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2020-03-31T08:42:55.000Z

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

Mar 31, 2020
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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 studies2–5
  • 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

  1. Martínez C et al. Potential survival benefit for patients receiving allogeneic hematopoietic stem cell transplantation after nivolumab therapy for relapse/refractory Hodgkin lymphoma: Real-life experience in Spain (Spanish Group of Lymphoma and Bone Marrow Transplantation, GELTAMO). Biol Blood Marrow Tr. 2020 Feb 14; S1083–8791(20)30087–2. DOI: 1016/j.bbmt.2020.02.003
  2. Beköz H et al. Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience. Ann Oncol. 2017 Oct 1; 28(10):2496–2502. DOI: 1093/annonc/mdx341
  3. Santoro A et al. Real-world data of nivolumab in classical Hodgkin lymphoma: results from the Italian expanded access programme. Blood. 2017; 130(S1):5171. DOI: 1182/blood.V130.Suppl_1.5171.5171
  4. Manson G et al. Long-term efficacy of anti-PD1 therapy in Hodgkin lymphoma with and without allogenic stem cell transplantation. Eur J Cancer. 2019 Jul; 115:47–56. DOI: 10.1016/j.ejca.2019.04.006
  5. Bair SM et al. Outcomes and toxicities of programmed death-1 (PD-1) inhibitors in Hodgkin lymphoma patients in the United States: A real-world, multicenter retrospective analysis. Oncologist. 2019 Jul; 24(7):955–962. DOI: 1634/theoncologist.2018-0538

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