Abstract
Background: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement–platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4–3·8). Methods: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18–90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Findings: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48–2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72–1·47]; p=0·89) were not significantly different between the two groups. Interpretation: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Funding: Amgen Inc.
| Original language | English (US) |
|---|---|
| Pages (from-to) | e117-e126 |
| Journal | The Lancet Haematology |
| Volume | 5 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 2018 |
ASJC Scopus subject areas
- Hematology
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In: The Lancet Haematology, Vol. 5, No. 3, 03.2018, p. e117-e126.
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}
TY - JOUR
T1 - Long-term follow-up for up to 5 years on the risk of leukaemic progression in thrombocytopenic patients with lower-risk myelodysplastic syndromes treated with romiplostim or placebo in a randomised double-blind trial
AU - Kantarjian, Hagop M.
AU - Fenaux, Pierre
AU - Sekeres, Mikkael A.
AU - Szer, Jeffrey
AU - Platzbecker, Uwe
AU - Kuendgen, Andrea
AU - Gaidano, Gianluca
AU - Wiktor-Jedrzejczak, Wieslaw
AU - Carpenter, Nancy
AU - Mehta, Bhakti
AU - Franklin, Janet
AU - Giagounidis, Aristoteles
N1 - Funding Information: As previously described, after the 2011 decision to stop the study drug treatment because of the increased risk of transformation to acute myeloid leukaemia for patients treated with romiplostim compared with those treated with placebo (based on the data available at that time), the 5-year follow-up data show that the acute myeloid leukaemia hazard ratio subsequently decreased with no increased risk of acute myeloid leukaemia for those who had been treated with romiplostim versus those who had been treated with placebo. 16 For the 25 patients treated with romiplostim in whom transient blast cell count increases were seen, blast counts decreased in most patients with available follow-up data, with persistent blast cell count increases reported in two patients. 16 In this long-term follow-up, we found that final 5-year HRs for progression to acute myeloid leukaemia or death for those initially receiving romiplostim versus those initially receiving placebo showed no significant differences. Thus, over the course of this trial, we found that romiplostim reduced platelet transfusions and bleeding with no long-term increase in acute myeloid leukaemia incidence or impact on survival. Subgroup analyses also showed no increased risk for acute myeloid leukaemia with romiplostim versus placebo when examined by characteristics such as baseline blasts, IPSS, IPSS-R, WHO classification, cytogenetics, baseline transfusion needs, and baseline platelet count and haemoglobin. However, these subgroup results should be interpreted with caution because many of the subgroups had small numbers of patients and few patients who developed acute myeloid leukaemia. Therefore, some associations might exist that our study did not have the statistical power to detect. We found that, in addition to romiplostim increasing the proportion of patients who achieved HI-P to 15 times that of placebo, treatment was also associated with increased levels of red blood cells and neutrophils, indicating possible trilineage responses. Our results provide additional information for haematologists treating patients with myelodysplastic syndromes with thrombopoietin receptor agonists; they will have to balance our new findings (ie, no increased risk of acute myeloid leukaemia with romiplostim treatment) with warnings or precautionary language in the prescribing information. 8 The safety DMC that recommended discontinuation of the study treatment noted a risk not just for acute myeloid leukaemia but for the diagnosis of and treatment for acute myeloid leukaemia because of increases in blast cell counts. Notably, romiplostim has been reported to be associated with transient increases in blast cell count in the absence of progression to acute myeloid leukaemia. 12 Specifically, should a patient develop increased blast cell counts, depending on that patient's other risk factors for acute myeloid leukaemia, it might not be feasible to wait the recommended 4 weeks after discontinuation of romiplostim to establish if the blast cell counts decreased. Instead, the treating physician would have to consider starting treatment for acute myeloid leukaemia before those 4 weeks elapsed, as occurred in the six patients in this study who were diagnosed with acute myeloid leukaemia solely because of starting anti-acute myeloid leukaemia therapy. That the study definition of acute myeloid leukaemia included patients diagnosed solely because of antileukaemic treatment can certainly be seen as a weakness of the study. However, the proportions of patients who developed acute myeloid leukaemia when defined only as having bone marrow or peripheral blasts of at least 20% (ie, excluding those previously diagnosed as having acute myeloid leukaemia on the basis of antileukaemic treatment alone) were not notably different between romiplostim and placebo (17 [10%] of 167 vs six [7%] of 83), indicating that similar results would have been obtained even without including the antileukaemic treatment acute myeloid leukaemia definition. Of note, half of the patients diagnosed with acute myeloid leukaemia in this study were classified as WHO category RAEB-1 at baseline, indicating that particular caution be taken in patients with excess blasts, as is supported by the results of an investigator-sponsored study of romiplostim in lower-risk myelodysplastic syndromes in which patients had less than 5% bone marrow blasts ( NCT02335268 , personal communication from UP). Another factor to consider is baseline thrombopoietin concentrations and transfusion history, because patients with lower baseline thrombopoietin and lower platelet transfusion burden have previously been shown to be more responsive to romiplostim. 