Medical and Pediatric Oncology 20: 165-168 (1992)
Isolated Breast Relapse After Allogeneic Bone Marrow Transplantation for Childhood Acute Lymphoblastic Leukemia Valentino Conter, MD, Paolo D’Angelo, MD, Attilio Rovelli, MD, Cornelio Uderzo, MD, Momcilo Jankovic, MD, Ciorgio Bratina, MD, and Giuseppe Masera, MD Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone mar-
row and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT i s still controversial.
Key words: childhood acute lymphoblastic leukemia, extramedullary relapse,
bone marrow transplantation
INTRODUCTION
Relapses represent the main cause of failure following bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL), with most of them occurring in the first 6-12 months in the bone marrow, more rarely in the central nervous system (CNS), testes, and other sites [ 1-31. Breast involvement in ALL is exceedingly rare as a site of isolated extramedullary relapse [4-61. No case of breast relapse has been reported following BMT. We report the case of an isolated relapse in the right breast of a girl at day +246 after allogeneic BMT for ALL in second complete remission (CR). CASE REPORT
Early pre-B ALL, L1 of the French-American-British (FAB) classification, was diagnosed when the patient was 10 years old in August 1984. She did not show evidence of extramedullary disease. No cytogenetic abnormalities were detected. No response was obtained to the initial induction therapy and alternative treatment was therefore given. Chemotherapy was discontinued in October 1986. A bone marrow relapse was diagnosed in March 1989. In May 1989, after achieving CR, the girl underwent allogeneic BMT from her HLA-identical sister. The conditioning regimen consisted of vincristine (1.5 mg/sqm iv push 0.3 mgisqdday continuous infusion X 5 days), fractionated total body irradiation 0 1992 Wiley-Liss, Inc.
+
(200 cGy b.i.d. X 3 days), and cyclophosphamide (1,800 mg/sqm/day iv X 2 days). Treatment and clinical course are detailed in Table I. Cyclosporin was given as prophylaxis against graft-versus-host disease (GVHD). From day +10 to +19 the patient presented acute skin-GVHD (grade 1-11). Marrow engraftment (PMN >500/p,1) was documented on day + 15. At day +23 she had a no-transfused platelet count of >50,OOO/pl. She was discharged on day +21 with oral cyclosporin and prednisone. On day +62 she was admitted to hospital for 2 weeks because of hemorrhagic cystitis and acute GVHD (cutaneous + intestinal), grade 11; thereafter she remained in good clinical and hematological condition. On day +246, the girl noticed, on physical selfexamination, a not aching mass in her right breast. Medical examination confirmed the presence of a movable and tough mass in the upper inner quadrant of the right breast, consistent with the diagnosis of breast fibroadenoma. The left breast was normal. Axillary adenopathy was not clinically evident. Bone marrow aspirate and CSF examination were normal as confirmed From the Pediatric Hematology Department, University of Milan, San Gerardo Hospital, Monza, Italy (V.C., P.D., A.R., C.U., M.J., G.M.) and Pathology Department, San Gerardo Hospital, Monza, Italy (G.B.) Received December 20, 1990; accepted June 27, 1991. Address reprint requests to Dr. Valentino Conter, Clinica Pediatrica dell’universita di Milano, Ospedale Nuovo San Gerardo, via Donizetti 106, 20052 Monza (Milano), Italy.
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Conter et al.
