Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT

Leukemia Research 33 (2009) 840–842

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Brief communication

Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT Takaaki Konuma, Jun Ooi ∗ , Satoshi Takahashi, Akira Tomonari, Nobuhiro Tsukada, Seiko Kato, Aki Sato, Fumihiko Monma, Senji Kasahara, Kaoru Uchimaru, Tohru Iseki, Arinobu Tojo, Shigetaka Asano Department of Hematology and Oncology, Institute of Medical Science, University of Tokyo, Tokyo, Japan

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Article history: Received 18 August 2008 Received in revised form 1 October 2008 Accepted 2 October 2008 Available online 7 November 2008 Keywords: Cord blood transplantation Second transplantation Leukemia Relapse Graft-versus-leukemia effect

a b s t r a c t There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100 mg/m2 and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT. © 2008 Elsevier Ltd. All rights reserved.

1. Introduction Relapsed leukemia is a serious complication after allogeneic stem cell transplantation (allo-SCT). Treatment options for leukemia relapsed after allo-SCT include withdrawal or discontinuation of immunosuppressive agents, chemotherapy, donor lymphocyte infusion and second allo-SCT. In such treatments, second allo-SCT is the only potentially curative therapy [1]. Recently, cord blood (CB) has been used as an alternative source of hematopoietic stem cells in unrelated allogeneic transplantation for adult [2–4]. Several studies showed that second allo-SCT using CB was useful for patients with graft failure after initial allo-SCT [5,6]. However, the efficacy for patients with leukemia relapsed after initial allo-SCT is unknown. Here, we, retrospectively, reviewed the results of myeloablative CB transplantation (CBT) as second allo-SCT in seven adult patients with leukemia relapsed after initial allo-SCT.

lative conditioning. Three patients had acute myeloid leukemia, three had acute lymphoblastic leukemia and one had chronic myeloid leukemia. Written informed consent for treatment was obtained from all patients. 2.1. First allo-SCT All patients received a myeloablative conditioning including four fractionated 12 Gy total body irradiation (TBI). The initial allograft was unrelated CB in four patients, matched related bone marrow (BM) in one, partially matched related BM in one and matched unrelated BM in one. The characteristics of the patients, allografts and outcomes of first allo-SCT are shown in Table 1. 2.2. Second allo-SCT

2. Patients and methods

All patients received a myeloablative conditioning including oral busulfan (BU) 1 mg/kg every 6 h for days −7, −6, −5 and −4, intravenous fludarabine (Flu) 25 mg/m2 for days −7, −6, −5 and −4, and cyclophosphamide (CY) 60 mg/kg for days −3 and −2. Two days after the completion of conditioning, patients received a single CB unit transplantation. Two patients received cyclosporine A (CSP) and methotrexate, and five patients received CSP only as a GVHD prophylaxis. Since original donors were not available, donor lymphocyte infusion or second allo-SCT using original donor was not performed for patients who received BM as first allograft.

Between October 2002 and February 2008, seven patients with leukemia, who relapsed after initial allo-SCT, received second allo-SCT using CB after myeloab-

3. Results

∗ Corresponding author at: Department of Hematology and Oncology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 1088639, Japan. Tel.: +81 3 3443 8111; fax: +81 3 5449 5429. E-mail address: [email protected] (J. Ooi).

The characteristics of the seven patients and CB units as second allograft are shown in Table 2. Among the patients, the median age was 26 years (range, 19–41 years), the median weight was 53 kg (range, 36–76 kg), the median number of cryopreserved nucleated cells was 2.88 × 107 kg−1 (range, 2.09–3.05 × 107 kg−1 )

0145-2126/$ – see front matter © 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2008.10.003

T. Konuma et al. / Leukemia Research 33 (2009) 840–842

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Table 1 Characteristics of first allogeneic SCT (SCT1). Case 1

2

3

4

5

6

7

Diagnosis Age, years/sex Prior therapy Donor type

CML 18/M HU Unrelated BM

Ph ALL 18/F ChemoTx CB

AML 36/F ChemoTx Related BM

AML 21/F ChemoTx CB

sAML 19/F None CB

ALL 40/F ChemoTx CB

No. of HLA disparitiesa Disease status at SCT Conditioning regimen GVHD prophylaxis Acute GVHD Chronic GVHD Duration of remission after SCT1, months

