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Dose-adjusted EPOCH with or without rituximab for NHL-associated HLH: Results from a phase II trial

May 17, 2019
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On 9 April, Jin-Hua Liang from the First Affiliated Hospital of Nanjing Medical University, Nanjing, CN, and colleagues, published in Haematologica1 results from a phase II trial in non-Hodgkin lymphoma (NHL). In this single-arm, open-label study (NCT01818908) the efficacy and safety of dose-adjusted chemotherapy with etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (EPOCH) with or without rituximab was assessed as first-line treatment for NHL-associated hemophagocytic lymphohistiocytosis (HLH).

HLH is a rare and often fatal disease that can occur as a secondary effect of NHL. No prospective clinical trials have evaluated potential first-line treatments for lymphoma-associated HLH.1 This trial investigated whether a combination of pharmacological agents aimed at treating NHL or HLH could provide an effective and well-tolerated treatment for patients with previously-untreated NHL-associated HLH. The primary endpoint of this phase II trial was overall response rate (ORR). Secondary endpoints included, progression-free survival (PFS), overall survival (OS) and the number of patients that experienced adverse events (AEs).

Study design & baseline characteristics

  • N = 55 enrolled patients with newly-diagnosed, histologically-confirmed NHL and either secondary B-cell NHL-HLH (B-NHL HLH; n = 26) or T-cell/natural killer cell NHL-HLL (T/NK-NHL HLL; n = 29)
  • Histology:
    • B-NHL HLL:
      • Diffuse large B-cell lymphoma (DLBCL) or DLBCL not otherwise specified (NOS): n = 7 patients
      • T-cell-/histiocyte-rich DLBCL: n = 1 patient
      • No specific subtype: n = 18 patients
    • T/NK-NHL HLL:
      • Angioimmunoblastic T-cell lymphoma (AITL): n = 2 patients
      • Anaplastic large cell lymphoma (ALCL), anaplastic lymphoma kinase (ALK) negative: n = 2 patients
      • Extranodal NK/T-cell lymphoma (ENKTL) nasal type: n = 7 patients
      • Aggressive NK cell leukemia (ANKL): n = 2 patients
      • Peripheral T-cell lymphoma (PTCL) NOS: n = 3 patients
      • No specific subtype: n = 13 patients
Table 1. Key baseline characteristics

Baseline characteristic

B-NHL HLL
(n = 26)

T/NK-NHL HLL (n = 29)

P  value

Median age (range)

53 (21–69)

43 (17–71)

0.002

Male patients

57.7%

51.7%

0.657

Disease stage IV

100%

100%

1

Bone marrow (BM) involvement

100%

100%

1

Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2

69.2%

100%

0.001

HLH diagnosis:

Fever

Hepatosplenomegaly

Cytopenias affecting ≥ 2 of 3 peripheral blood lineages

Hypertriglyceridemia and/or hypofibrinogenemia

Hemophagocytosis in BM or spleen or lymph nodes

Serum ferritin ≥ 500 ug/L

Soluble CD25


96.1%

76.9%

100%

 

76.9%

 

88.4%

100%

42.3%

 

100%

79.3%

100%

 

89.7%

 

100%

100%

72.4%

 

0.287

0.831

1

 

0.202

 

0.060

1

0.024

Extranodal site involvement    (≥ 2)

57.6%

51.7%

0.657

  • Dosing:
    • B-NHL HLL: six cycles of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R)
    • T/NK-NHL HLL: six cycles of DA-EPOCH
    • If necessary, intrathecal methotrexate (15 mg), cytarabine (50 mg) and dexamethasone (5 mg) were administered for central nervous system (CNS) prophylaxis (4−8 doses)
  • Follow-up assessments occurred every three months for one year; thereafter, every six months for two years and then yearly

Key findings

  • Median DA-EPOCH-R cycles for all B-NHL HLL patients (range): 6 (1–6)
  • Median DA-EPOCH cycles for all T/NK-NHL HLL patients (range): 2 (1–6)
  • ORR at the end of treatment:
    • B-NHL HLL (n = 26): 80.7% (n = 21) of patients
      • Of these responding patients, 57.1% (n = 12) successfully received autologous stem cell transplantation (ASCT)
    • T/NK-NHL HLL (n = 29): 13.8% (n = 4) of patients
  • In the B-NHL HLL group, at a median follow-up of 52 months (range, 35–75):
    • Five-year PFS: 56.7% ± 9.9%
    • Five-year OS: 73.1% ± 8.7%
    • For the patients who received ASCT (n = 12):
      • Five-year PFS: 100%
      • Five-year OS: 100%
    • In the T/NK-NHL HLL group, at the first follow-up (3 months) only one patient who achieved a complete response (CR) remained alive, thus:
      • Three-month PFS: 24.1% ± 7.9%
      • Three-month OS: 55.2 % ± 9.2%
      • Six-month PFS: 10.3% ± 5.7%
      • Six month OS: 24.1% ± 7.9%
      • Twelve-month PFS: 3.4% ± 3.4%
      • Twelve-month OS: 3.4% ± 3.4%
    • Exploratory univariate analysis for potential risk factors revealed the following:
      • B-NHL HLL: Shorter PFS and OS was observed in patients with International Prognostic Index (IPI) score = 4–5 (P = 0.012; P = 0.042) or age > 60 years (P =0.001; P =0.014)
      • T/NK-NHL HLL (n = 29): No statistically significant risk factors were observed (most patients progressed within three months)

Safety

  • Grade 3–4 thrombocytopenia occurred in 14.6% of cycles
  • Grade 3–4 neutropenia occurred in 43.9% of cycles
  • No cardiac complications occurred

Conclusions

The results of this phase II trial indicate that treatment with DA-EPOCH-R leads to improved outcomes in patients with B-NHL HLL and could potentially be considered as a front-line therapy in this population, followed by ASCT consolidation. DA-EPOCH did not improve the outcomes of patients with T/NK-NHL HLL, highlighting a current unmet medical need for these patients.

  1. Liang J.H. et al. Dose-adjusted EPOCH regimen as first-line treatment for non-Hodgkin's lymphoma-associated hemophagocytic lymphohistiocytosis: a single-arm, open-label, phase 2 trial. Haematologica. 2019 May 9. pii: haematol.2019.220301. DOI: 10.3324/haematol.2019.220301 [Epub ahead of print].
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