Second malignancy after treatment of childhood acute ... - Nature

Leukemia (2001) 15, 41–45  2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu

Second malignancy after treatment of childhood acute myeloid leukemia W Leung1,2,3, RC Ribeiro2,3, M Hudson1,2,3, X Tong4, DK Srivastava4, JE Rubnitz2,3, JT Sandlund2,3, BI Razzouk2,3, WE Evans3,5 and C-H Pui2,3 1

After Completion of Therapy Program, Departments of 2Hematology-Oncology, 4Biostatistics and Epidemiology, and 5Pharmaceutical Sciences, St Jude Children’s Research Hospital; and 3University of Tennessee, College of Medicine, Memphis, TN, USA

To investigate the cumulative incidence of second malignancy and the competing risk of death due to any other cause in patients who were treated for childhood acute myeloid leukemia (AML), we analyzed the outcomes in a cohort of 501 patients who were treated at St Jude Children’s Research Hospital between 1970 and 1996. Five patients developed a second cancer (two carcinomas of the parotid gland, one non-Hodgkin’s lymphoma, one supratentorial primitive neuroectodermal tumor, one acute lymphoblastic leukemia) as compared with 0.47 expected in the general population (standardized incidence ratio, 10.64; 95% confidence interval, 3.28 to 22.34). A third neoplasm (meningioma) developed in one patient. At 15 years after the diagnosis of AML, the estimated cumulative incidence of second malignancy was 1.34% ± 0.61%, whereas the cumulative incidence of death due to any other cause was 72.96% ± 2.14%. We concluded that although a more than 10fold increased risk of development of cancer was found in survivors of childhood AML as compared to the general population, the risk of this late complication is small when compared to the much larger risk of death because of the primary leukemia or the early complications of its treatment. Future studies should focus on improving treatments for primary AML while preventing second malignancies. Leukemia (2001) 15, 41–45. Keywords: second malignancy; childhood AML; competing risk

Introduction Acute myeloid leukemia (AML) is diagnosed in approximately 500 children in the United States each year and is four times less common than childhood acute lymphoblastic leukemia (ALL).1 Current chemotherapeutic regimens cure as many as 70 to 80% of children with ALL, but only 30 to 40% of those with AML.1 Although much is known about the incidence of and the risk factors for the development of late sequelae after treatment of childhood ALL, the late sequelae of treatment of childhood AML are largely unknown because there are few long-term survivors.2 Few complications of leukemia therapy are as devastating as a second cancer. To our knowledge, no studies have focused on the risk of second malignancy after the treatment of childhood AML. Here we report our findings of the cumulative incidence of second malignancy and the competing risk of death due to any other cause in a large cohort of patients who were treated for childhood AML at St Jude Children’s Research Hospital between 1970 and 1996. Patients and methods

Patient characteristics Between January 1970 and December 1996, 501 patients were enrolled on one of our AML treatment protocols. The Correspondence: W Leung, St Jude Children’s Research Hospital, 332 N Lauderdale Street, Memphis, TN 38105, USA; Fax: 901 521 9005 Received 28 July 2000; accepted 22 August 2000

mean age at the time of diagnosis of primary AML was 8.7 years (range, 1 day to 20.7 years). The mean age at the time of death or last follow-up was 13.1 years (range, 7.2 months to 39.1 years). Other characteristics of the patients at the time of diagnosis and the primary treatment protocols for AML are shown in Table 1. Details of the following protocols have been presented previously: AML70,3 AML72,4 AML76,5 AML80,6 AML83,7 AML87,8 and AML91.9

Follow-up procedure and review of second malignancies The routine follow-up procedures at the institution and the reporting of second neoplasms in long-term survivors have been described previously.10,11 Details of the clinical characteristics and treatment histories of the patients in whom a second malignancy developed were obtained from the medical records. All pathologic materials of the second malignancy were reviewed and classified by our pathologists. For patients in whom ALL developed after AML, detailed comparison of the diagnostic samples was performed by using flow cytometry, cytogenetic studies, and molecular genetic analysis to determine whether ALL represented a relapse or a clonal evolution (eg from a mixed-lineage leukemia) rather than a new leukemia. Four such cases of a ‘phenotypic switch’12 were found in the course of this study, and they were not considered to be secondary leukemias.

