Allogeneic hematopoietic stem cell transplantation for ... - Nature

Bone Marrow Transplantation, (1999) 23, 569–572  1999 Stockton Press All rights reserved 0268–3369/99 $12.00 http://www.stockton-press.co.uk/bmt

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan S Imashuku1, S Hibi1, S Todo1, M Sako2, M Inoue3, K Kawa3, K Koike4, A Iwai5, S Tsuchiya6, Y Akiyama7, T Kotani8, Y Kawamura8, M Hirosawa9, D Hasegawa10, Y Kosaka10, H Yamaguchi11, E Ishii11, K Kato12, M Ishii13 and H Kigasawa14 1

Kyoto Prefectural University of Medicine; 2Osaka City General Hospital; 3Osaka Medical Center Research Institute of Maternal and Child Health; 4Shinsyu University School of Medicine; 5Kagawa Children’s Hospital; 6Institute of Development, Aging and Cancer, Tohoku University; 7Kyoto University, Faculty of Medicine; 8Ishikawa Prefectural Chuo Hospital; 9Kitakyusyu Muncipal Medical Center; 10Kobe University School of Medicine; 11Saga Prefectural Kouseikan Hospital; 12Nagoya First Red Cross Hospital; 13 Nagoya Second Red Cross Hospital; and 14Kanagawa Children’s Medical Center, Japan

Summary: Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988–1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agentsunknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein–Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan– Meier analysis showed a 2-year event-free survival after SCT as 54.0 ⴞ 13.0%. Keywords: hemophagocytic syndrome; bone marrow transplantation; hematopoietic stem cell transplantation; familial erythrophagocytic lymphohistiocytosis; Epstein– Barr virus-related hemophagocytic syndrome Correspondence: Dr S Imashuku, Children’s Research Hospital, Kyoto Prefectural University of Medicine, Hirokoji, Kawaramachi, Kamigyoku, Kyoto, Japan 602-8566 Received 17 August 1998; accepted 22 October 1998

The international Histiocyte Society classifies the histiocytic disorders into three categories from class I to class III.1 The majority of hemophagocytic syndromes belong to class II with rare malignant histiocytosis falling in class III and is now considered consisting of primary (familial) and secondary (infection- or lymphoma-associated) hemophagocytic lymphohistiocytosis (HLH).2 Clinical features in patients with these hemophagocytic syndromes are similar and include idiopathic fever, cytopenias, liver dysfunction, hepatosplenomegaly, coagulopathy, in rare cases adenopathy, and the presence of hemophagocytosis in the bone marrow as well as other reticuloendothelial tissues. The basis of treatment for these disorders is corticosteroids and etoposide;2,3 however therapeutic value is limited in some types of hemophagocytic syndrome. Differential diagnosis is mainly focused upon familial erythrophagocytic lymphohistiocytosis (FEL) vs non-familial,4 because of the poor prognosis of FEL without hemopoietic stem cell transplantation (SCT). However, some cases of unproven familial, HLH with no proven infective origin (designated simply as HLH), and Epstein–Barr virus (EBV)-related HLH (EBVHLH) including natural killer large granular lymphocytic leukemia/lymphoma-associated hemophagocytic syndrome (EBV-NK-LGLL-HPS) take an aggressive clinical course.5,6 For such cases, SCT has also been used. To date, SCT or bone marrow transplantation (BMT) have been performed mainly for FEL7–16,17 and for some cases of EBVHLH.18–20 We report the multi-institutional experiences of SCT for 17 cases of hemophagocytic syndrome in Japan. Patients The survey identified 17 cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome who underwent allogeneic SCT in Japan between 1988 and 1998. Patients comprised six FEL, five HLH, of which two were most likely FEL with characteristic central nervous system (CNS) signs, and six EBV-HLH (Table 1). Of the six EBV-related cases, two cases were proved as T cell lineage from T cell receptor rearrangement studies, two cases were of natural killer cell lineage (EBV-NK-LGLLHPS), while in the remaining two cases cell lineage was

Allogeneic HSCT for patients with HPS in Japan S Imashuku et al

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Table 1 Patient No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Patient characteristics and treatment before SCT Age at onset/sex

