This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friedberg, J. W. Articles by Freedman, A. S. Search for Related Content PubMed PubMed Citation Articles by Friedberg, J. W. Articles by Freedman, A. S. Social Bookmarking                            What's this?

Outcome in Patients With Myelodysplastic Syndrome After Autologous Bone Marrow Transplantation for Non-Hodgkin's Lymphoma

From the Divisions of Adult Oncology and Biostatistics, Dana-Farber Cancer Institute; Departments of Medicine and Radiation Therapy, Brigham and Women's Hospital; and Departments of Medicine and Radiation Oncology, Harvard Medical School, Boston, MA.

Address reprint requests to Arnold S. Freedman, MD, Division of Adult Oncology, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115; email arnold_freedman{at}dfci.harvard.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: The absolute risk of myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for non–Hodgkin's lymphoma (NHL) exceeds 5% in several reported series. We report the outcome of a large cohort of patients who developed MDS after ABMT for NHL.

PATIENTS AND METHODS: Between December 1982 and December 1997, 552 patients underwent ABMT for NHL, with a uniform ablative regimen of cyclophosphamide and total body irradiation followed by reinfusion of obtained marrow purged with monoclonal antibodies. MDS was strictly defined, using the French-American-British classification system, as requiring bone marrow dysplasia in at least two cell lines, with associated unexplained persistent cytopenias.

RESULTS: Forty-one patients developed MDS at a median of 47 months after ABMT. The incidence of MDS was 7.4%, and actuarial incidence at 10 years is 19.8%, without evidence of a plateau. Patients who developed MDS received significantly fewer numbers of cells reinfused per kilogram at ABMT (P = .0003). Karyotypes were performed on bone marrow samples of 33 patients, and 29 patients had either del(7) or complex abnormalities. The median survival from diagnosis of MDS was 9.4 months. The International Prognostic Scoring System for MDS failed to predict outcome in these patients. Thirteen patients underwent allogeneic BMT as treatment for MDS, and all have died of BMT-related complications (11 patients) or relapse (two patients), with a median survival of only 1.8 months.

CONCLUSION: Long-term follow-up demonstrates a high incidence of MDS after ABMT for NHL. The prognosis for these patients is uniformly poor, and novel treatment strategies are needed for this fatal disorder.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
THE USE OF HIGH-DOSE therapy and autologous stem-cell transplantation (ASCT) has been shown to improve both disease-free and overall survival for selected patients with relapsed diffuse aggressive non–Hodgkin's lymphoma (NHL).¹ Selected patients with indolent lymphoma also experience extended disease-free with high-dose therapy compared with historical controls.^2,3 Although the acute treatment-related mortality with autotransplantation is now well below 5% in most series, with longer survival, late complications potentially become more significant causes of morbidity and mortality. Myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (AML) have emerged as major late complications of ASCT, particularly in patients with lymphoma, with actuarial risk at 10 years exceeding 10% in several series.^4-8

The International Prognostic Scoring System has found the prognosis of patients with primary MDS to depend on several factors, including karyotype, percentage of bone marrow blasts, and number of peripheral cytopenias.⁹ The only potentially curative therapy for primary MDS is allogeneic transplantation, which, if performed early in selected young patients, may have a favorable impact on overall survival.^10,11 MDS and AML that occur after chemotherapy or radiation exposure have a worse prognosis than primary disease.^12,13 Although allogeneic transplantation has also been used in patients with treatment-related MDS,higher relapse rates have been observed in this patient population.^14,15

The long-term prognosis and outcome of MDS after ASCT for lymphoma is largely unknown. Two forms of the disease have been identified, an "indolent" form manifested by persistent cytopenias years after transplant with or without clonal cytogenetic changes and an "aggressive" form with dysplasia in multiple cell lines, which, in short-term follow-up, behaves like other therapy-related MDS.¹⁶ In the present study, we report the follow-up of a large cohort of patients who developed "aggressive" MDS, defined by strict criteria, after autologous bone marrow transplantation (ABMT) for B-cell NHL. The estimated incidence for the development of post-ABMT MDS was 19.8% at 10 years. Risk factors for the development of MDS and prognostic factors for survival were also investigated. Finally, we describe the uniformly poor prognosis for these patients, including the outcome of allogeneic BMT as therapy for MDS after ABMT.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Selection of Patients and Treatment Protocol
Between 1982 and 1997, 552 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.^17,18 Patients were eligible for these ABMT protocols if they were younger than 65 years of age (physiologic) and either relapsed after standard chemotherapeutic regimens or had high-risk primary disease in first remission, as previously described.^3,19-24 For all patients, a minimal disease status had to be attained through chemotherapy, radiotherapy, or both before entry, as previously defined.²⁰ All protocols were approved by the Dana-Farber Cancer Institute Institutional Review Board, and informed consent was obtained before therapy.

Preparative therapy consisted of cyclophosphamide 60 mg/kg of body weight infused on each of 2 consecutive days before total-body irradiation (TBI). Before 1994, TBI was administered in fractionated doses (2 Gy) twice daily on 3 consecutive days (total of 12 Gy) in all but two patients. After 1994, all patients received seven fractions (14 Gy). Supportive care was provided, as previously described.²¹

Collection, Processing, and Infusion of Marrow
Bone marrow was obtained, treated in vitro with one or more antiB-cell monoclonal antibodies and rabbit complement, and cryopreserved, as previously described.²¹ Cells were rapidly thawed within 24 hours of the completion of radiotherapy and diluted in medium containing DNAase, as previously described.²¹

Follow-Up
All patients had routine physical examinations and laboratory studies, including complete blood cell count, after transplantation every 3 months for the first year, then every 6 months for the second year, then annually. Patients underwent bone marrow aspiration and core biopsy for persistently low peripheral counts without an alternative explanation.

