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Leukemia (2003) 17, 2101–2106 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu

Antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndromes S Yazji1,2, FJ Giles1,2, A-M Tsimberidou1,2, EH Estey1,2, HM Kantarjian1,2, SA O’Brien1,2 and R Kurzrock1,2 1 Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX, USA; and 2Department of Bioimmunotherapy, University of Texas, MD Anderson Cancer Center, Houston, TX, USA

The purpose of this study was to determine the efficacy of and tolerance to antithymocyte globulin (ATG)-based therapy in patients with myelodysplastic syndrome (MDS). Therapy consisted of ATG 40 mg/kg/day daily intravenously (i.v.) for 4 days; cyclosporine daily orally for 6 months with levels titrated between 200 and 400 mg/dl; and methylprednisone 1 mg/kg i.v. daily before each dose of ATG. Of 32 patients treated, 31 patients were evaluable. The median age was 59 years (range, 28–79 years). A total of 18 patients had refractory anemia (RA) or RA with ringed sideroblasts (RARS), 10 patients had RA with excess blasts (RAEB), two patients had RAEB in transformation, and one patient had chronic myelomonocytic leukemia. ATG, cyclosporine, and methylprednisone induced complete (N ¼ 4) or partial (N ¼ 1) remission in five patients (16% of total; RA, two patients; RARS, two patients; and RAEB, one patient). Durable complete remissions were observed in three of 18 patients (17%) with RA (N ¼ 1) or RARS (N ¼ 2) (12, 41 þ , and 60 þ months). The most common adverse events were fever and allergic reactions. Hepatic and renal dysfunction, albeit consistently reversible, occurred in 19 and 13% of the patients, respectively. In conclusion, an ATG-based regimen can produce durable complete remissions in a subset of patients with MDS. Leukemia (2003) 17, 2101–2106. doi: 10.1038/sj.leu.2403124 Published online 21 August 2003 Keywords: aplastic anemia; myelodysplastic syndrome

Introduction Myelodysplastic syndromes (MDS) are clonal hematologic stem cell disorders characterized by ineffective and dysplastic hematopoiesis leading to progressive anemia, leukopenia, and thrombocytopenia. Dependence on red blood cell and/or platelet transfusions is common.1–3 Patients succumb to infection or bleeding, or because of eventual progression to leukemia.4–7 Therapeutic options are limited.8 Management strategies used in MDS include growth factors9–18 and chemotherapy,19–21 as well as supportive care with antibiotics and transfusions.22 Allogeneic transplantation, although potentially curative, is a realistic option for only a small proportion of these patients due to patient age and the limited availability of appropriate donors.23 Induction chemotherapy with cytosine arabinoside-based regimens similar to those used to treat patients with acute myeloid leukemia is associated with some complete remissions, but with high treatment mortality.19,20 No therapy has been considered standard for MDS, although promising results with new drugs such as azacytidine may soon have an impact.24 Antithymocyte globulin (ATG) has been successfully used to treat pancytopenia resulting from severe aplastic anemia.25–27 There may be nosologic overlap between aplastic anemia and MDS, with both disorders characterized by cytopenias and a propensity to leukemic evolution, although the latter is less of a Correspondence: Dr R Kurzrock, Department of Bioimmunotherapy, Unit 422, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA; Fax: þ 1 713 745 2374 There was no research support for this study Received 12 May 2003; accepted 26 June 2003; Published online 21 August 2003

problem in aplastic anemia.28 We therefore investigated an ATG-based regimen in MDS. Our results suggest that durable responses can be achieved in a subset of MDS patients, especially those with refractory anemia (RA) or RA with ringed sideroblasts (RARS), despite the presence of significant dysplasia, hypercellularity, karyotypic abnormalities, or high numbers of ringed sideroblasts that would clearly distinguish their disorder from aplastic anemia.

