Lenalidomide (Revlimid) is an oral immunomodulatory agent approved in the United States in combination with dexamethasone for patients with multiple myeloma (MM) who have received one or more prior therapies and as a single agent for transfusion-dependent anemia due to low-/intermediate-1–risk myelodysplastic syndrome (MDS) associated with deletion 5q with/without additional cytogenetic abnormalities ( Dimopoulos et al., 2007 ; Celgene, 2013 ; Weber et al., 2007 ). Its mechanisms of action involve multiple processes that depend on the tumor type and microenvironment to collectively reduce tumor cell proliferation and survival ( Anderson, 2005 ; Chanan-Khan & Cheson, 2008 ; Hayashi et al., 2005 ; Kotla et al., 2009 ; Wu et al., 2008 ). The immunomodulatory properties of lenalidomide provide a basis for clinical investigations in patients with B-cell chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). This article reviews the efficacy and safety of lenalidomide in CLL and NHL, focusing on approaches for the advanced practitioner to improve patient quality of life through optimal management of side effects in patients receiving lenalidomide.
CLINICAL STUDIES IN LYMPHOID MALIGNANCIES
Relapsed/Refractory CLL
Early phase II investigations at Roswell Park Cancer Institute (RPCI) and M. D. Anderson Cancer Center (MDACC) focused on lenalidomide dose optimization in heavily pretreated patients with relapsed/refractory CLL for maximal activity without compromising safety ( Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ). Lenalidomide produced overall response rates (ORR) of 47% (21/45 patients, 9% complete response [CR], RPCI; Chanan-Khan et al., 2006 ) and 32% (14/44 patients, 7% CR, MDACC; Ferrajoli et al., 2008 ).
Tumor lysis syndrome (TLS) was observed in 2 of the first 29 patients who received 25 mg lenalidomide on days 1–21 of a 28-day cycle ( Chanan-Khan et al., 2006 ), prompting lower initial doses with subsequent dose escalation ( Figure 1 ; Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ). Grade 3/4 adverse events (AEs) were mainly hematologic, and included neutropenia (70% patients [RPCI], 41% of treatment courses [MDACC]) and thrombocytopenia (45% of patients and 15% of treatment courses, respectively). Fatigue, diarrhea, rash, and tumor flare reactions (TFRs) were common nonhematologic AEs, although they were mostly grade 1/2 ( Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ).
Based on phase II studies, the CLL-001 phase II/III trial compared starting doses of 10 vs. 25 mg/day lenalidomide in patients with heavily pretreated, relapsed/refractory CLL (see Figure 1 ; Wendtner et al., 2012b ). Patients had a median age of 65 years; 69% had bulky lymphadenopathy (> 5 cm), and 48% had high-risk genomic abnormalities. Four serious cases of TLS were observed in the first 18 patients, leading to a protocol amendment to identify the maximum tolerated dose (MTD, defined as the highest dose of a treatment that does not cause unacceptable side effects) escalation level with lower initial lenalidomide, added TLS prophylaxis, increased TLS/TFR monitoring, and the exclusion of any patients with severe renal dysfunction, who were defined as those having a history of renal failure that required dialysis ( Moutouh-de Parseval, Weiss, DeLap, Knight, & Zeldis, 2007 ).
Dose escalation from 2.5 mg/day lenalidomide, increasing in 5-mg increments every 28 days, achieved safe titration to 20 mg/day without reaching the MTD ( Wendtner et al., 2012b ). The most common grade 3/4 AEs were neutropenia (65%), thrombocytopenia (33%), and pneumonia (21%). The occurrence of 4% TLS and 44% TFR (10% grade 3) was successfully managed with treatment (e.g., nonsteroidal anti-inflammatory agents or corticosteroids) and/or temporary treatment interruption. A total of 58% of patients experienced ≥ 1 dose reduction/interruption due to AEs. Six patients reached the maximum dose of 20 mg; other dose levels of 15 mg (n = 10), 10 mg (n = 14), 5 mg (n = 6), and 2.5 mg (n = 16) were also achieved. Six patients (12%) achieved partial responses with 10 to 20 mg lenalidomide. Thirty patients (58%) had stable disease, including 7 at a maximum 2.5 mg. Median progression-free survival (PFS) was 24.1 weeks for all patients and 42.1 weeks for responders.