Classification of MDS
For the purposes of this study, MDS was strictly defined using the French-American-British (FAB) classification system and required bone marrow dysplasia in at least two cell lines, peripheral cytopenias, and the following blast counts in the bone marrow on review of aspirate smears: refractory anemia (RA), less than 5% blasts; refractory anemia with excess of blasts (RAEB), 5% to 20% blasts; refractory anemia with excess of blasts in transformation (RAEBT), 21% to 30% blasts; AML, more than 30% blasts; and refractory anemia with ringed sideroblasts (RARS), less than 5% blasts with more than 15% erythroid cells with ringed sideroblasts on iron stain.^9,25 Cytopenias are defined as a hemoglobin level of less than 10 g/dL, an absolute neutrophil count of less than 1,500/µL, and a platelet count of less than 100,000/µL. Patients with persistent cytopenias 6 months after transplant without significant marrow dysplasia were not included in the analysis as having MDS. Patients with an alternative explanation for cytopenias were also excluded. Cytogenetic analysis of bone marrow aspirates was performed at the discretion of the treating physician.

Evaluation and Statistical Methods
The primary end point for this analysis was the diagnosis of MDS, as described above. The time to diagnosis of MDS was measured from date of autologous transplant for NHL to date of diagnosis for patients who developed MDS. Patients who did not develop MDS were censored at death or at the date last known alive. Similar definitions were used for survival after the diagnosis of MDS. The Kaplan-Meier method was used to assess the cumulative incidence of MDS; confidence intervals (CIs) used Greenwood's formula for the calculation of SE.^26,27 The log-rank test was used to compare survival after diagnosis of MDS among subgroups of patients. Univariate analyses of factors that might be associated with the development of MDS were performed using the Wilcoxon rank sum test for continuous variables and Fisher's exact test for categorical variables. Logistic regression was used to investigate potential models for predicting the development of MDS.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics
Of 552 patients who underwent ABMT for B-cell NHL between 1982 and 1997, 322 were male; the median age was 44 years (range, 19 to 66 years). The histologies of these patients included indolent NHL (311 patients) and aggressive NHL (241 patients). Ninety-six patients underwent transplantation in first remission for indolent lymphoma, and 31 patients underwent transplantation in first remission for aggressive lymphoma after treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) as their only chemotherapy. The remainder of patients had relapsed or had disease that was refractory to initial chemotherapy. One hundred ninety patients were in complete remission (CR) at ABMT; 362 patients were in a minimal disease state. Ninety-nine patients received involved-field radiation therapy to sites of bulk disease before ABMT. Of these 552 patients, 351 remain alive, with a median follow-up time of 75 months.

Forty-one patients (27 males and 14 females) subsequently have developed MDS, as defined by strict FAB criteria.²⁵ The characteristics of these patients at the time of ABMT are summarized in Table 1. At the time of ABMT, the median age of these 41 patients was 46 years (range, 23 to 66 years). Histology of NHL at ABMT included 22 patients with follicular lymphoma, 17 patients with diffuse aggressive lymphoma, including four patients who presented initially with indolent NHL that had transformed to a more aggressive histology before ABMT, and two patients with mantle-cell lymphoma.

Prior Therapy
All patients who subsequently developed MDS received combination chemotherapy before transplant. Eleven patients, seven with follicular NHL and four with diffuse large B-cell NHL, underwent ABMT in first remission after receiving initial induction therapy with CHOP in standard doses (n = 9), CHOP + etoposide (CHOPE) (n = 1), or dose-escalated cyclophosphamide (n = 1). The remainder of the patients underwent transplantation in second or greater remission after receiving a median of three combination chemotherapy regimens (range, 2 to 5 regimens). Fourteen patients received etoposide at some point before ABMT. Sixteen patients received radiation to sites of disease before ABMT, and one patient received 1.5 Gy of TBI as therapy for follicular NHL 10 years before ABMT.

Autologous Transplant
The dose of TBI at transplant in the patients who subsequently developed MDS was 8.5 Gy in one patient, 10 Gy in one patient, 12 Gy in 36 patients, and 14 Gy in three patients. After bone marrow reinfusion, a granulocyte or granulocyte-macrophage colony-stimulating factor was administered to 24 of the 41 patients.

Diagnosis of MDS
At initial diagnosis of MDS, there were 19 patients with RA, 11 with RAEB, six with RAEBT or AML, and five with RARS (Table 2). Bone marrow cytogenetic data were available on 33 patients. According to criteria proposed by the International Prognostic Scoring System for MDS,⁹ four patients had a good prognosis karyotype, including one with del(20q), one with del(5q), and two normals. The remaining patients with available cytogenetics had poor prognosis karyotypes, including 14 with del(7) and 15 patients with complex abnormalities. The median time from ABMT to a diagnosis of MDS was 47 months (range, 12 to 129 months). At time of diagnosis of MDS, 29 patients were in remission and 12 patients had relapsed with NHL; the majority of these patients had not received further cytotoxic therapy since transplant. The absolute risk of developing MDS after ABMT for NHL was 7.4%. The Kaplan-Meier estimate of the risk of development of MDS at 8 years was 14.7% (90% CI, 10.59% to 18.9%), and 19.8% at 10 years (90% CI, 13.7% to 25.9%) (Fig 1).

View larger version (8K): [in this window] [in a new window]   Fig 1. Time to MDS after BMT. Inverse Kaplan-Meier estimate of the probability of MDS for 552 patients with NHL, after ABMT.

