Chimeric Antigen Receptor T-cell Therapy for Large B-cell Lymphoma: Who, When, and How?

Large B-cell lymphoma (LBCL) is a spectrum of aggressive B-cell malignancies with broad genetic and clinical heterogeneity.¹ Although frontline chemotherapy cures most patients, but those with relapsed or refractory disease usually die of lymphoma. Salvage chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard second-line approach to LBCL and cures up to 30–40% of eligible patients, but is restricted to younger, fit patients and is relatively ineffective in chemotherapy refractory disease.²

Chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have advanced the treatment of multiply relapsed LBCL and demonstrated promising rates of durable remission in up to 40% of cases including those with refractory disease. CAR-T cell therapy is a multistep process that includes leukapheresis of host T cells, transfer of the gene encoding CAR into the T-cell genome, ex vivo expansion and infusion of the CAR-T cells following the treatment of patients with lymphodepleting chemotherapy. This process requires weeks of processing so that patients with rapidly progressing and/or bulky disease are either considered unsuitable or require bridging therapy before infusion. This inherent selection bias has raised questions about the generalizability of CAR-T-cell clinical trial results across the entire population of LBCL.

Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are three different CAR-19 products that have been approved for the third-line treatment of LBCL based on pivotal phase 2 studies.^3–5 These products have important differences that include the costimulatory domains (CD28 for axicabtagene ciloleucel versus 4–1BB for tisagenlecleucel and lisocabtagene maraleucel) and the gene transfer method (retrovirus for axicabtagene ciloleucel versus lentivirus for tisagenlecleucel and lisocabtagene maraleucel). Despite these differences, all three CAR-T-cell products have demonstrated similar efficacy and toxicity profiles, but no clinical trials have directly compared these products.

The pivotal ZUMA-1 trial enrolled 111 patients with a variety of LBCL subtypes that were refractory to salvage chemotherapy or relapsed within 1 year of ASCT (Table).⁴ Only glucocorticoid bridging therapy was allowed and patients with impending organ-compromising disease were ineligible, resulting in axicabtagene ciloleucel infusion in 91% of patients at a median of 17 days after enrollment. The complete response rate was 54% and the 1-year progression-free survival was 44%. In contrast, the pivotal JULIET trial enrolled 165 patients with relapsed or refractory LBCL who had received at least 2 prior lines of therapy.³ An important eligibility difference was that bridging chemotherapy was allowed and administered in 92% of patients, thereby allowing the inclusion of patients with rapidly progressing and/or bulky disease. Only 67% of the enrolled patients received a tisagenlecleucel infusion after a median of 54 days, since many patients progressed before infusion, and were not included in the final analysis. The authors reported overall and complete response rates of 52% and 40% in the infused cohort, but an overall response rate of only 34% for all enrolled patients. Longer follow-up of these two studies shows similar outcomes with 2-year progression-free survival between 35–40% and 70–80% for complete responders.^6,7

Table 1 -.

Comparisons Across Trials

	ZUMA-1 (axicabtagene ciloleucel)	JULIET (tisagenlecleucel)	ZUMA-7 (axicabtagene ciloleucel arm)	BELINDA (tisagenlecleucel arm)	ZUMA-7 (SOC arm)	BELINDA (SOC arm)
Primary Endpoint	Overall response rate	Overall response rate	Event Free Survival	Event Free Survival after week 12	Event Free Survival	Event Free Survival after week 12
Patient Characteristics
- No. of Patients	N=111 (total cohort), N=101 (infused cohort)	N=165 (total cohort), N=111 (infused cohort)	N=180	N=162	N=179	N=160
- Median Age (range), years	58 (23–76)	56 (22–76)	58 (21–80)	60 (19–79)	60 (26–81)	58 (19–77)
- Age ≥65 years	24 (24%)	25 (23%)	51 (28%)	54 (33%)	58 (32%)	46 (29%)
Study eligibility
- Disease status	Refractory or <12m relapse after ASCT	Relapsed or refractory after 2 lines	Refractory or <12m relapse, ASCT-eligible	Refractory or <12m relapse, ASCT-eligible	Refractory or <12m relapse, ASCT-eligible	Refractory or <12m relapse, ASCT-eligible
	no impending organ compromise		no impending organ compromise		no impending organ compromise
- Bridging therapy	Steroids only	Chemotherapy optional (92% received)	Steroids only (36% received)	Chemotherapy optional (83% received)	n/a	n/a
CD19 positive	74 of 82 (90%)	49 of 72 (68%)	144 (80%)	not reported	134 (75%)	not reported
Histology
- DLBCL: NOS	77 (76%)	88 (79%)	126 (70)	101 (62%)	120 (67%)	112 (70%)
- HGBL-DH	not reported	19 of 70 (27%)	31 (17)	32 (20%)	25 (14%)	19 (12%)
- HGBL-NOS	0	0	0 (0%)	7 (4%)	1 (1%)	8 (5%)
- FL grade 3B	0	0	0 (0%)	5 (3%)	0 (0%)	1 (0.6%)
- PMBL	8 (8%)	0	0 (0%)	12 (7%)	0 (0%)	13 (8%)
- Other/missing	0	2 (2%)	23 (13%)	5 (3%)	33 (18%)	7 (4%)
Transformed lymphoma	16 (16%)	21 (19%)	19 (11%)	27 (17%)	27 (15%)	22 (14%)
Cell Of Origin
- GCB-like	49 (74%)	63 (57%)	109 (61%)	46 (28%)	99 (55%)	63 (39%)
- ABC-like	17 (26%)	45 (41%)	16 (9%)	52 (32%)	9 (5%)	42 (26%)
- Unclassified	0	0	17 (9%)	3 (2%)	14 (8%)	7 (4%)
- Missing/not applicable	35 (35%)	3 (3%)	38 (21%)	0 (0%)	57 (32%)	0 (0%)
Disease status at study entry
- Refractory to any therapy	80 (79%)	61 (55%)	133 (74%)	107 (66%)	131 (73%)	107 (67%)
- Relapsed	21 (21%)	50 (45%)	47 (26%)	55 (34%)	48 (26%)	53 (33%)
- Prior ASCT	21 (21%)	54 (49%)	n/a	n/a	n/a	n/a
On Study Characteristics
- Progressive disease prior to CAR-T	1 (1%)	~23%	2 (1%)	42 (26%)	n/a	n/a
- Crossover to CAR-T allowed on study	n/a	n/a	n/a	n/a	No (56% received off protocol)	Yes (51% crossed over)
- Received ASCT on study	n/a	n/a	n/a	n/a	64 (36%)	52 (33%)
- Received CAR-T infusion	101 (91%)	111 (67%)	170 (94%)	155 (96%)	n/a	n/a
- Enrollment to CAR-T infusion	~17 days	54 days	29 days	52 days	n/a	n/a
- Leukapheresis to CAR-T release	not reported	not reported	13 days	23.5 days (U.S.), 28 days (non-U.S.)	n/a	n/a
- CAR-T cell dose	2×106 CAR-T cells/kg	3 × 108 CAR-T cells	2×106 CAR-T cells/kg	2.9 × 108 CAR-T cells	n/a	n/a
Clinical Outcomes
- Overall Response Rate	82%	52% (efficacy cohort) 34% (ITT cohort)	83%	46%	50%	42%
- Complete Response Rate	54%	40% (efficacy cohort)	65%	28%	32%	28%
- Median follow-up	27.1m	40.3m	25m	10m	25m	10m
- 2-year PFS	~40%	~35%	~46%	not reported	27% (estimate)	not reported
- 2-year PFS in CR	72%	~80%	not reported	not reported	not reported	not reported
- 2-year OS	51%	~45%	61%	not reported	52%	not reported

