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Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by bone marrow failure, marrow dyspla- sia, and a tendency to evolve to ...
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2003 102: 3025-3027 Prepublished online June 26, 2003; doi:10.1182/blood-2002-11-3325

A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome Yogen Saunthararajah, Ryotaro Nakamura, Robert Wesley, Qiong J. Wang and A. John Barrett

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From bloodjournal.hematologylibrary.org by guest on June 6, 2013. For personal use only. NEOPLASIA

Brief report

A simple method to predict response to immunosuppressive therapy in patients with myelodysplastic syndrome Yogen Saunthararajah, Ryotaro Nakamura, Robert Wesley, Qiong J. Wang, and A. John Barrett

Immunosuppression with antithymocyte globulin (ATG) or cyclosporine (CSA) can be used to treat the cytopenia associated with myelodysplastic syndrome (MDS). Previously, we identified HLA-DR15, younger age, and shorter duration of red cell transfusion dependence as pretreat-

ment variables that correlate significantly with a response. Using these pretreatment variables we have devised a simple method to prospectively identify patients with low or high probabilities of response to immunosuppression. The ability of this system to predict response was con-

firmed in a separate cohort of 23 patients with MDS treated with immunosuppression. (Blood. 2003;102:3025-3027)

© 2003 by The American Society of Hematology

Introduction Myelodysplastic syndrome (MDS) is a clonal hematopoietic disorder characterized by bone marrow failure, marrow dysplasia, and a tendency to evolve to acute leukemia. MDS shares some of the features of acquired aplastic anemia (AA) and up to 30% of patients with MDS respond to immunosuppressive treatment with cyclosporine (CSA) or antithymocyte globulin (ATG) with sustained increases in red blood cell, granulocyte, and platelet production.1-5 The class II histocompatibility antigen DR15 (serologic split of HLA-DR2) is reported to be overrepresented in patients with AA.6-9 We noted a similar overrepresentation of HLA-DR15 in patients with MDS of the refractory anemia subtype.10 Furthermore, HLA-DR15, younger age, and a shorter duration of red cell transfusion dependence (RCTD) were pretreatment characteristics correlating significantly with a response to immunosuppression in multivariate analysis.10 In this study we have used these pretreatment variables to devise a simple method to predict the probability of response to immunosuppression in MDS. To validate the predicted probability of response (PPR), we assessed the correlation of the PPR with observed responses in a separate treatment cohort (the validation cohort). In multivariate analysis the PPR was the single best predictor of response.

0169 for combination ATG and CSA to treat the cytopenia of MDS (17 with refractory anemia [RA], 2 with refractory anemia with ring sideroblasts [RARS], 4 with refractory anemia with excess blasts [RAEB]). Twenty-one patients were receiving regular red cell transfusions for symptomatic anemia. Many of these patients were also thrombocytopenic (⬍ 20 ⫻ 109/L) or neutropenic (⬍ 0.5 ⫻ 109/L) or both (Table 1). Of the 2 patients not receiving regular red cell transfusions, one met the eligibility criteria because of transfusiondependent thrombocytopenia, and the other had neutropenia with recurrent infections. On comparison of the training and validation cohorts, nonstatistically significant differences were noted in age, the proportion of patients with hypocellular marrows, and the proportion with paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry (Table 1). Treatment regimen In the training cohort, 69 patients with MDS were treated with one course of ATG 40 mg/kg/d intravenously over 4 to 6 hours for 4 days and 13 patients were treated with CSA starting at 5 to 12 mg/kg/d, with dose adjustments to maintain therapeutic levels, and continued indefinitely if a response was noted by 6 months.10 The validation cohort received a combination of ATG and CSA at the same doses with ATG starting at day 0 and CSA at day 14. Response criteria

Study design Patient characteristics The minimum criteria used to diagnose MDS were as published.10 Characteristics of patients in the cohort used to identify pretreatment variables correlating with response (training cohort, n ⫽ 82) have previously been published.10 The validation cohort consisted of 23 patients with MDS enrolled on the National Heart, Lung and Blood Institute (NHLBI) Institutional Review Board–approved protocol 00-H-

For transfusion-dependent patients, response was defined as transfusion independence for red blood cells or platelets (ability to maintain a hemoglobin ⬎ 8 g/dL and a platelet count ⬎ 20 ⫻ 109/L without symptomatic indications for transfusions for a period of at least 6 weeks regardless of subsequent events). For nontransfusion-dependent patients, response was defined as the normalization of the absolute neutrophil count. PPR The following logistic regression equation with response as the dependent variable was derived from analysis of the training cohort:

From the University of Illinois at Chicago; and the National Heart Lung and Blood Institute, Bethesda, MD.

rm3150 (MC734), 900 S Ashland Ave, Chicago, IL 60607; e-mail: [email protected].

