|Year : 2019 | Volume
| Issue : 2 | Page : 61-65
Therapeutic benefits of lenalidomide in hematological malignancies
Mohammed Shafi Abdulsalam, Durai Mavalavan Vasudevan Manimoliyan
Department of Medical Oncology, Dr. Rela Institute and Medical Centre, Chennai, Tamil Nadu, India
|Date of Submission||06-Feb-2019|
|Date of Decision||13-Apr-2019|
|Date of Acceptance||22-Apr-2019|
|Date of Web Publication||24-May-2019|
Dr. Mohammed Shafi Abdulsalam
Dr. Rela Institute and Medical Centre, Chennai - 600 044, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Lenalidomide is an immunomodulatory agent, which has action against most of the hematological malignancies. Apart from its immunomodulation, it has other properties such as antiproliferation and antiangiogenesis. It is not only effective in myelodysplastic syndromes and myeloma, recent studies show its effective action on newly diagnosed and relapsed/refractory lymphomas as well. Addition of lenalidomide to standard therapy is associated with lesser central nervous system relapse in diffuse large B-cell lymphomas. Lenalidomide shows promising results in Hodgkin's lymphomas and leukemias (acute myeloid leukemia and chronic lymphocytic leukemia). Dose escalation may be an option in nonresponders with caution in side effects.
Keywords: Lenalidomide, lymphoma, myelodysplastic syndromes, myeloma
|How to cite this article:|
Abdulsalam MS, Manimoliyan DM. Therapeutic benefits of lenalidomide in hematological malignancies. Indian J Med Spec 2019;10:61-5
|How to cite this URL:|
Abdulsalam MS, Manimoliyan DM. Therapeutic benefits of lenalidomide in hematological malignancies. Indian J Med Spec [serial online] 2019 [cited 2020 Dec 3];10:61-5. Available from: http://www.ijms.in/text.asp?2019/10/2/61/258993
| Introduction|| |
Lenalidomide is an immunomodulatory drug (IMiD) and has effective actions against myelodysplastic syndromes (MDS) and myeloma cells. It has both direct and indirect effects against MDS cells. In 5q del MDS, lenalidomide acts by inhibiting of CDC25C phosphatase, an enzyme essential for proliferation and ubiquitination of CK1α and IKZF1 with subsequent degradation by proteasomes leading to cell arrest and apoptosis respectively. T-cell proliferation, NK cell activation and decreasing the production of pro-inflammatory cytokines (interleukin [IL]-1, IL-6, tumor necrosis factor-α) are important actions of lenalidomide., Cereblon is a protein encoded by CRBN gene essential for T cell stimulation mediated by IMiDs. Lenalidomide promotes the Cereblon-dependent degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors of IL-2 expression. De-repression of these factors leads to increased IL-2 expression, which stimulates T-cells., Immunomodulation, antiproliferation, antiangiogenesis, T-cell and NK activation are important effects of lenalidomide, thereby exerts its action on various hematological malignancies such as MDS, myeloma, and chronic lymphocytic leukemia (CLL). Thrombotic events and cytopenias are the important concerns regarding lenalidomide therapy, which are acceptable comparing to its benefit.,
| Myelodysplastic Syndromes|| |
Lenalidomide has action against both 5q del MDS and non-5q del MDS. However, it shows better results in 5q del MDS compared to non-5q del MDS. Complete cytogenetic response rate was higher among del 5q MDS (75%). It has better safety profile in transfusion-dependent del 5q MDS. Dose escalation results in higher cytogenetic response rate (50% [10 mg] vs. 25% [5 mg]). Transfusion independence rate and cytogenetic response rate in non-5q del MDS were 26.9% and 33.3%, respectively, in non-5q del MDS patients treated with 10 mg of lenalidomide. According to MDS-001 study, 43 patients received lenalidomide therapy, 56% of them had response and highest response rate was observed among 5q del MDS (83%). It results in high transfusion independence rate with reversal of cytologic and cytogenetic abnormalities in 5q del MDS (MDS-003 study). Cytopenias were the most common therapy related adverse events. Safety profiles of low-risk MDS patients were similar among non-del5q and del 5q.