In this issue of the Journal, we see the results of two randomized studies that compare the efficacy of CAR-T-cell therapy to ASCT as second-line treatment for LBCL but reach seemingly discordant conclusions.^8,9 In the ZUMA-7 study, Locke et al. compared axicabtagene ciloleucel (N=180) to ASCT (N=179) and demonstrated improved rates of complete response (65% vs. 32%) and superior event-free survival (hazard ratio (HR) 0.398; p<0.0001). Similar to the pivotal ZUMA-1 trial, patients could only receive glucocorticoids for bridging therapy and patients with impending organ- compromising disease were ineligible, resulting in CAR-T-cell infusions in 94% of patients with only 2 documented interim disease progressions. In the BELINDA study, Bishop et al. compared tisagenlecleucel (N=162) to ASCT (N=160) but observed no differences in complete response rates or event-free survival (HR 1.07; p=0.69). Like their pivotal Juliet trial, impending organ-compromising disease was not an exclusion criterion and bridging chemotherapy was allowed. Although 83% of patients received bridging therapy, 42 (26%) had progressive disease before CAR-T-cell infusion, but unlike the pivotal trial, they were not excluded from CAR-T cell infusion and were included in the final analysis.

How do we weigh these factors in assessing the disparate outcomes of these trials and their application across all patients with relapsed or refractory LBCL? First, the fact that ZUMA-7 did not allow bridging chemotherapy introduces a significant enrollment bias against patients with rapidly progressing or bulky disease as the protocol specifically excluded patients with a “requirement for urgent therapy due to tumor mass effects.” Previous studies show that patients who require systemic bridging therapy have a worse outcome than those who require no bridging therapy as this is a surrogate for more advanced and/or aggressive disease.¹⁰ Further, in the ZUMA-7 study, 36% of patients proceeded to ASCT compared to 33% of patients in BELINDA. Yet, one might have expected more patients on the BELINDA trial to have received ASCT since the study design allowed two salvage chemotherapy regimens while the ZUMA-7 study did not, suggesting that patients on the BELINDA study had a worse prognosis. Finally, only 7% of the patients on ZUMA-7 had activated B-cell genotype (ABC) LBCL, which further suggests skewed enrollment and may reflect the association of ABC LBCL with older patients and possibly more rapidly progressive disease.

The ZUMA-7 study clearly demonstrates that ASCT-eligible patients with relapsed or refractory LBCL whose disease is controllable with glucocorticoid bridging therapy alone should be prioritized for axicabtagene ciloleucel over ASCT as second-line therapy. The rapid processing and turnaround time for axicabtagene ciloleucel may have also contributed to the favorable clinical outcomes in ZUMA-7. The BELINDA study, however, demonstrates that it is premature to conclude that CAR-T-cell therapy is superior for all ASCT-eligible LBCL patients, particularly those with bulky and/or rapidly progressing disease that requires more aggressive bridging chemotherapy. Indeed, the factors that drive the “curative” potential of CAR-T-cell therapy may be fundamentally different than the factors that drive outcomes with ASCT, which are predominantly related to chemotherapy sensitivity. While chemotherapy sensitivity appears to have less influence on CAR-T efficacy, the presence of bulky and/or rapidly progressing disease may well be major barriers to successful outcomes with CAR-T cells. It is important to be clear about what the data show and what they do not show. Concluding that axicabtagene ciloleucel must be superior to tisagenlecleucel is the wrong inference from the data. The selection of suitable patients for the application of CAR-T cells is important. What has been learned is that not all “relapsed/refractory LBCL” patients are the same. Assessment of the various CAR-T constructs will require comparisons in comparable groups of patients. Neither study sheds any light on the important issues of the mechanism of resistance, the failure of persistent cells to expand in the face of relapse, and their functional defects.