Allogeneic Hematopoietic Cell Transplantation in Myelodysplastic Syndrome Patients

Key Concepts

• Hematopoietic cell transplantation provides a curative therapy for patients with myelodysplastic syndrome.

• The clonal karyotype is the strongest predictor of posttransplant relapse.

• The availability of human leukocyte antigen (HLA)-matched related and unrelated donors, HLA-haploidentical donors, and umbilical cord blood helps identify donors for the majority of patients.

• As myelodysplastic syndrome is primarily a disease of older age and quality of life is a top priority for most older individuals, discussions regarding transplantation in older patients must include not only the acute effects of transplantation but also the delayed effects.

Background

Myelodysplastic syndromes (MDS) are composed of a family of clonal hematopoietic diseases characterized by bone marrow failure and a predisposition to evolve into acute myeloid leukemia (AML). Despite the major progress in the understanding of the pathophysiology of MDS and recent advances in treatment with hypomethylating agents (HMA), MDS remains an incurable disease with standard forms of treatment. Allogeneic hematopoietic cell transplantation (HCT) is the only therapeutic option that has the potential to cure this disease, producing 25% to 60% long-term disease-free survival (DFS) depending on prognostic features. The current National Comprehensive Cancer Network (NCCN) guidelines recommend that MDS patients eligible for a transplantation procedure based on age and donor availability be considered for this therapy. MDS is currently the third most common indication for allogeneic HCT reported by the Center for International Blood and Marrow Transplantation Research (CIBMTR). MDS predominantly involves older individuals; more than 80% are reported to be older than 60 years. Reduced intensity conditioning (RIC) regimens allow allogeneic transplants to be performed, even into the eighth decade of life.

Allogeneic HCT is a high-risk, high-reward procedure. It is a major undertaking, requiring the full commitment of the patient and their caregivers. The patients typically are hospitalized for about 1 month for the conditioning regimen, transplantation, and initial hematologic recovery. They must be monitored very closely for the first 3 to 6 months during the time of greatest risk of complications including graft rejection, graft-versus-host disease (GvHD), and infection. Many patients will have GvHD that will require ongoing immunosuppressive therapy. Late complications may occur. There is a substantial risk of treatment-related mortality (TRM), which depends on patient, disease, and donor characteristics, and some patients who succumb early to complications may have their lives shortened compared to conservative management. Allogeneic HCT is, however, the only treatment capable of eradicating the disease and producing long-term DFS. Patients need to be highly motivated and determined to undergo the procedure. The role of HCT should be discussed with a patient early in the course of their disease. For those interested in undergoing allogeneic transplantation as a potentially curative treatment option, one should plan to proceed to the transplant at the point when it is most likely to be successful.

Who Will Benefit from Allogeneic Hematopoietic Cell Transplant?

The clinical course of MDS varies with survival from many years to only a few months depending on prognostic features. A number of prognostic indices have been developed for risk stratification that would guide the choice of therapy. The most commonly used scoring system is the International Prognostics Scoring System (IPSS) including number of blasts, cytopenia, and cytogenetics. IPSS separates patients into four distinct categories as low, intermediate-1, intermediate-2, and high risk. Median survival is longer than 5 years in low-risk disease but less than 1 year with high-risk disease. This system has several limitations. It is not a very precise predictor of prognosis in patients with lower risk disease and it attributes relatively little weight to cytogenetics. Therefore the IPSS has undergone revisions (IPSS-R) that take into consideration different subgroups of cytogenetic abnormalities and the depth of cytopenias, leading to the expansion of risk categories into five groups: “very good,” “good,” “intermediate,” “poor,” and “very poor” risk. Malcovati et al. also developed a time-dependent prognostic scoring system, the World Health Organization (WHO) classification-based prognostic scoring system (WPSS), incorporating WHO histologic subtype, karyotype, and transfusion requirement. This scoring determines the prognosis of MDS patients not only at diagnosis but also during their disease course and was able to identify different risk groups for overall survival (OS) with 5-year estimates of 80% in patients with low risk, 63% in those with intermediate, 40% in patients with high, and 16% in patients with very high risk.

The MDS scoring systems have been validated in the nontransplantation MDS cohort. However, IPSS, IPSS-R, and WHO scoring systems have been shown to have predictive values for HCT outcomes as well. DFS at 5 years after HCT was reported to be 60%, 36%, and 28% for low and intermediate-1, intermediate-2, and high-risk groups per IPSS scoring, respectively. The IPSS-R classification was also found to be an independent predictive factor for allogeneic transplant outcomes in 519 patients with primary MDS or oligoblastic AML (20%–29% bone marrow blasts). In that analysis, only patients with matched-related or matched-unrelated donors were included and the 5-year OS after HCT was found to be 71% in low, 58% in intermediate, 39% in high, and 23% in very high-risk patients. Similarly, in those risk groups, by competing risk analysis, the 5-year cumulative incidence of relapse was 4%, 12%, 23%, and 39%, respectively. Data also suggest that WHO or WPSS can predict post-HCT outcomes; 5-year survival was 51% to 80% for lower risk patients with refractory anemia (RA), refractory cytopenia and RA with excess blasts-1 (RAEB-1), but only 25% to 28% in those with a higher bone marrow blast percentage (5%–20%).