TABLE I. Clinical Summary of the Case* Date
Diagnosis
8/84 9/84 10186 3/89 5/89 2/90
ALL Resistant ALL CR BM relapse CR Breast relapse
I 1/90
CNS relapse
Treatment
Outcome
Chemotherapy" Chemotherapyb Off therapy ChemotherapyC BMT~ Local RT (30 Gy) chemotherapye
Resistant CR CR CR CR CR
+
*Abbreviations: ALL, acute lymphoblastic leukemia; CR, complete remission; BM, bone marrow; BMT, bone marrow transplantation; RT, radiotherapy; CNS, central nervous system; PDN, prednisone; VCR, vincristine; L- Ase, L-asparaginase; i.t. MTX, intrathecal methotrexate; DNM, daunomycin; IDMTX, intermediate dose methotrexate; 6-MP, 6-mercaptopurine; HDL-Ase, high-dose L-asparaginase; HDMTX, high-dose methotrexate; HDARA-C, high-dose cytosine arabinoside; CTX, cyclophosphamide; FTBI, fractionated total body irradiation; ARA-C, cytosine arabinoside. aChemotherapy: Induction: PDN, VCR, L- Ase, i.t. MTX. bChemotherapy: Induction: PDN, VCR, DNM, IDMTX (500 mg/sqm X 3). CNS prophylaxis: 6-MP, i.t. MTX cranial RT (24 Gy). Reinduction: VCR, PDN, DNM. Maintenance: 6-MP, MTX, VCR, PDN, HDL-Ase (25,000 IU/sqm X 20). CBFM REZ 87: Induction: VCR, HDMTX, PDN, L-Ase, HDARA-C, 6-MP. dConditioning regimen: VCR (1.5 mg/sqm push X 0.3 CTX (1,800 mg/sqm/day continuous infusion X 5 ) mg/sqm/day X 2) FTBI (200 cGy b i d . X 3 days). Themotherapy: VCR, PDN, MTX, 6-MP, CTX, ARA-C.
+
+
+
by morphology, cytochemistry, and immunophenotyping. Excisional biopsy of the mass was diagnostic for an extramedullary relapse of ALL (Figs. 1 , 2). Breast lesion specimens were fixed in 10% buffered formalin and either embedded in paraffin or deep frozen. Paraffin sections were stained with hematoxylin and eosin, Giemsa, PAS, and Gomori silver impregnation stains. Serial 5-pm sections from paraffin-embedded and frozen tissue blocks were stained with monoclonal antibodies CD1, CD2, CD4, CD8, CD19, CD22, Ki67 (Dako) by the alkaline phosphatase-anti-alkaline phosphatase (APAAP) technique. The lesion was 2.5 cm in diameter, and presented as a firm, whitish nodule with ill-defined margins. The mammary tissue was infiltrated by immature lymphatic cells that had clear nuclei with finely distributed chromatin and inconspicuous nucleoli. The cytoplasm was scanty and indistinct. The tumor cells were of uniform size and tended to infiltrate and destroy the glandular tissue. Marked fibrosis was observed. Immunohistochemically , the cells showed strong reactivity for CD19 and CD22. Ki67 labeled 30% of tumor cells nuclei, whereas few cells reacted with CD1, CD4, CD8, and CD2. The patient was treated with local radiotherapy to the right breast (30 Gy in 15 fractions) and mild chemotherapy (Spiers schedule) with rapid disappearance of the mass. The option of a second BMT was refused by the patient and her family. Therapy was continued with
Fig. 1. Lymphoblastic leukemia infiltrating and effacing the mammary tissue architecture (H & E, x 100).
Isolated Breast Relapse After BMT in ALL
167
Fig. 2. Lymphoblastic leukemia in the mammary tissue: nuclear membranes are prominent, nuclear chromatin is evenly dispersed, nucleoli are inconspicuous (H & E, X400).