| Myeloma and Other Plasma Cell Disorders|| |
Lenalidomide plus dexamethasone (Rd) is a backbone of most myeloma regimens. Rd therapy showed slight increase in survival benefit compared to melphalan-prednisone-thalidomide therapy in transplant ineligible myeloma patients with less hematological and neurological side effects (median progression-free survival [PFS]:25.5 months vs. 21.2 months and overall survival [OS]:59% vs. 51%). Addition of Bortezomib to Rd (VRd) results in improvement in PFS (43 months in VRd group vs. 30 months in Rd group) and OS (75 months in VRd group vs. 64 months in Rd group) with acceptable side effect profile. KRD regimen (carfilzomib + lenalidomide + dexamethasone) was associated with higher MRD negativity and longer PFS in newly diagnosed and smoldering myeloma. Among 28 patients with newly diagnosed myeloma, all of them achieved MRD negativity assessed by multiparametric flow cytometry. This regimen is also beneficial in relapsed myeloma. Rd plus Elotuzumab (Rd-Elo) showed overall response rate (ORR) of 79% versus 66% in Rd alone and median PFS was 19.4 months versus 14.9 months in Rd alone. After a median follow-up of 24.5 months, the rate of PFS at 1 year was 68% versus 57%; at 2 years, the rates were 41% versus 27%, respectively. Newer studies showed Rd in combination with oral proteasome inhibitor – ixazomib and anti-CD38 monoclonal antibody-Daratumumab showed better PFS., Lenalidomide is also effective in plasma cell leukemias (PCL) and Waldenström's macroglobulinemia (WM).,, Due to decreased occurrence of these conditions (PCL, WM), most of the available information are based case studies and case reports.
| Lymphomas (B-Cell and T-Cell Non-Hodgkin Lymphoma)|| |
Rituximab plus lenalidomide (R2) in untreated follicular lymphoma (advanced stage) showed similar efficacy compared to Rituximab plus chemotherapy. Response rate at 120 weeks was 48% in lenalidomide arm versus 53% in chemotherapy arm with PFS at 3 years was 77% versus 78%, respectively. Lenalidomide plus rituximab showed better response rate compared to lenalidomide alone in recurrent FL. Lenalidomide (R) crosses blood brain barrier. Central nervous system (CNS) relapse in diffuse large B-cell lymphomas was ~ 5% in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), whereas R2-CHOP results in 0.7% relapse rate. R2-CHOP therapy was associated with lower CNS relapse rate with promising results in nongerminal center B-cell type. Both in untreated and relapsed/refractory (Rel/Ref) lymphomas, lenalidomide therapy alone or combination with other therapies resulted in better ORR and complete response (CR) [Table 1].,,,,,,,, Among 18 patients with Maltoma treated with lenalidomide, ORR was 61%. In combination with Rituximab resulted in higher ORR (80%) and CR (54%). Late-onset remissions is one of the phenomena with the use of IMiDs in MALT lymphoma. Sufficient time should be provided to assess the response and to avoid unnecessary over treatment. Recent studies show clinical activity in T-cell lymphomas (TCL) as well. ORR was 42% in patients with Rel/Ref TCL treated with lenalidomide 25 mg/day. Another study showed ORR of 26%, median OS of 12 months with median PFS of 4 months among 39 analyzed patients with recurrent and refractory TCL, treated with 25 mg daily on days 1–21 of each 28-day cycle.
| Hodgkin's Lymphoma|| |
Among the 36 evaluable patients with relapsed or refractory classical Hodgkin lymphoma (HL) treated with lenalidomide, objective ORR and cytostatic ORR were 19% and 33%, respectively. Twelve patients showed response to treatment and eight patients had stable disease among 24 evaluable patients in another study. Available data show that lenalidomide has clinical activity in Rel/Ref HL. Overexpression of COX-2 in relapsed or refractory HL is associated with poor prognosis. COX-2 inhibition by Celecoxib along with lenalidomide showed clinical response in refractory HL.
