Supplement 11
A Review of Selected Presentations From the 2017 ASCO Annual Meeting • June 2-6, 2017 • Chicago, Illinois and the 14th ICML • June 14-17, 2017 • Lugano, Switzerland
Baseline Metabolic Tumor Volume Is an Independent Prognostic Factor for Relapsed and Refractory Hodgkin Lymphoma Patients Receiving PET-Adapted Salvage Therapy With Brentuximab Vedotin and Augmented ICE
Current treatments for Hodgkin lymphoma (HL) yield excellent response rates, and many patients experience prolonged disease-free survival. However, treatments continue to cause long-term toxicities, underscoring the need for new treatment paradigms. For patients with relapsed or refractory HL, negative results from 18F-fluorodeoxyglucose positron emission tomography (PET) imaging correlates with a positive outcome after high-dose chemotherapy and autologous stem cell transplant (SCT). At the 14th International Conference on Malignant Lymphoma (ICML), Dr Alison Moskowitz presented findings from a phase 2 study of PET-adapted salvage therapy with augmented ifosfamide, carboplatin, and etoposide (ICE) plus brentuximab vedotin.1 The study also evaluated clinical factors and serum markers as potential prognostic factors.
Eligible patients had relapsed or refractory HL after a single line of therapy and were eligible for transplant. Brentuximab vedotin (1.2 mg/kg) was administered on days 1, 8, and 15 in 28-day cycles. Patients in cohort 1 received 2 cycles of brentuximab vedotin, and patients in cohort 2 received 3 cycles. Patients with a negative PET scan following brentuximab vedotin proceeded to autologous SCT. Patients with a positive PET scan were treated with augmented ICE and then underwent autologous SCT. Augmented ICE consisted of 2 doses of ifosfamide (5000 mg/m2) in combination with mesna (5000 mg/m2) given in a continuous infusion over 24 hours on days 1 and 2; a single dose of carboplatin (area under the curve, 5) on day 3; and 3 doses of etoposide (200 mg/m2) every 12 hours on day 1. Serum cytokines and chemokines were measured at baseline and after administration of brentuximab vedotin. They included interferon (IFN) γ, thymus and activation-regulated chemokine (TARC), interleukin 6, interleukin 10, and tumor necrosis factor α. Metabolic tumor volume and total lesion glycolysis were measured at baseline, after brentuximab vedotin therapy, and after augmented ICE therapy.
The study included 45 patients in cohort 1 and 20 patients in cohort 2. In the entire study population, 52% were female, 45% had advanced-stage disease, and 52% had not responded to first-line therapy. Fifteen percent of patients had B symptoms, 37% had extranodal disease, and 25% had bulky disease. After treatment with brentuximab vedotin, 28% of patients exhibited a complete response (CR), defined as a Deauville score of 2 or lower. All of these patients proceeded to autologous SCT. In addition, 1 patient with a Deauville score of 3 proceeded directly to autologous SCT. Among 45 patients who received augmented ICE therapy, 31 (69%) achieved a CR. In total, 64 patients proceeded to autologous SCT, and 1 patient was lost to follow-up.
Three-year overall survival was 95%, and 3-year event-free survival was 82% (Figure 1). In a univariate analysis, reduced event-free survival was associated with older age (>45 years; P=.016), refractory disease (P=.033), B symptoms (P=.032), and advanced disease stage at relapse (P=.011). Baseline levels of TARC, metabolic tumor volume, and total lesion glycolysis also correlated with event-free survival (P<.001 for each). In a multivariate analysis, metabolic tumor volume and refractory disease remained predictive of event-free survival. Using an optimized cutoff value of 109.5 cm3 for metabolic tumor volume, the 3-year event-free survival was 92% among 48 patients with low metabolic tumor volume and 27% in the 12 patients with high metabolic tumor volume.
Reference
1. Moskowitz AJ, Schöder H, Gavane S, et al. Baseline metabolic tumor volume is an independent prognostic factor for relapsed and refractory Hodgkin lymphoma patients receiving PET-adapted salvage therapy with brentuximab vedotin and augmented ICE [ICML abstract 018]. Hematol Oncol. 2017;35(suppl S2).
Copanlisib in Patients With Relapsed or Refractory Indolent B-Cell Lymphoma (CHRONOS-1)
The phosphoinositide 3-kinase cascade represents a key sig-nal-ing pathway downstream of the B-cell receptor and affects B-cell growth, development, and survival. Copanlisib (BAY 80-6946) is an intravenous, pan–class I phosphoinositide 3-kinase inhibitor that has demon-strated strong binding activity against p110α and p110δ isoforms, with IC50 values of 0.5 nmol/L and 0.7 nmol/L, respectively.1 In phase 1/2 trials conducted in patients with relapsed or refractory indolent lymphoma, copanlisib demonstrated clinical activity and an acceptable safety profile. At the ICML, Dr Martin Dreyling presented results from the phase 2 CHRONOS-1 study (Open-Label, Uncontrolled Phase II Trial of Intravenous PI3K Inhibitor BAY80-6946 in Patients With Relapsed, Indolent or Aggressive Non-Hodgkin’s Lymphomas), which evaluated copanlisib in patients with relapsed or refractory indolent lymphoma.2 Eligible patients had indolent B-cell non-Hodgkin lymphoma (NHL), including follicular lymphoma, marginal zone lymphoma, small lymphocytic leukemia, and lymphoplasmacytoid/Waldenström macroglobulinemia. All patients had received at least 2 previous lines of treatment, which included rituximab and an alkylating agent. Copanlisib (60 mg) was administered intravenously on days 1, 8, and 15 of a 28-day cycle. The primary efficacy endpoint was the objective response rate (ORR) by independent radiologic review.3
The full analysis set of 142 patients included 104 with follicular lymphoma and 23 with marginal zone lymphoma. The 142 patients had a median age of 63 years. The median time since their most recent disease progression was 8.3 months, and they had received a median of 3 prior regimens. Stage III/IV disease was present in 80.3% of patients at baseline. The median duration of treatment was 22 weeks (range, 1-105 weeks), and 46 patients remained on treatment. Patients received a median 5.5 cycles of therapy.
The ORR was 59.2%, including a CR rate of 12.0% and a partial response (PR) rate of 47.2% (Table 1). Stable disease was observed in 29.6% of patients. In patients with follicular lymphoma, the ORR was 58.7%, including a CR rate of 14.4%. In patients with marginal zone lymphoma, the ORR was 69.6%, with a CR rate of 8.7%. Based on Kaplan-Meier analysis, the estimated median duration of response was 687 days in the entire study population, but decreased to 370 days in patients with follicular lymphoma. The estimated median progression-free survival (PFS) was 340 days (range, 0-736 days). In 91% of evaluable patients, the best response was tumor shrinkage.
The most common treatment-related adverse events (AEs) of any grade were transient hyperglycemia (49%), hyper-tension (29%), and neutropenia (25%). The most common treatment-related AEs of grade 3 or higher were also hyperglycemia (40%), hypertension (23%), and neutropenia (19%). Two nonfatal opportunistic infections were reported. Among the 6 patients who died, the cause of death was attributed to copanlisib in 3 cases (from lung infection, respiratory failure, and a thromboembolic event). Laboratory toxicities of interest included elevated alanine transaminase (occurring in 23%, mostly grade 1) and elevated aspartate transaminase (occurring in 28%, mostly grade 1). Copanlisib is being evaluated in phase 3 studies in patients with relapsed or refractory indolent NHL.
