Abstract
Treatment-specific responses and comprehensive disease characteristics are limited in black patients with cutaneous T-cell lymphoma (CTCL). These shortcomings prompted us to perform a subgroup analysis of black patients enrolled in the MAVORIC trial — an international, randomized, phase 3 trial comparing mogamulizumab vs. vorinostat in relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). Ten percent (N=37) of the entire MAVORIC population (N=372) identified as black. Significant clinical differences in black patients when compared to non-black patients included a younger median age at enrollment (53 vs. 66 years; P<0.001), an increased frequency of MF as opposed to SS (73% vs. 52.8%; P<0.001), and higher rates of earlier-stage disease (IB-IIA) at enrollment (37.8% vs. 21.2%; P=0.022). Mogamulizumab offered similar response rates and progression-free survival in black patients (7.57 months) compared to the entire MAVORIC population (7.7 months) and associated with a similar safety profile.
Introduction:
Cutaneous T-cell lymphomas (CTCL) are rare lymphoid neoplasms originating from skin-homing or skin-resident mature T-cells. Mycosis fungoides (MF) is the most common CTCL (≈50%), and initially has an indolent course, often requiring only skin directed therapies (1). Sézary syndrome (SS) is an even more rare (≈2%), aggressive, leukemic form of CTCL associated with lymphadenopathy, erythroderma, and intractable pruritus (2–4). Patients with advanced stage MF or SS have aggressive disease and poor survival, with few effective treatment options; although, two new drugs were recently approved and several more are in clinical development (5–7). The only curative therapy for MF and SS is an allogeneic stem cell transplant (8).
The incidence of CTCL in the United States is approximately 7 cases per million person-years with a median age at diagnosis of 55–60 years and a male predominance (M:F ratio 1.5) (3, 4, 9). The incidence of CTCL, particularly MF, is higher in black patients with a black-white incidence rate ratio of 1.5 (3, 9). Additionally, disease characteristics and outcomes in black patients with CTCL differ from non-black patients, including a younger age at diagnosis, a lower male to female ratio, and a higher cutaneous disease burden at diagnosis (9, 10). Several retrospective single institution and population-based studies suggest that black patients with MF have an inferior survival, compared to non-blacks, although other reports did not find a similar inferiority (9–17). Nonetheless, data regarding the comparative efficacy of both skin-directed and systemic therapies for CTCL in black vs. non-black patients are exceedingly rare, and no prospective dataset has been published (16, 17). Mogamulizumab— a glycoengineered anti-CCR4 monoclonal antibody— was recently approved for relapsed/refractory (R/R) MF/SS with improved response rates and progression-free survival (PFS) compared to a standard of care treatment, vorinostat (7). Herein, we report the clinical characteristics and therapeutic outcomes of black patients treated in the MAVORIC trial.
Patients and Methods:
The MAVORIC trial was an international, open-label, randomized phase 3 trial comparing mogamulizumab vs. vorinostat in stage IB-IVB relapsed or refractory (R/R) MF and SS. The complete study design, enrollment criteria, and results have been previously published (7). Briefly, all patients had progressed or were intolerant to at least one prior systemic therapy. Patients with large cell transformation (LCT), a prior allogeneic stem cell transplant, active autoimmune disease, and CNS metastases were excluded. CCR4 expression was not a requirement. Patients were randomized 1:1 and stratified by both clinical stage (IB-II vs. III-IV) and disease type (MF vs. SS). Patients received either intravenous mogamulizumab 1.0 mg/kg on days 1, 8, 15, and 22 of cycle 1 and on days 1 and 15 of subsequent cycles or vorinostat 400 mg PO daily in 28-day cycles. Patients with a global complete response could continue treatment up to 12 months. The primary endpoint was progression-free survival (PFS) based on investigator assessment. Responses were assessed using a global composite response score comprising the skin, blood, lymph node, and visceral compartments (18). Key secondary endpoints included overall response rate (ORR), duration of response, and quality of life scores. We conducted a subset analysis on the black patients who were enrolled in the intention-to-treat population (ITT). All statistics were done using SAS version 9.3.
Results:
Patient characteristics
A total of 372 patients were enrolled in the MAVORIC trial of which 37 (10%) self-identified as black. The clinical characteristics of these 37 black patients are outlined in table 1 and are compared to non-black patients in table 2. Nearly twice as many black patients were randomized to the mogamulizumab arm (N=24; 64.8%) compared to the vorinostat control arm (N=13; 35.1%). Treatment arm randomization was more balanced for non-black patients (48.4% mogamulizumab, 51.6% vorinostat). There were no statistically significant differences in baseline characteristics between the two treatment arms (table 1). Notably, with respect to skin disease burden, a comparable fraction of black patients with T2, T3, and T4 were randomized to each treatment arm. Likewise, the percentages of black patients with blood and/or nodal involvement in each treatment arm were similar. Only two black patients, both enrolled on the mogamulizumab arm, had visceral involvement (stage IVB).
