This article is more than 5 years old. Information may no longer be current.
Interim PET-CT may safely guide adapted treatment for Hodgkin lymphoma
Click Here to Manage Email Alerts
Omitting bleomycin from the standard ABVD regimen following a negative PET scan resulted in lower incidence of pulmonary adverse events among patients with advanced Hodgkin lymphoma, according to study results published in The New England Journal of Medicine.
Use of the de-escalated treatment also conferred comparable 3-year PFS; however, the rate did not meet the specified noninferiority margin.
Peter Johnson
ABVD — or doxorubicin, bleomycin, vincristine and dacarbazine — is associated with cure rates as high as 80% for patients with Hodgkin lymphoma.
Although escalated therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine (Mutalane, Sigma-Tau) and prednisone — known as the BEACOPP regimen — has been associated with longer survival than ABVD, the regimen also increases risk for permanent infertility, prolonged fatigue, and myelodysplasia or acute leukemia. These long-term effects are important to consider because Hodgkin lymphoma survivors often have a long life expectancy, according to the researchers.
“Based upon retrospective series looking at the ability of interim PET to predict the outcomes of treatment, we aimed to test the idea of modulating treatment in response to an early assessment of response to ABVD: Could we safely reduce the amount of treatment by omitting bleomycin in the group who had responded well?” Peter Johnson, MD, MA, FRCP, professor of medical oncology within Medicine at Southampton University and chief clinician at Cancer Research UK, told HemOnc Today. “Although the risk for severe toxicity from bleomycin is generally low, for the small number of patients who experience it, it can be life changing or even fatal.”
Researchers also wanted to test whether it is possible to reduce the use of consolidation radiotherapy, Johnson said.
“We used radiotherapy in less than 10% of patients in the RATHL trial, as compared to around half in our previous trials,” he said. “We have seen better survival figures than in our previous studies with less treatment overall, so it feels as though we are on the right track”
Johnson and colleagues adapted therapy based on interim PET/CT scans by de-escalating treatment for patients with a good outlook and intensifying it for patients with high risk for treatment failure.
The analysis included data from 1,203 patients (median age, 33 years; range, 18-79) with newly diagnosed advanced classic Hodgkin lymphoma. The majority of patients were men (54.5%; n = 656), 73.9% (n = 889) had an ECOG performance score of 0 and 61.3% (n = 738) had systemic B symptoms.
In total, 1,119 patients underwent an interim PET-CT following two cycles of ABVD therapy.
Researchers randomly assigned the 937 patients who had negative PET results to receive standard ABVD chemotherapy (n = 470) or de-escalated ABVD, which omitted bleomycin in cycles 3 through 6 (AVD; n = 465). Two patients did not undergo randomization due to a toxic adverse event and second cancer.
Patients who had positive PET findings (n = 172) received BEACOPP.
The difference in the 3-year PFS rate between randomized groups served as the primary outcome. Researchers conducted a noninferiority comparison to exclude a difference of five or more percentage points.
Median follow-up was 41.2 months (range, 2-79.7).
The rate of 3-year PFS was 85.7% (95% CI, 82.1-88.6) in the ABVD group and 84.4% (95% CI, 80.7-87.5) in the AVD group.
The absolute difference in the 3-year PFS rate was 1.6 percentage points (95% CI, –3.2 to 5.3).
“The aim was to exclude a difference of 5 percentage points at 3 years. The observed upper boundary of the 95% confidence interval (5.3 percentage points) was just over this margin, and this is probably due to the lower-than-expected 3-year PFS rate of 85.7% in the ABVD group, which would require more events to exclude a 5-percentage-point difference,” the researchers wrote.
The rate of 3-year OS was 97.2% (95% CI, 95.1-98.4) in the ABVD group and 97.6% (95% CI, 95.6-98.7) in the AVD group.
Overall, risk for disease progression, relapse and death did not significantly differ between the two groups (HR with AVD = 1.13; 95% CI, 0.81-1.57).
Patients in the ABVD group experienced more grade 3 or grade 4 respiratory events. In a longitudinal analysis, researchers calculated a –7.4 (95% CI, 5.1-9.7) percentage point absolute difference between the ABVD and AVD groups in change in lung diffusing capacity for carbon monoxide from baseline. This persisted at 1 year (absolute difference, –4.6 percentage points; 95% CI, 1.6-7.5)
Among patients with positive PET who proceeded to BEACOPP, the 3-year PFS was 67.5% (95% CI, 59.7-74.2) and 3-year OS was 87.7% (95% CI, 81.5-92.1). Researchers noted 74.4% of these patients had negative findings on a third PET-CT scan.
Eighty percent (n = 75) of patients in the BEACOPP group experienced a grade 3 or grade 4 adverse event, the most common of which were neutropenia (63%; n = 59) and infection (37%; n = 35).