| Plasmablastic Lymphoma and Posttransplant Lymphoproliferative Disorders|| |
Plasmablastic lymphoma (PL) is CD20-negative aggressive B-cell lymphoma. This condition requires aggressive chemotherapy regimens followed by autologous stem cell transplant. However, other options should be explored for transplant ineligible patients. Lenalidomide induces remission in PL. Posttransplant lymphoproliferative disorders (PTLD) are new entry in the hematological malignancies. Due to improved medical facilities and awareness, organ transplants are increasing around the world; there is also increase in PTLD. Only few case reports are available regarding the use of lenalidomide in PTLD. Lenalidomide provides better response in both B-cell PTLD and T-cell PTLD.,
| Acute and Chronic Leukemia|| |
Low-dose lenalidomide plus cytarabine induces complete remission in 33% of patients in a study. High-dose lenalidomide (50 mg/day) induces sustained morphologic and cytogenetic complete remission in two elderly patients with acute myeloid leukemia (AML). High-dose lenalidomide induction followed by low-dose maintenance produces durable remission in elderly patient with AML. Lenalidomide was used as initial therapy in 60 patients with CLL, OS was 82% at median follow-up of 4 years, and 35 patients (58%) responded to the treatment (25 CR and 10 PR). Among 44 patients with Rel/Ref CLL, continuous lenalidomide therapy (10 mg/day) with dose escalation (up to 25 mg/day) showed ORR of 32% and CR of 7%.
| Conclusion|| |
Lenalidomide is not only effective in Myeloma and MDS; it has action on lymphomas as well. Lenalidomide-based regimens such as R2-CHOP and R2 regimens may replace other aggressive chemotherapy regimens such as DA-EPOCH-R and hyper CVAD in the treatment of lymphomas. Even though the efficacy of lenalidomide in Rel/Ref Hodgkin's lymphoma and TCL is less compared to efficacy in B-cell non-HL, it will help small subset of patients with these conditions. Lenalidomide is a better alternative to other aggressive chemotherapy regimens particularly in elderly patients with poor performance status. As there are less number of cancer centers and intensive chemotherapy units in developing nations, lenalidomide-based therapies are better option in treating various hematological malignancies. There is a need for further studies in AML and CLL, as only smaller proportion of patients responds to lenalidomide alone or in combination with other drugs. Due to decreased incidence of PL and PTLD, efficacy of lenalidomide on such conditions requires multicenter studies. Dose escalation may be an option in nonresponders of some hematological malignancies. Immunotherapy era has changed most of the treatment regimens in hematological malignancies. Due to the advancement in medicine, the future will move toward oral and subcutaneous formulations in treating hematological malignancies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Chen C, Baldassarre F, Kanjeekal S, Herst J, Hicks L, Cheung M. Lenalidomide in multiple myeloma-a practice guideline. Curr Oncol 2013;20:e136-49.
Stahl M, Zeidan AM. Lenalidomide use in myelodysplastic syndromes: Insights into the biologic mechanisms and clinical applications. Cancer 2017;123:1703-13.
Gandhi AK, Kang J, Havens CG, Conklin T, Ning Y, Wu L, et al.
Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors ikaros and aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol 2014;164:811-21.
Kritharis A, Coyle M, Sharma J, Evens AM. Lenalidomide in non-Hodgkin lymphoma: Biological perspectives and therapeutic opportunities. Blood 2015;125:2471-6.
Kotla V, Goel S, Nischal S, Heuck C, Vivek K, Das B, et al.
Mechanism of action of lenalidomide in hematological malignancies. J Hematol Oncol 2009;2:36.
Menon SP, Rajkumar SV, Lacy M, Falco P, Palumbo A. Thromboembolic events with lenalidomide-based therapy for multiple myeloma. Cancer 2008;112:1522-8.
Fouquet G, Tardy S, Demarquette H, Bonnet S, Gay J, Debarri H, et al.
Efficacy and safety profile of long-term exposure to lenalidomide in patients with recurrent multiple myeloma. Cancer 2013;119:3680-6.
