Increasing Incidence of Late Second Malignancies After Conditioning With Cyclophosphamide and Total-Body Irradiation and Autologous Bone Mar
http://www.100md.com
《临床肿瘤学》
the Department of Medical Oncology, Department of Biostatistical Science, Dana-Farber Cancer Institute
Department of Medicine, Brigham and Women’s Hospital
Department of Medicine, Massachusetts General Hospital
Department of Medicine, Harvard Medical School, Boston, MA
James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY
ABSTRACT
PURPOSE: Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin’s lymphoma (NHL).
PATIENTS AND METHODS: Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti–B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board–approved questionnaire sent to the referring oncologists.
RESULTS: Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy.
CONCLUSION: Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.
INTRODUCTION
The use of high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT) has been shown to improve disease-free and overall survival in patients with relapsed chemosensitive diffuse large B-cell lymphoma.1 Multiple studies have now shown that patients with follicular non-Hodgkin’s lymphoma (NHL) can also achieve prolonged disease-free survival following ASCT.2-4 As a result of these studies, ASCT has become a standard treatment for lymphoma in the appropriate context.
Although the short-term mortality of ASCT is generally less than 5%, the risk of long-term complications remains significant. The incidence of treatment-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been estimated at 5% to 20% at 10 years post-ASCT.5-7 Specific risk factors for the development of MDS include older age, low stem-cell dose, use of peripheral blood stem cells, prior radiation therapy (XRT), extent and type of prior chemotherapy, and conditioning with total-body irradiation (TBI).5,6,8,9
Despite the well-described early incidence of MDS in this patient population, the incidence of secondary solid tumors is much less clear. Following allogeneic stem-cell transplantation (SCT), the risk of solid tumors has been reported to increase between two- and eight-fold in patients with a variety of hematologic malignancies treated with different conditioning regimens.10-12 A recent study of ASCT patients in British Columbia also found a two-fold increased risk of solid tumors.13
The risk of solid tumors has not been described in a uniformly treated, prospectively identified population of patients undergoing ASCT. We report this incidence in a cohort of 605 patients who underwent high-dose chemoradiotherapy and anti–B-cell monoclonal antibody–purged autologous bone marrow transplantation (ABMT) for NHL between 1982 and 1997. In the results reported below, we demonstrate that the 10-year incidence of all secondary malignancies is 21%, with 10.0% non-MDS malignancies. This incidence of solid tumors is high enough to warrant close surveillance, and a plateau in incidence of non-MDS secondary malignancies is unfortunately not evident.
PATIENTS AND METHODS
Selection of Patients and Treatment Protocol
Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL at Dana-Farber Cancer Institute. NHL histologies were defined by the International Working Formulation and the Revised European-American Lymphoma Classification.14 Patients were eligible for these protocols if they were younger than 65 years and had relapsed after standard chemotherapeutic regimens or had high-risk primary disease in first remission, as previously described.15 For all patients, a minimal disease status had to be attained through chemotherapy, XRT, or both, before entry. Additional criteria for entry included absence of comorbid disease of the heart, liver, kidney, and lung, and a Karnofsky status of greater than 80%.15 All protocols were approved by the Dana-Farber Cancer Institute institutional review board, and informed consent was obtained from all patients before therapy.
Conditioning consisted of cyclophosphamide 60 mg/kg infused on each of 2 consecutive days before TBI. TBI was administered in fractionated doses (2 Gy) twice daily on 3 consecutive days (total of 12 Gy) before 1994; after 1994, all patients received 14 Gy in seven fractions. Supportive care was provided as previously described.15
Collection, Processing, and Infusion of Marrow
Bone marrow was obtained, treated in vitro, and stored as previously described.15 No patients were excluded from the protocol after bone marrow harvest. The bone marrow cells from all patients were treated with at least one monoclonal antibody, including some combination of anti-B1, anti-B4 (CD19), anti-B5, and J5 (anti-CD10). After treatment, the cells were cryopreserved as previously described. Within 24 hours of the completion of TBI, the cryopreserved bone marrow cells were rapidly thawed and diluted in medium containing DNase as previously described.15 No subjects treated on these protocols received peripheral-blood stem cells.
Follow-Up
All patients had routine physical examinations and laboratory studies, including CBCs, every 3 months for the first year, then every 6 months for the second year, then annually following transplantation. Patients underwent bone marrow aspiration and core biopsy for persistently low peripheral blood counts without an obvious explanation.
For those patients alive but not continuing to obtain follow-up care at Dana-Farber Cancer Institute, an institutional review board–approved questionnaire specifically addressing relapse of disease and development of secondary malignancy was sent to the referring oncologist and primary care physician. Follow-up telephone calls to these physicians were made as necessary. Clinic notes and pathology reports documenting secondary malignancies were obtained when possible. A total of 87.4% of patients have follow-up data through 2002 to 2003, and 7.6% through 2000 to 2001. Only 5% of patients lack follow-up since 2000.
Classification of MDS
As in our previous report of MDS in this patient population,6 MDS was strictly defined using the French-American-British (FAB) classification system and required bone marrow dysplasia in at least two lineages with peripheral cytopenia(s); cytogenetic abnormalities were considered.6 Patients with persistent cytopenia after bone marrow transplantation (BMT) without significant marrow dysplasia or with alternative explanations for their cytopenias, were not considered to have MDS.