Materials and methods All patients gave written informed consent. The Institutional Review Board at the MD Anderson Cancer Center approved the protocol. An MD Anderson Cancer Center pathologist made the diagnosis of MDS on the basis of a review of bone marrow aspirate and biopsy. All patients had at least one of the following characteristics: significant dysplasia, ringed sideroblasts 415%, a hypercellular marrow, increased blasts, or karyotypic abnormalities. Patients were eligible if they had RA, RARS, RA with excess blasts (RAEB) or RAEB in transformation (RAEB-T) or chronic myelomonocytic leukemia (CMMoL)1 and adequate hepatic (bilirubin o2 mg/dl) and renal (creatinine o2 mg/dl) function. Paroxysmal nocturnal hemoglobinuria was excluded in all patients. Prior to treatment, all patients had a history and physical examination, a complete blood count with differential and platelet count, and renal and hepatic function tests, as well as a bone marrow aspiration, biopsy, and cytogenetics.

Treatment plan ATG (horse) was given at a dose of 40 mg/kg/day for 4 days administered intravenously (i.v.) over 4 h. A test dose of ATG (0.1 ml of 1:1000 dilution) was given intradermally on the day before the full dose to rule out an allergic reaction. Cyclosporine was given orally each day for 6 months unless toxicity supervened. The dose was titrated to maintain cyclosporine levels between 200 and 400 mg/dl. Methylprednisolone was given at 1 mg/kg daily i.v. before each dose of ATG. Thereafter, prednisone 60 mg orally daily was started and tapered off over a 1-month period of time.

Dose adjustments: Cyclosporine was reduced by 25% if serum bilirubin increased to greater than 2 mg/dl, alanine aminotransferase to greater than 300 mg/dl, serum creatinine increased to greater than 2 mg/dl, blood pressure increased 4150 mmHg (systolic) or 490 mmHg (diastolic) after adding nifedipine, or patients developed tremulousness or other central nervous system-related symptoms. A second similar dose reduction was made if toxicity recurred. If toxicity recurred for a third time, cyclosporine was discontinued.

Follow-up and supportive care: Patients were transfused with red blood cells if hemoglobin was less than 8 g/dl and with platelets for platelet counts less than 10  109/l. Patients were

ATG in MDS S Yazji et al

2102 monitored twice weekly for 1 month and then weekly, with a complete blood cell count with differential, renal and hepatic function tests, magnesium level, and blood pressure. Cyclosporine levels were measured weekly. Bone marrow aspirate and biopsy were performed every 4–12 weeks; cytogenetic analyses were obtained every 3–6 months.

Response end points Response criteria: A complete hematologic remission (CR) was defined as achievement of normal peripheral counts (absolute neutrophil counts, ANCs X1.5  109/l and platelets 4100  109/l) and normocellular bone marrow with less than 5% blasts accompanied by disappearance of organomegaly and karyotypic abnormalities lasting for at least 4 weeks. A partial hematologic remission (PR) was defined as restoration of normal peripheral blood count (ANC X1.5  109/l and platelets 4100  109/l) and at least 50% decrease in the size of organomegaly, but persistent elevation of blast count to more than 5 and p10% and/or persistent karyotypic abnormalities. Hematologic improvement was defined as: (i) tripling of platelet count and achievement of levels X20  109/l if baseline counts were p20  109/l, or doubling of platelet count and achievement of counts X50  109/l if baseline counts were X20  109/l and p50  109/l; (ii) achievement of transfusion independence if initially transfusion dependent; or rise in hemoglobin of X2 g/ dl if not initially transfusion independent; and (iii) doubling of ANC and achievement of count X1.0  109/l if initial count p1.0  109/l. All responses had to last at least 4 weeks. Progressive disease was defined as any patients who showed a doubling of bone marrow blast with a bone marrow blast reaching levels X20%. Owing to the delayed responses to ATG seen in aplastic anemia, response evaluation first took place at 3 months after treatment with ATG.

Results

Patients’ characteristics In all, 32 patients were registered on the protocol. One patient was inevaluable because his diagnosis was eventually determined to be large granular leukemia. The patients’ characteristics are listed in Table 1. Their median age was 59 years (range, 28–79 years); 18 patients (58%) were above 60 years of age. Of these, 21 patients (68%) were men. At the time of registration in the study, 10 patients (32%) had an ANC p0.5  109/l; 18 patients (58%) were transfusion dependent, and 21 patients (68%) were red blood cell transfusion dependent. A total of 11 patients (35%) had a diploid karyotype and 20 patients (65%) had chromosomal abnormalities (Table 1). (Protocol development and execution occurred before publication of the Cheson response criteria;29 however, reanalysis of data by these criteria does not alter the response rate.) All subtypes of MDS were represented (Table 1). Three patients had a history of another cancer before they developed MDS: largecell lymphoma, two patients and T-cell acute lymphoblastic leukemia, one patient. There were a wide variety of prior therapies (Table 2). The median number of prior therapies was 2 (range, 0–3).

