Risk of therapy-related myelodysplastic syndrome/acute leukemia following high-dose therapy and autologous bone marrow transplantation for non-Hodgkin’s lymphoma

C. Hosing+, M. Munsell, S. Yazji, B. Andersson, D. Couriel, M. de Lima, M. Donato, J. Gajewski, S. Giralt, M. Körbling, T. Martin, N. T. Ueno, R.E. Champlin and I.F. Khouri

Departments of Blood and Marrow Transplantation and Biostatistics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

Received 13 July 2001; revised 19 September 2001; accepted 23 October 2001.


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background

Several recent reports have suggested that patients with non-Hodgkin’s lymphomas (NHL) who undergo autologous stem cell transplantation (ASCT) are at increased risk of developing therapy-related myelodysplastic syndrome (tMDS) and acute myelogenous leukemia (tAML).

Patients and methods

We analyzed 493 patients with NHL who underwent ASCT at The University of Texas M.D. Anderson Cancer Center between January 1990 and August 1999.

Results

With a median follow-up time of 21 months after HDT, 22 patients developed persistent cytopenia in at least one cell line with morphologic or cytogenetic evidence of tMDS or tAML. Univariate analysis identified prior fludarabine therapy, bone marrow involvement with lymphoma, and total body irradiation (TBI) as significant risk factors for the development of tMDS/tAML (P <0.05). Multiple logistic regression analysis showed that TBI was independently associated with an increased risk of developing tMDS/tAML (P <0.01). Further analysis of the patients who received TBI revealed that patients receiving TBI in combination with cyclophosphamide and etoposide were more likely to develop tMDS/tAML than those who received TBI with cyclophosphamide or thiotepa (P <0.01). The median survival of patients developing tMDS/tAML was 7.5 months (range 0–32 months).

Conclusions

TBI, especially when used in combination with cyclophosphamide and etoposide as the pretransplant conditioning regimen, is a significant risk factor for the development of tMDS/tAML.

Key words: autologous transplantation, non-Hodgkin’s lymphoma, therapy-related acute myelogenous leukemia, therapy-related myelodysplasia


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
High-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) is an established therapy in the management of patients with non-Hodgkin’s lymphoma (NHL) in whom conventional chemotherapy has failed [18]. With improvement in supportive care measures, the transplant-related mortality rate has decreased to <5%, and patients are living longer after transplantation. Since the early 1990s, however, several reports have documented an increased risk of secondary malignancies including myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML) in long-term survivors of autotransplants [920].

The reported incidence of therapy-related MDS and AML (tMDS and tAML) following autologous transplantation has ranged from 2 to 8% in most studies, with cumulative risk varying widely, from 1.1% at 62 months [21] to 24.3% at 43 months [22]. This variation in incidence is most likely due to heterogeneity of the patient populations studied. The outcome in patients with tMDS/tAML has generally been poor even with aggressive chemotherapy, which in some patients has included allogeneic bone marrow transplantation [14, 23].

Factors contributing to the risk of tMDS/tAML are complex. Some authors have suggested that pretransplant therapy plays a more important role in the development of secondary malignancies than the transplant itself [22, 24]. Indeed, an increased risk of developing secondary malignancies has been described not only in patients undergoing ASCT, but also in long-term survivors of Hodgkin’s disease and NHL who do not receive HDT, indicating a definite role for standard chemotherapy [2528]. Exposure to alkylating agents and etoposide has been well documented to increase the risk of developing tMDS/tAML [29, 30].

Some of the factors that have been implicated in the development of tMDS/tAML after HDT are older age at transplant [10, 13, 19, 31, 32]; duration and types of prior chemotherapy, especially chemotherapy with alkylating agents, topoisomerase II inhibitors or purine analogs [10, 24, 33, 34]; radiation therapy, especially total body irradiation (TBI) [13, 32, 33, 35]; interval from diagnosis to transplant [10, 13, 33]; stem-cell dose [14]; source of stem cells [16, 19, 31]; priming with etoposide prior to stem-cell harvest [18]; number of prior transplants [13]; type of lymphoma [13]; bone marrow involvement with lymphoma [10]; and low platelet count at the time of HDT [33]. Secondary malignancies have also been described in patients undergoing ASCT for breast cancer [36, 37], multiple myeloma [38] and other disorders.