Table 1:
Clinical characteristics of black patients
| Mogamulizumab (N=24) | Vorinostat (N=13) | |
|---|---|---|
|
| ||
| Median age, years | 51.5 (25–78) | 57 (36–78) |
|
| ||
| Age group | ||
| <65 years, n (%) | 19 (79.2) | 12 (92.3) |
| ≥65 years, n (%) | 5 (20.8) | 1 (7.7) |
|
| ||
| Gender, n (%) | ||
| female | 10 (41.7) | 6 (46.2) |
| male | 14 (58.3) | 7 (53.8) |
|
| ||
| ECOG performance status, n (%) | ||
| 0 | 10 (41.7) | 8 (61.5) |
| 1 | 14 (58.3) | 5 (38.5) |
|
| ||
| Disease type, n (%) | ||
| Mycosis fungoides | 18 (75.0) | 9 (69.2) |
| Sézary syndrome | 6 (25.0) | 4 (30.8) |
|
| ||
| Clinical stage at enrollment, n (%) | ||
| IB-IIA | 9 (37.5) | 5 (38.5) |
| IIB-IVB | 15 (62.5) | 8 (61.5) |
|
| ||
| T-stage, n (%) | ||
| T2 | 11 (45.8) | 7 (53.9) |
| T3 | 3 (12.5) | 1 (7.7) |
| T4 | 10 (41.7) | 5 (38.5) |
|
| ||
| mSWAT score; median (range) | 97.5 (20.5–156.5) | 80 (17.4–105) |
|
| ||
| Blood involvement, n (%) | 18 (75.0) | 9 (69.2) |
|
| ||
| Nodal involvement, n (%) | 22 (91.7) | 10 (76.9) |
|
| ||
| Visceral involvement, n (%) | 2 (8.3) | 0 (0.0) |
|
| ||
| Prior systemic therapies, n (%) | ||
| Bexarotene | 19 (79.2) | 10 (76.9) |
| Methotrexate | 6 (25.0) | 2 (15.4) |
| Pralatrexate | 3 (12.5) | 1 (7.7) |
| Interferon | 8 (33.3) | 4 (30.8) |
| Brentuximab vedotin | 2 (8.3) | 0 (0.0) |
| Other chemotherapy | 4 (16.7) | 4 (30.8) |
Table 2:
Clinical characteristics of black patients compared to non-black patients
| Black patients (N=37) | Non-black patients (N=335) | P | |
|---|---|---|---|
|
| |||
| Median age, years | 53 (25–78) | 66 (25–101) | <0.001 |
|
| |||
| Age group | |||
| <65 years, n (%) | 31 (83.8) | 157 (46.9) | <0.001 |
| ≥65 years, n (%) | 6 (16.2) | 178 (53.1) | |
|
| |||
| Gender, n (%) | |||
| female | 16 (43.2) | 140 (41.8) | 0.865 |
| male | 21 (56.8) | 195 (58.2) | |
|
| |||
| Disease type, n (%) | |||
| Mycosis fungoides | 27 (73.0) | 177 (52.8) | 0.020 |
| Sézary syndrome | 10 (27.0) | 158 (47.2) | |
|
| |||
| Clinical stage at enrollment, n (%) | |||
| IB-IIA | 14 (37.8) | 71 (21.2) | 0.022 |
| IIB-IVB | 23 (62.2) | 264 (78.8) | |
The median age for black patients was 53 years (25–78) vs. 66 years (25–101) for the non-black patient cohort (P<0.001). Additionally, 83.8% of black patients were under the age of 65 years compared to only 46.9% of non-black patients (P<0.001). Twenty-one (57%) black patients were male. In terms of enrollment diagnosis, the fraction of black patients who entered the study with a diagnosis of MF (73%) was larger than that of non-black patients (52.8%), whereas a larger fraction of non-black patients had SS (42.7%) compared to black patients (27%) (P=0.020). With this, slightly more non-black patients were enrolled with advanced stage disease (IIB or greater) (78.8% for non-black patients vs. 62.2% for black patients) (P=0.022). Finally, the number of prior CTCL therapies between black patients and non-black patients and by treatment arm were similar. The median number of prior therapies for black patients randomized to mogamulizumab was 5.5 (2–19) vs. 5 (3–21) for vorinostat. The median number of prior lines of therapies for non-black patients randomized to mogamulizumab was 5 (1–25) vs. 5 (1–48) for vorinostat.
