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Contribution of Revised International Prognostic Scoring System Cytogenetics to Predict Outcome After Allogeneic Stem Cell Transplantation for Myelodysplastic Syndromes

A Study From the French Society of Bone Marrow Transplantation and Cellular Therapy

Gauthier, Jordan1,2; Damaj, Gandhi3; Langlois, Carole4; Robin, Marie5; Michallet, Mauricette6; Chevallier, Patrice7; Beguin, Yves8; N’guyen, Stéphanie9; Bories, Pierre10; Blaise, Didier11; Cornillon, Jérôme12; Clavert, Aline13; Mohty, Mohamad14; Huynh, Anne15; Thiébaut-Bertrand, Anne16; Vigouroux, Stéphane17; Duhamel, Alain4; Yakoub-Agha, Ibrahim1,2

doi: 10.1097/TP.0000000000000649
Original Clinical Science—General
Free

Background The prognosis of myelodysplastic syndromes (MDS) after allogeneic stem cell transplantation is critically determined by cytogenetic abnormalities, as previously defined by International Prognostic Scoring System (IPSS) cytogenetics. It has been shown that a new cytogenetic classification, included in the IPSS-R (cytogenetic-IPSS-R [C-IPSS-R]), can better predict the outcome of untreated MDS patients.

Methods In this study, we assessed the impact of the IPSS-R cytogenetic score (C-IPSS-R) on the outcome of 367 MDS patients transplanted from HLA-identical siblings or HLA allele-matched unrelated donors.

Results According to the C-IPSS-R, 178 patients (48%) fell in the good risk, 102 (28%) in the intermediate risk, 77 (21%) in the poor risk, and 10 (3%) in the very poor risk group. In multivariate analysis, after a median follow-up of 4 years, the poor and very poor-risk categories correlated with shorter overall survival (OS) (4-year OS, 32%; hazard ratio [HR], 1.59; P = 0.009 and OS, 10%; HR, 3.18; P = 0.002, respectively) and higher cumulative incidence of relapse (CIR) (CIR, 52%; HR, 1.82; P = 0.004 and CIR, 60%; HR, 2.44; P = 0.060, respectively).

Conclusions Overall, the C-IPSS-R changed the IPSS cytogenetic risk only in 8% of cases but identified a new risk group, the very poor C-IPSS-R category, with dismal outcome after allogeneic stem cell transplantation (10% 4-year OS, 60% 4-year CIR). Posttransplantation maintenance therapy should be investigated in prospective trials for patients with high-risk C-IPSS-R karyotypes.

In a French retrospective, multicenter study use of the revised International Prognostic Scoring System classification helps predict the outcome of untreated patients with a myelodysplastic syndrome, especially in the most severe cases.

1 CHRU Lille, Pôle Spécialités Médicales et Gérontologie, Service des Maladies du Sang, Secteur Allogreffe de Cellules Souches Hématopoïétiques, F59037, Lille, France.

2 Université de Lille, UFR Médecine F59000, Lille, France.

3 Hematology Department, Caen University Hospital, Amiens, France.

4 Department of Biostatistics, Lille University Hospital, Lille, France.

5 Hematology Department and Hematopoietic Stem Cell Transplantation Unit, Saint-Louis Hospital, Paris, France.

6 Hematology Department, Lyon-Sud Hospital, Lyon, France.

7 Hematology Department, Nantes, France.

8 Hematology Department CH-Liège, Liège, Belgium.

9 Hematology Department, Pitié-Salpêtrière Hospital, Paris, France.

10 Hematology Department, Strasbourg University Hospital, Strasbourg, France.

11 Hematopoietic Stem Cell Transplantation Unit, Paoli Calmettes Institute, Marseille, France.

12 Hematology Department, Loire Oncology Institute (ICL), Saint Priest en Jarez, France.

13 Hematology Department, Nantes University Hospital, Nantes, France.

14 Hematology Department, Saint-Antoine Hospital, Paris, France.

15 Hematology Department, Toulouse University Hospital, Toulouse, France.

16 Hematology Department, Grenoble University Hospital, Grenoble, France.

17 Hematology Department, Bordeaux University Hospital, Bordeaux, France.

Received 7 September 2014. Revision requested 5 November 2014.

