units of red blood cells, being transplanted from an human leukocyte antigen (HLA) non-identical donor, low performance status (Eastern Cooperative Oncology Group status >2), high co-morbidity index (HCT-CI score >3) and presence of portal hypertension.

Pre-transplant management

In retrospective studies, splenectomy before allo-SCT resulted in better engraftment probability, and decreased transfusion requirement.32, 33, 34, 35, 36, 37, 38 No study evaluated prospectively the effect of a protocol-based splenectomy before transplant.

Splenic irradiation has been proposed as a component of RIC regimens.39 A recent study from the Center for International Blood and Marrow Transplant Research (CIBMTR) failed to show any impact of splenectomy or splenic radiation on graft versus host disease (GvHD) or survival in patients with myeloid malignancies, including PMF.40

Ruxolitinib is the first JAK inhibitor approved by the US Food and Drug Administration and European Medicines Agency for use in patients with MPN-MF. Ruxolitinib might improve outcome after allo-SCT in patients with PMF by a beneficial impact on graft failure and acute GvHD.

A pooled analysis of published results in 63 patients who received ruxolitinib before allo-SCT and discontinued prior to conditioning, documented that 7 patients developed life-threatening adverse events, including cardiogenic shock and tumor lysis syndrome.41 In a study by Stubig et al.,42 22 patients with MPN-MF and a median age of 59 years received ruxolitinib before allo-SCT. OS was superior in patients who responded to ruxolitinib (n=12) in contrast to those patients who failed or lost their response (n=10).

Elevated pre-transplant ferritin levels have been reported to increase the risk of NRM and might influence the risk of acute and chronic GvHD, and blood stream infections.43, 44, 45, 46 However, in a recent prospective cohort study using liver magnetic resonance imaging to quantify liver iron content, there was no difference in the 1-year probability of OS, NRM, relapse, acute or chronic GvHD, organ failure, infections or hepatic veno-occlusive disease between groups with iron overload and those without.47 These results were confirmed in a metanalysis of four studies that used magnetic resonance imaging to estimate pre-allo-SCT liver iron content.48

Recommendations

Pre-transplant JAK inhibitor therapy with ruxolitinib is indicated in patients with a symptomatic spleen and/or constitutional symptoms.

The drug should be initiated at least 2 months before transplant and should be titrated to the maximum tolerated dose. Weaning starting 5–7 days prior to conditioning should be implemented in the attempt to avoid a rebound phenomenon, with the drug stopping the day before conditioning.

The evidence supporting improvement of transplant outcome with splenectomy is not sufficient to recommend splenectomy as a standard pre-transplant procedure.

Pre-transplant splenectomy in patients with refractory splenomegaly should be decided on a case-by-case basis. The Panel recommended that if splenectomy is performed, it should be in a controlled setting of registries or clinical trials.

Spleen irradiation before transplantation is frequently associated with complications (infections, hemorrhages) that could result in a delay of transplantation and, therefore, it is not recommended.

Severe iron overload should be prevented by carrying out the transplant earlier in transfusion-dependent patients. In patients with high numbers of previous red blood cell transfusions or high serum ferritin levels at transplantation, iron overload should be assessed by liver magnetic resonance imaging. Iron chelating therapy before transplant is indicated only in severely iron overloaded patients.

Donor selection

We analyzed the two available prospective multicenter trials with RIC allo-SCT in MPN-MF. The EBMT trial found that the cumulative incidence of NRM at 1 year was significantly lower among patients with completely matched donors in comparison with mismatched donors (12% vs 38%), and the cumulative incidence of NRM did not differ between the HLA-identical sibling and the 10/10 matched unrelated group (10% vs 13%).35 The MPN-Research Consortium found that with transplants from unrelated donors, the OS was 32%, significantly inferior to the sibling group (hazard ratio 3.9),16 but a difference between HLA-matched and HLA-mismatched unrelated transplants was not detected.

In the CIBMTR retrospective report, adjusted probabilities of survival at 5 years were 56% for matched sibling donors, 48% for well-matched unrelated donors and 34% for partially matched/mismatched unrelated donors.15

Haploidentical related donors provide an attractive alternative source of stem cells due to widespread availability and ease of stem cell procurement. Post-transplant cyclophosphamide has been shown to induce immune tolerance, and effective control of GvHD.49 No comparison studies on the outcomes of matched unrelated donor and haploidentical donors in PMF have been published to date.

