Abstract
Background:
This multicenter, randomized phase 2 trial evaluated complete response (CR), efficacy, and safety with ofatumumab and bendamustine and ofatumumab, bendamustine, and bortezomib in patients with untreated, high-risk follicular lymphoma (FL).
Methods:
Patients with grade 1–3a FL and either a FL international prognostic index (FLIPI) of 2 with one lymph node > 6 cm or FLIPI 3–5 were randomized to Arm A (ofatumumab, bendamustine, and maintenance ofatumumab) or to Arm B (ofatumumab, bendamustine, bortezomib and maintenance ofatumumab and bortezomib).
Results:
One hundred twenty-eight patients (Arm A=66 and Arm B=62) received treatment. Median age was 61 years, 61% had disease > 6 cm, 29% were FLIPI 2, and 71% FLIPI 3–5. In Arm A, 86% completed induction and 64% completed maintenance. In Arm B, 66% and 52% completed induction and maintenance. Dose modifications were required in 65% and 89% on Arms A and B, respectively. Clinically significant grade 3–4 toxicities included neutropenia (A=36%, B=31%), nausea/vomiting (A=0, B=8%), diarrhea (A=5%, B=11%), and sensory neuropathy (A=0, B=5%).
The estimated CR rates were 62% (95% CI: 50%−74%) and 60% (95% CI: 47%−72%) in Arms A and B, respectively (p=0.68). With a median follow-up of 3.3 years, the estimated 2-year progression-free (PFS) and overall survivals (OS) were 80% and 97% for Arm A, compared to 76% and 91% for Arm B.
Conclusions:
CR rates, PFS, and OS were not improved with the addition of bortezomib to ofatumumab and bendamustine in patients with high-risk FL. Although grade 3–4 toxicities were similar, more patients treated with bortezomib required dose modifications and early discontinuation.
Keywords: Ofatumumab, bendamustine, bortezomib, follicular lymphoma
Precis:
This randomized, multi-center phase II trial demonstrated no benefit with the addition of bortezomib to front-line ofatumumab and bendamustine in patients with high-risk FL, defined as a FLIPI score of 3–5 or FLIPI score of 2 with at least one lymph node > 6 cm. The OR was 91% with a CR of 60% and 2-year PFS of 75.6% in 62 patients treated with ofatumumab, bendamustine, and bortezomib, compared to an OR of 95%, CR of 62%, and 2-year PFS of 80.3% in 66 patients treated with ofatumumab and bendamustine.
Introduction
The follicular lymphoma international prognostic index (FLIPI) identifies 3 separate prognostic risk groups based on 5 clinical characteristics including age > 60 years, stage III-IV, hemoglobin < 12 g/dL, number of nodal areas > 4, and LDH above the upper limit of normal.1 Patients with 0–1 risk factors are classified as low risk, 2 adverse factors intermediate risk, and 3 or more risk factors high risk. For those patients with FLIPI 3–5, the expected 5-year OS is 52.5%, compared to 77.6% for intermediate and 90.6% for low-risk patients. In 2009, the FLIPI-2 score also incorporated lymph node diameter greater than 6 cm as a poor-risk factor.2 Use of these tools to identify high-risk patients is widely available and applicable in clinical practice.
The BRIGHT and StiL studies have previously demonstrated an overall response (OR) of 93–97%, complete response (CR) of 31–40%, and 3-year progression-free survival (PFS) of 70% with rituximab and bendamustine in patients with previously untreated indolent lymphoma.3,4 In these trials, 43–46% of the FL patients enrolled had FLIPI scores of 3 or higher; however, OR and PFS were not specifically provided for this high-risk group. In 2011, two multicenter phase 2 trials demonstrated significant activity with a combination of rituximab, bendamustine, and bortezomib in patients with relapsed FL.5,6 In these trials, standard doses of rituximab and bendamustine were combined with bortezomib 1.6 mg/m2 on days 1, 8, 15, and 22 or 1.3 mg/m2 on days 1, 4, 8, and 11. In relapsed patients, this 3-drug combination resulted in an OR of 83–88%, CR of 50–53%, and median PFS of 14.9 months.
As bortezomib was under evaluation in FL, novel anti-CD20 antibodies were also in development. Treatment with ofatumumab, an anti-CD20 antibody that binds to a CD20 epitope distinct from the rituximab binding site, resulted in OR of 20% in patients refractory to rituximab.7 When ofatumumab was combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in patients with previously untreated FL, OR and CR rates of 100% and 62% were reported.8 In FL patients with a FLIPI score of 3–5, 76% of patients achieved a CR. A subsequent study of ofatumumab-bendamustine in indolent NHL demonstrated an OR of 90% and 67% CR rate.9
Therefore, based on the efficacy of bortezomib combined with rituximab and bendamustine in patients with relapsed FL and the promising activity of the novel anti-CD20 antibody, ofatumumab, the Cancer and Leukemia Group B (CALGB; now part of the Alliance for Clinical Trials in Oncology) conducted CALGB 50904. This multicenter randomized phase 2 study was designed to assess the efficacy of ofatumumab and bendamustine and ofatumumab, bendamustine, and bortezomib in previously untreated patients with high-risk FL based on FLIPI score and disease bulk.
