Acute Leukemia

Specific abnormalities versus number of abnormalities and cytogenetic scoring systems for outcome prediction after allogeneic hematopoietic SCT for myelodysplastic syndromes

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Abstract

Newer cytogenetic scoring systems for myelodysplastic syndromes (MDSs), like cytogenetic stratification of the revised international prognostic scoring system (IPSS-R) or monosomal karyotype, may also improve outcome prediction after hematopoietic SCT (HCT). We compared the prognostic value of specific cytogenetic abnormalities, IPSS-R karyotype and monosomal karyotype for HCT outcome in 98 patients with MDS and AML post MDS. Higher-risk IPSS-R karyotype, 3q21q26 and transformation to AML before HCT were associated with increased cumulative incidence of relapse (CIR), whereas OS was adversely influenced by del 5q/−5, abnormalities of chromosomes 11 and 17 and cytogenetic IPSS-R very poor category. Karyotype with 2 abnormalities and no abnormalities of chromosomes 3, 5, 7, 11 and 17 was an independent prognostic factor of lower CIR (hazard ratio (HR)=0.2, P=0.01) and longer OS (HR=0.5, P=0.03). In conclusion, some specific cytogenetic abnormalities and high cytogenetic complexity, as reflected by IPSS-R very poor karyotype, rather than monosomal karyotype, were associated with higher CIR and shorter OS after HCT. Conversely, results were encouraging in patients lacking those abnormalities, who may be very good candidates for HCT.

Introduction

Myelodysplastic syndromes (MDSs) are clonal myeloid disorders characterized by ineffective hematopoiesis and a high incidence of transformation to AML.1,2 The International Prognostic Scoring System (IPSS) and, more recently, the revised IPSS (IPSS-R), are used in untreated patients with de novo disease to distinguish between lower- and higher-risk MDS according to number and depth of cytopenias, percentage of BM blasts and karyotype.3,4 Cytogenetic classification was recently refined in the design of the IPSS-R with the recognition of a broader spectrum of recurrent cytogenetic abnormalities, and was given a higher scoring weight than in the original IPSS.5 In parallel, in an effort to individualize prognostically important cytogenetic subgroups in myeloid disorders, monosomal karyotype (defined by 2 autosomal monosomies or one autosomal monosomy in the presence of structural abnomalities) was shown to be particularly unfavorable in AML patients.6

Allogeneic hematopoietic SCT (HCT) is the only curative therapy in MDS. A prognostic impact of cytogenetics on outcome after HCT for MDS has been validated, but the role of newer cytogenetic scoring systems in that context is currently under investigation.7, 8, 9, 10, 11

In this study, we analyzed the prognostic relevance of specific cytogenetic abnormalities, IPSS-R cytogenetic classification and monosomal karyotype in the setting of HCT for MDS and AML post MDS.

Materials and Methods

Patients

Ninety-eight consecutive patients with MDS or MDS/myeloproliferative neoplasm, according to FAB/WHO classifications, or AML post MDS, who had received HCT in four centers between 1993 and 2012 were retrospectively studied. Fourteen percent, 27 and 59% of the HCT were performed between 1993 and 2000, 2001 and 2006, and 2007 and 2012, respectively. Characteristics of the patients at the time of referral for HCT (defined here as baseline) are shown in Table 1. MDS was defined as secondary after a myeloproliferative neoplasm or a history of radiation and/or chemotherapy, that is, treatment-related MDS.

Table 1 Patient characteristics

Cytogenetics had been performed using conventional methods and documented according to International System for Human Cytogenetic Nomenclature. Cytogenetic classes included: (i) Specific cytogenetic abnormalities (abn), either individual or regrouped on the basis of common physiopathological background (as, for example, P53 inactivation in 17p deletion and monosomy 17) and shared prognostic information (as for chromosome 11 translocations and trisomy 11).5,12 In detail, the following abnormalities were individualized: Del 7q, monosomy 7 (−7), del 5q, monosomy 5/translocation 5 (−5), trisomy 8, 3q21q26 (inv(3)(q21q26.2) or t(3;3)(q21q26.2)), chromosome 11 (abn 11) (including t(v;11)(v;q23), del 11q with 2 additional abn and trisomy 11), chromosome 17 (abn 17) (including 17p−/−17 and del(17)(q23)); (ii) IPSS-R five-group cytogenetic classification, focusing on the very poor category (VPK);4,5 (iii) Presence of monosomal karyotype (MK), that is, at least two autosomal monosomies or one autosomal monosomy in combination with 1 structural abn.6 In the case of cytogenetic clonal evolution, the most recent karyotype before HCT was used. Cytogenetic groups are shown in Table 2.

