Lenalidomide can be safely combined with R-CHOP - Nature

Leukemia (2011) 25, 1877–1881 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu

ORIGINAL ARTICLE Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study GS Nowakowski1, B LaPlant2, TM Habermann1, CE Rivera3, WR Macon4, DJ Inwards1, IN Micallef1, PB Johnston1, LF Porrata1, SM Ansell1, RR Klebig1, CB Reeder5 and TE Witzig1 1

Division of Hematology, Mayo Clinic, Rochester, MN, USA; 2Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; 3Division of Hematology-Oncology, Mayo Clinic, Jacksonville, FL, USA; 4Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA and 5Division of Hematology-Oncology, Mayo Clinic, Scottsdale, AZ, USA

Lenalidomide was shown to have significant single-agent activity in relapsed aggressive non-Hodgkin’s lymphoma (NHL). We conducted a phase I trial to establish the maximum tolerated dose of lenalidomide that could be combined with R-CHOP (rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisone). Eligible patients were adults with newly diagnosed, untreated CD20 positive diffuse large cell or follicular grade III NHL. Patients received oral lenalidomide on days 1–10 with standard dose R-CHOP every 21 days. All patients received pegfilgrastim on day 2 of the cycle and aspirin prophylaxis. The lenalidomide dose levels tested were 15, 20 and 25 mg. A total of 24 patients were enrolled. The median age was 65 (35–82) years and 54% were over 60 years. Three patients received 15 mg, 3 received 20 mg and 18 received 25 mg of lenalidomide. No dose limiting toxicity was found, and 25 mg on days 1–10 is the recommended dose for phase II. The incidence of grade IV neutropenia and thrombocytopenia was 67% and 21%, respectively. Febrile neutropenia was rare (4%) and there were no toxic deaths. The overall response rate was 100% with a complete response rate of 77%. Lenalidomide at the dose of 25 mg/day administered on days 1 to 10 of 21-day cycle can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma. Leukemia (2011) 25, 1877–1881; doi:10.1038/leu.2011.165; published online 1 July 2011 Keywords: lenalidomide; R-CHOP; lymphoma; DLBCL; phase I; therapy

action than traditional cytotoxic chemotherapy, significantly improved the results of initial therapies.1–4 Based on these and other studies, R-CHOP (rituximab–cyclophosphamide, doxorubicin, vincristine, and prednisone) has become the standard of care therapy for patients with newly diagnosed aggressive B-cell lymphoma. Lenalidomide, an immunomodulatory agent, was shown to have significant activity in relapsed aggressive B-cell NHL.11–13 However, the role of lenalidomide in initial therapeutic intervention in aggressive lymphomas remains unknown. The mechanism of action of lenalidomide is complex and involves immune modulation,14 antiangiogenesis,15 modulation of the microenvironment and direct anti-tumor activity.16 The novel and distinct mechanisms of action of lenalidomide, from both traditional chemotherapy and rituximab, provide a strong rationale for the introduction of lenalidomide to upfront therapy in aggressive B-cell NHL. As the maximum tolerated dose (MTD) of lenalidomide in combination with R-CHOP was unknown, we initiated a phase I/II trial of lenalidomide in combination with R-CHOP to establish the safety and efficacy of this therapy in the treatment of patients with newly diagnosed aggressive B-cell NHL. Herein, we report the results of a phase I trial of this unique combination.

Patients and methods Introduction Approximately 40% of patients with aggressive B-cell nonHodgkin’s lymphoma (NHL) relapse following initial immunochemotherapy.1–5 Although a significant number of patients with relapsed aggressive NHL can be salvaged with intensive high-dose chemotherapy, the majority will succumb to the disease. Thus, the development of a more effective initial therapy in aggressive NHL is essential to improve long-term outcomes. Before the advent of rituximab, a number of dose-intensified cytotoxic therapies were introduced but these regimens failed to provide substantial improvement over the standard anthracycline based combination of cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) or CHOP-like chemotherapy.6–10 In contrast, the addition of rituximab, a monoclonal antibody with a different mechanism of Correspondence: Dr GS Nowakowski and Dr TE Witzig, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mails: [email protected] and [email protected] Received 16 February 2011; revised 20 April 2011; accepted 3 May 2011; published online 1 July 2011

