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Early PET scans guide de-escalation of therapy for advanced Hodgkin’s lymphoma
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ORLANDO, Fla. — PET scans performed following two cycles of the chemotherapeutic regimen BEACOPP can be safely used to guide subsequent treatment, according to results of an interim analysis of a phase 3 trial presented at the ASH Annual Meeting and Exposition.
These results support the delivery of ABVD chemotherapy — which includes doxorubicin, bleomycin, vinblastine and dacarbazine — without hindering disease control for patients with advanced-stage Hodgkin’s lymphoma who have a negative PET after two treatment cycles. However, PET positivity after two cycles of BEACOPP — which includes bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine (Matulane, Sigma Tau) and prednisone — appeared associated with a higher risk for disease progression.
“This approach allows to significantly reduce treatment-related immediate toxicity in most patients and provides a similar outcome compared with standard BEACOPP treatment,” Olivier Casasnovas, MD, of CHU Dijon Bourgogne in Dijon, France, said at the presentation.
Although escalated BEACOPP chemotherapy has demonstrated better disease control than the ABVD regimen, escalated BEACOPP also leads to higher immediate hematological toxicity and increased risks for a secondary myelodysplasia, leukemia and infertility.
Casasnovas and colleagues sought to determine if PET performed after two cycles of BEACOPP chemotherapy would identify patients who could step down to ABVD. They implemented this strategy into the AHL 2011 trial, which included patients with Hodgkin’s lymphoma aged 16 to 60 years.
The analysis included 823 patients with high-risk stage IIB or Ann Arbor stage III to stage IV Hodgkin’s lymphoma enrolled between May 2011 and May 2014, of whom 782 were eligible for the interim analysis.
The experimental arm of the study included 401 patients who underwent PET imaging after two cycles of BEACOPP. If PET positive, patients continued and received four additional cycles of escalated BEACOPP. If PET negative, patients instead received four cycles of ABVD.
The control arm included 381 patients who received the standard regimen of six cycles of BEACOPP regardless of PET status.
The primary endpoint was PFS.
After two cycles of BEACOPP, 12% of patients on the control arm and 13% on the experimental arm were PET positive.
Based on these results, 84% of the patients in the experimental arm received four cycles of ABVD and 13% continued with BEACOPP for four additional cycles.
Toxicities of grade 3 or worse appeared significantly higher among patients who remained on the BEACOPP regimen compared with those who de-escalated to ABVD. The patients remaining on BEACOPP had more frequent anemia (11% vs. 2%), leukopenia (85% vs. 72%), thrombocytopenia (44% vs. 13%) febrile neutropenia (6% vs. 3%) and sepsis (7% vs. 4%) than those who switched to ABVD.
Overall 24% of the patients who remained on BEACOPP experienced serious adverse events related to their treatment, including four deaths. Comparatively, 15% of patients who switched to ABVD experienced a serious adverse event, including one death (P < .002).
The researchers noted that 67% of those patients who experienced serious adverse events in the experimental arm had them occur prior to de-escalation.
The estimated rate of 2-year PFS was similar in both arms (91.6% in the control arm, 88.3% in the experimental arm) after a median follow-up of 16.3 months.
Significantly fewer patients who had positive PET achieved 2-year PFS in the entire cohort (72.9% vs. 92.8%; P < .0001). These results appeared comparable in the standard arm (75.1% vs. 94%) and the PET-driven experimental arm (70.8% vs. 91.6%; P ˂ .0001 for both). – by Anthony SanFilippo
Reference:
Casasnovas O, et al. Abstract 577. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The researchers report consultant/advisory and speakers bureau roles with and research funding from AbbVie, Calistoga Pharmaceuticals, Celgene, Genentech, Gilead, Janssen, Roche and Takeda.
Perspective
Back to TopDavid Straus, MD
There was a hypothesis promulgated by Volker Diehl, MD, PhD — the architect of the escalated BEACOPP program — that you have to hit hard first. That’s what was evaluated in this study in advanced-stage Hodgkin’s lymphoma by Casasnovas and colleagues.
Yet, the PET-positive patients in this study still did worse, so I do not think this shows a very effective strategy. Further, escalated BEACOPP subject most of the patients to significant toxicity. The toxicity tends to occur in the first few cycles, and everyone on this study received at least four cycles of BEACOPP before de-escalating.
It is unclear the role BEACOPP will have moving forward, but patients who de-escalated actually did better than those continuing on the regimen.
Because BEACOPP is very toxic, it is not used widely in North America. In fact, in some of the BEACOPP studies, treatment-related mortality was similar to that you see in autologous transplant — around 3%.
Further, you can salvage patients who receive the ABVD regimen and treat them with a more-intensive therapy, and a minority can undergo transplantation with the same toxicity as escalated BEACOPP.
This begs the question, why do you have to put everybody on that regimen to begin with?
Perspective
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Peter Martin, MD
People have realized for a long time that rather than increasing the intensity of therapy in patients with high-risk Hodgkin’s lymphoma, the regimen should start with high intensity that can be reduced if the patient shows they have chemotherapy-responsive disease early on.
That is supported by data that show escalated BEACOPP is a very effective treatment. It doesn’t improve OS, but it clearly improves disease-free control, so it makes sense for some patients with advanced-stage disease to start with a more intensive treatment and then back off.
The findings in this study will certainly have an impact on some centers in Europe. However, in the United States, outside of the pediatric population, most adults are treated with ABVD rather than escalated BEACOPP regardless of their risk factors. Thus, where ABVD is the standard of care, these data likely will not have an impact.
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