Robin et al.50 evaluated 35 umbilical cord blood transplants in MPN-MF reported to Eurocord. The 2-year OS and event free survival rates were 44% and 30%, respectively. All patients given total body irradiation-fludarabine-cyclophosphamide achieved neutrophil and platelet recovery, and the use of this regimen was associated with superior event free survival in the RIC population (44% vs 0%).

No comparison between PB and BM grafts in PMF have been reported. A phase III randomized trial comparing PB versus BM as cell sources for unrelated donor allo-SCT in which most patients received MAC regimens, reported no significant differences in OS but an increase in risk and severity of chronic GvHD with PB.51 In the data reported to the CIBMTR of RIC transplantations performed in the United States between 2000 and 2008 for acute myeloid leukemia, MDS or non-Hodgkin lymphoma, no significant differences in 5-year rates of survival were evidenced with PB compared with BM.52

Recommendations

Patients with IPSS, DIPSS or DIPSS+ intermediate-2- or high-risk disease lacking an HLA-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors such as HLA-mismatched unrelated donors, cord blood or HLA-haploidentical SCT.

Alternative donor sources may be effective, but the actual success rates and the incidence of complications such as graft failure and GvHD remain to be determined. Those patients should be enrolled in prospective clinical trials and data should be reported to registries.

The Panel agreed on considering PB as the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants.

Conditioning regimen

Allo-SCT in MPN-MF patients included in studies published since 1999 and comprising more than 20 patients, standard MAC regimens resulted in 1-year NRM rates ranging from 20 to 48% with more favorable results in fit young patients with less-advanced disease and better HLA matching.34, 36, 37, 38, 53, 54, 55, 56, 57, 58, 59, 60 Patients treated with cyclophosphamide combined with total body irradiation or busulfan (BU), with targeting of BU concentration, had a 5-year OS of 68%, compared with 46% in non-targeted regimens.54, 55

In the last decade, several studies have demonstrated feasibility of RIC regimens based on BU/fludarabine, melphalan/fludarabine, thiotepa/cyclophosphamide or treosulfan/fludarabine. Two large prospective studies of RIC in MPN-MF allo-SCT have been reported to date. The EBMT trial35 used an RIC regimen with fludarabine, BU and rabbit ATG in 33 transplants from sibling donors and 70 from unrelated donors. The results showed a cumulative incidence of NRM at 1 year of 16%, and an estimated 5-year OS of 67%. Patients >55 years of age had a 48% survival as opposed to 82% for younger patients. Survival correlated with intermediate- and high-risk Lille score at the time of transplantation.

In the study of MPN-Research Consortium,16 32 patients had a sibling donor and 34 an unrelated donor. The conditioning regimen included melphalan instead of BU, and ATG was administered only to recipients of the group receiving unrelated grafts. In the sibling group OS was 75% compared with 32% with unrelated donors.

In the CIBMTR retrospective analysis of RIC in PMF, the probability of survival at 5 years was 47%.15

A meta-analysis comparing the clinical outcomes and toxicity of RIC and MAC allo-SCT in patients with AML and MDS was analyzed as indirect evidence.61 In eight studies (two prospective and six retrospective) involving 6464 patients who received allo-SCT, OS and event free survival were similar in the RIC (n=1571) and MAC (n= 4893) arms. NRM, total chronic GvHD and extensive chronic GvHD were not significantly different between the two arms.

Recommendations

The optimal intensity of the conditioning regimen still needs to be defined. For patients with older age or with comorbidities, or both, a lower Intensity regimen is more appropriate, while for patients with advanced disease and good performance status a more intensive regimen should be selected.

A spectrum of RIC regimens and protocols has shown acceptable transplant-related mortality and overall survival

There is no direct evidence to recommend which of these regimens should be preferentially adopted. The Panel identified investigations in this area as a major unmet clinical need.

Regarding T-cell depletion, more experience has been gained with the use of ATG compared with alemtuzumab.