Accepted 31 October 2014.

The authors declare no conflict of interest.

This study was presented, in part at the French Society of Bone Marrow Trans-plantation and Cell Therapy (SFGM-TC) annual meeting, November 8–11, 2013, Lyon, France and at the European Bone Marrow Transplantation Congress, April 1–3, 2014, Milan, Italy.

J.G. participated in research design, in the writing of the paper and in data analysis. G.D. participated in the writing of the paper and in data analysis. C.L. participated in data analysis, M.R., M.M., P.C. Y.B., S.N., P.B., D.B.,, J.C., A.C., M.M., A.H., A.T.-B., S.V., and A.D. participated in the writing of the paper and in the performance of the research. I.Y.-A. participated in the research design, in the writing of the paper and in the performance of the research.

Correspondence: Ibrahim Yakoub-Agha, MD, PhD, UAM allogreffes de CSH, CHRU Lille, F-59037 Lille CEDEX, France. (Ibrahim.yakoub-agha@chru-lille.fr).

Myelodysplastic syndromes form a heterogeneous group of myeloid neoplasms with varying outcomes, mainly influenced by the cytogenetic abnormalities borne by the malignant clone. Common management of myelodysplastic syndrome (MDS) patients comprises best supportive care, hypomethylating agents (HMAs) or induction-type chemotherapy, although none of those treatments will prevent ineluctable progression or relapse. Because of its curative potential, allogeneic stem cell transplantation (allo-SCT) remains the best treatment option for MDS patients.1-4 The International Prognostic Scoring System (IPSS),5 the revised IPSS (IPSS-R),6 and the World Health Organization (WHO) classification–based scoring system (WPSS)7 are presently in use by clinicians to help risk stratification. Besides bone marrow blasts, cytopenias and transfusion requirement for the WHO classification–based scoring system, cytogenetic abnormalities make for the most adverse item in all the aforementioned scores. Several retrospective studies observed a sustained impact of IPSS-poor risk cytogenetics after allo-SCT, isolating patients with an increased risk of relapse.8 Karyotypic prognostication of MDS patients has been recently refined into a 5-group classification9 and included in the IPSS-R (C-IPSS-R).6 In a large retrospective study, Deeg et al10 observed a more discriminating effect of this new C-IPSS-R classification compared to IPSS cytogenetics to predict poor prognosis after allo-ST. Additionally, the presence of a monosomal karyotype (MK) was associated with poorer outcome, which was also observed in another study carried out by the European Society for Blood and Marrow Transplantation group.11 Monosomal karyotypes were included as well in a transplantation-risk index recently published by Della Porta et al.12

In this retrospective, multicenter study, we evaluated the impact of the C-IPSS-R classification on the outcome of a large cohort of MDS patients undergoing allo-SCT from HLA-identical siblings or 10/10 HLA allele-matched unrelated donors. Moreover, we assessed its contribution when compared to stratification by IPSS cytogenetics and according to the presence of an MK.

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MATERIALS AND METHODS

This study was approved by the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) board and conducted according to the declaration of Helsinki.

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Patient and Donor Characteristics

We analyzed 367 consecutive patients with MDS who underwent allo-SCT in 23 French and Belgian centers between January 1999 and December 2009. Morphological classification, according to French-American-British13 and WHO classifications14 was documented as a separate variable at initial diagnosis and at time of transplantation. Prior progression was defined as a change of WHO/French-American-British category, regardless of treatment, between diagnosis and transplant. Disease status at transplant was defined by 2 categories: “active disease” and “responders.” The “active disease” group was attributed in the following cases: stable disease, relapse after complete or partial remission, response failure or progressive disease after treatment according to International Working Group 2006 criteria.15 In addition, patients who received best supportive care only before transplantation were also included in the “active disease” group. When complete or partial remission International Working Group 2006 criteria were observed at transplant, patients were classified as “responders.” Patient characteristics at diagnosis and at transplant are summarized in Table 1 and Table 2, respectively.

