Patients with classical Hodgkin lymphoma experiencing disease progression after treatment with brentuximab vedotin have poor outcomes

Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease such as PD-1 inhibitors.

Abstract

Background

Brentuximab vedotin (BV) is a key therapeutic agent for patients with relapsed/refractory classical Hodgkin lymphoma (cHL). The outcomes of patients experiencing disease progression after BV are poorly described.

Patients and methods

We reviewed our institutional database to identify patients with cHL treated with BV who were either refractory to treatment or experienced disease relapse. We collected clinicopathologic features, treatment details at progression and outcome.

Results

One hundred patients met inclusion criteria, with a median age of 32 years (range 18–84) at progression after BV. The median number of treatments before BV was 3 (range 0–9); 71 had prior autologous stem cell transplant. The overall response rate (ORR) to BV was 57%, and the median duration of BV therapy was 3 months (range 1–25). After disease progression post-BV, the most common treatment strategies were investigational agents (n = 30), gemcitabine (n = 15) and bendamustine (n = 12). The cumulative ORR to therapy was 33% (complete response 15%). After a median follow-up of 25 months (range 1–74), the median progression-free (PFS) and overall survival (OS) were 3.5 and 25.2 months, respectively. In multivariate analysis, no factors analyzed were predictive of PFS; age at progression >45 years and serum albumin <40 g/l at disease progression were associated with increased risk of death. Among patients who achieved response to therapy, allogeneic stem cell transplantation was associated with a non-significant trend toward superior OS (P = 0.11).

Conclusions

Patients with BV-resistant cHL have poor outcomes. These data serve as a reference for newer agents active in BV-resistant disease.

introduction

Classical Hodgkin lymphoma (cHL) is now considered as one of the hematologic malignancies with among the most favorable outcomes. However, a substantial minority of patients are not cured with primary therapy [1]. Up to half of such patients may be cured with high-dose therapy and autologous stem cell transplantation (ASCT) [2, 3]. Before the development of targeted therapies, patients experiencing disease progression following ASCT had a poor prognosis, with a median post-progression survival of 1.3 years [4]. Multiagent chemotherapy regimens such as gemcitabine, vinorelbine and liposomal doxorubicin result in an ORR of 72%–75% in patients with HL and relapse post-ASCT [5, 6]. Brentuximab vedotin (BV) is an antibody–drug conjugate (ADC), comprising an anti-CD30 monoclonal antibody joined via a protease cleavable linker with the spindle inhibitor monomethyl aurostatin E (MMAE) [7]. CD30 is expressed on Hodgkin/Reed-Sternberg cells, and following binding of the ADC, MMAE is cleaved, undergoes endocytosis and results in microtubule disruption, cell cycle arrest and ultimately apoptosis [8]. BV has substantial activity in patients with cHL who experience disease relapse after ASCT [9] or allogeneic stem cell transplantation (alloSCT) [10], with result from a recent randomized study indicating a progression-free survival (PFS) benefit in patients treated with BV as consolidation post-ASCT [11]. However, the outcomes of patients who experience disease progression after treatment with BV are not well described. The purpose of this study was to analyze the characteristics, subsequent therapies and clinical outcomes of this population to provide a reference point for phase II studies evaluating emerging therapies in BV-treated patients.

