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Risk Factors Before Autologous Stem-Cell Transplantation for Lymphoma Predict for Secondary Myelodysplasia and Acute Myelogenous Leukemia

Matt Kalaycio, Lisa Rybicki, Brad Pohlman, Ronald Sobecks, Steven Andresen, Elizabeth Kuczkowski, Brian Bolwell

From the Departments of Hematology and Medical Oncology and Quantitative Health Sciences, The Cleveland Clinic Foundation, Taussig Cancer Center, Cleveland, OH

Address reprint requests to Matt Kalaycio, MD, 9500 Euclid Ave/R35, Cleveland, OH 44195; e-mail: kalaycm{at}ccf.org

	ABSTRACT

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PURPOSE: The risk factors for treatment-related myelodysplastic syndrome (t-MDS) and acute myelogenous leukemia (AML) after autologous stem-cell transplantation (ASCT) are similar to those that increase the risk of difficult stem-cell harvests. We reviewed our experience in 526 patients with lymphoma treated by ASCT to determine whether difficult stem-cell harvests predict for an increased risk of t-MDS/AML.

PATIENTS AND METHODS: Autologous peripheral stem cells were initially mobilized with granulocyte colony-stimulating factor (G-CSF; or granulocyte-macrophage colony-stimulating factor) alone (n = 334), etoposide and G-CSF (n = 166), or cyclophosphamide and G-CSF with or without etoposide (n = 26). Difficult harvests were those that required more than 5 days to collect enough stem cells and those that required additional attempts with etoposide and/or cyclophosphamide plus G-CSF (n = 52). All patients were then treated with high-dose chemotherapy alone and observed for outcome.

RESULTS: With a median follow-up time for surviving patients of 69 months, 20 patients developed t-MDS/AML, for an actuarial incidence of 6.8% at 10 years. Pretransplantation characteristics, including age, diagnosis of non-Hodgkin's lymphoma or Hodgkin's disease, bone marrow involvement, prior radiation therapy, prior exposure to chemotherapy, lactate dehydrogenase at the time of ASCT, disease status, and method of stem-cell mobilization, were then analyzed with respect to the subsequent development of t-MDS/AML. By multivariable analysis, prior exposure to radiation therapy, four or more chemotherapy regimens, and more than 5 days of apheresis needed to harvest enough stem cells were identified as independent risk factors for t-MDS/AML. Bootstrap analysis confirmed these results.

CONCLUSION: These results suggest that identifiable pretransplantation factors predict for t-MDS/AML after ASCT.

	INTRODUCTION

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The successful treatment of both Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) currently requires cytotoxic therapy that necessarily incurs a risk for subsequent clonal hematologic neoplasms. Treatment-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (AML) occurs after both standard and high-dose chemotherapy regimens with or without additional radiotherapy.¹ Recent evidence suggests that the cumulative incidence of t-MDS/AML is approximately 10% after treatment for lymphoma, whether or not high-dose chemo(radio)therapy is used.²

Risk factors for the development of t-MDS/AML after autologous stem-cell transplantation (ASCT) have been suggested by several studies. Heavily pretreated patients and patients exposed to long courses of alkylating agent chemotherapy consistently demonstrate a higher risk of t-MDS/AML.^3-6 The potential leukemogenic role of pre-ASCT radiation therapy for NHL is controversial,² but studies in patients with Hodgkin's lymphoma suggest a strong role for radiation in the pathogenesis of t-MDS/AML.⁷

The same factors that predict for subsequent t-MDS/AML after ASCT also predict for difficult stem-cell harvests before ASCT. Previous exposures to cytotoxic chemotherapy and radiation therapy adversely affect the ability to harvest peripheral-blood hematopoietic stem cells.^8-10 Despite difficulty collecting enough stem cells, once an adequate number of stem cells has been procured, ASCT may proceed with the expectation of normal hematopoietic recovery and a similar short-term survival as patients who have no difficulty collecting stem cells.^11,12 However, given the similar risk factors, patients with difficult stem-cell harvests may also have an increased risk of t-MDS/AML.

We have extensive experience with a non–total-body irradiation (TBI) –containing preparative regimen for ASCT and have used peripheral-blood stem cells (PBSCs) for hematopoietic reconstitution almost exclusively for the last 10 years.^8,13 We have reviewed our experience to better characterize the pre-ASCT factors that predict for subsequent t-MDS/AML.

