Leukemia (2016), 1–3 © 2016 Macmillan Publishers Limited All rights reserved 0887-6924/16 www.nature.com/leu
LETTER TO THE EDITOR
Results of a multicenter prospective phase II trial investigating the safety and efficacy of lenalidomide in patients with myelodysplastic syndromes with isolated del(5q) (LE-MON 5) Leukemia advance online publication, 26 January 2016; doi:10.1038/leu.2015.340
Herein we report on an open-label, nonrandomized, single-arm, multicenter-, phase II trial conducted by the German MDS-StudyGroup, evaluating the safety of lenalidomide in myelodysplastic syndrome (MDS) with isolated del(5q) and trying to identify patterns of disease progression (LE-MON5; EudraCT number: 2008‐001866‐10). The primary endpoint was safety, secondary endpoints were: response defined as transfusion independence on 56 consecutive days after enrollment, International Working Group (IWG) response criteria,1 including cytological and cytogenetic response, time to and duration of transfusion independence, frequency and time to disease progression, incidence and severity of adverse events (AE). In addition, the role of mitochondrial DNA (mtDNA) mutations in the context of treatment with lenalidomide was analyzed. In order to treat a homogenous patient population we performed a standardized screening procedure including central cytological and histological review of bone marrow and conventional karyotyping. Patients with the need of at least one red cell transfusion within 8 weeks prior to first administration of study drug belonging to the international prognostic scoring system low- or intermediate-1 risk groups with a medullary blast count of o5% and presence of an isolated del(5q) were included. The planned dose of lenalidomide was 10 mg/day, orally on days 1–21 (28-day cycle). Dose adjustment in case of AE was mandatory. The duration of treatment with lenalidomide was limited to 4 months, if there was no response, and was continued only in case of transfusion independence for longer than 4 weeks during the first 4 months of study treatment until reoccurrence of transfusion dependence or progressive disease. We also searched for somatic mutations of mtDNA that were previously detected by our group in the marrow of a proportion of patients with MDS.2 One-hundred forty-seven patients were screened, 91 patients met the inclusion criteria but in 2 patients treatment was not started. A total of 89 patients formed the safety- and full analysis set. Fifty-six patients (38%) were screening-failures because of discrepancy to the inclusion criteria in cytology (48%), histology (26%) and banding analyses (68%) (multiple discrepancies were possible). For 30 patients who failed screening, follow-up information on progression status was available. Of them 27% had progressed to high-risk MDS or acute myeloid leukemia (AML) by the cut-off date 30 April 2015. Five patients later underwent allogeneic stem cell transplantation and 8 patients were treated with lenalidomide outside the trial. Patient characteristics are summarized in Table 1. Median number of treatment cycles was 12 (1–48). Seventyeight patients received 10 mg lenalidomide as planned (88%); in 11 patients a dose reduction was necessary from the beginning because of renal insufficiency. Dose adjustment primarily due to Accepted article preview online 15 December 2015
cytopenias was necessary most often in cycle 2 (17/31 patients, 55%). A total of 60 (67%) patients achieved transfusion independence. The median increase of hemoglobin compared with screening was 3.6 g/dl (0.3–10.0). Of these patients, 44 (73%) remained transfusion independent until end of observation (median observation time was 20 months (1–44)), while 16 (27%) needed transfusions again. Median time to transfusion independence starting from the first day of study medication was 12 weeks. Table 1.
Patients´ characteristics Median (range)
Age
70 years (40–87)
Sex Female Male
n (%) 70 (79) 19(21)
FAB-classification RA RARS RAEB Missing data
77 8 1 3
WHO-classification MDS with isolated del (5q) RAEB I
88 (99) 1 (1)
ECOG 0 1 2 3 Missing data
39 39 6 2 3
IPSS risk groups Low Intermediate-1
52 (58) 37 (42)
IPSS-R risk groups Very low Low Missing data
19 (21) 69 (78) 1 (1)
Laboratory parameters HB WBC PLT
(87) (9) (1) (3)
(44) (44) (7) (2) (3)
median (range) 8.9 g/dl (5.7–11.5) 3.8 × 109/l (1.7–22.6) 269 × 109/l (69–1204)
Abbreviations: FAB, French-American-British; HB, hemoglobin; IPSS, international prognostic scoring system; MDS, myelodysplastic syndrome; PLT, platelets; RA, refractory anemia; RARS, refractory anemia with ring sideroblasts; RAEB, refractory anemia excess blasts; WBC, white blood cell count.