Outcome
Of the 41 patients with MDS, 34 have died of complications of MDS or treatment of underlying MDS. As of June 1999, seven patients remain alive with a median follow-up time of 8.3 months (range, 1 to 13 months). The median survival time from time of ABMT is 62 months (range, 13 to 132 months), and 9.3 months from the diagnosis of MDS (range, 1 to 26 months). The Kaplan-Meier estimate of the overall survival rate at 12 months after diagnosis of MDS is 32% (90% CI, 19% to 45%) (Fig 2).

View larger version (9K): [in this window] [in a new window]   Fig 2. Survival after MDS diagnosis. Kaplan-Meier estimate of probability of overall survival for 41 patients diagnosed with MDS after ABMT for NHL.

Thirteen patients underwent allogeneic BMT (Table 3). The FAB classification of these patients includes three patients with RA, five with RAEB, one with RAEBT, two with AML, and two with RARS. Six patients received T-cell–depleted grafts from HLA-matched siblings,²⁸ whereas five received matched unrelated donor grafts, one of which was T-cell depleted. One patient received a T-cell–depleted haplo-mismatched sibling donor graft, and one patient underwent a nonmyeloablative peripheral-blood stem-cell transplant from a matched sibling donor. The ablative regimen in the T-cell–depleted, matched related transplants consisted of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). Patients who received unmanipulated donor marrow also received busulfan and cyclophosphamide conditioning and a variety of regimens for graft-versus-host disease (GVHD) prophylaxis. The one patient who received a T-cell–depleted haplo-identical transplant was conditioned with busulfan, thiotepa, cyclophosphamide, and high-dose methylprednisolone. The characteristics of the patients who underwent allogeneic BMT were similar to the entire group of MDS patients, with no significant differences in age, histology, or previous therapy. All 13 of these patients died after allogeneic transplant, including 10 within the first 100 days after transplant (Table 3). Causes of death included sepsis in seven patients, hepatic veno-occlusive disease in two patients, and diffuse alveolar hemorrhage syndrome in one patient. Three patients died later, two of relapsed AML and one of chronic graft-versus-host disease. The median survival time from the diagnosis of MDS for the patients who underwent allogeneic BMT was 10.7 months and 1.8 months from the time of allogeneic transplant. There was no statistical difference in survival from ABMT (P = .19) or from diagnosis of MDS (P = .62) between those patients who received an allogeneic BMT and those who did not.

Twenty-eight patients did not undergo allogeneic transplantation for MDS. Detailed follow-up information is available for 23 of these patients. Seven received chemotherapy for MDS, including cytarabine, daunorubicin, or hydroxyurea. The remaining patients were treated with supportive care, including hematopoietic growth factors, transfusions, vitamin supplementation, and antibiotics. Two patients received brief pulses of corticosteroid therapy.

Predictors of MDS
Several variables, including disease status at transplant, patient age and sex, histology of lymphoma, race of patients, number of prior regimens of chemotherapy for NHL, interval from diagnosis of NHL to ABMT, radiation before ABMT, platelet count at ABMT, number of bone marrow cells harvested, and number of bone marrow mononuclear cells infused per kilogram at ABMT, were examined in univariate analysis to identify a subset of patients at increased risk of developing MDS. The median number of cells infused per kilogram at ABMT and radiation therapy before ABMT were the only variables that differed between those patients who did and those patients who did not subsequently develop MDS. For the group of 511 patients who underwent transplantation for NHL who did not develop MDS, the median number of cells reinfused was 3.95 x 10⁷ cells/kg. For those who subsequently developed MDS, the median number of mononuclear cells reinfused was 2.92 x 10⁷ cells/kg. This difference reached statistical significance (P = .0003). The median number of cells/kg harvested was 16.12 x 10⁹ for those patients who did not develop MDS and 14.74 x 10⁹ cells/kg for those who developed MDS. This difference did not meet statistical significance (P = .13). The number of CD34⁺ cells/kg was not enumerated for these patients. Sixteen (39%) of the 41 MDS patients received radiation therapy before ABMT compared with 86 (17%) of the 511 patients who did not develop MDS (P = .03).

A logistic regression model was designed to predict who would develop MDS. Candidate variables were prior radiation therapy, sex, age, race, histology at transplant, and median number of cells per kilogram. Again, median number of cells infused per kilogram and prior radiation therapy were the only significant predictors of subsequent MDS. The incidence of MDS was lower for patients who received 14 Gy of TBI (three of 104 patients) compared with other doses (P = .09). However, follow-up for patients receiving 14 Gy was significantly shorter.

Prognosis of MDS
In an attempt to identify prognostic variables for these patients, a number of factors, including FAB classification, cytogenetic karyotype, and the International Prognostic Score for MDS, were examined in univariate comparison of overall survival using the log-rank test. There was no significant difference in survival from ABMT or diagnosis of MDS of patients with RA, RARS, and RAEB who underwent transplantation compared with RAEBT and AML patients (P = .36). The del(7) is associated with a poor prognosis in de novo MDS, and the median survival time from diagnosis of MDS of 14 patients with del(7) was 7.9 months compared with 9.6 months for 19 patients without del(7) (P = .82). For the 33 patients with available cytogenetics who developed MDS, the International Prognostic Score was not predictive of MDS outcome (P = .29) (Table 4).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MDS and AML are well-recognized long-term complications of chemotherapy, specifically DNA-damaging agents. The peak incidence of MDS occurs 4 to 6 years after the initiation of cytotoxic therapy, although latency periods as short as 12 months and as long as 15 to 20 years have been reported.¹³ A large body of data supports a positive relationship between the cumulative dose of alkylating agents or topoisomerase II inhibitors and the risk of developing secondary AML.^29-32 An increased incidence of leukemia has also been linked to previous radiation exposure.^33,34 In one series of patients treated with low-dose TBI for NHL, the 15-year estimated cumulative incidence of MDS was 17%.³⁵ All of these patients were also treated with cytotoxic chemotherapy, suggesting that combined-modality therapy significantly increases the incidence of subsequent stem-cell disorders.

