Venetoclax plus R-CHOP as first-line treatment for DLBCL

The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP; R-CHOP) has improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL). However, some patient subgroups still have a poor prognosis due to resistance to CHOP chemotherapy, such as those who overexpress B-cell lymphoma-2 (Bcl-2).

The phase 1b stage of the CAVALLI study (NCT02055820) in patients with B-cell non-Hodgkin lymphoma, previously covered on the Lymphoma Hub, suggested promising activity with the addition of venetoclax, a Bcl-2 inhibitor, to R-CHOP or G-CHOP (obinutuzumab + CHOP), alongside a manageable safety profile. The aim of the phase II expansion part of the trial was to evaluate efficacy and safety in patients with previously untreated DLBCL, including those in high-risk subgroups, such as those with Bcl-2 overexpression (Bcl-2⁺). The results were published by Franck Morschhauser and colleagues in Blood,¹ and here we summarize their findings.

Study design

Patients aged ≥ 18 years were eligible if they had previously untreated DLBCL, an Eastern Cooperative Oncology Group performance status ≤ 2, and an International Prognostic Index 2–5. Individuals were not included if had received prior therapy for B-cell non-Hodgkin lymphoma, received an anthracycline, had central nervous system lymphoma, or had primary mediastinal DLBCL. Primary endpoints were safety and positron emission tomography (PET)-complete response (CR) at end of treatment. Secondary endpoints included progression-free survival (PFS) and overall survival. Clinical outcomes were compared with the R-CHOP control arm (patients with International Prognostic Index 2–5) from the GOYA/BO21005 study (NCT01287741).²

Bcl-2 and Myc expression were assessed by immunohistochemistry (IHC). Patients who co-expressed both proteins formed the double expressor lymphoma (DEL) subgroup.

Treatment schedule

• Venetoclax: 800 mg orally on Days 4–10 of cycle one and Days 1–10 of cycle two, in 21-day cycles.
• Rituximab: 375 mg/m² intravenously on Day 1 of cycles one to eight.
• CHOP: intravenous cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² on Day 1, and oral prednisolone 100 mg/day (with a 2.0 mg cap) on Days 1–5 for six to eight cycles.
• Hydration and a uric acid-lowering agent, such as allopurinol, was administered ≥ 72 hours prior to the first venetoclax dose for tumor lysis syndrome prophylaxis.
• Granulocyte-stimulating factor was included in later versions of the protocol for all cycles of CHOP.

Key results

Overall, 206 patients received venetoclax plus R-CHOP in CAVALLI, of which 104 patients overexpressed Bcl-2, and 80 comprised the DEL subgroup as they co-expressed Bcl-2 and Myc. In the GOYA R-CHOP control arm (n = 564), 151 and 124 patients were in the Bcl-2 IHC⁺ and DEL subgroups, respectively. Baseline characteristics were similar between studies, as shown in Table 1. Median follow-up was 32.2 months in CAVALLI at the data cutoff of June 28, 2019, and median follow-up was 29.6 months in GOYA on April 29, 2016.

Table 1. Characteristics of patients in CAVALLI and the R-CHOP arm of GOYA*

DEL, double expressor lymphoma; ECOG PS, Eastern Cooperative Oncology Group performance status; IHC, immunohistochemistry; IPI, International Prognostic Index; R-CHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone. *Adapted from Morschhauser, et al.1 †One patient in the GOYA study had an ECOG PS of 3. ‡Defined as an IHC score of 2+ or 3+. §DEL subgroup defined as patients who were Bcl-2 IHC+ and Myc IHC+.
Characteristic	CAVALLI: Venetoclax + R-CHOP (n = 206)	GOYA: R-CHOP (n = 564)
Median age, years (range)	65 (18–85)	62 (18–83)
Female, n (%)	93 (45)	267 (47)
ECOG PS, n (%)†                  0–1               2	172 (84) 34 (17)	476 (84) 87 (15)
IPI, %               2–3               4–5	155 (75) 51 (25)	455 (81) 109 (19)
Bcl-2 IHC, %               High‡                  Low	104 (58) 75 (42)	151 (49) 157 (51)
Myc IHC, %               Positive               Negative	133 (74) 46 (26)	248 (82) 56 (18)
DEL§, %	80 (45)	124 (41)

Efficacy

Clinical outcomes are presented in Table 2.