Letter to the Editor
2 Sixty-one (69%) patients were responders following the IWG criteria. Median time of response was 14 months (1–44 months) (maximum observation time 48 month). Hematologic improvement was observed in 60 (67%) patients (of those 28 complete remissions and 13 partial remissions). There was no relationship between age, gender, thrombocytopenia or dose of lenalidomide and hematologic response. Cytogenetic response could be evaluated in 59 patients. Of those, 49 patients responded (28 major and 21 minor responses, according to Cheson et al.1). All 28 patients with a major response achieved transfusion independence in comparison with 16 out of 21 patients with only a minor response (P = 0.01). Seven out of 10 patients became transfusion independent without achieving cytogenetic response. Cytogenetic response was further associated with lower probability of progression in terms of either loss of transfusion independence or evolution to higher-risk MDS or AML (P = 0.003). Twenty (23%) patients progressed either to refractory anemia excess blasts (RAEB) or AML. Three patients progressed to RAEB-I, 4 to RAEB-II, 3 first into RAEB-I and later into AML, 4 first into RAEBII and later into AML and 6 directly into AML. These sum up to 13 (15%) patients with AML transformation until 20 May 2015. Median time to AML transformation was 54.1 months after start of therapy. Cumulative risk for AML evolution was 8% after 2 and 14% after 4 years, respectively. Seven (35%) patients progressed to RAEB or AML during treatment phase. Fourteen patients progressed within 2 years after treatment start. The remaining six patients developed RAEB or AML up to 4 years after initiating treatment. Of note, IWG responders developed high-risk MDS or AML equally often as nonresponders. Hematologic responders lived longer than nonresponders (log-rank test P o 0.0001, median survival not reached vs 27 months). 90% of patients were alive after 2 years and 82% after 4 years (Figure 1). Sixteen (18%) patients died within the observation period. For the four patients, who died during treatment period, an AE was documented as reason for death (1 pneumonic sepsis, 2 ischemic apoplexes and 1 hemolytic anemia). The remaining 12 patients died during the follow-up period. In univariate Cox regression analyses, parameters positively associated with survival (Po0.1) were: IWG response, cytogenetic response and transfusion independence. Negative impact on survival was noted for development of RAEB or AML, loss of transfusion independence, higher age and high transfusion burden during the 8 weeks preceding treatment start. In multivariate Cox regression analysis with stepwise exclusion of parameters (Po0.05) high transfusion burden during the 8 weeks preceding treatment
Figure 1. Kaplan–Meier plot showing overall survival of all patients treated and IWG-responders vs IWG-nonresponders. Leukemia (2016) 1 – 3
start (P = 0.0088), progression to RAEB or AML (P = 0.0309) and higher age (P = 0.0464) negatively influenced survival. Eighty-eight (99%) patients had at least one AE that occurred or aggravated after treatment start. Most frequent AE were hematological AE (89%), infections (69%) and gastrointestinal disorders (66%). Eighty-five (96%) patients had at least one AE with CTC grade 3 or higher. Serious adverse events were observed in 50 (56%) patients. MtDNA markers were assessed in patients, who responded to lenalidomide, in order to see whether clone size is diminishing. The clonal mitochondrial marker disappeared in 12 of the 17 patients (70%). Cytogenetic follow-up was available in 15 of 17 patients. Of 15 patients with a cytogenetic response, 12 (80%) also showed disappearance of mtDNA marker. Our study shows that two-thirds of the patients achieve sustained transfusion independence, confirming the results of MDS-003 and MDS-004 studies.3,4 Surprisingly, the percentage of responders was not higher than in previous trials although we only included patients with isolated del(5q) and medullary blast count of less than 5%. Obviously, response to lenalidomide is not strictly linked to morphologic and cytogenetic characteristics of the disease, but might also be mediated by other effects of the drug on the microenvironment.5,6 One quarter of patients lost transfusion independence during treatment, while two-thirds remained transfusion independent