TABLE 1

TABLE 1

TABLE 2

TABLE 2

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Transplantation and Follow-Up Modalities

Transplantation modalities were made as homogenous as possible using the following inclusion/exclusion criteria: (i) Patients older than 18 years referred for first allo-SCT. (ii) Source of stem cell was marrow or blood from either a sibling or an HLA-A, −B, −Cw, −DR, and -DQ identical unrelated donor at allele level (so-called 10/10). Patients who received allo-SCT from an HLA-mismatched donor, cord blood, or T-cell–depleted graft, and patients with chronic myelo-monocytic leukemia were excluded. The participating centers were asked to verify the data recorded for each patient in the French Bone Marrow Transplantation Registry and to provide additional information. Quality of the data was controlled using a computerized search for discrepancy errors and vigorous on-site data verification of each file. The HLA matching was crosschecked with the data of the French Bone Marrow Donor Registry as previously described.16 Predonation work-ups in donors17 and follow-up after transplantation18-20 were conducted according to the SFGM-TC guidelines.21

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Cytogenetics

Cytogenetic analysis at diagnosis was performed using conventional procedures and documented with respect to the International System for Human Cytogenetic Nomenclature. Cytogenetic abnormalities were classified according to the C-IPSS-R classification designed by Shantz et al5 as well as the IPSS cytogenetic classification. The presence of an MK was also assessed and defined as the combination of 2 monosomies or 1 structural abnormality associated with 1 monosomy.22 Three patients who fell in the very good risk category were removed from the analysis, and 49 patients were excluded because their files lacked or provided incomplete cytogenetic data.

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Statistical Analysis

The analysis was performed on the reference date of April 1, 2011. Overall survival (OS) was defined as the interval from allo-SCT to death, regardless of the cause of death. Relapse was defined as the presence of more than 5% marrow blasts and/or reappearance of major myelodysplastic features associated with cytopenia and evidence of autologous reconstitution when chimerism was available. Nonrelapse mortality (NRM) was defined as death resulting from the graft procedure without evidence of relapse. All censored criteria were calculated from the time of transplantation. Distributions over time were estimated by the Kaplan-Meier product limit method. The log-rank test was used to determine the prognostic value of patient characteristics at transplant on OS. The occurrence of relapse and NRM was studied using a competing risk methodology. For the event of relapse, NRM was considered as the competing event. For NRM, the competing event was relapse. The cumulative incidence of each event was estimated using the Kalbfleish and Prentice method. The individual prognostic value of each variable was assessed by the Gray test (comparison of cumulative incidence curves using bivariate analyses). Variables having a significance level of P less than 0.15 in univariate analysis were introduced in a multivariable Cox regression model for OS, in a Fine and Gray model for relapse and NRM, with backward selection at level P less than 0.15. Adjusted hazard ratios and 95% confidence intervals (95% CI) were computed, and a P value of 0.05 or less was considered statistically significant. Statistical analyses were performed using the SAS and R software programs. The R package “cmprsk” was used for the Fine and Gray model.

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RESULTS

Patient Characteristics

At diagnosis, 114 (31%) of the 367 patients had refractory anemia (RA), RA with ringed sideroblasts or refractory cytopenia with multilineage dysplasia, 102 patients (28%) had RA with excess of blasts (RAEB-1 < 10%), 134 patients (36%) had RA with excess of blasts ranging from 10% to 19% (RAEB-2), and 17 patients (5%) had RAEB in transformation/ acute myeloid leukemia with marrow blasts between 20% and 30% (Tables 1 and 2).

