Poor clinical outcome of relapsed/refractory diffuse large B-cell lymphoma with MYC translocation treated with polatuzumab vedotin, bendamustine, and rituximab

SHORT COMMUNICATION

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma (NHL) and is characterized by the proliferation of large B-cells.¹ R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard therapy for first-line treatment, and almost 60% of patients can be cured. However, almost 40% of patients relapse or are refractory to R-CHOP.² Until recently, salvage chemotherapy followed by autologous stem cell transplantation (ASCT) has been the standard therapy for young patients with relapsed/refractory (R/R) DLBCL,³ but the treatment strategy for R/R DLBCL has changed with the introduction of chimeric antigen receptor-T (CAR-T) cell therapy, which has resulted in improved survival in R/R DLBCL.^4-6 However, CAR-T cell therapy may not be realistic for patients over 70 years of age who are not indicated for ASCT. Thus, salvage chemotherapy is the only treatment option for patients over 70 years old, and salvage chemotherapy with greater efficacy and safety is required. Polatuzumab vedotin is a novel antibody–drug conjugate. It consists of a monoclonal antibody against CD79b, which is a B-cell receptor component located on normal B-cells that is covalently conjugated to monomethyl auristatin, a microtubule-disrupting anti-mitotic agent.⁷ Polatuzumab vedotin in combination with bendamustine and rituximab (PBR) elicited a higher overall response rate (45% vs. 18%) and prolonged overall survival (OS) (12.4 vs. 4.7 months) in R/R DLBCL patients compared to patients who received bendamustine and rituximab (BR) in a phase 2 study.⁸ In Japan, PBR was approved for the treatment of adult patients with R/R DLBCL in March 2021. Although early phase studies of PBR were promising, there are still some unmet needs in elderly R/R DLBCL, and there is a lack of real-world PBR data in particular.

We conducted a retrospective observational study to collect real-world PBR data for R/R DLBCL. Consecutive patients with DLBCL who received salvage therapy with PBR between May 2021 and April 2023 at Oita Prefectural Hospital, Oita, Japan, were recruited. DLBCL was diagnosed according to the WHO classification revised fourth edition,¹ and a total of 26 patients were enrolled in the study. The response was determined according to the Lugano classification⁹ using computed tomography (CT) or ¹⁸F-fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT). Cell of origin (COO) was determined by immunohistochemical findings according to the Hans criteria.¹⁰ Overall response was defined as achievement of partial response (PR) or complete response (CR) at the end of treatment (EOT). Adverse events were evaluated by CTCAE Ver5.0. Survival probabilities were estimated by the Kaplan–Meier method. OS was calculated from the date of start of PBR to the date of death or last follow-up. Progression-free survival (PFS) was calculated from the date of start of PBR to the date of relapse, or death from any cause. Factors affecting OS and PFS were analyzed using the log-rank test in univariate analyses and the Cox proportional hazard model in multivariate analyses. The following variables were considered in the analyses of prognostic factors: age (<70 years vs. ≥70 years), National Comprehensive Cancer Network international prognostic index (NCCN-IPI) (low / low intermediate vs. high intermediate / high), prior therapy lines (<3 lines vs. ≥3 lines), primary refractory (non-refractory vs. refractory), COO (germinal center B-cell (GCB) vs. non-GCB), and MYC translocation (negative / unavailable vs. positive). Variables with p values of <0.1 in univariate analyses were entered into multivariate analyses. For all analyses, p values were two sided, and p<0.05 was considered statistically significant. All statistical analyses were performed with EZR software.¹¹ This study was approved by the ethics review board of Oita Prefectural Hospital, and patients’ informed consent was obtained in the form of opt-out on the website.

