Efficacy and safety of frontline rituximab, cyclophosphamide, doxorubicin and prednisone plus bortezomib (VR-CAP) or vincristine (R-CHOP) in a subset of newly diagnosed mantle cell lymphoma patients medically eligible for transplantation in the randomized, phase 3 LYM-3002 study

Abstract

This post-hoc subanalysis of the LYM-3002 phase 3 study assessed the efficacy and safety of substituting vincristine in rituximab, cyclophosphamide, doxorubicin and prednisone (R-CHOP; n = 42) for bortezomib (VR-CAP; n = 38) in a subgroup of 80 mantle cell lymphoma (MCL) patients aged <60 years who did not receive stem cell transplantation (SCT) despite medical eligibility. Complete response (CR)/unconfirmed CR (CRu) rates were 67 vs. 39% (odds ratio 3.69 [95% CI(confidence interval): 1.31, 10.41]; p = .012). After 40 months median follow-up, median progression-free survival by independent radiology committee with VR-CAP vs. R-CHOP was 32.6 vs. 12.0 months (hazard ratio (HR) 0.59 [95% CI: 0.31, 1.13]; p = .108); median overall survival was not reached vs. 47.3 months (HR 0.81 [95% CI: 0.33, 1.96]; p = .634). Adverse events included neutropenia (92/76%), thrombocytopenia (70/10%) and leukopenia (65/50%). VR-CAP represents a potential alternative to R-CHOP in combined and/or alternating regimens for younger, SCT-eligible MCL patients.

Keywords:

• Bortezomib
• frontline
• mantle cell lymphoma
• phase 3

Introduction

Mantle cell lymphoma (MCL) is an incurable, aggressive hematologic malignancy, accounting for 5–6% of all non-Hodgkin lymphomas (NHL). It has a poor prognosis, with a median survival of just 4–5 years [1–3]. In younger, fitter patients with advanced, newly diagnosed disease, aggressive therapy is recommended; this generally involves high-dose cytarabine-containing regimens plus rituximab followed by high-dose consolidation therapy and autologous stem cell transplantation (SCT) [4,5]. Rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) is included in many of these induction strategies and may be used in an alternating or sequential manner along with other cytotoxic chemotherapeutic agents such as cyclophosphamide, methotrexate and cisplatin. Older, less fit patients with newly diagnosed MCL are usually considered medically ineligible on the basis of age and/or comorbidity for high-dose therapy with or without SCT and guidelines recommend less aggressive therapy with regimens such as R-CHOP or bendamustine plus rituximab for these patients [4,5].

Common molecular abnormalities in MCL include reduced expression of p27 and constitutive activation of the NF-κB pathway, both of which are primarily regulated by proteasomal degradation [6,7]. Proteasome inhibition has therefore been investigated as a potential therapeutic option in MCL, with the first-generation proteasome inhibitor, bortezomib, now approved in the United States for the treatment of both newly diagnosed and relapsed MCL [8] and in the European Union for the treatment of patients with previously untreated MCL who are unsuitable for SCT [8,9]. Preclinical studies have shown that in addition to modulating the NF-κB pathway, bortezomib induces apoptosis in MCL cells through reactive oxygen species generation and by upregulating the proapoptotic protein Noxa [10].

The approval of bortezomib in newly diagnosed MCL was based on findings from the international, randomized, phase 3 LYM-3002 study [11] (NCT00722137), which compared the efficacy and safety of VR-CAP (bortezomib plus rituximab, cyclophosphamide, doxorubicin and prednisone) with R-CHOP in 487 patients with newly diagnosed MCL who were ineligible for or not considered for SCT. The LYM-3002 study met its primary endpoint, demonstrating a 59% improvement in progression-free survival (PFS) by independent radiology review committee (IRC) assessment, as well as significant improvements in the rates of complete response (CR)/unconfirmed CR (CRu), median duration of CR/CRu, and 4-year overall survival (OS) with VR-CAP versus R-CHOP. LYM-3002 also reported a manageable safety profile for VR-CAP; the most common grade ≥3 adverse events (AEs) associated with VR-CAP were hematologic in nature and included neutropenia, thrombocytopenia and leukopenia [11].