Patients and Methods
Eligibility Criteria
Patients with previously untreated, histologically confirmed FL, grade 1, 2, or 3a,10 and a FLIPI score1 of 3–5 or a FLIPI score of 2 with at least one lymph node or tumor mass > 6 cm were enrolled. All cases were reviewed centrally to confirm pathology. Other inclusion criteria were age ≥ 18 years, measurable disease ≥ 1 cm, Eastern Cooperative Oncology Group (ECOG) performance status of 0–2, absolute neutrophil count (ANC) ≥ 1000/μl, platelet count ≥ 75,000/μL, creatinine < 2.0 mg/dL, aspartate aminotransferase and alanine aminotransferase < 2.5 x the institutional upper limit of normal (ULN), and bilirubin < 2 x the ULN. No prior chemotherapy, radiotherapy, or immunotherapy was permitted. Patients with active hepatitis B or C infection were excluded; however, patients seropositive for hepatitis B were permitted to enroll provided that the hepatitis B DNA was undetectable at baseline, that they were monitored for evidence of hepatitis B reactivation with each treatment cycle, and that they received lamivudine (or equivalent) daily for up to 6 months after protocol treatment.
All patients provided a signed, institutional-review board approved, protocol-specific informed consent at study enrollment per federal and institutional guidelines. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Data quality was ensured by review of the data by the Alliance Statistics and Data Center and by the study chairperson in accordance with Alliance policies.
Study treatment
Patients were randomized 1:1 to Arm A (ofatumumab and bendamustine) or Arm B (ofatumumab, bendamustine, and bortezomib). Both arms consisted of ofatumumab 300 mg intravenously (IV) day 1 of cycle 1, then 1000 mg IV day 1 of cycles 2–6 in combination with bendamustine 90 mg/m2 days 1 and 2 of cycles 1–6. Arm B also included bortezomib 1.6 mg/m2 IV or subcutaneously (SQ) on days 1, 8, 15, and 22 during cycles 1–6. Cycle length was 35 days in both arms. After the completion of cycle 6, patients without disease progression could continue to receive ofatumumab maintenance 1000 mg IV day 1 every 8 weeks for 4 additional cycles on Arm A and ofatumumab maintenance 1000 mg IV day 1 with 1.6 mg/m2 bortezomib on days 1, 8, 15, and 22 every 8 weeks for 4 cycles on Arm B. All patients in Arm B were required to receive herpes zoster prophylaxis.
Patients unable to complete the full ofatumumab dose on day 1 despite supportive measures could continue it on day 2 at the physician’s discretion. Patients were required to have an ANC of ≥ 1000/μL and platelets ≥ 75,000/μL on day 1 of each cycle. Dose delays and reductions in bendamustine to 60 mg/m2 or 45 mg/m2 and bortezomib to 1.3 mg/m2 and 1.0 mg/m2 were required for patients with ANC < 1000 or platelets < 75,000 on day 1 or for febrile neutropenia. GCSF or pegfilgrastim could be administered on day 3 of Arm A or day 23 of Arm B in lieu of a dose reduction during induction cycles; however, growth factors were not permitted during maintenance treatment. Lastly, patients in Arm B with grade 2 neuropathy had the bortezomib reduced by one dose level. Grade 3 neuropathy required holding bortezomib until the neuropathy was grade 1 or less followed by a dose reduction in bortezomib by one dose level. Grade 4 neuropathy led to permanent discontinuation of bortezomib. Patients requiring more than 2 dose reductions in bortezomib or bendamustine or a greater than 3-week treatment delay discontinued study treatment.
Response was assessed according to 2007 International Working Group criteria.11 Computed tomography (CT) scan of the chest, abdomen, and pelvis was required after cycles 2, 4, and 6 of induction therapy and then every 4 months during maintenance therapy. At the completion of protocol treatment, patients were assessed by CT scan every 4 months for 2 years and then every 6 months until disease progression or a maximum of 10 years from study entry. Positron emission tomography-computed tomography (PET/CT) was performed at study entry, after cycle 2, and after cycle 6 of induction therapy. Bone marrow biopsy was required to confirm CR in patients with bone marrow involvement at study entry.
Statistical methods
The primary objective was to determine the CR rate with ofatumumab-bendamustine (Arm A) and with ofatumumab, bendamustine, and bortezomib (Arm B) in patients with previously untreated high-risk FL. Secondary objectives included assessment of toxicity, PFS, and overall survival (OS). At the time this trial was designed, Arm A had not been rigorously investigated in this high-risk FL population; therefore, a “pick the winner” type design that calls for randomization between two experimental regimens and employs a relaxed type 1 error (one sided 15%) was selected.12 Based on historical data from the BRIGHT and StiL studies3,4, the CR rate for Arm A was estimated to be 40%. An improvement in the CR rate to 60% for Arm B would be of strong interest. Utilizing a two-stage design,13 30 patients would initially be randomized to Arms A and B. If the number of CR in Arm B was ≥ Arm A, accrual would continue in the second stage. In the second stage, an additional 31 patients would be randomized to each arm, for a total sample size of 122 eligible patients. At the completion of accrual, if more CRs were observed in Arm B than Arm A, then Arm B would be accepted for further study. This design has a one-sided 15% type I error rate and power of 84% to detect an improvement of 20% in CR rate in Arm B, based on the two-stage Fisher’s exact test. Assuming 5% ineligibility, the target accrual was 130 patients, or 65 patients per arm.