This conservative dose-escalation approach with lenalidomide for heavily pretreated, bulky, high-risk CLL patients demonstrated safe titration from an initial dose of 2.5 mg up to 20 mg. Moreover, the use of TLS prophylaxis and monitoring may facilitate more rapid dose escalation or higher starting doses in future studies.
Based on these findings, a randomized, double-blind phase II trial (CLL-009; ClinicalTrials.gov Identifier NCT00963105 ) was initiated in relapsed/refractory CLL, with lenalidomide at 5, 10, or 15 mg daily (28-day cycles), with dose escalation in 5-mg increments every 28 days as tolerated to 25 mg/day ( Wendtner et al., 2012a ). The most common grade 3/4 AEs seen in 104 patients were neutropenia (67%), thrombocytopenia (38%), pneumonia (14%), TFR (14%), and fatigue (12%). Grade 3 TLS occurred in four patients (1 at 5 mg/day, 3 at 15 mg/day). Dose escalation to 25 mg/day was achieved in 24% of patients; the mean dose administered was 12 mg/day. The overall response rate was 38% (102/104 evaluable patients), including three patients with CR (3%).
B-Cell NHL
Indolent NHL
Indolent lymphomas comprise a group of incurable and generally slow-growing entities, of which follicular lymphoma (FL), marginal zone lymphoma, and small lymphocytic lymphoma (SLL) are the most common ( Armitage &s Weisenburger, 1998 ; Lunning & Vose, 2012 ). The phase II NHL-001 study of lenalidomide 25 mg/day on days 1 through 21 every 28 days produced a modest 23% ORR (10/43 patients), including 7% CR/CR unconfirmed (CRu) in heavily pretreated patients with refractory indolent lymphoma ( Witzig et al., 2009 ). Median PFS was 4.4 months, and median duration of response (DOR) was > 16.5 months, with 7/10 responses ongoing at 15 to 28 months. Adverse events were predictable; the most common grade 3/4 AEs were neutropenia (46%) and thrombocytopenia (19%). Tumor flare reactions occurred in 3/18 SLL patients and 1 FL patient but were not correlated with response. Studies continue to be conducted in indolent lymphomas (ClinicalTrials.gov Identifiers NCT00695786 , NCT01938001 , NCT01316523 , NCT01996865 , and NCT01476787 ).
Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) is an aggressive subtype of NHL initially treated with induction chemoimmunotherapy, but with relatively short duration and poor prognosis upon relapse ( Habermann et al., 2009 ). The NHL-002 and NHL-003 trials included 15 and 57 MCL patients receiving lenalidomide who achieved ORRs of 53% (20% CR) and 42% (21% CR), respectively ( Habermann et al., 2009 ; Witzig et al., 2011 ). Across the studies, grade 3/4 neutropenia and thrombocytopenia were reported in approximately 40% and 20% of patients, respectively. Results from the recent prospective phase II MCL-001 study (EMERGE) confirmed these findings in 134 heavily pretreated MCL patients who were relapsed/refractory to bortezomib ( Goy et al., 2013 ). Mantle cell lymphoma patients showed a 28% ORR (7.5% CR/CRu), with a durable median DOR of 16.6 months.
The most common grade 3/4 AEs were neutropenia (43%), thrombocytopenia (28%), and anemia (11%). Rash was reported in 30 patients (22%; grade 1/2 in 28 patients) and was manageable with antihistamines or low-dose steroids. Grade 1/2 TFR was reported in 13 patients (10%); there were no reports of TLS. The EMERGE study demonstrated predictable safety and durable activity of lenalidomide in heavily pretreated patients with advanced- stage relapsed/refractory MCL post-bortezomib, regardless of tumor burden, prior autologous stem cell transplantation (ASCT), or number of prior therapies ( Goy et al., 2013 ).
Diffuse Large B-Cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, has an aggressive clinical course with poor prognosis after first relapse. In a pooled analysis of patients from the NHL-002 and NHL-003 studies, 35/134 relapsed/refractory DLBCL patients achieved a 26% ORR (12% CR) and median 6.0-month DOR (10.4 months for responders). Consistent with other studies of lenalidomide, neutropenia (36%) and thrombocytopenia (21%) were the most common grade 3/4 AEs.
Diffuse large B-cell lymphoma can be divided into subgroups with distinct characteristics and prognoses based on gene expression profiling ( Hernandez-Ilizaliturri et al., 2011 ). In a retrospective analysis of 40 relapsed/refractory DLBCL patients, non–germinal center B-cell (non-GCB)–like vs. germinal center B-cell (GCB)–like patients treated with lenalidomide showed similar overall survival but significantly higher ORR (53% vs. 9%, p = .006), CR (24% vs. 4%), and median PFS (6.2 vs. 1.7 months, p = .004), respectively ( Hernandez-Ilizaliturri et al., 2011 ). These findings remain to be validated in future studies.