We present here an analysis of the incidence and risk factors associated with development of tMDS and tAML in patients who underwent HDT and ASCT for NHL at the M.D. Anderson Cancer Center between January 1990 and August 1999.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
Between January 1990 and August 1999, a total of 493 patients underwent HDT and autologous peripheral blood stem cell (PBSC) or bone marrow (BM) transplantation for NHL at the M.D. Anderson Cancer Center. Data were obtained from the Blood and Bone Marrow Transplant database and through chart review. The following parameters were recorded for each case: sex, age at diagnosis, histological type and stage at diagnosis, history of bone marrow involvement at any time prior to transplant, time from diagnosis to transplant, response to pretransplant chemotherapy, number of cycles of chemotherapeutic regimens prior to transplant with special attention to etoposide and fludarabine, source of stem cells (PBSC or BM), procedure of stem cell mobilization, conditioning regimen, history of radiation therapy, date of relapse, date of last follow-up and date of death. For patients who developed tMDS/ tAML, the date of diagnosis, French-American-British (FAB) classification, and cytogenetic findings were also recorded. The NHL were classified according to the International Working Formulation [39]. Table 1 gives the baseline characteristics of all 493 patients and Table 2 gives the transplant characteristics.


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Table 1. Baseline patient characteristics
 

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Table 2. Transplant characteristics
 
Stem cell procurement
Pelvic bone marrow harvest were performed under general anesthesia using standard techniques. In general, PBSC collections were done after chemotherapy and hematopoietic growth factor (granulocyte colony-stimulating factor, granulocyte/macrophage colony-stimulating factor and recombinant human stem-cell factor, either alone or in combination) administration or after growth factor administration alone. Following collection, a minority of harvests underwent in vitro B-cell purging using anti-CD19 monoclonal antibody, CD34 selection, or immune modulation with in vitro inoculation with IL-2 .

High-dose therapy and follow-up
Patients were treated on a variety of protocols depending on the type of lymphoma and the active protocol at the time of transplant. All protocols were approved by the Institutional Review Board at the M.D. Anderson Cancer Center. All patients signed informed consent forms. For those patients who received TBI-based regimens, the doses ranged from 8.5 Gy to 12 Gy, depending on the protocol. After discharge from the hospital, patients were followed at least weekly for 1 month, monthly for 3 months, every 3 months for 1 year, every 6 months for 3 years, and yearly thereafter. Staging studies performed at 1, 3, 6 and 9 months and 1 year, then every 6 months for 3 years and yearly thereafter included complete blood count, chemistry profile and computed tomography (CT) scans. All patients with indolent histology NHL had bone marrow aspiration and biopsy done with each re-staging work up. For patients with aggressive or intermediate histology NHL, bone marrow aspiration and biopsy was done if there was persistent, unexplained cytopenia in any of the three cell lines or at the discretion of the treating physician. Cytogenetic analysis was performed if there was cytopenia in any one cell line.

Diagnosis of tMDS or tAML
Myelodysplasia was defined as persistent unexplained cytopenia in at least one cell line after a period of engraftment, and either the bone marrow biopsy consistent with myelodysplasia using the FAB criteria [40, 41] or the presence of clonal cytogenetic abnormalities typically seen in tMDS or tAML. Cytogenetic analysis was done using a trypsin-Giemsa banding technique on cells obtained from bone marrow aspiration samples or peripheral blood at the time of suspected marrow dysfunction. Karyotypes were interpreted using the International System for Human Cytogenetic Nomenclature (ISCN) 1995 [42].

