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Originally published as JCO Early Release 10.1200/JCO.2003.07.160 on March 7 2003 © 2003 American Society for Clinical Oncology Secondary Myeloid Leukemia and Myelodysplastic Syndromes in Patients Treated for Hodgkin’s Disease: A Report From the German Hodgkin’s Lymphoma Study Group
From the First Department of Internal Medicine, University Hospital, Cologne, Germany; and the German Hodgkin’s Lymphoma Study Group (GHSG). Address reprint requests to Andreas Josting, MD, First Department of Internal Medicine, University Hospital Cologne, Joseph-Stelzmann-Str. 9, 50924 Cologne, Germany; email: andreas.josting{at}uni-koeln.de.
Purpose: To assess the incidence and outcome of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) in patients with Hodgkin’s disease (HD). Patients and Methods: Between 1981 and 1998, the GHSG conducted three trial generations for early, intermediate, and advanced HD involving a total of 5,411 patients (called HD1 through HD9). Results: A total of 46 patients with secondary AML/MDS were identified. The median age at diagnosis of leukemia was 47 years (range, 22 to 79 years). Primary therapy was as follows: radiotherapy alone (n = 4); doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD; n = 1); cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD or similar (n = 30); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) baseline (n = 2); and BEACOPP escalated (n = 9). Twelve patients developed AML/MDS after salvage therapy, including four patients who developed AML/MDS after high-dose chemotherapy with autologous stem-cell transplantation. Thirty-six of the secondary malignancies were AML, and 10 malignancies were MDS. After a median observation time of 55 months, incidence of secondary AML/MDS was 1%. Treatment for secondary AML/MDS was as follows: cytarabine (Ara-C)–containing regimens (6-thioguanin, cytarabine, daunorubicin [TAD]/high-dose cytarabine, mitoxantrone [HAM], HAM, Ida-Ara-C (idarubicin + Ara-C), Ida-Flag (idarubicin, fludarabin, Ara-C, G-CSF), and idarubicin, cytarabine, etoposide [ICE]+HAM; n = 11), TAD-chemotherapy (n = 5), other regimens (n = 3), no treatment or supportive care (n = 24), palliative oral chemotherapy (n = 3), and allogeneic stem cell transplantation (n = 9). After 24 months of observation, no difference in freedom from treatment failure and overall survival (2% and 8%, respectively) was observed in patients who developed AML or MDS. Conclusion: The prognosis of patients with secondary AML/MDS after primary HD is poor. Thus, emphasis should be made to improve initial treatment in an attempt to prevent this complication.
DEPENDING ON stage and risk factor profile, more than 80% of patients with Hodgkin’s Disease (HD) can be cured with first-line treatment.1 Long-term survivors are at risk for late treatment-related complications, such as infertility, cardiac or pulmonary dysfunction, or thyroid-related sequelae. Increased risk of secondary cancers has been observed after chemo- and radiotherapy. The malignancies most frequently associated with chemotherapy include acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).2–6 Treatment-related AML and MDS generally respond poorly to therapy. At present, there is no clear treatment strategy for secondary AML/MDS after HD, which is at least in part caused by the scarcity of data. Curative treatment strategies in secondary malignancies after HD are not yet standardized. Controversy exists about the value of hematopoietic stem cell transplantation. High-dose chemotherapy (HDCT) with allogeneic stem cell transplantation (ASCT) has resulted in some responses.7–9 However, review of the literature reveals little information about the long-term clinical outcome of treatment-related AML or MDS after treatment for HD. Therefore, we performed a retrospective analysis of 46 patients with secondary AML/MDS who were registered in the database of the German Hodgkin’s Lymphoma Study Group (GHSG). The purpose of the present analysis was to determine the incidence and treatment outcome in respect to long-term results.
Patient selection Between 1981 and 1998, 5,411 HD patients who were registered in the GHSG database were enrolled into three generations of clinical trials; called HD1 through HD9 (Table 1  ). To be eligible for participation in the trials, patients had to be between the ages of 16 and 75 years and had to have biopsy-proven HD at diagnosis. GHSG expert pathologists reviewed histology slides from 4,104 patients (76% of the total number of HD patients). Each patient signed informed-consent forms, which were based on institutional review board guidelines. All patients were treated according to the study protocols of the GHSG (Table 1). Analysis of survival for all patients recorded in the GHSG trial database was based on the data available as of June 2001.