Patients Eligible patients were X18 years of age (no upper age limit) with newly diagnosed untreated CD20 positive stages II–IV diffuse large B-cell lymphoma or grade 3 follicular lymphoma, and measurable disease defined as at least 1 lesion X1.5 cm in a single diameter. Patients were required to have Eastern Cooperative Group performance status 0–2; estimated cardiac ejection fraction X45%; absolute neutrophil count X1500/ml; platelet count of X100 000/ml; total bilirubin p1.5 upper limit of normal (ULN) or if total bilirubin was 41.5 ULN, the direct bilirubin must have been normal; alkaline phosphatase p3 ULN unless evidence of direct liver involvement by lymphoma then p5 ULN; aspartate transaminase p3 ULN unless evidence of direct liver involvement by lymphoma then p5 ULN and creatinine p2 ULN. Exclusion criteria were: pregnant or nursing women, human immunodeficiency virus infection, presence of central nervous involvement, posttransplant lymphoproliferative disorder, history of myocardial infarction within p6 months or therapy with erythroid stimulating agents. Patients with a history of life threatening or recurrent thrombosis/embolism were excluded unless they were on anticoagulation during the treatment.

Lenalidomide and R-CHOP GS Nowakowski et al

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Study design and treatment A phase I open-label dose escalation study was conducted to define MTD of lenalidomide administered on days 1–10 with standard dose R-CHOP-21 chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (capped at 2.0 mg), all on day 1; prednisone 100 mg/m2 on days 1–5) using a 3 þ 3 escalation design. After the MTD was determined, additional patients were accrued to that dose level to expand the safety database. Lenalidomide dose escalation levels were 15 mg, 20 mg and 25 mg. All patients received a pegfilgrastim 6 mg subcutaneous injection on day 2 (Figure 1). The treatment continued for a maximum of six cycles or until disease progression. All patients received low dose aspirin (ASA) prophylaxis (81 mg daily) unless fully anticoagulated for intercurrent conditions. Tumor lysis prophylaxis, antiemetics, infection prophylaxis and supportive care were as per the discretion of the treating physician.

Outcome measures Dose limiting toxicity (DLT) was defined as a toxicity during the first cycle of treatment that met one of the following criteria, where toxicity was defined as an adverse event at least possibly related to study treatment: (i) any grade 3 or higher non-hematological toxicity per NCI (National Cancer Institute) Common Terminology Criteria for Adverse Events v3.0; (ii) platelet count o25 000/ml for X7days or platelet nadir o10 000/ml at anytime; (iii) non-hematological toxicity requiring a delay of the next cycle of therapy for more than 7 days; (iv) failure to recover platelet count X75 000/ml and/or absolute neutrophil count X1500/ml by day 28. The latter two criteria were to ensure maintenance of the dose intensity and schedule of R-CHOP, a potentially curative therapy in this setting. All patients had positron emission tomography combined with non-contrast computed tomography at diagnosis. Responses were evaluated after two and six cycles of treatment by positron emission tomography with computed tomography using standard response criteria as published by Cheson et al.17

Statistical considerations The MTD was defined as the dose level below the lowest dose that induces DLT in at least one-third of patients (at least two of a maximum of six patients), or the highest dose evaluated if less than one-third of patients experienced DLTs at all dose levels. Once the MTD was determined, additional patients were

accrued to more fully assess the toxicities at that dose level, for a total of 18 patients treated at the MTD. MTD was evaluated using the first cycle of treatment; however, toxicity data were collected during all cycles and monitored for cumulative toxicity. Overall toxicity incidence was summarized, as well as toxicity profiles by dose level.

Ethics The study was approved by the Institutional Review Board and all patients provided written, informed consent to participate in the study. The study was registered with National Clinical Trial Registry - NCT00670358.

Results Between September 2008 and January 2010, 24 patients were enrolled (Table 1). The median age was 65 years; 54% of patients were over 60 and 29% of patients were 75 or older. A total of 20 patients had diffuse large B-cell lymphoma and 3 patients had grade 3A follicular lymphoma confirmed by central pathology review. One patient (dose level 2) was determined to be follicular grade 2 follicular lymphoma at the time of central pathology review. Three patients received 15 mg, three 20 mg and eighteen 25 mg of lenalidomide. All but three patients completed six cycles of therapy. One patient discontinued treatment after cycle 5 because of progressive disease, and two patients refused further treatment after one cycle (all dose level 3). Voluntary withdrawal in both cases was due to a desire to transfer care to a local center in proximity to the home address rather than continue to travel the distance to the participation sites for subsequent cycles.

Table 1

Patient characteristics N (%)a

Age, median (min., max.)