6-mercaptopurine (50 mgisqmiday) , methotrexate (20 mg/sqm/week), and vincristine (1.5 mg iv every second month). Following the breast relapse the patient remained in CR for 9 months when an isolated CNS relapse was diagnosed. DISCUSSION
The prognosis of ALL in childhood has improved markedly in the last 20 years, reaching a 5-year eventfree survival of 50-70% [7-lo]. Recurrent leukemia following chemotherapy for ALL remains the major cause of failure. The most frequent relapses are in the bone marrow. Isolated extramedullary relapses usually occur in the CNS or testes [11,12] and more rarely in eyes, ovaries, kidneys, muscles, the gastrointestinal tract, the pelvis, and bones [13-161. Unusual extramedullary relapses occur more rarely after BMT [l-31. We report the case of a breast relapse in a girl, 8 months after allogeneic BMT for ALL. She was transplanted for a marrow relapse that occurred 30 months after discontinuing first line treatment. The girl never showed extramedullary involvement before. Following breast relapse she received local radiotherapy and mild systemic chemotherapy and achieved promptly CR. Nine months later she presented with another isolated
extramedullary relapse (in the CNS), while still remaining in hematological remission. Treatment for any relapses after BMT in ALL, either with chemotherapy or with a second BMT, remains controversial [ 17,181. Data on treatment for isolated extramedullary relapses after BMT on the other hand are very limited. Generally, however, prognosis of any relapses after BMT is dismal. The course of the disease was unfavorable in our patient too. A second BMT [19] is in our opinion an option which can be considered in these patients. Our patient’s refusal of further aggressive therapy did not allow us to follow this approach. Large series of patients are needed to provide data on treatment and prognosis of isolated extramedullary relapses following BMT. ACKNOWLEDGMENTS
This work was supported by “Comitato M. L. Verga per lo studio e la cura della leucemia in etA pediatrica.” REFERENCES 1. Conter V, Rabbone ML, Jankovic M, Rossi MR, Placa F, Mazzola P, Uderzo C, Masera G: Isolated testicular relapse in a boy with acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Haematologica 74507-509, 1989.
168
Conter et al.
2. Cormier MG, Armin AR, Daneshgari F, Castelli M: Unusual extramedullary relapse of acute lymphoblastic leukemia in a bone marrow transplant patient. J Surg Oncol 36:29&294, 1987. 3. Weisdorf D, Arthur D, Rank J, Blazar B, Gajl-Peczalska K, Snover D: Gastric recurrence of acute lymphoblastic leukemia mimicking graft-versus-host disease. Br J Haematol 7 1559-564, 1989. 4. Ellegaard J, Bendix Hansen K, Boesen AM, Thorling K, Hokland P: Breast tumor as a first manifestation of extramedullary relapse in acute lymphoblastic leukaemia. Scand J Haematol33:288-294, 1984. 5 . Cheong SK, Chong SM: Acute lymphoblastic leukemia in relapse presenting as a breast lump: A case report. Med J Malaysia 40:46-48, 1985. 6. Sagar TG, Maitreyan V, Majhi U, Shanta V: Breast involvement in acute lymphoblastic leukaemia. J Assoc Physicians India 37~718-719, 1989. 7. Riehm H, Gadner H, Henze G, Kornhuber B, Lampert F, Niethammer D, Reiter A, Schellong G: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol Blood Transfusion 33:439450, 1990. 8. Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S , Cassady JR, Tarbell NJ, Blattner SR, Tentravahi R, Leavitt P, Sallan SE: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315:657-663, 1986. 9 Steinherz PG, Gaynon P, Miller DR, Reaman G, Bleyer A , Filklstein J, Evans RG, Meyers P, Steinherz LJ, Sather H, Hammond D: Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen-a new intensive therapy protocol: A report from the Children’s Cancer Study Group. J Clin Oncol 4:744-752, 1986. 10. Rivera GK, Mauer AM: Controversies in the management of childhood acute Iymphoblastic leukemia: Treatment intensifica-
11.
12.
13.
14.
15.
16.
17.
18.
19.