patients and methods

We reviewed our institutional databases to identify patients treated with BV at MD Anderson Cancer Center (MDACC) between June 2007 and January 2015. The inclusion criteria for this study were: (i) histologically confirmed diagnosis of cHL, (ii) treatment with BV for relapsed HL and (iii) subsequent disease progression at any time after treatment with BV. Patients' treated with BV as part of frontline HL therapy was excluded. The individual treating clinician determined post-progression treatment strategy in each case. Using electronic medical records, we collected baseline demographic and clinical features (sex, age, stage, the presence of constitutional symptoms, histologic subtype, hemoglobin, absolute lymphocyte count, white cell count, serum albumin, Eastern Cooperative Oncology Group performance status, presence of extranodal involvement and diameter of largest tumor) at diagnosis and at the time of post-BV progression. We collected the following data regarding prior treatment: chemotherapy regimen, use of radiotherapy, response and PFS to initial HL therapy, ASCT or alloSCT before BV and the outcome of last treatment before BV. We collected the following data in regard to BV therapy: median interval from HL diagnosis to commencing treatment, dose and schedule, number of cycles and duration of therapy, best response and post-BV PFS. At the time of progression post-BV, in addition to the clinical and laboratory factors mentioned above, we collected largest tumor diameter at progression and details regarding tissue biopsy including CD30 expression. Finally, we collected details regarding post-progression treatment including number and types of subsequent treatments, responses and survival data. Treatment responses were determined according to the 2014 Lugano Classification [12]. The Institutional Review Board of MD Anderson Cancer Center approved the study.

statistical analysis

The focus of this study was determining clinical outcomes (PFS and OS) following disease relapse after BV therapy. The secondary outcomes were analysis of the efficacy of subsequent therapeutic strategies and exploratory analysis of candidate prognostic factors for PFS and OS. The post-progression PFS and OS were defined as the time (in months) measured from date of confirmed disease relapse following BV to disease progression or death from any cause, and death from any cause, respectively. Unadjusted event time distributions were estimated using the method of Kaplan and Meier [13], and compared groups using the log-rank test. Cox proportional hazards model [14] was used to determine associations between candidate prognostic factors and post-progression PFS and OS. We employed a threshold for significance of P-value of <0.1 for inclusion in the multivariate analysis. Continuous variables were summarized using descriptive statistics such as median and range. Categorical variables were summarized using frequency tables and 95% confidence interval. The homogeneity of response rate across groups was tested using the χ² test. We used STATA version 12.1 (StataCorp, College Station, TX, USA) to perform all statistical analyses. P-values were two-sided and we considered values <0.05 to be significant.

results

baseline characteristics

We identified 97 patients meeting inclusion criteria for the study, with their baseline characteristics summarized in Table 1. Many patients received their initial treatment at other centers; hence, some clinical and laboratory data from this presentation are missing. The majority of patients had nodular sclerosing histology, stage III/IV disease and B symptoms at the time of initial diagnosis of HL. Most received ABVD initially, although a minority received a variety of other multiagent regimens containing alkylating agents ± anthracyclines. Approximately one-third of patients had lymphoma that was initially chemo-refractory. The median PFS to initial therapy was 10 months (range 0–106). At the time of second remission, ASCT was carried out in 66 (68%) patients and alloSCT in 4 (4%) patients. Of the remaining 27 patients who did not undergo consolidative transplant, the primary reason was failure to respond to therapy (n = 21, 75%), age or co-morbidities (n = 1, 4%), failed mobilization (n = 1, 4%), patient decision (n = 1, 4%), financial reasons (n = 1, 4%) or reason unknown (n = 2, 7%). The median PFS following initial stem cell transplant was 6.6 months (range 1–67); a further 10 patients underwent alloSCT after ASCT, but before treatment with BV. Thus, in total, 14 (14%) patients underwent alloSCT before receiving BV. Details regarding the outcome of the last therapy before BV were available in 84 patients, of whom 31 (36%) were refractory.

Table 1.

Baseline characteristics of patients before commencement of brentuximab vedotin

Characteristic (initial diagnosis)	Data	Result
Female	97	46 (47%)
Median age (range), years	97	28 (16–83)
Age >45		11 (11%)
Stage
1	97	2 (2%)
2		40 (43%)
3		23 (25%)
4		29 (31%)
B symptoms	94	55 (60%)
Histologic subtype
Nodular sclerosing	95	84 (88%)
Mixed cellularity		7 (7%)
Lymphocyte rich		1 (1%)
Unknown		3 (3%)
Hemoglobin <105 g/l	35	10 (29%)
Lymphocytes <0.6 × 109/l	33	4 (12%)
White cell count >15 × 109/l	34	11 (32%)
Albumin <40 g/l	31	19 (61%)
ECOG
0	61	51 (84%)
1		10 (16%)
Any extranodal site	80	22 (27%)
Max tumor bulk >10 cm	40	15 (37%)
International prognostic score
Good (0–1)	54	8 (15%)
Intermediate (2–3)		41 (76%)
High (4–7)		5 (9%)
Median prior lines of therapy (range)	94	3 (0–9)
Initial chemotherapy
ABVD	97	81 (84%)
AVD		4 (4%)
Other		11 (11%)
Initial radiotherapy	97	28 (29%)
Response to frontline therapy
CR	93	33 (35%)
PR		28 (30%)
SD		10 (11%)
PD		22 (24%)