Evaluation and Statistical Methods
The primary end point for this analysis was the pathologic diagnosis of a secondary malignancy, including invasive solid tumors and melanoma, in situ solid tumors, basal cell and squamous cell carcinomas of the skin, and MDS/AML. Basal cell and squamous cell carcinomas were included in the primary model due to their often recurrent or invasive nature in this patient population. The time to diagnosis of a secondary malignancy was measured from the date of ABMT for NHL to the date of pathologic diagnosis of the secondary malignancy. A cumulative incidence model was used to estimate the time to first secondary malignancy, identifying death as a competing risk; patients alive without secondary malignancies were censored. This permits the estimation of the rate of second tumors at a specified point in time. Additional cumulative incidence models differentiated between MDS/AML and other secondary malignancies. Risk factors for second malignancy investigated in these models as well as in the primary data set include follicular histology, transplantation in first or later remission, sex, history of involved-field XRT, total TBI dose, and age. Comparison of cumulative incidence curves used the Gray test.16
Progression-free survival was calculated from the day of marrow infusion (day 0) to the date of disease recurrence, or to the date last known alive and disease free. Overall survival was calculated from date of marrow infusion until death or date last known alive. Disease-free survival curves and time-to-relapse curves were estimated by the method of Kaplan and Meier, with CIs calculated using Greenwood’s formula.17,18
The expected number of malignancies was calculated from Surveillance, Epidemiology, and End Results (SEER) incidence rates per 100,000-person population using data from 1996 to 2000. Patients were divided into categories by age at transplantation (< 30, 30 to 39, 40 to 49, 50 to 59, and > 60 years), and rates were adjusted over 5-year follow-up intervals. Sex adjustment was also performed.
RESULTS
Patient Characteristics
A total of 605 patients underwent ABMT for B-cell NHL at Dana-Farber Cancer Institute between 1982 and 1997. The median age of the patient population at time of ABMT was 44 years, and 58% were male and 97% were white. Histologies at time of ABMT included 57% follicular lymphoma, 26% diffuse large B-cell lymphoma, 5% mantle cell lymphoma, and 12% other. ABMT was performed in first remission for indolent lymphoma in 96 patients and in first remission for aggressive lymphoma in 31 patients (21% of the total population). The remaining 477 patients had disease that failed to enter complete remission with initial therapy or that relapsed following chemotherapy. The median number of prior chemotherapy regimens for this group of patients was three. Twenty-seven percent of the patient population had received therapeutic XRT to sites of symptomatic or bulky disease before ABMT.
At a median follow-up of 9.5 years, 38.5% of patients were alive and free of disease. Forty-seven percent of patients have relapsed with their disease, of whom only 26% are still alive (11.5% of the total population). The overall mortality is 50%, with a median disease-free survival of 4.7 years, and overall survival, 9.4 years (95% CI, 7.8 to 11.6); 14.5% have died in remission (Table 1). Most of these patients died of secondary malignancy, infection, or organ failure, usually related to long-term toxicity of ABMT; one pulmonary death was due to chronic obstructive pulmonary disease, one infectious death was due to previously undiagnosed HIV, and two cases of cardiac death were possibly unrelated to ABMT (Table 1). Of the total patient population, 9.6% have died of secondary malignancy. Of these, 72% remained in complete remission following ABMT.
Incidence of Second Malignancies
At a median follow-up of 9.5 years, 42 cases of solid tumors have been observed, representing 6.9% of the patient population (Table 2). The most common individual tumors are those that are most common in the population, including breast and prostate cancer, but several unusual tumors were observed (Table 2). Eight cases of carcinoma in situ were included in the total, since in every case, these were significant malignancies (for example, breast ductal carcinoma in situ, melanoma in situ, and anal squamous cell carcinoma in situ). Thirty-nine patients had developed at least one nonmelanoma skin cancer, and 11 patients have had at least two. Six new hematologic malignancies were observed, including two cases of chronic lymphocytic leukemia and two cases of Hodgkin’s lymphoma, all in patients with prior follicular lymphoma; one case of acute lymphoblastic leukemia; and one case of a primary CNS lymphoma that lacked the t(14;18) present in the antecedent follicular NHL.
In our previous report, with a median follow-up of 5 years,6 41 cases of MDS/AML had been observed. Now, at a median follow-up of 9.5 years, 68 cases of MDS/AML have been observed, representing 11% of the total patient population (data not shown).
Sixteen patients have developed two or more malignancies. Five of these patients had both squamous cell carcinoma and basal cell carcinoma of the skin. Six had MDS and an additional malignancy.
Comparison of Observed to Expected Rate of Malignancy
The observed incidence of second malignancy was compared with that expected using SEER age- and sex-adjusted incidence rates in a population with similar person-years of follow-up. The expected incidence of all solid tumors, hematologic malignancies, and MDS/AML for this population is 18.05 per 100,000 person-years at risk, as compared with 112 SEER-reportable malignancies observed. The expected number of solid tumors and non-MDS hematologic malignancies is 17.8 per 100,000 person-years at risk, with 44 SEER-reportable malignancies observed. The observed and expected numbers of cases for selected solid tumors is presented in Table 3; in every tumor type, more cases were observed than expected. For MDS/AML, the expected number of cases is 0.27 per 100,000 person-years at risk, with 68 observed.