Secondary AML and MDS For patients who developed secondary AML or MDS, the following parameters were recorded: date of diagnosis, age at diagnosis, time between primary HD and secondary neoplasia, and type of treatment regimen for HD, including chemotherapy, radiotherapy, combined modality treatment, or high-dose chemotherapy (HDCT) with SCT. The attending physician made treatment decisions for secondary AML/MDS. French-American-British (FAB) criteria were used for classification of AML and MDS. Cytogenetic evaluations were performed from the early 1990s on.
Treatment of Secondary AML and MDS
The following chemotherapy regimens were used in the treatment of secondary AML/MDS: 6-thioguanin 100 mg/m2 PO days 3 through 9; cytarabine 100 mg/m2 intravenously (IV) days 1 through 2 and 100 mg/m2 every 12 hours IV days 3 through 8; and daunorubicin 60 mg/m2 IV days 3 through 5 (TAD); high-dose cytarabine 3 g/m2 every 12 hours IV days 1 through 3 and mitoxantrone 10 mg/m2 IV days 3 through 5 (HAM); idarubicin 10 mg/m2 IV days 1, 3, and 5; cytarabine 100 mg/m2 IV days 1 through 7; and etoposide 100 mg/m2 IV days 1 through 3 (ICE); cytarabine 100 mg/m2 IV days 1 through 2 and 100 mg/m2 every 12 hours IV days 3 through 8; daunorubicin 60 mg/m2 IV days 3 through 5; and 6-thioguanin 100 mg/m2 every 12 hours days 3 through 9 (DAE); mitoxantrone 10 mg/m2 IV days 4 through 8; cytarabine 100 mg/m2 days 1 through 8; and etoposide 100 mg/m2 IV days 4 through 8 (MAV); and cytarabine 2 x 1,000 mg/m2 IV days 1 through 5, and amsacrine 100 mg/m2 IV days 1 through 5 (MAMAC).
Statistical Analysis
Patient Characteristics Patient characteristics are shown in Table 3 . Of the 5,411 patients registered in the GHSG database, 46 were identified with secondary AML or MDS. Six (13%) of the 46 patients with secondary AML/MDS had early-stage disease, 16 (35%) had intermediate-stage disease, and 24 (52%) had advanced-stage disease at first diagnosis of HD. Primary treatment for HD consisted of radiotherapy alone in four patients (9%) and a combined modality treatment in 36 patients (78%). Twelve patients (26%) developed secondary AML/MDS after salvage therapy for relapsed HD, including four patients (9%) who underwent HDCT treatment with SCT. At the time of diagnosis of secondary AML or MDS, the median age was 47 years (range, 22 to 79 years). Subtypes of secondary AML or MDS are also given in Table 3, with 36 (78%) patients diagnosed with AML and 10 (22%) patients diagnosed with MDS.
The total number of patients treated with radiotherapy alone; adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD); different cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/ABVD; or COPP/adriamycin, bleomycin, and vinblastine (ABV)/ifosfamide, methotrexate, etoposide, and prednisone (IMEP) and bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) regimens are shown in Table 4 .
A total of 15 out of the 46 secondary AML/MDS patients had a cytogenetic evaluation performed (Table 5 ). Clonal chromosome aberrations were found in all 15 patients, with abnormalities being found on chromosomes 5 or 7 (n = 6) and rearrangements on chromosome 11 (n = 6). Chromosome analysis revealed a complex aberrant karyotype in six patients and a 45XO (one missing sex chromosome) in one patient.
Time of Occurrence and Relative Risk of Secondary AML or MDS The median follow-up times for each trial were as follows: HD1 through HD3, 124 months (n = 502); HD4 through HD6, 85 months (n = 1,929); and HD7 through HD9, 38 months (n = 2,980). After a median observation time (for all 5,411 patients) of 55 months, the cumulative relative risk of developing secondary AML/MDS was 1% (95% confidence interval [CI], 0.6% to 1.2%). The median interval between the end of HD initial therapy and the diagnosis of secondary AML/MDS was 12.5 months (range, 0 to 128 months). Eighty-nine percent of secondary AML or MDS cases occurred within 5 years of completing the initial therapy for HD. Secondary AML or MDS occurred in less than 12 months in 10 patients and after 5 years in five patients (Fig 1 ).
