Approaches to Managing Safety With Lenalidomide in Hematologic Malignancies

Lenalidomide is an oral immunomodulatory agent approved in relapsed multiple myeloma with dexamethasone, for transfusion-dependent anemia in myelodysplastic syndrome associated with deletion 5q, and in relapsed/progressive mantle cell lymphoma following bortezomib. In recent clinical trials, lenalidomide has shown promising activity in hematologic malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Starting doses and dosing schedules vary by malignancy, with lenalidomide started at a lower dose for CLL than for NHL or multiple myeloma. Certain adverse events (AEs) are common across tumor types (e.g., neutropenia, thrombocytopenia, fatigue), whereas others are more often associated with CLL patients (e.g., tumor lysis syndrome and tumor flare reaction). Effective management requires awareness of these differences as well as appropriate prophylaxis, monitoring, and treatment of AEs. 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. With these steps, lenalidomide can be administered safely, at the best starting doses and with minimal dose interruptions or reductions across hematologic malignancies.

L enalidomide (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 myelo-dysplastic 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 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.
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).
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; ClinicalTri-Use your smartphone to access information about the Revlimid REMS program.

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.

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.

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-   (Ferrajoli et al., 2008). c Lenalidomide dose administered per each 28-day cycle.   Miller et al. (2010). Celgene (2013). h Mitchell et al. (2007). 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. Severe, lifethreatening 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).
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).
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).

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.

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. l