In addition to enrolling patients who were considered by their treating physicians to be medically ineligible for SCT (for example because of advanced age or comorbidities that may have impacted their ability to tolerate SCT), the LYM-3002 study also initially enrolled patients who were medically eligible for but did not receive SCT due to non-medical reasons [11]. This prospectively allowed the enrollment of patients who refused SCT or for whom SCT was not financially viable, as well as patients from centers where bone marrow transplantation was not available. Eligibility for and actual use of SCT may vary from country to country, depending on national reimbursement guidelines. For example, in the EU, the rate of SCT for hematological malignancies may differ from that recommended by international experts, depending on national indices of standard of living, level of education and other socioeconomic factors [12], with eastern European countries, in general, having a lower rate of SCT than those in western Europe [13].

An early protocol amendmentwas implemented to limit heterogeneity and ensure interpretability of the study results, altered the inclusion criteria such that only patients who were medically ineligible for SCT could enroll in the study, subsequently excluding patients who were considered SCT-ineligible due to non-medical reasons. Thus, a small group of patients entered LYM-3002 who were medically eligible for but did not receive SCT due to non-medical reasons.

The inclusion of these SCT-eligible patients in the LYM-3002 study provided an opportunity to investigate the comparative efficacy and safety of VR-CAP and R-CHOP in a younger, fitter group of patients, a comparison that has not previously been conducted. Although R-CHOP alone is not the current standard of care for young, fit patients [4,5], the combination is incorporated into alternating or more intense induction regimens and it is possible that these regimens could be enhanced by the substitution of VR-CAP for R-CHOP. Thus, this post-hoc subanalysis was conducted to compare the efficacy and safety of VR-CAP and R-CHOP in a subgroup of patients from LYM-3002 who were aged <60 years and who were deemed to be medically eligible for SCT. Some study subjects who were initially assessed as SCT-ineligible by their treating physicians for medical reasons were, upon subsequent revision by an external medical monitor, deemed eligible for SCT and these patients were also captured and included in the subanalysis.

Methods

Study design and patients

The LYM-3002 study design has been reported previously [11]. Briefly, patients were aged ≥18 years and had newly diagnosed, measurable, stage II–IV, centrally confirmed MCL, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, and were ineligible for or not considered for SCT.

Patients were randomized 1:1 (stratified by International Prognostic Index [IPI] score and disease stage [American Joint Committee on Cancer NHL staging system]) to receive six 21-day cycles of VR-CAP or R-CHOP (or up to eight cycles if response was first documented at Cycle 6). The VR-CAP regimen comprised rituximab 375 mg/m² intravenously (IV) on Day 1, cyclophosphamide 750 mg/m² IV on Day 1, doxorubicin 50 mg/m² IV on Day 1, prednisone 100 mg/m² orally on Days 1–5 and bortezomib 1.3 mg/m² IV on Days 1, 4, 8 and 11. The R-CHOP dose/schedule was as for the VR-CAP regimen, with the exception that bortezomib was replaced by vincristine 1.4 mg/m² IV (maximum total dose 2 mg) on Day 1.

For the present subanalysis, only patients aged <60 years who were eligible for but did not receive SCT (referred to herein as SCT-eligible patients) were included. The study was conducted according to the principles set out in the Declaration of Helsinki, Good Clinical Practice guidelines and local regulatory requirements. The protocol was approved by relevant institutional review boards/ethics committees. All patients provided written informed consent. This trial was registered at www.clinicaltrials.gov as NCT00722137.