SIDE-EFFECT MONITORING AND MANAGEMENT IN LYMPHOID MALIGNANCIES
Hematologic toxicities consistently comprise the most common grade 3/4 AEs with lenalidomide, and nonhematologic toxicity varies across malignancies ( Table 1 ). Suggested monitoring and treatment recommendations for the most common AEs are based on the regulatory-approved indications in MM/MDS and clinical experiences with CLL and NHL ( Table 2 ; Celgene, 2013 ). A closer look at nonhematologic AEs is outlined below.
Tumor Lysis Syndrome
Tumor lysis syndrome is a group of metabolic derangements that may occur when malignant cells are rapidly killed, causing a massive release of intracellular metabolites into the bloodstream ( Coiffier, Altman, Pui, Younes, & Cairo, 2008 ). Symptoms include hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, cardiac arrhythmia, and uremia, which may lead to renal dysfunction and potentially acute renal failure. Risk factors include hematologic malignancies, bulky disease (> 10 cm), preexisting renal insufficiency, elevated baseline serum/plasma uric acid level > 7.5 mg/dL, dehydration, elevated lactic dehydrogenase level (> 2 times upper limit of normal), and rapid cytoreduction following treatment ( Coiffier et al., 2008 ; McGraw, 2008 ).
Tumor lysis syndrome was seen in 7/260 CLL patients (3%) receiving lenalidomide in a review of the Celgene Corporation database conducted in 2007, with all cases developing during the first 15 days of treatment ( Moutouh-de Parseval et al., 2007 ). Acute renal failure and/or cardiac arrhythmia were seen in 3/7 patients. Slow dose titration and TLS prophylaxis were subsequently initiated in the CLL-001 trial, including oral hydration (to promote urinary excretion of uric acid and phosphate) and allopurinol 300 mg daily (to prevent xanthine and hypoxanthine conversion into uric acid) 3 days prior to lenalidomide and continued for 3 cycles ( Wendtner et al., 2012b ). Tumor lysis syndrome prophylaxis with allopurinol 300 mg daily was provided on days 1 through 14 of the first cycle in a subsequent study of lenalidomide in CLL patients ( Badoux et al., 2011 ). These practices were carried over into the CLL-009 study to enable identification of the optimal starting dose of lenalidomide in CLL patients ( Wendtner et al., 2012b ).
Tumor Flare Reaction
Tumor flare reaction in CLL is characterized by a sudden and/or tender enlargement of the lymph nodes and/or spleen, often in association with low-grade fever and rash, and sometimes bone pain or increased white blood cells ( Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ). It is important for advanced practitioners to recognize TFR as a possible complication of therapy, as the associated signs and symptoms may be mistaken for disease progression ( Table 2 ).
Tumor flare reaction developed in 44% (10% grade 3) of CLL patients in the CLL-001 trial ( Wendtner et al., 2012b ). In the MDACC phase II trial, any-grade TFR was higher among patients with lymph nodes > 5 cm (53% vs. 15% for patients with 5 cm nodes; Ferrajoli et al., 2008 ). In the RPCI phase II study, TFR incidence (58% overall, 8% grade 3/4) was associated with advanced-stage CLL and younger age, but not with bulky disease ( Chanan-Khan et al., 2006 , 2011 ). Severe, life-threatening TFR that necessitated hospitalization was reported in four patients with relapsed/refractory CLL who received lenalidomide at a starting dose of 25 mg ( Andritsos et al., 2008 ). Tumor flare reaction was reported in 14% of patients overall in the CLL-009 study, at a similar incidence regardless of the starting dose of lenalidomide (5, 10, or 15 mg/day; Wendtner et al., 2012a ).
Tumor flare reaction usually occurs during the first treatment cycle, with a median time to onset of 6 days (range, 0–56) and a median time to resolution of 14 days (95% CI, 10-26), and the intensity of TFR may be positively correlated with achieving a CR with lenalidomide in CLL patients ( Chanan-Khan et al., 2011 ). Prophylaxis with low- dose oral prednisone (20 mg for 5 days followed by 10 mg for 5 days) decreased severity and delayed onset but did not reduce the incidence and may slow resolution ( Chanan-Khan et al., 2011 ). Tumor flare reaction has also been reported mainly within the first cycle of lenalidomide in relapsed MCL patients, including 13/134 patients (10%, all grade 1/2) in the MCL-001 study and 4/26 patients (15%; 3 grade 2) reported by Eve and Rule ( Eve & Rule, 2010 ; Goy et al., 2013 ).
