Highlights in Lymphoma From the 2014 European Hematology Association Congress

Brentuximab Vedotin as Single Agent in Refractory or Relapsed CD30-Positive Hodgkin Lymphoma: the French Name Patient Program Experience in 241 Patients

Current treatments fail to cure approximately 20% of patients with Hodgkin lymphoma.¹ For patients with relapsed or refractory Hodgkin lymphoma, the standard of care is salvage chemotherapy followed by autologous stem cell transplantation (SCT), which induces long-term remissions in approximately 50% of patients. For patients who experience relapse after autologous SCT, allogeneic SCT is often a reasonable option. However, effective agents are needed for failure after autograft.

CD30 is a member of the tumor necrosis factor superfamily of transmembrane receptors and is expressed on Hodgkin lymphoma cells. It modulates numerous cellular activities, including cell survival, proliferation, and death. It is expressed on activated T cells,
B cells, and natural killer cells. CD30 is not expressed on most normal cells, which makes it an excellent therapeutic target. Brentuximab vedotin is an antibody-drug conjugate that consists of an anti-CD30, immunoglobulin G1 antibody that is conjugated by a protease-cleavable dipeptide linker to the microtubule-disrupting agent monomethyl auristatin E (MMAE).² Bind—-ing to CD30 on the cell surface induces drug internalization, which is followed by disruption of the microtubule network, cell cycle arrest, and apoptosis. Brentuximab vedotin was first evaluated as a single agent in 102 patients with relapsed or refractory, CD30-positive leukemia or lymphoma, including 71% with primary refractory disease and 42% with disease that was refractory to the most recent prior therapy.³ The study demonstrated an overall response rate (ORR) of 75%, including a complete response (CR) rate of 34%. Median progression-free survival (PFS) for the study population was 5.6 months. A long-term update of the phase 2 study showed an estimated 3-year overall survival (OS) of 54%.⁴ This study led to accelerated approval of brentuximab vedotin by the US Food and Drug Administration in 2011.

Starting in January 2011, the French Name Patient Program made brentuximab vedotin available for patients with relapsed or refractory, CD30-positive Hodgkin lymphoma after failure of autologous SCT or after failure of at least 2 prior multiagent chemotherapy regimens in patients who were not candidates for autologous SCT. For the current retrospective study, data were available for 240 patients from 89 French treatment centers who had received brentuximab vedotin (1.8 mg/kg) once every 3 weeks.⁵ The study’s primary endpoint was the best response after treatment. Patients had a median age of 30 years, and the cohort was characterized by high-risk disease: 59% of patients had stage III or IV disease, 59% had received at least 1 transplant, and 16% had received prior allogeneic transplant. The median time to relapse following transplant was 6 months. Patients received a median 6 cycles of antibody therapy, and responses were assessed mainly based on the revised Cheson criteria.⁶

After a median 4 cycles of treatment, the ORR was 61%, including 34% CRs (Figure 1). However, after a median 6 cycles, the response rate decreased, with 24% CRs and 10% partial responses (PRs). Fifty-four percent of patients had progressive disease. In the 140 patients who demonstrated a response, the median duration of response was 8.4 months. After a median follow-up of 16 months, median PFS was slightly longer than 6 months. Median OS was not reached, with an estimated 1-year OS of 76% and 2-year OS of 58%. The drug demonstrated an acceptable toxicity profile, with no deaths linked to treatment. Grade 1/2 sensory neuropathy was observed in 27% of patients. Diarrhea was reported in 14% of patients. Hematologic toxicities of any grade included anemia (39%), thrombocytopenia (27%), and neutropenia (23%).

A separate study showed that brentuximab vedotin can be safely administered to Hodgkin lymphoma patients who have relapsed after autologous SCT, prior to reduced-intensity conditioning allogeneic SCT. After allogeneic SCT, 7 of 8 study patients remained progression-free after a median follow-up of 12 months.⁷ In the study by Perrot and colleagues, 54 patients who responded to antibody therapy received either autologous SCT (n=27) or allogeneic SCT (n=27).⁵ Median PFS was significantly increased in the patients who received consolidation therapy after treatment with brentuximab vedotin (19 months vs 9 months). The authors concluded that, owing to the short duration of response, transplantation with the intent to cure should be initiated rapidly in relapsed or refractory Hodgkin lymphoma patients who respond to antibody therapy.