Median age at the start of PBR was 75 years (range, 58–82 years), and 11/26 patients were male (42.3%). The subtypes of DLBCL were as follows: de-novo DLBCL, not otherwise specified (NOS) (n=18), double-hit lymphoma (n=1), intravascular large B-cell lymphoma (n=1), histological transformation from indolent B-cell lymphoma (n=5), and a metachronous DLBCL and peripheral T-cell lymphoma, NOS (n=1). The patient with metachronous DLBCL and PTCL-NOS had a history of PTCL-NOS, which was in remission at the time of DLBCL relapse. The median serum lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R) levels were 271 U/L (range, 142–1983 U/L) and 1165 U/mL (range, 403–6870 U/mL), respectively. In evaluation of COO, 14/26 (53.8%) of the patients showed GCB, 11/26 (42.3%) showed non-GCB, and one had no available data. IGH-MYC translocations were analyzed using the G-banding method or fluorescence in situ hybridization (FISH) in 16 patients, and 3 of 16 patients were positive for IGH-MYC translocations. The patients were pretreated with a median of one line (range, 1–7) prior to PBR treatment, and showed NCCN-IPI at the start of PBR, as follows: low 6/26 (23.1%), low intermediate 4/26 (15.3%), high intermediate 7/26 (26.9%), and high 9/26 (34.6%). The median observation period was 6.5 months (range, 1.9–19.7 months), and the median course of PBR was four courses (range, 1–6). Ten patients (38.4%) completed 6 courses of PBR, and 3 patients were still continuing PBR at the last observation of this study. Thirteen patients discontinued PBR for the following reasons: bridging to CAR-T (n=2), hematologic toxicity (n=2), debility (n=3), infection (n=2), and progression of lymphoma (n=4). No patient received stem cell transplantation after PBR. Polatuzumab vedotin and rituximab were administered in standard doses without dose reduction, but the bendamustine dose was reduced in 15/26 (57.6%) of patients due to older age, cytopenia, or infection during the course of treatment. Prophylaxis for infection consisted of sulfamethoxazole/trimethoprim or atovaquone for pneumocystis pneumonia in 100% (26/26), and acyclovir for herpes zoster in 96.1% (25/26). Adverse events of grade 3 to 5 were lymphopenia 23/26 (88.4%), neutropenia 16/26 (61.5%), anemia 10/26 (38.4%), thrombocytopenia 9/26 (38.4%), cytomegalovirus (CMV) reactivation 5/26 (19.2%), and other viral infections (COVID-19, n=1; herpes zoster, n=1) 2/26 (7.6%). No symptomatic diseases due to CMV were observed in 5 patients with CMV reactivation, and herpes zoster developed in 1 patient without acyclovir prophylaxis. One grade 5 adverse event was observed (COVID-19 pneumonia). In an evaluation of 21 patients, excluding 3 patients under treatment and 2 patients unavailable for treatment evaluation, the overall response rate at EOT and best response rates were 12/21 (57.1%) (CR 11/21 (52.3%) and PR 1/21 (4.7%)) and 15/21 (71.4%) (CR 11/21 (52.3%) and PR 4/21 (19%)), respectively. The survival rate at 12 months and the median duration of survival from the start of PBR were 59.7% and 14 months (95% confidence interval (CI), 6.4–NA) in OS, and 44.9% and 9.6 months (95% CI, 4.7–NA) in PFS, respectively. The results of univariate and multivariate analyses for survival are shown in Table 1. Univariate analysis identified statistically significant differences in NCCN-IPI and MYC translocation for OS and PFS. Multivariate analyses revealed that MYC translocation was an independent significant adverse factor for OS (hazard ratio (HR): 5.87, 95%CI: 1.12–30.75, p=0.035). The clinical data of 3 patients with MYC translocation are listed in Table 2. The disease types of the 3 patients were MYC/BCL2 with recurrent follicular lymphoma histological transformation, primary refractory MYC/BCL6 positive DLBCL, and non-GCB DLBCL that identified positive for MYC at recurrence. Only 1 of the 3 patients responded to PBR, and median OS after PBR was 4.1 months [range, 1.9–6.4 months].

Table 1. Univariate and multivariate analyses of overall survival and progression-free survival.

		OS				PFS
		Univariate		Multivariate		Univariate		Multivariate
	N=26	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Age
<70 years	11	Reference	0.17	-	-	Reference	0.081	Reference	0.30
≥70 years	15	2.81 (0.58–13.59)		-		3.55 (0.76–16.52)		2.38 (0.45–12.51)
NCCN-IPI
Low / LI	10	Reference	0.033	Reference	0.14	Reference	0.042	Reference	0.11
HI / High	16	6.98 (0.86–56.38)		4.92 (0.56–42.73)		4.41 (0.92–21.14)		3.88 (0.71–21.09)
Prior lines of chemotherapy
<3 lines	19	Reference	0.93	-	-	Reference	0.63	-	-
≥3 lines	7	0.93 (0.19–4.52)		-		0.69 (0.14–3.23)		-
Primary refractory
Non-refractory	21	Reference	0.24	-	-	Reference	0.068	Reference	0.058
Refractory	5	2.21 (0.55–8.87)		-		2.96 (0.86–10.20)		3.58 (0.95–13.48)
Cell of origin
GCB	14	Reference	0.50	-	-	Reference	0.80	-	-
Non-GCB	11	0.62 (0.14–2.60)		-		1.17 (0.33–4.07)		-
MYC translocation
Negative / unavailable	23	Reference	<0.001	Reference	0.035	Reference	0.002	Reference	0.098
Positive	3	9.73 (1.93–49.04)		5.87 (1.12–30.75)		7.41 (1.62–33.80)		4.02 (0.77–20.98)