Efficacy
With a median duration of follow-up of 17 months for the entire MAVORIC ITT population, the primary endpoint of investigator-assessed PFS was superior in patients randomized to mogamulizumab (7.7 months; 95% CI 5.7–10.3) compared to vorinostat (3.1 months; 95% HR 0.53; CI 0.41–0.69, stratified log-rank P<0.0001). In a predefined investigator-assessed subgroup analysis, with a median follow up of 20.8 months, PFS favored mogamulizumab over vorinostat for black patients at 7.57 vs. 3.9 months, respectively (HR 0.81; 95% CI 0.33–1.96) (figure 1). This PFS benefit with mogamulizumab in black patients was also confirmed by independent review at 6.77 months vs. 2.97 months (HR 0.74; 95% CI 0.32–1.71).
Figure 1:
A: Investigator-assessed progression-free survival in black patients
B: Investigator-assessed progression-free survival in black patients and non-black patients
Response rates, including confirmed ORR, in black patients were also superior with mogamulizumab. Based on independent review and after adjusting for disease stage and geographical region of enrollment, the confirmed ORR was 25% (95% CI 9.8–46.7) with mogamulizumab and 0% (95% CI 0.0–24.7) with vorinostat (RR 25.0; 95% CI −2.3–46.7, P=0.0430). Representative waterfall plots of best global responses for black patients randomized to mogamulizumab or vorinostat are depicted in figure 2. These findings were comparable to the ORR seen in non-black patients and by investigator assessment (table 3). In the skin compartment, the confirmed ORR was 41.7% (95% CI 22.1–63.4) with mogamulizumab vs. 7.7% (95% CI 0.2–36) with vorinostat (RR 34.0, 0.1–57.5; P=0.0472). In the blood compartment, the confirmed ORR was 72.2% (95% CI 46.5–90.3) with mogamulizumab vs. 11.1% (95% CI 0.3–48.3) with vorinostat (RR 61.61, 95% CI 13.0–84.3; P=0.0092). Nodal responses in black patients were few in both treatment arms with only 2 (9.1%) patients in the mogamulizumab arm and 1 (10%) patient in the vorinostat arm having an objective response. None of the 2 patients with visceral disease in the mogamulizumab arm responded. Responses by compartment to mogamulizumab in non-black patients were similar (42% skin, 66% blood, 16.7% nodal). Finally, when analyzed by disease subtype (MF vs. SS), a higher ORR was seen in black patients randomized to mogamulizumab compared to vorinostat for both MF (38.9% vs. 11.1%, respectively) and SS (16.7% vs. 0%, respectively).
Figure 2:
A: Best global response with mogamulizumab in black patients
B: Best global response with vorinostat in black patients
Table 3:
Investigator-assessed responses in black patients compared to non-black patients
| Mogamulizumab | Vorinostat | |
|---|---|---|
|
| ||
| Confirmed overall response, n (%) | ||
| Black patients | 7 (29.2) | 1 (7.7) |
| Non-black patients | 45 (27.8) | 8 (4.6) |
|
| ||
| Response by compartment, n (%) | ||
| Skin compartment | ||
| Black patients | 10 (41.7) | 1 (7.7) |
| Non-black patients | 68 (42.0) | 28 (16.2) |
| Blood compartment | ||
| Black patients | 13 (72.2) | 1 (11.1) |
| Non-black patients | 70 (66.0) | 22 (19.0) |
| Nodal compartment | ||
| Black patients | 2 (9.1) | 1 (10.0) |
| Non-black patients | 19 (16.7) | 4 (3.3) |
| Visceral compartment | ||
| Black patients | 0 (0.0) | N/A |
| Non-black patients | 0 (0.0) | 0 (0.0) |
|
| ||
| Best overall response by disease, n (%) | ||
| Black patients | ||
| Mycosis fungoides | 7 (38.9) | 1 (11.1) |
| Sézary syndrome | 1 (16.7) | 0 (0.0) |
| Non-black patients | ||
| Mycosis fungoides | 18 (20.7) | 8 (8.9) |
| Sézary syndrome | 39 (52) | 3 (3.6) |
There was no difference in overall survival in either treatment arm for the entire MAVORIC IIT population with a median overall survival (OS) not reached with mogamulizumab and 43.9 months with vorinostat (HR 0.93, 95% CI 0.61–1.43; P=0.9439). Due to the one-way crossover design and few deaths in the black patient cohort (N=5), differences in overall survival between the two treatments were not assessed in this cohort.