Stopping rules were incorporated into the study design to monitor for excessive infusion related toxicity and peripheral neuropathy in the first 20 patients enrolled in each arm. Details of the safety monitoring rules and their operating characteristics are described in the study protocol.
The primary analysis was based on the modified intent to treat (mITT) population, defined as eligible patients who received at least one dose of protocol therapy. The data lock date for all analyses was April 26, 2018. The primary comparison of CR rates between the two arms was based on Fisher’s exact test. The observed OR and CR rates and their 95% confidence intervals (CI) were estimated for Arm A and Arm B. The reverse Kaplan Meier method14 was used to estimate the extent of clinical follow-up maturity. PFS was defined as the time from study entry until progression or death, whichever occurred first. OS was defined as the time from study entry until death from any cause. Patients were censored at the date last known alive and/or progression free. PFS and OS were estimated utilizing the Kaplan-Meier method. Hazard ratios (HR) and their 95% CI from the Cox proportional hazards (PH) models were estimated to compare PFS and OS between treatment arms. In addition, an unplanned post hoc analysis was conducted to compare treatment efficacy in patient subgroups defined by baseline characteristics; forest plots were produced to visualize treatment effects in individual subgroups.
Results
Patient characteristics
From April 2011 through April 2016, 135 patients were accrued to the study, including 68 patients in Arm A and 67 in Arm B. Three patients (1 in Arm A and 2 in Arm B) never started protocol therapy and 4 patients (1 in Arm A and 3 in Arm B) were ineligible due to incorrect pathology in 2 patients and low FLIPI score in 2 patients. One hundred twenty-eight patients received at least one dose of protocol therapy and were evaluable for the primary endpoint.
Key patient characteristics by treatment arm are detailed in Table 1. Twenty-nine percent of patients had a pre-treatment FLIPI score of 2, 32% in Arm A and 26% in Arm B. The majority of patients had FLIPI scores of 3–4 at enrollment, 67% in Arm A and 71% in Arm B. Bulky disease > 6 cm was present in 65% and 57% of patients on Arms A and B, respectively. Twenty-two percent of patients had grade 3a histology and 65% had stage IV disease. There was no significant difference in baseline patient/disease characteristics by treatment arm (Table 1).
Table 1.
Patient characteristics by treatment arm
| Characteristic | Arm A (Ofatumumab-bendamustine) N=66 | Arm B (Ofatumumab-bendamustine-bortezomib), N=62 | P-value |
|---|---|---|---|
| Median age (range) | 61 (25–87) | 61.5(31–81) | 0.991 |
| Male | 38 (57.6%) | 30 (48.4%) | 0.382 |
| Grade | 0.132 | ||
| Grade 1–2 | 52 (78.8%) | 42 (67.7%) | |
| Grade 3a | 9 (14.8%) | 18(30.0%) | |
| Unknown | 5 (7.6%) | 2 (3.2%) | |
| Stage | 0.932 | ||
| Stage II | 1 (1.5%) | 1 (1.6%) | |
| Stage III | 21 (31.8%) | 21 (33.9%) | |
| Stage IV | 44 (66.7%) | 40 (64.5%) | |
| B-symptoms | 1.002 | ||
| No | 51 (78.5%) | 46 (79.3%) | |
| Yes | 14(21.5%) | 12 (20.7%) | |
| Unknown/not reported | 1 (1.5%) | 4 (6.5%) | |
| Elevated LDH | 0.452 | ||
| No | 48 (72.7%) | 41 (66.1%) | |
| Yes | 18(27.3%) | 21 (33.9%) | |
| Bulky disease > 6 cm | 0.36642 | ||
| No | 23 (34.8%) | 27 (43.5%) | |
| Yes | 43 (65.2%) | 35 (56.5%) | |
| FLIPI score | 0.832 | ||
| 2 | 21 (31.8%) | 16(25.8%) | |
| 3 | 33 (50.0%) | 34 (54.8%) | |
| 4 | 11 (16.7%) | 10(16.1%) | |
| 5 | 1 (1.5%) | 2 (3.2%) |
P-value determined by Kruskal Wallis Test.
P-value determined by Fisher’s Exact Test.