We analyzed 230 males (63%) and 137 females (37%) with a median age of 54 years (range, 20-70) at allo-SCT. The donor was an HLA-matched sibling in 229 cases (62%) and an HLA-matched unrelated donor in 138 (38%). The conditioning regimen was myeloablative conditioning (MAC) in 141 patients (38%) and reduced intensity conditioning/nonmyeloablative in 226 patients (62%).23 Peripheral blood stem cell was used in 68% and bone marrow stem cells in 32% of our patients. An excess of blasts in the marrow was observed in 159 patients (43%) of our patients. Overall, 118 of the 367 patients (32%) had progressed to more advanced disease before transplantation. A best supportive care approach had been offered to 146 patients (40%), whereas 237 patients (56%) had received either an HMA and/or induction-type chemotherapy. Median time to transplantation was 10 months and median follow-up after transplantation was 4 years (range, 3-142 months). In the poor IPSS karyotypes and intermediate risk C-IPSS-R subsets, median follow-up was of 69 months (range, 18-124) and 53 months (range, 3-134), respectively. The whole estimate for OS was of 45%, whereas cumulative incidence of relapse (CIR) and NRM were of 37% and 24%, respectively. Median time for neutrophil engraftment was of 17 days (range, 0-100). Grade 2 to 4 acute Graft Versus Host Disease (GVHD) was diagnosed in 142 patients (39%) and grade 3 to 4 acute GVHD in 66 patients (18%). Among the 322 patients alive after day 100, we observed chronic GVHD in 176 patients (55%) and extensive GVHD in 67 patients (33%).

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Cytogenetic Subgroups

Cytogenetic risk was, according to the C-IPSS-R, good, intermediate, poor, or very poor in 178 (48%), 102 (28%), 77 (21%), and 10 (3%) patients, respectively. The IPSS cytogenetic good risk group coincided completely with the C-IPSS-R good risk group (175 patients). Three patients in the IPSS intermediate risk group were classified as good risk by the C-IPSS-R classification and in those patients the following abnormalities were found: del 12p, del 5q with monosomy 11, del 5q with trisomy 21. Four patients with intermediate IPSS karyotypes fell in the C-IPSS-R poor risk group (all 4 patients carried chromosome 3 abnormalities). The IPSS high-risk patients were split into the IPSS-R intermediate (12 patients with del 7q), poor (73 patients), and very poor risk group (10 patients with complex karyotypes including more than 3 abnormalities). Overall, a change in the cytogenetic risk was only observed in 29 patients (8%).

We observed a MK in 63 (17%) patients. Considering C-IPSS-R, MKs were present in 1 (1%), 8 (8%), 46 (60%), and 8 (80%) patients within the good, intermediate, poor, and very poor risk groups, respectively. Among patients without an MK (n = 304) 177 (58%) fell in the good risk, 94 (31%) in the intermediate risk, 31 (10%) in the poor risk, and 2 (0.6%) in the very poor risk C-IPSS-R category. In those 2 patients, a complex karyotype with more than 3 abnormalities was found but without any monosomy. The following MKs were identified in patients with intermediate risk by C-IPSS-R (n = 8): monosomy 5 and trisomy 21, del 11q and monosomy 20, monosomy 5 and t(X;1), monosomy 5 and trisomy 8 in 2 patients, monosomy 9 and monosomy 11, monosomy 2 and trisomy 17, monosomy 5 and monosomy 11.

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Univariate Analysis

As shown in Table 3, classification by C-IPSS-R, IPSS cytogenetics and MKs significantly impacted OS and relapse. The OS and CIR according to C-IPSS-R categories are represented in Figure 1.

TABLE 3

TABLE 3

FIGURE 1

FIGURE 1

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Overall Survival

The C-IPSS-R (P = 0.004), the IPSS (P = 0.015) cytogenetic classification, and the presence of an MK (P = 0.006) were associated with shorter survival. Previous progression (P = 0.037), marrow blasts that are 5% or higher (P = 0.012), total body irradiation (P = 0.006), and platelet count of 73G/L or less at transplant (P = 0.002) also adversely impacted OS.

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Cumulative Incidence of Relapse

Patient age (P = 0.019), C-IPSS-R (P = 0.001), IPSS cytogenetics (P = 0.004), MKs (P < 0.001), marrow blasts that are 5% or higher (P = 0.013) and reduced intensity conditioning/nonmyeloablative (P = 0.006) were associated with higher CIR.

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Nonrelapse Mortality

Higher NRM was observed in patients with active disease at transplantation (P = 0.040) and in those allografted from an unrelated donor (P = 0.046). The MAC (P < 0.001) and antithymocyte globulin (P = 0.005) were also associated with higher NRM.

