Conditioning with cyclophosphamide/antithymocyte globulin ... - Nature

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allogeneic bone marrow transplantation from HLA-matched siblings in children with severe aplastic anemia. E Azuma1, S Kojima2, K Kato2, T Matsuyama2, ...
Bone Marrow Transplantation, (1997) 19, 1085–1087  1997 Stockton Press All rights reserved 0268–3369/97 $12.00

Conditioning with cyclophosphamide/antithymocyte globulin for allogeneic bone marrow transplantation from HLA-matched siblings in children with severe aplastic anemia E Azuma1, S Kojima2, K Kato2, T Matsuyama2, Y Yamada3, N Kondo3, H Sawada4, M Hanada4, T Shibata4 , N Tabata1, M Watanabe1, Y Shimono 1, T Deguchi1, M Umemoto1, M Higashikawa1, H Kawasaki 1, Y Komada1 and M Sakurai1 1

Department of Pediatrics and Clinical Immunology, Mie University School of Medicine, Mie; 2Japanese Red Cross Nagoya First Hospital, Nagoya; 3Department of Pediatrics, Gifu University School of Medicine, Gifu; and 4Department of Pediatrics, Mie General Medical Center, Mie, Japan

Summary: Graft rejection has been a problem after bone marrow transplantation for patients with severe aplastic anemia (SAA). Ten children with SAA were conditioned for bone marrow transplantation from HLA-identical siblings, using cyclophosphamide (CY, 50 mg/kg) plus antithymocyte globulin (ATG, 15 mg/kg ) for 4 successive days. Marrow was infused 36 h after the last dose of CY. Cyclosporin A and methotrexate were administered as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment at follow-up of 7–41+ months (mean, 25) without significant GVHD. Since investigators have used different sources, doses, and time schedules of ATG, we compared our results with other published reports. We conclude that CY/ATG conditioning is well tolerated and effective in children with SAA. Keywords: bone marrow transplantation; severe aplastic anemia; antithymocyte globulin

The treatment of choice for SAA is a bone marrow transplant (BMT) from an HLA-matched sibling.1 Survival rates of 62–82% following BMT from a matched sibling donor are now reported for the last 10 years.2 A major complication of BMT is graft rejection, which may occur early or months later. Various conditioning regimens have been reported to minimize graft rejection.2 While effective in reducing the incidence of rejection, most conditioning programs have associated risks. Irradiation may cause late cancer and problems with growth, development, and fertility.3–5 Storb et al6 had devised a regimen of CY/ATG to prepare patients for second marrow transplants after rejection of the first transplants. The regimen was well tolerated, and three quarters of the patients so treated had successful second grafts. This result suggested that the combination is more immunoCorrespondence: Dr E Azuma, Department of Pediatrics and Clinical Immunology, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514, Japan Received 20 November 1996; accepted 3 February 1997

suppressive than CY alone. Prompted by this success, Storb et al7 have used CY/ATG to condition patients with aplastic anemia for first transplant, resulting in 92% 3-year actuarial survival. Based on favorable experience in Seattle, Horstmann et al,8 Okamoto et al9 and Bunin et al10 reported similar results, using a different source, dose, and time schedule of ATG. Here, we report our results of CY/ATG conditioning in 10 children with SAA; a durable engraftment rate of 100% in a median follow-up of 25 months. Furthermore, in an effort to better understand the post-transplant experience of these patients, we compared current results with published reports. Patients and methods From June 1993 to April 1996, 10 consecutive children with severe aplastic anemia, as defined by the International Aplastic Anemia Study group,11 were transplanted with marrow from their HLA-identical siblings following conditioning with CY (50 mg/kg i.v.) and ATG (Lymphoglobulin, 15 mg/kg i.v.; Pasteur-Meriex, Lyon, France) for 4 days. CY and ATG were given on the same days. Marrow was infused 36 h after the last dose of CY. The day of marrow infusion was designated day 0. All patients received transplants for the first time. No patient received immunosuppressive therapy before transplantation. No patient was infected at the time of transplant. Informed consent had been obtained in all cases (parents). Patients were premedicated with methylprednisolone prior to ATG infusion. Postgrafting immunosuppression consisted of methotrexate (MTX) and cyclosporin A (CsA), as described.6 CsA levels from whole blood were adjusted to maintain 150–300 ng/ml. All patients were treated in laminar airflow isolation rooms with skin and gut decontamination. G-CSF was given intravenously starting on day 1– 6, and continued until the absolute neutrophil count .1000. Documentation of hematopoietic engraftment and assessment, grading and treatment of acute and chronic GVHD were performed as described previously.6 Acyclovir for prevention of herpes simplex virus infection was administered from day +1 to discharge. Results of the study were analyzed as of November 1996.

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Table 1

Outcome of marrow transplants in 10 children with severe aplastic anemia conditioned with cyclophosphamide and antithymocyte globulin

Patient No.

Recipient

Donor

Duration of SAA (months)

Age (years)

Sex

Age (years)

Sex

1 2 3 4 5 6 7 8 9 10

1.5 7 4 2 11 11 14 11 10 7

M M F F M F F F M F

5 10 0.8 5 14 8 20 17 8 9

M M F M M F F F F F

Average s.d.