Assessments and endpoints

In LYM-3002, response and disease progression were assessed per blinded IRC review and per investigator review, according to modified International Workshop to Standardize Response Criteria for non-Hodgkin lymphoma (IWRC) criteria [14]. Computed tomography scans were performed every two cycles (6 weeks) during treatment and every 6–8 weeks during follow-up (until progression, discontinuation, initiation of alternate therapy, or death). AEs were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v3.0. The specific endpoints evaluated in this subanalysis were PFS by IRC and investigator assessment, rates of CR/CRu, duration of CR/CRu, OS and safety.

Statistical analyses

Time-to-event endpoints (PFS and OS) in SCT-eligible patients were estimated via Kaplan-Meier methodology, with log-rank tests and Cox models (α = 0.05, two-sided) used for inter-arm comparisons. Response rate comparisons were made using the Cochran-Mantel-Haenszel Chi-squared test. All tests were stratified by IPI score and disease stage.

Results

Patients

Between May 2008 and December 2011, a total of 487 patients were enrolled into the LYM-3002 study (intent-to-treat [ITT] population: 243 VR-CAP, 244 R-CHOP). Of these, 80 patients (38 VR-CAP; 42 R-CHOP) were deemed by a retrospective medical monitor review to have been SCT-eligible (Figure 1). The reasons given at the commencement of the study by the treating physicians as to why these SCT-eligible patients could not undergo SCT (more than one reason may have been given for each patient) were age (19%), inability to tolerate high-dose therapy (9%), co-morbidity (23%), not considered suitable by investigator (15%) or other (46%). These patients were enrolled in countries in the EU (11%), North America region (1%) and the rest of world (88%; mainly China [36%] and Russia [23%]) (Supplementary Table 1). Demographics and baseline characteristics for the 80 SCT-eligible patients included in this analysis are summarized in Table 1. Compared with patients in the ITT population, SCT-eligible patients (VR-CAP and R-CHOP) were younger (median age 54 vs. 66 years) and tended toward a lower ECOG PS (0/1/2: 58/38/5 vs. 40/47/13%). Additionally, fewer SCT-eligible patients had bone marrow involvement at baseline (56 vs. 69%) compared with the ITT population. Unsurprisingly, due to the younger age of this subgroup, 24% of patients had an intermediate or high MCL International Prognostic Index (MIPI), compared with 70% in the overall LYM-3002 population [11]. Apart from these differences, baseline characteristics and stratification factors were generally similar between the VR-CAP and R-CHOP arms and were in line with the ITT population [11]. SCT-eligible patients in both VR-CAP and R-CHOP arms completed a median of six treatment cycles (VR-CAP: range 4–8; R-CHOP: range 1–8).

Figure 1. CONSORT diagram. HDT: high-dose therapy; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone. *Based on retrospective medical monitor review; age ≥60 years or medical reasons. ^†Reasons why patients did not undergo transplantation, as assessed by the treating physician at study commencement (more than one reason may have been recorded for each patient).

Table 1. Demographics and baseline characteristics of SCT-eligible patients.

	VR-CAP n = 38	R-CHOP n = 42	Total n = 80
Median age, years (range)	53 (38–59)	54 (34–59)	54 (34–59)
Male, n (%)	32 (84)	30 (71)	62 (78)
Race, n (%)
White/Asian	18 (47)/20 (53)	20 (48)/22 (52)	38 (48)/42 (53)
Disease stage at diagnosis,^a n (%)
II/III/IV	3 (8)/11 (29)/24 (63)	3 (7)/15 (36)/24 (57)	6 (8)/26 (33)/48 (60)
ECOG PS, n (%)^b
0/1/2	23 (61)/13 (34)/2 (5)	23 (55)/17 (41)/2 (5)	46 (58)/30 (38)/4 (5)
IPI score (risk category), n (%)
0–1 (low)	23 (61)	22 (52)	45 (56)
2 (low-intermediate)	10 (26)	15 (36)	25 (31)
3 (high-intermediate)	5 (13)	4 (10)	9 (11)
4–5 (high)	0	1 (2)	1 (1)
MIPI risk status, n (%)^c
Low/intermediate/high	30 (79)/5 (13)/3 (8)	31 (74)/8 (19)/3 (7)	61 (76)/13 (16)/6 (8)
MIPIb risk status, n (%)^b,^d
Low/intermediate/high	15 (63)/6 (25)/3 (13)	12 (46)/8 (31)/6 (23)	27 (54)/14 (28)/9 (18)
Ki-67 status, n (%)^d,^e
Positive/Negative	9 (38)/15 (63)	10 (38)/16 (62)	19 (38)/31 (62)
Elevated LDH, n (%)	9 (24)	14 (33)	23 (29)
Bone marrow involvement, n (%)	24 (63)	21 (50)	45 (56)