Disease

1 mo/M 8 mo/F 6 mo/F 2 mo/M 1 mo/M 6 mo/F 1 yr 3 mo/F 2 mo/F 2 yr 2 mo/F 8 yr/M 1 yr/F 4 yr/F 5 yr/M 7 yr/F 1 yr 3 mo/F 12 yr/F 18 yr/M

FEL FEL FEL FEL FEL FEL HLHa HLHa HLH HLH HLH EBV-HLH EBV-HLH EBV-HLH EBV-HLH EBV-NK-LGLL-HPS EBV-NK-LGLL-HPS

Treatment before SCT

Clinical status at SCT

VP16/Cs/IT MTX VP16/Cs VP16/Cs VP16/Cs VP16/Cs/MTX/IT MTX VP16/Cs/IT MTX/others VP16/Cs/IT MTX VP16/Cs/IT MTX VP16/Cs/ACOP VP16/Cs/CSA VP16/Cs/splenectomy VP16/Cs/ACOP/others VP16/Cs/ACOP/others VP16/Cs VP16/Cs/ACOP/others ProMACE-CYTABOM low dose CY

1 CR 1 CR 2 CR 2 CR 1 CR PR PR PR 2 CR PR PR PR PR PR 2 CR PR PR

Interval from diagnosis to SCT (months) 4 3 33 16 10 31 14 7 40 5 24 6 72 2 17 2 2

a With CNS lesions. Cs = corticosteroids; IT MTX = intrathecal methotrexate; ACOP = adriamycin/cyclophosphamide/Cs; CY = cyclophosphamide; CsA = cyclosporin A; ProMACE-CYTABOM = a combination of adriamycin/cyclosphosphamide/VP16/cytosine arabinoside/bleomycin/methotrexate/prednisolone.

not determined. Five of these EBV-related cases were confirmed to have clonally proliferating EBV-infected cells using a probe for a terminal repeat of EBV genome.21 None of the EBV-HLH cases was familial. Before SCT, all cases had been treated intensively with immuno-chemotherapy including corticosteroids and etoposide, or with malignant lymphoma-type multiagent chemotherapy such as ACOP (Table 1). The duration from diagnosis to SCT was median 10 (range 2–72) months. Among the cases where SCT took place after longer than 24 months, cases 3 and 9 underwent SCT in second complete remission while cases 6, 11 and 13 were in partial remission following fluctuating but persistent disease. Of these 17 cases, cases 1, 3, 12, 16 and 17 were previously documented as case reports.9,17–20

ditioning regimens were Bu/VP16/CY ⫾ ATG (10 cases), TBI/VP16/CY ⫾ CSI (four cases), TBI/CY ⫾ ATG (two cases), and TBI/Bu/L-PAM (one case). Drug doses used were: Bu (4 mg/kg/day or 35 mg/m2/day × 4 days), VP16 (40 mg/kg/day × 1 day), TBI (12 Gy/4 fractions), CY (60 mg/kg/day × 2 days for TBI and 50 mg/kg/day × 4 days for non-TBI regimens), ATG (2.5 mg/kg/day × 4 days), and L-PAM (70 mg/m2/day × 3 days). Five of the eight cases receiving conditioning regimens including TBI were EBVrelated. GVHD prophylaxis was with sMTX/CSA (MTX 10 mg/m2/dose at day +1, 10 mg/m2/dose at days +3, +6, and CsA 3 mg/kg/day) except for 3 patients who received FK506 (0.05–0.1 mg/kg/day, continuous infusion). Minor modifications of dose were made in some cases for both conditioning and GVHD regimens.

Stem cell transplantation Post-transplantation course As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. The CD34positive selection using the Isolex 50 magnetic cell separation system (Baxter Immunotherapy Division, Santa Ana, CA, USA) from haploidentical father (cases 7, 10) and PBSC collection from HLA-match sibling was carried out as previously described.18,22 In none of the cases were specific T cell depletion procedures employed. With bone marrow cells, the mononuclear cell number infused was a median 4.2 × 108/kg (range 1.0 × 108/kg to 4.8 x 108/kg) and with the two cord blood infusions 6.8–10 × 107/kg (as CFU-GM, 3.0–3.4 × 104/kg) were given. In the remaining two CD34-positive selections and one PBSC, CD34+ cell numbers infused were 1.0–1.3 × 107/kg. At the time of SCT, three cases were in first CR, four in second CR and 10 in PR (Table 1). Conditioning regimens and GVHD prophylaxis were chosen at the physician’s discretion. Con-