Safety
The comprehensive adverse events profile has been previously published (7). Notably, there were no new or alarming differences in safety signals in black vs. non-black patients. There was a slight increase in the rate of infusion reactions in black patients treated with mogamulizumab at 41.7% vs. 31.9%, but the rate of drug eruptions was similar at 25% vs. 24.4%.
Discussion:
To our knowledge, this is the largest depiction of the clinical characteristics and outcomes in a cohort of black patients with CTCL treated on clinical trial. The underrepresentation of black patients enrolled in clinical trials is well documented in other hematological cancers such as multiple myeloma (MM). Similar to CTCL, despite the increased incidence rate in black patients with MM (up to 20% of all newly diagnosed cases) there are very few patients (<5%) enrolled in clinical trials studying novel agents (19). The fact that 10% of patients enrolled on the MAVORIC trial identified as black is encouraging, considering the barriers to clinical trial enrollment for minorities (20). Moreover, this proportion is similar to the fraction of black patients with CTCL in the United States, based on recent Surveillance, Epidemiology, and End Results (SEER) registry data (13%), although less than the 19.2% of patients from the National Cancer Database (NCDB) (11, 12).
The general characteristics of black patients enrolled on MAVORIC paralleled those of existing US databases. The median age for black patients was 53 years and over a decade younger than the median age of non-black patients enrolled (66 years). Furthermore, over 80% of black patients were younger than 65 years while only 47% of non-black patients were under 65. This substantial age discrepancy is concordant with previous reports from the NCDB and SEER data, and also comparable to the median age of black patients with CTCL (45–49 years) from two large single-institution studies (9–12, 15).
An interesting finding in this cohort was the discrepancy in rates of MF vs. SS in black patients compared to non-black patients. Nearly three quarters (73%) of black patients in this cohort had MF vs. 52.8% in non-black patients. The increased incidence of CTCL in black patients compared to Caucasian patients is well known, but the actual incidence rate of SS vs. MF in black patients is not well documented (4, 9, 12). Additionally, more black patients enrolled had early-stage disease than non-black patients, but this was driven by significantly more cases of SS in non-black patients. However, it is noteworthy that the MAVORIC trial prohibited patients with large cell transformation from enrollment; hence, the possibility of excluding a notable portion of young female black patients, which in some reports have been noted to have more aggressive disease, should be taken into consideration (13). This may also explain the lack of a female predominance in this black patient cohort as noted in prior studies (10, 14, 15).
The results of this subgroup analysis support mogamulizumab as an effective and safe treatment for MF/SS in black patients with a better overall response, response by disease compartment, and a favorable PFS compared to vorinostat. The MAVORIC trial was not designed to stratify treatment arm by race, and notably, by random chance alone, more black patients were enrolled on the mogamulizumab arm.
At the time of this writing there were no other comprehensive prospective outcomes data in this patient population dedicated towards responses to specific treatments Two publications have reported that clinical responses to total skin electron beam therapy (TSEBT) were not inferior in black patients compared to non-black patients (16, 17). Interestingly, in one small analysis of black patients treated with TSEBT (N=33), those with T2 disease were reported to have improved OS compared to non-black patients with T2 disease receiving TSEBT (17). Certainly, these findings warrant confirmation in larger, prospective studies, and this TSEBT data contradicts other registry data suggesting inferior survival in black patients with CTCL (11, 12). The conflicting data may be explained by the lack of detailed implementation of and responses to different treatment modalities used in black vs. non-black patients in these registry data sets.
With respect to black patients responding to systemic therapy, the data are even more scarce. Notably, the phase III ALCANZA trial comparing brentuximab vedotin to methotrexate or bexarotene in CTCL enrolled 15 (12%) non-white patients. The treatment-specific outcomes of black patients in either treatment arm were not specified (6). Similarly, other effective systemic treatment options for advanced CTCL have not been substantiated in black patients (21–23).
Conclusion:
In summary, this report details clinical characteristic and outcomes of the largest prospectively treated cohort of black patients with MF and SS. Concordant with previous reports, the median age was significantly younger in black patients compared to non-black patients, but discordant with previous reports there was not a female predominance. MF predominated over SS in black patients in this cohort and mogamulizumab has promising activity in black patients with both MF and SS. Similar to non-black patients, responses were poor with vorinostat. Additional studies are needed to better elucidate CTCL in black patients, particularly regarding responses to specific treatments.
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