Statistical analysis The cumulative incidences of second cancer and death due to any other cause were estimated by using the method Table 1

Patient characteristics and primary treatment protocols

Characteristics

No. of patients (%)

Sex Male Female Race White Black Others Protocol AML70 AML72 AML76 AML80 AML83 AML87 AML91 POG/Others POG, Pediatric Oncology Group protocol.

258 (51.5) 243 (48.5) 413 (82.4) 82 (16.4) 6 (1.2) 12 25 96 95 79 67 95 32

(2.4) (5.0) (19.2) (19.0) (15.8) (13.4) (19.0) (6.4)

Second malignancy after childhood AML W Leung et al

42

described by Gray.13 The time during which a patient was at risk of a second cancer was defined as the time from the date of diagnosis of primary AML to the date of diagnosis of a second cancer, the date of death, or the date of last contact, whichever came first. The development of a second cancer and death due to any other cause were considered to be competing events. To calculate the standardized incidence ratio of second cancer, the number of person-years at risk for the study cohort were partitioned into 5-year age categories that were identical to those for the Surveillance, Epidemiology, and End Results (SEER) data of the National Cancer Institute.14 The standardized incidence ratio was calculated as the ratio of the number of observed cases to the number of expected cases determined by using the SEER statistics. The 95% confidence intervals were estimated by a method described by Vandenbroucke.15 Results Of the 501 patients, 326 (65.1%) died of primary AML, 26 (5.2%) died while AML was in remission, 144 (28.7%) were alive and free of a second malignancy, and 5 (1%) had a second malignancy. Of these five patients, two have died, two are alive, and one developed a third neoplasm (meningioma) and is alive (Table 2). The duration of follow-up for the 147 survivors was 10.6 ± 6.1 years since the diagnosis of AML. Of the 144 patients who were alive and free of a second malignancy, the median time since the last follow-up visit was 1.3 years (range, 0.3 to 4.5 years).

Second malignancies UPN1: A primitive neuroectodermal tumor developed in the frontal parietal area of the brain of a patient 9.2 years after the diagnosis of M5 AML and 8.6 years after the patient had received craniospinal irradiation for a CNS relapse. After Table 2

UPN Sex/ Race

resection of the brain tumor, the patient was treated with chemotherapy consisting of procarbazine, lomustine, vincristine, and etoposide and with craniospinal irradiation (35.2 Gy) with local boost (30.8 Gy). He died of progressive brain tumor. UPN2: A mucoepidermoid carcinoma of the parotid gland developed in a patient 3.6 years after the diagnosis of M4 AML and 3.1 years after she received high-dose busulfan and cyclophosphamide with autologous bone marrow transplant. The chemotherapeutic agents she received before transplant included azacytidine, cytarabine, daunorubicin, etoposide, and thioguanine. She received no radiation therapy before the development of the parotid tumor. She is free of disease 7.4 years after a parotidectomy and local irradiation (55 Gy). UPN3: A mucoepidermoid carcinoma of the parotid gland occurred in a patient 4.1 years after the diagnosis of M2 AML and 2.2 years after she received an allogeneic bone marrow transplant from her matched sibling. She is free of disease 10.9 years after a parotidectomy. UPN4: M4 AML in which the leukemic cells stained positively with myeloperoxidase, Sudan black, and alpha napthyl butyrate esterase was diagnosed in a fourth patient. The cytogenetic findings at the time of diagnosis were normal (46, XY). The patient was treated on protocol AML83 with etoposide, cytarabine, daunorubicin, thioguanine, azacytidine, amsacrine, vincristine, doxorubicin, and cyclophosphamide. Within 3 months after completing therapy for AML, he was found to have an early pre-B ALL that was characterized by a t(11;19)(q23;p13) and the absence of myeloperoxidase, Sudan black, and alpha napthyl butyrate esterase staining. The lymphoblasts were positive for CD19 and CD22, but were negative for CD10 and cytoplasmic immunoglobulin. The study at diagnosis was repeatedly rechecked to determine whether

Second malignancy after treatment of AML

Primary disease

AML relapse

Age at DX (years)

Protocol

Site

Latency Protocol (years)a

Second malignancy Radiation

Diagnosis

Cr, 24 Gy Sp, 15 Gy —

Supratentorial PNET

9.2

S, C, R

Mucoepidermoid carcinoma Mucoepidermoid carcinoma Acute lymphoblastic leukemia Non-Hodgkin’s lymphoma