References
1. Patnaik A, Appleman LJ, Tolcher AW, et al. First-in-human phase I study of copanlisib (BAY 80-6946), an intravenous pan-class I phosphatidylinositol 3-kinase inhibitor, in patients with advanced solid tumors and non-Hodgkin’s lymphomas. Ann Oncol. 2016;27(10):1928-1940.
2. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma (CHRONOS-1) [ICML abstract 108]. Hematol Oncol. 2017;35(suppl S2).
3. 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.
Brentuximab Vedotin in Combination With Nivolumab in Patients With Relapsed or Refractory Hodgkin Lymphoma
CD30 is a marker of the malignant Reed-Sternberg cells that characterize classical HL, and it is rarely expressed by normal cells.1 Brentuximab vedotin is an antibody-drug conjugate that targets CD30 and is conjugated to the microtubule-disrupting agent monomethyl auristatin E by a protease-cleavable linker. Binding to CD30 leads to internalization of the conjugate and endocytosis into a lysosome, where proteases release the monomethyl auristatin E. Subsequent binding of monomethyl auristatin E to tubulin induces cell cycle arrest and apoptosis. Nivolumab is a monoclonal antibody that binds to programmed death protein 1, a negative regulator of T-cell activation. By binding to this protein, nivolumab blocks the immune checkpoint pathway, thus preventing T-cell inactivation. Both brentuximab vedotin and nivolumab have demonstrated single-agent activity in patients with relapsed or refractory HL. By using the 2 drugs in combination, it may be possible to simultaneously provoke tumor cell killing and antigen release with brentuximab vedotin while inducing antitumor immune activation with nivolumab.
The combination of brentuximab vedotin and nivolumab was investigated in 2 trials of patients with relapsed or refractory HL. Dr Catherine Diefenbach presented preliminary results from 2 arms of the phase 1 E4412 trial at the ICML.2 This dose escalation and expansion trial used a 3-plus-3 design and an expansion cohort of 9 patients. Study participants received nivolumab (3 mg/kg) plus brentuximab vedotin (1.2 mg/kg in arm D and 1.8 mg/kg in arm E). The 2 drugs were administered together every 21 days for 16 cycles, and nivolumab could be continued for an additional year. Nineteen patients with confirmed relapsed or refractory HL were enrolled. Patients had a median age of 40 years (range, 21-70 years), and 9 patients (45%) were male. Patients had received a median of 3 prior therapies. Eight patients had received prior SCT, and 4 had received prior brentuximab vedotin.
Among 18 patients evaluable for response, the ORR was 89%, including a CR rate of 50% (95% CI, 26%-74%; Figure 2). The results included 2 CRs and 1 PR in patients who had received prior treatment with brentuximab vedotin. The 6-month PFS was 91% (95% CI, 75%-100%). The median overall survival was not reached, at a median follow-up of 6 months.
Grade 3 AEs included 1 event each of rash, pruritus, and neutropenia. The most common grade 1/2 AEs included transaminitis (n=9), peripheral sensory neuropathy (n=8), and rash (n=6). One patient experienced a grade 1/2 infusion reaction but was able to receive subsequent therapy after premedication. Two notable treatment-related AEs occurred among the 19 patients in the safety population. One patient in arm E experienced a dose-limiting toxicity characterized by grade 3 pneumonitis and grade 3 dyspnea, along with hypoxia and neutropenic enterocolitis. This patient fully recovered. One patient in the expansion cohort (arm F) developed grade 5 pneumonitis during cycle 2.
At the ICML, Dr Alex Herrera presented preliminary findings from a phase 1/2 study that examined brentuximab vedotin plus nivolumab in patients with relapsed or refractory HL.3 Enrolled patients had progressive disease after first-line treatment. Study treatment was administered in 21-day cycles for a maximum of 4 cycles. In cycle 1, patients received brentuximab vedotin on day 1 and nivolumab on day 8. For cycles 2 to 4, patients received both drugs on day 1 of each cycle. After an assessment following cycle 4, patients could undergo autologous SCT. Responses were assessed based on the Lugano classification.4
The 62 enrolled patients had a median age of 36 years, and 52% were female. Forty-five percent had primary refractory HL. Among 61 patients who received combination treatment, 53 completed 4 cycles of treatment, 5 remained on treatment, and 4 discontinued (based on decisions by the patient [n=2] or the investigator [n=1], and owing to an AE [n=1]).
Among 55 patients in the efficacy population, the ORR was 84% and included a CR rate of 64%. Four patients (7%) had stable disease, and 3 patients (5%) progressed on treatment. Twenty-nine patients initiated autologous SCT. A median of 4.7 × 106 CD34-positive cells/kg were collected. The median time to engraftment was 11.5 days for neutrophils and 16 days for platelets. Effects on the immune system were evaluated by peripheral blood analysis and included a decrease in CD30-positive T-regulatory cells after administration of brentuximab vedotin in cycle 1, with levels of CD8-positive T lymphocytes remaining stable. After treatment with the 2-drug combination, levels of CD4-positive T cells increased, and T-cell receptor sequencing demonstrated clonal expansion. Serum levels of TARC decreased with brentuximab vedotin alone and were accompanied by increased levels of IFN-γ and CXCL10.
Infusion-related reactions were obser-ved in 41% of patients; they occ-urred most frequently during infusion of brentuximab vedotin in cycle 2. Twenty-five percent of patients required dose interruptions. Grade 3 infusion-related reactions occurred in less than 5% of patients. Sixty patients (98%) developed treatment-emergent AEs prior to autologous SCT; these events were grade 3 in 28% and grade 4 in 5%. The most common treatment-emergent AEs were nausea (49%) and fatigue (33%), both grade 1. Outside of infusion-related reactions, potential immune-related AEs occurred in 72% of patients, including grade 3/4 events in 7%. Grade 1 diarrhea occurred in 25% of patients. Systemic corticosteroids were required in 4 patients, for treatment of grade 4 pneumonitis and colitis, grade 3 aspartate transferase elevation, grade 3 diarrhea and grade 2 colitis, and grade 2 pneumonitis.
References
1. Eichenauer DA, Engert A, Willemze R, et al. The evolving role of targeted drugs in the treatment of Hodgkin lymphoma. Expert Rev Hematol. 2017;105(10):1-8.
2. Diefenbach CS, Hong F, David K, et al. Safety and efficacy of combination of brentuximab vedotin and nivolumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412) [ICML abstract 073]. Hematol Oncol. 2017;35(suppl S2).
3. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ICML abstract 074]. Hematol Oncol. 2017;35(suppl S2).
4. Cheson BD, Fisher RI, Barrington SF, et al; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Español de Médula Ósea; German High-Grade Lymphoma Study Group; German Hodgkin’s Study Group; Japanese Lymphoma Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059-3068.