Table 1

Patients’ characteristics

Characteristic

No. of patients (%)

Patients registered Patients evaluablea Red blood cell transfusion dependent Platelet transfusion dependent

32 31 21 18

(100) (97) (68) (58)

Age (years) Median Range

59 28–79

Sex Male

21 (68)

Diagnosis RA/RARS RAEB RAEB-T CMMoL

18 10 2 1

(58) (33) (6) (3)

Kayrotype Diploid Monosomy 7 Trisomy 8 Monosomy 5 20q Trisomy 21 13q Insufficient metaphases Others

11 5 4 4 2 1 1 1 8

(35) (16) (13) (13) (7) (3) (3) (3) (26)

Abbreviations: CMMoL, chronic myelomonocytic leukemia; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-T, refractory anemia with excess blast in transformation.aOne patient was inevaluable because the diagnosis was large granular lymphocytic leukemia. Table 2 Prior therapy in 31 patients treated with ATG–cyclosporine and prednisone Prior therapy None Ara-C Splenectomy Cyclosporin A Amifostine G-CSF Etoposide Fludarabine/ARA-C/idarubicin Interferon-alpha Thiotepa IVIG BMT Daunorubicin Vincristine Interleukin-11 Topotecan GM-CSF H-CVAD Other multiagent chemotherapy

No. of patients (%) 8 6 3 3 3 3 3 2 2 2 2 2 2 2 2 2 1 1 3

(26) (19) (10) (10) (10) (10) (10) (6) (6) (6) (6) (6) (6) (6) (6) (6) (3) (3) (10)

Abbreviations: Ara-C, cytosine arabinoside; BMT, bone marrow transplantation; GM-CSF, granulocyte–macrophage colony-stimulating factor; G-CSF, granulocyte colony-stimulating factor; H-CVAD, hyperfractionated, cyclophosphamide, vincristine, adriamycin, and dexamethasone; IVIG, intravenous immunoglobulin.

Outcome and responses Of the 31 evaluable patients, five patients (16%) had a response (CR, four patients; PR, one patient; Tables 3 and 4). In addition, Leukemia

three patients had hematologic improvement (platelets, one patient; hemoglobin, one patient; platelets and hemoglobin, one patient). None of the responders had therapy-related MDS. The

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Table 3 Responses by diagnosis in 31 patients treated with ATG–cyclosporine and prednisone Diagnosis

No. of patients

CR (%)

PR (%)

RA/RARS RAEB RAEB-T CMML Total

18 10 2 1 31

3 (17) 1 (10) F F 4 (13)

1 (6) F F F 1 (3)

Overall response (%) 4 1 0 0 5

(22) (10) (0) (0) (16)

Abbreviations: CMML, chronic myelomonocytic leukemia; CR, complete hematologic remission; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RAEB-T, refractory anemia with excess blast in transformation; PR, partial hematologic remission.

median time to initial response was 2.5 months. The response was durable in three patients (12, 41 þ , and 60 þ months). The first of these patients (Case #3, Table 4) had a PR lasting 12 months after his first course of ATG; he then relapsed and was treated with a second course resulting in a 12-month CR (Figure 1). Retreatment for a third time was unsuccessful. Of the nonresponders, only one patient showed progression to leukemia during the 3-month evaluation period. Five patients (16%) died during the first 3 months after treatment. Three patients (all of whom were severely neutropenic at baseline) died from infection/sepsis. One patient died from progressive disease, and one patient (a Jehovah’s witness with a baseline hemoglobin of 3.4 gm/dl who refused red blood cell transfusion) died from anemia.

Feasibility The median duration of treatment with cyclosporine was 35 days (range, 1–305 days). In total, 22 patients (63%) required early cyclosporine discontinuation (range, 1–61 days) for the following reasons: hypertension, two patients; elevated bilirubin, three patients; elevated creatinine, four patients; infection, one patient; encephalopathy and cytomegalovirus antigenemia, one patient; poor patient compliance, one patient; persistent nausea/patient’s request, two patients; death (unrelated to cyclosporine as outlined above), five patients; and difficulty with follow-up for out-of-state patients in rural areas, three patients.