3.6

S, R

4.1

S

Alive/10.9+

2.6

C

Died/0.9

11.3

C, R

Alive/17.8+

1

M/W

0.8

AML83

CNS

0.6

—

2

F/B

14.7

—

—

—

3

F/W

5.5

POG8821 AutoBMT AML83

BM

0.5

M/W

1.0

AML83

—

—

R1, TBI, 15 Gy AlloBMT — —

M/W

10.2

AML70

CNS Testis BM

1.6 2.8 5.4

— — AML76

4 5

a

b

CS, 30 Gy T, 21 Gy —

Latency Therapy Status/length (years)a of survival after SMN (years) Died/1.3 Alive/7.4+

Years after the diagnosis of AML. This patient subsequently developed a third neoplasm (meningioma). M, male; F, female; W, white; B, black; Dx, diagnosis; AutoBMT, autologous bone marrow transplantation; CNS, central nervous system; BM, bone marrow; R1, relapse protocol;16 AlloBMT, allogeneic bone marrow transplant; Cr, cranial; Sp, spinal; TBI, total body irradiation; CS, craniospinal; T, testicular; PNET, primitive neuroectodermal tumor; S, surgery; C, chemotherapy; R, radiation to area of disease; SMN, second malignant neoplasm.

b

Leukemia


they contained the same t(11;19) seen in the ALL lymphoblasts, but the translocation was not found. Therefore this patient, unlike the four other patients mentioned in the Methods section, was considered to have a second malignancy instead of a phenotypic switch. He died of progressive ALL. UPN5: This patient experienced three relapses of AML in the CNS, the testicles, and the bone marrow, respectively. A non-Hodgkin’s lymphoma developed in the nasal septum 11.3 years after the diagnosis of AML and 9.5 years after craniospinal irradiation and was treated with local irradiation (20 Gy) and chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisone, 6-mercaptopurine, and methotrexate). Twenty-one years after the diagnosis of AML, 19 years after craniospinal irradiation, and 10 years after the diagnosis of lymphoma, a meningioma developed. The patient is free of disease 7.8 years after resection of the meningioma.

Incidence and competing risk of second malignancy Based on the SEER incidence rate of cancer in the general population, the expected number of patients with a second cancer was 0.47, but five were observed (standardized incidence ratio, 10.64; 95% confidence interval, 3.28 to 22.34). The estimated cumulative incidence of a second malignancy increased from 0.66% ± 0.38% (standard error, s.e.) at 5 years after the diagnosis of AML to 1.34% ± 0.61% (s.e.) at 15 years. This cumulative incidence of second cancer at 15 years was 54-fold less than the cumulative incidence of death due to other causes during the same period of time (72.96% ± 2.14% (s.e.)) (Figure 1). Discussion This is the first published report describing in detail the risk of second malignancy in a cohort of patients with childhood AML. Among the 501 patients, we found that survivors have a 10.6-fold greater risk of cancer than the general population; the estimated cumulative incidence of second cancers is

Figure 1 Cumulative incidence of second malignancy and death due to any other cause.

