Optimal timing of allogeneic hematopoietic stem cell transplantation in patients with myelodysplastic syndrome

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) represents the only curative treatment for patients with myelodysplastic syndrome (MDS), but involves non-negligible morbidity and mortality. Registry studies have shown that advanced disease stage at transplantation is associated with inferior overall survival. To define the optimal timing of allogeneic HSCT, we carried out a decision analysis by studying 660 patients who received best supportive care and 449 subjects who underwent transplantation. Risk assessment was based on both the International Prognostic Scoring System (IPSS) and the World Health Organization classification-based Prognostic Scoring System (WPSS). We used a continuous-time multistate Markov model to describe the natural history of disease and evaluate the effect of allogeneic HSCT on survival. This model estimated life expectancy from diagnosis according to treatment policy at different risk stages. Relative to supportive care, estimated life expectancy increased when transplantation was delayed from the initial stages until progression to intermediate-1 IPSS-risk or to intermediate WPSS-risk stage, and then decreased for higher risks. Modeling decision analysis on WPSS versus IPSS allowed better estimation of the optimal timing of transplantation. These observations indicate that allogeneic HSCT offers optimal survival benefits when the procedure is performed before MDS patients progress to advanced disease stages.

Figure 1

Markov continuous-time multistate models of the natural history of MDS. IPSS (A) and WPSS (B) risk scores were adopted as time-dependent indicators of the natural course of MDS. Allogeneic HSCT was modeled as a time-dependent covariate, and its effect on survival was estimated as a HR with respect to the “no allogeneic HSCT” category. Solid arrows represent transitions according to the natural course of the disease, while the effect of allogeneic HSCT on transitions is represented in each state by a dashed arrow.

Figure 2

Overall survival of MDS patients. Upper part: overall survival of patients belonging to the Pavia cohort stratified according to time-dependent IPSS (A) or time-dependent WPSS (B). Lower part: overall survival of patients belonging to the GITMO cohort stratified according to IPSS (C) or WPSS (D) scores evaluated at the time of allogeneic HSCT. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 3

Gain in expected survival since diagnosis according to IPSS and WPSS models under different transplant policies with respect to a nontransplantation policy. We assumed that the MDS patient was classified as low IPSS or very low WPSS risk at the time of diagnosis. Each policy was then evaluated for a set of different ages at diagnosis (between 30 and 65 years, with 5-year intervals, as shown in the boxes) and for different waiting times t (between 0 and 60 months since entering any disease state). [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Figure 4

Distribution of WPSS risks within the IPSS risk groups in the Pavia patients that were eligible for transplantation (age <65 years). Within the low IPSS risk group, WPSS identifies a subgroup of patients (13%, first column on the left) with multilineage dysplasia and/or transfusion-dependency that are classified as intermediate or high WPSS risk and would benefit from early transplantation. Within the intermediate-1 IPSS risk group, WPSS identifies about one third (34%, second column from left) of patients with no blast excess and without poor risk cytogenetics that are classified as very low or low WPSS risk and may benefit from delayed transplantation.

Figure 5

Schematic representation of the natural history of myelodysplastic syndrome according to IPSS or WPSS risk stratification. The Markov decision analysis performed in this study indicates that allogeneic hematopoietic stem cell transplantation offers optimal survival benefit when it is performed early in intermediate-1 IPSS risk or intermediate WPSS risk stage, respectively. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]