24 Caveats to keep in mind when interpreting these data include that although results are reported per treatment, all investigational product was discontinued in February, 2011, according to safety DMC recommendations. Therefore, we are reporting results from a partially completed study; we can only speculate on what results would have been had all patients completed the full course of their treatment to week 54, including the 69 patients (46 romiplostim and 23 placebo), 28% of the study population, who discontinued treatment as per the advice of the safety DMC. More patients might potentially have had blast cell count increases or acute myeloid leukaemia with longer exposure to romiplostim. However, notably, only two cases of acute myeloid leukaemia occurred in a group of 60 patients with lower-risk myelodysplastic syndromes who received a median of 1·5 years of romiplostim monotherapy in an extension study and corresponding parent studies. 10 Furthermore, the 5 years of long-term follow-up were observational in nature, with the only follow-up being to establish if patients had died or developed acute myeloid leukaemia, and any reported use of anti-acute myeloid leukaemia and anti-myelodysplastic syndromes therapies. As this was a long-term follow-up, the reported numbers of anti-acute myeloid leukaemia and anti-myelodysplastic syndromes treatments did not receive the same level of scrutiny as would have occurred during active treatment (ie, examination of study notes to confirm that appropriate categorisation occurred). Platelet counts, transfusions, and bleeding were not recorded in the long-term follow-up, nor were adverse events (other than death or acute myeloid leukaemia), so we cannot comment on long-term effects of romiplostim on efficacy or safety in these patients. Results from our study reflect romiplostim's profile as monotherapy for myelodysplastic syndromes in patients with lower-risk myelodysplastic syndromes. Although earlier phase 2 studies showed that romiplostim might be beneficial (in terms of platelet counts, bleeding, and platelet transfusions) in conjunction with azacitidine, 25 decitabine, 11 and lenalidomide 14 in patients with low, intermediate-1, or intermediate-2 IPSS risk myelodysplastic syndromes, further studies are needed to comprehensively analyse combination therapy. For example, these earlier studies lasted only four cycles (∼4 months), so we cannot state with certainty that further romiplostim treatment would not have led to increased diagnoses of acute myeloid leukaemia, though to our knowledge, no available data suggest this. In summary, data from this large placebo-controlled study with 5-year long-term follow-up show that romiplostim was able to increase platelet counts and decrease transfusions and bleeding in patients with myelodysplastic syndromes and severe thrombocytopenia. Despite initial concerns about increased acute myeloid leukaemia transformation in patients treated with romiplostim, long-term follow-up showed that treatment with romiplostim had no significant negative impact on acute myeloid leukaemia transformation or survival. Contributors All authors were involved in the acquisition of data, either through study sites or as part of the study teams, as well as analysis and interpretation of the data. Further, all authors contributed to the writing of the report through critical review, comments, and approval of early drafts of the report, and all authors approved the final draft for publication. Susanna Mac, a medical writer from Amgen Inc, drafted and revised the manuscript. Declaration of interests HMK has received an NIH grant for the MD Anderson Cancer Center Leukemia SPORE CA100632. JS reports consultancy and advisory board fees for Amgen and Alexion Australia, participation in a speakers' bureau for Alexion Australia, advisory board and speaker fees for Celgene, and personal fees and advisory board, travel, and speaker fees from Pfizer, Genzyme, and Shire. UP reports honoraria from Amgen, Celgene, Janssen, and Novartis. AK has received research funding from Celgene. GG reports personal fees from Janssen, AbbVie, Morphosys, Roche, Novartis, Karyopharm, and GlaxoSmithKline, and grants from Celgene. WW-J has received research grants from Amgen Inc, Celgene, Janssen, Novartis, and Roche; and has received honoraria for serving on advisory boards for AbbVie, Angelini, BMS, Celgene, Janssen, Roche, and Sandoz. NC, BM, and JF are Amgen Inc employees and shareholders. AG has served as a consultant for and received honoraria from Amgen Inc. PF and MAS have nothing to disclose. Acknowledgments This study ( NCT00614523 , also Amgen #20060198) and all analyses were funded by Amgen Inc. Medical writing assistance was provided by Susanna Mac, an employee of Amgen Inc. We would also like to thank all of the investigators, study staff, and patients who were part of this study. A full list of investigators is in the appendix p 7 . Publisher Copyright: © 2018 Elsevier Ltd
PY - 2018/3
Y1 - 2018/3
N2 - Background: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement–platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4–3·8). Methods: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18–90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Findings: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48–2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72–1·47]; p=0·89) were not significantly different between the two groups. Interpretation: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Funding: Amgen Inc.