Patients with peripheral T-cell lymphoma (PTCL) were also treated through the French Name Patient Program. Outcomes in PTCL patients are generally poor, with a median OS of 6.7 months in patients with relapsed or refractory disease.⁸ Brentuximab vedotin has shown activity in patients with relapsed or refractory anaplastic large cell lymphoma (ALCL), with an ORR of 86% and a CR rate of 57%.⁹ However, although ALCL is characterized by uniformly strong expression of CD30, expression in PTCL tumors is more variable. Data from 66 PTCL patients treated with brentuximab vedotin in the French Name Patient Program were retrospectively analyzed.¹⁰ Eighty-seven percent of patients had Ann Arbor stage III or IV disease, and 39% had primary refractory disease. CD30 expression levels were greater than 75% in 48.8%, 10% to 75% in 30.2%, and undetectable in 21.0% of tested cases. The 66 patients received a median 5 cycles of brentuximab vedotin, with 11 patients receiving concomitant chemotherapy. Based on Cheson 1999 criteria, CRs were observed in 33 patients (50%), with a median 4 cycles of treatment (range, 1-12) administered prior to the best response.¹¹ At the end of treatment, 30 patients (45%) were still in CR, and 21 (32%) had progressive disease. After a median follow-up of 13.4 months, median duration of response was 13.6 months (95% CI, 4.4 months-not reached), median PFS was 7.3 months (95% CI, 5.2-10.5 months), and median OS was 25.9 months (95% CI, 11.9-not reached). No new toxicities were observed. Median PFS was longer in patients whose tumors expressed CD30 at levels greater than 75% compared with less than 75% (P=.0076; Figure 2).

References

1. Colpo A, Hochberg E, Chen YB. Current status of autologous stem cell transplantation in relapsed and refractory Hodgkin’s lymphoma. Oncologist. 2012;17(1):80-90.

2. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30-monomethyl auristatin E conjugate with potent and selective antitumor activity. Blood. 2003;102(4):1458-1465.

3. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189.

4. Gopal AK, Chen R, Smith S, et al. The three-year follow-up data and characterization of long-term remissions from an ongoing phase 2 study of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 4382]. Blood. 2013;122(21 suppl).

5. Perrot A, Monjanel H, Bouabdallah R, et al. Brentuximab vedotin as single agent in refractory or relapsed CD30-positive Hodgkin lymphoma: the French Name Patient Program experience in 241 patients [EHA abstract S1293]. Haematologica. 2014;99(suppl 1):498.

6. Cheson BD, Pfistner B, Juweid ME, et al; International Harmonization Project on Lymphoma. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25(5):579-586.

7. Zallio F, Busca A, Mordini N, et al. Safety and efficacy of brentuximab vedotin (SGN-35) in Hodgkin lymphoma patients undergoing reduced intensity allogeneic stem cell transplant following a relapse after autologous transplant [EHA abstract P1129]. Haematologica. 2014;99(suppl 1):431.

8. Mak V, Hamm J, Chhanabhai M, et al. Survival of patients with peripheral T-cell lymphoma after first relapse or progression: spectrum of disease and rare long-term survivors. J Clin Oncol. 2013;31(16):1970-1976.

9. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196.

10. Mathilde L, Contejean A, Bossard C, et al. Brentuximab vedotin in refractory or relapsed peripheral T-cell lymphoma: the French Name Patient Program experience in 65 patients [EHA abstract P465]. Haematologica. 2014;99(suppl 1):151.

11. Cheson BD, Horning SJ, Coiffier B, et al; NCI Sponsored International Working Group. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol. 1999;17(4):1244-1253.

Subcutaneous Rituximab and Chemotherapy Achieves Similar Overall Response Rates to Intravenous Rituximab in First-Line Follicular Lymphoma: Efficacy and Safety Results of the Phase III SABRINA Study