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Subgroups Univariate Analysis

To evaluate the contribution of the C-IPSS-R, we applied this new classification to 95 patients with poor risk IPSS karyotypes and identified 2 groups with different outcomes. As displayed in Figure 2, CIR was significantly lower in patients with intermediate risk C-IPSS-R, compared to a group including both poor and very poor risk C-IPSS-R groups with relapse rates of 17% and 55%, respectively (P = 0.025). The C-IPSS-R reclassified a very few patients previously categorized as intermediate risk by IPSS cytogenetics. In this subgroup, 3 patients fell in the good risk category and 4 patients in the poor risk group. No difference was observed regarding relapse rates (n = 96, P = 0.402).

FIGURE 2

FIGURE 2

As shown in Figure 3, among 102 patients classified as C-IPSS-R intermediate risk, patients with MKs relapsed more often (63% vs 28%; P = 0.006) but had similar OS rates (29% vs 45%; P = 0.282). A trend toward higher relapse rates was also observed in C-IPSS-R poor risk patients with MKs (n = 77) but this did not reach statistical significance (61% vs 39%; P = 0.091, data not shown).

FIGURE 3

FIGURE 3

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Multivariate Analysis

Poor and very poor C-IPSS-R groups were independent risk factors for shorter OS (hazard ratio [HR], 1.56; 95% CI, 1.10-2.20; P = 0.012 and HR, 2.67; 95% CI, 1.33-5.35; P = 0.006, respectively), and higher CIR (HR, 1.82; 95% CI, 1.20-2.72; P = 0.004 and HR, 2.44; 95% CI, 0.93-5.27; P = 0.060, respectively). Marrow blasts at transplant that are 5% or higher was an independent risk factor for shorter OS (HR, 1.33; 95% CI, 1.00-1.75, P = 0.049) and higher CIR (HR, 1.46; 95% CI, 1.04-2.07; P = 0.034). Previous progression was associated with shorter OS but without reaching statistical significance (HR, 1.30; 95% CI, 0.97-1.74; P = 0.081). Patients who received total body irradiation had significantly shorter OS (HR, 1.38; P = 0.010). The MAC was associated with lower relapse rates (HR, 0.59; 95% CI, 0.40-0.85; P = 0.004, respectively). Two independent risk factors for higher NRM were identified: HLA-matched unrelated donors (HR, 1.57; 95% CI, 1.03-2.40; P = 0.035) and MAC regimens (HR, 2.17; 95% CI, 1.40-3.33, P < 0.001) (Table 4).

TABLE 4

TABLE 4

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DISCUSSION

Allo-SCT remains today the only therapeutic option to potentially cure patients suffering from MDS. However, high-risk cytogenetics strongly hinders the procedure. Because the IPSS-R cytogenetic classification was based on analysis of nontransplanted MDS patients, we wished to determine its contribution once compared to other cytogenetic classifications, such as IPSS cytogenetics and MKs. Pretransplant tumor burden, reflected by the percentage of marrow blasts, has been previously linked to adverse outcome3,24 and was also in our study an independent risk factor for relapse. We took into account that previous therapy influenced the percentage of marrow blasts at transplant and hence considered cytogenetics and marrow blasts separately, as opposed to other authors who studied the IPSS-R as a whole.12 Although the IPSS-R seems to help the risk-stratification of MDS patients at diagnosis, we find it challenging to use this new classification at the time of allo-SCT. As a matter of fact, the percentage of marrow blasts and cytopenias cannot be interpreted with accuracy at the time of transplant because the alteration of those parameters can result from either the efficacy or toxicity of the treatment administered before transplantation. Indeed, this prognostic tool relies on variables unmodified by therapy and determined specifically at diagnosis.6

Because clonal evolution is common in MDS during the course of the disease, cytogenetic evaluation before allo-SCT would be more appropriate. However, only cytogenetic evaluation at diagnosis was considered in our study because of the missing data. Of note, we observed similar results when analyzing cytogenetics at transplant despite the smaller number of patients (data not shown).