CR Rates in Relapsed/Refractory Aggressive B-NHL Treated With the CD19-Directed CAR T-Cell Product JCAR017 (TRANSCEND NHL 001)
JCAR017 is a CD19-directed chi-meric antigen receptor (CAR) T-cell product with a 4-1BB costimulatory domain and a defined combination of CD4-positive and CD8-positive T cells. At the 2017 American Society of Clinical Oncology (ASCO) meeting, Dr Jeremy Abramson presented findings from the phase 1 TRANSCEND NHL 001 trial (Study Evaluating the Safety and Pharmacokinetics of JCAR017 in B-Cell Non-Hodgkin Lymphoma [NHL]), a multicenter dose-finding study that evaluated lymphodepletion with fludarabine and cyclophosphamide followed by JCAR017 in patients with relapsed or refractory aggressive NHL.1 In addition to enrolling hard-to-treat patients, such as those with central nervous system involvement, the trial included patients with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, grade 3B follicular lymphoma, and mantle cell lymphoma. The regimen for lymphodepletion therapy consisted of fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), administered for 3 days. Patients received JCAR017 cells at 3 dose levels: dose level 1, 5 × 107 cells; dose level 2, 1 × 108 cells; and dose level 3, 1.5 × 108 cells. Although the original protocol included 1 or 2 T-cell treatments, the 2-dose schedule was suspended. After the final dose of JCAR017, patients transitioned to long-term follow-up, which will last up to 15 years.
The core group of patients consisted of those with relapsed/refractory DLBCL and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. This core group of patients will be enrolled in the upcoming pivotal trial of JCAR017. Patients in the full analysis cohort are those with an ECOG performance status of 2 or who have rare subtypes of DLBCL.
The T-cell product was available for 98% of the patients (86/88) who underwent apheresis, and the product met study specifications in 89% (78/88). In the core group, the ORR was 86% (38/44), with a CR rate of 59% (26/44). The 3-month ORR was 66% (21/32), with a CR rate of 50% (16/32). Among patients who had a response lasting 3 months and had follow-up data for at least 6 months, 90% (9/10) remained in response. In patients treated at the lowest dose level, the ORR was 58% (11/19), and the CR rate was 42% (8/19). In patients treated at dose level 2, the ORR was 78% (7/9), with a CR rate of 56% (5/9). These early data suggested a potential dose response.
As of the data cutoff on May 4, 2017, 97% of patients (37/38) who responded were alive and in follow-up (Figure 3). In the core group, severe cytokine release syndrome occurred in 2% (1/44) of patients, and 8 patients (18%) experienced severe neurotoxicity. Two-thirds of patients did not experience any cytokine release syndrome or neurotoxicity. One 82-year-old patient died on day 23 from diffuse alveolar damage that was considered related to lymphodepletion and engineered T-cell treatments. The patient was treated with antibiotic and antifungal agents as well as growth factors, after refusing mechanical ventilation.
For the full analysis set of 54 patients treated across all dose levels, the ORR was 76% (41/54), and the CR rate was 52% (28/54). The 3-month ORR was 51% (21/41), with a 3-month CR rate of 39% (16/41).
Among 55 patients in the safety population, the most common treatment-emergent AEs were neutropenia (35%), cytokine release syndrome (35%), and fatigue (31%). However, most patients (60%) did not experience cytokine release syndrome or neurotoxicity. There was 1 case of severe cytokine release syndrome, and 9 patients experienced severe neurotoxicity. No deaths occurred from cytokine release syndrome or neurotoxicity, and there was no relationship between dose and toxicity. Cytokine release syndrome occurred in 3% of patients (1/30) treated at dose level 1,
but no cases were observed in the 19 patients treated at dose level 2. The severe neurotoxicity rate was 20% (6/30) at dose level 1 and 11% (2/19) at dose level 2. To manage these toxicities, 11% of patients (6/55) received tocilizumab and 24% (13/55) received dexamethasone. Enrollment of the TRANSCEND NHL 001 pivotal cohort will begin in late 2017. The trial will evaluate treatment with an optimized JCAR017 T-cell product.
Reference
1. Abramson JS, Palomba L, Gordon L, et al. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001) [ASCO abstract 7513].
J Clin Oncol. 2017;35(15 suppl).
Outcomes by CD30 Expression in Patients With CTCL Receiving Brentuximab Vedotin Vs Physician’s Choice in the Phase 3 ALCANZA Study
CD30 expression is generally high in primary cutaneous anaplastic large cell lymphoma (pcALCL), with at least three-fourths of cells typically expressing the marker.1 However, the cells of mycosis fungoides show variable levels of CD30 expression, and CD30 is only rarely expressed in the cells of some patients.2,3 The phase 3 ALCANZA study (A Phase 3 Trial of Brentuximab Vedotin [SGN-35] Versus Physician’s Choice [Methotrexate or Bexarotene] in Patients With CD30-Positive Cutaneous T-Cell Lymphoma) evaluated brentuximab vedotin vs physician’s choice of methotrexate or bexarotene in previously treated patients with CD30-positive mycosis fungoides or pcALCL.4 The patients with mycosis fungoides had 2 or more skin biopsies from separate skin lesions obtained at screening, and patients with pcALCL had at least 1 skin biopsy. Biopsies with at least 10% CD30-positive lymphoid cells compared with a negative control were considered CD30-positive.
This open-label, international, mul-ticenter study randomly assigned 66 patients to brentuximab vedotin vs 65 to the physician’s choice of methotrexate or bexarotene. Rates of ORR lasting at least 4 months (ORR4) were 56% with brentuximab vedotin vs 13% in the control arm (P<.0001). The CR rate was 16% vs 2%, respectively (adjusted P=.0046). PFS was superior with brentuximab vedotin, at 16.7 months vs 3.5 months (adjusted P<.0001). Brentuximab ved-otin also reduced symptoms (–27.96 vs –8.62; adjusted P<.0001).
Dr Youn Kim and colleagues analyzed the subgroup of patients with mycosis fungoides in the ALCANZA study.5 Results were presented at the ASCO meeting and the ICML. The analysis compared response among patients with at least 10% CD30-positive cells in all biopsies vs those with at least 1 biopsy that showed less than 10% CD30-positive cells. At screening, 68% of mycosis fungoides patients (125/184) and 94% of the pcALCL patients (44/47) were CD30-positive. Biopsies from mycosis fungoides patients showed high interlesional variability, and 44% of these patients (55/125) had at least 1 biopsy with low or undetectable CD30. Fifty patients with mycosis fungoides were enrolled into each treatment arm.
ORR4 was higher in mycosis fungoides patients with CD30 expression in at least 10% of biopsy cells compared with patients showing CD30 expression in less than 10% of cells (57.1% vs 40.9%). Terciles for CD30 expression were established, and the ORR4 was superior with brentuximab vedotin vs physician’s choice across all ranges. Median PFS was superior with brentuximab vedotin vs physician’s choice in mycosis fungoides patients with less than 10% CD30-positive cells (27.9 months vs 2.3 months; hazard ratio [HR], 0.125; 95% CI, 0.044-0.355) and in those with at least 10% CD30-positive cells (17.2 months vs 3.5 months; HR, 0.176; 95% CI, 0.072-0.432). Approximately one-third of mycosis fungoides patients were excluded from the trial based on low CD30 expression. However, 9 of 22 enrolled patients with mycosis fungoides who achieved ORR4 had at least 1 biopsy with fewer than 10% CD30-positive cells, suggesting that some patients with low CD30 expression may benefit from treatment with brentuximab vedotin. Baseline CD30 expression levels did not correlate with toxicity.