Post-transplant management

Persistence or occurrence of splenomegaly, graft failure and liver dysfunction were the issues highlighted by the Panel as critical in post-transplant mangement of patients with PMF.

A recent study monitored the spleen size using ultrasound or computed tomography scans in patients who received RIC allo-SCT for PMF.62 In all 10 patients analyzed, a progressive reduction of splenomegaly was documented within 12 months post transplant.

Engraftment failure was reported to occur in 8–17% patients transplanted after RIC.15, 16, 31 Lower degrees were reported in a large prospective study from EBMT,35 where engraftment failure occurred in only 2 of 103 MPN-MF patients. In that study, however, 11% received an additional stem cell boost after transplantation because of poor graft function.

No studies were identified evaluating preoperative regimens for allo-SCT in the population of patients with hepatic insufficiency and PMF. Indirect evidence was dervied from the review by Bodge et al.63

Recommendations

In patients with splenomegaly at the time of transplant, monitoring of spleen size with ultrasound after allo-SCT is an acceptable method as a complement to physical examination.

Persistence of splenomegaly in the early post-transplant phase (1 year) should be considered the normal process of disease clearance and does not need specific management, unless there is pancytopenia. In those patient with persistent splenomegaly and complete donor cell chimerism, splenectomy may be an option, but it is not without risks. JAK inhibition in this setting has not been tested so far, and potential negative effects on hematopoiesis should be taken into consideration.

Persistence of splenomegaly late after transplantation, when associated with incomplete donor chimerism, is typically a sign of disease persistence or recurrence. Treatment may consist in reduction of immunosuppression, donor lymphocyte infusion (DLI) or both. JAK2 inhibitors alone may reduce the spleen size and persistent constitutional symptoms, but there is no evidence that suggests modulation of donor cell chimerism or clearance of minimal residual disease.

New or worsening splenomegaly after allo-SCT should raise the suspicion of hepatic veno-occlusive disease, post-transplant lymphoproliferative disorders, infections or relapse of PMF.

In the presence of poor graft function, BM assessment by trephine biopsy, in no case earlier than 6 months post-transplant, is necessary to assess cellularity and persistence of fibrosis and osteosclerosis.

Chimerism studies on PB CD3+ cells and unfractionated BM cells are necessary to establish the degree of donor cell engraftment and may assist in the decision regarding withdrawal of immunosuppression.

In patients with poor graft function, defined as single, bi- or trilineage cytopenia with full donor chimerism and absence of active GvHD, myelosuppressive agents (ganciclovir, trimethoprim-sulfamethoxazole and mycophenolate mofetil) should be removed.

In patients with poor graft function, use of growth factors (EPO, G-CSF) is recommended for anemia or neutropenia, respectively.

The experience with the use of thrombopoietin analogs post allo-SCT is limited, and the drug should be used in a controlled setting (registries or clinical trials).

In patients with late decline of graft function who have full donor chimerism and no evidence of active GvHD, the direct ‘booster’ infusion (without prior re-conditioning) of donor hemopoietic stem cells (usually after CD34 selection) is recommended.

In patients with graft failure and no autologous reconstitution, the only available option is a second transplant.

For patients with hepatic impairment before transplantation who are candidates for allo-SCT, the Panel recommended to use a reduced intensity regimen avoiding liver toxic agents.

Management and prevention of relapse after transplant

About 10–18% of PMF patients transplanted with MAC regimens experience relapse within 3 years post transplant.34, 36, 54, 56 Relapse rates after RIC range from 29 to 43%.15, 35

Estimates of benefits and risks of DLI and second allo-SCT in PMF were derived from a study reporting the multicenter experience on the use of a two-step salvage strategy including DLIs and a second RIC allo-SCT from an alternative donor in 30 patients with MPN-MF who relapsed (n=27) or experienced graft failure after allo-SCT.64 Responses were observed in 10 of 26 patients (39%). Notably, all 10 responders achieved stable remissions and required no additional treatment. Rates of acute and chronic GvHD after DLI were 12% and 36%, respectively. Further, the study showed an association of GvHD with the development of a graft versus myelofibrosis effect, which already had been suggested by other investigators.64, 65, 66 The second RIC allo-SCT produced an overall response rate of 80%, and a 1-year OS and PFS of 82% and 70%, respectively. The 1-year cumulative NRM and cumulative relapse incidence was 6% and 24%, respectively. Despite the use of an alternative donor for the second allo-SCT in the majority of cases, the rate of acute (47%) and chronic (46%) GvHD was acceptable. Concerning those patients who previously received DLI, the use of the second HSCT after a median of 5 months (range, 2–13 months) from the last DLI application did not seem to increase the rates of acute and chronic GvHD, and was well tolerated.