ECOG, Eastern Cooperative Oncology Group; SCT, stem cell transplant; BV, brentuximab vedotin; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; ABVD, doxorubicin, bleomycin, vinblastine and dacarbazine; AVD, doxorubicin, vinblastine, dacarbazine.

BV treatment details

The median interval from initial diagnosis to commencing BV was 2.7 (range 0.6–27.1) years. BV was administered as a single agent in 95 (95%) of patients. It was given as second, third, fourth and fifth or later line of therapy in 4 (4%), 18 (18%), 33 (33%), 18 (18%) and 24 (24%), respectively. The median number of cycles of BV administered was 4 (range 2–27). Among 90 patients who received BV as a single agent and underwent formal response assessment, the overall response rate (ORR) to BV was 56%, whereas 44% were BV refractory (‘primary BV resistance’). The main reason for discontinuation of BV was disease progression (n = 76, 78%); 10 patients (10%) electively discontinued BV in remission order to receive stem cell transplantation, 4 (4%) due to toxicities (neuropathy [n = 2], thrombocytopenia [n = 1] and unspecified [n = 1]), 4 (4%) due to patient decision and 3 (3%) for other reasons, including the end of treatment protocol (n = 2) and loss of insurance (n = 1).

characteristics, treatment and outcomes at post-BV progression

The characteristics of patients at the time of documented disease progression following BV therapy are presented in Table 2. Only a minority of patients underwent lymph node biopsy at disease progression; however, among those, CD30 staining by immunohistochemistry on Reed-Sternberg cells was present in 14/18 (78%) of biopsies. Data regarding treatment at disease progression following BV were available in 83 patients. Four received no treatment, due to poor performance status and/or patient decision. The response rates among the 79 patients who received treatment are summarized in Table 3. The most common approach was enrollment on to clinical trial protocols. The ORR among patients treated with gemcitabine- and bendamustine-based regimens was numerically greater than other approaches; however, this difference was not significant (P = 0.64). In intention-to-treat analysis, the net ORR for treatment strategies immediately after BV was 34% [complete response (CR) 15%]. After a median observation period of 25 months (range 1–76) post-BV progression, 65 patients have experienced disease progression or died with a median PFS of 3.5 months, with no patients sustaining remission beyond 18 months (Figure 1A). Forty-six patients have died due to lymphoma (n = 18, 39%), unknown cause (n = 18, 39%), sepsis (n = 7, 15%), therapy-related acute myeloid leukemia (n = 1, 2%), respiratory failure from infection and pulmonary embolism (n = 1, 2%) and motor vehicle accident (n = 1, 2%), with a median OS of 25.2 months (Figure 1B). In univariate analysis, the type of therapy did not significantly impact on OS (Table 3). However, patients who received no treatment of post-BV progression had markedly increased risk of death (hazard ratio [HR] 17.2 [95% CI 3.5–85.2], P < 0.001).

Table 2.

