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Reinduction with vincristine, prednisolone, daunorubicin, l-asparaginase, teniposide and cytarabine was undertaken. He entered second remission and an allo-.
Bone Marrow Transplantation, (1998) 22, 397–399  1998 Stockton Press All rights reserved 0268–3369/98 $12.00 http://www.stockton-press.co.uk/bmt

Case report Isolated testicular relapse after bone marrow transplant with total body irradiation and testicular boost in acute lymphoblastic leukemia CK Li1, MMK Shing1, KW Chik1, WH Kwan2, DH Lai1, TF Leung1 and PMP Yuen1 Departments of 1Paediatrics and 2Clinical Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China

Summary:

Case report

A 7-year-old boy with Phⴙ ALL received an allogeneic BMT in second remission. Conditioning included cyclophosphamide 60 mg/kg for 2 days, TBI 2 Gy twice daily for 3 days (12 Gy) and a single testicular boost of 4 Gy. He remained in hematological remission after BMT but developed isolated testicular relapse at 17 months. He underwent orchiectomy of the affected testis, 24 Gy testicular radiotherapy and systemic chemotherapy. He remains in remission 24 months after the testicular relapse. This is the first report of isolated testicular relapse which received a testicular irradiation boost included in the conditioning. Keywords: testicular relapse; BMT; acute lymphoblastic leukemia

A 7-year-old child presented with pallor and bleeding. His initial white cell count was 207 × 109/l. Bone marrow confirmed common ALL antigen positive ALL. Cytogenetic study of bone marrow showed the Philadelphia chromosome. Induction chemotherapy consisted of vincristine, prednisolone and l-asparaginase; consolidation treatment including daunorubicin, etoposide, cytarabine and thioguanine. Allogeneic BMT in first remission was planned because of the very high-risk nature of the ALL. While awaiting BMT, he had a bone marrow relapse 4 months after diagnosis. Reinduction with vincristine, prednisolone, daunorubicin, l-asparaginase, teniposide and cytarabine was undertaken. He entered second remission and an allogeneic bone marrow transplant was performed 2 months later. The donor was his one antigen mismatched mother. Conditioning consisted of cyclophosphamide 60 mg/kg i.v. for 2 days, followed by total body irradiation using AP:PA 6 Mev photon giving 2 Gy twice daily for 3 days. The total dose was 12 Gy at the mid-point of the plane of the umbilicus, and the dose rate was 10 cGy per min. A 4 Gy single dose of testicular irradiation was given on the last day of TBI with 8 Mev electron beam. The nucleated cell dose of the non-T cell-depleted marrow was 5.3 × 108/kg. Graftversus-host disease (GVHD) prophylaxis was cyclosporin A 3 mg/kg/day i.v. and methotrexate i.v. for four doses, after transplant. The patient had neutrophils ⬎0.5 × 109/l for 3 consecutive days on day 17 post-BMT. Grade I acute GVHD occurred on day 21 which was controlled by an increase of cyclosporin A. The patient was confirmed to be in bone marrow remission after BMT by cytology and cytogenetic study. Serial fluorescent in situ hybridisation (FISH) using X and Y probes showed complete donor chimerism. At 4 months after BMT, he developed chronic GVHD involving skin, liver and gut which was treated with steroids and cyclosporin A. The chronic GVHD was under control and immunosuppressive treatment was stopped 14 months after BMT. Seventeen months after BMT, the patient noted an enlarged left testis. Biopsy confirmed leukemia infiltration. Bone marrow and cerebrospinal fluid, however, showed no evidence of relapse. Cytogenetic and molecular studies of bone marrow did not show the Ph+ translocation. The child thus had an isolated testicular relapse.

Allogeneic bone marrow transplant (BMT) is the recommended treatment for relapsed acute lymphoblastic leukemia (ALL) in children, especially for those with early relapse.1 The results of BMT depend mainly on the duration of first remission and sites of relapse, and long-term survival varies between 20 and 55%.2,3 The major causes of failure after transplant are relapse of leukemia and regimenrelated mortality. Bone marrow is the commonest site of relapse and extramedullary relapse occurs much less commonly. The testes are one of the common sites of relapse after chemotherapy in boys with ALL.4 Total body irradiation (TBI) is usually included as part of the conditioning regimen; however, the total dose of TBI to the testes may not be adequate to prevent testicular relapse. Many centers have adopted the policy of giving an additional testicular boost to the testes in addition to TBI. Since the implementation of additional testicular boost, isolated testicular relapse has not been reported. We report here a case of isolated testicular relapse after BMT with TBI and testicular boost as conditioning.

Correspondence: Dr CK Li, Department of Paediatrics, Prince of Wales Hospital, Shatin, Hong Kong Received 19 January 1998; accepted 22 March 1998