AB - Background: Treatment options for thrombocytopenia in myelodysplastic syndromes are scarce. As described previously in a randomised phase 2 study (n=250), 58 weeks of romiplostim treatment in patients with International Prognostic Scoring System (IPSS)-defined lower-risk (low-risk or intermediate-1 risk) myelodysplastic syndromes led to reduced platelet transfusions (p<0·0001) and increased International Working Group-defined haematological improvement–platelet rates (p<0·0001) versus placebo. However, the study drug was discontinued because of the potential risk for progression to or incorrect diagnosis or treatment for acute myeloid leukaemia, based on an acute myeloid leukaemia interim hazard ratio (HR) of 2·5; the subsequent 58-week acute myeloid leukaemia HR was 1·2 (95% CI 0·4–3·8). Methods: This study is a 5-year follow-up of a phase 2, multicentre, double-blind trial of romiplostim treatment in patients with lower-risk myelodysplastic syndromes. Eligible patients were recruited at 109 centres in North America, Europe, Russia, and Australia, were aged 18–90 years, and had platelets of 20 × 109 per L or less with or without a history of bleeding or 50 × 109 platelets per L or less with a history of bleeding. Patients were randomly assigned by interactive voice response system with stratification by baseline platelet count (≥20 × 109 per L or <20 × 109 per L) and IPSS risk (low or intermediate-1) to receive either placebo or 750 μg romiplostim subcutaneously once per week for 58 weeks. The primary outcomes for this long-term follow-up were survival and progression to acute myeloid leukaemia. Progression to acute myeloid leukaemia was defined as either 20% blasts or more after 4 weeks from romiplostim discontinuation; as per pathology; or by initiation of antileukaemia treatment. The primary outcome was assessed per protocol in all patients with available data. This study is registered with ClinicalTrials.gov, NCT00614523. Findings: Patients were recruited from July 21, 2008, to Dec 16, 2010. 167 patients were assigned to receive romiplostim treatment and 83 were assigned to receive placebo. 210 (84%) of 250 patients entered the 5-year long-term follow-up (139 patients in the romiplostim group and 83 in the placebo group). At the end of follow-up, proportions of patients with acute myeloid leukaemia (20 [12%] of 167 in the romiplostim group vs nine [11%] of 83 in the placebo group; HR 1·06 [95% CI 0·48–2·33]; p=0·88) and proportions who died (93 [56%] vs 54 [54%]; HR 1·03 [0·72–1·47]; p=0·89) were not significantly different between the two groups. Interpretation: Following the decision to stop the study drug, 5-year long-term follow-up HRs for transformation to acute myeloid leukaemia and HRs for death did not differ between patients treated with romiplostim and those treated with placebo, indicating that use of romiplostim is probably not associated with any increased risk of acute myeloid leukaemia or death, despite initial concerns. Funding: Amgen Inc.
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UR - http://www.scopus.com/inward/citedby.url?scp=85041588011&partnerID=8YFLogxK
U2 - 10.1016/S2352-3026(18)30016-4
DO - 10.1016/S2352-3026(18)30016-4
M3 - Article
C2 - 29396092
AN - SCOPUS:85041588011
SN - 2352-3026
VL - 5
SP - e117-e126
JO - The Lancet Haematology
JF - The Lancet Haematology
IS - 3
ER -