Table 2 Cytogenetic classifications and number of abnormalities

Advanced disease pre-HCT was defined according to CIBMTR criteria for MDS, by AML transformation or use of AML-like induction regimen (intensive chemotherapy) or hypomethylating agents, or 10% BM blasts; otherwise MDS status was defined as early, with treatment including supportive care, transfusions and growth factors.13 Percentage of BM blasts was evaluated at two time points, baseline and immediately before the onset of the conditioning regimen. Prior disease progression was defined as progression before HCT from lower to higher-risk MDS (or to AML), according to conventional IPSS and/or cytogenetic clonal evolution.

Transplant procedures

Donors were HLA-identical siblings, matched unrelated donors (URDs) (8/8 antigens), mismatched URDs (6 or 7/8 antigens) and double unit cord blood (CB) in 64%, 15%, 14% and 7% of cases, respectively. Mismatched URDs were used mainly after 2007 (Supplementary Figure 1). HLA-typing was serological during the earliest period and DNA-based, high resolution, from 2000 onwards. Source of stem cells, besides CB, was BM, peripheral blood and combined BM and peripheral blood in 17, 82 and 1 of cases, respectively. CMV IgG patient/donor status was +/+ or − in most cases.

The conditioning regimen was myeloablative (mainly BU-CY) and reduced intensity (Fludarabine-BU-antithymocyte globulin (ATG) or Fludarabine-BCNU-Melphalan) in 72% and 28% of cases, respectively. GVHD prophylaxis consisted of CsA and short-term MTX plus ATG for URD transplants, and by CsA and mycophenolate mofetil for reduced intensity. Clinically significant acute and chronic GVHD occurred in 35.2% and 53.6% of patients, respectively.

Four patients received subsequent allogeneic transplants for relapse after the first allogeneic HCT. In detail, three patients received a second allogeneic transplant and one patient a third allogeneic transplant (uncensored observations with respect to OS). For those patients, outcomes were analyzed from the time of first allogeneic HCT.

Statistical methods

Transplant outcomes were analyzed after exclusion of CB transplants because of high non-relapse mortality (NRM) observed in that group. OS after HCT was estimated using the Kaplan–Meier method.14 OS curves were compared using the log-rank test.15 Cumulative incidences of relapse (CIRs) and of NRM were considered competing risks and were calculated and compared using the Gray test.16 Relapse was censored at the time of hematological relapse.

Percentage of BM blasts was analyzed as a dichotomous variable using the cutoff of 10%. Multivariate analysis on potential predictive variables for OS and CIR was conducted with the Cox model and Fine and Gray test, respectively.16,17 Variables associated with outcome at the 20% level in univariate analyses were introduced in the model for multivariate analysis; a stepwise selection procedure was performed to finally select those variables. All calculations were performed with R version 2.8.1.

Results

Patient characteristics

Ninety-eight patients were included, of median age 50 years, including four patients aged 18 years (Table 1). MDS was secondary in 16% cases and had occurred after aplastic anemia (n=3), polycythemia vera (n=1), de novo AML (n=3), ALL (n=1), Hodgkin lymphoma (n=2), non-Hodgkin lymphoma (n=1), solid tumor with use of chemo- or radiotherapy (n=4) and use of radioiodine (n=1). Prior chemotherapy included autologous HCT conditioning in two cases. Median disease duration before HCT was 10 months (range 1–105) and 34% patients had experienced prior disease progression. Median baseline percentage of BM blasts was 15% vs 4% immediately before HCT, with decrease resulting from cytoreduction before transplantation (P<0.0001 by paired t-test). Median interval between referral and HCT was 6 months (range 1–41). At transplant, advanced disease and high IPSS accounted for 75.5% and 65% cases, respectively.