tion, CNS leukemia, and prognostic factors. Sem Hernatol 24:12-26, 1987. Nesbit ME, Sather HN, Ortega J: Effect of isolated central nervous system leukemia in bone marrow remission and survival in childhood acute lymphoblastic leukemia: Association with pretreatment patient characteristics and treatment. A report for Children’s Cancer Study Group. Lancet i:1381-1387, 1981. Bowman WP, Aur RJA, Hustu HO, Rivera GK: Isolated testicular relapse in acute lymphocytic leukemia of childhood: Categories and influence on survival. J Clin Oncol 2:924-929, 1984. Bunin NJ, Pui CH, Hustu HO, Rivera GK: Unusual extramedullary relapses in children with acute lymphoblastic leukemia. J Pediatr 109:665-668, 1986. Jankovic M, Masera G , Uderzo C, Cattoretti G , Conter V , Ceppellini C, Miglior M, Lasagni F, Lambertenghi E, Parravicini C, Mosca L: Recurrences of isolated leukemic hypopion in a child with acute lymphoblastic leukemia. Cancer 57:380-384, 1986. Chu JY, Cradock TV, Danis RK, Tennant NE: Ovarian tumor as manifestation of relapse in acute lymphoblastic leukemia. Cancer 481377-379, 1981. Uderzo C, Santamaria M, Locasciulli A , Merati I, Di Lelio A, Conter V, Masera G: Abdominal mass as manifestation of isolated extramedullary relapse in a child with acute lymphoblastic leukemia. Haematologica 72545-547, 1987. Arnold R, Bunjes D, Hertenstein B, Hoffmann T, Schmeiser T, Weiss M, Wiesneth M, Heit W, Heimpel H: Leukemic relapse after BMT: Therapeutic strategies. Bone Marrow Transplant 5 suppl. 2:78, 1990. Bostrom B, Woods WG, Nesbit ME, Krivit W, Kersey J, Weisdorf D, Haake R, Goldman AI, Ramsay NK: Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation. J Clin Oncol 5:37&381, 1987. Wagner JE, Santos GW, Burns WH, Sara1 R: Second bone marrow transplantation after leukemia relapse in 11 patients. Bone Marrow Transplant 4:115-118, 1989.
Isolated Breast Relapse After Allogeneic Bone Marrow Transplantation for Childhood Acute Lymphoblastic Leukemia Valentino Conter, MD, Paolo D’Angelo, MD, Attilio Rovelli, MD, Cornelio Uderzo, MD, Momcilo Jankovic, MD, Ciorgio Bratina, MD, and Giuseppe Masera, MD Unusual sites of relapses following bone marrow transplantation (BMT) for childhood acute lymphoblastic leukemia (ALL) are rarely reported. We report the case of a 16-year-old girl who presented with an isolated right breast relapse 8 months after allogeneic BMT for ALL in second remission. Biopsy showed an ALL infiltrate. Bone mar-
row and CSF were normal. The girl never showed before extramedullary involvement. She was treated with local radiotherapy and mild systemic chemotherapy. Nine months after breast relapse, she presented an isolated central nervous system relapse. The treatment of isolated extramedullary relapses following BMT i s still controversial.
Key words: childhood acute lymphoblastic leukemia, extramedullary relapse,
bone marrow transplantation
INTRODUCTION
Relapses represent the main cause of failure following bone marrow transplantation (BMT) for acute lymphoblastic leukemia (ALL), with most of them occurring in the first 6-12 months in the bone marrow, more rarely in the central nervous system (CNS), testes, and other sites [ 1-31. Breast involvement in ALL is exceedingly rare as a site of isolated extramedullary relapse [4-61. No case of breast relapse has been reported following BMT. We report the case of an isolated relapse in the right breast of a girl at day +246 after allogeneic BMT for ALL in second complete remission (CR). CASE REPORT
Early pre-B ALL, L1 of the French-American-British (FAB) classification, was diagnosed when the patient was 10 years old in August 1984. She did not show evidence of extramedullary disease. No cytogenetic abnormalities were detected. No response was obtained to the initial induction therapy and alternative treatment was therefore given. Chemotherapy was discontinued in October 1986. A bone marrow relapse was diagnosed in March 1989. In May 1989, after achieving CR, the girl underwent allogeneic BMT from her HLA-identical sister. The conditioning regimen consisted of vincristine (1.5 mg/sqm iv push 0.3 mgisqdday continuous infusion X 5 days), fractionated total body irradiation 0 1992 Wiley-Liss, Inc.