Disease characteristics of patients at the time of documented progression following therapy with brentuximab vedotin

Characteristic at progression post-BV	With data	Result
Median age (range), years	89	32 (18–84)
Age >45		14 (14%)
Stage	84
1		2 (3%)
2		25 (30%)
3		18 (21%)
4		39 (46%)
B symptoms	86	7 (8%)
Hemoglobin <105 g/l	51	18 (35%)
Lymphocytes <0.6 × 109/l	46	19 (41%)
White cell count >15 × 109/l	82	4 (5%)
Albumin <40 g/l	82	23 (28%)
ECOG	81
0		33 (41%)
1		44 (54%)
2		3 (4%)
3		1 (1%)
Any extranodal site	88	31 (35%)
Disease progression during BV therapy	97	72 (74%)
Disease progression after BV diagnosed by imaging	92	92 (100%)
Maximum tumor diameter ≥4 cm	69	18 (26%)
Biopsy carried out	88	18 (20%)
Biopsy CD30 positive by immunohistochemistry	18	14 (78%)
Median number of treatments after BV	86	2 (0–8)

ECOG, Eastern Cooperative Oncology Group; SCT, stem cell transplant; BV, brentuximab vedotin.

Table 3.

Responses to therapy at disease progression following brentuximab vedotin

Treatment	n	Eval	CR (%)	PR (%)	ORR (%)	mPFS (months)	mOS (months)
Investigational agent	28	28	4 (14)	3 (11)	7 (25)	2.4	47.7
Gemcitabine	15	12	4 (27)	4 (27)	8 (53)	2.1	NR
Bendamustine	12	11	2 (17)	4 (33)	6 (50)	3.7	34.0
Other alkylator	6	4	1 (17)	1 (17)	2 (33)	5.0	9.5
BV retreatment	6	4	0 (0)	2 (33)	2 (33)	3.5	10.4
Platinum based	4	4	0 (0)	1 (25)	1 (25)	0.9	25.2
ASCT	3	3	1 (33)	0 (0)	1 (33)	a	11.9
Other	5	1	0 (0)	0 (0)	0 (0)	a	24.9
Total	79	67 (85)	12 (15)	15 (19)	27 (34)	3.5	25.2

Patients in whom no response was recorded were considered not to have responded. Five patients were not treated and were excluded for response analysis.

^aToo few observations to allow the estimate of PFS.

P = 0.61 for difference in response rates between groups (χ²).

BV, brentuximab vedotin; ASCT, autologous stem cell transplant; eval, evaluated; CR, complete response; PR, partial response; ORR, overall response rate; mPFS, median progression-free survival; mOS: median overall survival.

Figure 1.

(A) Progression-free survival and (B) overall survival from the date of documented disease progression following treatment with brentuximab vedotin (all patients). Overall survival from the time of progression post-BV according to the consolidation strategy, (C) among all patients, irrespective of response and (D) among patients achieving a response to initial salvage therapy only. OS, overall survival; PFS, progression-free survival; auto, autologous stem cell transplant; allo, allogeneic stem cell transplantation; BV, brentuximab vedotin.

Following therapy on post-BV disease progression, 26 patients (all of whom achieved responses) underwent consolidative stem cell transplantation: autologous in 8, at a median of 9 (range 1–15) months post-BV progression and allogeneic in 18 patients, a median of 6 (range 1–10) months post-BV progression. None of the 8 patients consolidated with ASCT had previously undergone a high-dose procedure, whereas 17 patients receiving alloSCT had previously undergone ASCT. Of those patients with sufficiently detailed follow-up data available, post-transplant progression was observed in 3 of 4 (75%) of patients consolidated with ASCT and 6 of 13 (46%) patients consolidated with alloSCT. After a median observation period of 30 (range 20–69) months post-transplant, the 2-year OS rates from the date of transplant were 69% (95% CI 21%–91%) and 93% (95% CI 61%–99%) of patients following ASCT and alloSCT, respectively. Considering all patients irrespective of response, consolidation with alloSCT was associated with reduced risk of death compared with those patients not receiving any transplant (HR 0.07 [95% CI 0.01–0.49], P = 0.008). Among patients who received ASCT, the improvement in OS was non-significant (HR 0.34 [95% CI 0.08–1.43], P = 0.14, Figure 1C). However, when restricting analysis only to patients who achieved a response to post-BV therapy among those who achieved a response to initial therapy, alloSCT was associated with a non-significant trend toward benefit in OS (HR 0.17 [95% CI 0.02–1.44], P = 0.11, Figure 1D).

