Understanding the short- and long-term toxicity of therapies for Hodgkin lymphoma (HL) is important for guiding treatment decisions, especially for patients in which the benefits of intensified therapy would outweigh the adverse event (AE) risks and for patients in which less aggressive treatment would continue to be effective.
In a prospective, randomized, controlled trial published in the New England Journal of Medicine, Peter Johnson, MD, from the Cancer Research UK Centre and the University of Southampton in Southhampton, England, and authors evaluated a response-adapted chemotherapeutic approach in patients with previously untreated advanced classic HL, questioning whether interim positron emission tomography-computed tomography (PET–CT) scans could identify patients with good outlook who could de-escalate therapy and those at higher risk for treatment failure who could safely escalate therapy.
Dr. Johnson and colleagues enrolled 1,214 patients into the trial (median age = 33 years; range = 18-79 years). Patients underwent baseline PET–CT scan and received two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); 1,119 patients then underwent an interim PET–CT scan.
Patients were eligible for the study if they had previously untreated advanced classic HL (defined as an Ann Arbor stage 2B-4 with adverse features, including bulky disease [>33% of the transthoracic diameter or >10 cm elsewhere] or at least three involved sites) confirmed by histologic analysis. All patients also had to be eligible to receive a full course of combination chemotherapy.
PET–CT scans were evaluated on a five-point scale measuring uptake of residual F-18 fluorodeoxyglucose at involved sites, with scores 1-3 indicating a negative scan and scores 4-5 indicating a positive scan:
- score 1 (n=111; 9.9%)
- score 2 (n=483; 43.2%)
- score 3 (n=343; 30.7%)
- score 4 (n=144; 12.9%)
- score 5 (n=38; 3.4%)
Patients with scores 1-3 were randomly assigned to continue ABVD through cycle 6 (ABVD group; n=470) or to omit bleomycin in cycles 3-6 (AVD group; n=465). Two patients were excluded from randomization, and 10 patients did not receive the assigned therapy. A total of 458 patients in the ABVD group (97.9%) and 446 in the AVD group (97.6%) completed six full cycles of treatment.
Patients with scores 4-5 received escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP group; n=78) or BEACOPP-14 (n=94). Six of these patients withdrew from the study, and four elected to continue with ABVD.
Clinical evaluations were conducted every three months during the first year, every four months during the second year, every six months in the third year, and annually thereafter.
After a median follow-up of 41.2 months (range = 2-79.7 months), researchers observed 142 events of disease progression, relapse, or death in the patients who had negative interim PET–CT scans, with similar outcomes in the ABVD and AVD groups (hazard ratio [HR] for AVD=1.13 [95% CI 0.81-1.57]; p=0.48). The three-year progression-free survival (PFS) rate (the study's primary outcome) was 85.7 percent in the ABVD group (95% CI 82.1-88.6) and 84.4 percent in the AVD group (95% CI 80.7-87.5).
No baseline characteristics were associated with observable differences in PFS; however, the HR favored ABVD for patients with systemic B symptoms (including weight loss, night sweats, and fever; HR=1.76; 95% CI 1.04-2.97).
OS rates were also similar in the ABVD and AVD groups: 97.2 percent (95% CI 95.1-98.4) versus 97.6 percent (95% CI 95.6-98.7).
Among the positive interim PET–CT cohort, therapy escalation was effective in "roughly two-thirds of cases," the authors noted, with a three-year PFS rate of 67.5 percent (95% CI 59.7-74.2). The OS rate was 87.8 percent (95% CI 81.5-92.1).
"We have shown that de-escalating therapy by stopping the administration of bleomycin after negative interim PET–CT scan is safe and effective," Dr. Johnson told ASH Clinical News.
Though its inclusion in the earlier cycles might have a positive effect on disease control, its omission was associated with reduced toxic effects, including fatigue and respiratory events.
Any-grade AEs occurred in:
- 16% of those receiving ABVD in cycles 1-2 (n=188)
- 31% of those receiving ABVD in cycles 3-6 (n=143)
- 21% of those receiving AVD in cycles 3-6 (n=96)
- 55% of those receiving BEACOPP-14 (n=96)
- 60% of those receiving BEACOPP (n=47)
The incidence of any pulmonary or upper respiratory event was slightly lower among patients receiving ABVD and AVD:
- 1% of those receiving ABVD in cycles 1-2 (n=8)
- 3% of those receiving ABVD in cycles 3-6 (n=15)
- 1% of those receiving AVD in cycles 3-6 (n=3)
- 4% of those receiving BEACOPP-14 (n=4)
- 5% of those receiving BEACOPP (n=4)
"Although the results fall just short of the specified non-inferiority margin, the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects but not significantly lower efficacy than with continued ABVD," Dr. Johnson and colleagues wrote.
The researchers analyzed potential predictors of treatment failure after a negative PET–CT scan and found that advanced disease (defined as higher Ann Arbor stage at baseline) was associated with the risk of disease progression (TABLE).
The study is limited by its short follow-up, which was not long enough to draw any definite conclusions. In addition, future research should examine optimizing chemotherapy prior to the PET scan, as more effective treatment seems likely to result in less recurrences in the PET-negative group. In addition, incorporating newer agents such as brentuximab vedotin into the initial therapy might be a way to achieve this without producing too much toxicity. Better treatments for the PET-positive group are also needed.
Johnson P, Federico M, Kirkwood A, et al. Adapted treatment guided by interim PET–CT scan in advanced Hodgkin's lymphoma. N Engl J Med. 2016;374:2419-29.
|TABLE. Therapeutic Outcomes in Each Treatment Cohort|
|All eligible patients
|Alive without disease progression (n)||402||391||117||999|
|Alive after disease progression (n)||49||57||33||142|
(95% CI 82.1-88.6)
(95% CI 80.7-87.5)
(95% CI 59.7-74.2)
(95% CI 80.2-84.7)
(95% CI 95.1-98.4)
(95% CI 95.6-98.7)
(95% CI 81.5-92.1)
(95% CI 94.4-96.8)
|Ann Arbor stage 3/4 and age â‰¤60 years|
(95% CI 76.5-86.5)
(95% CI 76.3-86.4)
(95% CI 52.9-72.9)
(95% CI 76.3-82.9)
(95% CI 92.2-97.9)
(95% CI 94.8-99.1)
(95% CI 78.9-93)
(95% CI 92.5-96.2)
|*This includes all patients who received BEACOPP and BEACOPP-14 (the escalated dose).
â€ This includes patients who dropped out before randomization, declined BEACOPP, or were ineligible for the randomized comparison owing to a non-protocol PET–CT scan after two cycles of ABVD.
ABVD = doxorubicin, bleomycin, vinblastine, and dacarbazine; AVD = doxorubicin, vinblastine, and dacarbazine; BEACOPP = bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine procarbazine, and prednisone; HL = Hodgkin lymphoma; PFS = progression-free survival; OS = overall survival