Study Treatment
Sixty-six patients started treatment with ofatumumab and bendamustine in Arm A and 62 patients started treatment with ofatumumab, bendamustine, and bortezomib in Arm B. Figure 1 provides details on induction and maintenance treatment and reasons for treatment discontinuation in each arm. Eighty-six percent of patients in Arm A completed all 6 cycles of induction therapy, compared to 66% for Arm B. For Arm A, 64% patients completed induction and 4 cycles of maintenance ofatumumab therapy. For Arm B, only 52% completed the planned 6 cycles of induction and 4 maintenance ofatumumab/bortezomib cycles. Twelve patients in Arm A and 9 patients in Arm B came off study for adverse events, with ofatumumab infusion, cytokine release, or allergic reactions (n=4, 3 in Arm A and 1 in Arm B) and neutropenia (n=5, 3 in Arm A and 2 in Arm B) the most common causes of discontinuation. Four patients in Arm A and 10 patients in Arm B stopped study treatment due to disease progression.
Figure 1.
Study treatment
Table 2 demonstrates the number of dose modifications for induction and maintenance therapy by study arm. In Arm A, 36% and 84% of the patients completed all treatments without any dose delays or reductions during the induction and maintenance phases, respectively. In contrast, for Arm B, only 16% and 51% of patients had no dose modifications during the induction and maintenance phases, respectively. Overall, 35% versus 11% of patients in Arms A and B, respectively, completed induction and maintenance without a dose delay or reduction. Thirty-eight percent of patients on Arm A and 13% on Arm B received pegfilgrastim or filgrastim
Table 2.
Dose modifications (reductions and delays) by study arm for induction and maintenance treatment
| Arm A, Ofatumumab and bendamustine (n=66) | Arm B, Ofatumumab, bendamustine and bortezomib, n=62 | |||
|---|---|---|---|---|
| Induction: 6 cycles planned No. (%) | Maintenance: 4 cycles planned No. (%) | Induction: 6 cycles planned No. (%) | Maintenance: 4 cycles planned No. (%) | |
| Total patients treated | 66 (100) | 52 (78%) | 62 (100) | 41 (66) |
| Patients with 0 dose reductions or delays | 24 (36) | 44 (84) | 10 (16) | 21 (51) |
| Patients with 1 dose reduction or delay | 26 (39) | 6 (12) | 27 (44) | 13 (32) |
| Patients with 2 dose reduction or delays | 9 (14) | 2 (4) | 13 (21) | 4 (10) |
| Patients with 3 or more dose reduction or delays | 7 (11) | 0 | 12 (19) | 3 (7) |
Efficacy
At the interim analysis, there were 29 patients on Arm A and 31 on Arm B. Twelve patients (41%) on Arm A and 13 patients (42%) on Arm B achieved a CR, allowing the study to proceed to stage 2. For the final efficacy analysis, 41 of 66 patients (62%; 95% CI: 50–74%) in Arm A and 37 of 62 (60%; 95% CI: 47–72%) patients in Arm B achieved a CR. There was no statistically significant difference in the CR rates between Arms A and B (Fisher’s exact test, p-value = 0.68). In an ad hoc multivariable logistic regression model adjusting for FLIPI score, the odds ratio for CR (Arm B vs. Arm A) is 0.91 (95% CI: 0.45–1.87, p=0.80). The forest plot provided in Figure 2 demonstrates that no subgroup benefitted from the addition of bortezomib to induction and maintenance therapy. The estimated OR rates in Arm A and Arm B are 95% (95% CI: 90 – 100%) and 90% (95% CI: 83 – 98%), respectively.
Figure 2.
Forest plot for subgroup analysis of CR by treatment arm: Arm A received ofatumumab and bendamustine and Arm B received ofatumumab, bendamustine, and bortezomib
With a median follow-up of 3.3 years (95% CI: 3.1–3.7), 21 patients have progressed in Arm A and 16 patients have progressed in Arm B. As shown in Figure 3, the estimated 2-year PFS for Arm A is 80.3% (95% CI: 70.8–91%) and 75.6% (95% CI: 65.2–87.7%) for Arm B. PFS was not significantly different between treatment arms (HR = 0.94, 95% CI: 0.51 – 1.74).
Figure 3.
Progression-free survival by treatment arm: Arm A received ofatumumab and bendamustine and Arm B received ofatumumab, bendamustine and bortezomib.
Three patients have died in Arm A from progression, disseminated intravascular coagulation not attributed to study treatment or disease related, and metastatic lung cancer. In Arm B, seven patients have died including 4 with disease progression, 1 from sepsis during treatment, and 2 of unknown cause. Estimated 2-year OS by Kaplan Meier method was 96.8% (95% CI: 92.6–100%) for Arm A and 91.2% (95% CI: 84.2–98.9%) for Arm B (p value = 0.1301, Figure 4). OS was not significantly different between treatment arms (HR = 2.73, 95% CI = 0.70– 10.55).
Figure 4.
Overall survival by treatment arm: Arm A received ofatumumab and bendamustine and Arm B received ofatumumab, bendamustine and bortezomib.
Toxicity
Grade 3–4 adverse events that were at least possibly related to study treatment are summarized in Table 3. Sixty-eight percent of patients on Arm A and 66% of patients on Arm B experienced grade 3–4 hematologic events. Neutropenia and lymphopenia were most common, occurring in 36% and 52% of patients on Arm A and in 31% and 55% of patients in Arm B, respectively.
Table 3.
