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Puediulr J p n 1991; 33: 548 - 557)

Allogeneic Bone Marrow Transplantation in Childhood Leukemia S h u n i c h i Kato, M.D., Ph.D., Miharu Yabe, M.D., Ph.D., Hiromasa Yabe, M.D., Ph.D. Chidori K u b o t a , M.D., Tomoyuki H i n o h a r a , M.D.,

Kinya Hattori, M.D. and Osamu Shinohara, M.D., Ph.D.

Allogeneic bone marrow transplantation was performed in 94 patients with hematologic malignancies or other various diseases during the period between March 1982 and hovember 1990 at Tokai University Hospital. Projected disease-free survival rates of HLA genotypically identical marrow recipients were 88.9% for chronic myeloid leukemia transplanted in the first chronic phase (N=9), 90.9% for acute leukemia in the first complete remission (N = IS), 54.5% for acute leukemia in later remissions (N = 14), 62.5% for solid tumors (N = 8) and 0% for patients transplanted in relapse (N = 7). The rate for HLA-mismatched marrow recipients with leukemia was 27.8% (N = 16). For patients with non-neoplastic diseases it was 100% regardless of HLA-compatibility (N = 26). The quality of life in long-term surviving pediatric marrow recipients has been acceptable. Common abnormalities among survivors are long-lasting hypogonadism due to radiation and subclinical impairment of lung function in the first year post-BMT. About two-thirds of children experienced a transient decrease in growth velocity in the immediate posttransplant period. Key Words

Bone marrow transplantation, Graft-versus-host disease, Cytomegalovirus pneumonia, Quality of life

Introduction Substantial progress has been made in the treatment of childhood leukemia in the past 30 hears [I]. Modern intensive chemotherapy can produce complete remission (CR) in over 9 S , of children with acute lymphoblastic leuhemia ( A L L ) and long-term disease-free Kt.cei\ed May 10. 1991 Corrc\pondence address: Shunichi Kato. M.D.. 1'h.D. Ikpurtnient of Pediatrics. Tokai l'niversity School of Medicine. Rohceidai. Isehara-,hi. Kanagawa 259-1 I . Japm

survival is achieved in up to 80%, of children with standard risk features. Recently more than half of high-risk A L L children have been cured by intensive chemotherapy. However, there is still a subgroup of extremely high-risk patients ( B cell phenotype, Ph' positive, infant younger than 1 year old), whose survival cannot be expected by chemotherapy alone. Chemotherapy yielded long-term survivors in only 20-30%, of children with acute nonlymphoblastic leukemia (ANLL) until the middle of the eighties [2]. Several new protocols employing intensification or consolidation chemotherapy have produced remark-

Allogrrzeic BM T in childiood leukemia ( 129) 549

able progress, with 5-year disease-free survival rates of 40-50% [3, 41. There has been little progress in chemotherapy for children with chronic myelocytic leukemia (CML), regardless of Ph' chromosome positivity. Allogeneic bone marrow transplantation (BMT) was initially used in patients with advanced leukemia, which resulted in longterm survival in 10-20% of cases [5]. As transplant technique and supportive care progressed, and as patients transplanted during remissions behaved much better than those transplanted in relapse, the indication for BMT changed rapidly from relapse phase to remission phase. The indication for BMT in leukemia has always been considered in the balance of progress in chemotherapy, and therefore has been changed from time to time. We report our results of allogeneic BMT in children with leukemia or malignant lymphoma and the quality of life in long-term surviving marrow recipients.

Patients and Methods Patients population Allogeneic bone marrow transplantation was performed on 94 patients with hematologic

malignancies, bone marrow failure or various genetic diseases between March 1982 and November 1990. Twenty-one patients with ANLL (12 in first CR, 5 in second CR, 4 at relapse), 25 with ALL (7 in first CR, 10 in second CR, 4 in third or subsequent CR, 4 at relapse), 14 C M L (9 in first chronic phase (CP), I in second CP, I at blast crisis, 3 of juvenile type), 7 with non-Hodgkin's lymphoma (NHL) (all in first CR) and 1 with neuroblastoma received marrow grafts from HLA identical siblings ( N = 53), HLA partially matched family members (N = 14) or unrelated HLA-matched volunteer donor ( N = I ) . Twenty-six other patients with aplastic anemia, immunodeficiency or other inborn metabolic errors were transplanted in the same period and were included in analysis of the quality of life in long-term survivors.