65 (35, 82)

Sex Male Female

14 (58) 10 (42)

ECOG performance status 0 1 2

10 (42) 11 (46) 3 (13)

Ann arbor stage II III IV

3 (13) 8 (33) 13 (54)

IPI risk Low Low-intermediate High-intermediate High

Figure 1 Treatment schema. Lenalidomide was administered on days 1–10 with RCHOP-21 chemotherapy (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (capped at 2.0 mg), all on day 1 and prednisone 100 mg/m2 on days 1–5). All patients received a pegfilgrastim 6 mg subcutaneous injection on day 2. P, pegfilgrastim, R, rituximab. Leukemia

Lymphoma type DLBCL FL grade 3A FL grade 2

6 7 9 2

(25) (29) (38) (8)

20 (83) 3 (13) 1 (4)

Abbreviations: DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; FL, follicular lymphoma; IPI, international prognostic index. a Unless otherwise noted.


1879 Table 2 Grade 3 and 4 adverse events at least possibly related to the treatment (all cycles) Toxicity

Grade 3

4

N

%

N

%

Hematologic Anemia Neutropenia Thrombocytopenia

4 5 2

17 21 8

1 16 5

4 67 21

Infection/febrile neutropenia Febrile neutropenia Urinary tract infection Pneumonia Skin infection

1 1 1 1

4 4 4 4

and refusal for one cycle in one patient. In the patients who had interruptions, two patients discontinued lenalidomide because of thrombosis despite ASA prophylaxis after two and four cycles, and one patient discontinued after five cycles due to persistent grade 4 thrombocytopenia after two dose reductions. One additional patient had a dose reduction of lenalidomide due to thrombocytopenia related to treatment but did not require an interruption. At least one agent of R-CHOP was dosereduced in two patients. Grade 2 sensory neuropathy related to treatment was seen in 5 of 24 (20%) patients. One patient experienced grade 3 sensory and motor neuropathy related to treatment and discontinued vincristine; neuropathy improved after withholding vincristine despite continuation of lenalidomide. One patient had multiple dose reductions due to nonhematologic toxicities related to treatment.

Treatment response

Neurologic Peripheral motor neuropathy Peripheral sensory neuropathy

1 1

4 4

Vascular Venous thrombosis

2

8

Constitutional symptoms Fatigue Dehydration

1 1

4 4

Safety There were no events that fit the criteria listed in the DLT definition during cycle 1. Therefore, as no DLTs were seen and no patient died from toxicity, the dose of lenalidomide 25 mg/day on days 1–10 was recommended for the phase II study dose. Hematological and non-hematological toxicities during cycles 1–6 that were at least possibly related to treatment are summarized in Table 2. Grade 3 non-hematological toxicities were seen in 21% of patients; grades 4 and 5 were not seen. Several events occurred that fit the criteria listed in the DLT definition but were not classified as DLT as they occurred during cycles 2–6 rather than cycle 1. Grade 3 and 4 hematological toxicities associated with complications. Although grade 3 and 4 neutropenia was present in 21% and 67%, respectively, neutropenia was of short duration and only one patient developed neutropenic fever requiring hospitalization. Grade 3 and 4 thrombocytopenia occurred in 8% and 21% of patients, respectively, but there were no hemorrhagic complications. There were no delays in chemotherapy due to cytopenias and of 133 cycles administered, there were six treatment delays (5%) in five patients. Treatment was delayed in one patient after cycle 2 due to a grade 3 skin infection unrelated to treatment. This patient later developed grade 3 deep venous thrombosis related to treatment following a long car ride and had treatment held again for 1 week after cycle 4. Two patients had dose delays of 9 and 21 days, respectively, due to pneumonia (1 grade 2, 1 grade 3) related to treatment; one of these patients omitted lenalidomide for one cycle and the other had dose reduction of lenalidomide. Other reasons for dose delays were scheduling conflict (one cycle) and hospitalization for grade 4 chest pain unrelated to treatment (one cycle). Lenalidomide was interrupted during seven of 133 cycles (5%) in five patients due to grade 4 hematological toxicity related to treatment (three cycles in one patient), grade 3 thrombosis related to treatment (one cycle each in two patients), and grade 1 dermatologic toxicity (one cycle) related to treatment

Responses were seen in 3/3 patients at dose level 1 (two partial responses (PR), one complete response (CR)), 3/3 patients at dose level 2 (one PR, two CR), and 16/18 patients at dose level 3 (2 PR, 14 CR). The two patients at dose level 3 who did not achieve a response withdrew from participation in the study before the first scheduled response assessment per study protocol. They continued treatment with R-CHOP off study and both achieved CR. The overall response rate in the 22 patients remaining on the study who were assessed for response was 100% (95% CI: 85–100%) and CR rate was 77% (95% CI: 55–92%). Five patients have had disease progression and one patient has died because of disease progression. Median followup for patients is 7 months (range: 2–20 months). The median duration of response has not yet been reached.