	PATIENTS AND METHODS

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From January 1993 through December 2001, 526 adult patients with either HD or NHL were treated with ASCT at the Cleveland Clinic Foundation. Data regarding treatment received before ASCT were obtained from medical records provided to us by referring physicians either retrospectively or at the time of the initial patient evaluation. After ASCT, patient outcome data were captured prospectively and accessed through the Cleveland Clinic Transplant Center Unified Transplant Database. All patients were treated on clinical trials approved by the institutional review board of the Cleveland Clinic Foundation, and all patients provided signed informed consent.

Stem-Cell Harvesting and Processing
PBSCs were mobilized with granulocyte colony-stimulating factor (G-CSF) 10 µg/kg/d (n = 517; 94%) or granulocyte-macrophage colony-stimulating factor 250 µg/m² (n = 9; 2%) for 10 days beginning 5 days before leukapheresis. Beginning in January 1996, some stem cells were mobilized with the combination of chemotherapy (usually cyclophosphamide alone) and G-CSF in patients for whom PBSC harvesting was unsuccessful with G-CSF alone. Beginning in May 1998, nearly all stem cells were initially mobilized with etoposide 2 g/m² in addition to G-CSF to avoid the problem of difficult or inadequate PBSC harvest yields. Stem-cell harvesting began when the WBC count recovered to more than 5,000/µL after the etoposide-induced nadir.

After mobilization by any method, patients received standard leukapheresis on a COBE Spectra (Gambro, Lakewood, CO) machine for 5 days or until enough stem cells were collected. Before October 1995, a minimum total nucleated cell (TNC) dose of 10 x 10⁸/kg was required. After October 1995, the minimum CD34⁺ stem-cell dose needed to proceed to ASCT was 2 x 10⁶/kg. Patients who failed to achieve the minimum TNC or CD34⁺ stem-cell dose in 5 days were mobilized again by a different method. Patients initially mobilized with G-CSF alone were subsequently mobilized with chemotherapy plus G-CSF, and patients initially mobilized with chemotherapy were subsequently mobilized with high-dose G-CSF (16 to 30 µg/kg/d) alone. Leukapheresis was then attempted until the minimum TNC or CD34⁺ stem-cell dose was achieved or until the treating physician deemed that enough stem cells had been obtained. Patients who failed second mobilization or did not collect the minimal dose of TNC or CD34⁺ stem cells in the absence of a bone marrow harvest did not proceed to ASCT and are not included in this study.

Bone marrow was harvested in addition to mobilized PBSCs in 17 patients and was infused in all 17 patients. Before 1993, eight patients had bone marrow stored for future use, but at the time of relapse, PBSCs were also collected. In 1993, we routinely collected both marrow and PBSCs in seven patients until we were sure that our stem-cell collection technique was adequate. Bone marrow was harvested after a failed attempt at stem-cell mobilization in two patients.

Preparative Regimens
All patients were treated with the same preparative regimen. Oral busulfan 1 mg/kg was administered every 6 hours for 14 doses. Etoposide 50 to 60 mg/kg was administered as a continuous infusion over 2 days, and cyclophosphamide 60 mg/kg was administered intravenously over 2 hours on 2 consecutive days. The details of administration and supportive care have been previously described.¹³ G-CSF was administered to all patients to accelerate neutrophil recovery beginning on either the day after stem-cell infusion or 5 days after infusion.¹⁴

Follow-Up
After ASCT, patients were observed either at the Cleveland Clinic or at their local oncologist's office. Data regarding relapse and long-term complications were solicited at various intervals from the local oncologist's office and verified at the Cleveland Clinic whenever possible. The diagnosis of t-MDS/AML was made according to the histologic criteria of the French-American-British classification system¹⁵ and confirmed by the demonstration of clonal cytogenetic abnormalities whenever possible.

Statistical Analysis
Categoric variables are summarized as frequency counts and percentages; continuous variables are summarized as medians and ranges. The following 19 variables were analyzed as potential risk factors for t-MDS/AML: year of transplantation, age at transplantation, sex, race, diagnosis, bone marrow involvement at diagnosis, prior radiation therapy, number of prior chemotherapy regimens, exposure to fludarabine, stage, Eastern Cooperative Oncology Group performance status, elevated lactate dehydrogenase level at the time of transplantation, bulk of largest mass, disease status, mobilization regimen, need for salvage mobilization, days of apheresis, TNCs collected, and source of hematopoietic stem cells. Cox proportional hazards analysis was used to identify univariable and multivariable risk factors for t-MDS/AML. All variables, regardless of significance in univariable analysis, were analyzed in the multivariable analysis. A stepwise selection procedure was used with a variable entry criterion of P < .10 and a variable retention criterion of P < .05. Because only 20 patients developed t-MDS/AML and three risk factors were identified by multivariable analysis, the robustness of the model was questionable. To address this concern, the analysis was supplemented by bootstrap resampling variable selection.¹⁶ One thousand samples of size 526 were drawn with replacement from the original data. Stepwise Cox proportional hazards analysis was performed on each of the 1,000 samples using a variable entry criterion of P < .10 and a variable retention criterion of P < .05. Results for each of the 19 variables that were included in this analysis are summarized as the frequency of appearance in the 1,000 bootstrap analyses; variables with more than 50% inclusion in the 1,000 models were considered to be reliable prognostic factors for t-MDS/AML. All analyses were performed using SAS software (SAS Institute, Cary, NC). All statistical tests were two sided, and P < .05 was used to indicate statistical significance.