1.34% at 15 years after the initial diagnosis of AML. Misclassification and incomplete ascertainment of cases of second cancer were unlikely in this study because of the comprehensive pathologic studies and reviews and because of the close monitoring of survivors through a dedicated tumor registry at a single institution. This feature of our study is illustrated by the fact that four cases of ALL were reported to the registry but were excluded from this analysis because of genetic evidence of clonal evolution. Tumors such as meningioma and basal cell carcinoma of the skin are generally not included in the estimation of standardized incidence ratio because these tumors are not reported by the SEER program. Although numerous studies have reported the risk of second malignancy among survivors of childhood cancer,17–28 the risk among survivors of AML has been unclear. Some of these prior studies did not include patients with a primary diagnosis of AML, while others did not distinguish the primary diagnosis of ALL from that of AML.17–24 We found only four studies that reported the number of patients with a primary diagnosis of AML who were in the cohort; either no second cancer or only one second cancer was reported for these four studies with a small number of patients (38 to 163 patients).25–28 Comparison of the findings of these four studies with those of our study is not possible because information about the person-years at risk or the cumulative incidence of second cancer in the survivors of AML was not reported. Several studies have estimated the risk of second malignancy in patients treated for childhood ALL.29–32 The cumulative incidence was estimated to be approximately 2.5% at 15 years after the diagnosis of ALL. Irradiation is one of the most common risk factors for the development of a second malignancy after the treatment of ALL.29–34 Three of the five second cancers and the third neoplasm reported herein occurred in the irradiated field. One of the patients developed a parotid gland carcinoma following autologous bone marrow transplantation (BMT) without irradiation. Prior studies have demonstrated that approximately 25% of the secondary parotid tumors develop in patients who did not receive any radiation therapy.35 Even when total body irradiation (TBI) is not part of the preparatory regimen before BMT, the high-dose chemotherapy itself may be carcinogenic,36–38 although the risk is estimated to be at least three-fold less than that associated with conditioning regimens containing single-dose (⬎10 Gy) or fractionated TBI (⬎13 Gy).36,39 For patients with childhood leukemia who have undergone allogeneic BMT with or without TBI, the cumulative risk of solid cancer has been estimated to be as high as 11% at 15 years after BMT, with no difference in risk between patients with childhood ALL and those with AML.39 The probability of competing risks must be considered in the estimation of the cumulative incidence of second cancer. This consideration is particularly important for a disease such as AML, which carries a high competing risk of death due to disease progression or early treatment complications. In this study, we found a very high cumulative incidence of death unrelated to second cancer (73% at 15 years after diagnosis). This incidence is more than 50-fold higher than the cumulative incidence of second malignancy. Statistically, the use of the Kaplan–Meier method would be inappropriate in estimating the cumulative incidence of second cancer because this method fails to take into account the hazard of competing risks and it overestimates the true cumulative incidence of second cancer.40 Clinically, these results underscore the importance of future strategies for improving the treatment of primary AML while preventing the development of a second

43

Leukemia


44

malignancy. If survival rates continue to improve (resulting in decreasing competing risk), the incidence of second malignancy will be higher than that described herein. Besides second malignancy, survivors of childhood AML are also at risk for the development of other late sequelae. A recent study shows that less than half of the patients who survive more than 10 years after the diagnosis of childhood AML survive without late sequelae.2 With further intensification of treatment such as the use of bone marrow transplantation, the risk of second malignancy and other late squelae may increase further. This study has several limitations. First, although the ascertainment of cases was vigorous and resulted in high internal validity, the external generalizability remains to be proved. Second, although this study included more than 500 patients, the number of survivors with second cancers was small. Therefore, analysis of risk factors for a second malignancy could not be performed. In conclusion, survivors of childhood AML have a 10-fold greater risk of cancer than the general population. However, the incidence of this late complication is much less than the incidence of death due to primary AML and early treatment complications. Future strategies should focus on improving treatment of primary AML while preventing the development of second malignancies and other late sequelae.

Acknowledgements This work was supported in part by grants CA-20180 and CA21765 from the National Institutes of Health, by a Center of Excellence grant from the State of Tennessee, and by the American Lebanese Syrian Associated Charities (ALSAC). We thank Dr Julia Cay Jones for scientific editing, Ms Annette Stone for data management, and Ms Pam Hays for registry management.

References 1 Pui CH. Childhood leukemias. N Engl J Med 1995; 332: 1618– 1630. 2 Leung W, Hudson MM, Strickland DK, Phipps S, Srivastava DK, Ribeiro RC, Rubnitz JE, Sandlund JT, Kun LE, Bowman LC, Razzouk BI, Mathew P, Evans WE, Pui CH. Late effects of treatment in survivors of childhood acute myeloid leukemia. J Clin Oncol 2000; 18: 3273–3279. 3 Fleming I, Simone J, Jackson R, Johnson W, Walters T, Mason C. Splenectomy and chemotherapy in acute myelocytic leukemia of childhood. Cancer 1974; 33: 427–434. 4 Dahl GV, Simone JV, Hustu HO, Mason C. Preventive central nervous system irradiation in children with acute nonlymphocytic leukemia. Cancer 1978; 42: 2187–2192. 5 Dahl GV, Kalwinsky DK, Murphy S, Look AT, Amadori S, Kumar M, Novak R, George SL, Mason C, Mauer AM, Simone JV. Cytokinetically based induction chemotherapy and splenectomy for childhood acute nonlymphocytic leukemia. Blood 1982; 60: 856–863. 6 Dahl GV, Kalwinsky DK, Mirro J Jr, Look AT, Pui CH, Murphy SB, Mason C, Ruggiero M, Schell M, Johnson FL. Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission. J Clin Oncol 1990; 8: 295– 303. 7 Kalwinsky D, Mirro J Jr, Schell M, Behm F, Mason C, Dahl GV. Early intensification of chemotherapy for childhood acute nonlymphoblastic leukemia: improved remission induction with a fivedrug regimen including etoposide. J Clin Oncol 1988; 6: 1134– 1143. Leukemia

