The Hematologist

March-April 2019, Volume 16, Issue 2

Transplantation and Myelofibrosis: A Little Medicine and a Little Art

Tania Jain, MBBS Fellow, Adult Bone Marrow Transplantation Service
Memorial Sloan Kettering Cancer Center, New York, NY
Jeanne Palmer, MD Consultant, Division of Hematology and Medical Oncology
Mayo Clinic, Phoenix, AZ

Published on: February 19, 2019

Allogeneic stem cell transplantation (HCT) has established the potential to induce molecular and morphological remissions in patients with myelofibrosis. However, there have always been unique concerns with transplantation. Unlike, for example, patients with acute leukemia, patients with myelofibrosis, historically, have had higher toxicities from HCT, possibly due to splenomegaly, marrow fibrosis, or debilitation from the disease. These are in addition to the classical toxicities of the procedure, including organ damage from the conditioning regimen, graft-versus-host disease, relapse, and graft failure. To weigh the “risk versus benefit” balance in favor of benefit to patients, it becomes imperative to identify the right patient at the right time in the disease course to consider them for HCT. Adding another layer of thinking to this decision-making process is the advent of nontransplantation options such as JAK inhibitors and others in the pipeline that improve symptoms and, arguably, improve survival.1,2 Thus far, no comparative randomized data exist between HCT and nontransplantation therapeutic options to assess the magnitude of benefit of HCT in these patients. Hence, most decisions about HCT and the timing thereof are derived by logical extrapolation from available retrospective and registry data.

Disease Factors

Myelofibrosis is a chronic malignancy, the morbidity of which typically evolves over years. For the past decade, decision making for HCT often has been based on two scoring systems: the Dynamic International Prognostic Scoring System (DIPSS) and the DIPSS-Plus. These prognostic metrics were developed to track risk profile over time.3,4 They have also helped establish the timeline for HCT in patients with myelofibrosis. An expert panel recommends consideration of HCT for patients younger than 70 years with DIPSS or DIPSS Plus scores of intermediate-2 or higher, and for intermediate-1 risk patients younger than 65 years if they have refractory/transfusion-dependent anemia, peripheral blasts higher than 2 percent, or adverse cytogenetics, mainly derived from the poor median overall survival of five or fewer years in this subset of patients.5 A retrospective comparison between HCT and nontransplantation therapies from two international multicenter databases, in patients younger than 65 years who never received JAK inhibitors, showed benefit of HCT approach in patients with intermediate-2 and high-risk DIPSS.6

Neither of these scoring systems, however, takes into account molecular mutations, which have been associated with more aggressive disease phenotypes or with early transformation to blast-phase disease, a dire development. To amend that, Mutation-Enhanced International Prognostic Score Systems (MIPSS70 and MIPSS70-Plus), and subsequently, MIPSS70-Plus version 2.0, have been described for patients 70 years or younger to include clinical factors along with cytogenetic and molecular mutations in a prognostic model.7,8 Presence of one or two high-risk mutations such as ASXL1, EZH2, SRSF2, or IDH1/2, and absence of CALR type 1 mutation added additional risk factors in the MIPSS70-Plus model. In version 2.0, the U2AF1 Q157 mutation, a very high-risk cytogenetic category and gender-based hemoglobin stratification, was included in the scoring model. Using retrospective or registry datasets, efforts to apply these newer systems to the question of when to transplant, and in whom, have been published. For example, the former, a four-tiered MIPSS70-Plus classification, suggests watchful monitoring for low-risk disease while considering HCT for high- and very high-risk disease.8 Similarly, for the five-tier MIPSS70-Plus version 2.0, HCT is recommended for high- and very high-risk patients, while non-HCT management is recommended for very low-, low-, and intermediate-risk patients.7 Of note, these scoring systems were developed and validated in patients with “primary” myelofibrosis but are often applied to post-polycythemia vera or post-essential thrombocythemia myelofibrosis with similar principles. That being said, there is a specific prognostic scoring system that has been developed for patients with secondary myelofibrosis who are older than 65 years, with time to secondary myelofibrosis greater than 15 years, who have previous thrombosis and constitutional symptoms, hemoglobin lower than 10 g/dL, and circulating blasts of 1 percent or higher.9 This scoring system has not yet undergone rigorous validation with regard to transplant outcomes.

The utility of these scoring systems walks closely with identification of changes in clinical course of the patient. Transitions such as worsening transfusion requirements, increasing blasts, the appearance or deterioration of constitutional symptoms can be ominous signs and should be recognized early to enable timely initiation of treatments, including consideration for HCT. Data suggest that patients with three or more mutations may have limited response to JAK inhibitors, and hence, these patients may be the ones to start thinking of HCT at the first indication of clinical deterioration.10 Further, there are data that suggest that HCT may benefit patients with high-risk chromosomes11 and somatic mutations.12,13

Patient Factors

For HCT, “the older the age, the worse the outcomes” is a generally accepted phenomenon. This is especially relevant in myelofibrosis because the median age at diagnosis is older than 65 years. With recent improvements in supportive therapy and the popularity of reduced-intensity conditioning, the age limit for HCT continues to shift upward. In myelofibrosis, HCT with reduced-intensity conditioning has been reported in patients older than 70 years with some success.14 This also shows that chronological age itself might not be as informative as in combination with performance status and comorbidities.