An analysis of candidate prognostic factors for their relationship to PFS and OS post-BV is provided in Table 4. Having received ≥4 prior treatments before BV and primary (versus secondary) BV resistance were adversely prognostic for PFS; however, neither factor remained significant by multivariate analysis. The duration of BV treatment <3 months, serum albumin <40 g/l and age >45 years (both measured at the time of documented disease progression post-BV) were associated with inferior OS by univariate analysis; only age >45 and albumin <40 g/l retained association with inferior OS by multivariate analysis.

Table 4.

Cox proportional hazard ratios for association between listed candidate factors, progression-free and overall survival

Candidate factor	PFS				OS
	Univariate		Multivariate		Univariate		Multivariate
	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value	HR (95% CI)	P-value
Before commencing BV
No prior treatments ≥4	0.53 (0.28–1.01)	0.06	0.65 (0.31–1.34)	0.24	1.59 (0.87–2.87)	0.13	–	–
Duration of BV therapy <3 months	1.37 (0.75–2.47)	0.31	–	–	1.86 (1.00–3.48)	0.05	1.78 (0.92–3.44)	0.08
BV refractory	2.18 (1.13–4.18)	0.02	1.75 (0.84–3.67)	0.13	1.13 (0.62–2.07)	0.70	–	–
At progression post-BV
Age >45	1.00 (0.48–2.10)	0.98	–	–	2.29 (1.15–4.57)	0.02	2.14 (1.04–4.44)	0.04
Albumin <40 g/l	1.74 (0.82–3.68)	0.14	–	–	3.24 (1.67–6.29)	0.001	3.16 (1.51–6.62)	0.002
Hemoglobin <105 g/l	1.95 (0.78–4.85)	0.14	–	–	1.79 (0.81–3.96)	0.15	–	–
Lymphocyte count <0.6 × 109/l	1.89 (0.73–4.93)	0.19	–	–	2.01 (0.90–4.52)	0.09	1.07 (0.44–2.64)	0.88
White cell count >15 × 109/l	1.32 (0.46–3.77)	0.60	–	–	0.44 (0.06–3.24)	0.42	–	–
Largest tumor diameter >4 cm	1.00 (0.46–2.13)	0.99	–	–	1.25 (0.61–2.55)	0.54	–	–
Any extranodal site	0.84 (0.46–1.56)	0.59	–	–	0.91 (0.48–1.73)	0.78	–	–

Bold type indicates variables that were significantly associated with either PFS or OS in multivariate analysis.

BV, brentuximab vedotin; PFS, progression-free survival; OS, overall survival.

discussion

Our study highlights the persistent challenge of achieving durable disease control in patients with relapsed/refractory cHL following failure of BV therapy. The median PFS was only 3.5 months. Irrespective of the choice of post-BV treatment regimen, no patients remained in remission for 18 months after initiation of therapy. We were unable to identify prognostic factors associated with PFS. Due to heterogeneous post-BV treatments and relatively small numbers within each treatment subgroups, we are unable to comment meaningfully on their relative efficacy. Prospective trials in this patient population are required to address this question more systemically. Zinzani et al. [15] described a multi-institutional observational series of 27 patients treated with bendamustine, which resulted in an ORR of 56% and median duration of response (DOR) of 5 months. Gemcitabine-based regimens have activity of 41%–68% in relapsed/refractory BV-naïve cHL [16, 17] and based on our data, the ORR appears similar in BV-treated patients. Around one-third of patients in our study were treated on clinical trials at the time of disease progression after BV therapy, reflective of the academic focus of our institution. However, many patients seen at our center are both willing and able to travel long distances, and thus are not necessarily reflective of community practice. This selection bias somewhat limits the generalizability of our findings, and outcomes among patients with BV-resistant disease outside academic centers may be less favorable. The time period studied included brief overlap with the availability of programmed cell death-1 (PD-1) inhibitors on investigational protocols at our center. These agents have promising clinical activity. The IgG4 PD-1 blocking monoclonal antibody nivolumab was evaluated in a phase I study that included 23 patients with heavily pretreated cHL, of whom 78% were enrolled after ASCT, 78% received previous BV and 65% received ≥4 lines of therapy [18]. The ORR was 87% (CR 26%) and the median OS was not reached; in results that were recently updated, with a median of 86 weeks of observation, responses have allowed five patients to pursue alloSCT and 7 of 10 patients electing not to pursue transplant benefited from remission duration >1 year [19]. Another humanized PD-1 monoclonal antibody, pembrolizumab, was explored in the phase Ib KEYNOTE-013 study that pre-specified prior treatment with BV as an inclusion criterion [20]. Among the 31 patients enrolled, 68% had received >4 prior lines of therapy and 71% had received prior ASCT. In updated results, the ORR was 65% (CR 16%) and after a median follow-up of 9.7 months, the median DOR had not been reached [20]. It is apparent that both of these agents will substantially alter the prognosis of patients who are resistant to BV. However, at the time of writing both agents remain investigational, with phase II registrational studies for both nivolumab (NCT02181738) and pembrolizumab (NCT02453594) in relapsed/refractory cHL ongoing. Our data will serve as a useful reference point for these pivotal trials and other future novel agents.

