Alemtuzumab plus CHOP in elderly patients with PTCL: Results from a phase III trial

Despite recent efforts to improve outcomes, survival in patients with peripheral T-cell lymphoma (PTCL) remains poor. First-line treatment for the most common PTCL subtypes is anthracycline-based chemotherapy such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP plus etoposide (CHOEP); these regimens achieve a cure in only 20–50% of patients. Furthermore, the majority of patients diagnosed with PTCL are aged 60 years or older, and so are generally less eligible for more intense therapies like autologous and allogeneic stem cell transplantation. Therefore, treatments with improved efficacy are needed for elderly patients with PTCL.

Anti-T-cell directed therapy, using the CD52 antigen expressed on normal lymphocytes and most T-cell lymphoma subtypes represents a potential target for therapy. Alemtuzumab, a recombinant humanized monoclonal antibody directed against CD52, showed promising results in three non-randomized phase II studies investigating alemtuzumab in combination with CHOP (A-CHOP) in patients with PTCL. Based on these findings, the phase III DSHNHL2006-1B/ACT2 trial (NCT00725231) was initiated in 52 study sites by the German Lymphoma Alliance (formerly known as German High-Grade Lymphoma Study Group), in collaboration with the Austrian Group of Medical Tumor Therapy, Lymphoma Study Association, France, Haemato Oncology Foundation for Adults in the Netherlands, and the Nordic Lymphoma Group, to evaluate A-CHOP in elderly patients with PTCL.

On May 7, 2020, the results of the trial were published in Leukemia by Gerald Wulf from the University Medical Center Göttingen, Germany, and colleagues, on behalf of the study investigators.¹

Study design

• This prospective, open-label, randomized study recruited patients aged 61–80 years old with previously untreated PTCL with all stages of disease, except those with disease Stage I N, with International Prognostic Index (IPI) 0 (except if age > 60), and without bulky tumor
• PTCL subtypes included:
  • PTCL not otherwise specified
  • Angioimmunoblastic T-cell lymphoma
  • Anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (until second protocol amendment)
  • Perifollicular variant of T-cell lymphoma
  • Follicular variant of T-cell lymphoma
  • Intestinal T/natural killer (NK)-cell lymphoma (± enteropathy)
  • Extranodal NK/T-cell lymphoma, nasal type

• Patients were stratified by center, IPI factors, bulky disease (≥ 7.5 cm), histology (extranodal NK/T-cell lymphoma, nasal type, yes or no) and age (≤ 70 vs > 70 years), and were randomized 1:1 to receive CHOP or A-CHOP in the following regimens:
• • CHOP: Six courses of CHOP-14 with granulocyte colony-stimulating factor support
  • A-CHOP: CHOP-14 with the addition of 60 mg alemtuzumab given by subcutaneous injection at Day 1 of each chemotherapy cycle, totaling 360 mg. As of the second protocol amendment, the alemtuzumab dose was reduced to 30 mg in Cycles 1–4 of the chemotherapy, totaling 120 mg
• Mandatory anti-infective measures included prophylactic antiviral and antibiotic agents, and monitoring for cytomegalovirus and Epstein-Barr virus
• Primary endpoint: Event-free survival (EFS)
• Secondary endpoints included: Complete remission (CR) rate, overall response rate, overall survival (OS) and safety and tolerability

Patient characteristics

• In total, 116 patients were randomized, 58 in each arm
• Baseline characteristics were generally balanced across treatment arms with slightly more males, and patients with PTCL not otherwise specified in the A-CHOP arm (Table 1)

Table 1. Selected baseline patient characteristics

A-CHOP, alemtuzumab and CHOP; AILT, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified
Characteristic	A-CHOP (n = 58)	CHOP (n = 58)
Sex, male/female, %	66/34	50/50
Age, median (range)	69 (60–80)	69 (61–80)
ECOG > 1, %	21	19
Stage III/IV, %	83	83
IPI > 3, %	26	22
Bulky disease, %	9	10
B-symptoms, %	53	66
Subtype, % PTCL-NOS AILT ALK-negative ALCL Other	38 45 6 12	24 45 7 24

Key safety findings

• Overall adherence to the treatment protocol was good, with more patients completing CHOP-14 (n = 46; 79%) compared with patients receiving all cycles of A-CHOP (n = 33; 57%)
• The incidence of non-hematological Grade 3–5 adverse events was similar in both groups
• Grade 3/4 hematological adverse events were more frequent in the A-CHOP arm (Table 2)
• The number of patients with Grade 3–5 infections was significantly higher in the A-CHOP arm (40% vs 21%, p = 0.026); this difference was mainly due to an increase in cytomegalovirus infections under treatment with alemtuzumab
• A total of five treatment-related deaths occurred and all were caused by infections (n = 4 [10%] in the A-CHOP arm, and n = 1 [3%] in the CHOP arm)
• The cumulative incidence of secondary neoplasms was slightly higher in the A-CHOP arm than in the CHOP arm (eight vs six cases, respectively) with four cases of aggressive B-cell lymphoma occurring in the A-CHOP arm in patients with angioimmunoblastic T-cell lymphoma, who had moderate Epstein-Barr virus-positive B-cell infiltrates at diagnosis  
• A total of four cases of carcinoma occurred in the A-CHOP arm (one case each of skin, colon, lung, and breast cancer) and two cases in the CHOP arm (one case each of skin, and colon cancer)

Table 2. Hematological adverse events, Grade 3–4

A-CHOP, alemtuzumab and CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone
Event	A-CHOP	CHOP
Leukocytopenia, Grade 4	35/50 (70%)	22/41 (54%)
Thrombocytopenia, Grades 3 and 4	8/42 (19%)	4/30 (13%)
Anemia, Grades 3 and 4	17/58 (29%)	11/57 (19%)

Efficacy results

• The primary endpoint of EFS was not met:
  • EFS at 3 years was 27% (95% CI, 15%–39%) in the A-CHOP arm vs 24% (95% CI, 12%–35%) in the CHOP arm (p = 0.248)
  • Median observation time: 54 months
• CR rate and overall response rate were numerically higher in the A-CHOP arm than in the CHOP arm (Table 3)
• Kaplan-Meier estimates suggested a trend toward worse OS for patients in the A-CHOP arm. Overall, 39 (67%) patients in the A-CHOP arm and 30 (52%) patients in the CHOP arm died
• Multivariate analysis conformed that IPI > 1, male sex, and bulky disease predicted worse patient outcome, confirming previous results

Table 3. Treatment response

A-CHOP, alemtuzumab and CHOP; CHOP, cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete remission; ORR, overall response rate
Response	A-CHOP (n = 58)	CHOP (n = 58)
ORR, n (%)	42 (72)	38 (66)
CR or unconfirmed CR, n (%)	35 (60)	25 (43)
Partial response, n (%)	7 (12)	13 (22)

Conclusions

The addition of alemtuzumab to CHOP increased response rates, but showed no improvement in survival. Furthermore, A-CHOP was associated with increased rates of infection, despite prophylactic measures, and secondary malignancies. The authors concluded that A-CHOP failed to improve the outcome for elderly patients with PTCL because the positive effects were outweighed by complications of alemtuzumab therapy. Of note, the estimated 5-year OS in the CHOP arm was 39%, which is in-line with that reported in registry-based observations, and reinforces the urgent need for improved treatment options in elderly patients with PTCL.¹