Statistical analysis
The primary end point for the study was the development of tMDS/tAML. Fisher’s exact test was used to identify significant differences between the proportions of patients with and without tMDS/tAML for several categorical factors. The odds ratio (OR) and its 95% confidence interval (CI) were calculated for those factors found to be significantly different (P <0.05) in the two groups of patients. Student’s two-sample t-test was used to test for differences between patients with and without tMDS/tAML for factors measured on a continuous scale. The risk of developing tMDS/tAML after ASCT was calculated using the competing risks statistical analysis as described by Gooley et al. [43]. A Kaplan–Meier curve was used to estimate the survival rate from diagnosis of tMDS/tAML. A multiple logistic regression analysis was performed with stepwise variable selection to determine which factors were independently important in predicting tMDS/tAML.


    Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
A total of 493 patients with NHL underwent HDT and ASCT during the study period (232 patients received PBSC, 232 received BM and 29 received both). With a median follow-up period of 21 months (range 1–104 months), 22 of 493 patients developed tMDS or tAML. The cumulative probability of developing tMDS/tAML was 14.2% at 5 years after transplant (Figure 1). For those patients who developed tMDS/tAML, the median time to diagnosis of tMDS/tAML was 30 months (range 3–61 months) after HDT and 5.9 years (range 6 months to 14.5 years) from diagnosis of NHL.



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Figure 1. Cumulative incidence of developing tMDS/tAML after HDT and ASCT. Kaplan–Meier estimate of overall survival after diagnosis of tMDS/tAML. Dotted lines show the upper and lower limits of confidence intervals at each time point.

 
FAB classification and cytogenetic analysis
Of the 22 patients who developed tMDS/tAML, two were found to have tAML at evaluation, 11 had tMDS (two of the 11 later progressed to tAML), three had hypocellular/inadequate samples (one was later diagnosed as refractory anemia with excess blasts, or RAEBT) and six had no dysplasia at the time of diagnosis. All nine patients with hypocellular/inadequate samples or no morphological evidence of myelodysplasia in the marrow at the time of diagnosis had unexplained persistent cytopenias in at least one cell line and/or cytogenetic changes that are typically associated with tMDS/tAML (Tables 3 and 4). Four of the 22 patients had received additional chemotherapy after transplant prior to developing tMDS/tAML (three for relapse after HDT and one for failure to achieve complete remission). Five of the 22 patients had recurrence of their NHL after HDT (two developed tMDS prior to documented relapse of their NHL and three were diagnosed with relapse and tMDS at the same time). Thirteen patients had no documented evidence of lymphoma at the time of diagnosis of tMDS/tAML.


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Table 3. FAB classification, treatment and survival in patients with tMDS/tAML
 

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Table 4. Cytogenetic analysis in patients developing tMDS/tAML
 
The cytogenetic findings at the time of diagnosis of tMDS/tAML are given in Table 4. One patient had cytogenetic analysis done at an outside institution (No. 1), the details of which are not available. One patient (No. 16) had a bone marrow morphological picture typical of MDS, but cytogenetic analysis was not done. Of the 20 patients with tMDS/tAML for whom cytogenetic data were available, 16 (80%) had involvement of chromosome 5 or 7 and 8 (40%) had a complex karyotype (more than five cytogenetic abnormalities). Data on pretransplant cytogenetic analysis were available for one patient only (no cytogenetic abnormality).

Risk factors for development of tMDS/tAML
A univariate analysis identified prior fludarabine therapy (OR = 3.37; 95% CI 1.03 to 9.59), bone marrow involvement with lymphoma at any time before HDT (OR = 3.35; 95% CI 1.25 to 9.88), use of TBI as pretransplant conditioning regimen (OR = 4.49; 95% CI 1.71 to 12.62), and use of cyclophosphamide/etoposide/TBI as pretransplant conditioning regimen (OR = 5.95; 95% CI 2.26 to 15.89) as significant risk factors for development of tMDS/tAML (P <0.05).