Rash
Grade 1/2 rash is relatively common with lenalidomide in CLL and NHL, often presenting as generalized pruritic, macular, and/or raised erythema ( Miller, Musial, Whitworth, & Chanan-Khan, 2010 ). In clinical studies, rash was reported in 40% of CLL patients and approximately 30% of NHL patients; grade 3 events were uncommon at < 5% ( Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ; Wendtner et al., 2012b ; Wiernik et al., 2008 ; Witzig et al., 2011 ). Rash was also observed in 46% of patients with indolent lymphoma who received combination lenalidomide and rituximab therapy in a phase II study; most cases were grade 1/2 ( Nelson et al., 2012 ). Rash may be associated with TFR or caused by treatment.
Treatment of rash is directed by severity of symptoms and may include observation, oral or topical antihistamines, oral or topical steroids, or in severe cases, discontinuation of lenalidomide. Hypersensitivity reactions include rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis (0.02% based on postmarketing reports of lenalidomide use for MM, myelofibrosis, and amyloidosis), in which cytotoxicity causes separation of the epidermis from the dermis ( Castaneda, Brandenburg, Bwire, Burton, & Zeldis, 2009 ).
Deep Vein Thrombosis and Pulmonary Embolism
Lenalidomide may carry a thromboembolic risk in CLL and NHL. Grade 3/4 pulmonary embolism was observed in 3/52 patients (6%) in the CLL-001 trial ( Wendtner et al., 2012b ), and grade 3 deep vein thrombosis occurred in 5/217 patients (2%) in the NHL-003 trial ( Witzig et al., 2011 ). Although rare, thrombotic events are potentially life threatening. Consideration of daily prophylactic low-dose aspirin is warranted in patients not currently receiving anticoagulant therapy (e.g., warfarin; Miller et al., 2010 ).
Other Adverse Events
Grade 3/4 infections (e.g., pneumonia) were reported in CLL, likely reflective of prior treatment and the general immunocompromised nature of the disease ( Miller et al., 2010 ). Grade 3/4 infection-related AEs occurred in 40% of patients in the CLL-001 study, including 21% with pneumonia ( Wendtner et al., 2012b ). Severe infections complicated 6% of treatment cycles in the phase II MDACC trial ( Ferrajoli et al., 2008 ) but were less common in the RPCI phase II trial at 4% ( Chanan-Khan et al., 2006 ). Non-Hodgkin lymphoma patients were less prone to infections during treatment: 4% grade 3/4 pneumonitis in NHL-002 and 3% grade 3/4 pneumonia in NHL-003; see Table 1 ( Wiernik et al., 2008 ; Witzig et al., 2011 ).
The incidence of predominantly grade 1/2 fatigue is common in both CLL and NHL. Fatigue increased from baseline following initiation of lenalidomide in CLL and was present at baseline (29%) and during treatment (73%) in the RPCI study ( Chanan-Khan et al., 2006 ). Four patients had grade 3/4 fatigue, which resolved completely in two cases during continued lenalidomide. Any-grade fatigue was common in NHL patients in both the NHL-002 (49% overall, 6% grade 3) and NHL-003 (28% overall, 5% grade 3) studies without the need for dose interruption or reduction; monitoring/management recommendations are outlined in Table 2 ( Chanan-Khan et al., 2006 ; Wiernik et al., 2008 ; Witzig et al., 2011 ).
Diarrhea and constipation are the most common gastrointestinal complications associated with lenalidomide ( Chanan-Khan et al., 2006 ; Ferrajoli et al., 2008 ; Wiernik et al., 2008 ; Witzig et al., 2011 ). Common interventions (e.g., diet modification and laxative use) have effectively managed these AEs ( Miller et al., 2010 ).
Second Primary Malignancies After Lenalidomide Use
Patients with cancer are at increased risk of developing second primary malignancies (SPMs), which are influenced by multiple factors, including age and prolonged exposure to chemotherapy (especially alkylating agents) and radiation ( Barista et al., 2002 ; Decaudin et al., 2000 ; Dimopoulos et al., 2012 ; Palumbo, Freeman, Weiss, & Fenaux, 2012 ; Romaguera et al., 2005 ). Limited SPM data are reported, with the majority of information in relapsed/refractory MM.