Rituximab plus chemotherapy followed by rituximab maintenance is standard treatment for follicular lymphoma. Current rituximab formulations are administered intravenously, and often require hours for a single treatment. The availability of a subcutaneous formulation of rituximab that achieves equivalent rituximab serum concentrations would both increase patient convenience and reduce the costs associated with long infusion times. SABRINA (A Study of MabThera [Rituximab] Subcutaneous Vs. MabThera [Rituximab] Intravenous in Patients With Follicular Non-Hodgkin’s Lymphoma) was a 2-stage, phase 3 study designed to demonstrate noninferiority of 3-week cycles of fixed-dose subcutaneous rituximab vs intravenous rituximab. Pharmacokinetic noninferiority was demonstrated in the first stage of the study based on the subcutaneous:intravenous serum concentration ratio of 1.62 (90% CI, 1.36-1.94).¹ Provisional analysis based on 127 randomized patients demonstrated comparable efficacy. In stage 2, an additional 283 patients were randomized to assess the efficacy and safety of the subcutaneous formulation.² Follicular lymphoma patients received intravenous rituximab plus chemotherapy for the first treatment cycle, then subcutaneous rituximab at 1400 mg or intravenous rituximab at 375 mg/m² plus chemotherapy every 3 weeks for induction cycles 2 through 8, followed by subcutaneous rituximab or intravenous rituximab maintenance every 8 weeks. Chemotherapy consisted of either a maximum of 8 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or 8 cycles of cyclophosphamide, vincristine, and prednisone. Data from 410 patients from stages 1 and 2 were combined for the efficacy and safety analysis. Previously untreated patients with confirmed CD20-positive grade 1, 2, or 3a follicular lymphoma were randomized to receive subcutaneous rituximab or intravenous rituximab. Patients were stratified based on Follicular Lymphoma International Prognostic Index (FLIPI) score, type of chemotherapy, and region. In each arm, approximately two-thirds of patients received CHOP, with the remainder receiving cyclophosphamide, vincristine, and prednisone.

At the end of induction, the investigator-assessed ORR was 83.4% (95% CI, 77.6%-88.2%) for subcutaneous rituximab vs 84.4% (95% CI, 78.7%-89.1%) for intravenous rituximab(Figure 3). Rates of CR, including unconfirmed CR (CRu), were 32.7% for subcutaneous rituximab and 31.7% for intravenous rituximab. After a median follow-up of 14.4 months, adverse events (AEs) were reported in 93% of subcutaneous patients vs 92% of intravenous patients. The majority of AEs were of grade 2 or lower, including 90% of AEs in the subcutaneous arm and 88% of AEs in the intravenous arm. The proportion of patients with at least 1 AE of grade 3 or higher was 49% in the subcutaneous rituximab arm vs 47% in the intravenous rituximab arm, with serious AEs reported in 29% vs 26% of patients, respectively. The most commonly reported serious AEs were infections (10% in the subcutaneous arm vs 8% in the intravenous arm) and neutropenia (6% vs 4%, respectively). Neutropenia and anemia occurred in 5% or fewer patients in each arm. Administration-related reactions were predominantly grade 1 or 2 and occurred in 47% of subcutaneous rituximab patients and 33% of intravenous rituximab patients, with the increase for subcutaneous rituximab patients arising mainly from grade 1 injection site erythema (10% vs 0%).

References

1. Davies A, Merli F, Mihaljevic B, et al. Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study. Lancet Oncol. 2014;15(3):343-352.

2. Davies A, Merli F, Mihaljević B, et al. Subcutaneous rituximab and chemotherapy achieves similar overall response rates to intravenous rituximab in first-line follicular lymphoma: efficacy and safety results of the phase III SABRINA study [EHA abstract S652]. Haematologica. 2014;99(suppl 1):225.

Increased Rituximab (R) Doses Eliminate Increased Risk and Improve Outcome of Elderly Male

Patients With Aggressive CD20+ B-Cell Lymphomas: the SEXIE-R-CHOP-14 Trial of the DSHNHL

The addition of rituximab to CHOP (R-CHOP) has improved outcome in diffuse large B-cell lymphoma (DLBCL).¹ The RICOVER-60 (Combination Chemotherapy With or Without Rituximab in Treating Older Patients With Non-Hodgkin’s Lymphoma) trial, conducted by the German High Grade Non-Hodgkin Lymphoma study group, investigated 6 vs 8 cycles of CHOP-14 or R-CHOP–14 in elderly non-Hodgkin lymphoma (NHL) patients.² The study randomized 1222 patients, ages 61 to 80 years, to 1 of the 4 treatment arms. Using 6 cycles of CHOP-14 as the comparator, the other 3 regimens showed improvements in 3-year event-free survival. PFS improved with 6 and 8 cycles of R-CHOP–14 (P<.0001 and P=.0001, respectively). Improved OS was observed only with 6 cycles of R-CHOP–14 (relative risk, 0.63, 95% CI, 0.38-0.67; P=.0031). Multivariate analysis showed an increased risk of progression for male patients compared with female patients who had received rituximab (relative risk, 1.592; P=.004), with 4-year PFS rates of 15% for men vs 22% for women. Serum trough levels of rituximab were approximately one-third lower in men, consistent with the increased risk of progression, and pharmacokinetics demonstrated that elderly women have a significantly slower clearance than elderly men, producing higher serum levels and longer exposure times. Extending the pharmacokinetic analysis to younger patients did not reveal significant differences in rituximab clearance based on patient sex. Therefore, elderly men have significantly slower rituximab clearance times than elderly women, younger men, and younger women.