	RESULTS

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The characteristics of the 526 patients are listed in Table 1. Most of the 405 patients treated for NHL had either large-cell lymphoma (n = 228; 56%) or follicular lymphoma (n = 110; 27%) by the revised European-American classification of lymphoid neoplasms.¹⁷ However, we included large T-cell and peripheral T-cell lymphomas in the group of patients categorized as having large-cell lymphoma because they were largely treated identically.

PBSC harvesting followed G-CSF alone in 334 patients, etoposide and G-CSF in 166 patients, and cyclophosphamide with or without etoposide in combination with G-CSF in 26 patients (Table 2). Fifty-two patients experienced failure to mobilize enough stem cells with the initial attempt and were then mobilized with an alternative regimen (salvage mobilization). There was a higher rate of t-MDS/AML in patients who required salvage mobilization (P = .002). There were 126 patients (24%) who required more than five leukaphereses to collect an adequate number of CD34⁺ stem cells. There was also a higher rate of t-MDS/AML in patients who required greater than five leukaphereses (P < .001).

Fludarabine was administered to 42 patients before ASCT. No patients with HD were treated. Thirty-one patients (28%) with low-grade lymphoma were treated with fludarabine. Among the subset of NHL patients, there was no significant increased risk for t-MDS/AML in patients with low-grade NHL compared with patients with other histologies of NHL (P = .26), whereas fludarabine exposure remained a significant risk factor (P < .001). Furthermore, patients exposed to fludarabine were more likely to require more than five leukaphereses (P < .001) and more likely to require salvage stem-cell mobilization (P = .002). However, among 492 patients treated with less than four courses of chemotherapy before ASCT, 28 (5.7%) had received fludarabine, but among 34 patients treated with at least four courses of prior chemotherapy, 14 (41.2%) had received fludarabine. Thus, fludarabine exposure was correlated with the number of prior chemotherapy cycles administered.

Univariable risk factors for t-MDS/AML are listed in Table 3. In multivariable analysis, 5 or more days of apheresis, prior radiation therapy, and four or more prior chemotherapy regimens were found to be independent risk factors for the development of t-MDS/AML (Table 4; Fig 1). Bootstrap analysis identified the same three prognostic factors. Therefore, the risk factors that were identified as statistically significant by traditional analysis were confirmed by the bootstrap analysis. All analyses suggest that a difficult stem-cell harvest, which is defined by an inability to mobilize enough stem cells in 5 or fewer days of leukapheresis, is a risk factor for subsequent t-MDS/AML after adjusting for other known risk factors.

View larger version (11K): [in this window] [in a new window]   Fig 1. The risk of treatment-related myelodysplastic syndrome and acute myelogenous leukemia (t-MDS/AML) after autologous stem-cell transplantation is increased if (A) 5 or more days of leukapheresis is required to harvest enough stem cells, (B) prior radiation therapy is administered, or (C) four or more courses of chemotherapy are administered before autologous stem-cell transplantation.

	DISCUSSION

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In contrast to studies exploring the incidence of t-MDS/AML that include patients treated with either TBI- or non-TBI–based preparative regimens, none of our patients were treated with TBI. Some studies treating patients with either TBI- or non-TBI–based preparative regimens have implicated TBI as a risk factor for t-MDS/AML. Darrington et al²⁶ noted an increased risk of t-MDS/AML after ASCT in patients older than age 40 years and in patients treated with TBI. In that study, no patients with NHL treated without TBI developed t-MDS/AML, but the cumulative incidence for patients treated with TBI was 8% at 5 years (P = .03). Micallef et al²⁹ reported similar findings in a study of 3,205 patients reported to the European Group for Blood and Marrow Transplantation lymphoma registry. Hosing et al³⁰ also noted an increased risk for t-MDS/AML when TBI was used for ASCT in patients with NHL, particularly when combined with etoposide and cyclophosphamide. An increased risk for t-MDS/AML was noted by Metayer et al³¹ for patients treated with 13.2 Gy of TBI but not for patients treated at doses of 12 Gy or less. Although other studies have not implicated TBI as a risk factor for t-MDS/AML,^5,32 the low risk of t-MDS/AML noted after non-TBI regimens^22,33,34 argues against the application of TBI in the treatment of lymphoma with ASCT.