Discussion The clinical benefit of the addition of rituximab to cytotoxic chemotherapy suggests that an improvement of the initial therapy may depend on the introduction of combinations containing agents with a novel mechanism of action rather than chemotherapy dose intensification. Lenalidomide with its significant single agent activity and distinct pleiotropic mechanism of action is a strong candidate for the introduction to upfront therapy of aggressive B-cell NHL.14–16 There are three plausible approaches of introducing lenalidomide to upfront therapy: (i) lenalidomide maintenance following initial chemoimmunotherapy, (ii) addition of concomitant lenalidomide treatment to chemoimmunotherapy or (iii) both. Based on the in vitro synergy of lenalidomide with rituximab and cytotoxic therapy,18,19 as well as the potential impact on microenvironment mediated drug resistance,20,21 we elected to first test the combination approach. The addition of concurrent lenalidomide to R-CHOP is challenging because of the potential for overlapping hematological toxicity that may result in a negative impact on the dose intensity of R-CHOP, a potentially curative regimen in this setting. Accordingly, our principal concern in the selection of the dose schedule and definition of MTD was to avoid affecting the intensity of R-CHOP therapy. Hence, the duration of lenalidomide was limited to days 1–10 of a cycle to facilitate hematological recovery before next cycle of therapy while allowing for synergy with chemotherapy during concomitant therapy. Any toxicity resulting in a delay of a subsequent cycle of therapy by more than 1 week was to be considered dose limiting, as potentially affecting the dose intensity of R-CHOP. Also, all patients received pegfilgrastim support on Leukemia


1880 day 2. We mandated standard pegfilgrastim use because of the fact that we have no upper age limit on participation in the study and that leaving its use to the discretion of the treating physician would likely result in significant heterogeneity and resulting difficulties in establishing MTD reliably. Indeed, the majority of the enrolled patients would be candidates for white blood cell growth factor use according to current guidelines.22 Importantly, the addition of lenalidomide at this dose and schedule did not result in treatment delay due to delayed hematological recovery. Similarly, thrombocytopenia duration was short and not associated with bleeding complications. There were no treatment-related deaths, and the nonhematological toxicities were modest. Sensory neuropathy grade 2 was seen in 5 of 24 patients and 1 patient experienced grade 3 sensory and motor neuropathy. The neuropathy developed after a number of chemotherapy cycles (median of three cycles), and stabilized or improved after withholding of vincristine despite continuation of lenalidomide. Therefore, neuropathy most likely represented vincristine toxicity rather than lenalidomide effect. Indeed, the incidence of neuropathy appears to be similar to that reported with CHOP and R-CHOP alone.8,23 Lenalidomide use, particularly in combinations, is associated with an increased risk of thrombosis.24,25 ASA has been reported to be an effective prophylaxis, and was mandated in this study.25 Two of 24 patients (8%) experienced DVT while on therapy despite ASA; lenalidomide was then restarted after patients were therapeutically anticoagulated without further problems. Recent meta-analysis estimated the risk of thrombosis in NHL patients at 6%,26 a rate similar to that seen in our study. However, because of small number of patients, clearly more data from the ongoing phase II study is needed to reliably estimate the risk of thrombosis with this combination, and ASA prophylaxis is mandated in the phase II study. The median age of patients diagnosed with diffuse large B-cell lymphoma is 64, and older individuals are in particular need of better initial therapy as the relapse rate is higher and many will not tolerate intensive salvage chemotherapy and/or stem cell transplantation.27 We therefore did not have an upper age limit for eligible patients in this study to make the results applicable to elderly patients as well. Indeed, the median age in our study was 65, where 54% of patients were over 60 and 29% were 75 or older. Importantly, the regimen was well tolerated in the elderly population, and differences in toxicity based on age were not significantly different in patients of age 65 and older vs those younger than 65 for either hematological toxicity (100 vs 82%, P ¼ 0.20) or non-hematological toxicity (23 vs 18%, P ¼ 1.00). Although the MTD was not reached, 25 mg daily in relapsed refractory disease with a known toxicity profile is a well established biologically effective dose.11,19,28 There is little evidence to support further dose escalation, therefore, this dose was moved forward to the phase II part of the study. The extension of lenalidomide beyond 10 days is under investigation. In conclusion, lenalidomide can be safely combined with R-CHOP in the initial chemotherapy of aggressive B-cell lymphoma and this combination is well tolerated. The ongoing phase II study will provide a better estimate of the toxicity and long-term efficacy of this combination. Ultimately, a randomized trial may be needed to confirm benefits of this novel combination.

Conflict of interest The authors declare no conflict of interest. Leukemia

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