No studies have been performed so far using JAK inhibitors after allo-SCT. The Panel identified evaluation of ruxolitinib therapy after transplant as a critical unmet need.

Recommendations

Disease-specific markers such as karyotypic abnormality, JAK2V617F, CALR and MPL mutations should be monitored to detect minimal residual disease after allo-SCT. Timing of analysis should be paired with chimerism determination.

In patients with evidence of minimal residual disease or with decreasing donor cell chimerism after transplantation, discontinuation of immune-suppressive drugs, DLI or both are appropriate strategies to avoid clinical relapse.

To avoid severe GvHD, an escalating dose scheme is recommended.

No recommendation for prophylactic DLI can be provided.

In patients who relapse after allo-SCT and do not have severe GVHD, reduction of the doses of immunosuppressive drugs or DLI are the treatment strategies of choice.

In patients who failed to achieve complete remission after DLI, and who are deemed fit to undergo the procedure, a second allo-SCT may be considered.

In patients relapsing with constitutional symptoms or splenomegaly, JAK inhibitor treatment is recommended, but remains experimental.

Discussion

The recommendations of this report were generated by a panel of experts to strike a balance between the results of research and clinical practice. The construct validity of the consensus was assured by group discussion by which all important issues were considered, and multiple viewpoints were integrated into the decision-making process in an explicit and unbiased manner.

The results of this project may be compared with those of others produced by group discussion. The British Committee for Standard In Hematology in 2012 published recommendations on the treatment of patients with MPN-MF, including allo-SCT.67 The recommendations issued by the British Panel were more straightforward than ours in indicating when MAC or RIC transplantation should be considered, reflecting the more scanty evidence on benefit of RIC at that date (Table 2).

Table 2 Recommendations published in the last 5 years on allo-SCT in MPN-MF

The critical appraisal of evidence on allo-SCT in MPN-MF allowed the Panel to highlight unmet clinical needs regarding transplantation in PMF. Lack of sufficient data on the outcomes of different conditioning regimens for RIC allo-SCT were identified as a major unmet need. This challenge is now being addressed in a prospective multicenter phase II trial of GITMO that compares BU/fludarabine with thiotepa/fludarabine RIC regimens prior to allo-SCT for the treatment of MPN-MF (NCT01814475). Similarly, the need for better evidence on the outcome of transplantation from mismatched donors was singled out by the Panel. Finally, the Panel acknowledged considerable uncertainty regarding the precise timing of all-SCT in patients who are receiving ruxoltinib, and the use of ruxolitinib after transplantation. These challenges are now being addressed in a prospective multicenter phase II study of the MPD-Research Consortium (NCT01790295) in which ruxolitinib is administered to eligible MF patients for 60 days prior to definitive allo-SCT.

References

  1. 1

    Mesa RA, Green A, Barosi G, Verstovsek S, Vardiman J, Gale RP . MPN-associated myelofibrosis (MPN-MF). Leuk Res 2011; 35: 12–13.

  2. 2

    Tefferi A . Primary myelofibrosis: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol 2014; 89: 915–925.

  3. 3

    Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 2011; 29: 761–770.

  4. 4

    Dokal I, Jones L, Deenmamode M, Lewis SM, Goldman JM . Allogeneic bone marrow transplantation for primary myelofibrosis. Br J Haematol 1989; 71: 158–160.

  5. 5

    Gupta V, Hari P, Hoffman R . Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood 2012; 120: 1367–1379.

  6. 6

    Williams PL, Webb C . The Delphi technique: a methodological discussion. J Adv Nurs 1994; 19: 180–186.