None

4

None

2

Ph ALL 28/F ChemoTx Partially matched related BM 2

2

2

CP2

CR1

CR1

CR2

Non CR

Non CR

CR1

TBI 12 Gy + CA + CY

TBI 12 Gy + CY

TBI 12 Gy + CA

TBI 12 Gy + CA + CY

TBI 12Gy + CY

TBI 12 Gy + CA + CY

TBI 12 Gy + CA + CY

FK + MTX I (skin1) Limited 8

CSP + MTX II (skin3) Limited 12

CSP + MTX I (skin1) None 46

CSP + MTX I (skin1) Limited 51

CSP + MTX II (skin3) Extensive 51

CSP + MTX II (skin3) Extensive 27

CSP + MTX I (skin1) Limited 7

SCT, stem cell transplantation; CML, chronic myeloid leukemia; ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; sAML, myelodysplastic syndrome-related secondary AML; M, male; F, female; HU, hydroxyurea; ChemoTx, chemotherapy; BM, bone marrow; CB, cord blood; CP, chronic phase; CR1, first complete remission; CR2, second complete remission; CR, complete remission; TBI, total body irradiation; CA, cytosine arabinoside; CY, cyclophosphamide; FK, tacrolimus; MTX, methotrexate; CSP, cyclosporine. a HLA disparities defined as the low resolution for HLA-A and -B and the high resolution for HLA-DRB1.

Table 2 Outcomes of second allogeneic SCT (SCT2). Case

SCT1–SCT2, months Relapse to SCT2, months Prior therapy Body weight, kg TNC, ×107 kg−1 CD34, ×105 kg−1 No. of HLA disparitiesa (recipient vs. second graft) No. of HLA disparitiesa (first vs. second graft) Disease status at SCT Neutophil recoveryb , days Platelet recoveryc , days Acute GVHD Chronic GVHD Survival after SCT2, months Cause of death

1

2

3

4

5

6

7

12 4 ChemoTx, imatinib, splenic irradiation 53 2.62 0.90 3

17 5 ChemoTx

53 7 ChemoTx

57 6 ChemoTx

54 2 ChemoTx

29 1 None

10 2 ChemoTx

37 2.89 1.21 4

54 2.96 2.00 2

57 2.33 0.96 2

76 2.09 0.46 2

43 2.88 0.85 2

36 3.05 1.03 2

3

5

2

3

3

2

2

BC NA NA NA NA 2 Disease progression

Relapse 17 41 II (skin3) None 13 Relapse after CR

CR 13 31 I (skin2) Limited 40+

CR 20 73 I (skin2) Limited 34+

CR 20 NA III (skin2,gut3,liver3) Extensive 18 Meningoencephalitis

Relapse 16 67 0 Limited 21+

CR 18 72 0 None 4+

SCT, stem cell transplantation; TNC, total nuclear cell; CD34, CD34-positive cell; ChemoTx, chemotherapy; BC, blast crisis; CR, complete remission; NA, not available. a HLA disparities defined as the low resolution for HLA-A and -B and the high resolution for HLA-DRB1. b Neutrophil recovery time was defined as the first day of the achievement of an absolute neutrophil count of 0.5 × 109 L−1 for 3 consecutive days. c Platelet recovery time was defined as the first day of the achievement of an absolute platelet count 50 × 109 L−1 without the support of transfusions for 7 continuous days.

and the median number of cryopreserved CD34-positive cells was 0.96 × 105 kg−1 (range, 0.46–2.00 × 105 kg−1 ). The median time between first and second allo-SCT was 29 months (range, 10–57 months). The median time from relapse after first allo-SCT to second allo-SCT was 4 months (range, 1–7 months). Among six patients who received one or more courses of chemotherapy before second allo-SCT, four patients achieved complete remission (CR) with full first donor chimerism. All but one patient had myeloid reconstitution and median time to more than 0.5 × 109 L−1 absolute neutrophil count was 17.5 days (range, 13–20 days). A self-sustained platelet count more than 50 × 109 L−1 was achieved in five patients at a median time of 67 days (range, 31–73 days). All patients with myeloid reconstitution showed full second donor chimerism. Grades II–IV acute GVHD occurred in two of six evaluable patients and extensive type chronic GVHD occurred in one of five evaluable