Defining MDS after ASCT is complicated because many patients have prolonged cytopenias after transplantation without evidence of subsequent transformation to AML. Traweek et al³⁶ described 10 patients with clonal chromosomal abnormalities that developed after ASCT for Hodgkin's disease and NHL, five of whom did not have a syndrome consistent with clinical MDS. Morphologic analysis and follow-up of these patients has revealed two distinct patterns of MDS after ASCT: an aggressive form, with marrow dysplasia, typical cytogenetic changes, and rapid transformation to leukemia, and a more indolent form associated with transient cytogenetic changes and minimal intermittent marrow dysplasia. Unlike the aggressive form, indolent MDS changes do not necessarily progress to leukemic transformation even after years of follow-up and, in fact, revert to normal in some cases. In the present study, the incidence and median time to develop aggressive MDS were similar to those reported in the other series, with actuarial rates at 10 years of almost 20% without evidence of a plateau with prolonged follow-up.

Several studies have reported the development of MDS after ASCT for NHL where the cumulative 5-year incidence ranged from 8% to 14%.^5-7 Similar to the present series, the median time from ASCT to a diagnosis of MDS in these reports was approximately 3.5 years. When cytogenetics were performed, virtually all patients had abnormalities of chromosome 5 and/or 7 or complex abnormalities.^5,6 Previous cytogenetic studies have also demonstrated more numerous abnormalities in patients with secondary MDS who received radiation compared with those who only received chemotherapy before developing MDS.³⁷ Although the present series only included patients who received TBI-containing ablative regimens, the majority of reported posttransplant MDS patients have also received TBI. This is in contrast to the estimated incidence of MDS in series of patients with breast cancer who underwent ASCT with chemotherapy-only conditioning; the risk was lower, only 3% at 5 years.^38-40

Two recently reported series have examined clinical risk factors for subsequent development of MDS after ASCT. Almost 5,000 patients with lymphoma have undergone ASCT in the European Bone Marrow Transplant Registry, and only 68 patients developed MDS.⁴¹ This incidence is lower than other series; however, the median follow-up in this registry series was only 3 years. Multivariate analysis revealed age at transplant, TBI conditioning, long interval between diagnosis of lymphoma and transplant, and low-grade histology as independent variables predicting for subsequent MDS. The amount of previous chemotherapy, including alkylating agent exposure, was not found to be a significant factor. In another series from the City of Hope Cancer Center, none of these factors were found to be predictive in 22 patients who developed MDS after ASCT for NHL and Hodgkin's disease.⁴² In that series, pre-BMT exposure to topoisomerase II inhibitors increased the risk of MDS with chromosomal 11q23 abnormalities.

In our series, patients who developed MDS received a significantly lower median number of cells reinfused than the entire group of patients despite the similar total number of cells harvested. Furthermore, involved field radiotherapybefore ABMT increased the risk of MDS. Stem-cell exhaustion and depletion has been elicited in vitro by serial transplantation of bone marrow into lethally irradiated mice and exposure of bone marrow to combinations of cytotoxic drugs and cytokines.^43-46 In the setting of low-stem cell number, reconstitution of bone marrow clearly represents a great proliferative stress, which may increase susceptibility to irreversible DNA damage associated with MDS. Alternatively, the lower mononuclear stem-cell number infused may be a surrogate marker for marrow stem-cell damage before ABMT. Prospective studies will be needed to evaluate this issue further, but ensuring adequate numbers of CD34 cells before transplant may decrease subsequent incidence of MDS. Limiting local radiotherapy may also decrease the risk of development of MDS.

Allogeneic BMT is the only potentially curative therapy for patients with primary MDS.^10,11,47 Cytogenetics, according to the International Prognostic Scoring System, have been found to strongly predict outcome of allogeneic BMT in patients with primary MDS.⁴⁸ In a series from Vancouver, Canada only 6% of patients with primary MDS and poor-risk cytogenetics were alive and in remission 7 years after allogeneic BMT.⁴⁸ Data on allogeneic BMT for patients with secondary AML from previous chemotherapy exposure are limited, but in the largest series from Seattle, WA, the 5-year disease-free survival was only 7.8%.¹⁴

The current series is the only published experience of allogeneic BMT for MDS after ASCT for NHL. All 13 patients died, the majority as a complication of transplant and only two of relapsed AML. Clearly, allogeneic BMT, even with selective T-cell depletion, does not represent a viable salvage option for MDS after ASCT because of conditioning-related mortality. These patients may be good candidates for nonmyeloablative conditioning regimens and subsequent donor lymphocyte infusions to immunologically ablate residual dysplastic clones.⁴⁹

The lack of effective therapy for this fatal syndrome emphasizes the importance of further investigation into the pathogenesis of MDS after ASCT and the need to identify features that predict patients at risk. It remains unknown whether MDS arises from reinfused damaged stem cells or is a direct result of conditioning therapy. Clonal hematopoiesis detected by X-linked clonality analysis after ABMT has been shown to predict the development of MDS, although a significant proportion of NHL patients have clonal hematopoiesis at the time of transplant.^50,51 Telomere length in stem cells has been shown to be abnormal in primary MDS and after ASCT in a variety of settings.^52,53 Critically shortened telomeres result in an increased incidence of cellular cytogenetic abnormalities and have been hypothesized to contribute to leukemic transformation.⁵⁴ Patients with abnormally shortened telomeres from cytotoxic chemotherapy, before ASCT or as a result of ASCT, need to be evaluated prospectively to determine a potentially increased risk of subsequent MDS.