  7. 7

    Delbecq AL, van de Ven AH, Gustafson DH . Group Techniques for Program Planning: A Guide to Nominal Group and Delphi Processes. Scott, Foresman and Co: : Glenview, IL, USA, 1975.

  8. 8

    Dupriez B, Morel P, Demory JL, Lai JL, Simon M, Plantier I et al. Prognostic factors in agnogenic myeloid metaplasia: a report on 195 cases with a new scoring system. Blood 1996; 88: 1013–1018.

  9. 9

    Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood 2009; 113: 2895–2901.

  10. 10

    Passamonti F, Cervantes F, Vannucchi AM, Morra E, Rumi E, Pereira A et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood 2010; 115: 1703–1708.

  11. 11

    Gangat N, Caramazza D, Vaidya R, George G, Begna K, Schwager S et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol 2011; 29: 392–397.

  12. 12

    Ditschkowski M, Elmaagacli AH, Trenschel R, Gromke T, Steckel NK, Koldehoff M et al. Dynamic International Prognostic Scoring System scores, pre-transplant therapy and chronic graft-versus-host disease determine outcome after allogeneic hematopoietic stem cell transplantation for myelofibrosis. Haematologica 2012; 97: 1574–1581.

  13. 13

    Scott BL, Gooley TA, Sorror ML, Rezvani AR, Linenberger ML, Grim J et al. The Dynamic International Prognostic Scoring System for myelofibrosis predicts outcomes after hematopoietic cell transplantation. Blood 2012; 119: 2657–2664.

  14. 14

    Alchalby H, Yunus DR, Zabelina T, Kobbe G, Holler E, Bornhäuser M et al. Risk models predicting survival after reduced-intensity transplantation for myelofibrosis. Br J Haematol 2012; 157: 75–85.

  15. 15

    Gupta V, Malone AK, Hari PN, Ahn KW, Hu ZH, Gale RP et al. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2014; 20: 89–97.

  16. 16

    Rondelli D, Goldberg JD, Isola L, Price LS, Shore TB, Boyer M et al. MPD-RC 101 prospective study of reduced-intensity allogeneic hematopoietic stem cell transplantation in patients with myelofibrosis. Blood 2014; 124: 1183–1191.

  17. 17

    Kröger N, Giorgino T, Scott BL, Ditschkowski M, Alchalby H, Cervantes F et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years with primary myelofibrosis. Blood 2015; 125: 3347–3350.

  18. 18

    Tefferi A, Pardanani A, Gangat N, Begna KH, Hanson CA, Van Dyke DL et al. Leukemia risk models in primary myelofibrosis: an International Working Group study. Leukemia 2012; 26: 1439–1441.

  19. 19

    Guglielmelli P, Lasho TL, Rotunno G, Score J, Mannarelli C, Pancrazzi A et al. The number of prognostically detrimental mutations and prognosis in primary myelofibrosis: an international study of 797 patients. Leukemia 2014; 28: 1804–1810.

  20. 20

    Vannucchi AM, Lasho TL, Guglielmelli P, Biamonte F, Pardanani A, Pereira A et al. Mutations and prognosis in primary myelofibrosis. Leukemia 2013; 27: 1861–1869.

  21. 21

    Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC et al. Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2. N Engl J Med 2013; 369: 2391–2405.

  22. 22

    Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med 2013; 369: 2379–2390.

  23. 23

    Tefferi A, Guglielmelli P, Lasho TL, Rotunno G, Finke C, Mannarelli C et al. CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. Leukemia 2014; 28: 1494–1500.

  24. 24

    Alchalby H, Zabelina T, Stübig T, van Biezen A, Bornhäuser M, Di Bartolomeo P et al. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation: a study from the Myeloproliferative Neoplasm Subcommittee of the CMWP of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2014; 20: 279–281.

  25. 25

    Ciurea SO, de Lima M, Giralt S, Saliba R, Bueso-Ramos C, Andersson BS et al. Allogeneic stem cell transplantation for myelofibrosis with leukemic transformation. Biol Blood Marrow Transplant 2010; 16: 555–559.