^a American Joint Committee on Cancer NHL disease staging system.

^b Sum of percentages may not equal 100% due to rounding.

^c MIPI was not in place at study commencement, therefore IPI was used at baseline.

^d Assessed in Ki-67-evaluable patients (n = 24 VR-CAP; n = 26 R-CHOP; n = 50 total).

^e Based on a cutoff of 10% Ki-67 expression on an ordinal scale.

ECOG PS: Eastern Cooperative Oncology Group performance status; IPI: International Prognostic Index; LDH: lactate dehydrogenase; MIPI: Mantle Cell Lymphoma International Prognostic Index; MIPIb: MIPI with biologic component; NHL: non-Hodgkin lymphoma; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; SCT: stem cell transplant; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone.

Response

Rates and duration of CR/CRu per IRC assessment and per investigator assessment in response-evaluable SCT-eligible patients are summarized in Table 2. CR/CRu rates by IRC were 67% with VR-CAP versus 39% with R-CHOP (OR [odds ratio] = 3.69 [95% CI: 1.31, 10.41]; p = .012) and by investigator assessment, which may more accurately reflect assessments made in real-life clinical practices, were 50 vs. 29%, respectively (OR = 2.19 [95% CI: 0.81, 5.92]; p = .126). In comparison, in the ITT population, CR/CRu rates by IRC were 53% with VR-CAP versus 42% with R-CHOP (OR = 1.69 [95% CI: 1.15, 2.48]; p = .007) and by investigator were 41 vs. 28%, respectively (OR = 1.88 [95%CI: 1.26, 2.82]; p = .002) [11]. Median duration of CR/CRu by IRC assessment was 45.9 months with VR-CAP versus 28.6 months with R-CHOP, and by investigator assessment was 48.0 months versus not reached (NR), respectively. In the ITT population, median duration of CR/CRu by IRC assessment was 42.1 months with VR-CAP versus 18.0 months with R-CHOP and by investigator assessment was 49.8 months versus 18.7 months, respectively [11].

Table 2. CR rates and duration of CR in SCT-eligible patients.

	VR-CAP	R-CHOP	OR^b (95%CI)	p value
CR rates, n (%)	n = 36	n = 41
IRC assessment
Overall rate of CR^a	24 (67)	16 (39)	3.69 (1.31, 10.41)	.012
CR	19 (53)	15 (37)
CRu	5 (14)	1 (2)
Investigator assessment
Overall rate of CR^a	18 (50)	12 (29)	2.19 (0.81, 5.92)	.126
CR	17 (47)	11 (27)
CRu	1 (3)	1 (2)
Median duration of CR,^a months (95% CI)
IRC assessment	n = 24	n = 16
	45.9 (19.6, NE)	28.6 (7.4, NE)	–	–
Investigator  assessment	n = 18	n = 12
	48.0 (30.1, NE)	NR (10.3, NE)	–	–

^a CR/CRu verified by bone marrow and LDH.

^b Cochran-Mantel-Haenszel estimate with IPI and disease stage as stratification factors (an OR >1 indicates an advantage for VR-CAP).

CI: confidence interval; CR: complete response; CRu: unconfirmed complete response; IPI: International Prognostic Index; SCT: stem cell transplant; IRC: independent review committee; LDH: lactate dehydrogenase; NE: not estimable; NR: not reached; OR: odds ratio; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone.