Of the 14 patients with tMDS/tAML who received TBI as part of the conditioning regimen, six received a dose of 10.2 Gy and eight a dose of 12 Gy. Age at diagnosis, gender, stage at diagnosis, histology, number of treatment episodes before transplant, type of cell support (BM, PBSC or both), chemopriming with etoposide, and the use of cytokines for mobilization of stem cells were not significant factors for the development of tMDS/tAML.

Because TBI has been described previously as a significant risk factor for the development of tMDS/tAML [13, 32, 33, 35], we did a multivariate analysis of the 146 patients who received TBI as part of the conditioning regimen. Those patients who received TBI in combination with cyclophosphamide and etoposide were more likely to develop tMDS/tAML than those patients who received TBI with cyclophosphamide or thiotepa (12/91 and 2/55, respectively) (P <0.01) (Table 2). However, the median follow up for patients who received TBI with etoposide and cyclophosphamide was 46 months (range 5–191), whereas the median follow-up time for patients receiving TBI with cyclophosphamide or thiotepa was only 9 months (range 4–185 months).

Neither prior fludarabine therapy nor bone marrow involvement were found to be significant risk factors in the subgroup of patients who received TBI (P = 0.10 and 0.74, respectively).

Outcomes
Table 3 outlines the treatments administered for tMDS/tAML. Six of the 22 patients received supportive care only, 14 re-ceived chemotherapy/bioimmunotherapy (four of these also underwent allogeneic related or matched unrelated donor transplantation), and two received additional chemotherapy for relapsed lymphoma but no specific treatment for tMDS/tAML. The median survival duration of patients who de- veloped tMDS/tAML was 7.5 months (range 0–32 months) (Figure 2).



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Figure 2. Kaplan–Meier estimate of overall survival after diagnosis of tMDS/tAML. Dotted lines show the upper and lower limits of confidence intervals at each time point.

 

    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
HDT and ASCT is being used increasingly in the treatment of lymphoid malignancies as well as in the management of other cancers. Since the early 1990s, however, several reports have documented an increased incidence of tMDS and tAML in long-term survivors of ASCT [920]. The exact mechanism by which HDT predisposes to development of tMDS/tAML is unknown, but several theories have been proposed, including altered microenvironment, damage to stem cells that survive HDT, and the state of immune incompetence following transplantation. In our series, the cumulative probability of developing tMDS/tAML was 14.2% at 5 years after ASCT. For those patients who developed tMDS/tAML, the median time to development was 30 months (range 3–61 months), an interval similar to those reported in most other series [1018]. A univariate analysis revealed that prior fludarabine therapy, bone marrow involvement with lymphoma at any time prior to transplantation, and use of TBI as conditioning regimen were significant risk factors for the development of tMDS/tAML in our population (P <0.05).

The use of TBI has been reported previously as a significant risk factor for the development of tMDS/tAML by several authors [13, 32, 33, 35]. Travis et al. [44] found that even low-dose TBI (5.2 Gy to active BM) was associated with an increased risk of developing secondary leukemias in patients with NHL. In a study by Micallef et al. [10], no new cases of tMDS/tAML were observed after the TBI-based conditioning regimens were changed to chemotherapy-based regimens. The follow-up duration in that study, however, was short. Increased risk of tMDS/tAML in patients undergoing ASCT without TBI-based regimens has also been documented [16].

An interesting finding in our study was that patients whose pretransplant conditioning regimen included a combination of TBI, etoposide and cyclophosphamide were at significantly higher risk of developing tMDS/tAML than patients who received TBI with either cyclophosphamide or thiotepa alone (P <0.01), although the median follow-up was longer in the former group (46 versus 9 months).

Prior fludarabine therapy and bone marrow involvement with lymphoma prior to transplantation have been shown to be risk factors for the development of tMDS/tAML after HDT [10]. Standard-dose therapy with purine analogs has also been shown to increase the risk of developing secondary leukemias [45, 46], and following fludarabine therapy with ASCT probably compounds this risk.