References
1. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005;105(10):3768-3785.
2. Edinger JT, Clark BZ, Pucevich BE, Geskin LJ, Swerdlow SH. CD30 expression and proliferative fraction in nontransformed mycosis fungoides. Am J Surg Pathol. 2009;33(12):1860-1868.
3. Benner MF, Jansen PM, Vermeer MH, Willemze R. Prognostic factors in transformed mycosis fungoides: a retrospective analysis of 100 cases. Blood. 2012;119(7):1643-1649.
4. Prince HM, Kim YH, Horwitz SM, et al; ALCANZA study group. Brentuximab vedotin or physician’s choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial. Lancet. 2017;381(9873):1203-1210.
5. Kim YH, Prince HM, Whittake S, et al. Outcomes by CD30 expression in patients with CTCL receiving brentuximab vedotin (BV) vs physician’s choice (PC) in the phase 3 ALCANZA study [ICML abstract 66]. Hematol Oncol. 2017;35(suppl S2).
Bendamustine Plus Rituximab Versus CHOP Plus Rituximab as First-Line Treatment in Patients With Indolent Lymphomas: Nine-Year Updated Results From the StiL NHL1 Study
Bendamustine plus rituximab was compared with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in the phase 3 NHL1 trial of treatment-naive patients with indolent lymphoma or mantle cell lymphoma.1 This open-label, multicenter, investigator-initiated, noninferiority trial was conducted by the Studiengruppe Indolente Lymphome. The study enrolled patients between September 2003 and August 2008, and 420 were eligible for response. Eligible patients were adults with newly diagnosed stage III/IV indolent lymphoma or mantle cell lymphoma and a World Health Organization performance status of 0 to 2. After stratification by lymphoma subtype, patients were randomly assigned to receive a maximum of 6 cycles of either bendamustine (90 mg/m2) on days 1 and 2 in 28-day cycles; or cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) on day 1, plus prednisone (100 mg daily) for 5 days in 21-day cycles. All patients also received rituximab (375 mg/m2) on day 1 of each cycle. PFS was the primary endpoint, with a noninferiority margin of 10%.
As Dr Mathias Rummel reported at the ASCO meeting, the initial analysis included 215 patients in the bendamustine/rituximab arm and 205 in the R-CHOP arm.2 Patients had a median age of 62 years. Three-fourths of patients had stage IV disease, and 64% had bone marrow involvement. B symptoms were present in 29% to 37% of patients in each arm, and bulky disease was present in 30%
to 33%.
After a median follow-up of 45 months, median PFS was 69.5 months for patients treated with bendamustine/rituximab vs 31.2 months in the R-CHOP arm (HR, 0.58; 95% CI, 0.44-0.74; P=.0000148). Bendamus-tine/rituximab improved PFS in pat-ients with follicular lymphoma (P=.0072), mantle cell lymphoma (P=.0061), and Waldenström macro-globulinemia (P=.0033). The time to next treatment was not reached for bendamustine/rituximab vs 42.3 months for R-CHOP (HR, 0.52; 95% CI, 0.39-0.69; P<.0001). Although erythematous skin reactions were more common with bendamustine/rituximab, the 2-drug combination showed better tolerability than R-CHOP in rates of alopecia (P<.0001), hematologic toxicity (P<.0001), infections (P=.0025), peripheral neuropathy (P<.0001), and stomatitis (P<.0001).
At the ASCO meeting, Dr Rummel presented updated results from the trial, after a median follow-up of 117 months.2 Main objectives for the follow-up analysis included overall survival, time to next treatment, and secondary malignancies, with additional endpoints of salvage regimens administered after cessation of study treatment and causes of death. The updated analysis showed a significant benefit in median time to next treatment for bendamustine/rituximab compared with R-CHOP (not reached vs 56.0 months; HR, 0.55; 95% CI, 0.41-0.73; P<.0001). Patients in the bendamustine/rituximab arm required fewer second-line treatments for disease progression (36% vs 53%). In the bendamustine/rituximab arm, the most common second-line salvage regimen was R-CHOP (administered to 27 patients, vs 2 in the R-CHOP arm). In the R-CHOP arm, the most common second-line salvage regimen was bendamustine/rituximab (administered to 52 patients, vs 2 in the
bendamustine/rituximab arm).
Survival was similar for patients in both arms, with a 10-year overall survival of 70.3% for bendamustine/rituximab and 66.3% for R-CHOP (HR, 0.82; 99% CI, 0.59-1.16; P=.2665). The 10-year overall survival was superior for patients who achieved a CR vs a PR (80.8% vs 66.5%; HR, 0.50; 95% CI, 0.36-0.77; P=.0011; Figure 4). Among the subset of patients who achieved a CR or PR (91.9%), overall survival was similar in both treatment arms (HR, 0.81; 95% CI, 0.55-1.17; P=.2630). Of the 133 deaths that occurred during the trial, 86 were caused by relapsed lymphoma.
Most patients in the study (63%) had normal levels of lactate dehydrogenase (LDH), and these patients had a superior median overall survival compared with patients whose LDH levels were low (not reached vs 127 months; HR, 0.45; 95% CI, 0.29-0.61; P<.001). In patients with normal levels of LDH, 10-year overall survival was superior with bendamustine/rituximab vs R-CHOP (80.0% vs 72.2%; HR, 0.61; 95% CI, 0.37-1.00; P=.0499). In patients with elevated LDH, however, both treatments had a similar overall survival at 10 years (HR, 1.01; 95% CI, 0.63-1.63; P=.9576). Among the 279 patients with follicular lymphoma, 54.5% had a Follicular Lymphoma International Prognostic Index (FLIPI) score of 0 to 2, and the remainder had a score of 3 to 5. Ten-year overall survival was 83.8% in patients with low FLIPI scores vs 58.0% in those with high scores (HR, 0.33; 95% CI, 0.22-0.54; P<.0001).
Secondary malignancies occurred in 37 patients (17%) in the bendamustine/rituximab arm (for a total of 39 events) and 40 patients (20%) in the R-CHOP arm (for a total of 47 events). These malignancies arose in the prostate, colon or stomach, bronchi, kidney or urothelium, breast, and other areas. Two patients in each arm developed myelodysplastic syndrome, and 1 patient in the R-CHOP arm developed acute myeloid leukemia.
References
1. Rummel MJ, Niederle N, Maschmeyer G, et al; Study group indolent Lymphomas (StiL). 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. Lancet. 2013;381(9873):1203-1210.
2. Rummel M, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study [ASCO abstract 7501]. J Clin Oncol. 2017;35(15 suppl).