In conclusion, long-term follow-up of a large group of patients confirms the preliminary reports of a high incidence of MDS as a late complication of ASCT for NHL. The prognosis of these patients is uniformly poor, and allogeneic BMT, as presently performed, is not a salvage treatment option because of excessive toxicity in this patient population. TBI combined with cytotoxic therapy as conditioning seems to increase the risk of MDS. These sobering results mandate investigation into alternative conditioning regimens, as well as the molecular genetics of these disorders, in an attempt to prevent this devastating complication.

	ACKNOWLEDGMENTS

 
Supported by National Institutes of Health grant no. CA66996

We thank the nurses, adult oncology fellows, and social workers of the Dana-Farber Cancer Institute and the medical housestaff of the Brigham and Women's Hospital and Beth Israel Hospital for their excellent care of these patients. The hematopathology section at the Brigham and Women's Hospital reviewed every bone marrow biopsy specimen. Aspirate smears were reviewed by Pearl Leavitt at Dana-Farber. We particularly thank Ramana Tantravahi, MD, and his staff at the Dana-Farber Cancer Institute cytogenetics laboratory for processing the specimens and collating the reports. We also thank the technicians of the Connell-O'Reilly Cell Manipulation Laboratory and the Blood Component Laboratory of Dana-Farber Cancer Institute for processing the bone marrows.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Philip T, Guglielmi C, Hagenbeek A, et al: Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med333:1540-1545, 1995[Abstract/Free Full Text]

2. Rohatiner A, Johnson P, Price C, et al: Myeloablative therapy with autologous bone marrow transplantation as consolidation therapy for recurrent follicular lymphoma. J Clin Oncol12:1177-1124, 1994[Abstract/Free Full Text]

3. Freedman A, Neuberg D, Mauch P, et al: Long term followup of autologous bone marrow transplantation in patients with relapsed follicular lymphoma. Blood (in press)

4. Stone R, Neuberg D, Soiffer R, et al: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol12:2535-2542, 1994[Abstract/Free Full Text]

5. Miller J, Arthur D, Litz C, et al: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy. Blood83:3780-3786, 1994[Abstract/Free Full Text]

6. Darrington D, Vose J, Anderson J, et al: Incidence and characterization of secondary myelodysplastic syndrome following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol12:2527-2534, 1994[Abstract/Free Full Text]

7. Anderson J, Vose J, Kessinger A: Myelodysplastic syndrome after autologous transplant for lymphoma. Blood84:3988-3989, 1994[Free Full Text]

8. Stone R: Myelodysplastic syndrome after autologous transplantation for lymphoma: The price of progress? Blood83:3437-3440, 1994[Free Full Text]

9. Greenberg P, Cox C, LeBeau M, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood89:2079-2088, 1997[Abstract/Free Full Text]

10. Sutton L, Chastang C, Ribaud P, et al: Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: A long-term study of 71 patients. Blood88:358-365, 1996[Abstract/Free Full Text]

11. Runde V, de Witte T, Arnold R, et al: Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: Early transplantation is associated with improved outcome. Bone Marrow Transplant21:255-261, 1998[Medline]

12. Levine E, Bloomfield C: Leukemias and myelodyplastic syndromes secondary to drug, radiation, and environmental exposures. Semin Oncol19:47-84, 1992[Medline]

13. Karp J, Smith M: The molecular pathogenesis of treatment-induced (secondary) leukemias: Foundations for treatment and prevention. Semin Oncol24:103-113, 1997[Medline]

14. Anderson J, Gooley T, Schoch G, et al: Stem cell transplantation for secondary acute myeloid leukemia: Evaluation of transplantation as initial therapy or following induction chemotherapy. Blood89:2578-2585, 1997[Abstract/Free Full Text]

15. Ballen K, Gilliland D, Guinan E, et al: Bone marrow transplantation for therapy-related myelodysplasia: Comparison with primary myelodysplasia. Bone Marrow Transplant20:737-743, 1997[Medline]

16. Wilson C, Traweek S, Slovak M, et al: Myelodysplastic syndrome occurring after autologous bone marrow transplantation for lymphoma: Morphologic features. Am J Clin Pathol108:369-377, 1997[Medline]

17. National Cancer Institute sponsored study of classification of non-Hodgkin's lymphomas: Summary and description of a working formulation for clinical usage—The non-Hodgkin's lymphoma classification project. Cancer49:2112-2135, 1982[Medline]

18. Harris N, Jaffe E, Stein H, et al: Perspective: A revised European American classification of lymphoid neoplasm—A proposal from the International Lymphoma Study Group. Blood84:1361-1392, 1994[Free Full Text]

19. Takvorian T, Canellos GP, Ritz J, et al: Prolonged disease-free survival after autologous bone marrow transplantation in patients with non-Hodgkin's lymphoma with poor prognosis. N Engl J Med316:1499-1505, 1987[Abstract]

20. Freedman AS, Takvorian T, Anderson KC, et al: Autologous bone marrow transplantation in B-cell non-Hodgkin's lymphoma: Very low treatment-related mortality in 100 patients in sensitive relapse. J Clin Oncol8:1-8, 1990[Free Full Text]

21. 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. Blood77:2524-2529, 1991[Abstract/Free Full Text]

22. Freedman A, Takvorian T, Neuberg D, et al: Autologous bone marrow transplantation in poor-prognosis intermediate-grade and high-grade B-cell non-Hodgkin's lymphoma in first remission: A pilot study. J Clin Oncol11:931-936, 1993[Abstract/Free Full Text]

23. Freedman A, Gribben J, Neuberg D, et al: High dose therapy and autologous bone marrow transplantation in patients with follicular lymphoma during first remission. Blood88:2780-2786, 1996[Abstract/Free Full Text]