Our results also implicate local, subtotal radiation therapy administered before ASCT as a risk factor for t-MDS/AML. In the absence of ASCT, the risk of t-MDS/AML is also increased when radiation is administered with or without chemotherapy.^7,18,35-37 In a careful review, Armitage et al² concluded that pre-ASCT exposure to radiation does not significantly increase the risk of t-MDS/AML after ASCT for NHL. Whether the same holds true for patients with HD, who are generally treated with more radiation than patients with NHL, seems less certain.

Fludarabine has been implicated as a risk factor for difficult hematopoietic stem-cell harvests.^38-40 Micallef et al²⁹ further implicated fludarabine as a risk factor for t-MDS/AML after ASCT. In the absence of ASCT, fludarabine has also been implicated as a risk factor for t-MDS/AML.^41-44 Although fludarabine is typically administered only to patients with low-grade lymphomas, our analysis accounted for histology, and fludarabine remained a significant risk factor among patients with NHL. However, fludarabine exposure correlated with the number of chemotherapy cycles administered, and fludarabine did not remain a significant risk factor in multivariate analysis, whereas the number of prior cycles of chemotherapy did. Given the relatively favorable long-term outcome of patients with low-grade lymphomas treated by ASCT,³³ caution should be exercised before exposing patients to multiple cycles of chemotherapy when ASCT is being considered as a potential treatment option.

Some authors have suggested that mobilization strategies using etoposide might increase the risk of t-MDS/AML after TBI-containing preparative regimens.^32,45 Our data corroborate the observation of others indicating no apparent increased risk,^31,46 particularly when a non-TBI–containing preparative regimen is used. On the contrary, the high incidence of monosomy 7 in our patients with t-MDS/AML further implicates the use of alkylating agents and radiotherapy in the pathogenesis.

As might be expected from a review of known risk factors for both difficult stem-cell harvests and t-MDS/AML, we demonstrate that difficult stem-cell harvests predict for t-MDS/AML after ASCT. Clearly, though, an increased number of aphereses is not by itself likely to increase the risk of t-MDS/AML. More likely, a difficult stem-cell harvest serves as a marker for marrow that has already been damaged. Unfortunately, such a compromised marrow status cannot always be identified before harvesting by methods such as morphologic review or standard karyotypic analysis. Whether or not screening with fluorescent in situ hybridization for common clonal abnormalities such as monosomy 7 before ASCT will identify patients at risk remains to be determined.^47,48

Despite the known association of difficult stem-cell harvests with radiation therapy and previous exposure to repeated cycles of chemotherapy, our analysis controlled for these variables and still found that difficult stem-cell harvesting was independently associated with the risk of developing t-MDS/AML. The difficulty manifested as a requirement for more than five leukaphereses to collect enough stem cells to proceed. Because lymphoma patients at increased risk for t-MDS/AML can be identified by risk factors present before ASCT, they should be informed of their increased risk before the administration of additional cytotoxic therapy.

	Authors’ Disclosures of Potential Conflicts of Interest

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Brian Bolwell Amgen Inc (A) Amgen Inc (A)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Author Contributions

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Conception and design: Matt Kalaycio, Lisa Rybicki, Brian Bolwell Administrative support: Elizabeth Kuczkowski, Brian Bolwell Provision of study materials or patients: Matt Kalaycio, Brad Pohlman, Ronald Sobecks, Steven Andresen, Brian Bolwell Collection and assembly of data: Matt Kalaycio, Lisa Rybicki, Elizabeth Kuczkowski Data analysis and interpretation: Matt Kalaycio, Lisa Rybicki, Ronald Sobecks, Brian Bolwell Manuscript writing: Matt Kalaycio, Lisa Rybicki, Brad Pohlman, Ronald Sobecks, Brian Bolwell Final approval of manuscript: Matt Kalaycio, Lisa Rybicki, Brad Pohlman, Ronald Sobecks, Brian Bolwell

 

	ACKNOWLEDGMENTS

 
We are indebted to the nurses and staff of the Cleveland Clinic's Bone Marrow Transplant Program and M50 for their hard work and dedication.

	NOTES

 
Presented in part at the 45th Annual Meeting of the American Society of Hematology, San Diego, CA, December 6-9, 2003.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 5, 2006; accepted May 26, 2006.

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