Grade 3–4 adverse events
| Arm A, ofatumumab and bendamustine, n=66 | Arm B, ofatumumab, bendamustine and bortezomib, n=62 | |
|---|---|---|
| Hematologic Adverse events | 45 (68.2%) | 41 (66.1%) |
| Lymphopenia | 34 (51.5%) | 34 (54.8%) |
| Neutropenia | 24 (36.4%) | 19 (30.6%) |
| Anemia | 3 (4.5%) | 4 (6.5%) |
| Thrombocytopenia | 2 (3%) | 3 (3.2%) |
| Non-hematologic Adverse events | 17 (25.8%) | 33 (53.2%) |
| Abdominal pain | 1 (1.5%) | 2 (3.2%) |
| Anorexia | 0 | 1 (1.6%) |
| Allergic reaction | 3 (4.5%) | 4 (6.5%) |
| Anaphylaxis | 1 (1.5%) | 1 (1.6%) |
| Atrial fibrillation | 0 | 1 (1.6%) |
| Back pain | 0 | 1 (1.6%) |
| Cecal infection | 1 (1.5%) | 0 |
| Cytokine release | 0 | 1 (1.6%) |
| Dehydration | 1 (1.5%) | 1 (1.6%) |
| Decreased ejection fraction | 1 (1.5%) | 0 |
| Diarrhea | 3 (4.5%) | 7 (11.3%) |
| Dyspnea | 1 (1.5%) | 0 |
| Fatigue | 3 (4.5%) | 8 (12.9%) |
| Headache | 0 | 1 (1.6%) |
| Febrile neutropenia | 1 (1.5%) | 2 (3.2%) |
| Hypercalcemia | 1 (1.5%) | 0 |
| Hyperglycemia | 2 (3%) | 0 |
| Hypoalbuminemia | 0 | 2 (3.2%) |
| Hypokalemia | 2 (3%) | 1 (1.6%) |
| Hyponatremia | 1 (1.5%) | 1 (1.6%) |
| Hypophosphatemia | 0 | 2 (3.2%) |
| Hypoxia | 1 (1.5%) | 1 (1.6%) |
| Infusion reactions | 0 | 1 (1.6%) |
| Infections | 1 (1.5%) | 2 (3.2%) |
| Lung Infection | 1 (1.5%) | 1 (1.6%) |
| Mucositis | 1 (1.5%) | 0 |
| Nausea | 0 | 5 (8.1%) |
| Neuropathy-sensory | 0 | 3 (4.8%) |
| Neuropathy-motor | 0 | 1 (1.6%) |
| Pneumonitis | 1 (1.5%) | 0 |
| Rash acneiform | 1 (1.5%) | 0 |
| Rash maculopapular | 1 (1.5%) | 0 |
| Sepsis | 2 (3%) | 1 (1.6%) |
| Skin infection | 1 (1.5%) | 3 (4.8%) |
| Syncope | 0 | 3 (4.8%) |
| Vomiting | 0 | 5 (8.1%) |
Twenty-six percent of patients on Arm A compared to 53% of patients on Arm B experienced at least one grade 3–4 non-hematologic adverse event. Arm B patients experienced higher rates of fatigue, nausea and vomiting, and diarrhea. Grade 3–4 infections were observed in 4 patients on Arm A and 6 patients on Arm B. Febrile neutropenia occurred in only 1 patient on Arm A and 2 patients on Arm B. One patient died from sepsis within 1 month of cycle 5 of induction treatment on Arm B. Lastly, grade 3–4 peripheral sensory neuropathy occurred in 3 patients on Arm B, with grade 3–4 motor neuropathy in 1 patient.
Second malignancies were reported in 3 patients in Arm A including melanoma occurring 3 months from study entry, non-small cell lung cancer 3 months from study entry, and pancreatic neuroendocrine tumor 18 months from study entry. In Arm B, 4 patients developed second malignancies with non-melanoma skin cancer at 14 months from study entry, melanoma at 15 months, papillary thyroid cancer at 15 months, and renal cell carcinoma at 22 months.
Discussion
This randomized, multi-center phase II trial demonstrated no benefit with the addition of bortezomib to front-line ofatumumab and bendamustine in patients with high-risk FL. In 62 patients treated with ofatumumab, bendamustine, and bortezomib and a median follow-up of 3.3 years, the OR was 91% with a CR of 60% and 2-year PFS of 75.6%, compared to an OR of 95%, CR of 62%, and 2-year PFS of 80.3% with ofatumumab and bendamustine. Furthermore, toxicity was higher with the addition of bortezomib, with more patients requiring dose modifications and fewer patients able to complete all planned induction and maintenance cycles. Toxicities included higher rates of grade 3–4 fatigue, nausea, vomiting, and neuropathy. In an unplanned analysis, no subgroup of patients defined by baseline patient/disease characteristics appeared to benefit from the addition of bortezomib. Therefore, intensification of standard front-line chemoimmunotherapy with the addition of bortezomib is not recommended for patients with FL.