Results of a Phase II Study of Brentuximab Vedotin in the First-Line Treatment of Hodgkin Lymphoma Patients Considered Unsuitable for Standard Chemotherapy (BREVITY)
At the ICML, Dr Adam Gibb presented results of the phase 2 BREVITY trial (A Study of Brentuximab Vedotin in Patients With Hodgkin Lymphoma Unsuitable for Chemotherapy Due to Age, Frailty or Co-Morbidity), which evaluated the efficacy and tolerability of brentuximab vedotin in treatment-naive HL patients who were unfit for standard treatment based on age, frailty, or comorbidities.1 The single-arm trial had a response-adaptive, Simon 2-stage design and required 30 evaluable patients. The primary outcome was complete metabolic response by centrally reviewed PET-computed tomography (CT) after 4 cycles of brentuximab vedotin monotherapy. The study enrolled several types of treatment-naive patients: those with HL of stage 2 with B symptoms and/or mediastinal bulk (any age); those with stage 2, 3, or 4 disease with cardiorespiratory compromise (any age); and those ages 60 years or older with an ECOG performance status of 3 or higher who were considered unfit for standard chemotherapy. Brentuximab vedotin was administered once every 3 weeks at a dose of 1.8 mg/kg. If patients developed toxicity, the dose was reduced to 1.2 mg/kg. Patients who exhibited a response after 4 doses of brentuximab vedotin continued to receive up to 16 cycles, for as long as an ongoing response was confirmed by PET/CT imaging every 4 weeks. Exploratory, blinded PET/CT was performed after cycle 2.
From February 2014 to October 2015, 38 patients were recruited at 12 centers in the United Kingdom. Patients had a median age of 76 years (range, 59-90 years), and 58% were male (Table 2). Eighty-one percent of patients had stage III/IV disease, 71% of patients had B symptoms, and 13% had bulky disease. Fifty-eight percent had extranodal involvement, and half had an ECOG performance status of 3 or greater. Thirty-five patients were evaluable for toxicity, and 31 were evaluable for response. Patients received a median of 4 cycles of treatment (range, 1-16 cycles).
The median PFS was 7.4 months (95% CI, 5.3-10.2 months). The rate of complete metabolic response after 4 treatment cycles was 26% (95% CI, 14%-43%), and the ORR was 84% (95% CI, 67%-93%). The complete metabolic response rate observed from PET/CT imaging after treatment cycle 2 was 32% (95% CI, 17%-52%). There was a significant correlation between interim PET/CT imaging results after cycle 2 and PET/CT imaging results after cycle 4 (Rho, 0.67; P<.001). Among 31 evaluable patients, 28 developed progressive disease.
Dose reductions owing to toxicity occurred in 14 patients throughout 28 cycles, and 11 patients stopped treatment owing to an AE. Among 716 reported AEs, 626 (88%) were grade 1/2. The most common AEs of grade 3 or higher were infection, myelosuppression, and neuropathy, and 27 patients (77%) experienced at least 1 AE of grade 3 or higher.
Reference
1. Gibb A, Pirrie S, Linton K, et al. Results of a phase II study of brentuximab vedotin in the first line treatment of Hodgkin lymphoma patients considered unsuitable for standard chemotherapy (BREVITY) [ICML abstract 069]. Hematol Oncol. 2017;35(suppl S2).
First-Line Treatment of iNHL or MCL Patients With BR or R-CHOP/R-CVP: Results of the BRIGHT 5-Year Follow-Up Study
The BRIGHT trial (Study of Bendamustine Hydro-chloride and Rituximab [BR] Compared With R-CVP or R-CHOP in the First-Line Treatment of Patients With Advanced Indolent Non-Hodgkin’s Lymphoma [NHL] or Mantle Cell Lymphoma [MCL]) evaluated the safety and efficacy of bendamustine/rituximab vs R-CHOP or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) as first-line treatment of indolent NHL or mantle cell lymphoma.1 Eligible patients had CD20-positive, treatment-naive, indolent NHL, including grade 1 or 2 follicular lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone B-cell lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type, nodal marginal zone B-cell lymphoma, or mantle cell lymphoma. All patients required treatment, as indicated by the presence of B symptoms, a large tumor mass, lymphoma-related complications, or hyperviscosity syndrome attributed to monoclonal gammopathy. The study excluded patients with chronic lymphocytic leukemia/small lymphocytic lymphoma, grade 3 follicular lymphoma, or transformed disease.
In this open-label, noninferiority phase 3 trial, patients were randomly assigned to receive 6 cycles of bendamustine/rituximab in 21-day cycles vs R-CHOP or R-CVP in 28-day cycles, with 2 additional treatment cycles permitted based on the investigator’s discretion. Supportive therapy was provided based on the standard of care of each treatment center. An independent review committee assessed responses. The primary objective was to determine whether the CR rate with bendamustine/rituximab was noninferior to that of standard immunochemotherapy, with a threshold CR rate of 88% of the rate obtained with standard therapy. The safety population included patients who had received at least 1 dose of the study drug. Patients were monitored yearly for at least 5 years, with a protocol amendment in 2012 for monitoring every 6 months.
The efficacy analysis included 213 patients in the bendamustine/rituximab arm and 206 in the standard treatment arm. The CR rate was noninferior with bendamustine/rituximab, based on a CR rate of 31% with the 2-drug combination vs 25% with standard treatment (CR-rate ratio, 1.26; P=.0225 for noninferiority). The CR rate with bendamustine/rituximab was not statistically superior to standard immunochemotherapy (P=.1269).
The 2 treatment arms demonstrated different safety profiles. Patients treated with bendamustine/rituximab showed increased rates of any-grade drug hypersensitivity (17% vs 6%; P<.05), any-grade vomiting (29% vs 13%; P<.01), and grade 3/4 lymphopenia (61% vs 33%; P<.0001). Patients treated with R-CHOP or R-CVP had higher rates of any-grade peripheral neuropathy (44% vs 9%; P<.0001), any-grade alopecia (51% vs 4%; P<.0001), and grade 3/4 neutropenia (87% vs 39%; P<.0001). In addition to reductions in dyspnea, constipation, and fatigue associated with bendamustine/rituximab, quality of life was superior based on cognitive, physical, social, and emotional functioning, as well as global health status.2
Dr Ian Flinn presented results from 5-year follow-up of the BRIGHT study at the ASCO meeting and the ICML.3 The evaluable population included 213 patients in the bendamustine/rituximab arm and 206 in the immunochemotherapy arm. Median follow-up was 65.0 months for the bendamustine/rituximab arm and 64.1 months for the immunochemotherapy arm. Five-year PFS was 65.5% for patients in the bendamustine/rituximab arm vs 55.8% for patients in the immunochemotherapy arm (HR, 0.61; 95% CI, 0.45-0.85; P=.0025). When stratified by lymphoma type, 5-year PFS in patients with indolent NHL was 70.3% with bendamustine/rituximab vs 62.0% with R-CHOP or R-CVP (HR, 0.70; 95% CI, 0.49-1.01; P=.0582; Figure 5). In patients with mantle cell lymphoma, 5-year PFS was 39.7% with bendamustine/rituximab vs 14.2% with immunochemotherapy (HR, 0.40; 95% CI, 0.21-0.75; P=.0035).