throughout the study. As our study population was homogeneous due to the rigid screening procedures and strict inclusion criteria we were not able to identify parameters that predict response besides achievement of cytogenetic response. Progression to AML was observed in 15% of patients, the 2-year cumulative risk of AML evolution was 8% and the 4-year cumulative risk was 14%. This proportion is comparable to the untreated population of patients with MDS with isolated del(5q) as previously reported by our group and others,7,8 as well as other treated populations.3,9,10 Thus, there is no clinical evidence for a propagation of the malignant cell clone by lenalidomide. Major cytogenetic response was demonstrated in 47% of the patients with a high correlation with achievement of transfusion independence, although there were patients with a persisting del (5q) clone achieving transfusion independence. This indicates that cytogenetic response is not a prerequisite for hematologic response. High transfusion burden, higher age and progression to AML are major parameters associated with a worse outcome even in the relatively small cohort of our study population. These findings are in line with well-known data on prognosis in low-risk MDS in general11–13 as high transfusion burden reflects the degree of hematopoietic insufficiency, progression to AML reflects clonal expansion. Responding patients had a longer median survival time as compared to nonresponders. As there was no difference with regard to higher-risk MDS- or AML-progression the survival benefit of the responders might be an effect of improvement of hematopoiesis. The number of adverse events in patients undergoing treatment with lenalidomide was relatively high, primarily due to cytopenias leading to infections. Nevertheless, treatment had to be stopped only in a minority of patients due to side effects. In summary, treatment of transfusion dependent MDS patients with an isolated del(5q) and a medullary blast count of o 5% with lenalidomide is efficient and safe. However, still a minority of patients does not respond and some patients progress to leukemia that cannot be foreseen by means of conventional cytogenetics, histology and cytology. Potentially, new techniques such as next generation sequencing with mutation analysis or frequent sequential cytogenetic follow-up by CD34-FisH of peripheral blood will be able to better characterize patients, who are at a high risk for treatment failure and disease progression.14,15 © 2016 Macmillan Publishers Limited
Letter to the Editor
CONFLICT OF INTEREST The trial was supported by Celgene, by providing the compound, supporting data monitoring and technical processing of bone marrow biopsies. ES obtained travel grant for attending symposia from Celgene. ArGi obtained personal financial interests from Celgene. DH obtained research support, honorarium and attending symposia from Celgene. UP obtained honoraria and research funding from Celgene. FN obtained honoraria and research funding from Celgene. KG obtained honoraria from Celgene. RFS obtained research support from Celgene. AL obtained research funding from Celgene. KS obtained travel grant for attending symposia from Celgene. GeBu obtained research support, travel grants and honoraria from Celgene. PS obtained financial support for training events from Celgene. NG obtained honoraria and research funding from Celgene. UG obtained speaker honorarium and research support from Celgene. The remaining authors declare no conflicts of interest.
ACKNOWLEDGEMENTS The trial was supported by Celgene, providing the compound, supporting data monitoring and technical processing of bone marrow biopsies. ES wrote the paper, analyzed the data and approved the final version; ArGi performed centralized cytology, contributed essential data and approved the final version; DH performed cytogenetic banding analyses, contributed essential data and approved the final manuscript; GuBu performed centralized histology and approved the final version; UP, FN, KG, RFS, ArGa, FB, ML, AL, PS, UB, NG, GeBu and RH contributed essential data and approved the final version; KS performed cytogenetic banding analyses and approved the final manuscript; MW performed research and approved the final version and UG designed the research, contributed essential data, analyzed the data and approved the final version.