+
(200 cGy b.i.d. X 3 days), and cyclophosphamide (1,800 mg/sqm/day iv X 2 days). Treatment and clinical course are detailed in Table I. Cyclosporin was given as prophylaxis against graft-versus-host disease (GVHD). From day +10 to +19 the patient presented acute skin-GVHD (grade 1-11). Marrow engraftment (PMN >500/p,1) was documented on day + 15. At day +23 she had a no-transfused platelet count of >50,OOO/pl. She was discharged on day +21 with oral cyclosporin and prednisone. On day +62 she was admitted to hospital for 2 weeks because of hemorrhagic cystitis and acute GVHD (cutaneous + intestinal), grade 11; thereafter she remained in good clinical and hematological condition. On day +246, the girl noticed, on physical selfexamination, a not aching mass in her right breast. Medical examination confirmed the presence of a movable and tough mass in the upper inner quadrant of the right breast, consistent with the diagnosis of breast fibroadenoma. The left breast was normal. Axillary adenopathy was not clinically evident. Bone marrow aspirate and CSF examination were normal as confirmed From the Pediatric Hematology Department, University of Milan, San Gerardo Hospital, Monza, Italy (V.C., P.D., A.R., C.U., M.J., G.M.) and Pathology Department, San Gerardo Hospital, Monza, Italy (G.B.) Received December 20, 1990; accepted June 27, 1991. Address reprint requests to Dr. Valentino Conter, Clinica Pediatrica dell’universita di Milano, Ospedale Nuovo San Gerardo, via Donizetti 106, 20052 Monza (Milano), Italy.
166
Conter et al.
TABLE I. Clinical Summary of the Case* Date
Diagnosis
8/84 9/84 10186 3/89 5/89 2/90
ALL Resistant ALL CR BM relapse CR Breast relapse
I 1/90
CNS relapse
Treatment
Outcome
Chemotherapy" Chemotherapyb Off therapy ChemotherapyC BMT~ Local RT (30 Gy) chemotherapye
Resistant CR CR CR CR CR
+
*Abbreviations: ALL, acute lymphoblastic leukemia; CR, complete remission; BM, bone marrow; BMT, bone marrow transplantation; RT, radiotherapy; CNS, central nervous system; PDN, prednisone; VCR, vincristine; L- Ase, L-asparaginase; i.t. MTX, intrathecal methotrexate; DNM, daunomycin; IDMTX, intermediate dose methotrexate; 6-MP, 6-mercaptopurine; HDL-Ase, high-dose L-asparaginase; HDMTX, high-dose methotrexate; HDARA-C, high-dose cytosine arabinoside; CTX, cyclophosphamide; FTBI, fractionated total body irradiation; ARA-C, cytosine arabinoside. aChemotherapy: Induction: PDN, VCR, L- Ase, i.t. MTX. bChemotherapy: Induction: PDN, VCR, DNM, IDMTX (500 mg/sqm X 3). CNS prophylaxis: 6-MP, i.t. MTX cranial RT (24 Gy). Reinduction: VCR, PDN, DNM. Maintenance: 6-MP, MTX, VCR, PDN, HDL-Ase (25,000 IU/sqm X 20). CBFM REZ 87: Induction: VCR, HDMTX, PDN, L-Ase, HDARA-C, 6-MP. dConditioning regimen: VCR (1.5 mg/sqm push X 0.3 CTX (1,800 mg/sqm/day continuous infusion X 5 ) mg/sqm/day X 2) FTBI (200 cGy b i d . X 3 days). Themotherapy: VCR, PDN, MTX, 6-MP, CTX, ARA-C.
