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Therapy-Related Myelodysplasia and Secondary Acute Myelogenous Leukemia After High-Dose Therapy With Autologous Hematopoietic Progenitor-Cell Support for Lymphoid Malignancies

From the Imperial Cancer Research Fund Medical Oncology Unit, Departments of Medical Oncology and Haematology, St Bartholomew’s Hospital, London; and Imperial Cancer Research Fund Centre for Statistics in Medicine, Institute of Health Sciences, Oxford, United Kingdom.

Address reprint requests to Ama Z.S. Rohatiner, MD, Imperial Cancer Research Fund Medical Oncology Unit, Department of Medical Oncology, St Bartholomew’s Hospital, 45 Little Britain, West Smithfield, London EC1A 7BE, United Kingdom; email a.rohatiner@ icrf.icnet.uk.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate the incidence of and risk factors for therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML), after high-dose therapy (HDT) with autologous bone marrow or peripheral-blood progenitor-cell support, in patients with non-Hodgkin’s lymphoma (NHL).

PATIENTS AND METHODS: Between January 1985 and November 1996, 230 patients underwent HDT comprising cyclophosphamide therapy and total-body irradiation, with autologous hematopoietic progenitor-cell support, as consolidation of remission. With a median follow-up of 6 years, 27 (12%) developed tMDS or sAML.

RESULTS: Median time to development of tMDS or sAML was 4.4 years (range, 11 months to 8.8 years) after HDT. Karyotyping (performed in 24 cases) at diagnosis of tMDS or sAML revealed complex karyotypes in 18 patients. Seventeen patients had monosomy 5/5q-, 15 had -7/7q-, seven had -18/18q-, seven had -13/13q-, and four had -20/20q-. Twenty-one patients died from complications of tMDS or sAML or treatment for tMDS or sAML, at a median of 10 months (range, 0 to 26 months). Sixteen died without evidence of recurrent lymphoma. Six patients were alive at a median follow-up of 6 months (range, 2 to 22 months) after diagnosis of tMDS or sAML. On multivariate analysis, prior fludarabine therapy (P = .009) and older age (P = .02) were associated with the development of tMDS or sAML. Increased interval from diagnosis to HDT and bone marrow involvement at diagnosis were of borderline significance (P = .05 and .07, respectively).

CONCLUSION: tMDS and sAML are serious complications of HDT for NHL and are associated with very poor prognosis. Alternative strategies for reducing their incidence and for treatment are needed.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
HIGH-DOSE THERAPY (HDT) with autologous bone marrow or peripheral-blood progenitor-cell (PBPC) support is increasingly being used as consolidation of remission for non-Hodgkin’s lymphoma (NHL).^1-6 With improved supportive care measures and better patient selection, the early treatment–related mortality is now less than 5%, and up to 46% of selected patients can be considered cured.⁵

Prior chemotherapy is a well-documented risk factor for therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML) after treatment for lymphoid malignancies.^7-10 The incidence and risk vary between studies and different diseases, due in part to cohort differences in terms of age; duration, intensity, and type of therapy; and length of follow-up. The median time to development of tMDS or sAML following therapy is 4 to 5 years, with the highest risk being between 2 and 5 years.¹¹ Since the first report in 1993,¹² the development of tMDS or sAML after HDT has become increasingly recognized.^13,14 The crude incidence varies from 2% to 8%, with a 5-year actuarial incidence of 4% to 18%.^15-21 Although both pretransplantation and transplant-related factors likely contribute to this problem, it remains unclear which, if any, have a more important role.^{15,16,18,20-25}

Therefore, we performed an analysis of the incidence of and risk factors for tMDS and sAML after HDT with autologous bone marrow or PBPC support in 230 patients treated for NHL over a 12-year period at St Bartholomew’s Hospital (SBH). The clinical course and outcome of the 27 patients who developed tMDS or sAML are presented. Eight of the latter cases were included in a study involving cases drawn from the European Bone Marrow Transplantation Lymphoma Registry.²⁰

	PATIENTS AND METHODS

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Patients
The study population comprised 230 patients who underwent cyclophosphamide therapy and total-body irradiation (TBI) as consolidation of remission after chemotherapy for NHL between January 1985 and November 1996.^2,26,27

From 1992 on, pre-HDT cytogenetic analysis was performed routinely; patients with abnormal karyotypes at this stage did not proceed to HDT, because of the risk of developing tMDS or sAML.²⁸ Baseline and transplant characteristics for all 230 patients and for those who subsequently developed tMDS or sAML (27 patients) are outlined in Table 1.