A cumulative incidence model was used to estimate the rate of second tumors, using death as a competing risk (Fig 1). The 10-year incidence of secondary malignancies in this model is 21%, with a 41% death rate in patients without a second malignancy. The 10-year incidence of all non-MDS/AML tumors, including nonmelanoma skin cancers, is 10.0%, with a 15-year projected incidence of 14.8%. Although the incidence of MDS/AML levels off at 14.2% at 15 years, the incidence of all other tumors continues to increase without evidence of a plateau (Fig 1).
Risk Factors for Secondary Malignancy
Patient characteristics were investigated for their ability to predict the incidence of second malignancies. Age divided into quartiles proved the most potent risk factor, with a 15% incidence of second malignancy in patients 19 to 37 years of age at time of transplantation, compared with a 31% incidence in patients aged 51 to 66 years (Fig 2; P = .0002, Kruskal-Wallis test). The incidence of second malignancies in patients who received XRT before transplantation was 28%, as compared with 20% in those who did not receive XRT (P = .08, Fisher’s exact test). No effect of transplantation in first remission, sex, or follicular histology was observed.
These risk factors were also investigated in the cumulative incidence model, which takes into account both time and death as competing risks. Age at or above the median (ie, 44 years) at time of transplantation was confirmed as a significant predictor of the incidence of both solid tumors and MDS/AML (P = .00007 for all second malignancies). Prior XRT had no significant effect when all second malignancies were considered together; however, when MDS/AML was considered separately from all other tumors, the association we previously reported6,19 between prior XRT and MDS/AML was again observed (P = .03). The impact of TBI dose was investigated in this model by comparing subjects treated before or after 1994, when the regimen was changed from 12 to 14 Gy; no effect of TBI dose on the risk of solid tumors or MDS/AML was observed (data not shown).
Patients with follicular NHL were noted to have a 24% rate of second malignancies at 10 years, compared with 18% for all other histologies (P = .03). A highly significant difference in solid malignancies was noted (Fig 3; P = .002), with no significant difference in MDS/AML observed (P = .87; data not shown). Age does not contribute to this increased risk of solid malignancies, as the median age of patients with follicular NHL is slightly less than that of the overall population (data not shown). Follicular NHL patients have a significantly lower likelihood of death without second malignancy (P < 10–8; data not shown), due primarily to a lower rate of death from disease; as a result, they have more accumulated years in which to develop solid malignancies. The observed rate of second malignancy per person-year of observation is similar among patients with follicular and intermediate grade lymphoma, whether in remission or relapsed (data not shown). This observation suggests that the increased rate of secondary solid tumors in patients with follicular lymphoma is primarily related to longer survival.
Outcome of Secondary Malignancies
To date, the majority of solid tumors were localized at presentation and are in remission following local therapy. Of the hematologic malignancies, three are in complete remission, one has not required therapy, and two are newly diagnosed. To date, the mortality attributable to solid or hematologic malignancies not including MDS is 6.25%, but likely will increase to at least 10.4%. Of the 68 patients with MDS/AML, 11 remain alive (16.1%), with the mortality attributable to MDS/AML, 80.9%.
DISCUSSION
High-dose chemotherapy and SCT result in long-term disease-free survival of many patients with hematologic malignancies, but with significant long-term side effects. In this cohort of 605 patients who underwent uniform conditioning with cyclophosphamide and TBI followed by purged ABMT for NHL, the 10-year incidence of secondary malignancies is 21%, with a 10% incidence of solid or other hematologic malignancies, and an 11% incidence of MDS/AML. Age is the primary risk factor for second malignancy, with prior XRT a risk factor for MDS/AML, and follicular histology a risk factor for solid malignancies. In the entire cohort to date, these malignancies have directly resulted in a 9.6% mortality.
The incidence of solid tumors observed in this cohort is significantly higher than that previously reported in the literature. The risk of solid tumors at 3- to 5-year follow-up after allogeneic SCT is increased between two- and eight-fold, with projected absolute risks ranging from 2.2% to 12% at 10 to 12 years.10-12,20,21 Increased relative risks have been reported for cancers of the thyroid, skin, oropharynx, liver, brain, and soft tissues,10-12,20,21 with risk factors including chronic or acute graft-versus-host disease (GVHD), age at BMT, involved-field XRT, and male sex.10-12,20 Estimates of solid tumor incidence at 3- to 5-year follow-up after ASCT are generally lower, ranging from 1.0% to 4.9% at 10 years, and to 7.6% at 15 years.10,12,13,22 Our data, with nearly 10 years of follow-up, suggest that this incidence will continue to rise over at least 15 to 20 years without evidence of a plateau. The incidence of secondary solid malignancies following treatment for Hodgkin’s disease also continues to rise throughout the second decade after treatment,23,24 and several studies in allogeneic SCT patients have projected similar trends.11,20,25 Our data provide confirmation of this increasing late incidence and extend it to long-term survivors of ABMT.
The risk factors for development of second malignancies after SCT remain controversial. The primary risk factor for any second malignancy in this study is increased patient age at transplantation, in a population of adults whose median age is 44 years. Multiple other studies of ASCT and allogeneic SCT have found similar results.9,13,26 However, certain studies that included a significant proportion of children have found the highest risk of second malignancy to be in patients younger than 10 years at transplantation.11,12,25 A reasonable hypothesis to explain these data is that very young age, presumably due to rapid growth, as well as older age, presumably due to accumulated genetic damage, are both associated with risk for second malignancy.