A retrospective review of 11 lenalidomide studies in relapsed/refractory MM showed 52 invasive SPMs in 3,846 patients, for an overall incidence rate of 2.08 per 100 patient-years ( Altekruse et al., 2010 ; Dimopoulos et al., 2012 ; Palumbo et al., 2012 ). In more recent studies in patients with relapsed/refractory MCL receiving lenalidomide, 3/134 (2%) patients in MCL-001 and 2/57 (3.5%) in NHL-003 reported invasive SPMs ( Goy et al., 2013 ; Zinzani et al., 2013 ). To date, the incidence of SPMs with lenalidomide treatment is comparable to the rate of 2.1 per 100 patient-years expected in the general population of older adults ( Altekruse et al., 2010 ).
Risk Counseling
Counseling and education of patients regarding potentially life-threatening risks should be conducted at regular intervals before and throughout treatment. Patients must be informed of significant neutropenia and thrombocytopenia risks that may require dose modification, transfusions, and/or growth factor administration. Patients must also be informed regarding thromboembolic risks and instructed to immediately report symptoms such as shortness of breath, difficulty breathing, chest pain, or swelling of the extremities.
Prevention of fetal risk is an educational priority for patients receiving lenalidomide, given that it is a thalidomide analog. Females of childbearing potential should have two negative pregnancy tests before starting treatment and must use two forms of birth control until 4 weeks after treatment discontinuation. Males taking lenalidomide must use contraceptives during any sexual contact with a female with childbearing potential, and they must refrain from donating sperm.
Lenalidomide, marketed as Revlimid, is only available through the Revlimid Risk Evaluation and Mitigation Strategy (REMS), a restricted distribution program. Only certified prescribers and pharmacies can prescribe and dispense lenalidomide to patients who are enrolled and meet all the conditions of the REMS program.
DOSING SCHEDULES AND OPTIMIZATION IN MM, CLL, AND NHL
Current dosing schedules are outlined in Figure 2 . Dose adjustments are recommended for renal impairment initially or from resultant cytopenia/other grade 3/4 AEs. The dosing schedule in MM provided a basis for that in relapsed/refractory NHL, as shown in the NHL-001, NHL-002, and NHL-003 studies ( Wiernik et al., 2008 ; Witzig et al., 2011 ; Witzig et al., 2009 ). A lower initial lenalidomide dose of 20 mg/day may be needed to minimize toxicity when used in combination, as shown in relapsed/refractory MCL with lenalidomide plus rituximab ( Wang et al., 2012 ). Patients with CLL require a lower starting dose (e.g., 5–10 mg/day) to minimize TLS/TFR risks, with dose escalation every 28 days as tolerated ( Wendtner et al., 2012a ).
DISCUSSION
Recent clinical trials support the activity of lenalidomide in lymphoid malignancies, including CLL and NHL, and show that dose levels and certain toxicities differ across cancer types. The lenalidomide schedule used in MM also appears to be appropriate for NHL, but a lower starting dose was used in CLL to minimize certain AEs. Hematologic toxicity, mainly neutropenia and thrombocytopenia, is common across malignancies; therefore regular monitoring is recommended. Tumor flare reaction and TLS are potentially serious toxicities seen in CLL. Other AEs, such as rash, fatigue, diarrhea, and infection, can generally be managed with conventional strategies.
Advanced practitioners are pivotal in providing the appropriate prophylaxis, patient counseling, monitoring, and treatment for common toxicities that enables lenalidomide to be administered in a safe manner at optimal dose levels as an active therapy in hematologic malignancies.
Acknowledgments
Medical writing assistance in the preparation of this manuscript was provided by Barry M. Weichman, PhD, and Julie Kern, PhD, CMPP, with Bio Connections LLC and funded by Celgene Corporation. The authors are fully responsible for content and editorial decisions for this manuscript.
Ms. Blumel has received consulting fees from Celgene; Dr. Broadway-Duren has no financial disclosures to report.
1 Altekruse S. F. Kosary C. L. Krapcho M. Neyman N. Aminou R. Waldron W. Edwards B. K. SEER cancer statistics review, 1975-2007 Bethesda, MD National Cancer Institute 2010 Retrieved from http://seer.cancer.gov/csr/1975_2007/.