Submitted November 5, 2002; accepted June 19, 2003. Prepublished online as Blood First Edition Paper, June 26, 2003; DOI 10.1182/blood-2002-11-3325. Y.S. and R.N. contributed equally to this work.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.

Reprints: Yogen Saunthararajah, University of Illinois at Chicago, MBRB

© 2003 by The American Society of Hematology

BLOOD, 15 OCTOBER 2003 䡠 VOLUME 102, NUMBER 8

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BLOOD, 15 OCTOBER 2003 䡠 VOLUME 102, NUMBER 8

SAUNTHARARAJAH et al

Table 1. Comparison of pretreatment variables in training and validation patient cohorts Pretreatment variable

Training cohort, n ⴝ 82

Validation cohort, n ⴝ 23

P

62 (55, 69)

58.0 (40, 65)

.08‡

9.2 (3.0, 25.2)

13.0 (6.0, 30.0)

.43‡

Median age, y (first and third quartiles) Median duration of RCTD, mo (first and third quartiles) DR15⫹ (%)

29/77 (38)

8/23 (35)

.80§

Hypocellular bone marrow (%)*

20/82 (24)

2/23 (9)

.10§

Less than 5% bone marrow blasts (%)

60/82 (73)

19/23 (83)

.35§

Normal cytogenetics (%)

53/82 (65)

15/21 (71)

.55§

Pancytopenia (%)†

38/82 (46)

8/23 (35)

.32§

8/77 (10)

5/23 (22)

.15§

24/82 (29)

7/23 (30)

.91§

PNH present by flow cytometric analysis (%) Response to immunosuppression (%)

*Cellularity less than 30%. †Platelets less than 50 ⫻ 109/L, red cell transfusion dependence, and absolute neutrophils less than 500 ⫻ 109/L. ‡Kruskal-Wallis test for medians. §␹2 test.

loge p/1⫺p ⫽ 8.3 ⫺ 0.156 (age in years) ⫺ 0.148 (duration of RCTD in months) ⫹ 2.14 (HLA-DRB1 15 status: 1 for present, 0 for absent), where p is the probability of a response. The c-index (concordance probability) to measure association of predicted probabilities and associated responses was 0.933 (values of ‘c’ near 0.5 indicate that the model is no better than a coin-flip; values near 1.0 indicate superior performance of the model). To generate a simplified prediction system integrating the 3 pretreatment variables of age, duration of RCTD, and HLA-DR15, we first converted the units for duration of RCTD to months. Then, to obtain approximately whole number values for the coefficients for age and duration of RCTD we multiplied both sides of the logistic regression equation by 6.67. By rounding to whole numbers the coefficients for age and RCTD in the logistic regression equation, the sum of the patient’s age in years and duration of RCTD in months is readily calculated. This sum, depending on the patient’s DR15 status, indicates the PPR (Table 2). In the training cohort, the mean ⫾ SD PPR among actual responders was 0.7 ⫾ 0.3 and among nonresponders 0.12 ⫾ 0.18 (distributions were normal). Based on this observation, a PPR range of 0.41 to 1.0 (41%-100%) is designated “high PPR” and a PPR range of 0 to 0.4 (0%-40%)is designated “low PPR” (Table 2). In the training cohort, this choice of cutoffs for PPR categorization generated the largest c-index (0.85) in logistic regression. Statistical analyses The “freq”(␹2 and Fisher tests), “ttest” (t test), “anova” (Kruskal-Wallis test), and “logistic” (logistic regression) procedures in SAS (SAS Institute, Cary, NC) version 8.1 were used to analyze for differences between pretreatment variables in cohorts and to assess the association between variables and response.

duration of transfusion independence was 10 weeks; the remaining 6 patients had durable responses with the median transfusion-free survival not reached at the 2-year follow-up. Comparison of PPR to observed response to immunosuppression in the validation cohort

Based on Table 2, 14 of the 23 patients had a low and 9 a high PPR. In univariate analysis, PPR (low, high), age, and PNH detected by flow cytometry were significantly associated (P ⬍ .05) with a response to immunosuppression (Table 3). In multivariate analyses using the 3 variables significantly associated in univariate analysis (PPR, age, and presence of PNH), only the PPR (which integrates age, duration of RCTD, and DR15 status) significantly correlated with response (Table 3). The observed responses (ORs) were compared to the PPR (low, high). Responses to immunosuppression occurred in 6 of 9 patients with a high PPR and 1 of 14 patients with a low PPR (Table 4; Fisher exact test, P ⫽ .005). HLA-DR15 may help identify that subset of MDS patients with immune-mediated marrow failure, a finding we have discussed previously.10 Reasons for the association of age and