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He was reinduced with systemic chemotherapy which included vincristine, l-asparaginase, prednisolone, teniposide and cytarabine. The left testis was surgically removed 1 month after induction chemotherapy. Histology showed diffuse leukemic cell infiltration, but the right testicular biopsy showed no leukemia cells. Radiotherapy to the whole scrotum, including the right spermatic cord up to the right inguinal ring, was administered 2 months after relapse at 2 Gy per fraction × 12 doses, ie total 24 Gy. He received maintenance chemotherapy which included rotating pairs of vincristine, prednisolone; etoposide, cyclophosphamide; 6-mercaptopurine, oral methotrexate; teniposide and cytarabine. The child remains in remission 24 months after the testicular relapse, and 40 months after BMT. Chimerism study by FISH showed complete donor chimerism. Cytogenetic and molecular studies of the bone marrow showed no residual Ph+ leukemia. Discussion Bone marrow transplant is indicated for relapsed ALL or high-risk ALL in first remission in children. The major cause of failure is recurrence of leukemia after transplant. The sites of relapse are mainly bone marrow or bone marrow combined with extramedullary organs.2,5 Isolated extramedullary relapse after transplant is less common. In the early 1980s, some series reported a high incidence of isolated testicular relapse in up to 25% of boys, despite total body irradiation from 12 to 15.75 Gy.5,6 Some centers advocated pretransplant testicular biopsy,7 but this was not widely practiced due to poor predictive value. Most centers now adopt the approach of booster testicular radiotherapy in addition to TBI.2,3,5 A total radiation dose of 18 Gy to the testes is usually delivered when TBI is employed as part of the conditioning regimen for BMT in ALL patients. This 18 Gy dosage was based on effective CNS control with prophylactic cranial irradiation. Late effects on fertility and endocrine function are anticipated. Since the institution of testicular boost radiotherapy, isolated testicular leukemia has not been reported. We reported a boy who was transplanted in CR2 with TBI 12 Gy (2 Gy twice daily for 3 days), and an additional testicular boost 400 cGy on the third day of TBI. The equivalent testicular radiation dose was 17 Gy of conventional 2 Gy fractions. Our radiation dosage to the testes was similar to reports from other centers.8 This boy developed isolated testicular relapse 17 months post-transplant. We detected no bone marrow disease by cytogenetic or molecular methods. Peripheral blood FISH showed complete donor chimerism. We believe that the relapse was limited to the testes only. Chronic GVHD has been shown to be associated with a lower risk of marrow relapse after transplant.5 Our patient had chronic GVHD and the bone marrow remained in continuous remission after BMT. The graftversus-leukemia effect associated with GVHD may protect the child from marrow relapse. However, there has been no report of GVHD involving the testes, and whether the testicular relapse was related to absence of a graft-versusleukemia effect in the testes is unknown. There is one report of a child achieving hematological remission after

donor lymphocyte infusion for post-BMT relapse, who later developed testicular relapse.9 Treatment of isolated testicular relapse is not well established due to small numbers of cases. From the experience of treating testicular relapse in ALL patients after chemotherapy, systemic reinduction in addition to local treatment is probably justified for post-transplant relapse patients. However, these patients have already received prior radiotherapy, usually as part of TBI, posing the possibility of radio-resistance of leukemia cells in the testes. Our approach of orchiectomy with a further 24 Gy testicular radiotherapy may be safer than radiotherapy alone. The morbidity from orchiectomy is unlikely to be more than that of radiotherapy twice. Even though there has been a report of long-term survival after local treatment to the testes without systemic chemotherapy, numbers are too small to permit this to be the recommended treatment.5 Systemic chemotherapy with high-dose methotrexate, without testicular radiotherapy, has recently been shown to be effective in treatment of testicular relapse.10 However, posttransplant patients usually do not tolerate high-dose chemotherapy well which might hinder the deliverance of highdose chemotherapy. The long-term prognosis of isolated testicular relapse after BMT is not certain due to small numbers of cases. However, four of seven patients in one series have been reported to be long-term survivors.5 In conclusion, isolated testicular relapse after BMT may still occur despite TBI with a testicular boost up to 17 Gy. Aggressive local therapy with systemic chemotherapy may result in long-term remission. References 1 Pui CH. Acute lymphoblastic leukemia. Pediatr Clin North Am 1997; 44: 831–846. 2 Uderzo C, Valsecchi MG, Bacigalupo A et al. Treatment of childhood acute lymphoblastic leukemia in second remission with allogeneic bone marrow transplantation and chemotherapy: ten-year experience of the Italian Bone Marrow Transplantation Group and the Italian Pediatric Hematology Oncology Association. J Clin Oncol 1995; 13: 352–358. 3 Dopfer R, Henze G, Bender-Go¨tze C et al. Allogeneic bone marrow transplantation for childhood acute lymphoblastic leukemia in second remission after intensive primary and relapse therapy according to the BFM- and CoALL-protocols: results of the German Cooperative Study. Blood 1991; 78: 2780– 2783. 4 Grundy RG, Leiper AD, Stanhope R, Chessels JM. Survival and endocrine outcome after testicular relapse in acute lymphoblastic leukaemia. Arch Dis Child 1997; 76: 190–196. 5 Sanders JE, Flournoy N, Thomas ED et al. Marrow transplant experience in children with acute lymphoblastic leukemia: an analysis of factors associated with survival, relapse, and graftversus-host disease. Med Pediatr Oncol 1985; 13: 165–172. 6 Ashford RF, Cassoni AM, Bowcock S et al. Isolated testicular relapse after bone marrow transplantation for acute lymphoblastic leukaemia. Lancet 1983; 2: 228. 7 Cairo M, Weetman RM, Baehner RL. Isolated testicular leukemia following bone marrow transplant for acute lymphocytic leukemia. The need for pretransplant testicular biopsies. Am J Pediatr Hematol Oncol 1982; 4: 41–44. 8 Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989; 62: 679–694.

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9 Atra A, Miller B, Shepard V et al. Donor lymphocyte infusion for childhood acute lymphoblastic leukaemia relapsing after bone marrow transplantation. Br J Haematol 1997; 97: 165– 168.

10 van den Berg H, Langeveld NE, Veenhof CH, Behrendt H. Treatment of isolated testicular recurrence of acute lymphoblastic leukemia without radiotherapy. Report from the Dutch Late Effects Study Group. Cancer 1997; 79: 2257–2262.

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