This study demonstrated significant efficacy with bendamustine based chemoimmunotherapy in patients with FL with high-risk features at diagnosis. Specifically, the OR rate of over 90% and CR rate of 60% observed in this trial compares favorably with historical data from the BRIGHT and StiL studies where OR rates of 93–97% and CR rates of 31–40% with rituximab-bendamustine were reported.3,4 Of note, the lower bounds of the 95% CI for CR rate in CALGB 50904 exceeded the historical CR rate of 40% in both study arms (95% CI: 50%−74% and 47%−72% for Arms A and B, respectively). However, these data should be interpreted with caution as the observed differences in efficacy could be attributed to differences in patient populations, treatment, and response assessment. The BRIGHT and StiL trials enrolled fewer high-risk FL then CALGB 50904, as the FL patients all had grade 1–2 disease and 43–46% had FLIPI scores of 3–5, compared to 71% of patients with FLIPI scores of 3–5 and 21% with grade 3a disease in CALGB 50904. Despite the higher risk FL patients enrolled CALGB 50904, the 2-year PFS of 76–80% in Arms A and B was similar to historical 2-year PFS of 70% with R-bendamustine, perhaps due to the use of the novel anti-CD20 antibody ofatumumab or the use of maintenance therapy that was not permitted in the BRIGHT or StiL trials. FDG PET was also not routinely utilized to confirm CR in these trials, which may also explain the lower historical CR rate, yet similar PFS. Lastly, despite the high-risk FLIPI scores and the fact that > 50% of patients had bulky disease, it is possible that CALGB 50904 may have enrolled more favorable patients as the eligibility criteria did not require enrolled patients to have a need for treatment with B-symptoms, cytopenias, bulky disease, or large tumor burden as required for study enrollment on the BRIGHT and StiL studies.
Other studies adding bortezomib to rituximab and bendamustine induction with rituximab maintenance have demonstrated similar efficacy to CALGB 50904. In a multi-center phase 2 study, Flinn and colleagues found an OR of 94%, CR of 66%, and a 3-year PFS of 72% with rituximab, bendamustine, and bortezomib in 37 patients with FL.15 In that trial, only 16% of patients had a FLIPI score of 3–5 and maintenance rituximab was permitted. The ECOG-ACRIN Cancer Research Group conducted a multicenter phase 2 trial evaluating the addition of bortezomib to rituximab-bendamustine followed by maintenance treatment with rituximab.16 Bortezomib was administered at 1.3 mg/m2 twice weekly during the initial 6 induction cycles but was not included in the maintenance cycles. In that trial, 57% of patients had FLIPI 3–5 and 87% of patients were able to complete the 6 induction cycles containing bortezomib, higher than the 66% completion rate in the current trial. However, despite the greater bortezomib dose intensity, CR rate and PFS were not significantly different in the rituximab-bendamustine-bortezomib (CR 74%, 3-year PFS 81%) and rituximab-bendamustine (CR 71%, 3-year PFS 76%) arms. Lastly, several other single arm phase 2 trials have examined bortezomib combined with rituximab, RCHOP, or RCVP (rituximab, cyclophosphamide, vincristine, and prednisone), demonstrating OR rates of 76–100% and CR rates of 44–66%, similar to CALGB 50904.17–19 Therefore, in conjunction with CALGB 50904, these trials confirm that the addition of bortezomib to front-line immunochemotherapy does not appear to improve outcomes in patients with standard or high risk FL.
CALGB 50904 was not designed to assess the contribution of ofatumumab to the chemotherapy regimen over standard rituximab-bendamustine, as both study arms received ofatumumab. However, several trials have examined novel anti-CD20 antibodies in combination with bendamustine or CHOP for newly diagnosed FL.8,9,20 Combined ofatumumab and bendamustine or CHOP demonstrates high OR rates of 90–100% and CR rates of 62–67% in patients with untreated indolent NHL. Recently, the Gallium trial demonstrated that obinutuzumab based chemotherapy was superior to rituximab based therapy, with a 3-year PFS of 80% utilizing obinutuzumab plus chemotherapy with maintenance therapy compared to 73% with rituximab-chemotherapy and maintenance in patients with untreated advanced stage FL (p=0.001).20 In that trial, more than half the patients received bendamustine in combination with obinutuzumab and 41% of patients had a FLIPI score of 3–5. OR rates of 89% and CR rates of 19% were observed in the obinutuzumab arm, compared to OR rates of 97% and CR rates of 23% with rituximab-chemotherapy; however, these responses were based on CT imaging and not FDG-PET. Adverse events occurred more frequently with obinutuzumab, including higher rates of infusion toxicity, neutropenia, infections, thrombocytopenia, and second malignancy. Sixteen percent of patients discontinued study treatment with obinutuzumab-chemotherapy due to adverse events, similar to the 18% rate of discontinuation observed in Arm A of this trial. Increased rates of infection and second malignancies were also noted in those patients treated with obinutuzumab and bendamustine (16.7% and 6.7%, respectively), compared with obinutuzumab-CHOP or obinutuzumab-CVP (5.1% and 4.5%, respectively). Second malignancies were observed in 7 patients on both arms of CALGB 50904 including melanoma, non-small cell lung, renal, neuroendocrine, and thyroid malignancies within 3–22 months from study entry. With the limited follow-up, it is difficult to ascertain if these malignancies were truly secondary to study therapy; however, the variety of malignances reported with similar findings in the Gallium trial is worrisome. Therefore, while these novel anti-CD20 antibodies may improve PFS when combined with bendamustine, longer follow-up is needed to assess their impact on OS, particularly with possible increased risks of infections and second malignancies.