patients. No patient developed veno-occulsive disease of the liver. One patient developed grade II heart failure and required diuretics and dobutamine. One patient developed meningoencephalitis of varicella-zoster virus. Two patients died of relapse on 2 and 13 months after second allo-SCT and one patient died of meningoencephalitis on 18 months second allo-SCT. Four patients are alive and three of four patients are free of disease on 34, 21 and 4 months after second allo-SCT. One patient relapsed on 35 months after second allo-SCT, but she is alive at the time of analysis. 4. Discussion Previous reports have suggested that the only potentially curative therapy for leukemia relapsed after allogeneic SCT is second allo-SCT. However, the incidences of treatment-related mortality

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T. Konuma et al. / Leukemia Research 33 (2009) 840–842

(TRM) have been reported to be high and several reports of second allogeneic SCT for relapsed leukemia showed disease-free survival rates of 20–30% [1]. Since all patients received 12 Gy TBI for initial allo-SCT conditioning in our study, we used BU/CY and Flu regimen for second allo-SCT. The addition of Flu to BU/CY regimen might be effective in terms of engraftment after CBT. Despite the use of myeloablative conditioning, the incidence of TRM was very low in our study. However, one patient, who received second allo-SCT with shortest interval between first and second allo-SCT, developed grade II heart failure. This case suggests that severity of regimen-related toxicity after second allo-SCT might be associated with time interval between the first and second allo-SCT. Although it remains unclear whether the use of different donor at second allo-SCT is better than the same donor of first transplant [7,8], the different graft-versus-leukemia effect after second allo-SCT might be induced by the use of a different donor from initial donor. Although the number of patients was small and the observation period was limited, these results suggest that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT. Conflict of interest The authors have no conflict of interest to disclose. Acknowledgements The authors are indebted to the medical and nursing staff who cared for patients in this study and thank Maki Monna-Oiwa for her

secretarial assistance. Contributions. T.K., J.O., S.T., and S.A. designed the study; T.K., J.O., S.T., A.T., N.T., S.K., A.S., F.M., S.K., K.U., T.I., and A.T. performed patients’ care; and T.K., and J.O. wrote the paper. References [1] Giralt SA, Champlin RE. Leukemia relapse after allogeneic bone marrow transplantation: a review. Blood 1994;84:3603–12. [2] Laughlin MJ, Eapen M, Rubinstein P, Wagner JE, Zhang MJ, Champlin RE, et al. Outcomes after transplantation of cord blood or bone marrow from unrelated donors in adults with leukemia. N Engl J Med 2004;351: 2265–75. [3] Rocha V, Labopin M, Sanz G, Arcese W, Schwerdtfeger R, Bosi A, et al. Transplants of umbilical-cord blood or bone marrow from unrelated donors in adults with acute leukemia. N Engl J Med 2004;351:2276–85. [4] Takahashi S, Iseki T, Ooi J, Tomonari A, Takasugi K, Shimohakamada Y, et al. Singleinstitute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies. Blood 2004;104:3813–20. [5] Fernandes J, Rocha V, Robin M, de Latour RP, Traineau R, Devergie A, et al. Second transplant with two unrelated cord blood units for early graft failure after haematopoietic stem cell transplantation. Br J Haematol 2007;137: 248–51. [6] Kawamori Y, Yakushijin K, Okamura A, Nishikawa S, Minagawa K, Shimoyama M, et al. Successful engraftment in reduced-intensity cord blood transplantation (CBT) as a salvage therapy for graft failure after primary CBT in adults. Transplantation 2007;83:1281–2. [7] Duus JE, Stiff PJ, Choi J, Parthasarathy M, Rodriguez T, Toor AA. Second allografts for relapsed hematologic malignancies: feasibility of using a different donor. Bone Marrow Transplant 2005;35:261–4. [8] Hosing C, Saliba RM, Shahjahan M, Estey EH, Couriel D, Giralt S, et al. Disease burden may identify patients more likely to benefit from second allogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia. Bone Marrow Transplant 2005;36:157–62.