Outcome of Secondary AML or MDS Median survival after AML/MDS diagnosis was 4 months (range, 0 to 76 months) in the entire group of patients and 10 months (range, 3 to 28 months) in the subgroup of patients who underwent SCT. Ten (22%) patients died within a month after the diagnosis of secondary AML or MDS, 18 patients died within 6 months, and 11 patients died within 1 year. Thus, 85% (39 of 46) of patients with secondary AML/MDS did not survive for more than 1 year after diagnosis. Two patients survived more than 5 years after diagnosis. These two surviving patients were diagnosed with AML promyelocytic leukemia (M3) and MDS refractory anemia with excess of blasts (RAEB), respectively. Thirty-four (74%) patients died of secondary AML or MDS itself; seven (15%) patients died of transplant-related complications, including five from pneumonia after allogeneic SCT and two from acute graft-versus-host disease (GVHD); and two (4%) patients died of therapy-related conditions (eg, pneumonia).
After 24 months of observation, FFTF and OS were 2% and 8%, respectively (Fig 2
In principle, an analysis of both the relative and absolute risks calculated for the various initial treatment protocols would be useful; however, in this study, the number of patients with secondary AML in each treatment protocol was too small to allow statistically significant differences to be observed. This lack of statistical power is illustrated by Table 6 , which lists the calculated (absolute) risks and their 95% CIs for the nine chemotherapy protocols (irrespective of accompanying radiotherapy) and for extended-field (EF) and involved-field (IF) radiotherapy (irrespective of accompanying chemotherapy).
All CIs overlapped considerably, indicating that the calculated risks resulting from the various treatment protocols do not differ statistically significantly. Initial treatment with the escalated BEACOPP protocol appears to be associated with more patients developing secondary AML than does radiotherapy alone or two double cycles of the "older" chemotherapy protocols (COPP/ABVD, ABVD, or COPP/ABV/IMEP). Interestingly, we have already analyzed the risk of developing AML after initial treatment with COPP/ABVD, baseline BEACOPP, and escalated BEACOPP chemotherapy protocols using data from the HD9 trial for advanced-stage Hodgkin’s disease, and we have found that the risk of developing AML is statistically significantly elevated after using escalated BEACOPP compared with COPP/ABVD.11 Because the method of analysis of the data from the HD9 trial was a randomized comparison, the risk estimates may be more believable than those based on comparisons between different trials, as is the case in this retrospective analysis, in which the patient populations under comparison may not necessarily be similar in terms of age, stage of HD, radiotherapy, salvage therapy, and so forth. Therefore, a comparison of AML risk between patients, whether using absolute risk, relative risk, or absolute excess risk, is not appropriate for this study.
The following findings emerge from this study: first, after a median follow-up of 5 years, the cumulative risk of secondary AML or MDS in HD patients in the database of the GHSG is low (1%); second, the majority of secondary AML/MDS cases occurred within the first year after completion of initial therapy; third, the outcome of patients diagnosed with secondary AML/MDS is extremely poor, with only 4% (two of 46) of patients surviving longer than 5 years; fourth, the outcome of patients receiving allogeneic SCT does not differ from those who received conventional or no therapy; and fifth, there is no difference in the outcome (either FFTF or OS) in AML or MDS patients. Although several reports exist that document the incidence and risk factors for developing secondary AML or MDS after primary HD,3,4,12–14 little is known about treatment outcome and prognostic factors for these patients. The incidence of secondary AML/MDS following conventional chemotherapy ranges from 0.8% to 6.3% after 6 to 20 years.3,4,12–14 Historically, the actuarial risk has decreased in recent studies.15,16 The cumulative probability of developing AML or MDS after SCT for lymphoma varies from 4.3% to 14.2% at 5 years.6,17,18 The comparatively low incidence of AML/MDS in our cohort (1% at 5 years) may result from different treatment regimes and from the different leukemogenic potential of the chemotherapy drugs used in our trials. For example, mechlorethamine was replaced by cyclophosphamide in all GHSG trials. A variety of risk factors associated with the development of secondary AML/MDS have been found. For example, a positive relationship has been found between the cumulative dose of alkylating agents or topoisomerase II inhibitors and the risk of developing secondary AML/MDS.19 In addition, an increased incidence of leukemia has also been linked to previous radiation exposure.20 Older