24. Freedman A, Neuberg D, Mauch P, et al: Cyclophosphamide, doxorubicin, vincristine, prednisone dose intensification with granulocyte colony-stimulating factor markedly depletes stem cell reserve for autologous bone marrow transplantation. Blood90:4996-5001, 1997[Abstract/Free Full Text]

25. Bennett J, Catovsky D, Daniel M, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol51:189-199, 1982[Medline]

26. Kaplan E, Maier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc53:457-481, 1958

27. Mantel N: Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep50:163-170, 1966[Medline]

28. Soiffer R, Murray C, Mauch P, et al: Prevention of graft-versus-host-disease by selective depletion of CD6 positive T lymphocytes from donor bone marrow. J Clin Oncol7:1191-1200, 1992

29. Tucker M, Meadows A, Boice J: Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst78:459-464, 1987

30. Kaldor J, Day N, Clarke E: Leukemia following Hodgkin's disease. N Engl J Med322:7-13, 1990[Abstract]

31. Kaldor J, Day N, Pettersson F: Leukemia following chemotherapy for ovarian cancer. N Engl J Med322:1-6, 1990[Abstract]

32. Ratain M, Rowley J: Therapy related acute myeloid leukemia secondary to inhibitors of topoisomerase II: From the bedside to target genes. Ann Oncol3:107-111, 1992[Abstract/Free Full Text]

33. Kodama K, Mabuchi K, Shigematsu I: A long-term cohort study of the atomic bomb survivors. J Epidemiol6:95-105, 1996

34. Greaver M: Aetiology of acute leukemia. Lancet349:344-349, 1997[Medline]

35. Travis L, Weeks J, Curtis R, et al: Leukemia following low-dose total body irradiation and chemotherapy for non-Hodgkin's lymphoma. J Clin Oncol14:565-571, 1996[Abstract/Free Full Text]

36. Traweek S, Slovak M, Nadamanee A, et al: Clonal karyotypic hematopoietic cell abnormalities occurring after autologous bone marrow transplantation for Hodgkin's disease and Non-Hodgkin's lymphoma. Blood84:957-963, 1994[Abstract/Free Full Text]

37. Whang-Peng J, Young R, Lee E, et al: Cytogenetic studies in patients with secondary leukemia/dysmyelopoietic syndrome after different treatment modalities. Blood71:403-414, 1988[Abstract/Free Full Text]

38. Wheeler C, Khurshid A, Ibrahim J, et al: Low incidence of post-transplant myelodysplasia/acute leukemia in NHL patients autotransplanted after cyclophosphamide, carmustine, and etoposide. Blood 90:385b, 1997 (abstr)

39. Laughlin M, McGaughey D, Crews J, et al: Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant. J Clin Oncol16:1008-1012, 1998[Abstract]

40. Roman-Unfer R, Bitran J, Hanauer S, et al: Acute myeloid leukemia and myelodysplasia following intensive chemotherapy for breast cancer. Bone Marrow Transplant16:163-168, 1995[Medline]

41. Milligan D, Ruiz de Elvira M, Goldstone A, et al: Secondary leukemia and myelodysplasia after auto-grafting for lymphoma: Results from the EBMT. Blood 92:439a, 1998 (abstr)

42. Krishnan AS, Bhatia R, Slovak M, et al: Risk factors for development of therapy-related leukemia (t-MDS/t-AML) following autologous transplantation (ABMT) for lymphoma. Blood 92:493a, 1998 (abstr)

43. Siminovitch L, Till J, McCulloch E: Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J Cell Comp Physiol64:23-32, 1964

44. Mauch P, Rosenblatt M, Hellman S: Permanent loss in stem cell self renewal capacity following stress to the marrow. Blood72:1193-1196, 1988[Abstract/Free Full Text]

45. Mauch P, Hellman S: Loss of hematopoietic stem cell self-renewal after bone marrow transplantation. Blood74:872-875, 1989[Abstract/Free Full Text]

46. Hornung R, Longo DL: Hematopoietic stem cell depletion by restorative growth factor regimens during repeated high-dose cyclophosphamide therapy. Blood80:77-83, 1992[Abstract/Free Full Text]

47. Arnold R, de Witte T, van Biezen A, et al: Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: An EBMT survey. Bone Marrow Transplant21:1213-1216, 1998[Medline]

48. Nevill T, Fung H, Shepherd J, et al: Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood92:1910-1917, 1998[Abstract/Free Full Text]

49. Khouri I, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol16:2817-2824, 1998[Abstract]

50. Legare R, Gribben J, Maragh M, et al: Prediction of therapy-related acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) after autologous bone marrow transplant (ABMT) for lymphoma. Am J Hematol56:45-51, 1997[Medline]

51. Mach-Pascual S, Legare R, Lu D, et al: Predictive value of clonality assays in patients with non-Hodgkin's lymphoma undergoing autologous bone marrow transplant: A single institution study. Blood91:4496-4503, 1998[Abstract/Free Full Text]

52. Boultwood J, Fidler C, Kusec R, et al: Telomere length in myelodysplastic syndromes. Am J Hematol56:266-271, 1997[Medline]

53. Engelhardt M, Ozkaynak M, Drullinsky P, et al: Telomerase activity and telomere length in pediatric patients with malignancies undergoing chemotherapy. Leukemia12:13-24, 1998[Medline]

54. Ball S, Gibson F, Rizzo S, et al: Progressive telomere shortening in aplastic anemia. Blood91:3582-3592, 1998[Abstract/Free Full Text]

Submitted April 14, 1999; accepted July 22, 1999.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				R. M. Stone How I treat patients with myelodysplastic syndromes Blood, June 18, 2009; 113(25): 6296 - 6303. [Full Text] [PDF]