Progression-free survival

After a median follow-up of 40 months (for all patients in LYM-3002), according to IRC assessment, 45 of 80 (56%) SCT-eligible patients had died or experienced disease progression. Median PFS was 32.6 months with VR-CAP versus 12.0 months with R-CHOP (HR = 0.59 [95% CI: 0.31, 1.13]; p = .108) (Figure 2), in comparison with 24.7 versus 14.4 months, respectively (HR = 0.63 [95% CI: 0.50, 0.79]; p < .001) in the ITT population [11]. By investigator assessment, death or disease progression had occurred in 43 of the SCT-eligible patients (54%) by 40 months. Median PFS was 42.6 months with VR-CAP versus 20.6 months with R-CHOP (HR = 0.54 [95% CI: 0.28, 1.03]; p = .058) (Supplementary Figure 1), in comparison with 30.7 versus 16.1 months, respectively (HR = 0.51 [95% CI: 0.41, 0.65]; p < .001) in the ITT population [11]. The sample size of the SCT-eligible population was insufficient to adequately compare the arms; thus, the PFS comparison of VR-CAP and R-CHOP should be considered descriptive rather than statistical.

Figure 2. PFS by IRC in SCT-eligible patients. CI: confidence interval; HR: hazard ratio; IRC: independent review committee; NE: not estimable; PFS: progression-free survival; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SCT: stem cell transplant; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone.

Overall survival

After a median follow-up of 40 months (for all patients in LYM-3002), median OS with VR-CAP versus R-CHOP in SCT-eligible patients was NR versus 47.3 months (HR = 0.81 [95% CI: 0.33, 1.96]; p = .634) (Table 3). As only 24 (30%) deaths had occurred at the time of this analysis, these data are still immature. In the ITT population, median OS with VR-CAP versus R-CHOP was NR versus 56.3 months (HR = 0.80 [95% CI: 0.59, 1.10]; p = .173) [11]. OS at four years was 74.1% in SCT-eligible patients with VR-CAP versus 48.7% with R-CHOP, compared with 64.4 vs. 53.9%, respectively, in the ITT population [11].

Table 3. OS in SCT-eligible patients.

	VR-CAP n = 38	R-CHOP n = 42
Events, n (%)	9 (24)	15 (36)
Median OS, months (95% CI)	NR (56.0, NE)	47.3 (36.3, NE)
HR (95% CI)	0.81 (0.33, 1.96)
p value	.634
4-year OS rate (95%CI)	74.1 (54.0, 86.5)	48.7 (28.5, 66.2)

CI: confidence interval; HR: hazard ratio; NE: not estimable; NR: not reached; OS: overall survival; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SCT: stem cell transplant; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone.

Safety

All SCT-eligible patients experienced at least 1 any-grade treatment-emergent AE; 95 and 93% of patients in the VR-CAP and R-CHOP arms, respectively, had drug-related AEs. The most common any-grade AEs were neutropenia (92 vs. 76%), thrombocytopenia (70 vs. 10%), leukopenia (65 vs. 50%), anemia (46 vs. 40%), pyrexia (41 vs. 14%), lymphopenia (32 vs. 14%) and peripheral sensory neuropathy (each 24%) (Table 4).

Table 4. Any-grade AEs in ≥10% of SCT-eligible patients in either arm and corresponding grade ≥3 AEs.