HDT and Follow-Up
The myeloablative regimen for all patients comprised cyclophosphamide therapy (60 mg/kg x 2 days) and fractionated TBI (2 Gy bid x 3 days). Within 24 hours of the last dose of radiation, the cryopreserved cells were thawed and reinfused. Patients were followed up monthly for the first 3 months and quarterly thereafter. A full blood count was performed at each visit. Each patient had a computed tomographic scan, bone marrow aspiration, and a trephine biopsy approximately 3 months after HDT. Surveillance computed tomographic scans, bone marrow aspiration, and a trephine biopsy were performed annually in each patient with follicular lymphoma and otherwise when clinically indicated. Cytogenetic analysis of bone marrow was not routinely performed at follow-up.

Diagnosis of tMDS and sAML
French-American-British (FAB) criteria were used in diagnosing MDS and AML.³³ All bone marrow aspirates and trephine biopsy specimens were reviewed (by J.A.) to confirm the diagnosis and assign the FAB subtype. Cytogenetic analysis was performed using standard G-banding techniques.³⁴ Abnormal clones were described using International System for Human Cytogenetic Nomenclature criteria.³⁵ Five patients who developed cytogenetic abnormalities without meeting any morphologic criteria for MDS or AML were not included in the analysis.

Statistical Analysis
The variables analyzed as potential risk factors for tMDS or sAML were sex, histologic diagnosis (classified according to Kiel criteria³⁶ [ie, B-cell low-grade lymphoma, B-cell high-grade lymphoma, or T-cell lymphoma]), bone marrow involvement at diagnosis, disease stage at diagnosis (stage I or II v stage III or IV), number of prior treatment episodes (one, two, or three), exposure to fludarabine, prior radiotherapy, transformation to high-grade histology before HDT, age at the time of HDT, remission status at the time of HDT (first or second remission v third or later remission; complete remission v partial remission), time from diagnosis to HDT, type of support (bone marrow or PBPCs), in vitro purging, type of in vitro treatment (anti-CD20 plus complement v multiple antibodies plus complement v CD34-positive selection), logarithmic count of reinfused mononuclear cells, time to neutrophil engraftment (neutrophil count 0.5 x 10⁹/L and 1.0 x 10⁹/L), time to platelet engraftment (platelet count 20 x 10⁹/L and 50 x 10⁹/L), recurrence after HDT, and interval from HDT to recurrence.

Univariate analysis on categoric predictors was performed using the ² test when expected cell counts were greater than five; otherwise, the Fisher’s exact test was used. Logistic regression was used in the case of continuous predictors. The Mann-Whitney U test was used for differences between medians. Mononuclear cell counts were logarithmic because of skew. CD34 counts were not performed, because this study involved both bone marrow and PBPCs and therefore CD34 counts were only available in a minority of patients. Multivariate analysis was performed using the Cox proportional hazards model³⁷; the proportionality assumption and goodness of fit of the latter were checked by fitting time-dependent covariates and inspecting both Martingale and Schoenfeld residuals. Interaction terms were fitted between independent variables. Sensitivity analyses were performed to check the effects of missing data. The cumulative incidence of tMDS or sAML and actuarial survival were calculated using the product-limit method of Kaplan and Meier.³⁸

	RESULTS

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Patients Who Developed tMDS or sAML
At a median follow-up of 6 years (range, 10 days to 13 years; one patient died 10 days after reinfusion of bone marrow), 27 patients had developed tMDS or sAML: 16 had MDS, 10 had MDS evolving into AML, and one had sAML. Crude incidence was 12%; actuarial risk at 5 and 10 years was 14.2% (95% confidence interval, 7.6% to 20.4%) and 36.5% (95% confidence interval, 20.6% to 50.1%), respectively (Fig 1). Baseline clinical characteristics are listed in Table 1. The median time to development of MDS was 9.1 years (range, 2.7 to 21.6 years) after diagnosis of NHL and 4.4 years (range, 0.9 to 8.8 years) after HDT. Most patients presented with cytopenia; 15 patients had anemia, 12 had neutropenia, and 20 had thrombocytopenia. For the purpose of this analysis, anemia was defined as a hemoglobin level 10 g/dL, neutropenia as an absolute neutrophil count 1.0 x 10⁹/L, and thrombocytopenia as a platelet count 100 x 10⁹/L. The diagnoses are listed in Table 2.