Cytogenetic subgroups

A total of 15.3 and 8.2% patients had 3 and 5 abnormalities, respectively (Table 2). Specific abnormalities were regrouped, whenever possible, on the basis of common physiopathological background and shared prognostic information, as follows: Del 7q, −7, del 5q, −5, trisomy 8, 3q21q26, abn 11 and abn 17. Monosomy 7 and trisomy 8 were the more frequent abn. Translocations involving chromosomes 5 and 7 consisted in t(5:?)(q22:q?) (one case) and t(1:7)(q11:q11) (two cases, in association with del 7q or −7). Abn 11 comprised t(2:11)(p21:q25) associated with monosomy 11, t(11:20)(q11:q13.3) (one case each), del 11q within complex karyotypes (two cases) and i(11)(q10) (one case). Abn 17 occurred as 17p−/−17 (three cases) and del 17q23 (one case). Other cytogenetic findings included isolated i(17q), t(6;9), t(2;18), t(13;20), one case each, and two cases of polyploidy.

Trisomy 8 was more frequently isolated, whereas del 5q, −5 and abn 11 were associated with higher numbers of abn per karyotype, as compared with other subgroups (P=0.04).

By cytogenetic IPSS classification, karyotype was poor in 28% of cases, and by cytogenetic IPSS-R classification, very poor in 11.8%. MK was present in 15.3% patients. Thirty percent and 70% of patients with MK had IPSS-R poor karyotype and VPK, respectively. Conversely, 90% patients with VPK had MK. Median number of abn was higher in patients with MK than in patients with no monosomal abnormal karyotype (4 vs 1, respectively, P<0.0001), although when considering only patients with 2 abn as implied by the definition of MK, the difference in number of abn between patients with and without MK was not significant (median 4 vs 2 abn, P=0.81).

Considering other pre-transplant and transplant characteristics, the following differences were observed between cytogenetic groups: Secondary MDS was more frequent in patients with −5 (P=0.01) and, as a trend, patients with trisomy 8 had lower percentage of BM blasts (P=0.07), those with 3q21q26 had higher percentage of BM blasts (P=0.14), and mismatched URD was offered more often in patients with VPK and MK (P=0.19 in both cases), as compared with patients without the aforementioned abnormalities (shown in Supplementary Table 1).

Treatments prior to transplantation

A total of 55.6% patients had received some form of disease-altering therapy before HCT, including intensive chemotherapy and/or azacitidine (Table 1). In particular, 71% patients with BM blasts 10% received intensive chemotherapy. Response rate to intensive chemotherapy and relapse rate before HCT were 68% and 16.6%, respectively. Median number of azacitidine cycles was 5 (range 1–11). Overall response rate to azacitidine and relapse rate before HCT were 62.5% and 30%, respectively.

Transplant outcomes

Median follow-up after HCT was 54 months (range 5–201 months) and 5-year CIR, cumulative incidence of NRM and OS after HCT were 24.9%, 45.3% and 30.6%, respectively. Median OS was 13 months.

Five of seven patients transplanted from a CB donor died from non-relapse causes. After exclusion of CB HCT because of very high early NRM (adopted for analysis thereafter), 5-year CIR, NRM and OS were 25.8%, 42.5% and 32.5%, respectively.

Prognostic factors of relapse

Individual abnormalities associated with increased CIR were del 7q (5-year CIR 100% vs 21% in patients with or without the abn, P=0.02) and 3q21q26 (60% vs 22%, P=0.02) (Table 3 and Figure 1). Monosomy 7 was not found to significantly affect CIR. The 5-year CIR was 12%, 31%, 38% for IPSS good, intermediate and poor karyotype (P=0.10), 0%, 12%, 36%, 36%, 33% for IPSS-R very good, good, intermediate, poor and very poor karyotype (P=0.18), and 24 and 25% in MK and non-monosomal karyotype (P=0.97). Other factors associated with increased CIR in univariate analysis included transformation to AML before HCT, baseline BM blasts 10% and use of intensive chemotherapy, regardless of achievement of complete remission. In multivariate analysis, 3q21q26, IPSS-R karyotype and transformation to AML before HCT were independent predictive factors of CIR (HR=3.8, P=0.002; HR=1.5, P=0.04; HR=4.9, P=0.001, respectively).