In conclusion, the addition of bortezomib to ofatumumab and bendamustine does not improve OR, CR, or PFS in patients with previously untreated FL. Although this study took 5 years to accrue, the trial demonstrates that studies are feasible in high-risk FL and that excellent OR, CR, and durable remissions occur with bendamustine-based chemotherapy in this population despite the adverse prognostic features. Serious infusion reactions, infections, and second malignancies can occur when anti-CD20 antibodies are combined with bendamustine and physicians need to monitor acute and late risks of therapy. With longer follow-up, we hope to gain further insight into the expected survival of patients with high-risk FL treated with chemoimmunotherapy. Future studies with novel agents (including lenalidomide, PI3 kinase inhibitors, and Bcl-2 inhibitors) should target this population and improved clinical and biologic predictors of high-risk disease should be developed to guide therapy.
Acknowledgements:
The following institutional networks have participated in this study: Altru Cancer Center, Grand Forks, ND, Grant Seeger; Cancer Research Consortium of West Michigan NCORP, Grand Rapids, MI, Kathleen Yost, UG1CA189860; Cancer Research for the Ozarks NCORP, Springfield, MO, Jay Carlson, UG1CA189822; Dartmouth College - Norris Cotton Cancer Center LAPS, Lebanon, NH, Konstantin Dragnev, U10CA180854; Eastern Maine Medical Center Cancer Care, Brewer, ME, Thomas Openshaw; Heartland Cancer Research NCORP, Decatur, IL, Bryan Faller, UG1CA189830; Hematology Oncology Associates of Central New York-East Syracuse, East Syracuse, NY, Jeffrey Kirshner; Iowa-Wide Oncology Research Coalition NCORP, Des Moines, IA, Robert Behrens, UG1CA189816; Mayo Clinic LAPS, Rochester, MN, Steven Alberts, U10CA180790; Mercy Clinic Oklahoma Communities Inc-Norman, Norman, OK, Vikki Canfield; Metro Minnesota Community Oncology Research Consortium, Saint Louis Park, MN, Daniel Anderson, UG1CA189863; Michigan Cancer Research Consortium NCORP, Ann Arbor, MI, Philip Stella, UG1CA189971; Montana Cancer Consortium NCORP, Billings, MT, Benjamin Marchello, UG1CA189872; Mount Sinai Medical Center, Miami Beach, FL, Michael Schwartz; The Ohio State University Comprehensive Cancer Center LAPS, Columbus, OH, Claire Verschraegen, U10CA180850; Sinai Hospital of Baltimore, Baltimore, MD, Marvin Feldman; Southeast Clinical Oncology Research (SCOR) Consortium NCORP, Winston-Salem, NC, James Atkins, UG1CA189858; State University of New York Upstate Medical University, Syracuse, NY, Stephen Graziano; Toledo Clinic Cancer Centers-Toledo, Toledo, OH, Rex Mowat; UC San Diego Moores Cancer Center, La Jolla, CA, Barbara Parker; UCSF Medical Center-Mount Zion, San Francisco, CA, Charalambos Andreadis; UNC Lineberger Comprehensive Cancer Center LAPS, Chapel Hill, NC, Thomas Shea, U10CA180838; University of Chicago Comprehensive Cancer Center LAPS, Chicago, IL, Hedy Kindler, U10CA180836; University of Illinois, Chicago, IL, John Quigley; University of Missouri - Ellis Fischel, Columbia, MO, Puja Nistala; University of Oklahoma Health Sciences Center LAPS, Oklahoma City, OK, Adam Asch, U10CA180798; VCU Massey Cancer Center Minority Underserved NCORP, Richmond, VA, Steven Grossman, UG1CA189869; Wake Forest University Health Sciences, Winston-Salem, NC, Heidi Klepin; Washington University - Siteman Cancer Center LAPS, Saint Louis, MO, Nancy Bartlett, U10CA180833; Weill Medical College of Cornell University, New York, NY, Scott Tagawa; and West Virginia University Healthcare, Morgantown, WV, Richard Goldberg.
Support:
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology), U10CA180833, U10CA180850, and UG1CA189858. Also supported in part by funds from Novartis (GSK). K.A. Blum is supported by NIH-K24CA201524. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of Interest Disclosure:
This trial was supported in part by funds from Novartis (GSK). Dr. Beth Christian receives clinical research funding provided to her institution from Teva pharmaceuticals. Dr. Bruce Cheson receives consulting fees from Abbvie, Astra Zeneca, Roce-Genentech, TG Therapeutics, Epizyme, Morphosys, and Celgene. Dr. Cheson receives clinical research funding to his institution from Abbvie, Astra Zeneca, Roche-Genentech, TG Therapeutics, Epizyme, Celgene and Trillium. Dr. Eric Hsi serves on advisory boards for Seattle Genetics, Jazz, and Celgene. Dr. Hsi receives research funding to his institution from Abbvie and Eli Lilly. Dr. Nina Wagner-Johnston serves on advisory boards for Bayer and JUNO. Dr. Nina Wagner-Johnston receives clinical research funding provided to her institution from Astex, Merck, and Regeneron. The remaining authors have no additional conflicts to disclose.