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;352:549-57.
Fenaux P, Giagounidis A, Selleslag D, Beyne-Rauzy O, Mufti G, Mittelman M, et al.
Arandomized phase 3 study of lenalidomide versus placebo in RBC transfusion-dependent patients with low-/Intermediate-1-risk myelodysplastic syndromes with del5q. Blood 2011;118:3765-76.
Santini V, Almeida A, Giagounidis A, Gröpper S, Jonasova A, Vey N, et al.
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 2016;34:2988-96.
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;355:1456-65.
Almeida A, Santini V, Gröpper S, Jonasova A, Vey N, Giagounidis A, et al
. Safety of lenalidomide (LEN) 10mg in non-del(5q) versus del(5q) in the treatment of patients (Pts) with lower-risk myelodysplastic syndromes (MDS): Pooled analysis of treatment-emergent adverse events (TEAEs). Blood 2015;126:2880.
Benboubker L, Dimopoulos MA, Dispenzieri A, Catalano J, Belch AR, Cavo M, et al.
Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N
Engl J Med 2014;371:906-17.
Durie BG, Hoering A, Abidi MH, Rajkumar SV, Epstein J, Kahanic SP, et al.
Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial. Lancet 2017;389:519-27.
Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, et al.
Treatment with carfilzomib-lenalidomide-dexamethasone with lenalidomide extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 2015;1:746-54.
Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al.
Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N
Engl J Med 2015;372:142-52.
Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al.
Elotuzumab therapy for relapsed or refractory multiple myeloma. N
Engl J Med 2015;373:621-31.
Moreau P, Masszi T, Grzasko N, Bahlis NJ, Hansson M, Pour L, et al.
Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N
Engl J Med 2016;374:1621-34.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al.
Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N
Engl J Med 2016;375:1319-31.
Pietrantuono G, Guariglia R, Martorelli MC, Villani O, D'Auria F, Musto P. Efficacy of lenalidomide in primary plasma cell leukemia. Blood 2007;110:4835.
Jimenez-Zepeda VH, Reece DE, Trudel S, Chen CI, Tiedemann RE. Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone (RVD) for the treatment of secondary plasma cell leukaemia. Blood 2013;122:5398.
Fouquet G, Guidez S, Petillon MO, Louni C, Ohyba B, Dib M, et al.
Lenalidomide is safe and active in waldenström macroglobulinemia. Am J Hematol 2015;90:1055-9.
Morschhauser F, Fowler NH, Feugier P, Bouabdallah R, Tilly H, Palomba ML, et al.
Rituximab plus lenalidomide in advanced untreated follicular lymphoma. N
Engl J Med 2018;379:934-47.
Leonard JP, Jung SH, Johnson J, Pitcher BN, Bartlett NL, Blum KA, et al.
Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 2015;33:3635-40.
Ayed AO, Chiappella A, Pederson L, Laplant BR, Congiu AG, Gaidano G, et al.
CNS relapse in patients with DLBCL treated with lenalidomide plus R-CHOP (R2CHOP): Analysis from two phase 2 studies. Blood Cancer J 2018;8:63.
Ruan J, Martin P, Shah BD, Schuster SJ, Smith SM, Furman RR, et al
. Sustained remission with the combination biologic doublet of lenalidomide plus rituximab as initial treatment for mantle cell lymphoma: A multi-center phase II study report [abstract]. Blood 2014;124:625.
Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, et al.
Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: A phase 1/2 clinical trial. Lancet Oncol 2012;13:716-23.
Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, et al.
An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol 2011;22:1622-7.
Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, et al.
Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: Phase II MCL-001 (EMERGE) study. J Clin Oncol 2013;31:3688-95.
Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, et al.
Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: A phase II study. J Clin Oncol 2015;33:251-7.
Fehniger TA, Larson S, Trinkaus K, Siegel MJ, Cashen AF, Blum KA, et al.
Aphase 2 multicenter study of lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood 2011;118:5119-25.
Morschhauser F, Fitoussi O, Haioun C, Thieblemont C, Quach H, Delarue R, et al.