E Schuler1, A Giagounidis2, D Haase3, K Shirneshan3, G Büsche4, U Platzbecker5, F Nolte6, K Götze7, RF Schlenk8, A Ganser9, A Letsch10, F Braulke3, M Lübbert11, G Bug12, P Schafhausen13, U Bacher3, N Gattermann1, M Wulfert1, R Haas1 and U Germing1 1 Department for Hematology, Oncology and Clinical Immunology, University Hospital, Heinrich-Heine-University, Duesseldorf, Germany; 2 Department of Hematology, Oncology and Palliative Care, Marien Hospital Duesseldorf, Duesseldorf, Germany; 3 University Medicine Goettingen, Clinics of Hematology and Medical Oncology, Goettingen, Germany; 4 Hannover Medical School, Institute of Pathology, Hannover, Germany; 5 Department of Hematology, University Hospital Dresden, Dresden, Germany; 6 Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany; 7 Department of Internal Medicine, Technical University of Munich, Munich, Germany; 8 Department of Internal Medicine, University Hospital Ulm, Ulm, Germany; 9 Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany; 10 Department of Hematology and Oncology, Charité, Benjamin Franklin University, Berlin, Germany; 11 University Hospital Freiburg, Internal Medicine, Freiburg, Germany; 12 Department of Internal Medicine, University Hospital Frankfurt, Frankfurt, Germany and
© 2016 Macmillan Publishers Limited
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Department of Oncology, Hematology, BMT with section Pneumology, Hubertus Wald Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, Germany E-mail:
[email protected] REFERENCES 1 Cheson BD, Bennett JM, Kantarjian H, Pinto A, Schiffer CA, Nimer SD et al. Report of an international working group to standardize response criteria for myelodysplastic syndromes. Blood 2000; 96: 3671–3674. 2 Wulfert M, Kupper AC, Tapprich C, Bottomley SS, Bowen D, Germing U et al. Analysis of mitochondrial DNA in 104 patients with myelodysplastic syndromes. Exp Hematol 2008; 36: 577–586. 3 List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456–1465. 4 Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M et al. A randomized phase 3 study of lenalidomide versus placebo in RBC transfusiondependent patients with Low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011; 118: 3765–3776. 5 Geyh S, Oz S, Cadeddu RP, Frobel J, Bruckner B, Kundgen A et al. Insufficient stromal support in MDS results from molecular and functional deficits of mesenchymal stromal cells. Leukemia 2013; 27: 1841–1851. 6 Ferrer RA, Wobus M, List C, Wehner R, Schonefeldt C, Brocard B et al. Mesenchymal stromal cells from patients with myelodyplastic syndrome display distinct functional alterations that are modulated by lenalidomide. Haematologica 2013; 98: 1677–1685. 7 Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P et al. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study. Leukemia 2012; 26: 1286–1292. 8 Mallo M, Cervera J, Schanz J, Such E, Garcia-Manero G, Luno E et al. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia 2011; 25: 110–120. 9 Kuendgen A, Lauseker M, List AF, Fenaux P, Giagounidis AA, Brandenburg NA et al. Lenalidomide does not increase AML progression risk in RBC transfusiondependent patients with Low- or Intermediate-1-risk MDS with del(5q): a comparative analysis. Leukemia 2013; 27: 1072–1079. 10 List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352: 549–557. 11 Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Sole F et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood 2012; 120: 2454–2465. 12 Malcovati L, Germing U, Kuendgen A, Della Porta MG, Pascutto C, Invernizzi R et al. Time-dependent prognostic scoring system for predicting survival and leukemic evolution in myelodysplastic syndromes. J Clin Oncol 2007; 25: 3503–3510. 13 Giagounidis AA, Germing U, Haase S, Hildebrandt B, Schlegelberger B, Schoch C et al. Clinical, morphological, cytogenetic, and prognostic features of patients with myelodysplastic syndromes and del(5q) including band q31. Leukemia 2004; 18: 113–119. 14 Jadersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Gohring G et al. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol 2011; 29: 1971–1979. 15 Braulke F, Jung K, Schanz J, Gotze K, Muller-Thomas C, Platzbecker U et al. Molecular cytogenetic monitoring from CD34+ peripheral blood cells in myelodysplastic syndromes: first results from a prospective multicenter German diagnostic study. Leuk Res 2013; 37: 900–906.
Leukemia (2016) 1 – 3
