Alemtuzumab and CHOP for aggressive T-cell lymphoma

On 18 February 2019, Elizabeth Phillips from Cancer Research UK and University College London Cancer Trials Center, London, UK and colleagues, published in Leukemia & Lymphoma the results of a phase I trial investigating the efficacy and safety of alemtuzumab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) combination for the treatment of aggressive T-cell lymphoma.

Despite the low long-term survival rates with CHOP, it remains the standard of care for most aggressive T-cell lymphomas. In this phase I, dose escalation trial, the authors investigated the possibility of combining CHOP chemotherapy with alemtuzumab, as a potential regimen against aggressive T-cell lymphoma. Alemtuzumab is a monoclonal, humanized, anti-CD52 antibody that has been used as monotherapy in cases of T-cell prolymphocytic leukemia and relapsed or refractory (R/R) T-cell lymphoma. The primary endpoint of this study was to assess the toxicity of the combination treatment and establish a maximum tolerated dose (MTD) for alemtuzumab. Secondary endpoints, included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS).

Study design & baseline characteristics

• N = 18 patients, aged ≥ 18 with Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 and with either of the following aggressive T-cell lymphomas:
  • Peripheral T-cell lymphoma (PTCL): n =8
  • Angioimmunoblastic T-cell lymphoma: n = 5
  • Anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma: n =3
  • Subcutaneous panniculitis-like T-cell lymphoma: n =1
  • Enteropathy-associated T-cell lymphoma: n = 1
• Median patient age (range): 58 (37–71) years
• Dosing (6–8 treatment cycles of 21 days each):
  • CHOP:
    • Cyclophosphamide: 750 mg/m²
    • Doxorubicin: 50 mg/m²
    • Vincristine: 1.4 mg/m²
    • Prednisolone: 100 mg
  • Alemtuzumab:
    • Cohort 1 (n = 3): 30 mg subcutaneously (SC) with each CHOP cycle
    • Cohort 2 (n = 15): 60 mg SC with each CHOP cycle (except for Day 1 and 3: 30 mg)
    • Both cohorts received two alemtuzumab test doses were given prior to cycle 1 to reduce allergic reactions (3 mg and 10 mg)
  • 3 + 3 design:
    • Dose escalation was permitted if 0 or ≤ 1 patients experienced dose-limiting toxicities (DLTs) during the first three cycles
    • Dose escalation was stopped if ≥ 2 DLTs occurred among six patients
  • Consolidation with autologous stem cell transplant was not allowed
  • Patients received prophylactic aciclovir, co-trimoxazole and antifungals. Granulocyte colony stimulating factor (G-CSF) was given as secondary prophylaxis
  • Responses were assessed by computed tomography (CT) after treatment cycles 3 and 6

Key results

• Patients who completed ≥ 6 cycles of CHOP-alemtuzumab treatment: 61% (n = 11/18)
• Median total alemtuzumab dose received per cohort:
  • Cohort 1: 223 mg (range, 193–223)
  • Cohort 2: 253 mg (range, 10–373)
• Median interval between consecutive treatment cycles (range): 24.5 (20–35) days
• ORR: 55.6%
  • Complete response (CR): 44.4% (n =8)
  • Partial response (PR): 11.1% (n = 2)
  • Progressive disease (PD): 38.9% (n = 7)
    • One lymphoma-related death occurred
  • Two-year PFS rate (n = 18): 38.9% (95% CI, 16.4–61.4)
  • Two-year OS rate (n = 18): 60.6% (95% CI, 37.9–83.3)
  • At a median follow-up of 25.5 months:
    • Five patients (27.8%) were still alive and progression-free
    • Nine deaths occurred:
      • Lymphoma-related: n = 8
      • Treatment-related: n = 1 (bronchopneumonia)

Safety

• DLTs occurred in 22.2% (n = 4) patients:
  • One in cohort 1 (cycle 6), and three in cohort 2 (cycle 1, 3, and 6, respectively)
• The most common Grade 3–5 hematological adverse events (AEs) were:
  • Neutropenia: 94% (n = 17)
  • Thrombocytopenia: 44% (n = 8)
• The most common non-hematological Grade 3–5 AEs were:
  • Infection: 50% (n = 9)
  • Fever: 28% (n = 5)
  • Fatigue: 22% (n = 4)
  • Diarrhea: 11% (n = 2)
  • Nausea: 11% (n = 2)
  • Vomiting: 11% (n = 2)
• Inpatient hospital admission was required for 72.2% of patients (n = 13) due to febrile and/or infective episodes
  • Median inpatient admission (range): 4.5 (0–59) days
  • Median intravenous antimicrobial administration (range): 3 (0–14) days
• There were no significant differences in toxicity between the two alemtuzumab cohorts

Conclusions

• Alemtuzumab-CHOP therapy-associated toxicity was high in aggressive T-cell lymphoma patients
• The optimum alemtuzumab dose with CHOP requires further exploration
• Response rates to alemtuzumab-CHOP were modest and not overtly different than responses to CHOP alone, in T-cell lymphoma patients