				S. Chakraborty, C.-L. Sun, L. Francisco, M. Sabado, L. Li, K. L. Chang, S. Forman, S. Bhatia, and R. Bhatia Accelerated Telomere Shortening Precedes Development of Therapy-Related Myelodysplasia or Acute Myelogenous Leukemia After Autologous Transplantation for Lymphoma J. Clin. Oncol., February 10, 2009; 27(5): 791 - 798. [Abstract] [Full Text] [PDF]

				J. W. Friedberg Secondary malignancies after therapy of indolent non-Hodgkin's lymphoma Haematologica, March 1, 2008; 93(3): 336 - 338. [Full Text] [PDF]

				J. W. Friedberg, P. Cohen, L. Chen, K. S. Robinson, A. Forero-Torres, A. S. La Casce, L. E. Fayad, A. Bessudo, E. S. Camacho, M. E. Williams, et al. Bendamustine in Patients With Rituximab-Refractory Indolent and Transformed Non-Hodgkin's Lymphoma: Results From a Phase II Multicenter, Single-Agent Study J. Clin. Oncol., January 10, 2008; 26(2): 204 - 210. [Abstract] [Full Text] [PDF]

				A. Z.S. Rohatiner, L. Nadler, A. J. Davies, J. Apostolidis, D. Neuberg, J. Matthews, J. G. Gribben, P. M. Mauch, T. A. Lister, and A. S. Freedman Myeloablative Therapy With Autologous Bone Marrow Transplantation for Follicular Lymphoma at the Time of Second or Subsequent Remission: Long-Term Follow-Up J. Clin. Oncol., June 20, 2007; 25(18): 2554 - 2559. [Abstract] [Full Text] [PDF]

				L. Farina and P. Corradini Current role of allogeneic stem cell transplantation in follicular lymphoma Haematologica, May 1, 2007; 92(5): 580 - 582. [Full Text] [PDF]

				J. G. Gribben, D. Zahrieh, K. Stephans, L. Bartlett-Pandite, E. P. Alyea, D. C. Fisher, A. S. Freedman, P. Mauch, R. Schlossman, L. V. Sequist, et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia Blood, December 15, 2005; 106(13): 4389 - 4396. [Abstract] [Full Text] [PDF]

				J. R. Brown and A. S. Freedman In Reply: J. Clin. Oncol., November 1, 2005; 23(31): 8121 - 8122. [Full Text] [PDF]

				R. Bhatia, K. Van Heijzen, A. Palmer, A. Komiya, M. L. Slovak, K. L. Chang, H. Fung, A. Krishnan, A. Molina, A. Nademanee, et al. Longitudinal Assessment of Hematopoietic Abnormalities After Autologous Hematopoietic Cell Transplantation for Lymphoma J. Clin. Oncol., September 20, 2005; 23(27): 6699 - 6711. [Abstract] [Full Text] [PDF]

				J. R. Brown, H. Yeckes, J. W. Friedberg, D. Neuberg, H. Kim, L. M. Nadler, and A. S. Freedman Increasing Incidence of Late Second Malignancies After Conditioning With Cyclophosphamide and Total-Body Irradiation and Autologous Bone Marrow Transplantation for Non-Hodgkin's Lymphoma J. Clin. Oncol., April 1, 2005; 23(10): 2208 - 2214. [Abstract] [Full Text] [PDF]

				A. T. Look Molecular Pathogenesis of MDS Hematology, January 1, 2005; 2005(1): 156 - 160. [Abstract] [Full Text] [PDF]

				J. W. Friedberg Radioimmunotherapy for Non-Hodgkin's Lymphoma Clin. Cancer Res., December 1, 2004; 10(23): 7789 - 7791. [Full Text] [PDF]

				S. Montoto, A. Lopez-Guillermo, A. Altes, G. Perea, A. Ferrer, M. Camos, L. Villela, F. Bosch, J. Esteve, F. Cervantes, et al. Predictive value of Follicular Lymphoma International Prognostic Index (FLIPI) in patients with follicular lymphoma at first progression Ann. Onc., October 1, 2004; 15(10): 1484 - 1489. [Abstract] [Full Text] [PDF]

				J. Czyz, R. Dziadziuszko, W. Knopinska-Postuszuy, A. Hellmann, L. Kachel, J. Holowiecki, J. Gozdzik, J. Hansz, A. Avigdor, A. Nagler, et al. Outcome and prognostic factors in advanced Hodgkin's disease treated with high-dose chemotherapy and autologous stem cell transplantation: a study of 341 patients Ann. Onc., August 1, 2004; 15(8): 1222 - 1230. [Abstract] [Full Text] [PDF]

				S. Smeland, A. K. Blystad, S. O. Kvaloy, I. M. Ikonomou, J. Delabie, G. Kvalheim, J. Hammerstrom, G. F. Lauritzsen, and H. Holte Treatment of Burkitt's/Burkitt-like lymphoma in adolescents and adults: a 20-year experience from the Norwegian Radium Hospital with the use of three successive regimens Ann. Onc., July 1, 2004; 15(7): 1072 - 1078. [Abstract] [Full Text] [PDF]

				K. van Besien, F. R. Loberiza Jr, R. Bajorunaite, J. O. Armitage, A. Bashey, L. J. Burns, C. O. Freytes, J. Gibson, M. M. Horowitz, D. J. Inwards, et al. Comparison of autologous and allogeneic hematopoietic stem cell transplantation for follicular lymphoma Blood, November 15, 2003; 102(10): 3521 - 3529. [Abstract] [Full Text] [PDF]

				T. A. Lister High-Dose Therapy for Follicular Lymphoma Revisited: Not If, but When? J. Clin. Oncol., November 1, 2003; 21(21): 3894 - 3896. [Full Text] [PDF]