Duration of response was 65.5 months in the bendamustine/rituximab arm vs 56.9 months in the R-CHOP/R-CVP arm (HR, 0.66; 95% CI, 0.47-0.92; P=.0134). The 5-year duration of response for patients with indolent NHL was 70.5% with bendamustine/rituximab vs 62.4% with standard treatment (HR, 0.73; 95% CI, 0.50-1.07; P=.1051). In patients with mantle cell lymphoma, the 5-year duration of response was 39.7% with bendamustine/rituximab vs 15.9% with R-CHOP/R-CVP (HR, 0.47; 95% CI, 0.24-0.91; P=.0231). The 5-year overall survival for the entire cohort was 81.6% with bendamustine/rituximab vs 85.0% with immunochemotherapy (HR, 1.15; 95% CI, 0.72-1.84; P=.5461). The 5-year overall survival was similar for both treatments in the subgroups of patients with indolent NHL (P=.3316) and mantle cell lymphoma (P=.6894). The 5-year event-free survival was superior with bendamustine/rituximab vs immunochemotherapy for the overall study population (P=.002) and for mantle cell lymphoma patients (P=.0005), but the difference was not significant for patients with indolent NHL (P=.0944).
Maintenance treatment with rit–uximab was administered to 43% of patients in the bendamustine/rituxi-mab arm and 45% of patients in the con-trol arm. Twenty-two percent of patients in the bendamustine/rituximab arm received second-line treatment vs 34% in the R-CHOP/
R-CVP arm.
There were 40 deaths in the bendamustine/rituximab arm and 32 in the R-CHOP/R-CVP arm. Causes of death included disease progression (16 in the bendamustine/rituximab arm and 16 in the R-CHOP/R-CVP arm), complications associated with SCT or reason not reported (3 vs 6), cardiovascular events (7 vs 2), respiratory events (3 vs 1), infection (6 vs 3), and secondary malignancy excluding transformed NHL (5 vs 3). In an exploratory analysis, secondary malignancies were more frequent among patients treated with bendamustine/rituximab (19% vs 11%; P=.022). Secondary malignancies included transformed NHL/DLBCL (5 cases in the bendamustine/rituximab arm vs 7 in the R-CHOP/R-CVP arm), basal cell carcinoma (9 vs 4), squamous cell carcinoma of the skin (12 vs 2), melanoma (2 vs 1), myelodysplastic syndrome (1 vs 1), and other solid malignancies (19 vs 11).
References
1. 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(19):2944-2952.
2. Burke JM, van der Jagt RH, Kahl BS, et al. Differences in quality of life between bendamustine-rituximab and R-CHOP/R-CVP in patients with previously untreated advanced indolent non-Hodgkin lymphoma or mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2016;16(4):182-190.
3. Flinn I, van der Jagt R, Chang J, et al. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: results of the BRIGHT 5-year follow-up study [ASCO abstract 7500]. J Clin Oncol. 2017;35(15 suppl).
Brentuximab Vedotin Consolidation to Reduce Radiation Use in Patients With Limited Stage Non-Bulky Hodgkin Lymphoma: an Update From a Phase 2 Clinical Trial
HL accounts for 16% of cancers in patients ages 15 to 24 years.1 Standard treatment for limited-stage HL consists of 4 to 6 cycles of chemotherapy, with or without consolidation radiotherapy. Although standard treatment cures approximately 90% of patients with limited-stage HL, some patients have a diminished lifespan or other delayed, treatment-related complications, such as secondary malignancies and cardiovascular disease. At the ICML, Dr Steven Park presented updated results from a multicenter phase 2 trial that investigated induction treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by consolidation with brentuximab vedotin in patients with treatment-naive, limited-stage, nonbulky HL.2 The primary objective was to determine the proportion of patients with PET-negative disease after study treatment, with a goal of achieving PET negativity and avoiding radiation in at least 85% of patients. Patients initially received 2 cycles of ABVD followed by interim PET imaging. Patients with favorable disease and a negative PET scan proceeded to consolidation with brentuximab vedotin (1.8 mg/kg) administered once every 3 weeks for 6 cycles. The remaining patients received an additional 2 to 4 cycles of ABVD, depending on risk factors and PET imaging results, and then received consolidation with brentuximab vedotin.
The 40 evaluable patients had a median age of 29 years (range, 19-68 years), and 45% had unfavorable disease. Most patients (92.5%) received 4 or fewer cycles of ABVD, and 27.5% received 2 cycles. One patient was treated with radiation for progressive disease. Toxicities of grade 3 or higher associated with brentuximab vedotin included neutropenia (7.5%), peripheral neuropathy (2.5%), and rash (2.5%). One patient developed pancreatitis and died from sepsis and hepatic failure. Pancreatitis and sepsis are rare, known complications associated with brentuximab vedotin.
After 2 cycles of ABVD, 72.5% of patients achieved PET-negative disease, as determined by a Deauville score of less than 3 (Table 3). After completion of brentuximab vedotin consolidation therapy, 37 of 39 evaluable patients (94.9%) had PET-negative disease. After a median follow-up of 22 months, estimated 2-year PFS was 92%, and estimated 2-year overall survival was 97%. Among the 37 patients who achieved PET-negative disease at the end of brentuximab vedotin treatment, all avoided radiation and remained in remission, and these patients had an estimated 2-year PFS of 100%. The authors concluded that, in patients with nonbulky, limited-stage HL, consolidation with brentuximab vedotin may enable reduced use of radiation therapy while achieving excellent survival outcomes for the majority of patients.
References
1. Brugières L, Brice P. Lymphoma in adolescents and young adults. Prog Tumor Res. 2016;43:101-114.
2. Park SI, Olajide O, Reddy NM, et al. Brentuximab vedotin consolidation to reduce radiation use in patients with limited stage non-bulky Hodgkin lymphoma: an update from a phase 2 clinical trial [ICML abstract 070]. Hematol Oncol. 2017;35(suppl S2).
Highlights in Lymphoma From the 2017 ASCO Meeting and the 14th ICML: Commentary
Craig H. Moskowitz, MD
Steven A. Greenberg Chair in Lymphoma Research
Clinical Director, Division of Hematologic Oncology
Attending Physician, Lymphoma and Adult BMT Services
Member, Memorial Sloan Kettering Cancer Center
Professor of Medicine, Weill Medical College of Cornell University
New York, New York
Several studies in lymphoma presented at the 2017 American Society of Clinical Oncology (ASCO) meeting and the 14th International Conference on Malignant Lymphoma (ICML) have the potential to impact practice. New data and updated analyses were presented on copanlisib, tazemetostat, brentuximab vedotin, chimeric antigen receptor (CAR) T-cell therapy, bendamustine, and lenalidomide.
Copanlisib
At the ICML, Dr Martin Dreyling presented results from the pivotal phase 2 CHRONOS-1 trial, which evaluated copanlisib in patients with relapsed or refractory indolent lymphoma.1 The study population included patients with the indolent lymphomas: follicular lymphoma, marginal zone lymphoma, or small lymphocytic lymphoma. CHRONOS-1 can be viewed as the registration trial for copanlisib, which is a pan-class I phosphoinositide 3-kinase inhibitor. Unfortunately, copanlisib is given intravenously and not orally. The difficult dosing schedule consists of 60 mg administered intravenously on days 1, 8, and 15 of a 28-day cycle.