  26. 26

    Lussana F, Rambaldi A, Finazzi MC, van Biezen A, Scholten M, Oldani E et al. Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: a report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 2014; 99: 916–921.

  27. 27

    Cherington C, Slack JL, Leis J, Adams RH, Reeder CB, Mikhael JR et al. Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase. Leuk Res 2012; 36: 1147–1151.

  28. 28

    Kennedy JA, Atenafu EG, Messner HA, Craddock KJ, Brandwein JM, Lipton JH et al. Treatment outcomes following leukemic transformation in Philadelphia-negative myeloproliferative neoplasms. Blood 2013; 121: 2725–2733.

  29. 29

    Sorror ML, Storb RF, Sandmaier BM, Maziarz RT, Pulsipher MA, Maris MB et al. Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 2014; 32: 3249–3256.

  30. 30

    Wong KM, Atenafu EG, Kim D, Kuruvilla J, Lipton JH, Messner H et al. Incidence and risk factors for early hepatotoxicity and its impact on survival in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2012; 18: 1589–1599.

  31. 31

    Bacigalupo A, Soraru M, Dominietto A, Pozzi S, Geroldi S, Van Lint MT et al. Allogeneic hemopoietic SCT for patients with primary myelofibrosis: a predictive transplant score based on transfusion requirement, spleen size and donor type. Bone Marrow Transplant 2010; 45: 458–463.

  32. 32

    Li Z, Gooley T, Applebaum FR, Deeg HJ . Splenectomy and hemopoietic stem cell transplantation for myelofibrosis. Blood 2001; 97: 2180–2181.

  33. 33

    Martino R, Altés A, Muñiz-Díaz E, Brunet S, Sureda A, Domingo-Albós A et al. Reduced transfusion requirements in a splenectomized patient undergoing bone marrow transplantation. Acta Haematol 1994; 92: 167–168.

  34. 34

    Robin M, Tabrizi R, Mohty M, Furst S, Michallet M, Bay JO et al. Allogeneic haematopoietic stem cell transplantation for myelofibrosis: a report of the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC). Br J Haematol 2011; 152: 331–339.

  35. 35

    Kröger N, Holler E, Kobbe G, Bornhäuser M, Schwerdtfeger R, Baurmann H et al. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Blood 2009; 114: 5264–5270.

  36. 36

    Ballen KK, Shrestha S, Sobocinski KA, Zhang MJ, Bashey A, Bolwell BJ et al. Outcome of transplantation for myelofibrosis. Biol Blood Marrow Transplant 2010; 16: 358–367.

  37. 37

    Patriarca F, Bacigalupo A, Sperotto A, Isola M, Soldano F, Bruno B et al. Allogeneic hematopoietic stem cell transplantation in myelofibrosis: the 20-year experience of the Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Haematologica 2008; 93: 1514–1522.

  38. 38

    Stewart WA, Pearce R, Kirkland KE, Bloor A, Thomson K, Apperley J et al. The role of allogeneic SCT in primary myelofibrosis: a British Society for Blood and Marrow Transplantation study. Bone Marrow Transplant 2010; 45: 1587–1593.

  39. 39

    Ito T, Akagi K, Kondo T, Kawabata H, Ichinohe T, Takaori-Kondo A . Splenic irradiation as a component of a reduced-intensity conditioning regimen for hematopoietic stem cell transplantation in myelofibrosis with massive splenomegaly. Tohoku J Exp Med 2012; 228: 295–299.

  40. 40

    Akpek G, Pasquini MC, Logan B, Agovi MA, Lazarus HM, Marks DI et al. Effects of spleen status on early outcomes after hematopoietic cell transplantation. Bone Marrow Transplant 2013; 48: 825–831.

  41. 41

    Ballinger TJ, Savani BN, Gupta V, Kroger N, Mohty M . How we manage JAK inhibition in allogeneic transplantation for myelofibrosis. Eur J Haematol 2015; 94: 115–119.

  42. 42

    Stübig T, Alchalby H, Ditschkowski M, Wolf D, Wulf G, Zabelina T et al. JAK inhibition with ruxolitinib as pretreatment for allogeneic stem cell transplantation in primary or post-ET/PV myelofibrosis. Leukemia 2014; 28: 1736–1738.

