Belinostat in patients with R/R angioimmunoblastic T-cell Lymphoma

In Western populations, 10–15% of all non-Hodgkin lymphomas are peripheral T-cell lymphomas (PTCLs). Patients with PTCLs have poor long-term survival and often relapse after firstline treatment. Currently, four histone deacetylase inhibitors (HDACis) have been approved globally for patients with relapsed or refractory (R/R) PTCL.¹ Belinostat, a hydroxamic acid-based HDACi, was the second HDACi to receive U.S. Food and Drug Administration (FDA) accelerated approval for the treatment of R/R PTCL. Approval was based on the BELIEF study (NCT00865969), where monotherapy with belinostat produced complete and durable responses with a manageable safety profile in patients with R/R PTCL.¹

In the BELIEF study, a higher overall response rate was seen among patients with R/R angioimmunoblastic T-cell lymphoma (AITL). Therefore, Ahmed Sawas and colleagues carried out an unplanned analysis of the AITL patient subgroup. These results have recently been published in a letter to the editor of the journal Leukemia & Lymphoma.¹

Study design and patient characteristics

• In total, 129 patients with histologically confirmed PTCL who experienced failure with, or were refractory to, ≥ 1 prior systemic therapy were enrolled in the study between May 2009 and August 2011. They were treated at 62 sites across North America, Europe, Israel, and South Africa
  • Of this population, 22 patients had AITL
• Belinostat was administered at a dose of 1,000 mg/m² as daily 30-minute infusions on Days 1–5, every 21 days
• Primary endpoint: Overall response rate (ORR)
• Secondary endpoints: Duration of response, progression-free survival, and overall survival
• Baseline characteristics can be seen in Table 1

Table 1. Selected baseline patient characteristics¹

AITL, angioimmunoblastic T-cell lymphoma; CHOP, cyclophosphamide + doxorubicin + vincristine + prednisone; ECOG, Eastern Cooperative Oncology Group
Characteristic	Overall (n = 120)	AITL (n = 22)
Sex, male/female, %	51.7/48.3	36.4/63.6
Age (years), %
< 65	50.8	31.8
≥ 65	49.2	68.2
Median (range)	64.0 (29–81)	69.5 (48–78)
ECOG performance status, %
0–1	77.5	72.8
2	21.7	27.3
3	0.8	0.0
Median time from initial diagnosis, months (range)	12.0 (2.6–266.4)	13.9 (4.8–93.4)
Bone marrow involvement, %
No	54.2	45.5
Yes	29.2	36.4
Intermediate/not assessed	16.7	18.1
Ann Arbor stage at study entry, %
I	4.2	0.0
II	9.1	9.0
III	35.0	40.9
IV	50.0	50.0
Prior systemic therapy
Median systemic therapies (range)	2.0 (1–8)	1.5 (1–5)
Multi-agent regimens, %
CHOP or CHOP-like	96.7	95.5
Platinum-containing	31.7	31.8
Other	36.7	36.4
Single-agent regimens, %
Pralatrexate	8.3	0.0
Other	20.0	9.1
Radiation, %	—	22.7
Stem cell transplantation, %	—	18.2
Baseline platelet count (≥ 50,000/µL), %
< 100,000 µL	16.7	22.7
≥ 100,000 µL	83.3	77.3

 Results

• The ORR of the overall population was 25.8%
• Intention-to-treat analysis showed that the ORR for patients with AITL was 45.5% (95% CI, 24–68%), with a median time to response of 11.7 weeks (range, 4.7–24.4)
  • Complete response was 18% and partial response was 27.3%
  • Stable disease was shown in 9.1% of patients, and progressive disease in 31.8%
  • Three patients were not evaluable
• The longest response was 30.5 months, and 2/10 responding patients had a duration of response longer than 23 months
• Responses differed depending on prior therapy, as seen in Table 2, suggesting there may be some cross-resistance with belinostat and prior chemotherapy

 Table 2. ORR by pretreatment characteristics¹

CR, complete response; ECOG, Eastern Cooperative Oncology Group; NE, not evaluable; ORR, overall response rate; PD, progression of disease; PR, partial response; SD, stable disease
Pretreatment characteristic	Overall ORR, % (n = 120)	AITL ORR, % (n = 22)
Baseline bone marrow involvement
Yes	30.8	50.0
No	22.9	50.0
Indeterminate	25.0	100.0
NE	8.3	0.0
Baseline platelet count (≥50,000/µL)
< 100,000 µL	28.0	40.0
≥ 100,000 µL	15.0	47.1
Response to last systemic therapy
CR	48.2	71.4
PR	28.6	40.0
SD	25.0	16.7
PD	8.1	33.3
NE	27.2	100.0
ECOG performance status
0	29.3	50.0
1	15.4	16.7
2	42.3	66.7
3	—	—

 

• At a median follow-up of 21.5 months, the mean duration of response for both the entire population and the AITL population was 13.6 months
• The median progression-free survival was 1.6 (95% CI, 1.4–2.7) vs 4.2 (95% CI, 1.5–13.9) months for the entire population vs the AITL population
• The median overall survival was 7.9 (95% CI, 6.1–13.9) vs 9.2 (95% CI, 6.8–21.5) months for the entire population vs the AITL population
• Treatment-emergent adverse events (TEAEs) occurred in 96.9% of the overall population, and 50% of the AITL patients
  • The most common TEAEs were nausea (41.9%), fatigue (37.2%), and pyrexia (34.9%) in the overall population, and nausea (27.3%) and pyrexia (22.7%) in the AITL population
  • Grade 3–4 TEAEs were reported in 61.2% of all patients and in 31.8% of the AITL population
  • The most common treatment-related adverse events in the AITL subset were nausea (22.7%), anemia (13.6%), and thrombocytopenia (13.6%)

 Conclusion

In this subset analysis, the ORR to belinostat was higher in patients with AITL compared with the entire population. This finding is consistent with previous reports of other HDACis. Belinostat induced durable responses in patients with R/R AITL, with 37% of responders having an ongoing response after a median follow-up of 2 years. The authors suggest that AITL may represent a subtype of PTCL with a unique vulnerability to HDACis. The safety data also suggest that belinostat is better tolerated in patients with AITL.

Limitations of this study include the small cohort size and that the analysis was unplanned.