+
+
+
by morphology, cytochemistry, and immunophenotyping. Excisional biopsy of the mass was diagnostic for an extramedullary relapse of ALL (Figs. 1 , 2). Breast lesion specimens were fixed in 10% buffered formalin and either embedded in paraffin or deep frozen. Paraffin sections were stained with hematoxylin and eosin, Giemsa, PAS, and Gomori silver impregnation stains. Serial 5-pm sections from paraffin-embedded and frozen tissue blocks were stained with monoclonal antibodies CD1, CD2, CD4, CD8, CD19, CD22, Ki67 (Dako) by the alkaline phosphatase-anti-alkaline phosphatase (APAAP) technique. The lesion was 2.5 cm in diameter, and presented as a firm, whitish nodule with ill-defined margins. The mammary tissue was infiltrated by immature lymphatic cells that had clear nuclei with finely distributed chromatin and inconspicuous nucleoli. The cytoplasm was scanty and indistinct. The tumor cells were of uniform size and tended to infiltrate and destroy the glandular tissue. Marked fibrosis was observed. Immunohistochemically , the cells showed strong reactivity for CD19 and CD22. Ki67 labeled 30% of tumor cells nuclei, whereas few cells reacted with CD1, CD4, CD8, and CD2. The patient was treated with local radiotherapy to the right breast (30 Gy in 15 fractions) and mild chemotherapy (Spiers schedule) with rapid disappearance of the mass. The option of a second BMT was refused by the patient and her family. Therapy was continued with
Fig. 1. Lymphoblastic leukemia infiltrating and effacing the mammary tissue architecture (H & E, x 100).
Isolated Breast Relapse After BMT in ALL
167
Fig. 2. Lymphoblastic leukemia in the mammary tissue: nuclear membranes are prominent, nuclear chromatin is evenly dispersed, nucleoli are inconspicuous (H & E, X400).
6-mercaptopurine (50 mgisqmiday) , methotrexate (20 mg/sqm/week), and vincristine (1.5 mg iv every second month). Following the breast relapse the patient remained in CR for 9 months when an isolated CNS relapse was diagnosed. DISCUSSION
The prognosis of ALL in childhood has improved markedly in the last 20 years, reaching a 5-year eventfree survival of 50-70% [7-lo]. Recurrent leukemia following chemotherapy for ALL remains the major cause of failure. The most frequent relapses are in the bone marrow. Isolated extramedullary relapses usually occur in the CNS or testes [11,12] and more rarely in eyes, ovaries, kidneys, muscles, the gastrointestinal tract, the pelvis, and bones [13-161. Unusual extramedullary relapses occur more rarely after BMT [l-31. We report the case of a breast relapse in a girl, 8 months after allogeneic BMT for ALL. She was transplanted for a marrow relapse that occurred 30 months after discontinuing first line treatment. The girl never showed extramedullary involvement before. Following breast relapse she received local radiotherapy and mild systemic chemotherapy and achieved promptly CR. Nine months later she presented with another isolated
extramedullary relapse (in the CNS), while still remaining in hematological remission. Treatment for any relapses after BMT in ALL, either with chemotherapy or with a second BMT, remains controversial [ 17,181. Data on treatment for isolated extramedullary relapses after BMT on the other hand are very limited. Generally, however, prognosis of any relapses after BMT is dismal. The course of the disease was unfavorable in our patient too. A second BMT [19] is in our opinion an option which can be considered in these patients. Our patient’s refusal of further aggressive therapy did not allow us to follow this approach. Large series of patients are needed to provide data on treatment and prognosis of isolated extramedullary relapses following BMT. ACKNOWLEDGMENTS
This work was supported by “Comitato M. L. Verga per lo studio e la cura della leucemia in etA pediatrica.” REFERENCES 1. Conter V, Rabbone ML, Jankovic M, Rossi MR, Placa F, Mazzola P, Uderzo C, Masera G: Isolated testicular relapse in a boy with acute lymphoblastic leukemia following allogeneic bone marrow transplantation. Haematologica 74507-509, 1989.
168
Conter et al.