The role of radiation exposure in inducing second malignancies, either as conditioning with TBI or as involved-field XRT, also remains controversial. Although a majority of studies have found a significant association between conditioning with TBI and subsequent MDS/AML,5,9,26 the literature is quite divided as to the impact of TBI on subsequent solid tumor incidence, with reports of both significant risk11,12,20,25 and no risk.10,27 The effect of TBI is difficult to assess in our study since all patients received it, but this exposure is a possible contributor to the incidence of secondary malignancy in this cohort. Of note is the significantly lower incidence of both solid tumors and MDS/AML seen in patients conditioned with cyclophosphamide, carmustine, and etoposide (CBV) at our institution, albeit at significantly shorter median follow-up.28 The impact of involved-field XRT on secondary malignancy is less well-studied. In our previous report on this patient population, 13% of patients who received external-beam XRT developed MDS, as compared with 6.5% of those who did not receive XRT.19 Our current data do not demonstrate an effect of XRT on the overall incidence of secondary malignancies or on solid tumors, but do confirm this previously reported association with MDS/AML, which has also been observed in other studies.8,22
In our cohort, a novel association was observed between underlying follicular lymphoma and a higher incidence of non-MDS secondary malignancies. Since the rate of second malignancy per person-year of observation is similar in patients with follicular and all other lymphomas, this association is likely to be primarily due to longer survival in patients with follicular lymphoma, which allows more time for the development of solid tumors. However, it is difficult to rule out a small contribution from either the biology of follicular lymphoma (which may predispose to the development of second malignancies to a greater extent than other lymphomas) or from greater prior exposure to chemotherapy or XRT. The extent of prior therapy does affect the incidence of MDS/AML, but the effect on solid tumors is much less clear, particularly since the incidence of solid tumors in lymphoma patients treated with standard chemotherapy is close to background.29-31 Exposure to prior therapy is therefore unlikely to be a major culprit in the higher incidence of non-MDS malignancy, but rather longer survival and possibly a small contribution from the biology of follicular lymphoma.
In conclusion, NHL patients uniformly conditioned with cyclophosphamide and TBI for purged ABMT have a 21% rate of second malignant neoplasms at 10-year follow-up—approximately evenly divided between solid malignancies and MDS/AML. These malignancies have been responsible for the death of 9.6% of the patients, due primarily to the extremely poor outcome of MDS/AML, but with increasing recent deaths due to solid tumors. The increasing incidence of non-MDS malignancies without evidence of a plateau is likely to lead to a continued increase in the morbidity and mortality of solid tumors during the next decade of observation. This high and still increasing incidence of late second malignancies significantly increases the treatment-related mortality of ABMT, which has generally been thought to have the advantage of low mortality in comparison with allogeneic SCT. Systematic studies are needed to define the optimal screening and follow-up required to minimize the morbidity and mortality of second malignancies in long-term survivors of ABMT. Furthermore, given the known curative potential of ASCT in NHL and the still higher risks of allogeneic SCT, optimization of the ASCT procedure, including less toxic prior therapies, alternative conditioning regimens, and better understanding of the underlying biology, are needed to reduce long-term complications.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We are indebted to the nurses, medical oncology fellows, house staff, and social workers of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, for their excellent care of these patients. We thank the technicians of the Connell-O’Reilly Cell Manipulation Laboratory and the Blood Component Laboratory of the Dana-Farber Cancer Institute for processing of the bone marrow.
NOTES
Supported in part by the Clinical Investigator Training Program (J.R.B.): Harvard/Massachusetts Institute of Technology Health Sciences and Technology—Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc.
Presented in part at the Annual Meeting of the American Society of Hematology, San Diego, CA, December 8, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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Schouten H, Qian W, Kvaloy S, et al: High-dose therapy improves progression-free survival and survival in relapsed follicular non-Hodgkin’s Lymphoma: Results from the randomized European CUP trial. J Clin Oncol 21:3918-3927, 2003
Apostolidis J, Gupta R, Grenzelias D, et al: High-dose therapy with autologous bone marrow support as consolidation of remission in follicular lymphoma: Long-term clinical and molecular follow-up. J Clin Oncol 18:527-536, 2000
Freedman AS, Neuberg D, Mauch P, et al: Long-term follow-up of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood 94:3325-3333, 1999
Darrington DL, Vose JM, Anderson JR, et al: Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 12:2527-2534, 1994
Friedberg JW, Neuberg D, Stone RM, et al: Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 17:3128-3135, 1999
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Krishnan A, Bhatia S, Slovak ML, et al: Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: An assessment of risk factors. Blood 95:1588-1593, 2000
Milligan DW, Ruiz de Elvira MC, Kolb H-J, et al: Secondary leukemia and myelodysplasia after autografting for lymphoma: Results from the EBMT. Br J Haematol 106:1020-1026, 1999
Baker KS, DeFor TE, Burns LJ, et al: New malignancies after blood or marrow stem-cell transplantation in children and adults: Incidence and risk factors. J Clin Oncol 21:1352-1358, 2003
Curtis RE, Rowlings PA, Deeg HJ, et al: Solid cancers after bone marrow transplantation. N Engl J Med 336:897-904, 1997
Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464-471, 2001
Forrest DL, Nevill TJ, Naiman SC, et al: Second malignancy following high-dose therapy and autologous stem cell transplantation: Incidence and risk factor analysis. Bone Marrow Transplant 32:915-923, 2003
Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84:1361, 1994
Freedman AS, Ritz J, Neuberg D, et al: Autologous bone marrow transplantation in 69 patients with a history of low grade B cell non-Hodgkin’s lymphoma. Blood 77:2524-2529, 1991
Gray R: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988
Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457, 1958
Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep 50:163, 1966
Friedberg JW, Neuberg D, Monson J, et al: The impact of external beam radiation therapy prior to autologous bone marrow transplantation in patients with non-Hodgkin’s lymphoma. Biol Blood Marrow Transplant 7:446-453, 2001
Deeg HJ, Socie G, Schoch G, et al: Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: A joint Seattle and Paris analysis of results in 700 patients. Blood 87:386-392, 1996
Socie G, Henry-Amar M, Cosset JM, et al: Increased incidence of solid malignant tumors after bone marrow transplantation for severe aplastic anemia. Blood 78:277-279, 1991
Bolwell BJ, Kalaycio M, Sobecks R, et al: Secondary malignancy after autologous stem cell transplantation (ABMT) for non-Hodgkin’s lymphoma and Hodgkin’s disease using a busulfan containing preparative regimen. Blood 100:113a, 2002
Nyandoto P, Muhonen T, Joensuu H: Second cancer among long-term survivors from Hodgkin’s disease. Int J Radiat Oncol Biol Phys 42:373-378, 1998
van Leeuwen FE, Klokman WJ, Hagenbeek A, et al: Second cancer risk following Hodgkin’s disease: A 20 year follow-up study. J Clin Oncol 12:312-325, 1994
Socie G, Curtis RE, Deeg HJ, et al: New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 18:348-357, 2000
Armitage JO, Carbone PP, Connors JM, et al: Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. J Clin Oncol 21:897-906, 2003
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Wheeler C, Khurshid A, Ibrahim J, et al: Incidence of post transplant myelodysplasia/acute leukemia in non-Hodgkin’s lymphoma patients compared with Hodgkin’s disease patients undergoing autologous transplantation following cyclophosphamide, carmustine, and etoposide (CBV). Leuk Lymphoma 40:499-509, 2001
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Department of Medicine, Brigham and Women’s Hospital
Department of Medicine, Massachusetts General Hospital
Department of Medicine, Harvard Medical School, Boston, MA
James P. Wilmot Cancer Center, University of Rochester Medical Center, Rochester, NY
ABSTRACT
PURPOSE: Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin’s lymphoma (NHL).
PATIENTS AND METHODS: Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti–B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board–approved questionnaire sent to the referring oncologists.
RESULTS: Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy.
CONCLUSION: Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.
INTRODUCTION
The use of high-dose chemoradiotherapy and autologous stem-cell transplantation (ASCT) has been shown to improve disease-free and overall survival in patients with relapsed chemosensitive diffuse large B-cell lymphoma.1 Multiple studies have now shown that patients with follicular non-Hodgkin’s lymphoma (NHL) can also achieve prolonged disease-free survival following ASCT.2-4 As a result of these studies, ASCT has become a standard treatment for lymphoma in the appropriate context.
Although the short-term mortality of ASCT is generally less than 5%, the risk of long-term complications remains significant. The incidence of treatment-related myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) has been estimated at 5% to 20% at 10 years post-ASCT.5-7 Specific risk factors for the development of MDS include older age, low stem-cell dose, use of peripheral blood stem cells, prior radiation therapy (XRT), extent and type of prior chemotherapy, and conditioning with total-body irradiation (TBI).5,6,8,9
Despite the well-described early incidence of MDS in this patient population, the incidence of secondary solid tumors is much less clear. Following allogeneic stem-cell transplantation (SCT), the risk of solid tumors has been reported to increase between two- and eight-fold in patients with a variety of hematologic malignancies treated with different conditioning regimens.10-12 A recent study of ASCT patients in British Columbia also found a two-fold increased risk of solid tumors.13
The risk of solid tumors has not been described in a uniformly treated, prospectively identified population of patients undergoing ASCT. We report this incidence in a cohort of 605 patients who underwent high-dose chemoradiotherapy and anti–B-cell monoclonal antibody–purged autologous bone marrow transplantation (ABMT) for NHL between 1982 and 1997. In the results reported below, we demonstrate that the 10-year incidence of all secondary malignancies is 21%, with 10.0% non-MDS malignancies. This incidence of solid tumors is high enough to warrant close surveillance, and a plateau in incidence of non-MDS secondary malignancies is unfortunately not evident.
PATIENTS AND METHODS
Selection of Patients and Treatment Protocol
Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL at Dana-Farber Cancer Institute. NHL histologies were defined by the International Working Formulation and the Revised European-American Lymphoma Classification.14 Patients were eligible for these protocols if they were younger than 65 years and had relapsed after standard chemotherapeutic regimens or had high-risk primary disease in first remission, as previously described.15 For all patients, a minimal disease status had to be attained through chemotherapy, XRT, or both, before entry. Additional criteria for entry included absence of comorbid disease of the heart, liver, kidney, and lung, and a Karnofsky status of greater than 80%.15 All protocols were approved by the Dana-Farber Cancer Institute institutional review board, and informed consent was obtained from all patients before therapy.