age, number and type of prior courses of chemoradiotherapy, exposure to radiotherapy before transplantation, and use of total-body irradiation in the conditioning regimen have also been been shown to be related to the development of secondary AML/MDS after HDCT with SCT.4,21 Certain cytogenetic abnormalities and the latency period between previous anticancer treatment and the development of secondary AML/MDS depends on the use of chemotherapy drugs. The latency period is shorter after topoisomerase II inhibitors (eg, 2 to 3 years) and longer after alkylating agents (eg, 3 to 8 years). Although our data confirm that most of the secondary AML/MDS cases occur within the first year after completion of initial therapy, further alkylating agent–induced secondary neoplasias might be expected at later dates. Several authors have reported poor outcome after diagnosis of secondary AML/MDS in primary HD patients. Neugut et al19 have reported an estimated survival time at 12 months of 10% for therapy-related AML/MDS. Furthermore, Harrison et al20 have reported actuarial 5- and 10-year survival rates of 17.4% and 8.7%, respectively, from the British National Lymphoma Investigation (BNLI) group database. In our analysis, FFTF and OS at 2 years were 2% and 8%, respectively, for all patients. Patients with secondary AML/MDS are frequently referred for allogeneic SCT if donor availability, age, and medical condition permit. However, the feasibility of transplantation in treatment-related AML/MDS appears to be overestimated. In our analysis, transplantation was only practical in a small percentage of patients with secondary AML/MDS. Less than 35% (15 of 46) of our patients would have been eligible for transplantation, taking into account the fact that 28 patients died within 6 months after diagnosis of AML and that an additional three patients were older than 60 years. Although different studies20,22 have reported 5-year disease-free survival figures of 16% and 24.4%, respectively, after SCT, the patients in these studies represent only a small selected subgroup of all patients with secondary AML/MDS. Friedberg et al23 reported the outcome of 41 patients who developed secondary MDS after autologous SCT for treatment of non-Hodgkins’s lymphoma. In another study,24 13 patients underwent allogeneic bone-marrow transplant (BMT) as treatment for MDS. All of those patients either died of BMT-related complications (11 patients) or had a relapse (two patients); median survival was only 1.8 months, which underlines the high treatment-related mortality of allogeneic SCT in MDS patients Some authors claim tailor-made protocols with regard to the cytogenetic findings. Patients with a favorable karyotype (eg, inv(16), t(8,21)) should be treated as for de novo AML cases, whereas palliative treatment or experimental approaches should be considered for patients with a complex aberrant karyotype.8,25 In our cohort, only 15 cytogenetic analyses were available. This relatively low number might be because of the fact that the patients in our study had been treated since the early 1980s, when cytogenetic analysis was not common. Interestingly, however, favorable karyotypes were not found in our cohort, which might be an additional explanation for their poor outcome. A better outcome is seen in patients with favorable risk cytogenetics than in those with nonfavorable risk cytogenetics.26 The poor OS of the GHSG cohort does not allow us to detect differences in the outcome of patients who undergo transplantation versus conventionally treated patients or between AML or MDS. Therefore, the question arises: What can be done to improve the outlook for all patients with secondary AML/MDS to avoid over- or undertreatment? The poor outcome of AML/MDS patients underlines the need to evaluate new treatment strategies. At present, untreatable patients should be identified at an early stage and should be given palliative treatment or, alternatively, new treatment options. To circumvent the problems, such as toxicity and treatment-related mortality, inherent to allografting, engraftment of allogeneic stem cells after immunosuppressive therapy combined with myelosuppressive, but nonmyeloablative, therapy (ie, "minitransplants") has been assessed. Several groups have recently updated their experience with nonmyeloablative conditioning regimens.27,28 New agents, such as farnesyl transferase inhibitors (ras inhibitors) or drug-antibody conjugates should be explored. In conclusion, the prognosis of patients with secondary AML/MDS after primary HD is poor, and allogeneic BMT as it is presently performed is not a treatment option because of excessive toxicity. Emphasis, therefore, should be made on improving the initial treatment in HD patients in an attempt to prevent secondary complications.
This article was published ahead of print at www.jco.org.
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