2. Cormier MG, Armin AR, Daneshgari F, Castelli M: Unusual extramedullary relapse of acute lymphoblastic leukemia in a bone marrow transplant patient. J Surg Oncol 36:29&294, 1987. 3. Weisdorf D, Arthur D, Rank J, Blazar B, Gajl-Peczalska K, Snover D: Gastric recurrence of acute lymphoblastic leukemia mimicking graft-versus-host disease. Br J Haematol 7 1559-564, 1989. 4. Ellegaard J, Bendix Hansen K, Boesen AM, Thorling K, Hokland P: Breast tumor as a first manifestation of extramedullary relapse in acute lymphoblastic leukaemia. Scand J Haematol33:288-294, 1984. 5 . Cheong SK, Chong SM: Acute lymphoblastic leukemia in relapse presenting as a breast lump: A case report. Med J Malaysia 40:46-48, 1985. 6. Sagar TG, Maitreyan V, Majhi U, Shanta V: Breast involvement in acute lymphoblastic leukaemia. J Assoc Physicians India 37~718-719, 1989. 7. Riehm H, Gadner H, Henze G, Kornhuber B, Lampert F, Niethammer D, Reiter A, Schellong G: Results and significance of six randomized trials in four consecutive ALL-BFM studies. Haematol Blood Transfusion 33:439450, 1990. 8. Clavell LA, Gelber RD, Cohen HJ, Hitchcock-Bryan S , Cassady JR, Tarbell NJ, Blattner SR, Tentravahi R, Leavitt P, Sallan SE: Four-agent induction and intensive asparaginase therapy for treatment of childhood acute lymphoblastic leukemia. N Engl J Med 315:657-663, 1986. 9 Steinherz PG, Gaynon P, Miller DR, Reaman G, Bleyer A , Filklstein J, Evans RG, Meyers P, Steinherz LJ, Sather H, Hammond D: Improved disease-free survival of children with acute lymphoblastic leukemia at high risk for early relapse with the New York regimen-a new intensive therapy protocol: A report from the Children’s Cancer Study Group. J Clin Oncol 4:744-752, 1986. 10. Rivera GK, Mauer AM: Controversies in the management of childhood acute Iymphoblastic leukemia: Treatment intensifica-
11.
12.
13.
14.
15.
16.
17.
18.
19.
tion, CNS leukemia, and prognostic factors. Sem Hernatol 24:12-26, 1987. Nesbit ME, Sather HN, Ortega J: Effect of isolated central nervous system leukemia in bone marrow remission and survival in childhood acute lymphoblastic leukemia: Association with pretreatment patient characteristics and treatment. A report for Children’s Cancer Study Group. Lancet i:1381-1387, 1981. Bowman WP, Aur RJA, Hustu HO, Rivera GK: Isolated testicular relapse in acute lymphocytic leukemia of childhood: Categories and influence on survival. J Clin Oncol 2:924-929, 1984. Bunin NJ, Pui CH, Hustu HO, Rivera GK: Unusual extramedullary relapses in children with acute lymphoblastic leukemia. J Pediatr 109:665-668, 1986. Jankovic M, Masera G , Uderzo C, Cattoretti G , Conter V , Ceppellini C, Miglior M, Lasagni F, Lambertenghi E, Parravicini C, Mosca L: Recurrences of isolated leukemic hypopion in a child with acute lymphoblastic leukemia. Cancer 57:380-384, 1986. Chu JY, Cradock TV, Danis RK, Tennant NE: Ovarian tumor as manifestation of relapse in acute lymphoblastic leukemia. Cancer 481377-379, 1981. Uderzo C, Santamaria M, Locasciulli A , Merati I, Di Lelio A, Conter V, Masera G: Abdominal mass as manifestation of isolated extramedullary relapse in a child with acute lymphoblastic leukemia. Haematologica 72545-547, 1987. Arnold R, Bunjes D, Hertenstein B, Hoffmann T, Schmeiser T, Weiss M, Wiesneth M, Heit W, Heimpel H: Leukemic relapse after BMT: Therapeutic strategies. Bone Marrow Transplant 5 suppl. 2:78, 1990. Bostrom B, Woods WG, Nesbit ME, Krivit W, Kersey J, Weisdorf D, Haake R, Goldman AI, Ramsay NK: Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation. J Clin Oncol 5:37&381, 1987. Wagner JE, Santos GW, Burns WH, Sara1 R: Second bone marrow transplantation after leukemia relapse in 11 patients. Bone Marrow Transplant 4:115-118, 1989.