Table 4

2103

Toxicity The toxicity profile of ATG, cyclosporine, and prednisone was qualitatively similar to that seen for this combination in aplastic anemic patients (Table 5).26,29 The most common adverse events were fever and allergic reactions. However, early discontinuation of cyclosporine was more common than in aplastic anemia, perhaps because of the elderly nature of MDS patients. Hepatic and renal dysfunction occurred in 19 and 13% of the patients, respectively, and were generally reversible after lowering the dose of cyclosporine or discontinuing this drug. Other serious side effects included allergic (nonfatal) reaction to ATG (N ¼ 1), serum sickness due to ATG (N ¼ 1), and a myocardial infarction (N ¼ 1).

Discussion The diagnostic challenge in distinguishing aplastic anemia from MDS arises from the subtle overlap between the two diseases, mainly in patients with hypoplastic marrow and insufficient metaphases for cytogenetic analyses.26,28,30–39 Although the presence of megakaryocyte or granulocyte dysplasia is a feature of MDS in a hypoplastic marrow (hypoplastic MDS), erythroid hyperplasia may also occur in aplastic anemia.28 In aplastic anemia, pancytopenia is believed to be caused, at least in part, by T-cell-mediated progenitor cell inhibition, but susceptibility of hematopoiesis to attack by T cells may also exist in MDS.30,31 The implications of chromosomal abnormalities in patients with aplastic anemia remains unclear,28 and in many cases their presence is considered de facto evidence for progression to MDS.40 Even so, some studies suggest that clonal hematopoiesis occurs in aplastic anemia and this observation together with the fact that a subset of patients with aplastic anemia evolve to MDS and even leukemia further indicates linkage with MDS.41–47 ATG is cytolytic to T cells and both ATG and cyclosporine inhibit T-cell function, especially the production of suppressor lymphocytes.48,49 In addition to its immunosuppressive action, ATG has been shown to have direct effects on hematopoietic progenitor cells, in that it increases colony formation from primitive hematopoietic cells.50–52 ATG restores hematopoiesis in many patients with aplastic anemia.26,27,53 In a multicenter

Baseline characteristics of respondersa

Case Dx no.

Baseline Baseline Baseline Baseline ANC platelets Hgb cytogenetics (  109/l ) (  109/l ) (g/dl)

#1

RA

2.1

18

10.2

#2

RA

8.4

10

o8

#3

RARS

2.6

5

o8

#4

RARS

0.9

7

o8

#5

RAEB

2.0

39

8.9

Prior therapies

Monosomy 7, Noneb trisomy 21 Diploid IVIG, steroids, liposomal doxorubicin, splenectomy 13q Steroids, splenectomy Diploid Noneb Monosomies 7 and 5

B12, B6, folate acid

RBC transfusion Platelet Bone marrow Response Response dependence transfusion duration % % (duration) (mos) Cellularity Blasts No

No

45

2

PR

3

Yes (12 months)

Yes

5

1

CR

41+

Yes (24 months) Yes (6 months) No

Yes

100

0

CR

12

Yes

20

0.5

CR

60+

No

35

CR

1

18

Abbreviations: ANC, absolute neutrophil count; CR ¼ complete remission; Hgb ¼ hemoglobin; IVIG ¼ intravenous immunoglobulin; RBC ¼ red blood cells; PR ¼ partial remission; mos, months.aAll patients were off therapy for over 3 months. Splenectomy had been performed over 1 year prior to ATG treatment.bThese patients had a history of large-cell lymphoma and were previously treated with multiagent chemotherapy. Chemotherapy had been stopped approximately 3 years before entering the study. Leukemia

ATG in MDS S Yazji et al

2104

Figure 1 ANCs, hemoglobin (Hgb), and platelet (PLT) counts in a patient with RARS treated with ATG, cyclosporine, and prednisone. The patient achieved a partial remission that lasted for 12 months. He relapsed and, after retreatment with the same regimen, he achieved a complete remission that lasted for 12 months.