	VR-CAP n = 37		R-CHOP n = 42
AEs, n (%)	Any-grade	Grade ≥3	Any-grade	Grade ≥3
Any AE	37 (100)	35 (95)	42 (100)	34 (81)
Neutropenia	34 (92)	33 (89)	32 (76)	28 (67)
Thrombocytopenia	26 (70)	22 (59)	4 (10)	0
Leukopenia	24 (65)	21 (57)	21 (50)	13 (31)
Anemia	17 (46)	6 (16)	17 (40)	6 (14)
Pyrexia	15 (41)	1 (3)	6 (14)	0
Lymphopenia	12 (32)	8 (22)	6 (14)	5 (12)
Peripheral sensory  neuropathy	9 (24)	2 (5)	10 (24)	1 (2)
Fatigue	7 (19)	1 (3)	3 (7)	0
Cough	7 (19)	0	2 (5)	0
Alopecia	6 (16)	0	6 (14)	0
Constipation	6 (16)	0	4 (10)	0
Diarrhea	6 (16)	2 (5)	4 (10)	1 (2)
Nausea	5 (14)	0	6 (14)	0
Abdominal distension	5 (14)	0	2 (5)	0
Abnormal hepatic function	5 (14)	1 (3)	2 (5)	0
Hypertension	5 (14)	1 (3)	0	0
Neuralgia	5 (14)	1 (3)	0	0
Febrile neutropenia	4 (11)	3 (8)	6 (14)	5 (12)
Asthenia	4 (11)	0	2 (5)	0
Upper respiratory tract  infection	4 (11)	0	2 (5)	1 (2)
Decreased appetite	4 (11)	0	2 (5)	0
Pain in extremity	4 (11)	1 (3)	1 (2)	0
Oropharyngeal pain	4 (11)	1 (3)	0	0
Vomiting	2 (5)	0	5 (12)	0
Hypoesthesia	2 (5)	0	4 (10)	0

AE: adverse event; R-CHOP: rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone; SCT: stem cell transplant; VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin and prednisone.

Grade ≥3 AE rates in SCT-eligible patients were 95% with VR-CAP versus 81% with R-CHOP; 95 vs. 76% of these, respectively, were drug-related. Grade ≥3 AEs were mainly hematologic, most commonly neutropenia (89 vs. 67%), thrombocytopenia (59 vs. 0%) and leukopenia (57 vs. 31%) (Table 4).

Rates of serious AEs (SAEs) were 19% in both arms of the subanalysis; 14% of patients in each arm had drug-related SAEs. SAEs reported in ≥5% of patients in either arm with VR-CAP versus R-CHOP were febrile neutropenia (5 vs. 7%), neutropenia (5% each) and sepsis (5 vs. 0%). The number of patients discontinuing treatment due to AEs (n = 2 VR-CAP, n = 1 R-CHOP) and with grade 5 AEs (each n = 2) was similar between the arms. Dose modifications with VR-CAP versus R-CHOP were 22 (60%) vs. 9 (21%) in SCT-eligible patients.

Discussion

This retrospective analysis of data from the pivotal LYM-3002 study demonstrates a significant improvement in CR/CRu rates by IRC with VR-CAP compared with R-CHOP in younger, SCT-eligible MCL patients, consistent with findings in the overall LYM-3002 patient population [11]. Improvement in PFS by IRC or OS did not reach statistical significance, although the small sample size was likely insufficient to determine this. Notably, a CR/CRu rate of 67% (by IRC) was demonstrated, with a median CR/CRu duration of 45.9 months.

CR post-induction is a viable measure to compare efficacy across studies, as PFS and OS are influenced by the later receipt of SCT. The CR rate observed in our study was achieved with a fixed duration of VR-CAP treatment (4 months; 6–8 cycles) in the absence of maintenance therapy. Response rates achieved with other, less aggressive induction therapies in patients with previously untreated MCL include 31% CR with bendamustine/rituximab [15], 95% CR with bendamustine/rituximab/cytarabine [16], 52% CR and 61% CR/CRu with cladribine/rituximab [17,18] and 64% CR with lenalidomide/rituximab [19]. The data in these studies are likely to be more heavily weighted towards a population ineligible for transplant or intensive therapy for medical reasons, so it cannot be directly compared with the results observed in our study of SCT-eligible patients.