• In the CAVALLI study, independent review committee-assessed PET-CR rates were similar to the overall population in both the Bcl-2 IHC⁺ and DEL subgroups and were also comparable to the GOYA cohort.
• Although independent review committee-assessed overall response rates were similar overall, rates were numerically greater in the CAVALLI study compared with GOYA within both the Bcl-2 IHC⁺ and DEL populations.
• After a median follow-up of 32.2 months, investigator-assessed 2-year PFS was greater in patients in CAVALLI compared with the matched GOYA cohort, particularly in the Bcl-2 IHC⁺ subgroup.

Table 2. Efficacy outcomes for patients treated with venetoclax + R-CHOP in CAVALLI compared with the R-CHOP cohort in GOYA^*

CI, confidence interval; CR, complete response; DEL, double expressor lymphoma; HR, hazard ratio; IHC, immunohistochemistry; ORR, overall response rate; OS, overall survival; PET-CR, positron emission tomography-complete response; PFS, progression-free survival; R-CHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone. *Adapted from Morschhauser, et al.1 †PET-CR and ORR were assessed by an independent review committee, and PFS was investigator-assessed. ‡Delta CR stated for PET-CR, and HR stated for PFS and OS, adjusted for baseline covariates, including age, sex, Eastern Cooperative Oncology Group performance status, body mass index, International Prognostic Index, bulky disease, disease stage, lactate dehydrogenase, and cell of origin subtype. §DEL subgroup defined as patients who were Bcl-2 IHC+ and Myc IHC+.
Outcome†	CAVALLI: Venetoclax plus R-CHOP	GOYA: R-CHOP	Delta CR or HR (95% CI)‡
PET-CR, n (%)               Overall               Bcl-2 IHC+                  DEL§	143 (69) 67 (64) 53 (66)	354 (63) 91 (60) 75 (61)	6 (0–13) 2 (0–12) 2 (0–14)
ORR, n (%)               Overall               Bcl-2 IHC+                  DEL§	171 (83) 86 (83) 67 (84)	452 (80) 117 (77) 95 (77)	— — —
2-year PFS, %               Overall               Bcl-2 IHC+                  Bcl-2 IHC−                  DEL§	80 78 83 72	67 62 75 61	0.61 (0.43–0.87) 0.55 (0.34–0.89) 0.77 (0.39–1.50) 0.77 (0.46–1.29)
2-year OS, %               Overall               Bcl-2 IHC+                  Bcl-2 IHC−                  DEL§	86 83 90 79	81 75 83 77	0.72 (0.48–1.10) 0.67 (0.38–1.19) 0.90 (0.41–1.98) 0.95 (0.50–1.79)

Safety

The overall rate of adverse events (AEs) and serious AEs was greater in CAVALLI compared with GOYA, however the mortality rate was not increased (Table 3). The most common AEs of any grade in CAVALLI vs GOYA were neutropenia (68% vs 41%), infections and infestations (63% vs 46%), nausea (52% vs 27%), fatigue (40% vs 18%), and diarrhea (39% vs 14%). Moreover, Grade 3/4 hematologic AEs were more frequent in CAVALLI compared with GOYA (Table 3).

Overall, 95% of patients in CAVALLI experienced venetoclax-related AEs, including blood and lymphatic system disorders (74%) and gastrointestinal disorders (65%). Venetoclax-related neutropenia occurred in 61% of patients and febrile neutropenia in 27%.

Table 3. AEs reported in CAVALLI and the R-CHOP arm of GOYA

AE, adverse event; R-CHOP, rituximab + cyclophosphamide + doxorubicin + vincristine + prednisolone; SAE, serious adverse event. *Adapted from Morschhauser, et al.1
AE, %	CAVALLI: Venetoclax plus R-CHOP (n = 206)	GOYA: R-CHOP (n = 564)
Any AE	99	94
SAE	56	41
Fatal AE	2	5
AE leading to withdrawal	24	10
Grade 3/4 AE               Neutropenia               Febrile neutropenia               Anemia               Infections and infestations               Thrombocytopenia               Leucopenia               Pneumonia	86 68 31 24 23 22 10 4	66 39 16 9 16 2 10 5

Conclusion

The authors concluded that the efficacy of venetoclax + R-CHOP was promising, with similar PET-CR rates to the R-CHOP control arm of GOYA overall and in the Bcl-2 IHC⁺ and DEL subgroups. Furthermore, the Bcl-2 IHC⁺ subgroup showed prolonged 2-year PFS in CAVALLI compared with GOYA, suggesting specific potential for the use of venetoclax alongside R-CHOP in this high-risk population, which warrants further investigation.

Although there was a high incidence of AEs in CAVALLI compared with GOYA, particularly with regards to myelosuppression, these events were manageable and did not result in increased mortality.