7.9 4.3

9.7 5.8

Transfusion (U)

Engraftment GVHD (days) acute/chronic

RBC

Platelet

3 2 3 4 2 5 4 2 2 2

9 7 7 10 5 14 4 8 6 8

70 13 16 7 13 15 4 5 3 11

17 21 11 13 12 12 33 20 19 14

2.9 1.1

7.8 2.8

15.7 19.6

17.2 6.6

No No No No No/limited No No No No No

Survival (months)

41+ 38+ 34+ 31+ 27+ 26+ 20+ 15+ 13+ 7+ 25.2+

Table 2 Comparison of cyclophosphamide/antithymocyte globulin conditioning regimen for marrow transplants in patients with severe aplastic anemia using different sources, doses, and time schedules of antithymocyte globulin Investigators (year)

No. Age (years) patients (median)

Dose (source) of anti-thymocyte globulin

GVHD prophylaxis

GVHD

Graft failure

Acutea Chronic Storb (1994) Horstmann (1995)

39 9

2–52 (24.5) 30 mg/kg × 3 (horse, Upjohn) 7–30 (25)

30 mg/kg × 4 (rabbit, Fresenius)

CsA/MTX

3

11

2

36

10–61 (30)

CsA/MTX

0

0

0

8

20–37 (30)

CsA/steroid CsA

0 1

0 0

0 1

1 11

13 7–55 (26)

0

1

0

10

7–41 (25)

4 (6%)

12 (17%)

3 (4%)

66 (93%)

Okamoto (1996) Bunin (1996)

1 12

16 4 mg/kg × 4 (rabbit, Pasteur-Meriex) 1.5–16 (3) 30 mg/kg × 3 (horse, Upjohn)

This study (1996)

10

1.5–14 (8) 15 mg/kg × 4 (horse, Pasteur-Meriex) CsA/MTX

Total (%)

71

a

Durable Follow-up in engraftment months (median)

Acute = acute GVHD >grade 3.

Results Patient–donor characteristics The clinical characteristics of the patients are shown in Table 1. The median age of patients with SAA was 7.9 years. All had developed SAA of idiopathic etiology. Three patients (Nos 3, 4 and 6) had received prior therapy with steroids, G-CSF, M-CSF, CsA, or androgen, and all had received transfusions; red blood cells (RBC) and platelets were administered 4–14 units (mean, 7.8) and 3–70 units (mean, 15.7), respectively. None developed anti-HLA antibody. Patients received 4.1 × 108/kg donor mononuclear cells (mean 4.1; range, 2.4–5.6). Patient No. 7 developed herpes zoster at 9 months post-transplant. Other patients did not show viral reactivation post-transplant. Engraftment and GVHD Table 1 summarizes the transplantation data and results. All 10 patients showed evidence of hematopoietic engraftment as determined by rising peripheral blood counts, marrow cellularity, and blood genetic marker studies. The median time to reach absolute neutrophil counts of 500 was 17.2 days post-transplant (range, 11–33). One patient (No. 7)

showed delayed engraftment because of sepsis after day 5. No patients developed acute GVHD. One patient developed limited chronic GVHD. One patient (No. 1) developed hepatic veno-occlusive disease which was successfully treated. ATG toxicity was limited to transient reactions in the form of skin rashes and/or fevers in eight of 10 patients. Followup for these patients is from 7–41+ months (median, 25.2) with durable engraftment rate of 100%. The Karnofsky score is 100%. Second cancers or other serious long-term sequelae of the conditioning regimen have not been observed during the current follow-up.

Discussion Transfusions increase the risk of sensitization, and subsequent graft rejection in patients with SAA following BMT.2 Given the difficulty in avoiding transfusions before transplant, more effective approaches have been explored to reduce the risk of graft rejection. Despite the unequivocal success with the irradiation-based regimens, concern has been raised by a publication reporting a high incidence of secondary malignancies.5 However, the treatment of SAA with immunosuppressive therapy alone also has an

Marrow graft for aplastic anemia in children E Azuma et al

increased incidence of second malignancy.5 Storb et al6 devised CY/ATG (30 mg/kg/day × 3 days; horse; Upjohn, Kalamazoo, MI, USA) as a conditioning regimen for BMT from HLA-matched siblings, resulting in an excellent outcome. Subsequently, other investigators have independently utilized similar approaches with different sources, doses, and time schedules of ATG. Horstman et al8 administered ATG (rabbit; Fresenius, Bad Homburg, Germany) at a higher dose (30 mg/kg/day × 4 days). Okamoto et al9 used rabbit ATG (Pasteur-Meriex) at 4 mg/kg/day for 4 days. Bunin et al10 followed Storb’s regimen. Table 2 lists the current approaches to SAA with CY/ATG regimen. Three of 71 patients (4%) rejected the graft. Sixty-six of 71 patients (93%) achieved durable engraftment. Acute GVHD (> grade 3) was 6% and chronic GVHD is 17%. Presumably, the addition of ATG to CY provided sufficient immunosuppression to overcome sensitization to minor histocompatibility antigens expressed on donor cells that leads to rejection of the first graft.6 It is still to be determined from these studies whether or not the CY/ATG conditioning regimen can be used in SAA patients with multiple transfusions, although Storb et al6 showed some in multiply transfused patients achieved durable engraftment with CY/ATG. Several factors were to the advantage of children in the current study, including younger patient age, short time to transplant, relatively low number of transfusions, and marrow dose. Furthermore, a low incidence of acute GVHD has been reported in Japanese patients possibly due to genetic homogeneity.12 The sample size is small and follow-up duration is short in the present series and it would not be appropriate to assume that 100% survival would be expected if another 10 patients were treated. Nevertheless, the data presented here are encouraging for preparation of children with SAA with an HLA-matched sibling.

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