Nivolumab treatment followed by consolidation with allo-HSCT is associated with favorable outcomes in patients with relapsed/refractory Hodgkin lymphoma

Nivolumab is an immune checkpoint inhibitor approved for the treatment of classical Hodgkin lymphoma (cHL) after failure of autologous hematopoietic stem cell transplantation (auto-HSCT) and brentuximab vedotin (Bv) treatment, or three or more prior lines of systemic therapy. Results from the CheckMate 205 trial on nivolumab in patients with relapsed and refractory (R/R) cHL reported durable responses and an acceptable safety profile. Limited data exist on the impact of nivolumab on transplant outcomes.

Here, we present the results of a retrospective, multicenter study, recently published in Biology of Blood and Marrow Transplantation. Carmen Martínez and colleagues aimed to determine efficacy and safety of nivolumab for treatment of patients with R/R cHL and its impact on transplant outcomes, in a real-life context.¹

Study design and patient characteristics¹

• Eligible patients were ≥ 18 years with R/R cHL and treated with at least one cycle of nivolumab between September 2015 and May 2018
• Primary endpoint: overall response rate (ORR)
• Secondary endpoints: complete remission (CR) rate, safety, and clinical outcomes after auto- or allogeneic hematopoietic stem cell transplantation (allo-HSCT)
• Seventy-four patients, with the following characteristics, were included in the study:
  • Median age: 32 years (range, 17–78)
  • Median number of therapy lines prior to nivolumab: four (range, 1–15)
  • Previous HSCT: 38 patients (51.4%):
    • auto-HSCT, n = 33 (44.6%)
    • allo-HSCT, n = 5 (6.8%)
  • Patients previously treated with Bv: 97.3%
  • Patients with advanced disease at nivolumab initiation: 70.3%
• Dose of nivolumab: 3 mg/kg (n = 69; 93.2%) or 4 mg/kg (n = 1; 1.4%), once every 2 weeks (dose unknown, n = 4)
• Median number of cycles: eight (1–89), with most patients (n = 53; 72%) receiving treatment for ≤ 6 months

Results¹

Safety

Adverse events (AEs) were reported in 56.8% of patients, with the most common (> 5%) being

• Infection: 20.3%
• Hepatitis: 9.5%
• Diarrhea: 9.5%
• Rash/erythema: 9.5%
• Neutropenia: 8%
• Anemia: 6.7%
• Fever: 6.7%
• Hypothyroidism: 5.4%

Referral for transplantation (41.7%) and disease progression (37.5%) were the main reasons for nivolumab discontinuation. Two patients died due to severe AEs: one was heavily pre-treated and died because of Grade 5 hepatitis, nephritis, and Steven–Johnson syndrome after the first dose of nivolumab; the other patient received four previous therapy lines and died due to Grade 5 pneumonitis after two cycles of nivolumab.

Efficacy

Nivolumab response was evaluable in 72 patients:

• Median time to best response: 3 months (range, 0.5–13.5)
• ORR: 59.7%
  • CR: 30.6%
  • Partial remission (PR): 29.1%
• Stable disease (SD): 12.5%
• Lymphoma progression: 27.8%

Of all evaluable patients (n = 72), six (8.3%) were alive and showing a response to nivolumab without additional treatment. After a median follow-up for survivors at 22 months (range, 6.8–42.8):

• Probability of 2-year overall survival (OS): 52% (95% confidence interval [CI], 44.9–59.9)

 

Efficacy in patients who did not proceed to auto- or allo-HSCT (n = 29)

In patients who did not proceed to HSCT:

• Median cycles of nivolumab: 12 (range, 1–89)
• CR: 17.2%
• PR: 27.6%
• SD: 10.3%
• Progression of lymphoma: 44.8%
• Sixteen patients died
• Disease status at the last follow-up:
  • CR: eight patients
  • PR: three patients
  • SD: one patient
  • Progressive disease (PD): 17 patients
• After a median follow-up of 17.5 months (5.1–32) for surviving patients:
  • 2-year OS: 21%
  • 2-year progression-free survival (PFS): 18%

 

Efficacy in patients who proceeded to HSCT (n = 42)

Of the 42 patients who proceeded to HSCT, three underwent auto-HSCT, 38 underwent allo-HSCT, and one underwent tandem auto-allo-HSCT. Of the three patients who underwent auto-HSCT:

• all achieved CR after nivolumab
• all sustained CR at 12, 14, and 19 months of follow-up post-transplant

Of the 39 patients proceeding to allo-HSCT:

• Median doses of nivolumab: eight (range, 4–44)
• Median time from the last dose of nivolumab to allo-HSCT: 1.9 months (0.5–5.7)
• After a median follow-up for survivors of allo-HSCT at 18.4 months (4.2–45.7):
  • Median PFS and OS: not reached
  • Estimated 2-year PFS: 69.4%
  • Estimated 2-year OS: 71.9%

 

Comparison analysis of allo-HSCT (n = 27) vs no allo-HSCT (n = 13), to assess the benefit from allo-HSCT as consolidation therapy

The comparison analysis was restricted to patients achieving CR/PR after nivolumab, and the results are presented in Table 1.

Table 1. Patients’ characteristics and outcomes

Characteristics and outcomes of patients	Allo-HSCT n = 27	No allo-HSCT n = 13	p
At nivolumab initiation: Age, years (range) Extranodal disease, n (%) Number of prior systemic therapy lines, median (range) Prior auto-HSCT, n (%) Prior allo-HSCT, n (%)	32 (17–49) 13 (48.1) 4 (3–6)   11 (40.7) 0	41 (26–78) 12 (92.3) 6 (2–15)   10 (76.9) 4 (30.8)	< 0.0001 0.007 0.002   0.032 0.002
N of nivolumab cycles, median (range)	7 (4–44)	16 (1–89)	0.009
OS, %	77.5	46.2	0.126
PFS, %	73.9	27.2	0.025

allo-HSCT, allogeneic hematopoietic stem cell transplantation; auto-HSCT, autologous hematopoietic stem cell transplantation; OS, overall survival; PFS, progression-free survival

*Value indicated in bold is not statistically significant

Conclusion

• This study, analyzing data regarding nivolumab use in R/R cHL patients in Spain, showed similar response rates to those reported previously in other real-life studies^2–5
• After a median follow-up of 18 months, patients achieving CR/PR after nivolumab who underwent allo-HSCT showed a favorable OS and a significant improvement in PFS in comparison with patients not undergoing allo-HSCT¹