View larger version (11K): [in this window] [in a new window]   Fig 1. Reverse Kaplan-Meier estimate of cumulative incidence of tMDS or sAML for 230 patients after HDT for NHL.

Outcome
Twenty-one of the 27 patients died from complications of tMDS or sAML or treatment for tMDS or sAML, at a median of 10 months (range, 0 to 26 months) from the time of development of tMDS or sAML (Fig 2). The clinical courses of the 27 patients are outlined in Table 2. Sixteen patients died without evidence of recurrent lymphoma.

View larger version (8K): [in this window] [in a new window]   Fig 2. Overall survival by Kaplan-Meier estimate for 27 patients after diagnosis of tMDS or sAML.

Six patients remained alive at a median follow-up of 6.2 months (range, 2 to 22 months) after diagnosis of MDS. Two patients (one of whom had concomitant prostate cancer with bone marrow involvement) were receiving transfusion support. Three patients, two with refractory anemia and one with AML, were recently treated with antilymphocyte globulin.³⁹ The remaining patient underwent nonmyeloablative allogeneic sibling bone marrow transplantation (BMT).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Although the major cause of failure of HDT is recurrent lymphoma, in this series tMDS or sAML occurred in 21 of 27 patients in whom there was no evidence of recurrence. At a median follow-up of 6 years after HDT, 106 of 230 patients had died; 21 (20%) of these deaths were due to tMDS or sAML. Thus tMDS or sAML is an important cause of death after HDT and a major cause for concern. The 12% incidence of tMDS or sAML (27 of 230 patients) and the 5-year cumulative incidence of 14.2% in our study are similar to those in previous reports.^{15,16,18,19,40-42} In some reports, the incidence among patients with Hodgkin’s disease was equal to that among patients with NHL.^15,18 Only patients with NHL were enrolled onto our study; none of the 36 patients at SBH who underwent HDT for Hodgkin’s disease during this same period developed tMDS or sAML (J. Shamash, personal communication, July 1999).

The major question concerning the development of tMDS or sAML is the following: Which factors play an etiologic role—prior alkylator therapy and the cumulative damage to bone marrow stem cells, the HDT itself, or a combination of both? Although prior treatment was heterogeneous, all patients had received alkylating agents before HDT. The 5-year estimated risk of tMDS or sAML after long-term alkylator therapy or low-dose radiation is 7%.^43,44 Alkylating agents are typically associated with complete or partial loss of chromosomes 5 and/or 7 and have a latency period of approximately 5 years.^45,46 The majority of patients with secondary disease in this study fit into this cytogenetic category, but at SBH, the incidence of tMDS or sAML in patients with follicular lymphoma who have not received HDT is extremely low.^47,48 In a report from the University of Arkansas on patients with multiple myeloma who were undergoing HDT, patients who developed MDS had received extensive therapy before HDT.⁴⁹ Both this group of patients and the group that underwent only one cycle of standard chemotherapy before proceeding to HDT received a non-TBI conditioning regimen.

However, prior therapy is not the only factor involved in the development of tMDS or sAML. At the Dana-Farber Cancer Institute, patients undergoing HDT as consolidation of first remission of follicular lymphoma with minimal prior therapy still had a significant incidence of MDS (6.5%).³ It remains unclear why the combination of prior therapy and HDT in patients with follicular lymphoma increases the risk of tMDS or sAML. If the HDT itself is causing (or at least contributing to) the development of tMDS or sAML, is it the residual cells that have survived the myeloablative therapy or the reinfused stem cells that give rise to the clonal abnormality? Gene-marking studies have shown that reinfused bone marrow cells contribute to relapse in patients with acute leukemia after autografting⁵⁰; it should therefore be possible to identify which cells give rise to a secondary leukemic clone. However, no study to date has demonstrated that reinfused progenitor cells contribute to tMDS or sAML. It has been postulated that the bone marrow microenvironment after HDT, together with re-engraftment stress, results in growth of stem cells (within the reinfused marrow) that have sustained chemotherapy-induced mutations that are not detectable by standard G-banding analysis before HDT. Alternatively, the damaged stem cells may be at risk for mutations because of the altered bone marrow milieu after HDT.