Engraftment occurred in 16 of the 17 cases. The exception was a case receiving CD34-positive selection (Table 2). Acute GVHD was not observed in six cases, grade I/II in 10 cases while severe hepatic veno-occlusive disease occurred in one case (case 6). During the post-SCT course, four cases relapsed, of whom three died at 5, 14 and 15 months, respectively. One case is alive with active disease, on therapy. Apart from deaths after relapse, two deaths in remission were due to fatal post-SCT EBV-positive T cell lymphoma in one FEL case (case 5) and to extensive chronic GVHD in another FEL case (case 6). Cases 16 and 17 of EBV-NK-LGLL-HPS were previously reported as successful transplants;18,20 however, the current follow-up revealed that both relapsed at 12 and 8 months later, and subsequently died. As of the end of September 1998, 10 cases are alive without disease and with ⬎90% Karnofsky score with post-SCT remission


Table 2 Patient No.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

571

Characteristics of SCTs Donor (HLA)

Sibling (match) Sibling (match) URD (match) URD (5/6) URD (match) URD (match) Father (haplo) Father (5/6) Sibling (match) Father (haplo) URD (match) Sibling (match) URD (match) Sibling (identical) URD (match) Sibling (match) Sibling (match)

Sources

BM BM CB CB BM BM CD34 BM BM CD34 BM BM BM BM BM BM PBSC

Conditioning regimen

Bu/VP16/CY Bu/VP16/CY Bu/VP16/CY Bu/VP16/CY Bu/VP16/CY/ATG TBI/VP16/CY Bu/VP16/CY Bu/VP16/CY Bu/VP16/CY TBI/VP16/CY TBI/CY/ATG TBI/Bu/LPAM TBI/CSI/VP16/CY Bu/VP16/CY TBI/VP16/CY TBI/VP16/CY TBI/CY

GVHD prophylaxis

sMTX/CSA sMTX/CSA sMTX/CSA sMTX/CSA sMTX/CSA FK506 sMTX/CSA sMTX/CSA sMTX/CSA FK506 sMTX/CSA sMTX/CSA FK506 sMTX/CSA sMTX/CSA sMTX/CSA sMTX/CSA

Engraftment

Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes

aGVHD

Grade Grade Grade Grade None Grade None Grade Grade None Grade None Grade None Grade Grade None

II I I II IV (VOD) I I I I I II

Relapse Outcome (duration of post SCT remission, months)a No No No No No No No No Yes Yes No No No No No Yes Yes

ASD (147+) ASD (83+) ASD (13+) ASD (7+) Died, at 4 mb (3) Died, at 12 m (11) AWD (0) ASD (15+) AWD (14) Died at 5 m (3) ASD (57+) ASD (29+) ASD (41+) ASD (17+) ASD (3.5+) Died at 14 m (12) Died at 15 m (8)

a

As of September 1998. Fatal post SCT EBV-positive T cell lymphoma. Haplo = haploidentical; CSI = craniospinal irradiation; VOD = veno-occlusive disease; ASD = alive without disease; AWD = alive with disease.

b

durations of 3.5 to 147 months, while two post-SCT cases (cases 7 and 9) are still on therapy for residual/relapsed disease. CNS disease developed in only two cases during treatment before SCT (cases 7 and 8), and MRI brain scans remain positive but not progressive in one successfully transplanted HLH case (case 8). Mild chronic GVHD has been noted in only one case (case 11). Although in this series seven allogeneic SCTs were performed from URD (two cord blood, five bone marrow cells), only one severe or fatal GVHD case occurred and five remain in post-SCT remission. One of the two transplants using selected CD34-positive stem cells from the haploidentical father rejected, and the other (case 10) resulted in a poor outcome following cytomegalovirusenteritis and pneumonia in association with reactivation of HLH. The Kaplan–Meier estimate (mean ⫾ s.e.) of event-free survival at 2 years for all 17 cases was 54.0 ⫾ 13.0% (95% confidence interval). Information on chimerism in the long-term survivors is not available apart from case 9, who has been studied because of postSCT relapse and shown to have mixed chimeric status by micro-satellite studies.23 Discussion Among the various disorders belonging to the hemophagocytic syndrome, allogeneic BMT has mostly been described for patients with FEL or HLH.7–16,19 because FEL has a very poor prognosis unless patients undergo BMT. The 4 year survival of FEL/HLH was 10.1% without BMT while it was 66.0% with BMT, as reported by Arico et al.16 More recently, SCTs for patients with EBV-related HLH have also been undertaken18–20 because aggressive EBV-HLH are often fatal. We report SCTs for 11 cases of FEL/HLH and six cases of EBV-HLH including EBV-NK-LGLL-HPS (Table 1). In these 17 cases of hemophagocytic syndrome, the peak onset ages for FEL/HLH (median 6 months) and