  43. 43

    Armand P, Kim HT, Cutler CS, Ho VT, Koreth J, Alyea EP et al. Prognostic impact of elevated pretransplantation serum ferritin in patients undergoing myeloablative stem cell transplantation. Blood 2007; 109: 4586–4588.

  44. 44

    Kim YR, Kim JS, Cheong JW, Song JW, Min YH . Transfusion-associated iron overload as an adverse risk factor for transplantation outcome in patients undergoing reduced-intensity stem cell transplantation for myeloid malignancies. Acta Haematol 2008; 120: 182–189.

  45. 45

    Kataoka K, Nannya Y, Hangaishi A, Imai Y, Chiba S, Takahashi T et al. Influence of pretransplantation serum ferritin on nonrelapse mortality after myeloablative and nonmyeloablative allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2009; 15: 195–204.

  46. 46

    Dadwal SS, Tegtmeier B, Liu X, Frankel P, Ito J, Forman SJ et al. Impact of pretransplant serum ferritin level on risk of invasive mold infection after allogeneic hematopoietic stem cell transplantation. Eur J Haematol. 2015; 94: 235–242.

  47. 47

    Trottier BJ, Burns LJ, DeFor TE, Cooley S, Majhail NS . Association of iron overload with allogeneic hematopoietic cell transplantation outcomes: a prospective cohort study using R2-MRI-measured liver iron content. Blood 2013; 122: 1678–1684.

  48. 48

    Armand P, Kim HT, Virtanen JM, Parkkola RK, Itälä-Remes MA, Majhail NS et al. Iron overload in allogeneic hematopoietic cell transplantation outcome: a meta-analysis. Biol Blood Marrow Transplant 2014; 20: 1248–1251.

  49. 49

    Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant 2008; 14: 641–650.

  50. 50

    Robin M, Giannotti F, Deconinck E, Mohty M, Michallet M, Sanz G et al. Unrelated cord blood transplantation for patients with primary or secondary myelofibrosis. Biol Blood Marrow Transplant 2014; 20: 1841–1846.

  51. 51

    Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012; 367: 1487–1496.

  52. 52

    Eapen M, Logan BR, Horowitz MM, Zhong X, Perales MA, Lee SJ et al. Bone marrow or peripheral blood for reduced-intensity conditioning unrelated donor transplantation. J Clin Oncol 2015; 33: 364–369.

  53. 53

    Deeg HJ, Gooley TA, Flowers ME, Sale GE, Slattery JT, Anasetti C et al. Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood 2003; 102: 3912–3918.

  54. 54

    Kerbauy DMB, Gooley TA, Sale GE, Flowers ME, Doney KC, Georges GE et al. Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. Biol Blood Marrow Transplant 2007; 13: 355–365.

  55. 55

    Guardiola P, Anderson JE, Bandini G, Cervantes F, Runde V, Arcese W et al. Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Société Française de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood 1999; 93: 2831–2838.

  56. 56

    Daly A, Song K, Nevill T, Nantel S, Toze C, Hogge D et al. Stem cell transplantation for myelofibrosis: a report from two Canadian centers. Bone Marrow Transplant 2003; 32: 35–40.

  57. 57

    Ditschkowski M, Beelen DW, Trenschel R, Koldehoff M, Elmaagacli AH . Outcome of allogeneic stem cell transplantation in patients with myelofibrosis. Bone Marrow Transplant 2004; 34: 807–813.

  58. 58

    Abelsson J, Merup M, Birgegård G, WeisBjerrum O, Brinch L, Brune M et al. The outcome of allo-HSCT for 92 patients with myelofibrosis in the Nordic countries. Bone Marrow Transplant 2012; 47: 380–386.

  59. 59

    Nivison-Smith I, Dodds AJ, Butler J, Bradstock KF, Ma DD, Simpson JM et al. Allogeneic hematopoietic cell transplantation for chronic myelofibrosis in Australia and New Zealand: older recipients receiving myeloablative conditioning at increased mortality risk. Biol Blood Marrow Transplant 2012; 18: 302–308.