Aphase 2, multicentre, single-arm, open-label study to evaluate the safety and efficacy of single-agent lenalidomide (Revlimid) in subjects with relapsed or refractory peripheral T-cell non-Hodgkin lymphoma: The EXPECT trial. Eur J Cancer 2013;49:2869-76.
Toumishey E, Prasad A, Dueck G, Chua N, Finch D, Johnston J, et al.
Final report of a phase 2 clinical trial of lenalidomide monotherapy for patients with T-cell lymphoma. Cancer 2015;121:716-23.
Querfeld C, Rosen ST, Guitart J, Duvic M, Kim YH, Dusza SW, et al.
Results of an open-label multicenter phase 2 trial of lenalidomide monotherapy in refractory mycosis fungoides and Sézary syndrome. Blood 2014;123:1159-66.
Kiesewetter B, Troch M, Dolak W, Müllauer L, Lukas J, Zielinski CC, et al.
Aphase II study of lenalidomide in patients with extranodal marginal zone B-cell lymphoma of the mucosa associated lymphoid tissue (MALT lymphoma). Haematologica 2013;98:353-6.
Kiesewetter B, Greil R, Willenbacher W, Neumeister P, Fridrik MA, Markus R. AGMT MALT-2: A phase II study of rituximab plus lenalidomide in patients with extranodal marginal zone B-Cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). Blood 2015;126:3973.
Kiesewetter B, Troch M, Mayerhoefer ME, Dolak W, Simonitsch-Klupp I, Raderer M, et al.
Delayed efficacy after treatment with lenalidomide or thalidomide in patients with mucosa-associated lymphoid tissue lymphoma. Oncologist 2016;21:72-5.
Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, et al.
Multicenter phase II study of lenalidomide in relapsed or recurrent adult T-cell leukemia/Lymphoma: ATLL-002. J Clin Oncol 2016;34:4086-93.
Böll B, Fuchs M, Reiners KS, Engert A, Borchmann P. lenalidomide in patients with relapsed or refractory Hodgkin lymphoma. Blood 2010;116:2828.
Garcia-Recio M, Martinez-Serra J, Mestre F, Bento L, Gines J, Ramos R, et al.
Complete response associated with lenalidomide and celecoxib in a case of primary refractory Hodgkin lymphoma. Onco Targets Ther 2018;11:6599-603.
Castillo JJ, Bibas M, Miranda RN. The biology and treatment of plasmablastic lymphoma. Blood 2015;125:2323-30.
Schmit JM, DeLaune J, Norkin M, Grosbach A. A case of plasmablastic lymphoma achieving complete response and durable remission after lenalidomide-based therapy. Oncol Res Treat 2017;40:46-8.
Läubli H, Tzankov A, Juskevicius D, Degen L, Rochlitz C, Stenner-Liewen F. Lenalidomide monotherapy leads to a complete remission in refractory B-cell post-transplant lymphoproliferative disorder. Leuk Lymphoma 2016;57:945-8.
Portell C, Nand S. Single agent lenalidomide induces a response in refractory T-cell posttransplantation lymphoproliferative disorder. Blood 2008;111:4416-7.
Visani G, Ferrara F, Di Raimondo F, Loscocco F, Sparaventi G, Paolini S, et al.
Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients. Leukemia 2014;28:967-70.
Fehniger TA, Byrd JC, Marcucci G, Abboud CN, Kefauver C, Payton JE, et al.
Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13. Blood 2009;113:1002-5.
Bansal D, Vij K, Chang GS, Miller CA, DiPersio JF, Vij R, et al.
Lenalidomide results in a durable complete remission in acute myeloid leukemia accompanied by persistence of somatic mutations and a T-cell infiltrate in the bone marrow. Haematologica 2018;103:e270-e273.
Strati P, Keating MJ, Wierda WG, Badoux XC, Calin S, Reuben JM, et al.
Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 2013;122:734-7.
Ferrajoli A, Lee BN, Schlette EJ, O'Brien SM, Gao H, Wen S, et al.
Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008;111:5291-7.