Conditioning consisted of cyclophosphamide 60 mg/kg infused on each of 2 consecutive days before TBI. TBI was administered in fractionated doses (2 Gy) twice daily on 3 consecutive days (total of 12 Gy) before 1994; after 1994, all patients received 14 Gy in seven fractions. Supportive care was provided as previously described.15
Collection, Processing, and Infusion of Marrow
Bone marrow was obtained, treated in vitro, and stored as previously described.15 No patients were excluded from the protocol after bone marrow harvest. The bone marrow cells from all patients were treated with at least one monoclonal antibody, including some combination of anti-B1, anti-B4 (CD19), anti-B5, and J5 (anti-CD10). After treatment, the cells were cryopreserved as previously described. Within 24 hours of the completion of TBI, the cryopreserved bone marrow cells were rapidly thawed and diluted in medium containing DNase as previously described.15 No subjects treated on these protocols received peripheral-blood stem cells.
Follow-Up
All patients had routine physical examinations and laboratory studies, including CBCs, every 3 months for the first year, then every 6 months for the second year, then annually following transplantation. Patients underwent bone marrow aspiration and core biopsy for persistently low peripheral blood counts without an obvious explanation.
For those patients alive but not continuing to obtain follow-up care at Dana-Farber Cancer Institute, an institutional review board–approved questionnaire specifically addressing relapse of disease and development of secondary malignancy was sent to the referring oncologist and primary care physician. Follow-up telephone calls to these physicians were made as necessary. Clinic notes and pathology reports documenting secondary malignancies were obtained when possible. A total of 87.4% of patients have follow-up data through 2002 to 2003, and 7.6% through 2000 to 2001. Only 5% of patients lack follow-up since 2000.
Classification of MDS
As in our previous report of MDS in this patient population,6 MDS was strictly defined using the French-American-British (FAB) classification system and required bone marrow dysplasia in at least two lineages with peripheral cytopenia(s); cytogenetic abnormalities were considered.6 Patients with persistent cytopenia after bone marrow transplantation (BMT) without significant marrow dysplasia or with alternative explanations for their cytopenias, were not considered to have MDS.
Evaluation and Statistical Methods
The primary end point for this analysis was the pathologic diagnosis of a secondary malignancy, including invasive solid tumors and melanoma, in situ solid tumors, basal cell and squamous cell carcinomas of the skin, and MDS/AML. Basal cell and squamous cell carcinomas were included in the primary model due to their often recurrent or invasive nature in this patient population. The time to diagnosis of a secondary malignancy was measured from the date of ABMT for NHL to the date of pathologic diagnosis of the secondary malignancy. A cumulative incidence model was used to estimate the time to first secondary malignancy, identifying death as a competing risk; patients alive without secondary malignancies were censored. This permits the estimation of the rate of second tumors at a specified point in time. Additional cumulative incidence models differentiated between MDS/AML and other secondary malignancies. Risk factors for second malignancy investigated in these models as well as in the primary data set include follicular histology, transplantation in first or later remission, sex, history of involved-field XRT, total TBI dose, and age. Comparison of cumulative incidence curves used the Gray test.16
Progression-free survival was calculated from the day of marrow infusion (day 0) to the date of disease recurrence, or to the date last known alive and disease free. Overall survival was calculated from date of marrow infusion until death or date last known alive. Disease-free survival curves and time-to-relapse curves were estimated by the method of Kaplan and Meier, with CIs calculated using Greenwood’s formula.17,18
The expected number of malignancies was calculated from Surveillance, Epidemiology, and End Results (SEER) incidence rates per 100,000-person population using data from 1996 to 2000. Patients were divided into categories by age at transplantation (< 30, 30 to 39, 40 to 49, 50 to 59, and > 60 years), and rates were adjusted over 5-year follow-up intervals. Sex adjustment was also performed.
RESULTS
Patient Characteristics
A total of 605 patients underwent ABMT for B-cell NHL at Dana-Farber Cancer Institute between 1982 and 1997. The median age of the patient population at time of ABMT was 44 years, and 58% were male and 97% were white. Histologies at time of ABMT included 57% follicular lymphoma, 26% diffuse large B-cell lymphoma, 5% mantle cell lymphoma, and 12% other. ABMT was performed in first remission for indolent lymphoma in 96 patients and in first remission for aggressive lymphoma in 31 patients (21% of the total population). The remaining 477 patients had disease that failed to enter complete remission with initial therapy or that relapsed following chemotherapy. The median number of prior chemotherapy regimens for this group of patients was three. Twenty-seven percent of the patient population had received therapeutic XRT to sites of symptomatic or bulky disease before ABMT.
At a median follow-up of 9.5 years, 38.5% of patients were alive and free of disease. Forty-seven percent of patients have relapsed with their disease, of whom only 26% are still alive (11.5% of the total population). The overall mortality is 50%, with a median disease-free survival of 4.7 years, and overall survival, 9.4 years (95% CI, 7.8 to 11.6); 14.5% have died in remission (Table 1). Most of these patients died of secondary malignancy, infection, or organ failure, usually related to long-term toxicity of ABMT; one pulmonary death was due to chronic obstructive pulmonary disease, one infectious death was due to previously undiagnosed HIV, and two cases of cardiac death were possibly unrelated to ABMT (Table 1). Of the total patient population, 9.6% have died of secondary malignancy. Of these, 72% remained in complete remission following ABMT.
Incidence of Second Malignancies
At a median follow-up of 9.5 years, 42 cases of solid tumors have been observed, representing 6.9% of the patient population (Table 2). The most common individual tumors are those that are most common in the population, including breast and prostate cancer, but several unusual tumors were observed (Table 2). Eight cases of carcinoma in situ were included in the total, since in every case, these were significant malignancies (for example, breast ductal carcinoma in situ, melanoma in situ, and anal squamous cell carcinoma in situ). Thirty-nine patients had developed at least one nonmelanoma skin cancer, and 11 patients have had at least two. Six new hematologic malignancies were observed, including two cases of chronic lymphocytic leukemia and two cases of Hodgkin’s lymphoma, all in patients with prior follicular lymphoma; one case of acute lymphoblastic leukemia; and one case of a primary CNS lymphoma that lacked the t(14;18) present in the antecedent follicular NHL.