  60. 60

    Shanavas M, Messner HA, Atenafu EG, Kim DH, Kuruvilla J, Lipton JH et al. Allogeneic hematopoietic cell transplantation for myelofibrosis using fludarabine-, intravenous busulfan- and low-dose TBI-based conditioning. Bone Marrow Transplant 2014; 49: 1162–1169.

  61. 61

    Zeng W, Huang L, Meng F, Liu Z, Zhou J, Sun H . Reduced-intensity and myeloablative conditioning allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and myelodysplastic syndrome: a meta-analysis and systematic review. Int J Clin Exp Med 2014; 7: 4357–4368.

  62. 62

    Ciurea SO, Sadegi B, Wilbur A, Alagiozian-Angelova V, Gaitonde S, Dobogai LC et al. Effects of extensive splenomegaly in patients with myelofibrosis undergoing a reduced intensity allogeneic stem cell transplantation. Br J Haematol 2008; 141: 80–83.

  63. 63

    Bodge MN, Culos KA, Haider SN, Thompson MS, Savani BN . Preparative regimen dosing for hematopoietic stem cell transplantation in patients with chronic hepatic impairment: analysis of the literature and recommendations. Biol Blood Marrow Transplant 2014; 20: 622–629.

  64. 64

    Klyuchnikov E, Holler E, Bornhäuser M, Kobbe G, Nagler A, Shimoni A et al. Donor lymphocyte infusions and second transplantation as salvage treatment for relapsed myelofibrosis after reduced-intensity allografting. Br J Haematol 2012; 159: 172–181.

  65. 65

    Byrne JL, Beshti H, Clark D, Ellis I, Haynes AP, Das-Gupta E et al. Induction of remission after donor leucocyte infusion for the treatment of relapsed chronic idiopathic myelofibrosis following allogeneic transplantation: evidence for a ‘graft versus myelofibrosis’ effect. Br J Haematol 2000; 108: 430–433.

  66. 66

    Kröger N, Alchalby H, Klyuchnikov E, Badbaran A, Hildebrandt Y, Ayuk F et al. JAK2-V617F-triggered preemptive and salvage adoptive immunotherapy with donor-lymphocyte infusion in patients with myelofibrosis after allogeneic stem cell transplantation. Blood 2009; 113: 1866–1868.

  67. 67

    Reilly JT, McMullin MF, Beer PA, Butt N, Conneally E, Duncombe A et al. Guideline for the diagnosis and management of myelofibrosis. Br J Haematol 2012; 158: 45–471.

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Correspondence to G Barosi.

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NMK declares speakers’ bureau and research funding from Sanofi and Novartis; FC declares consulting and speakers’ bureau from Novartis, AOP and Baxter; DM declares honoraria, speakers’ bureau and research funding from Novartis; AR declares consulting from Piere Fabre Pharma, and Travels from Piere Fabre Pharma and Novartis; EO declares travel expenses for Novartis, Bristol Meyers Squibb and Sanofi; CH declares honoraria and speakers’ bureau from Novartis, Sanofi and Shire. GB declares consulting from Celgene; DN declares speakers’ bureau and travels from Novartis; TB declares consulting, speakers’ bureau from Novartis and Shire; RM declares honoraria and consulting from Novartis, and funding from Incyte, Gilead, Genentech; VG declares honoraria, consulting, and research funding from Novartis and Incyte; AMV declares consulting and speakers’ bureau from Novartis; MD declares consulting from MSD Sharp and Dohme, and research funding from Biosciences; URP declares research funding from CTI Pharma and Otsuka; DR declares consulting from Incyte, and speakers’ bureau from Sanofi. The remaining authors declare no conflict of interest.

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NMK and GB designed the research; GB did the systematic review of literature; NMK, JHD, EO, AB and DN wrote the first draft of the recommendations; TB, AR, RM, AT, MG, VG, CH, HA, AMV, FC, MR, MD, VF, DM, KB, URP, FP and DR criticized the first draft of the recommendations and provided important input in the text of the recommendations; GB wrote the first draft of the manuscript; and all the authors approved the final version of the manuscript.

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Kröger, N., Deeg, J., Olavarria, E. et al. Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group. Leukemia 29, 2126–2133 (2015). https://doi.org/10.1038/leu.2015.233

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