2 Anderson Kenneth C Lenalidomide and thalidomide: mechanisms of action--similarities and differences. Seminars in hematology 2005 42 S3 8 16344099 10.1053/j.seminhematol.2005.10.001
3 Andritsos Leslie A Johnson Amy J Lozanski Gerard Blum William Kefauver Cheryl Awan Farrukh Smith Lisa L Lapalombella Rosa May Sarah E Raymond Chelsey A Wang Da-Sheng Knight Robert D Ruppert Amy S Lehman Amy Jarjoura David Chen Ching-Shih Byrd John C Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 26 2519 2525 18427150 10.1200/JCO.2007.13.9709 PMC4312490
4 Armitage J O Weisenburger D D New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 1998 16 2780 2795 9704731 10.1200/JCO.1998.16.8.2780
5 Badoux Xavier C Keating Michael J Wen Sijin Lee Bang-Ning Sivina Mariela Reuben James Wierda William G O’Brien Susan M Faderl Stefan Kornblau Steven M Burger Jan A Ferrajoli Alessandra Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 2011 118 3489 3498 21725050 10.1182/blood-2011-03-339077 PMC4123422
6 Barista I Cabanillas F Romaguera J E Khouri I F Yang Y Smith T L Strom S S Medeiros L J Hagemeister F B Is there an increased rate of additional malignancies in patients with mantle cell lymphoma? Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2002 13 318 322 11886011 10.1093/annonc/mdf042
7 Castaneda Carmen P Brandenburg Nancy A Bwire Robert Burton Graham H Zeldis Jerome B Erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis in lenalidomide-treated patients. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009 27 156 157 19047275 10.1200/JCO.2008.20.3737
8 Celgene 2013 Revlimid (lenalidomide) package insert Retrieved from http://www.revlimid.com/wp-content/uploads/2013/11/PI.pdf
9 Chanan-Khan Asher A Cheson Bruce D Lenalidomide for the treatment of B-cell malignancies. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 26 1544 1552 18285605 10.1200/JCO.2007.14.5367
10 Chanan-Khan Asher Miller Kena C Lawrence David Padmanabhan Swaminathan Miller Austin Hernandez-Illatazurri Francisco Czuczman Myron S Wallace Paul K Zeldis Jerome B Lee Kelvin Tumor flare reaction associated with lenalidomide treatment in patients with chronic lymphocytic leukemia predicts clinical response. Cancer 2011 117 2127 2135 21523725 10.1002/cncr.25748
11 Chanan-Khan Asher Miller Kena C Musial Laurie Lawrence David Padmanabhan Swaminathan Takeshita Kenichi Porter Carl W Goodrich David W Bernstein Zale P Wallace Paul Spaner David Mohr Alice Byrne Catriona Hernandez-Ilizaliturri Francisco Chrystal Cynthia Starostik Petr Czuczman Myron S Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2006 24 5343 5349 17088571 10.1200/JCO.2005.05.0401
12 Coiffier Bertrand Altman Arnold Pui Ching-Hon Younes Anas Cairo Mitchell S Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 26 2767 2778 18509186 10.1200/JCO.2007.15.0177
13 Czuczman M. Vose J. Zinzani P. L. Reeder C. Buckstein R. Haioun C. Witzig T. Lenalidomide monotherapy is clinically active in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL): A pooled analysis of data form phase II studies (NHL-002/003) [Abstract 574]. Haematologica 2010 95(suppl 2)
14 Decaudin D Brousse N Brice P Haioun C Bourhis J H Morel P Van Hoof A Souleau B Quesnel B Gisselbrecht C Efficacy of autologous stem cell transplantation in mantle cell lymphoma: a 3-year follow-up study. Bone marrow transplantation 2000 25 251 256 10673695 10.1038/sj.bmt.1702135
15 Dimopoulos Meletios A Richardson Paul G Brandenburg Nancy Yu Zhinuan Weber Donna M Niesvizky Ruben Morgan Gareth J A review of second primary malignancy in patients with relapsed or refractory multiple myeloma treated with lenalidomide. Blood 2012 119 2764 2767 22323483 10.1182/blood-2011-08-373514