Dr Michael Pfreundschuh pre-sented results from the SEXIE-R-CHOP-14 study, which investigated whether an increased dose of rituximab could reduce the hazard for progression in elderly men compared with elderly women.³ The phase 2 trial enrolled patients ages 61 to 80 years with CD20-positive DLBCL. Rituximab was dosed at the standard 375 mg/m² for the 120 women and 500 mg/m² for the 148 men. The female patients had worse prognostic factors, including more advanced disease stage, elevated lactose dehydrogenase, and worse Eastern Cooperative Oncology Group performance status (ECOG PS). Treatment adherence was excellent for both male and female patients, and 98% of all patients received median relative doses of rituximab and myelosuppressive drugs. The target doses of 3000 mg/m² for women and 4000 mg/m² for men were achieved. Men demonstrated a higher serum trough concentration of rituximab. However, rituximab levels decreased faster in men, and therefore their exposure to the drug was only slightly increased.

The increased dose of rituximab in men was not associated with increased toxicities. Three-year PFS was 74% in men vs 68% in women (P=.396), and 3-year OS was 82% vs 72%, respectively (P=.111; Figure 4). Multivariate analysis adjusting for International Prognostic Index (IPI) factors showed that the hazard ratio (HR) associated with male sex was 0.9 for PFS (P=.817) and 0.8 for OS (P=.317). Data from SEXIE-R-CHOP-14 were compared with those from the earlier RICOVER-60 trial² in a multivariate analysis that adjusted for IPI risk factors as well as older age (>70 years). The increased dose in the SEXIE-R-CHOP-14 trial was associated with a reduced risk for an event in PFS (HR, 0.7; P=.128) for male patients. The male vs female HR for PFS was 0.8 (P=.613) in the SEXIE-R-CHOP-14 trial and 1.6 in RICOVER-60 (P=.004). In the SEXIE-R trial, the male vs female HR for OS was 0.7 (P=.252) vs 1.4 (P=.063) in RICOVER-60. Dr Pfreundschuh concluded that rituximab dosed at 500 mg/m² in men eliminates their increased risk of disease progression or death. Younger patients had unfavorable pharmacokinetics compared with elderly women, and therefore increasing the rituximab dose in younger male and female patients might also improve outcomes. Moreover, it is possible that the standard dose of 375 mg/m² in elderly women is suboptimal.

References

1. Sehn LH, Donaldson J, Chhanabhai M, et al. Introduction of combined CHOP plus rituximab therapy dramatically improved outcome of diffuse large B-cell lymphoma in British Columbia. J Clin Oncol. 2005;23(22):5027-5033.

2. Pfreundschuh M, Schubert J, Ziepert M, et al; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008;9(2):105-116.

3. Pfreundschuh M, Held G, Zeynalova S, et al. Increased rituximab (R) doses eliminate increased risk and improve outcome of elderly male patients with aggressive CD20+ B-cell lymphomas: the SEXIE-R-CHOP-14 trial of the DSHNHL [EHA abstract S1347]. Haematologica. 2014;99(suppl 1):524.

Phase 3 Study of Frontline Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone Plus Vincristine (R-CHOP) or Bortezomib (VR-CAP) in Transplantation-Unsuitable Mantle Cell Lymphoma (MCL) Patients

Mantle cell lymphoma (MCL), an aggressive type of NHL, is currently incurable. Standard first-line therapy, such as R-CHOP, results in limited PFS rates in patients with newly diagnosed disease. Bortezomib is approved for relapsed MCL and could improve outcomes if incorporated into first-line therapy. Dr Tadeusz Robak presented the primary analysis of a study investigating whether using bortezomib in place of vincristine in R-CHOP therapy could improve outcomes in newly diagnosed MCL patients who are unsuitable for bone marrow transplantation.¹ The study was performed at 128 centers in 22 countries throughout Europe, North America, South America, and Asia. Eligible patients had stage II to IV disease and an ECOG PS of 0 to 2. Diagnosis was performed locally and confirmed at a central laboratory; the concordance rate was 97%. After stratification based on IPI score and disease stage, patients were evenly randomized to receive a minimum of six 21-day cycles of rituximab (375 mg/m²), cyclophosphamide (750 mg/m²), doxorubicin (50 mg/m²) on day 1, and prednisone (100 mg/m²) on days 1 through 5, plus either intravenous bortezomib (1.3 mg/m²) on days 1, 4, 8, and 11 (VR-CAP) or intravenous vincristine (1.4 mg/m²) on day 1 (R-CHOP). For patients with a confirmed response following the sixth treatment cycle, 2 additional courses of treatment were allowed. The study’s primary endpoint was PFS by independent radiology review. Secondary endpoints included ORR, CR, OS, time to response, and response duration. The most important statistical assumption was a 40% improvement in the duration of PFS, from 18 months for R-CHOP to 25 months for VR-CAP. The design required 295 events to provide 80% power to detect such an improvement. Two interim safety analyses, plus a final analysis for safety and efficacy, were planned.