Since 2012, the IPSS-R has been a standard for evaluation of risk-based clinical outcomes, and design of therapeutic strategies and clinical trials based on prognostic risk-based features. The European LeukemiaNet and the American NCCN MDS practice guidelines recommend treatment based on the IPSS-R, age, and performance status. On the other hand, a new molecular IPSS system is expected.

Over the last decade, a number of very important studies have been published describing comprehensive analysis of the incidence and clinical impact of multiple genetic lesions in MDS. Bejar and colleagues used next generation sequencing (NGS) and mass spectrometry to identify relevant mutations in 439 MDS patients. In particular, mutations of TP53, EZH2, ETV6 , and ASXL1 were found to be significantly associated with more rapid disease progression and increased risk of mortality. Since then, multiple other studies describing the mutational landscape of MDS and its potential prognostic and therapeutic implications have been published. Despite the differences in the study designs and mutational techniques applied, mutations of RUNX1 , TP53 , or EZH2 have consistently been associated with an adverse prognosis while mutations in the splicing factor SF3B1 are associated with very favorable outcomes and prolonged survival. Bejar et al. also addressed the effect of molecular lesions on prognosis after HCT and showed that mutations in TP53, TET2 , and DNMT3A were associated with decreased OS. Three-year OS in patients without these mutations was 59% versus 19% in patients with these mutations. A large CIBMTR cohort was also studied for somatic mutations and confirmed that presence of TP53 mutation was associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations after allogeneic HCT ( Fig. 18.1 ). The negative impact of TP53 mutations on survival after transplantation among patients with MDS was independent of clinical factors such as age, Karnofsky performance-status score, and hematologic variables. Despite that, as many as 20% to 25% TP53 -mutated patients survived > 2 years, indicating there is clinical benefit with HCT in this poor-risk population. This study also indicated that presence of RAS pathway mutations was associated with shorter survival because of relapse while the presence of JAK2 mutations was associated with shorter survival because of nonrelapse mortality (NRM). We recently reported our experience for the prognostic impact of somatic mutations on disease outcomes in 225 MDS patients transplanted MD Anderson Cancer Center (MDACC). Our results revealed that when cytogenetics and somatic mutations were integrated for prognosis, there were four distinct risk groups for disease relapse after HCT: high-risk (very-poor cytogenetics by IPSS-R or presence of DNMT3A mutation), intermediate-risk (good/very good, intermediate, or poor cytogenetics by IPSS-R with the presence of RAS -pathway mutations), low-risk (poor cytogenetics by IPSS-R and the absence of both RAS -pathway and DNMT3A mutations), and very-low-risk group (good/very good or intermediate cytogenetics by IPSS-R and the absence of both RAS- pathway and DNMT3A mutations). The cumulative incidence of progression at 2-years was 56%, 42%, 26%, and 6% in the respective risk groups. In our analyses, patients with very-poor cytogenetic by IPSS-R had a high frequency of TP53 mutations (76%) and 70% of the observed TP53 mutations occurred in patients with very-poor risk cytogenetics. Therefore in the final model, TP53 mutation was not included. It is obvious that additional studies investigating the impact of specific mutations on treatment outcomes (transplant and nontransplant) are required to better inform clinicians and patients, especially in patients with lower-risk category (i.e., IPSS-R, low/intermediate) who carry high-risk mutations. These emerging data will have a significant impact not only on our ability to prognosticate patients with MDS, but also in potentially identifying transplant candidates.

As indicated, therapy-related MDS (t-MDS) has a poor prognosis; this entity is not considered in the IPSS prognostic system and most of the published prognostic models. Litzow et al. reported that allogeneic HCT is effective for patients with t-MDS, particularly before evolution to AML. This was a CIBMTR study including 868 persons with t-AML or t-MDS receiving allogeneic HCT from 1990 to 2004. TRM and relapse were 41% and 27% at 1 year and 48% and 31% at 5 years, respectively. DFS and OS were 32% and 37% at 1 year and 21% and 22% at 5 years, respectively. In multivariate analysis, four risk factors had adverse impact on survival: age older than 35 years, poor-risk cytogenetics, t-AML not in remission or advanced t-MDS, a donor other than a human leukocyte antigen (HLA)–identical sibling or a partially or well-matched–unrelated donor. Five-year survival for subjects with none, 1, 2, 3, or 4 of these risk factors was 50%, 26%, 21%, 10%, and 4%, respectively ( P < .001). Prompt referral for allogeneic HCT is recommended for patients who are transplant candidates.

Thus, recent risk classification systems and the identification of genetic mutations are identifying patients with “high-risk” MDS who should be considered for HCT early in the disease course. It is also obvious that we need more innovative therapy approaches with HCT to overcome the poor prognosis of those patients.