In our previous report, with a median follow-up of 5 years,6 41 cases of MDS/AML had been observed. Now, at a median follow-up of 9.5 years, 68 cases of MDS/AML have been observed, representing 11% of the total patient population (data not shown).
Sixteen patients have developed two or more malignancies. Five of these patients had both squamous cell carcinoma and basal cell carcinoma of the skin. Six had MDS and an additional malignancy.
Comparison of Observed to Expected Rate of Malignancy
The observed incidence of second malignancy was compared with that expected using SEER age- and sex-adjusted incidence rates in a population with similar person-years of follow-up. The expected incidence of all solid tumors, hematologic malignancies, and MDS/AML for this population is 18.05 per 100,000 person-years at risk, as compared with 112 SEER-reportable malignancies observed. The expected number of solid tumors and non-MDS hematologic malignancies is 17.8 per 100,000 person-years at risk, with 44 SEER-reportable malignancies observed. The observed and expected numbers of cases for selected solid tumors is presented in Table 3; in every tumor type, more cases were observed than expected. For MDS/AML, the expected number of cases is 0.27 per 100,000 person-years at risk, with 68 observed.
A cumulative incidence model was used to estimate the rate of second tumors, using death as a competing risk (Fig 1). The 10-year incidence of secondary malignancies in this model is 21%, with a 41% death rate in patients without a second malignancy. The 10-year incidence of all non-MDS/AML tumors, including nonmelanoma skin cancers, is 10.0%, with a 15-year projected incidence of 14.8%. Although the incidence of MDS/AML levels off at 14.2% at 15 years, the incidence of all other tumors continues to increase without evidence of a plateau (Fig 1).
Risk Factors for Secondary Malignancy
Patient characteristics were investigated for their ability to predict the incidence of second malignancies. Age divided into quartiles proved the most potent risk factor, with a 15% incidence of second malignancy in patients 19 to 37 years of age at time of transplantation, compared with a 31% incidence in patients aged 51 to 66 years (Fig 2; P = .0002, Kruskal-Wallis test). The incidence of second malignancies in patients who received XRT before transplantation was 28%, as compared with 20% in those who did not receive XRT (P = .08, Fisher’s exact test). No effect of transplantation in first remission, sex, or follicular histology was observed.
These risk factors were also investigated in the cumulative incidence model, which takes into account both time and death as competing risks. Age at or above the median (ie, 44 years) at time of transplantation was confirmed as a significant predictor of the incidence of both solid tumors and MDS/AML (P = .00007 for all second malignancies). Prior XRT had no significant effect when all second malignancies were considered together; however, when MDS/AML was considered separately from all other tumors, the association we previously reported6,19 between prior XRT and MDS/AML was again observed (P = .03). The impact of TBI dose was investigated in this model by comparing subjects treated before or after 1994, when the regimen was changed from 12 to 14 Gy; no effect of TBI dose on the risk of solid tumors or MDS/AML was observed (data not shown).
Patients with follicular NHL were noted to have a 24% rate of second malignancies at 10 years, compared with 18% for all other histologies (P = .03). A highly significant difference in solid malignancies was noted (Fig 3; P = .002), with no significant difference in MDS/AML observed (P = .87; data not shown). Age does not contribute to this increased risk of solid malignancies, as the median age of patients with follicular NHL is slightly less than that of the overall population (data not shown). Follicular NHL patients have a significantly lower likelihood of death without second malignancy (P < 10–8; data not shown), due primarily to a lower rate of death from disease; as a result, they have more accumulated years in which to develop solid malignancies. The observed rate of second malignancy per person-year of observation is similar among patients with follicular and intermediate grade lymphoma, whether in remission or relapsed (data not shown). This observation suggests that the increased rate of secondary solid tumors in patients with follicular lymphoma is primarily related to longer survival.
Outcome of Secondary Malignancies
To date, the majority of solid tumors were localized at presentation and are in remission following local therapy. Of the hematologic malignancies, three are in complete remission, one has not required therapy, and two are newly diagnosed. To date, the mortality attributable to solid or hematologic malignancies not including MDS is 6.25%, but likely will increase to at least 10.4%. Of the 68 patients with MDS/AML, 11 remain alive (16.1%), with the mortality attributable to MDS/AML, 80.9%.
DISCUSSION
High-dose chemotherapy and SCT result in long-term disease-free survival of many patients with hematologic malignancies, but with significant long-term side effects. In this cohort of 605 patients who underwent uniform conditioning with cyclophosphamide and TBI followed by purged ABMT for NHL, the 10-year incidence of secondary malignancies is 21%, with a 10% incidence of solid or other hematologic malignancies, and an 11% incidence of MDS/AML. Age is the primary risk factor for second malignancy, with prior XRT a risk factor for MDS/AML, and follicular histology a risk factor for solid malignancies. In the entire cohort to date, these malignancies have directly resulted in a 9.6% mortality.
