|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 2019 Aug 19];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.
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Conflicts of interest
There are no conflicts of interest.
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