Eventually, it’s about striking the balance between anticipated benefit in disease features and risks from transplant-related mortality based on an individual’s overall health and performance status. Fine tuning of this assessment relies on experience and appreciation of disease transitions. The art lies in close follow-up and enquiry into the symptoms, leading to some understanding of the disease biology in an individual patient.

What Lies Ahead?

As illustrated in this article, while expert panel recommendations have been established, many aspects related to timing and the point of maximal benefit remain shrouded in the “no data zone.” Additionally, myelofibrosis being a relatively uncommon malignancy, it is almost obligatory to conduct collaborative efforts.

Transplantation versus nontransplantation options. Most established recommendations are based on the data available from the pre–JAK inhibitor era. Whether the same holds true with improvements attributed to JAK inhibitors remains a question. A randomized study to compare HCT versus non-HCT options would be difficult to conduct. However, a current Center for International Blood and Marrow Transplant Research initiative is enrolling patients older than 55 years, to compare outcomes of patients undergoing HCT with those of an age-matched historical cohort (NCT02934477), which would shed some light towards this.

While on ruxolitinib. In real-world clinical scenarios, another challenging question is what is the best window to HCT when patients have improvement in symptoms while on JAK inhibitors. Is it when patients have the maximal response from JAK inhibitors or when they begin to lose the clinical response, such as at the return of the constitutional symptoms or splenomegaly? This can be feasibly studied in a randomized fashion as a collaborative effort.

Should you transplant if there are too many mutations? It also remains unknown whether the high risk portended by mutation status is overcome by HCT — information that can provide additional insight into identifying patients who may benefit from HCT consideration at an earlier course in the disease (or not) and that might offer a quantification of benefit from HCT in these patients.

To Transplant or Not to Transplant?
 CharacteristicTransplant?
PatientAge < 65-70 years, good performance status, no/minimal comorbiditiesYes, considering disease factors
Age > 70 years, good performance status, no/minimal comorbiditiesIndividualized evaluation considering disease/ donor factors; recommend reduced intensity conditioning
Age < 65 years, poor performance status, or comorbiditiesIndividualized decision considering disease/ donor factors
DiseaseDIPSS/DIPSS Plus score = intermediate-2 or highYes, considering patient factors
DIPSS score = intermediate-1, age < 65 years, high risk cytogenetics, or molecular mutations (IDH1/2, SRSF2, SF3B1 in primary or post-PV or post-ET and EZH2, ASXL1 in primary MF), or peripheral blood blasts >2% or transfusion refractory anemiaYes, considering patient factors
MIPSS70 Plus high risk/ very high riskYes, considering patient factors
MIPSS70 Plus version 2.0 high/ very high riskYes, considering patient factors
MIPSS70 Plus/ MIPSS70 Plus version 2.0 intermediate risk with worsening clinical featuresYes, considering patient factors
Donor availabilityHLA matched related or unrelated donorYes, considering patient and disease factors
HLA haploidentical family member or umbilical cord bloodIndividualized decision considering patient and disease factors

Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; HLA, human leukocyte antigen; MF, myelofibrosis; MIPSS, Mutation-Enhanced International Prognostic Score System; PV, polycythemia vera.

References

  1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med. 2012;366:799-807.
  2. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and-II pooled analyses. J Hematol Oncol. 2017;10:156.
  3. Passamonti F, Cervantes F, Vannucchi AM, et al. A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group Myeloproliferative Neoplasms Research and Treatment). Blood. 2010;115:1703-1708.
  4. Gangat N, Caramazza D, Vaidya R, 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.
  5. Kröger NM, Deeg JH, 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. 2015;29:2126-2133.
  6. Kröger N, Giorgino T, Scott BL, et al. Impact of allogeneic stem cell transplantation on survival of patients less than 65 years of age with primary myelofibrosis. Blood. 2015;125:3347-3350.
  7. Tefferi A, Guglielmelli P, Lasho TL, et al. MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for primary myelofibrosis. J Clin Oncol. 2018;36:1769-1770.
  8. Guglielmelli P, Lasho TL, Rotunno G, et al. MIPSS70: Mutation-Enhanced International Prognostic Score System for transplantation-age patients with primary myelofibrosis. J Clin Oncol. 2018;36:310-318.
  9. Passamonti F, Giorgino T, Mora B, et al. A clinical-molecular prognostic model to predict survival in patients with post polycythemia vera and post essential thrombocythemia myelofibrosis. Leukemia. 2017;31:2726-2731.
  10. Patel KP, Newberry KJ, Luthra R, et al. Correlation of mutation profile and response in patients with myelofibrosis treated with ruxolitinib. Blood. 2015;126:790-797.
  11. Tefferi A, Partain DK, Palmer JM, et al. Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis. Am J Hematol. 2018;93:649-654.
  12. Tamari R, Rapaport F, Zhang N, et al. Impact of high molecular risk mutations on transplant outcomes in patients with myelofibrosis. Biol Blood Marrow Transplant. 2019; doi: 10.1016/j.bbmt.2019.01.002. [Epub ahead of print].
  13. Kröger N, Panagiota V, Badbaran A, et al. Impact of molecular genetics on outcome in myelofibrosis patients after allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2017;23:1095-1101.
  14. Samuelson S, Sandmaier BM, Heslop HE, et al. Allogeneic haematopoietic cell transplantation for myelofibrosis in 30 patients 60-78 years of age. Br J Haematol. 2011;153:76-82.

Conflict of Interests

Dr. Jain and Dr. Palmer indicated no relevant conflicts of interest. back to top