Of the total study population, 62 patients died, (ABVD, n = 19; AVD, n = 17; BEACOPP, n = 22), 24 of whom died of Hodgkin lymphoma.
“I hope that clinicians will recognize the value of interim PET in modulating treatment for Hodgkin lymphoma: less for those who are doing well, and more for those whose lymphoma shows a degree of resistance,” Johnson said. “Most importantly, I hope it will mean that people who have been cured of Hodgkin lymphoma are at less risk for long-term side effects in the future.”
There are still two important areas where clinicians can improve, Johnson added.
“We would like to optimize the chemotherapy before the PET scan, as more effective treatment seems likely to result in less recurrences in the PET–negative group,” he said. “Incorporating newer agents such as brentuximab vedotin [Adcetris, Seattle Genetics] into the initial therapy might be a way to achieve this without producing too much toxicity.
Secondly, we need better treatments for the PET–positive group,” Johnson added. “Newer agents such as antibody-drug conjugates or antibodies targeting the PD-1/PD-L1 pathway may be a way to do this.”– by Nick Andrews
For more information:
Peter Johnson, MD, MA, FRCP , can be reached at johnsonp@soton.ac.uk.
Disclos ure: Johnson reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
Back to Top
Stefan K. Barta, MD, MS, MRCP
Johnson and colleagues describe the outcomes of 1,135 patients treated with two cycles of doxorubicin, bleomycin, vincristine and dacarbazine (ABVD) for advanced-stage Hodgkin lymphoma — defined as Ann Arbor stage IIB to IV, or stage IIA with adverse feature — treated at 138 centers across Europe, Australia and New Zealand. ABVD was followed by de-escalation to AVD with the omission of bleomycin for cycles 3 to 6, or escalation to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Mutalane, Sigma-Tau]), based on an interim PET/CT. Researchers interpreted a Deauville score of 1, 2 and 3 in the interim PET/CT as negative, whereas a Deauville score of 4 or 5 was positive.
Outcomes for patients with Hodgkin lymphoma have been excellent with multiagent chemotherapy. The focus of many currently ongoing research studies is to assess whether response to therapy using an interim PET scan can be used to de-escalate therapy for patients who are bound to do well and avoid overtreatment and long-term toxicities, such as second cancers, infertility, pulmonary and cardiac damage. Studies also are assessing whether interim PET can guide the decision to escalate therapy for patients who will ultimately have a high risk for relapse.
This study provides several important insights.
Firstly, the omission of bleomycin from ABVD after a negative-interim PET scan after two cycles of ABVD appears safe without a clinically important loss of efficacy. Although the upper boundary of the 95% confidence interval for 3-year PFS just exceeded the 5% mark required to demonstrate noninferiority of the de-escalation strategy with omission of bleomycin — the observed upper boundary of the 95% CI was 5.3 percentage points — a 1.6% difference in PFS at 3 years translates into a number-needed-to-treat of 62.5 patients with ABVD instead of AVD to prevent one relapse. This needs to be opposed against the one excess adverse event for every one of 10 patients, and one additional pulmonary or upper respiratory event for every one in 40 patients treated without the omission of bleomycin after a negative interim PET — or, the “number-needed-to-harm.”
Further, 3-year OS was not impacted by the omission of bleomycin. Median follow-up for this study was only 41.2 months after randomization, and additional differences in long-term toxicities might only become apparent many years later. Therefore, one could argue that omission of bleomycin in patients with advanced Hodgkin lymphoma who have a negative-interim PET scan after two cycles of ABVD should become the new standard of care based on Johnson and colleagues’ findings.
Secondly, escalation to BEACOPP might improve outcomes for some patients with a positive-interim PET/CT. However, this conclusion is less clear, as there was no randomization between treatments for patients with a positive-interim PET/CT, and the researchers were only able to compare outcomes for this group of patients with historical controls.
Thirdly, the study findings also suggest that consolidative radiation therapy can be omitted safely for patients who have a negative-interim PET/CT, even if they had bulky disease at diagnosis, although this was neither a primary nor secondary outcome of the study.
In general, the study findings confirm the results of other trials in early- and advanced-stage Hodgkin lymphoma, suggesting the utility of interim PET/CT to guide further therapy, especially de-escalation in interim PET–negative patients to reduce the significant risk for immediate- and long-term toxicities while maintaining excellent outcomes.
Nevertheless, the best strategy for patients with a positive-interim PET/CT after two cycles of ABVD remains to be determined. Further, ongoing studies that evaluate the substitution of bleomycin by the immunotoxin brentuximab vedotin (Adcetris, Seattle Genetics) in ABVD and BEACOPP might redefine the best upfront regimen for patients with Hodgkin lymphoma in the near future.
Click Here to Manage Email Alerts