The trial included 142 patients. The overall response rate was nearly 60%, and the complete response rate was 12%. Data were similar across the subtypes of lymphoma. The clinical benefit rate was nearly 91%. Copanlisib was fairly well-tolerated. There was a 14% incidence of lung-related issues, either infection or pneumonitis. Colitis was minimal. It seems likely that these data will lead the US Food and Drug Administration to approve copanlisib in patients with relapsed or refractory indolent lymphoma.
Tazemetostat
At the ICML plenary session, Dr Franck Morschhauser discussed results from a phase 2 multicenter study of the EZH2 inhibitor tazemetostat in patients with relapsed or refractory non-Hodgkin lymphoma.2 The study had 4 cohorts: follicular lymphoma with an EZH2 mutation; follicular lymphoma without the mutation, but with increased expression of the protein; diffuse large B-cell lymphoma (DLBCL) with the mutation; and DLBCL without the mutation. Tazemetostat is administered orally twice a day.
The study enrolled more than 165 patients. The highlight of the data was an 85% response rate in patients with follicular lymphoma and the EZH2 mutation. Patients with DLBCL and the mutation had a response rate of only 29%. Tazemetostat was fairly well-tolerated. Occasional thrombocytopenia was seen. This therapy and similar agents that target EZH2 will be extensively studied over the next year, and it is expected that they will be approved in NHL.
Brentuximab Vedotin
Several studies evaluated brentuximab vedotin in various aspects of Hodgkin lymphoma management. In the BREVITY trial, brentuximab vedotin was given as first-line treatment in patients who were unsuitable for standard chemotherapy.3 The patients’ median age was 76 years, and their characteristics were typical for an elderly population. The study followed a standard Simon 2-phase design. The primary endpoint was complete response rate. Patients received the standard dose of brentuximab vedotin.
The trial provided data for 30 evaluable patients. Unfortunately, the median number of cycles was only 4, and 14 patients had to stop treatment because of toxicity or other adverse events. The overall response rate was 84%. The complete metabolic response after 4 cycles of brentuximab vedotin was only 26%, which did not meet the predefined level of 40%. It appears that single-agent brentuximab vedotin will not become a standard treatment option in this patient population.
A second study tested whether brentuximab vedotin can replace radiotherapy in patients with limited, early-stage Hodgkin lymphoma.4 This multicenter phase 2 study enrolled 41 patients. The primary endpoint was the rate of patients without disease according to positron emission tomography (PET) after doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by brentuximab vedotin. Nearly all the patients had a complete response. For this regimen to move forward, a randomized trial must compare maintenance with brentuximab vedotin vs radiation therapy.
Two updates were provided for trials evaluating brentuximab vedotin and nivolumab. These trials were previously presented at the 2016 American Society of Hematology (ASH) meeting.5,6 Dr Alex Herrera presented updated results from a study of brentuximab vedotin and nivolumab used as a pretransplant salvage regimen.7 Dr Catherine Diefenbach presented data on the use of brentuximab vedotin and nivolumab as a palliative regimen in patients with relapsed/refractory Hodgkin lymphoma, some of whom had undergone stem cell transplant.8
After 6 further months of follow-up, both of these studies continued to show a stable complete response rate exceeding 60%. This regimen, administered in the outpatient setting, was well-tolerated. There is always a concern regarding pneumonitis when these drugs are combined, but that incidence thus far was low. The initial results of the study by Dr Herrera appear consistent with previous reports of studies using standard platinum-based salvage chemotherapy, and this approach may be less toxic.7 The study will provide posttransplant data when they are mature. The study by Dr Diefenbach is now adding ipilimumab to the brentuximab vedotin/nivolumab platform in an effort to improve the complete response rate.8
My colleagues and I at Memorial Sloan Kettering Cancer Center presented results from a study that evaluated whether baseline metabolic tumor volume can be used as a pretransplant risk factor in patients with relapsed or refractory Hodgkin lymphoma.9 Many previous studies have found that a negative pretransplant PET scan predicts for outcome and cure after autologous stem cell transplant.10 Our study found that a presalvage metabolic tumor volume of less than 109.5 cm3 was associated with a cure in 44 of 48 patients. Among the 12 patients with a higher metabolic tumor volume, only 4 were in remission. Future studies will be needed to confirm the association. However, this risk factor can be a tool for nuclear medicine physicians. In theory, patients with low baseline metabolic tumor volume at the time of relapse may be able to avoid stem cell transplant. This is a research question, however, and one must keep in mind that nearly 85% of patients with low metabolic tumor volume were cured with high-dose therapy/autologous stem cell transplant.
CAR T-Cell Therapy
There were several studies of CAR-modified T cells. At the ASCO meeting, Dr Jeremy Abramson discussed a multicenter trial of JCAR017, a second-generation, CD19-directed, 4-1BB CAR-modified T-cell product.11 JCAR017 uses both CD8 and CD4 in a 1:1 ratio. The study enrolled patients with relapsed/refractory DLBCL, grade 3 follicular lymphoma, mantle cell lymphoma, or primary mediastinal B-cell lymphoma. All patients underwent standard lymphodepletion with fludarabine and cyclophosphamide.
This ongoing study has enrolled 54 patients. Dr Abramson presented data for patients with DLBCL. Two patients developed severe cytokine-release syndrome. Severe neurotoxicity occurred in 16 patients. Thus far, the overall response rate was 76%, and 52% of the patients achieved a complete response. The follow-up is short, however, at 3 months. Further follow-up will be necessary to determine whether the complete responses are durable.
At the ICML, Dr Craig Sauter presented results of a phase 1 trial of 19-28z in patients with relapsed or refractory B‐cell non‐Hodgkin lymphoma who had been treated with high-dose therapy and autologous stem cell transplant.12 The aim was to use 19-28z to target minimal residual disease. Among the 15 patients who were treated, 10 experienced toxicity: either grade 2 to 4 neurotoxicity or cytokine release syndrome. These toxicities were reversible with tocilizumab and corticosteroids. The study had a long median follow-up of 31 months. Unfortunately, the 2-year progression-free survival was only 30%, the same as that seen in patients with DLBCL who undergo standard autologous transplant.
When comparing these 2 studies, it should be remembered that these CAR T-cell therapies are different constructs. The study by Dr Abramson had patients with significant amounts of tumor vs minimal residual disease, which may be related to both the response rates as well as the toxicity profile.11 This study is continuing to enroll patients. The idea of giving CAR-modified T cells after autologous stem cell transplant is likely not sustainable.
Bendamustine
At ASCO, there were 2 important presentations evaluating bendamustine and rituximab. Dr Ian Flinn provided 5-year follow-up data for the BRIGHT study, which compared bendamustine and rituximab vs rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) in patients with untreated indolent lymphoma.13 The 5-year data suggested that there was no difference in overall survival between any of the treatments. The progression-free survival was clearly improved by bendamustine and rituximab among patients with mantle cell lymphoma. For the other subtypes of lymphoma, however, only marginal improvement was seen with the bendamustine/rituximab combination. An interesting observation was that the toxic death rate was higher in the bendamustine/rituximab arm, which might be secondary to an increased risk of secondary cancers.
It is fairly clear from this data set that bendamustine/rituximab was superior to R-CVP. Bendamustine/rituximab had similar results, however, to R-CHOP. Physicians must decide on their optimal program for indolent lymphoma, as they have more than one choice.