Table 3. Association of pretreatment variables with response in validation cohort Association with response in univariate analyses, P *

Association with response in multivariate analyses, P †

PPR, n ⫽ 23

.002

.009

Age, n ⫽ 23

.02

.77

.007

.35

.21



Pretreatment variable

Results and discussion Response to immunosuppression in the validation cohort

Of the 23 patients in the validation cohort, 7 met criteria for response to the combination of ATG and CSA. All responding patients were red cell transfusion dependent before treatment and met response criteria for red cell transfusion independence. Of the 7 responders, 5 were pancytopenic and 2 bicytopenic before treatment; all responses were pancellular. In one responder, the

Presence of PNH by flow cytometry, n ⫽ 5/23 Blasts less than 5%, n ⫽ 19/23 Duration of RCTD, n ⫽ 23 HLA DR15⫹, n ⫽ 8/23

.49



.14



.46



Normal cytogenetics, n ⫽ 15/21 Hypocellular bone

Table 2. PPR to immunosuppression in MDS

marrow, n ⫽ 2/23

.79



Patient’s age, y ⴙ duration of RCTD, mo

Tricytopenia, n ⫽ 2/23

.10



DR15ⴚ patients

DR15ⴙ patients

⬎ 57

⬎ 71

Low (0%-40%)

ⱕ 57

ⱕ 71

High (41%-100%)

PPR

— indicates not applicable. *Logistic regression for age and duration of transfusion dependence, ␹2 test for other variables. †Logistic regression with backward selection.

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PREDICTING RESPONSE TO ATG/CSA THERAPY IN MDS

Table 4. Association between PPR and OR in the validation cohort* PPR Low (0%-40%) High (41%-100%)

No response

Response

13

1

3

6

*Fisher exact test P ⫽ .005.

duration of RCTD with response to immunosuppression are not known. Speculatively, prolonged RCTD may indicate prolonged immune-mediated marrow damage and stem cell depletion. Similarly, older patients may have fewer hematopoietic stem

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cells.11 Stem cell depletion might limit recovery of normal stem cells after immunosuppression. Other pretreatment variables of predictive value (eg, identification of PNH clones) that could improve the scoring system may be identified through analysis of a larger training cohort. In conclusion, the proposed scoring system, using HLA-DR15, age, and duration of RCTD, provides a useful method to identify those MDS patients most likely to respond to immunosuppression. These pretreatment variables are also relevant to the design and evaluation of immunosuppression trials for MDS.

References 1. Tichelli A, Gratwohl A, Wuersch A, Nissen C, Speck B. Antilymphocyte globulin for myelodysplastic syndrome. Br J Haematol. 1988;68:139-140. 2. Molldrem JJ, Leifer E, Bahceci E, et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med. 2002;137:156-163. 3. Biesma DH, van den Tweel JG, Verdonck LF. Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer. 1997;79:15481551. 4. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ. Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol. 1997;99:699-705. 5. Jonasova A, Neuwirtova R, Cermak J, et al. Cy-

closporin A therapy in hypoplastic MDS patients and certain refractory anaemias without hypoplastic bone marrow. Br J Haematol. 1998;100: 304-309. 6. Nimer SD, Ireland P, Meshkinpour A, Frane M. An increased HLA DR2 frequency is seen in aplastic anemia patients. Blood. 1994;84:923-927. 7. Nakao S, Takamatsu H, Chuhjo T, et al. Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporinedependent aplastic anemia. Blood. 1994;84: 4257-4261. 8. Ihan O, Beksac M, Arslan O, et al. HLA DR2: a predictive marker in response to cyclosporine therapy in aplastic anemia. Int J Hematol. 1997; 66:291-295.

9. Shao W, Tian D, Liu C, Sun X, Zhang X. Aplastic anemia is associated with HLA-DRB1*1501 in northern Han Chinese. Int J Hematol. 2000;71: 350-352. 10. Saunthararajah Y, Nakamura R, Nam JM, et al. HLA-DR15 (DR2) is overrepresented in myelodysplastic syndrome and aplastic anemia and predicts a response to immunosuppression in myelodysplastic syndrome. Blood. 2002;100: 1570-1574. 11. Champion KM, Gilbert J, Asimakopoulos F, Hinshelwood S, Green A. Clonal haemopoiesis in normal elderly women: implications for the myeloproliferative disorders and myelodysplastic syndromes. Br J Haematol. 1997;97:920-926.