16 Dimopoulos Meletios Spencer Andrew Attal Michael Prince H Miles Harousseau Jean-Luc Dmoszynska Anna San Miguel Jesus Hellmann Andrzej Facon Thierry Foà Robin Corso Alessandro Masliak Zvenyslava Olesnyckyj Marta Yu Zhinuan Patin John Zeldis Jerome B Knight Robert D Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. The New England journal of medicine 2007 357 2123 2132 18032762 10.1056/NEJMoa070594
17 Eve Heather E Rule Simon A J Lenalidomide-induced tumour flare reaction in mantle cell lymphoma. British journal of haematology 2010 151 410 412 20880113 10.1111/j.1365-2141.2010.08376.x
18 Ferrajoli Alessandra Lee Bang-Ning Schlette Ellen J O’Brien Susan M Gao Hui Wen Sijin Wierda William G Estrov Zeev Faderl Stefan Cohen Evan N Li Changping Reuben James M Keating Michael J Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 2008 111 5291 5297 18334676 10.1182/blood-2007-12-130120 PMC4082321
19 Goy Andre Sinha Rajni Williams Michael E Kalayoglu Besisik Sevgi Drach Johannes Ramchandren Radhakrishnan Zhang Lei Cicero Sherri Fu Tommy Witzig Thomas E 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. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2013 31 3688 3695 24002500 10.1200/JCO.2013.49.2835 PMC4879693
20 Habermann Thomas M Lossos Izidore S Justice Glen Vose Julie M Wiernik Peter H McBride Kyle Wride Kenton Ervin-Haynes Annette Takeshita Kenichi Pietronigro Dennis Zeldis Jerome B Tuscano Joseph M Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. British journal of haematology 2009 145 344 349 19245430 10.1111/j.1365-2141.2009.07626.x
21 Hayashi Toshiaki Hideshima Teru Akiyama Masaharu Podar Klaus Yasui Hiroshi Raje Noopur Kumar Shaji Chauhan Dharminder Treon Steven P Richardson Paul Anderson Kenneth C Molecular mechanisms whereby immunomodulatory drugs activate natural killer cells: clinical application. British journal of haematology 2005 128 192 203 15638853 10.1111/j.1365-2141.2004.05286.x
22 Hernandez-Ilizaliturri Francisco J Deeb George Zinzani Pier L Pileri Stefano A Malik Farhana Macon William R Goy Andre Witzig Thomas E Czuczman Myron S Higher response to lenalidomide in relapsed/refractory diffuse large B-cell lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like phenotype. Cancer 2011 117 5058 5066 21495023 10.1002/cncr.26135
23 Kotla V. Goel S. Nischal S. Heuck C. Vivek K. Das B. Verma A. Mechanism of action of lenalidomide in hematological malignancies Journal of Hematology & Oncology 2009 2 36 19674465 10.1186/1756-8722-2-36 PMC2736171
24 Lunning Matthew A Vose Julie M Management of indolent lymphoma: where are we now and where are we going. Blood reviews 2012 26 279 288 23063143 10.1016/j.blre.2012.09.004 PMC3632507
25 McGraw Beth At an increased risk: tumor lysis syndrome. Clinical journal of oncology nursing 2008 12 563 565 18676323 10.1188/08.CJON.563-565
26 Miller Kena C Musial Laurie Whitworth Amy Chanan-Khan Asher Management of patients with chronic lymphocytic leukemia treated with lenalidomide. Clinical journal of oncology nursing 2010 14 491 499 20682505 10.1188/10.CJON.491-499
27 Mitchell Sandra A Beck Susan L Hood Linda Edwards Moore Karen Tanner Ellen R Putting evidence into practice: evidence-based interventions for fatigue during and following cancer and its treatment. Clinical journal of oncology nursing 2007 11 99 113 17441401 10.1188/07.CJON.99-113
28 Moutouh-de Parseval L. A. Weiss L. DeLap R. J. Knight R. D. Zeldis J. B. Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. Journal of Clinical Oncology 2007 25(31) 5047 17971612 10.1200/JCO.2007.14.2141
29 Nelson K. Samaniego F. Hagemeister F. Lacerte L. Kwak L. W. Neelapu S. Fowler N. Dermatologic side effects of lenalidomide and rituximab in indolent lymphoma.2012 Pan Pacific Lymphoma Conference 2012
30 Palumbo Antonio Freeman John Weiss Lilia Fenaux Pierre The clinical safety of lenalidomide in multiple myeloma and myelodysplastic syndromes. Expert opinion on drug safety 2012 11 107 120 22066855 10.1517/14740338.2011.619975