The incidence of solid tumors observed in this cohort is significantly higher than that previously reported in the literature. The risk of solid tumors at 3- to 5-year follow-up after allogeneic SCT is increased between two- and eight-fold, with projected absolute risks ranging from 2.2% to 12% at 10 to 12 years.10-12,20,21 Increased relative risks have been reported for cancers of the thyroid, skin, oropharynx, liver, brain, and soft tissues,10-12,20,21 with risk factors including chronic or acute graft-versus-host disease (GVHD), age at BMT, involved-field XRT, and male sex.10-12,20 Estimates of solid tumor incidence at 3- to 5-year follow-up after ASCT are generally lower, ranging from 1.0% to 4.9% at 10 years, and to 7.6% at 15 years.10,12,13,22 Our data, with nearly 10 years of follow-up, suggest that this incidence will continue to rise over at least 15 to 20 years without evidence of a plateau. The incidence of secondary solid malignancies following treatment for Hodgkin’s disease also continues to rise throughout the second decade after treatment,23,24 and several studies in allogeneic SCT patients have projected similar trends.11,20,25 Our data provide confirmation of this increasing late incidence and extend it to long-term survivors of ABMT.
The risk factors for development of second malignancies after SCT remain controversial. The primary risk factor for any second malignancy in this study is increased patient age at transplantation, in a population of adults whose median age is 44 years. Multiple other studies of ASCT and allogeneic SCT have found similar results.9,13,26 However, certain studies that included a significant proportion of children have found the highest risk of second malignancy to be in patients younger than 10 years at transplantation.11,12,25 A reasonable hypothesis to explain these data is that very young age, presumably due to rapid growth, as well as older age, presumably due to accumulated genetic damage, are both associated with risk for second malignancy.
The role of radiation exposure in inducing second malignancies, either as conditioning with TBI or as involved-field XRT, also remains controversial. Although a majority of studies have found a significant association between conditioning with TBI and subsequent MDS/AML,5,9,26 the literature is quite divided as to the impact of TBI on subsequent solid tumor incidence, with reports of both significant risk11,12,20,25 and no risk.10,27 The effect of TBI is difficult to assess in our study since all patients received it, but this exposure is a possible contributor to the incidence of secondary malignancy in this cohort. Of note is the significantly lower incidence of both solid tumors and MDS/AML seen in patients conditioned with cyclophosphamide, carmustine, and etoposide (CBV) at our institution, albeit at significantly shorter median follow-up.28 The impact of involved-field XRT on secondary malignancy is less well-studied. In our previous report on this patient population, 13% of patients who received external-beam XRT developed MDS, as compared with 6.5% of those who did not receive XRT.19 Our current data do not demonstrate an effect of XRT on the overall incidence of secondary malignancies or on solid tumors, but do confirm this previously reported association with MDS/AML, which has also been observed in other studies.8,22
In our cohort, a novel association was observed between underlying follicular lymphoma and a higher incidence of non-MDS secondary malignancies. Since the rate of second malignancy per person-year of observation is similar in patients with follicular and all other lymphomas, this association is likely to be primarily due to longer survival in patients with follicular lymphoma, which allows more time for the development of solid tumors. However, it is difficult to rule out a small contribution from either the biology of follicular lymphoma (which may predispose to the development of second malignancies to a greater extent than other lymphomas) or from greater prior exposure to chemotherapy or XRT. The extent of prior therapy does affect the incidence of MDS/AML, but the effect on solid tumors is much less clear, particularly since the incidence of solid tumors in lymphoma patients treated with standard chemotherapy is close to background.29-31 Exposure to prior therapy is therefore unlikely to be a major culprit in the higher incidence of non-MDS malignancy, but rather longer survival and possibly a small contribution from the biology of follicular lymphoma.
In conclusion, NHL patients uniformly conditioned with cyclophosphamide and TBI for purged ABMT have a 21% rate of second malignant neoplasms at 10-year follow-up—approximately evenly divided between solid malignancies and MDS/AML. These malignancies have been responsible for the death of 9.6% of the patients, due primarily to the extremely poor outcome of MDS/AML, but with increasing recent deaths due to solid tumors. The increasing incidence of non-MDS malignancies without evidence of a plateau is likely to lead to a continued increase in the morbidity and mortality of solid tumors during the next decade of observation. This high and still increasing incidence of late second malignancies significantly increases the treatment-related mortality of ABMT, which has generally been thought to have the advantage of low mortality in comparison with allogeneic SCT. Systematic studies are needed to define the optimal screening and follow-up required to minimize the morbidity and mortality of second malignancies in long-term survivors of ABMT. Furthermore, given the known curative potential of ASCT in NHL and the still higher risks of allogeneic SCT, optimization of the ASCT procedure, including less toxic prior therapies, alternative conditioning regimens, and better understanding of the underlying biology, are needed to reduce long-term complications.
Authors’ Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
Acknowledgment
We are indebted to the nurses, medical oncology fellows, house staff, and social workers of the Dana-Farber Cancer Institute and Brigham and Women’s Hospital, for their excellent care of these patients. We thank the technicians of the Connell-O’Reilly Cell Manipulation Laboratory and the Blood Component Laboratory of the Dana-Farber Cancer Institute for processing of the bone marrow.
NOTES
Supported in part by the Clinical Investigator Training Program (J.R.B.): Harvard/Massachusetts Institute of Technology Health Sciences and Technology—Beth Israel Deaconess Medical Center, in collaboration with Pfizer Inc.
Presented in part at the Annual Meeting of the American Society of Hematology, San Diego, CA, December 8, 2003.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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