The main findings in our study were that patients classified at diagnosis in the C-IPSS-R high-risk categories (poor and very poor risk) experienced higher relapse rates and shorter OS after allo-SCT. These findings are in line with aforementioned studies.10,12 As expected, we also found an independent impact of poor risk IPSS cytogenetics and MKs on posttransplantation outcomes (data not shown), which has already been reported by others.8,11

Because many clinicians still commonly use the IPSS, we investigated how the C-IPSS-R could contribute to more accurate prognostication by changing the cytogenetic risk of our patients. Considering their former IPSS cytogenetic group, a change in prognostic category after applying C-IPSS-R was only observed in 8% of cases. In a study reported by the Seattle group, this percentage was higher (about 17%), in contrast with our study.10 At first glance, cytogenetic risk only seems to be modified in a small number of patients. Consequently, we took a closer look at the outcome and the specific chromosomal abnormalities observed in these subsets. In patients labeled poor risk according to IPSS cytogenetics, the C-IPSS-R classification distinguished 13 intermediate risk patients with significantly lower relapse rates (Figure 2). Indeed, IPSS cytogenetics overlook the better prognosis associated with isolated del(7q), which was identified in all these IPSS-R intermediate/IPSS poor cytogenetic risk patients. Interestingly, patients with chromosome 3 abnormalities (n = 4), which were previously considered as intermediate risk by IPSS, were moved to the poor risk C-IPSS-R group. Besides these observations, a change of cytogenetic risk category after applying the C-IPSS-R was only observed in about 8% of patients compared to their previous IPSS cytogenetic risk. If cytogenetic risk only changed in a few patients, the C-IPSS-R defined a group of patients with very poor outcome, represented by the very poor risk category, with a 60% cumulative incidence of relapse and 10% OS. Unlike what has been previously described,10,12 a limited number of patients (n = 10) was included in the very poor risk group in our study. The study design could be responsible for this low percentage because we systematically excluded allo-SCT from donor with HLA mismatch. Given the urgent need for allo-SCT, most patients with very complex karyotypes are more likely to receive such grafts.

In accordance with other studies,10-12,25 MKs were in our patients a strong risk factor for adverse outcome after allo-SCT. Two independent studies called into question the prognostic value of MKs in cohorts of nontransplanted MDS patients.26,27 Recently, Kelaidi et al28 reported similar findings in 98 MDS patients undergoing allo-SCT. They argued that the additional karyotypic abnormalities frequently associated with MKs (such as complex and very complex karyotypes), and not MKs themselves, account for their negative influence on outcome. After multivariate analysis taking into account karyotype complexity, they concluded that MKs do not affect outcome independently. In line with these findings, 86% of MKs (n = 54) in our study were already considered as poor or very poor risk by the C-IPSS-R. Nonetheless, we observed MKs in a small number of patients (n = 8) classified as intermediate risk by the C-IPSS-R, which were at higher risk for relapse (Figure 3) but did not experience significantly shorter survival. We conclude that if MKs are unlikely to refine classification by the C-IPSS-R, their prognostic impact within intermediate IPSS-R karyotypes remains to be investigated in a larger cohort.

Overall, our study confirms the prognostic value of the C-IPSS-R classification in patients with MDS undergoing allo-SCT. Particularly in patients with poor IPSS cytogenetics, this classification is more discriminant and distinguishes a very poor risk group with dismal outcome. How should we manage patients with very poor C-IPSS-R risk? In 2 recent studies published under the aegis of the SFGM-TC group, Damaj et al16,29 concluded that the absence of cytoreductive therapy (intensive chemotherapy or azacytidine) did not alter outcome after allo-SCT. In addition, Itzykson et al30 reported that patients with complex karyotypes respond poorly and transiently to azacytidine. In patients fit for the procedure, we therefore encourage early and upfront allo-SCT in patients with very poor C-IPSS-R karyotypes.31 This approach could be followed by posttransplant preventive strategies, such as HMAs32,33 and/or donor lymphocyte infusions.34

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ACKNOWLEDGMENTS

The authors would like to thank Mor Sény Gueye for collecting and checking data on site. Special thanks go to Nicole Raus, the SFGM-TC data manager. Ibrahim Yakoub-Agha would like to thank the “Association Capucine” for their support in his research.

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