CinicalTrials.gov Identifier:
References
- 1.Solal-Céligny P, Roy P, Colombat P, et al. Follicular Lymphoma International Prognostic Index. Blood 2004;104:1258–65. [DOI] [PubMed] [Google Scholar]
- 2.Federico M, Bellei M, Marcheselli L, et al. Follicular Lymphoma International Prognostic Index 2: A New Prognostic Index for Follicular Lymphoma Developed by the International Follicular Lymphoma Prognostic Factor Project. Journal of Clinical Oncology 2009;27:4555–62. [DOI] [PubMed] [Google Scholar]
- 3.Flinn IW, van der Jagt R, Kahl BS, et al. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood 2014;123:2944–52. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. The Lancet 2013;381:1203–10. [DOI] [PubMed] [Google Scholar]
- 5.Fowler N, Kahl BS, Lee P, et al. Bortezomib, Bendamustine, and Rituximab in Patients With Relapsed or Refractory Follicular Lymphoma: The Phase II VERTICAL Study. Journal of Clinical Oncology 2011;29:3389–95. [DOI] [PubMed] [Google Scholar]
- 6.Friedberg JW, Vose JM, Kelly JL, et al. The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma. Blood 2011;117:2807–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Czuczman MS, Fayad L, Delwail V, et al. Ofatumumab monotherapy in rituximab-refractory follicular lymphoma: results from a multicenter study. Blood 2012;119:3698–704. [DOI] [PubMed] [Google Scholar]
- 8.Czuczman MS, Hess G, Gadeberg OV, et al. Chemoimmunotherapy with ofatumumab in combination with CHOP in previously untreated follicular lymphoma. British Journal of Haematology 2012;157:438–45. [DOI] [PubMed] [Google Scholar]
- 9.Czuczman MS, Kahanic S, Forero A, et al. Results of a phase II study of bendamustine and ofatumumab in untreated indolent B-cell non-hodgkin’s lymphoma. Annals of Hematology 2015;94:633–41. [DOI] [PubMed] [Google Scholar]
- 10.Swerdlow S, Campo E, Harris N, et al. WHO classification of tumors of hematopoietic and lymphoid tissues. World Health Organization Classification of Tumors; Lyon, France: IARC; 2008:2375–90. [Google Scholar]
- 11.Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant Lymphoma. Journal of Clinical Oncology 2007;25:579–86. [DOI] [PubMed] [Google Scholar]
- 12.Wieand H Randomized phase II trials: What does randomization gain? J Clin Oncol 2005;23:1794–5. [DOI] [PubMed] [Google Scholar]
- 13.Jung S DA S. Randomzed phase II cancer clinical trials. J Biopharm Stat 2014;24:802–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Korn E Censoring distributions as a measure of follow-up in survival analysis. Stat Med 1986;5:255–60. [DOI] [PubMed] [Google Scholar]
- 15.Flinn IW, Thompson DS, Boccia RV, et al. Bendamustine, bortezomib, and rituximab produces durable complete remissions in patients with previoulsy untreated, low grade lymphoma. British Journal of Haematology 2017;180:365–73. [DOI] [PubMed] [Google Scholar]
- 16.Evens AM, Hong F, Habermann TM, et al. A 3-arm randomized phase II trial bendamustine/rituximab therapy in untreated high risk follicular lymphoma (FL): Bortezomib induction or novel IMID continuation (BIONIC) study from the ECOG-ACRIN Cancer Research Group. Blood 2017;130:abstract 482. [Google Scholar]
- 17.Evens AM, Smith MR, Lossos IS, et al. Frontline bortezomib and rituimab for the treatment of newly diagnosed high tumor burden indolent non-Hodgkin lymphoma: a multicenter phase II study. British Journal of Haematology 2014;166:514–20. [DOI] [PubMed] [Google Scholar]
- 18.Cohen JB, Switchenko JM, Sinha R, et al. A phase II study of bortezomib added to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone in patients with previously untreated indolent non-Hodgkin’s lymphoma. British Journal of Haematology 2015;171:539–46. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Sehn LH, MacDonald D, Rubin S, et al. Bortezomib added to R-CVP is safe and effective for previously untreated advanced stage follicular lymphoma: A phase II study by the National Cancer Institute of Canada Clinical Trials Group. Journal of Clinical Oncology 2011;29:3396–401. [DOI] [PubMed] [Google Scholar]
- 20.Marcus R, Davies A, Ando K, et al. Obinutuzumab for the First-Line Treatment of Follicular Lymphoma. New England Journal of Medicine 2017;377:1331–44. [DOI] [PubMed] [Google Scholar]