				A. Josting, S. Wiedenmann, J. Franklin, M. May, M. Sieber, J. Wolf, A. Engert, and V. Diehl Secondary Myeloid Leukemia and Myelodysplastic Syndromes in Patients Treated for Hodgkin's Disease: A Report From the German Hodgkin's Lymphoma Study Group J. Clin. Oncol., September 15, 2003; 21(18): 3440 - 3446. [Abstract] [Full Text] [PDF]

				M. Benesch and H. J. Deeg Hematopoietic Cell Transplantation for Adult Patients With Myelodysplastic Syndromes and Myeloproliferative Disorders Mayo Clin. Proc., August 1, 2003; 78(8): 981 - 990. [Abstract] [PDF]

				J. O. Armitage, P. P. Carbone, J. M. Connors, A. Levine, J. M. Bennett, and S. Kroll Treatment-Related Myelodysplasia and Acute Leukemia in Non-Hodgkin's Lymphoma Patients J. Clin. Oncol., March 1, 2003; 21(5): 897 - 906. [Abstract] [Full Text] [PDF]

				C. Metayer, R. E. Curtis, J. Vose, K. A. Sobocinski, M. M. Horowitz, S. Bhatia, J. W. Fay, C. O. Freytes, S. C. Goldstein, R. H. Herzig, et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study Blood, March 1, 2003; 101(5): 2015 - 2023. [Abstract] [Full Text] [PDF]

				M. Hunault-Berger, N. Ifrah, and P. Solal-Celigny Intensive therapies in follicular non-Hodgkin lymphomas Blood, July 30, 2002; 100(4): 1141 - 1152. [Full Text] [PDF]

				C. Gisselbrecht, E. Lepage, T. Molina, B. Quesnel, G. Fillet, P. Lederlin, B. Coiffier, H. Tilly, J. Gabarre, F. Guilmin, et al. Shortened First-Line High-Dose Chemotherapy for Patients With Poor-Prognosis Aggressive Lymphoma J. Clin. Oncol., May 15, 2002; 20(10): 2472 - 2479. [Abstract] [Full Text] [PDF]

				C. Hosing, M. Munsell, S. Yazji, B. Andersson, D. Couriel, M. de Lima, M. Donato, J. Gajewski, S. Giralt, M. Korbling, et al. Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin's lymphoma Ann. Onc., March 1, 2002; 13(3): 450 - 459. [Abstract] [Full Text] [PDF]

				A. Rambaldi, M. Lazzari, C. Manzoni, E. Carlotti, L. Arcaini, M. Baccarani, T. Barbui, C. Bernasconi, G. Dastoli, G. Fuga, et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma Blood, February 1, 2002; 99(3): 856 - 862. [Abstract] [Full Text] [PDF]

				M. Engelhardt, J. Finke, N. Rufer, T. H. Brummendorf, B. Chapuis, C. Helg, P. M. Lansdorp, and E. Roosnek Does telomere shortening count? Blood, August 1, 2001; 98(3): 888 - 890. [Full Text] [PDF]

				D. M. Lillington, I. N.M. Micallef, E. Carpenter, M. J. Neat, J. A.L. Amess, J. Matthews, N. J. Foot, B. D. Young, T. A. Lister, and A. Z.S. Rohatiner Detection of Chromosome Abnormalities Pre-High-Dose Treatment in Patients Developing Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After Treatment for Non-Hodgkin's Lymphoma J. Clin. Oncol., May 1, 2001; 19(9): 2472 - 2481. [Abstract] [Full Text] [PDF]

				S. J. Horning, R. S. Negrin, R. T. Hoppe, S. A. Rosenberg, N. J. Chao, G. D. Long, B. W. Brown, and K. G. Blume High-dose therapy and autologous bone marrow transplantation for follicular lymphoma in first complete or partial remission: results of a phase II clinical trial Blood, January 15, 2001; 97(2): 404 - 409. [Abstract] [Full Text] [PDF]

				O. W. Press, J. F. Eary, T. Gooley, A. K. Gopal, S. Liu, J. G. Rajendran, D. G. Maloney, S. Petersdorf, S. A. Bush, L. D. Durack, et al. A phase I/II trial of iodine-131-tositumomab (anti-CD20), etoposide, cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas Blood, November 1, 2000; 96(9): 2934 - 2942. [Abstract] [Full Text] [PDF]

				N. Mounier, C. Gisselbrecht, J. W. Friedberg, D. Neuberg, and A. S. Freedman Myelodysplasia After Autotransplantation J. Clin. Oncol., October 19, 2000; 18(19): 3446 - 3447. [Full Text] [PDF]

				C. Haioun, E. Lepage, C. Gisselbrecht, G. Salles, B. Coiffier, P. Brice, A. Bosly, P. Morel, C. Nouvel, H. Tilly, et al. Survival Benefit of High-Dose Therapy in Poor-Risk Aggressive Non-Hodgkin's Lymphoma: Final Analysis of the Prospective LNH87-2 Protocol--A Groupe d'Etude des Lymphomes de l'Adulte Study J. Clin. Oncol., August 16, 2000; 18(16): 3025 - 3030. [Abstract] [Full Text] [PDF]

				J. Pedersen-Bjergaard, M. K. Andersen, and D. H. Christiansen Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation Blood, June 1, 2000; 95(11): 3273 - 3279. [Abstract] [Full Text] [PDF]

				J. O. Armitage Myelodysplasia and Acute Leukemia After Autologous Bone Marrow Transplantation J. Clin. Oncol., March 1, 2000; 18(5): 945 - 945. [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Friedberg, J. W. Articles by Freedman, A. S. Search for Related Content PubMed PubMed Citation Articles by Friedberg, J. W. Articles by Freedman, A. S. Social Bookmarking                            What's this?