Skip to main content
SpringerLink
Log in

Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndromes (MDS)—ViLen-01 protocol

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Abstract

Azacitidine treatment is effective in higher risk MDS (HR-MDS), with less than 50 % response, lasting 2 years. Aza and lenalidomide (Len) have a potential synergistic effect. ViLen-01 phase IIa trial includes 6-month induction (Aza 75 mg/m2/day, days 1–5, Len 10 mg/day, days 6–21, every 28 days), 6-month consolidation (Aza 75 mg/m2/day, days 1–5, every 28 days), and 12-month maintenance (Len 10 mg/day, days 1–21, every 28 days). Response was evaluated according to IWG criteria. Totally, 25 patients enrolled, with an average of 76.3 years old (60–87), and 88 % with major comorbidities. Thirteen patients completed induction, 7 proceeded for consolidation, and 2 for maintenance. The overall response rate (ORR) was 72 % (18/25), with 6 (24 %) for CR, 3 (12 %) for marrow CR, and 9 (36 %) for hematologic improvement (HI). The 7 non-responding patients were on the study 3 days to 4.1 months. At 6 months, 4 of 6 evaluable patients achieved complete cytogenetic response and 2 with del (5q) at diagnosis. Adverse events (AEs) were as expected in these patients: grades III–IV, mainly hematologic—thrombocytopenia (20 patients) and neutropenia (13 patients). The common non-hematologic AEs were infections (14 patients), nausea (7), vomiting (7), diarrhea (7), and skin reactions (5). The median progression-free survival (PFS) was 12 ± 1.36 months, with median overall survival (OS) of 12 ± 1.7 months. Quality of life (FACT questionnaire) data were available for 12 patients with a tendency towards improved QoL. This trial with elderly HR-MDS patients with an expected poor prognosis demonstrates a high (72 %) response rate and a reasonable expected safety profile but a relatively short PFS and OS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A et al (2009) Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10(3):223–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Malcovati L, Hellström-Lindberg E, Bowen D, Adès L, Cermak J, Del Cañizo C et al (2013) Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood 122(17):2943–2964

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sekeres MA, Cutler C (2014) How we treat higher-risk myelodysplastic syndromes. Blood 123(6):829–836

    Article  CAS  PubMed  Google Scholar 

  4. Silverman LR, Mckenzie DR, Peterson BL, Cancer and Leukemia Group B et al (2006) Further analysis of trials with azacitidine in patients with myelodysplastic syndromes: studies 8421, 8921 and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 24(24):3895–3903

    Article  CAS  PubMed  Google Scholar 

  5. Navada SC, Silverman LR, Hearn KP et al (2015) A phase II study of the combination of oral rigosertib and azacitidine in patients with myelodysplastic syndromes (MDS). The 57th Annual Meeting of the American Society of Hematology (ASH). Blood 126(23):Abs # 910

    Google Scholar 

  6. List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D et al (2005) Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 352(6):549–7

    Article  CAS  PubMed  Google Scholar 

  7. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E et al (2006) Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 355(14):1456–1465

    Article  CAS  PubMed  Google Scholar 

  8. Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M et al (2011) A randomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with del5q. Blood 118(14):3765–3776

    Article  CAS  PubMed  Google Scholar 

  9. Giagounidis A, Mufti GJ, Mittelman M, Sanz G, Platzbecker U, Muus P et al (2014) Outcomes in RBC transfusion-dependent patients with low-/intermediate-1-risk myelodysplastic syndromes with isolated deletion 5q treated with lenalidomide: a subset analysis from the M. Eur J Haematol 93(5):429–438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Raza A, Reeves JA, Feldman EJ, Dewald GW, Bennett JM, Deeg HJ et al (2008) Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 111(1):86–93

    Article  CAS  PubMed  Google Scholar 

  11. Santini V Almeida A, Giagounidis A, et al. (2016) Randomized phase III study of lenalidomide versus placebo in RBC-transfusion dependent patients with lower- risk non-del (5q) myelodysplastic syndromes and ineligible for or refractory to erythropoiesis-stimulating agents. J Clin Oncol. June 27, (Epub)