Table 3 Factors predictive of CIR
Figure 1
figure1

Cumulative incidence of relapse according to cytogenetic abnormalities. Black line: presence of abnormality; gray line: absence of abnormality. IPSS and IPSS-R KT: solid line: good; dashed line: intermediate; dotted line: poor group; dashdot: very poor. KT=karyotype.

Prognostic factors of OS

Increased BM blast percentage (baseline and before conditioning), mismatched URD, 3 abn, −7/del 7q, del 5q, abn 11, IPSS-R VPK, MK and, as trend, abn 17 and IPSS poor karyotype, were associated with decreased OS in univariate analysis (Table 4 and Figure 2). Median OS was 47, 11, 13 and 5.5 months in IPSS-R good, intermediate, poor and very poor karyotype, respectively (P=0.02) (Supplementary Figure 2). After adjustment for BM blasts percentage, prognostically significant cytogenetic groups were del 5q, abn 11, abn 17 and VPK (HR=3.1, P=0.02; HR=3.7, P=0.01; HR=2.8, P=0.05; HR=2.4, P=0.03, respectively; Figure 3), but not MK.

Table 4 Univariate analysis of OS
Figure 2
figure2

OS according to cytogenetic abnormalities. Black line: presence of abnormality; gray line: absence of abnormality. KT=karyotype.

Figure 3
figure3

Hazard ratios of OS adjusted on percentage of BM blasts at HCT evaluation according to cytogenetic groups (vertical bar=1). The box size denotes precision.

In multivariate analysis, del 5q, abn 11 and VPK, but not IPSS poor karyotype or MK, were independent prognostic factors (Table 5). Abn 17 was associated with shorter OS as a trend (HR=2.8, P=0.09), but the number of patients was very low. Though of variable significance, depending on the cytogenetic group introduced in multivariate analysis, use of matched URD was protective on OS.

Table 5 Cox models of OS

To delineate a favorable cytogenetic profile, we combined karyotypes with up to two abnormalities other than abn 3, 5, 7, 11 and 17, a group representing 61% of patients with evaluable karyotype. That favorable cytogenetic group, which included trisomy 8, was associated with lower CIR (5-year CIR 12.5% vs 45.8% in the remaining patients, P=0.002; Figure 1) and longer OS (median 47 vs 10 months, P=0.01), independently from AML transformation or baseline BM blast percentage (favorable cytogenetic group, CIR: HR=0.2, P=0.01, OS: HR=0.5, P=0.03; AML transformation, CIR: HR=4.3, P=0.001; % blasts, OS: HR=1.02, P=0.04).

Prognostic factors of NRM

Among baseline and HCT parameters, a significant or borderline association with NRM was found for disease duration (HR=1.01, P=0.04), abn 11 (HR=3, P=0.03) and treatment with azacitidine (HR=1.9, P=0.07). In multivariate analysis, disease duration and abn 11 were associated with significantly higher NRM (HR=1.01, P=0.03; HR=2.8, P=0.04, respectively).

Discussion

The need for prognostic refinement in HCT for MDS has been increasing in parallel with its indications and demand. Disease status and cytogenetic classification, specifically poor-risk IPSS cytogenetic group, have been recognized as the most important disease-related determinants for outcome after HCT.7, 8, 9, 10, 11 In this study, we focused on specific cytogenetic abnormalities as well as newer cytogenetic prognostic scores in the setting of HCT.

The span of the series covered almost 20 years of HCT. The median age was thus somewhat lower than that of most series of MDS patients, due to more stringent age restrictions during the earlier period of the cohort.

We found that the adverse effect on OS of specific abnormalities such as del 5q, abn 11 and abn 17 was stronger than that of IPSS karyotype, although the impact of those specific abnormalities on CIR was not significant, possibly because of high NRM, which could have obscured CIR. A possible explanation for high NRM was that mismatched URD transplants were offered more often to patients with advanced disease and poor-risk cytogenetics. The attenuating effect of NRM on relapse events persisted after elimination of CB transplants and was not particularly affected by time during this relatively long time series. In addition to the limitation of high NRM, the number of patients within the subgroups of specific aberrations was low. Therefore, results on single abnormalities should be interpreted with caution until larger patient cohorts are studied.