8 Arnaout MK, Radomski KM, Srivastava DK, Tong X, Belt JR, Raimondi SC, Behm FG, Santanta VM, Crom WR, Mirro J, Ribeiro RC. Treatment of childhood acute myelogenous leukemia with an intensive regimen (AML-87) that individualizes etoposide and cytarabine dosages: short- and long-term effects. Leukemia 2000 (in press). 9 Hurwitz CA, Krance R, Schell MJ, Santana VM, Brenner MK, Ribeirio R, Roberts WM, Mahmoud H, Belt J, Crom W. Current strategies for treatment of acute myeloid leukemia at St Jude Children’s Research Hospital. Leukemia 1992; 6(suppl 2): 39–43. 10 Beaty O III, Hudson MM, Greenwald C, Luo X, Fang L, Wilimas JA, Thompson EI, Kun LE, Pratt CB. Subsequent malignancies in children and adolescents after treatment for Hodgkin’s disease. J Clin Oncol 1995; 13: 603–609. 11 Leung W, Hudson M, Zhu Y, Rivera GK, Ribeiro RC, Sandlund JT, Bowman LC, Evans WE, Kun L, Pui CH. Late effects in survivors of infant leukemia. Leukemia 2000; 14: 1185–1190. 12 Pui CH, Raimondi SC, Head DR, Schell MJ, Rivera GK, Mirro J Jr, Crist WM, Behm FG. Characterization of childhood acute leukemia with multiple myeloid and lymphoid markers at diagnosis and at relapse. Blood 1991; 78: 1327–1337. 13 Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 1988; 16: 1141–1154. 14 Ries LAG, Eisner MP, Kosary CL (eds). SEER Cancer Statistics Review, 1973–1997. National Cancer Institute: Bethesda, MD, 2000. 15 Vandenbroucke JP. A shortcut method for calculating the 95 per cent confidence interval of the standardized mortality ratio. Am J Epidemiol 1982; 115: 303–304. 16 Mirro J Jr, Kalwinsky DK, Grier HE, Santana VM, Mason C, Murphy SB, Dahl GV. Effective reinduction therapy for childhood acute nonlymphoid leukemia using simultaneous continuous infusions of teniposide and amsacrine. Cancer Chemother Pharmacol 1989; 24: 123–127. 17 Li FP, Cassady JR, Jaffe N. Risk of second tumors in survivors of childhood cancer. Cancer 1975; 35: 1230–1235. 18 Mike V, Meadows AT, D’Angio GJ. Incidence of second malignant neoplasms in children: results of an international study. Lancet 1982; 2: 1326–1331. 19 Meadows AT, Baum E, Fossati-Bellani F, Green D, Jenkin RD, Marsden B, Nesbit M, Newton W, Oberlin O, Sallan SG. Second malignant neoplasms in children: an update from the Late Effects Study Group. J Clin Oncol 1985; 3: 532–538. 20 Olsen JH. Risk of second cancer after cancer in childhood. Cancer 1986; 57: 2250–2254. 21 de Vathaire F, Schweisguth O, Rodary C, Francois P, Sarrazin D, Oberlin O, Hill C, Raquin MA, Dutreix A, Flamant R. Long-term risk of second malignant neoplasm after a cancer in childhood. Br J Cancer 1989; 59: 448–452. 22 Blatt J, Olshan A, Gula MJ, Dickman PS, Zaranek B. Second malignancies in very long-term survivors of childhood cancer. Am J Med 1992; 93: 57–60. 23 Olsen JH, Garwicz S, Hertz H, Jonmundsson G, Langmark F, Lanning M, Lie SO, Moe PJ, Moller T, Sankila R. Second malignant neoplasms after cancer in childhood or adolescence. Nordic Society of Paediatric Haematology and Oncology Association of the Nordic Cancer Registries. Br Med J 1993; 307: 1030–1036. 24 de Vathaire F, Hawkins M, Campbell S, Oberlin O, Raquin MA, Schlienger, Shamsaldin A, Diallo I, Bell J, Grimaud E, Hardiman C, Lagrange JL, Daly-Schveitzer N, Panis X, Zucker JM, SanchoGarnier H, Eschwege F, Chavaudra J, Lemerle J. Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment. Br J Cancer 1999; 79: 1884–1893. 25 Hawkins MM, Draper GJ, Kingston JE. Incidence of second primary tumours among childhood cancer survivors. Br J Cancer 1987; 56: 339–347. 26 Terracini B, Pastore G, Zurlo MG, Masera G, Fossati-Bellani F, Castello M, Tamaro P, Massolo F, Rosati D, Biddau PF. Late deaths and second primary malignancies among long-term survivors of childhood cancer: an Italian multicentre study. Eur J Cancer Clin Oncol 1987; 23: 499–504. 27 Rosso P, Terracini B, Fears TR, Jankovic M, Fossati Bellani F, Arrighini A, Carli M, Cordero di Montezemolo L, Garre ML, Guazzelli C. Second malignant tumors after elective end of therapy for