  12. Fehniger TA, Uy GL, Trinkaus K, Nelson AD, Demland J, Abboud CN et al (2011) A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia. Blood 117(6):1828–1833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag D, Jang JH et al (2015) International phase 3 study of azacitidine vs conventional care regimens in older patients with newly diagnosed AML with > 30% blasts. Blood 126(3):291–299

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Huls G (2015) Azacitidine in AML: a treatment option? Blood 126(3):283–284

    Article  CAS  PubMed  Google Scholar 

  15. Sekeres MA, Tiu RV, Komrokji R, Lancet J, Advani AS, Afable M et al (2012) Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 120(25):4945–4951

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sekeres MA, List AF, Cuthbertson D, Paquette R, Ganetzky R, Latham D et al (2010) Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes. J Clin Oncol 28(13):2253–2258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sekeres MA, O’Keefe C, List AF, Paulic K, Afable M II, Englehaupt R et al (2011) Demonstration of additional benefit in adding lenalidomide to azacitidine in patients with higher-risk myelodysplastic syndromes. Am J Hematol 86(1):102–103

    Article  PubMed  Google Scholar 

  18. Pollyea DA, Kohrt HE, Gallegos L, Figueroa ME, Abdel-Wahab O, Zhang B et al (2012) Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia. Leukemia 26(5):893–901

    Article  CAS  PubMed  Google Scholar 

  19. Finelli C, Clissa C, Follo MY et al (2014) Addition of lenalidomide (LEN) to azacitidine (AZA) (combined vs sequential treatment) in high-risk myelodysplastic syndromes (mds): a randomized phase II multicenter study. 56th annual meeting, the American Society of Hematology 2014. Blood 124(21):Abs # 4648

    Google Scholar 

  20. Kenealy M, Benson W, Stevenson W et al (2015) The addition of lenalidomide to azacitidine achieves higher responses but no improvement in twelve month clinical benefit or PFS: main analysis of Australian ALLG MDS4 trial. Leuk Res 39(S1):Abs # 13

    Google Scholar 

  21. DiNardo CD, Daver N, Jabbour E et al (2015) A final report: sequential azacitidine and lenalidomide in patients with high-risk myelodysplastic syndromes and acute myeloid leukaemia: a single-arm phase 1/2 study. Lancet Haematol 2:e 12–e 20

    Article  Google Scholar 

  22. Ades L, R’cher C, Stamatoullas A et al (2015) A phase I–II study of the efficacy and safety of lenalidomide (LEN) combined to azacitidine (AZA) in higher-risk MDS and AML with del (5q)—a study by The Groupe Francophone des Myelodysplasias (GFM). The 57th Annual Meeting of the American Society of Hematology (ASH). Blood 126(23):Abs # 2892

    Google Scholar 

  23. Narayan R, Garcia JS, Percival ME et al (2016) Sequential azacitidine plus lenalidomide in previously treated elderly patients with acute myeloid leukemia and higher risk myelodysplastic syndrome. Leuk Lymphoma 57:609–615

    Article  CAS  PubMed  Google Scholar 

  24. Sekeres MA, Othus M, List AF et al (2015) Additional analyses of a randomized phase II study of azacitidine combined with lenalidomide or with vorinostat vs azacitidine monotherapy in higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML): North American Intergroup Study SWOG S1117. The 57th Annual Meeting of the American Society of Hematology (ASH). Blood 126(23):Abs # 908

    Google Scholar 

  25. Mittelman M. Filanovsky K., Rosenbaum H. et al. Azacitidine and lenalidomide combination in higher-risk myelodysplastic syndromes—preliminary results of the Vi-Len-01 protocol. The 55th Annual meeting of the American Society of Hematology (ASH), New Orleans, Louisiana, December 2013, Abs. #1576

  26. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al (1997) International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89(6):2079–2088

    CAS  PubMed  Google Scholar 

  27. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108(2):419–425

    Article  CAS  PubMed  Google Scholar 

  28. Cella D (1997) The Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale: a new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34(3 Suppl):13–19