In this analysis, older age, prior fludarabine therapy, and longer interval from diagnosis to HDT were associated with development of tMDS or sAML. In vitro treatment per se was statistically significant on univariate analysis but was not significant when compared between groups (anti-CD20 and complement v multiple antibodies and complement v CD34-positive selection). This is probably due to the fact that the majority of patients in whom the mononuclear cell fraction was treated in vitro had an underlying diagnosis of follicular lymphoma; thus these factors were linked.

All patients underwent cyclophosphamide therapy and TBI (the myeloablative regimen used); therefore, a conclusion cannot be drawn about whether the choice of agents is an important factor. In two studies, TBI was found to play a significant role in the development of MDS.^15,25 After the publication of these reports, and when the emerging problems of tMDS and sAML were recognized at SBH, the HDT conditioning regimen for NHL was changed in December 1996 from cyclophosphamide therapy plus TBI to chemotherapy with carmustine, etoposide, cytarabine, and melphalan. Since that time, no patient treated with this regimen has developed tMDS or sAML. Whether this is simply a function of the latency period or is a true decrease in incidence remains to be seen with longer follow-up.⁵¹ Other factors previously reported as being associated with the development of tMDS or sAML are lower platelet counts at the time of HDT, older age,¹⁶ and HDT using PBPCs rather than bone marrow progenitor cells.^18,21 In a recent study involving cases drawn from the European Bone Marrow Transplantation Registry, older age at transplantation, TBI conditioning, greater number of transplantations, longer interval between diagnosis and transplantation, and histologic diagnosis of low-grade lymphoma were found to be significant predictors for tMDS and sAML.²⁰ It was also suggested recently that purine analogs are associated with the development of tMDS and sAML.^22-25

All of the patients in our series had cytopenia or dysplastic morphologic changes characteristic of MDS; 24 of 27 patients for whom cytogenetic data were available had typical poor-risk karyotypic abnormalities, including complete or partial monosomy 5 or 7 and complex clones. Although the majority of patients showed global genomic instability, with the presence of complex rearrangements that could not be fully characterized on G-banding, a few patients had simple karyotypes. The latter patients showed either complete loss of chromosome 7 or partial deletion of chromosome 5, which implies that these represent one of the initiating events. In fact, 23 of 24 patients karyotyped showed one of these chromosomal abnormalities, suggesting that these genetic alterations play a critical role in the development of secondary disease. Precisely which gene or genes are involved remains to be elucidated, and with the advent of more advanced techniques (eg, multicolor fluorescence in situ hybridization), recurrent structural abnormalities may also be shown to exist in this patient subset.

Five additional patients, not included in this series, had abnormal cytogenetic findings after HDT but morphologically normal bone marrow. None of these patients had the typical complex karyotype seen in the other 24 patients. Five patients have previously been reported to have cytogenetic abnormalities without hematologic evidence of MDS; during follow-up, only two became cytopenic.¹⁹ It has also been reported that 50% of sporadically tested patients may have karyotypic abnormalities after BMT, despite normal hematologic parameters.¹³ The significance of such clonal abnormalities after HDT, in the setting of a normal blood count, is thus unclear.

Treatment of tMDS and sAML remains unsatisfactory, with the majority of patients dying less than 2 years after diagnosis.⁵² The present study, in which median survival after diagnosis of tMDS or sAML was 10 months, confirms this. Although allogeneic BMT remains the only curative therapy for primary MDS,⁵³ the treatment results for secondary MDS are conflicting.^54,55 In a recent study by Friedberg et al,⁵⁶ 11 of 34 patients who developed tMDS or sAML after autologous BMT for NHL underwent allogeneic BMT as treatment for the tMDS or sAML. All died, 10 from treatment-related toxicity and one from recurrent lymphoma. It remains to be seen whether nonmyeloablative allogeneic BMT^57-59 can produce a graft-versus-leukemia/lymphoma effect without the high treatment-related mortality of conventional allogeneic transplantation.

tMDS and sAML are serious consequences after HDT as consolidation of remission of NHL. Because no effective treatment presently exists, strategies to minimize the risk of development of tMDS and sAML should be sought. These findings should be taken into account in future studies of the role of HDT for NHL.

	ACKNOWLEDGMENTS

 
We thank the nurses and doctors of the Bodley Scott Unit and Paget Day Ward for caring for these patients, Andrew Norton, MD, for review of the pathology, and Margaret Cresswell for preparing the manuscript.

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Submitted July 14, 1999; accepted October 19, 1999.

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