The study randomized 487 patients evenly into the 2 treatment arms, which were well balanced for demographics and baseline characteristics. Patients had a median age of 66 years, and approximately three-fourths were male. Seventy-four percent of patients had stage IV MCL, and 54% had an IPI score of at least 3. The majority of patients received at least 6 courses of treatment, with 17% of R-CHOP and 13% of VR-CAP patients receiving 8 courses by protocol. Treatment was completed by 82% of patients in the R-CHOP arm and 80% of patients in the VR-CAP arm. The majority of patients received all planned doses of rituximab, cyclophosphamide, doxorubicin, and prednisone. The analysis was predicated on the occurrence of 165 events in the R-CHOP arm and 133 events in the VR-CAP arm. After a median follow-up of 40 months, PFS was 14.4 months for patients treated with R-CHOP and 24.7 months for patients treated with VR-CAP (HR, 0.63; P<.001; Figure 5). A similar difference was observed based on investigator evaluations (16.1 months for R-CHOP vs 30.7 months for VR-CAP; HR, 0.51; P<.001). A subgroup analysis showed that the only patients who did not benefit from VR-CAP were from North America; however, this group included only 14 patients. Median time to progression as assessed by independent review was 16.1 months for the R-CHOP arm vs 30.5 months for the VR-CAP arm (HR, 0.58; P<.001).

VR-CAP induced a higher rate of CR plus CRu (53% vs 42%; odds ratio, 1.7; P=.007), although the ORR was similar in both arms (92% with VR-CAP vs 90% with R-CHOP; odds ratio, 1.4; P=.275). Median OS was 56.3 months for patients treated with R-CHOP and had not been reached for the experimental arm (HR, 0.80; P=.17). Median time to response was shorter with VR-CAP (1.4 months vs 1.6 months), and the duration of CR was 24 months longer in patients treated with VR-CAP. Four-year OS was 64.4% for patients treated with VR-CAP vs 53.9% with R-CHOP. The majority of deaths occurred from progressive disease (23% of patients in the R-CHOP arm and 18% in the VR-CAP arm). In each arm, 7% of patients died from AEs. Grade 3 or higher AEs occurred in 85% of R-CHOP patients vs 93% of VR-CAP patients. AEs observed in at least 10% of patients in either arm included neutropenia (67% with R-CHOP vs 85% with VR-CAP), leukopenia (29% vs 44%), thrombocytopenia (6% vs 57%), lymphopenia (9% vs 28%), anemia (14% vs 15%), and febrile neutropenia (14% vs 15%). Despite the difference in thrombocytopenia rates in the 2 arms, the rates of bleeding events were similar. Peripheral neuropathy of any grade occurred in 29% of R-CHOP patients vs 30% of VR-CAP patients, with grade 3 or higher peripheral neuropathy occurring in 4% of R-CHOP patients vs 8% of VR-CAP patients. However, time to onset was longer and events showed earlier improvement in patients who received VR-CAP. Serious AEs occurred in 30% of the R-CHOP arm vs 38% of the VR-CAP arm. There were similar rates of treatment discontinuation owing to AEs (7% in the R-CHOP arm vs 9% in the VR-CAP arm) and mortality from drug-related deaths while on treatment (3% vs 2%). A final analysis of OS data is expected in June 2017.

Reference

1. Robak T, Huang H, Jin J, et al. Phase 3 study of frontline rituximab, cyclophosphamide, doxorubicin, and prednisone plus vincristine (R-CHOP) or bortezomib (VR-CAP) in transplantation-unsuitable mantle cell lymphoma (MCL) patients [EHA abstract S1345]. Haematologica. 2014;99(suppl 1):523