Table 5 Toxicity in 31 patients with MDS treated with ATG–cyclosporine and prednisone Toxicity

Any grade (%)

Fever Allergic reaction Transaminitis Renal insufficiency Hypertension Headache Rash Myocardial infarction Vasculitis Nausea/vomiting Malaise Tremor

30 13 6 4 3 2 2 1 1 1 1 1

(47) (42) (19) (13) (10) (7) (7) (3) (3) (3) (3) (3)

Grades 3–4 (%) 1 (3) 1 (6) 3 (10) N/A N/A N/A 1 (3) 1 (3) N/A N/A N/A N/A

Abbreviations: N/A, nonapplicable.

trial of ATG in 150 patients with aplastic anemia, the 3-month rates of transfusion independence and clinical improvement in the subgroup with severe aplastic anemia were 31 and 47%, respectively.27 Intensive immunosuppression with ATG combined with cyclosporine has been shown to induce high rates of response (over 75%) and survival (72% at 2 years) and is associated with low incidence of evolution to MDS.26,54 Leukemia

In the current study, which included only patients with MDS, the overall response rate (CR and PR) was 16%, and three of 18 patients (17%) with RA/RARS achieved durable CRs. The response rate was 26% if patients with hematologic improvement were also included. All responders clearly qualified for an MDS diagnosis (Table 4). Two of the responders had ringed sideroblasts 415% including one patient with a 13q chromosome abnormality and 100% marrow cellularity, and two responders had poor prognostic abnormalities such as monosomies 7 and 5; and all responders had significant dysplasia (Table 4). Other investigators have also investigated the role of ATG in MDS.33,55–58 In the study by Molldrem et al,55 the rate of attainment of red blood cell transfusionindependence in patients with MDS (N ¼ 61) treated with ATG (40 mg/kg/day aily for 4 days) was higher (34%) than that of our study. However, their patient population had more favorable pretreatment characteristics in terms of MDS subtype (77% of the patients had RA or RARS compared to 58% in our study) and cytogenetics (normal, 54% (Molldrem et al 55) vs 35% in our study). Similarly, Killick et al 58 noted a 50% hematologic response rate and improvement in 20 evaluable patients, most of whom had RA and diploid cytogenetics. Other smaller studies have also demonstrated that immunosuppressive therapy has activity, especially in patients with hypoplastic MDS. Biesma et al 33 reported that two patients with hypoplastic MDS responded to ATG and cyclosporine; resolution of transfusion requirements was noted

ATG in MDS S Yazji et al

2105 in three out of four patients treated with cyclosporine in one study (List AF et al. Blood 1992; 80: 28a; abstract) and in five of six patients treated with ATG in another study (Mineisha S et al. Blood 1994; 84: 315a; abstract). The mechanism of response to ATG is not clear, although it has been suggested that patients with RA who respond to ATG have CD8 þ T-cell clones that mediate major histocompatibility complex-I-restricted suppression of granulocyte–macrophage colony-forming units (CFU-GM) and that these cells are replaced by polyclonal T cells that do not suppress CFU-GM after ATG treatment.31 The current study is comparable with previous studies in terms of toxicity.26,29 Fever and urticaria are common adverse events occurring on the first and second day of administration of ATG. Corticosteroids ameliorate serum sickness,49 as it occurs less frequently with regimens incorporating prednisone with or without cyclosporine,53 than with ATG alone.38,49,59 Transaminitis and renal insufficiency are common adverse events with the use of cyclosporine. Causes of death in the current study (mainly infections) were similar to those reported with ATG, prednisone, or cyclosporine regimens in aplastic anemia.29,54,60 The rate of early discontinuation of cyclosporine was, however, high compared to that reported in studies with aplastic anemia, perhaps because the MDS population is older. In conclusion, an ATG-based regimen has activity in patients with MDS. Some responses in individuals with RA/RARS are durable and in one patient, a 12-month response was induced a second time after relapse. A synthesis of the literature suggests that responses are especially common in hypoplastic RA patients with diploid cytogenetics.31,56 These results may be a reflection of the continuum between aplastic anemia and hypoplastic RA. However, patients with hypercellular disease and chromosomal abnormalities may also respond, albeit less frequently. These observations suggest that further application of this modality, especially in RA/RARS patients with severe cytopenias, is warranted.

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