HR, hazard ratio; 95%CI, 95% confidence interval; NCCN-IPI, National Comprehensive Cancer Network international prognostic index; LI, low intermediate; HI, high intermediate; GCB, germinal center B-cell.

Table 2. Characteristics, treatments, responses, and outcomes in three patients with MYC translocation.

	Age/sex	Histological subtype	Assessment of MYC translocation	NCCN-IPI at PBR	Relapse/refractory	Prior lines of chemotherapy	Course of PBR	Best response of PBR	Survival from start of PBR (months)	Outcome	Cause of death
1	74/M	DLBCL-NOS	G-banding*1	High intermediate	Relapsed	2	6	SD	6.4	Died	Lymphoma
2	78/M	DLBCL transformed of FL	G-banding*2 and FISH	High	Relapsed	2	4	PR	4.1	Died	Lymphoma
3	77/F	HGBCL with MYC and BCL6 translocation	G-banding*3 and FISH	High	Primary refractory	3	3	PD	1.9	Died	Lymphoma

DLBCL-NOS, diffuse large B-cell lymphoma-not otherwise specified; FL, follicular lymphoma; HGBCL, high-grade B-cell lymphoma; NCCN-IPI, National Comprehensive Cancer Network international prognostic index; FISH, fluorescence in situ hybridization; PBR, polatuzumab vedotin/bendamustine/rituximab; SD, stable disease; PD, progressive disease.

*¹: 50, X, -Y, -1, add(1)(q32), del(6)(q?), +add(7)(q22), t(8;14)(q24;q32), +del(9)(q?), del(13)(q?), del(15)(q?), add(16)(q11.2), +18, add(18)(p11.2)x2, +der(?)t(?;1)(?;q21), +mar1x2; *²: 48, XY, del(6)(q?), +8, der(8)t(8;14)(q24;q32)x2, add(10)(q22), del(11)(q?), add(12)(p11.2), add(14)(q32), +mar1; *³: 78, XXX, +X, der(1)(qter→q21::p36.1→qter)x2, add(3)(q27), ?t(3;14)(q27;q32), +5, +6, ?t(8;14)(q24;q32)x2, -9, +13, +16, add(16)(q12.1)x2, +17, -18, +21, +22, +3mar.

In the GO29365 study, PBR resulted in a significantly higher CR rate and reduced risk of death in patients with transplantation-ineligible R/R DLBCL, compared with BR.⁸ In our retrospective study, the results of overall response rate and survival closely approximated those of the GO29365 study and other several reports of PBR for R/R DLBCL in real-world practice.^12-15 PBR is an effective treatment option for elderly patients with R/R DLBCL; however, the present patients with MYC-translocation-positive DLBCL had significantly poor survival. The pooled PBR cohort in the GO29365 study included few cases of DLBCL with MYC translocation (Burkitt lymphoma [n = 1, 1%] and high-grade B-cell lymphoma with MYC and BCL2, and/or BCL6 translocation [n = 5, 5%]). In the largest scale real-world study that included 14/133 (10.5%) patients with double-hit or triple-hit DLBCL, the best response to PBR was reported to be 38.5%, which was inferior to the best response of whole cohort (57.0%), refractory to most recent treatment (44.2%), or transformed lymphoma (70.0%) groups.¹⁵ These data suggest an important unmet need in elderly patients with MYC-translocation-positive R/R DLBCL who cannot receive intensive treatment.

There are some serious limitations of our study, including the small sample size, short observation period, and retrospective nature of the study. In addition, as MYC translocation was not evaluated in all patients, the incidence of MYC-translocation-positive DLBCL may have been underestimated in this study. Validation of the present results in analysis that includes a larger number of patients is necessary to enable further development of new treatment options for MYC-translocation-positive DLBCL.