    CAS  PubMed  Google Scholar 

  29. Duong VH, Lin K, Reljic T, Kumar A, Al Ali NH, Lancet JE et al (2013) Poor outcome of patients with myelodysplastic syndrome after azacitidine treatment failure. Clin Lymphoma Myeloma Leuk 13(6):711–715

    Article  CAS  PubMed  Google Scholar 

  30. Nazha A, Sekeres MA, Garcia-Manero G et al (2014) Outcomes of patients with myelodysplastic syndromes (MDS) who achieve stable disease after treatment with hypomethylating agents (HMA). The 56th Annual Meeting, the American Society of Hematology (ASH) 2014. Blood 124(21):Abs # 3273

    Google Scholar 

  31. Adès L, Eclache V, Gardin C, Boehrer S, Leroux G, Martiat P et al (2010) Efficacy of lenalidomide in an sAML patient with del 5q relapsing after reduced-intensity allogeneic stem cell transplantation performed in complete remission. Bone Marrow Transplant 45(4):791–792

    Article  PubMed  Google Scholar 

  32. Sekeres MA, Gundacker H, Lancet J, Advani A, Petersdorf S, Liesveld J et al (2011) A phase 2 study of lenalidomide monotherapy in patients with deletion 5q acute myeloid leukemia: Southwest Oncology Group Study S0605. Blood 118(3):523–528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R et al (2002) Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol 20(10):2429–2440

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgment

The authors thank

• Celgene (and NeoPharm) for an unrestricted grant

• Israel Society of Hematology

• Elmar

Author information

Authors and Affiliations

  1. Department of Medicine A, Tel Aviv Sourasky Medical Center, 6 Weizmann St., Tel Aviv, 64239, Israel

    Moshe Mittelman, Ilya Kirgner, Yair Herishanu, Chava Perri & Howard S. Oster

  2. Sackler Medical Faculty, Tel Aviv University, Tel Aviv, Israel

    Moshe Mittelman, Pia Raanani, Ilya Kirgner, Yair Herishanu, Chava Perri, Martin Ellis & Howard S. Oster

  3. Kaplan Medical Center, Rehovot, Israel

    Kalman Filanovsky

  4. Hebrew University, Jerusalem, Israel

    Kalman Filanovsky & Neta Goldschmidt

  5. Rambam Medical Center, Haifa, Israel

    Yishai Ofran & Hanna Rosenbaum

  6. Technion, Haifa, Israel

    Yishai Ofran & Hanna Rosenbaum

  7. Rabin Medical Center, Petah Tikva, Israel

    Pia Raanani

  8. Western Galilee Medical Center, Nahariya, Israel

    Andrei Braester

  9. Bar-Ilan University, Safed, Israel

    Andrei Braester

  10. Hadassah Medical Center, Hebrew University, Jerusalem, Israel

    Neta Goldschmidt

  11. Meir Medical Center, Kfar-Saba, Israel

    Martin Ellis

Authors
  1. Moshe Mittelman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kalman Filanovsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yishai Ofran
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanna Rosenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pia Raanani
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrei Braester
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Neta Goldschmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ilya Kirgner
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yair Herishanu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chava Perri
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Martin Ellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Howard S. Oster
    View author publications

    You can also search for this author in PubMed Google Scholar

Consortia

for The Israel Myelodysplastic Syndrome Working Group (MDS-WG)

Corresponding author

Correspondence to Moshe Mittelman.

Ethics declarations

Conflict of interest

The study was an investigator-initiated trial (IIT) that was supported by an unrestricted grant from Celgene.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mittelman, M., Filanovsky, K., Ofran, Y. et al. Azacitidine-lenalidomide (ViLen) combination yields a high response rate in higher risk myelodysplastic syndromes (MDS)—ViLen-01 protocol. Ann Hematol 95, 1811–1818 (2016). https://doi.org/10.1007/s00277-016-2776-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00277-016-2776-x

Keywords

Search

Navigation