28

29

30

31

32

33

a first cancer in childhood: a multicenter study in Italy. Int J Cancer 1994; 59: 451–456. Green DM, Zevon MA, Reese PA, Lowrie GS, Gaeta JF, Pearce JI, Michalek AM, Stephens EA. Second malignant tumors following treatment during childhood and adolescence for cancer. Med Pediatr Oncol 1994; 22: 1–10. Neglia JP, Meadows AT, Robison LL, Kim TH, Newton WA, Ruymann FB, Sather HN, Hammond GD. Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 325: 1330–1336. Nygaard R, Garwicz S, Haldorsen T, Hertz H, Jonmundsson GK, Lanning M, Moe PJ. Second malignant neoplasms in patients treated for childhood leukemia. A population-based cohort study from the Nordic countries. The Nordic Society of Pediatric Oncology and Hematology (NOPHO). Acta Paediatr Scand 1991; 80: 1220–1228. Kimball Dalton VM, Gelber RD, Li F, Donnelly MJ, Tarbell NJ, Sallan SE. Second malignancies in patients treated for childhood acute lymphoblastic leukemia. J Clin Oncol 1998; 16: 2848– 2853. Kubota M, Akiyama Y, Koishi S, Sawada M, Usami I, Lin YW, Watanabe K, Takimoto T. Second malignancy following treatment of acute lymphoblastic leukemia in children. Int J Hematol 1998; 67: 397–401. Relling MV, Rubnitz JE, Rivera GK, Boyett JM, Hancock ML, Felix CA, Kun LE, Walter AW, Evans WE, Pui CH. High incidence of secondary brain tumours after radiotherapy and antimetabolites. Lancet 1999; 354: 34–39.

34 Walter AW, Hancock ML, Pui CH, Hudson MM, Ochs JS, Rivera GK, Pratt CB, Boyett JM, Kun LE. Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children’s Research Hospital. J Clin Oncol 1998; 16: 3761–3767. 35 Kaste SC, Hedlund G, Pratt CB. Malignant parotid tumors in patients previously treated for childhood cancer: clinical and imaging findings in eight cases. Am J Roentgenol 1994; 162: 655–659. 36 Curtis RE, Rowlings PA, Deeg HJ, Shriner DA, Socie G, Travis LB, Horowitz MM, Witherspoon RP, Hoover RN, Sobocinski KA, Fraumeni JF Jr, Boice JD Jr. Solid cancers after bone marrow transplantation. N Engl J Med 1997; 336: 897–904. 37 Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood 1998; 91: 1833–1844. 38 Kolb HJ, Socie G, Duell T, Van Lint MT, Tichelli A, Apperley JF, Nekolla E, Ljungman P, Jacobsen N, van Weel M, Wick R, Weiss M, Prentice HG. Malignant neoplasms in long-term survivors of bone marrow transplantation. Ann Intern Med 1999; 131: 738– 744. 39 Socie G, Curtis RE, Deeg HJ, Sobocinski KA, Filipovich AH, Travis LB, Sullivan KM, Rowlings PA, Kingma DW, Banks PM, Travis WD, Witherspoon RP, Sanders J, Jaffe ES, Horowitz MM. New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 2000; 18: 348–357. 40 Gooley TA, Leisenring W, Crowley J, Storer BE. Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med 1999; 18: 695–706.

45

Leukemia