A PET-adapted approach for the treatment of early-stage bulky classic Hodgkin lymphoma

The standard care for patients with early-stage, unfavorable bulky classic Hodgkin lymphoma (cHL) is a combination of chemotherapy and radiotherapy. However, radiotherapy is associated with long-term consequences and toxicities. The CALGB-50604 ALLIANCE trial (NCT01132807) has previously demonstrated that four cycles of chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) show durable progression-free survival (PFS) for a majority of patients with early-stage, nonbulky HL and an interim negative positron emission tomography (PET) scan. At the 2021 ASCO Annual Meeting, Ann S. LaCasce¹ presented the findings from the CALGB-50801 ALLIANCE study (NCT01118026) evaluating the efficacy and safety of response-adapted therapy based on PET in patients with bulky stage I and II HL. The hypothesis was that PET-negative patients do not require radiotherapy, whilst PET-positive patients will benefit from escalation to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) + radiotherapy. The key findings are summarized below.

Study design

A single-arm, phase II clinical trial of response-adapted PET therapy in patients aged ≥18 years, with stage IA−IIB cHL, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0−2, and bulky disease >10 cm or mediastinal mass > 0.33 maximal intrathoracic diameter on chest x-ray. Eligible patients who had received PET following two cycles of chemotherapy (PET2), received treatment as shown in Figure 1. PET-negative was defined as Deauville 1−3 and PET-positive as Deauville 4−5.

ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; Esc BEACOPP, escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; IFRT, involved-field radiation therapy; PET2, positron emission tomography following two cycles of chemotherapy.
*Adapted from LaCasce et al.¹ 

 

• The primary endpoint was PFS, defined as the time from study enrollment to disease progression or death. Secondary endpoints included pulmonary toxicity and hematologic/infectious toxicities.
• The primary endpoint was met when hazard ratio (HR) for PET2-positive vs PET2-negative was <4.1 (one-sided; p = 0.04).

Baseline characteristics

Median age of patients was 30 years (range, 18−58) and included 53% women. 78% of patients were PET2-negative, and majority of the patients had stage II disease (Table 1).

Table 1. Baseline characteristics*

ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ECOG-PS, Eastern Cooperative Oncology Group performance status; PET2, positron emission tomography following two cycles of chemotherapy. *Adapted from LaCasce et al.1
Characteristic	Total (N = 94)	PET2-negative (n = 73)	PET2-positive (n = 21)	p value
Sex, Female, %	53	56	43	0.33
Age, median (range)	30 (18−58)	30 (18−58)	28 (19−56)	0.39
Stage, %				0.78
IA/IAE	7	8	5	—
IB	2	3	0	—
IIA/IIAE	39	41	33	—
IIB/IIBE	51	48	62	—
ECOG-PS, %				0.14
0	68	71	57	—
1	31	29	38	—
2	1	0	5	—
Prior ABVD, %	16	18	10	0.51

Results

Efficacy

• Median follow-up was 58.4 months (range, 0−117.4 months).
• Primary endpoint for PFS was met (HR = 1.03; 85% upper confidence bound = 2.38).
• At 3 years, the estimated PFS was 90% (95% CI, 77−100) and 93% (95% CI, 87−99) in PET2-positive and PET2-negative patients, respectively.
• At a median follow-up of 66.2 months (range, 2.9−117.4 months), the estimated overall survival was 94% (95% CI, 84−100) and 99% (95% CI, 96−100) in PET2-positive and PET2-negative patients (HR = 1.2, 95% CI, 0.12−11.60), respectively.
• One patient died in the PET2-positive arm, due to lymphoma and pneumonia, and three patients died in the PET2-negative arm due to lymphoma, anaplastic astrocytoma, and chronic obstructive pulmonary disease.

Safety

• All six cycles of bleomycin were received in 70% and 76% of PET2-negative and PET2-positive patients, respectively.
• Grade ≥3 pulmonary toxicities occurred in 8% of the PET2-negative patients; none occurred in the PET2-positive patients (Table 2).
• Grade 4 neutropenia was as expected in PET2-negative patients, at 74%, compared to 57% in PET2-positive patients.
• PET2-negative patients had very few occurrences of thrombocytopenia and no occurrence of sepsis.

Table 2. Adverse events*

PET2, positron emission tomography following two cycles of chemotherapy. *Adapted from LaCasce et al.1 †51 of 73 received all six cycles of bleomycin. ‡16 of 21 received all six cycles of bleomycin.
Adverse event, %	Any grade	Grade 3	Grade 4
Pulmonary: PET2-negative†
Cough	62	3	0
Dyspnea	58	3	0
Hypoxia	1	1	0
Pneumonitis	4	1	0
Pulmonary: PET2-positive‡
Cough	62	0	0
Dyspnea	33	0	0
Hypoxia	0	0	0
Pneumonitis	0	0	0
Hematologic/infectious: PET2-negative
Neutropenia	93	12	74
Thrombocytopenia	8	1	1
Febrile neutropenia	8	8	0
Sepsis	0	0	0
Hematologic/infectious: PET2-positive
Neutropenia	100	29	57
Thrombocytopenia	71	14	14
Febrile neutropenia	10	10	0
Sepsis	5	0	5

Conclusion

This first prospective study restricted to patients with bulky stage I/II cHL, demonstrated excellent PFS in all patients treated with PET-adapted therapy, including 78% of PET-negative patients for which radiotherapy or exposure to escalated BEACOPP was not required. Based on these results the investigators recommend omitting radiotherapy in PET2-negative patients who receive six cycles of ABVD. However, the study was limited by a small number of PET2-positive patients and a nonrandomized study design. Further studies comparing the efficacy, safety, and cost of novel agents with PET-adapted therapy are suggested.