Transplantation procedures Preconditioning consisted of a high dose of cyclophosphamide (CY, 60 mg/ kg/day X 2) and fractionated total body irradiation (TBI, 12 Gy in 6 fractions) in the first 13 patients (Regimen A), Regimen A+high dose of cytosine arabinoside (Ara C 3 g / m 2 X 10) in the next 9 (Regimen B), and CY of Regimen

%standard risk=ftrst CR of acute leukemia/NHL or first CP of CML high risk =more advanced stages

Fig. 1 : Three conditioning regimens for bone marrow transplantation in leukemia and lymphoma.

Vol. 33 No. 4 August 1991

550 ( 130) hato 1'1 Nt. B substituted by a high dose ofetoposide (VP16. 60nigjkg in one dose for 8-hour injection) in the most recent 35 patients (Regimen C) (Fig. I). Prevention of G V H D was attempted with methotrexate (MTX) alone, cyclosporine A (CYA) alone or CYA plus short-term MTX. G V H D and its severity was diagnosed according to the Seattle criteria [5]. All patients were isolated in laminar air flow rooms (LAF, Class 100) and were given non-absorbable antibiotics as gut decontamination during the neutropenic period. They were also given intravenous gamma-globulin preparations (IVIG) and acyclovir as prophylaxis against cytomegalovirus (CMV). herpes simplex virus (HSV) and varicella zoster virus (VZV) infections. Recombinant granulocyte colony-stimulating factor (rG-CSF) [6],recombinant granulocyte macrophage colony-stimulating factor (rGM-CSF) o r human urinary macrophage colony-stimulating factor (huMCSF, P-100) [7] were administered to the most recent patients in an attempt to hasten leukocvte recovery and to reduce severe bacterial or fungal infections. Most patients received CMV negative blood products after transplantation [8]. Follow-up evaluation Clinical evaluation included height, weight. physical examination. EKG. cardiac UCG, cheat X-P. skull CT scan, EEG. spirometry. lung perfusion and or ventilation scan, endocrinological studies and examination by dermatologists and rehabilitation specialists at various intervals.

Results S u n i\,al I-ortc-two of 60 patients with leukemia. 5 of 8 patients with solid tumors and all of 26 patients with non-neoplastic diseases art: currently surviving 1 to 105 months posttransplant. with a median follow-up time of 22 month5 (.January I . 1991). The type of leukemia, disease status at time of transplant and histocompatibility matching

+

+

between thc donor and the recipient gave significant differences in the outcome. Projected disease-free survival (DFS) rates of HLA genotypically identical marrow recipients were 88.9% for C M L transplanted in the first C P (N = 9), 90.99;, for ALL o r ANLL in the first CR ( N = 15), 54.5% for ALL or ALL in later remissions ( N = 14), 62.5% for solid tumors ( N = 8 ) and 0% for patients transplanted in relapse ( N = 7). D F S rate of H LA-mismatched marrow recipients was 27.8% (Fig. 2). Three different conditioning regimens were compared. The proportion of standard risk patients (first CR of acute leukemia/NHL o r first CP of C M L ) and high risk (more advanced stages) was not statistically different in each group (Fig. I). D F S rates of HLAidentical marrow recipients with leukemia or N H L were 61.5% for Regimen A ( N = 13). 55.6q for Regimen B ( N = 9 ) and 83.3%, for Regimen C (N=28), and the differences between C and the other two regimens were statistically significant ( P ; and 10 the nurses, technologists and other support staff at Tokai University Hospital whose manv contributions made these studies possible. I hcic studies were partly supported by a Grant-in-Aid l.or ('anccr Research (I-j), a Pediatric Research Grant ( 3 0 4 ) and ii Grant ( 2 6) for Neurology and Psychiatry Research from the Japanese Ministry of Health and W L'Il a rc.

We are indebted

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Allogeneic bone marrow transplantation in childhood leukemia.

Allogeneic bone marrow transplantation was performed in 94 patients with hematologic malignancies or other various diseases during the period between ...
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