Compared with the overall LYM-3002 population, CR/CRu rates in this SCT-eligible subgroup were higher for VR-CAP (SCT-eligible: 67%; overall: 53%) and slightly lower for R-CHOP (SCT-eligible: 39%; overall: 42%). Median PFS was also longer with VR-CAP in the SCT-eligible subgroup compared with the overall LYM-3002 population (32.6 vs. 24.7 months). For R-CHOP, median PFS was slightly shorter in the SCT-eligible group compared with the overall population (12.0 vs. 14.4 months).

The toxicity profiles of VR-CAP and R-CHOP in SCT-eligible patients included in this analysis were comparable with those observed in the overall LYM-3002 patient population [11], with no new safety signals. Higher rates of mainly hematologic toxicities were observed with VR-CAP than with R-CHOP, consistent with the AEs associated with bortezomib-based therapy in MCL [20–22].

Our results suggest that bortezomib may enhance response when added to frontline regimens, a finding that is supported by results from early-phase studies. In a phase 1 study, bortezomib was administered in combination with rituximab-hyperCVAD (rituximab, cyclophosphamide, doxorubicin, vincristine and dexamethasone) alternating with rituximab, methotrexate and cytarabine in 20 previously-untreated MCL patients aged 18–79 years [23]. Toxicity was primarily hematological and did not differ from that observed with a similar regimen without bortezomib. In a subsequent phase 2 study, rituximab, bortezomib, modified hyper-cyclophosphamide, doxorubicin, vincristine and dexamethasone (VcR-CVAD) was associated with an overall response rate of 95%, with 68% CR and a manageable safety profile of primarily hematologic toxicities (neutropenia, thrombocytopenia) in previously untreated MCL patients. No difference in PFS or OS between those who received subsequent rituximab maintenance therapy or SCT was identified [24].

Our analysis is limited by its retrospective subgroup nature; as the analysis was not pre-planned, it was not necessarily powered to address the reported endpoints and the small sample size clearly limits interpretation of the results. Other limitations include the potential for selection bias in a post-hoc subgroup and the lack of economic considerations in this study. The data must therefore be interpreted with caution; although generally supportive of the treatment effect demonstrated with VR-CAP versus R-CHOP in the overall LYM-3002 population, patient numbers are too small to draw definitive conclusions. Furthermore, the differences in PFS and OS were not statistically significant, likely due to the immaturity of the data.

Perhaps the most significant limitation of the analysis is that R-CHOP is not the current standard of care for young, fit patients and as a result, the results of our subanalysis are not directly applicable to current clinical practice in this patient population. The findings would have been more informative if the comparator regimen was one of the more aggressive, cytarabine-based regimens used for patients who are medically eligible for SCT. Our findings do suggest, however, that VR-CAP is a viable alternative to R-CHOP in frontline regimens for young, fit patients, such as the alternating R-CHOP/R-DHAP (rituximab, dexamethasone, cisplatin, cytarabine) or sequential R-CHOP/RICE (rituximab, ifosfamide, carboplatin, etoposide) regimens recommended by the National Comprehensive Cancer Network [5]. Investigation into the clinical efficacy and safety of such combinations may be warranted.

Overall, the data from this subanalysis of the LYM-3002 study clearly demonstrate that VR-CAP has superior efficacy to R-CHOP with a manageable safety profile in young, fit MCL patients and thus may be an attractive substitute for R-CHOP in more intense/alternating induction regimens.

Potential conflict of interest

Disclosure forms provided by the authors are available with the full text of this article online at https://doi.org/10.1080/10428194.2017.1365855

Acknowledgements

The authors would like to acknowledge Helen Johns of FireKite, an Ashfield company, part of UDG Healthcare plc, for writing support during the development of this manuscript and complied with Good Publication Practice 3 ethical guidelines (Battisti WP, et al. Ann Intern Med 2015;163:461–4).

Additional information

Funding

Janssen Research and Development10.13039/100005205Millennium Pharmaceuticals, Inc.This work was supported by Janssen Research and Development, LLC and co-funded by Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.