Despite these limitations, CIR was adversely affected by 3q21q26 and del 7q. Of note, the median number of additional abnormalities in 3q21q26 and del 7q was only +1 in each case, in contrast to del 5q/−5 and abn 11, which were associated with the highest cytogenetic complexity (+5 additional abn), suggesting that a combined qualitative and quantitative criterion should be used when considering specific abnormalities. Of note, although del 5q/−5, −7/del 7q and abn 11 are in general associated with secondary MDS, treatment-related or secondary character of MDS, as compared with de novo MDS, was not prognostic per se.

One of the main findings of this study was that, in contrast to the previously mentioned adverse abnormalities, a favorable cytogenetic group excluding abn 3, 5, 7, 11, 17 and including up to two abn, could be identified. Of note, trisomy 8+1 abn was included in this category. This group, found in approximately half of the patients, was associated with a particularly low risk of relapse (10%) and a higher probability of long term survival (40% at 5 years). Hence, using cytogenetics, the proportion of patients that would predictably benefit from HCT with achievement of higher rates of cure, could be expanded to include a subset of patients with favorable cytogenetic profile combined with otherwise standard risk characteristics (for example, lower BM blast percentage), for whom early HCT is a particular challenge, but also a subset of advanced disease but favorable cytogenetics.

We also assessed the predictive value of newer prognostic cytogenetic systems, that is, IPSS-R karyotype, including VPK, and MK. The proportion of patients with IPSS-R VPK and with MK was similar to that found in other MDS transplant series10,11 (Table 6). Despite considerable overlap between VPK and MK and although we did not perform a formal comparison between the two cytogenetic groups, VPK was found to be more powerful than MK in predicting OS after HCT. In particular, VPK significantly affected OS in multivariate analysis, whereas the significance of MK was borderline. In line with our findings, recent studies have questioned the relative importance of MK in MDS and secondary AML (sAML) as compared with burden of cytogenetic complexity.18, 19, 20, 21, 22, 23

Table 6 Studies on post-transplant outcomes in MDS according to cytogenetics

IPSS-R cytogenetic classification predicted OS more efficiently than IPSS cytogenetic classification, a finding consistent with those of a larger series of MDS/sAML patients who underwent HCT10 (Table 6), suggesting that IPSS-R cytogenetic classification may indeed refine prognosis not only in untreated patients but also after HCT. In addition, IPSS-R cytogenetic classification as a five-group score, but not MK, was predictive of increased CIR, possibly as a result of the additional impact of 3q21q26 and del 7q found within non-MK (60% in each case). However, MK prevailed over poor-risk IPSS cytogenetic group for OS, a result also found in MDS/sAML patients with abn 7 who underwent HCT11 (Table 6).

Evidence from this and other studies on the role of cytoreductive treatment before HCT for MDS is inconclusive.24 As the use of chemotherapy could select for a group of patients with intrinsic characteristics (for example, better performance status, worst prognosis), its role versus no cytoreduction versus hypomethylating agents should be addressed by prospective trials. Likewise, the role of azacitidine could not be evaluated here because of its recent introduction and because azacitidine was administered to small numbers of patients. As suggested by other studies, hypomethylating agents should probably be integrated in therapeutic algorithms for MDS candidates for HCT.25

Recipients of mismatched URD or CB fared less well in this study than those of matched donors, with no significant difference between HLA-identical siblings and matched URD. In particular, CB transplants were associated with excessive overall and NRM.

In conclusion, we demonstrated that specific chromosomal abnormalities such as abn 3, 5, 7, 11, 17 and groups of high cytogenetic complexity like IPSS-R VPK and, possibly to a lesser extent, of MK, clearly determined, along with disease burden, prognosis of allogeneic HCT in MDS. Alternative HCT modalities should be explored in patients carrying those abnormalities, such as innovative conditioning regimens, development of methods for early detection of relapse and pre-emptive therapy, and second transplants. Conversely, results were encouraging in the absence of such adverse cytogenetics, prompting expansion of the use of HCT in MDS patients with favorable cytogenetic profiles.

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Acknowledgements

CK is indebted to Professor Pierre Fenaux for critical reviewing of the manuscript

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Correspondence to C Kelaidi.

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