EBV-HLH (median 6 years) were significantly different, suggesting that the two disorders may be distinct. However, our results after SCTs are similar between these groups. SCT is now considered to be essential in the treatment of FEL and may be an indication for some cases of refractory/aggressive EBV-HLH. The important issue is that when no HLH-matched sibling donor is available, what is the best alternative donor choice for SCT and how does clinical status at the time of BMT affect outcome. Previously, successful FEL transplants were mostly from HLH-identical siblings,9,10,15 although the case reported by Ahmed et al,8 one of the five cases described by Blanche et al10 and two of the four cases by Baker et al15 died. On the other hand, one successful URD-BMT was reported by Kapaun et al,11 two unsuccessful cases by Bolme et al12 and 16 cases by Baker et al,15 of whom nine died. Baker et al15 concluded that favorable outcome was associated with clinical remission status at the time of BMT. Bolme et al12 recommended BMT as the treatment of choice in HLH, particularly if an HLH-identical related donor is available, since the prognosis for URD transplants was not as good as that for sibling donor transplants. More recently, Jabado et al14 reported a total of 17 BMTs for 14 FELs using 13 HLA-nonidentical related donors and one matched unrelated donor. They obtained sustained engraftment in 11 of 17 FEL cases using a conditioning regimen including anti-adhesion molecules with T cell depletion. Their results are promising for hemophagocytic syndromes which urgently need SCT but have no available HLA-matched donor. In this report, 10 of the 17 cases were in PR at SCT. Seven received stem cells from HLA-matched siblings, another seven from URD, two from haploidentical fathers and one from a one-locus mismatch father. Of seven URD transplants, five were transplanted with bone marrow cells, and two with cord blood without T cell depletion. For SCT from the haploidentical father, CD34-positive selection using the Isolex 50 magnetic cell separation system was


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employed. Overall, 10 of the 17 cases (58.8%) are alive without disease with a 2-year event-free survival of 54.0%. This is very encouraging because more than half of the cases were transplanted from donors other than HLAmatched siblings and in partial remission. It should be emphasized that severe acute and chronic GVHD occurred in only one case and that cord blood was available for two of the seven URD recipients in this report. We believe that for hemophagocytic syndrome cord blood transplants are promising and may be preferable for patients lacking an HLA-matched sibling donor rather than a CD34+ cell preparation from a haploidentical donor. However, refined transplant procedures as suggested recently by Collins et al13 and Jabado et al14 may be worth attempting for patients without HLA-matched donors. One case of extensive and fatal chronic GVHD, one fatal T cell lymphoma and four post-SCT relapses occurred during follow-up of our cases. It should be emphasized that two cases previously reported as successful transplants18,20 subsequently relapsed and both died. Clearly, longer follow-up is necessary for all transplanted cases concerning late relapses and other complications, particularly for five of the seven survivors who received a conditioning regimen including TBI in childhood. Evaluation of chimeric status in long-term survivors may help assess the quality of remission as previously reported by Landman-Parker et al.24 In conclusion, allogeneic SCT is the treatment of choice for FEL/HLH as well as for aggressive EBV-HLH even if an HLA-matched sibling donor is not available. Alternative URD sources such as bone marrow/PBSC or cord blood are of value and may provide a better outlook for patients with these fatal disorders.

Acknowledgements The authors thank Yasuko Hashimoto for her assistance in preparation of the manuscript.

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