It is noteworthy that once patients experienced disease progression following BV treatment, we did not find evidence of an association between prior BV response, the number of therapies before BV or duration of BV therapy and either PFS or OS. The only pretreatment variables associated with the outcome were age >45 at disease progression and hypoalbuminemia. Both factors are unsurprising and serve as de facto ‘global’ markers of patient comorbidity and fitness for subsequent therapies, and are independently associated with inferior OS in treatment-naïve advanced stage patients with cHL (forming part of the International Prognostic Score) [21]. The role of consolidative transplant after subsequent therapy merits further discussion. AlloSCT was the more common approach as the majority of patients had already received ASCT before BV therapy. We observed marked heterogeneity in outcomes, with relatively favorable results among the minority of patients who underwent consolidative alloSCT. The 2-year OS of 93% post-transplant are encouraging in the context of the poor outcomes among patients who did not undergo consolidation. However, these data have numerous caveats, including retrospective study design, limited cohort size, and the presence of both selection and guarantee time bias. We attempted to deal with selection bias by restricting analysis to patients achieving response to initial therapy. Although we are unable to conclusively demonstrate a survival benefit in favor of alloSCT, given the short PFS observed irrespective of treatment regimen, among transplant candidates who respond to therapy and have an available stem cell source, our data suggest that the approach is still worth considering, particular if access to newer agents on investigational protocols is limited. The role of alloSCT in BV-resistant patients should ideally be explored in prospective clinical trials and may still be an option in patients achieving responses to PD-1 inhibitors after BV failure [19].

In the 20% of patients who underwent confirmatory biopsy at time of imaging-detected disease progression, CD30 expression by immunohistochemistry persisted in 78% of samples, indicating that CD30 down-regulation may not be the major mechanism of BV resistance. These results are consistent with those reported by Chen et al. [22], who reviewed tissue biopsies in 10 patients with cHL that progressed after BV therapy and found CD30 expression to be retained. Based on their analysis of in vitro and patient samples, they concluded that acquired resistance to MMAE and multi-drug resistance-1 up-regulation may play more important roles in resistance to BV therapy. Further bedside-to-bench studies are needed to better understand the precise mechanism of primary and secondary BV resistance, as other ADCs incorporating MMAE (such as polatuzumab vedotin) are in clinical development [23].

conclusion

Patients with BV-resistant cHL have poor outcomes, with brief disease control and a median OS post-BV progression of ∼2 years. These data serve as a comparator for newer agents active in BV-resistant disease.

funding

None declared.

disclosure

CYC, DC, AS, SH, YO, SZ, NHF, JER, FT, FBH, LEF, JRW, MW, LJN, SSN, FS, MAR, PA and YN have declared no conflicts of interest. MAF received research funding and honoraria and is a member of advisory board in Seattle Genetics, received research funding and honoraria from Takeda, and received research funding and is a member of advisory boards in from BMS and MERCK.