In the present study the number of chemotherapeutic regimens administered prior to ASCT was not found to be statistically significant for the development of tMDS/tAML. However, we would like to mention that although seven out of 22 patients who developed tMDS/tAML had received only one chemotherapeutic regimen prior to transplantation, in four out of seven patients the administered regimen was more intensive than CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) alone.

Diagnosis of tMDS/tAML after HDT can pose a challenge, as most patients do not meet the established criteria for FAB classification [17, 47, 48]. In many of these patients, the bone marrow may be hypoplastic or fibrotic, even in the absence of tMDS. In these cases, the diagnosis may be established on the basis of unexplained persistent cytopenias or characteristic cytogenetic abnormalities. In our analysis of 22 patients with tMDS/tAML, three had hypocellular or inadequate marrow samples at the time of diagnosis (one was later diagnosed as having RAEBT) and six had no morphological evidence of dysplasia. However, all of them had persistent cytopenias in at least one cell line and cytogenetic changes commonly observed in tMDS/tAML. Some authors have demonstrated the presence of karyotypic abnormalities without cytopenias or dysplasia after transplant, the significance of which is unclear. In a study by Imrie et al., 11% of patients developed cytogenetic abnormalities following ASCT, but after a median follow-up duration of 70 months, none of the patients developed tMDS/tAML [49].

The most common cytogenetic abnormalities described in tMDS/tAML are deletions or loss of the long arms of chromosomes 5 or 7 [50, 51]. This is most likely related to therapy with alkylating agents. In our series, 16 of 20 (80%) for whom data was available had involvement of chromosome 5 or 7, and eight of 20 (40%) had a complex karyotype. Balanced translocations involving chromosome bands 11q23 or 21q22 have been reported in patients who receive chemotherapy with topoisomerase II inhibitors [5254]. The risk appears to be dose dependent and is very high in patients receiving >4 g/m2 [55, 56]. More recently, Krishnan et al. [18] demonstrated that use of etoposide for mobilization of PBSC is a significant risk factor for the development of tAML with 11q23/21q22 abnormalities. However, the number of events in their study was small. In our study, 150 of the 493 patients (30.4%) received etoposide for stem cell mobilization, but no patient developed abnormalities involving 11q23/21q22. This needs to be further clarified, as etoposide in combination with ifosfamide is not only a very effective agent for mobilization of stem cells in patients with NHL and Hodgkin’s disease, but has the additional advantage of providing good tumor control [57, 58].

One of the limitations of our study is that data on pretransplant cytogenetics were not available for all patients. Several reports have indicated that chromosomal abnormalities are present in a significant proportion of patients prior to transplantation, most likely as a result of prior chemotherapy [59, 60].

The treatment of tMDS/tAML has been unsatisfactory in general, although two patterns of presentation have been recognized. Wilson et al. [47] observed that some patients present with an indolent form characterized by persistent cytopenias with or without clonal cytogenetic abnormalities. In others, the course is more ‘aggressive’, and these patients usually present with dyspoietic changes and multiple chromosomal abnormalities. In our study, the median survival duration was 7.5 months (range 0–32 months) and the overall survival rate was 16% at 2 years (95% CI 5% to 50%) from diagnosis of tMDS/tAML in spite of aggressive therapy that included allogeneic stem cell transplantation; this rate is similar to those reported by others [14, 23, 61].

Although ASCT has improved outcomes in several malignancies, development of tMDS/tAML in long-term survivors continues to be a serious complication with poor overall outcome. The contribution of TBI to the development of secondary leukemias seems to be convincing on the basis of available studies, and efforts must be made to design better and less toxic preparative regimens.


    Footnotes
 
+ Correspondence to: Dr C. Hosing, Department of Blood and Marrow Transplantation, The University of Texas M.D. Anderson Cancer Center, PO Box 423, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Tel: +1-713-792-8750; Fax: +1-713-794-4902; E-mail: cmhosing@mdanderson.org Back


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 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
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