31 Romaguera Jorge E Fayad Luis Rodriguez Maria A Broglio Kristine R Hagemeister Frederick B Pro Barbara McLaughlin Peter Younes Anas Samaniego Felipe Goy Andre Sarris Andreas H Dang Nam H Wang Michael Beasley Virginia Medeiros L Jeffrey Katz Ruth L Gagneja Harish Samuels Barry I Smith Terry L Cabanillas Fernando F High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2005 23 7013 7023 16145068 10.1200/JCO.2005.01.1825
32 Wang Michael Fayad Luis Wagner-Bartak Nicolaus Zhang Liang Hagemeister Fredrick Neelapu Sattva S Samaniego Felipe McLaughlin Peter Fanale Michelle Younes Anas Cabanillas Fernando Fowler Nathan Newberry Kate J Sun Luhong Young Ken H Champlin Richard Kwak Larry Feng Lei Badillo Maria Bejarano Maria Hartig Kimberly Chen Wendy Chen Yiming Byrne Catriona Bell Neda Zeldis Jerome Romaguera Jorge Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. The Lancet. Oncology 2012 13 716 723 22677155 10.1016/S1470-2045(12)70200-0
33 Weber Donna M Chen Christine Niesvizky Ruben Wang Michael Belch Andrew Stadtmauer Edward A Siegel David Borrello Ivan Rajkumar S Vincent Chanan-Khan Asher Alban Lonial Sagar Yu Zhinuan Patin John Olesnyckyj Marta Zeldis Jerome B Knight Robert D Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. The New England journal of medicine 2007 357 2133 2142 18032763 10.1056/NEJMoa070596
34 Wendtner C. Hallek M. Fraser G. Michallet A. S. Hillmen P. Duerig J. Chanan-Khan A. Updated interim results of the safety and efficacy of different lenalidomide starting dose regimens in patients with relapsed or refractory (rel/ref) chronic lymphocytic leukemia (CLL) (CC-5013-CLL-009 Study) [Abstract 3925]. Blood (ASH Annual Meeting Abstracts) 2012a 120(21)
35 Wendtner Clemens-Martin Hillmen Peter Mahadevan Daruka Bühler Andreas Uharek Lutz Coutré Steven Frankfurt Olga Bloor Adrian Bosch Francesc Furman Richard R Kimby Eva Gribben John G Gobbi Marco Dreisbach Luke Hurd David D Sekeres Mikkael A Ferrajoli Alessandra Shah Sheetal Zhang Jennie Moutouh-de Parseval Laure Hallek Michael Heerema Nyla A Stilgenbauer Stephan Chanan-Khan Asher A Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leukemia & lymphoma 2012b 53 417 423 21879809 10.3109/10428194.2011.618232
36 Wiernik Peter H Lossos Izidore S Tuscano Joseph M Justice Glen Vose Julie M Cole Craig E Lam Wendy McBride Kyle Wride Kenton Pietronigro Dennis Takeshita Kenichi Ervin-Haynes Annette Zeldis Jerome B Habermann Thomas M Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin’s lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2008 26 4952 4957 18606983 10.1200/JCO.2007.15.3429
37 Witzig T E Vose J M Zinzani P L Reeder C B Buckstein R Polikoff J A Bouabdallah R Haioun C Tilly H Guo P Pietronigro D Ervin-Haynes A L Czuczman M S An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin’s lymphoma. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2011 22 1622 1627 21228334 10.1093/annonc/mdq626
38 Witzig Thomas E Wiernik Peter H Moore Timothy Reeder Craig Cole Craig Justice Glen Kaplan Henry Voralia Michael Pietronigro Dennis Takeshita Kenichi Ervin-Haynes Annette Zeldis Jerome B Vose Julie M Lenalidomide oral monotherapy produces durable responses in relapsed or refractory indolent non-Hodgkin’s Lymphoma. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2009 27 5404 5409 19805688 10.1200/JCO.2008.21.1169
39 Wu Lei Adams Mary Carter Troy Chen Roger Muller George Stirling David Schafer Peter Bartlett J Blake lenalidomide enhances natural killer cell and monocyte-mediated antibody-dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clinical cancer research : an official journal of the American Association for Cancer Research 2008 14 4650 4657 18628480 10.1158/1078-0432.CCR-07-4405
40 Zinzani P L Vose J M Czuczman M S Reeder C B Haioun C Polikoff J Tilly H Zhang L Prandi K Li J Witzig T E Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 2013 24 2892 2897 24030098 10.1093/annonc/mdt366 PMC3811905