Dr Mathias Rummel presented 10-year follow-up data from the StiL study, which compared bendamustine and rituximab vs R-CHOP in patients with indolent lymphomas.14 The analysis included 420 patients who were evaluable for response. Nearly two-thirds of patients had follicular lymphoma. Bendamustine and rituximab improved progression-free survival in the entire cohort, with a highly significant hazard ratio of 0.58. This improvement was driven primarily by patients with mantle cell lymphoma and follicular lymphoma. The time to next treatment was also superior for bendamustine and rituximab vs R-CHOP. However, there was no difference in overall survival. Important prognostic factors were a complete response, elevated levels of lactate dehydrogenase, and a poor-risk score on the Follicular Lymphoma International Prognostic Index. There was also no difference in secondary malignancies. This data set suggests that the combination of bendamustine and rituximab offers patients a long-term improvement in progression-free survival. However, in my opinion, neither of the bendamustine/rituximab studies is so convincing that this treatment should always be the first choice of therapy for these lymphoma subtypes.
Dr Paula Cramer and colleagues evaluated bendamustine followed by obinutuzumab and venetoclax in patients with chronic lymphocytic leukemia. Results were presented at the ICML plenary session.15 This open-label phase 2 study employed an interesting strategy: bendamustine was given for debulking, and then followed by obinutuzumab and venetoclax in induction and maintenance. The primary endpoint was overall response rate, and the secondary endpoint was minimal residual disease. The analysis included 34 patients who were treatment-naive and 29 with relapsed/refractory disease. The patient population was well-balanced, and 19% had the 17p abnormality. Among the patients who started treatment, 60 were able to complete all courses. The overall response rate was nearly 100%. Six patients had a complete response, and 36 had a partial response. An interesting finding was that 89% of patients were negative for minimal residual disease by flow cytometry in the peripheral blood. The treatment regimen was well-tolerated, and it will likely move forward into a randomized trial.
Lenalidomide Plus Rituximab
The randomized phase 3b MAGNIFY study evaluated lenalidomide plus rituximab followed by maintenance therapy in 234 patients with follicular lymphoma, marginal zone lymphoma, or mantle cell lymphoma.16 All patients were first treated with lenalidomide plus rituximab. Patients who responded were then randomly assigned to maintenance with lenalidomide plus rituximab or rituximab alone. Dr David Andorsky provided data for 128 evaluable patients with follicular lymphoma.16 Patients had previously received bendamustine and rituximab or regimens incorporating R-CHOP or R-CVP. These patients had experienced an early relapse or were double-refractory (to both rituximab and chemotherapy). The overall response rate was very respectable, at 45% in those with double-refractory disease and 47% in the early-relapsed patients. The complete response rate was 21% in both groups. The median duration of response had not been reached. These results are encouraging, and the study continues to enroll patients.
Disclosure
Dr Moskowitz has received research support from Seattle Genetics, Merck, and Pharmacyclics. He is a member of the Scientific Advisory Boards of Seattle Genetics, Merck, and Celgene.
References
1. Dreyling M, Santoro A, Mollica L, et al. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma (CHRONOS-1) [ICML abstract 108]. Hematol Oncol. 2017;35(suppl S2).
2. Morschhauser F, Salles G, McKay P, et al. Interim report from a phase 2 multicenter study of tazemetostat, an EZH2 inhibitor, in patients with relapsed or refractory B-cell non-Hodgkin lymphomas [ICML abstract 004]. Hematol Oncol. 2017;35(suppl S2).
3. Gibb A, Pirrie S, Linton K, et al. Results of a phase II study of brentuximab vedotin in the first line treatment of Hodgkin lymphoma patients considered unsuitable for standard chemotherapy (BREVITY) [ICML abstract 069]. Hematol Oncol. 2017;35(suppl S2).
4. Park SI, Olajide O, Reddy NM, et al. Brentuximab vedotin consolidation to reduce radiation use in patients with limited stage non-bulky Hodgkin lymphoma: an update from a phase 2 clinical trial [ICML abstract 070]. Hematol Oncol. 2017;35(suppl S2).
5. Herrera AF, Bartlett NL, Ramchandren R, et al. Preliminary results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ASH abstract 1105]. Blood. 2016;128(suppl 22).
6. Diefenbach CS, Hong F, David KA, et al. A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412 arms D and E) [ASH abstract 1106]. Blood. 2016;128(suppl 22).
7. Herrera AF, Moskowitz AJ, Bartlett NL, et al. Interim results from a phase 1/2 study of brentuximab vedotin in combination with nivolumab in patients with relapsed or refractory Hodgkin lymphoma [ICML abstract 074]. Hematol Oncol. 2017;35(suppl S2).
8. Diefenbach CS, Hong F, David K, et al. Safety and efficacy of combination of brentuximab vedotin and nivolumab in relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN cancer research group (E4412) [ICML abstract 073]. Hematol Oncol. 2017;35(suppl S2).
9. Moskowitz AJ, Schöder H, Gavane S, et al. Baseline metabolic tumor volume is an independent prognostic factor for relapsed and refractory Hodgkin lymphoma patients receiving PET-adapted salvage therapy with brentuximab vedotin and augmented ICE [ICML abstract 018]. Hematol Oncol. 2017;35(suppl S2).
10. Moskowitz AJ, Yahalom J, Kewalramani T, et al. Pretransplantation functional imaging predicts outcome following autologous stem cell transplantation for relapsed and refractory Hodgkin lymphoma. Blood. 2010;116(23):4934-4937.
11. Abramson JS, Palomba L, Gordon L, et al. CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T-cell product JCAR017 (TRANSCEND NHL 001) [ASCO abstract 7513]. J Clin Oncol. 2017;35(15 suppl).
12. Sauter C, Riviere I, Senechal B, et al. A phase I trial of 19-28X CAR-T cells post-high dose therapy and autologous transplantation (HDT-AST) for relapsed and refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL) [ICML abstract 129]. Hematol Oncol. 2017;35(suppl S2).
13. Flinn I, van der Jagt R, Chang J, et al. First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: results of the BRIGHT 5-year follow-up study [ASCO abstract 7500]. J Clin Oncol. 2017;35(15 suppl).
14. Rummel M, Maschmeyer G, Ganser A, et al. Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent lymphomas: nine-year updated results from the StiL NHL1 study [ASCO abstract 7501]. J Clin Oncol. 2017;35(15 suppl).
15. Cramer P, von Tresckow J, Bahlo J, et al. Bendamustine (B), followed by obinutuzumab (G) and venetoclax (A) in patients with chronic lymphocytic leukemia (CLL): CLL2-BAG trial of the German CLL Study Group (GCLLSG) [ICML abstract 006]. Hematol Oncol. 2017;35(suppl S2).
16. Andorsky DJ, Yacoub A, Melear J, et al. Phase IIIb randomized study of lenalidomide plus rituximab (R2) followed by maintenance in relapsed/refractory NHL: analysis of patients with double-refractory or early relapsed follicular lymphoma (FL) [ASCO abstract 7502]. J Clin Oncol. 2017;35(15 suppl).