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Interim PET scans predict relapse of non-bulky early-stage Hodgkin’s lymphoma
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ORLANDO, Fla. — Interim PET scans served as a biomarker for relapse in patients with non-bulky, stage I to stage II Hodgkin’s lymphoma who received ABVD chemotherapy, according to initial study findings presented at the ASH Annual Meeting and Exposition.
Further, defining PET negative as a Deauville score of 1 to 3 identified a population with favorable PFS, results showed.
However, intensifying therapy among PET-positive patients may not prolong their PFS.
Among patients with non-bulky stage I and stage II Hodgkin’s lymphoma, interim PET scans after one to three cycles of ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) predict relapse rates of 10% or less among those who are PET negative. Thus, interim PET can help clinicians identify patients who should receive intensified therapy.
“It’s very important to limit the radiation therapy because it is an important cause of late mortality and late morbidity,” study researcher David J. Straus, MD, an internist and hematologic oncologist at Memorial Sloan Kettering Cancer Center, told HemOnc Today.
Straus and colleagues sought to evaluate whether using interim PET after two ABVD cycles would reduce short- and long-term toxicities and lead to improved PFS among newly diagnosed patients with non-bulky stage I to stage II Hodgkin’s lymphoma.
The investigators enrolled 164 previously untreated patients (median age, 31 years; range, 18-58; men, n = 88) between May 15, 2010 and May 4, 2012. Ninety percent of patients had stage IIA disease, and all patients were PET positive prior to treatment.
After interim PET following two cycles of ABVD, PET-negative patients — defined as a Deauville score 1 to 3 and PET activity less than liver uptake — remained on the ABVD regimen for two more cycles, whereas PET-positive patients, or those who had Deauville scores 4 to 5, switched to more intensive chemotherapy with escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine [Matulane, Sigma Tau] and prednisone) plus 3,060 cGy involved-field radiation therapy.
Median follow-up was 2 years. At that time, 144 patients had adequate follow-up for assessment, 91% of whom were PET negative.
“Using Deauville criteria increased the number of PET-negative patients compared with more stringent criteria for PET negativity,” Straus said. “This actually increased the number of patients not getting radiation therapy compared with trials that use the Deauville scores 1-2 — or PET activity less than uptake in large vessels in the chest and heart — like the RAPID trial, by 16%, which was the most important finding.
“Most patients with this early-stage disease are going to be PET negative and are going to do fine without radiation therapy and just four cycles of chemotherapy, thereby saving them from the risks of radiation therapy,” Straus added.
Six percent (n = 8) of the PET-negative patients relapsed or progressed, equating to an estimated rate of 3-year PFS of 92% in this cohort. Conversely, 31% (n = 4) of PET-positive patients failed — which included three instances of relapse and one suicide — for an estimated 3-year PFS rate of 66%. Based on these data, the HR for PET-negative vs. PET-positive PFS was 6.04 (95% CI, 1.82-20.08).
The primary objective of the trial was to meet a 3-year PFS rate of at least 85% (95% CI, 79-92) among PET-negative patients who remained on ABVD. The secondary objective was to improve outcomes among PET-positive patients who received escalated therapy (HR ˂ 3.84).
“It does not look like intensifying treatment with more intensive chemotherapy with escalated BEACOPP and radiation therapy is really solving the problem,” Straus said. “Interim PET is a very useful biomarker, but we don’t know what to do about it. Fortunately there are new drugs like brentuximab vedotin [Adcetris, Seattle Genetics] and immunotherapy with checkpoint inhibitors. There is a real opportunity to test use of these agents for these patients.”
Toxicity was minimal for all patients. Seventy-one percent of patients experienced grade 3 or grade 4 neutropenia. Other adverse events included grade 3 febrile neutropenia (5%), grade 3 decreased carbon monoxide diffusing capacity (1%), grade 3 decreased left ventricular ejection fraction (1%), sensory neuropathy (grade 3, 2%; grade 4, 1%) and grade 4 moto neuropathy (1%). – by Anthony SanFilippo
Reference:
Straus DJ, et al. Abstract 578. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: Straus reports research funding from Millennium Pharmaceuticals. Please see the full abstract for the other researchers’ relevant financial disclosures.
Perspective
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Peter Martin, MD
This trial adds more evidence for something we have been seeing over the past several years.
A National Cancer Institute of Canada Clinical Trials Group study used CT scans to reduce treatment intensity in younger patients with low-risk early-stage Hodgkin’s lymphoma. More recently, the RAPID trial evaluated the same question.
Now, considering those two trials plus the data from Straus and colleagues, it is becoming overwhelmingly clear that there is a group of patients with low-risk disease who can be cured with less treatment.
The outcomes without radiation therapy can be very good. That is not to say patients may not incur some additional benefit from involved-nodal radiotherapy, but it is definitely clear some young people can do very well without radiotherapy.
It is hard in this day and age to advocate for the use of radiation therapy, especially with old-fashioned involved-field radiotherapy; however, you could still argue that is the standard of care in many centers.
It will be interesting to see how many centers start to adopt this as a standard of care, and to see how the National Comprehensive Cancer Network interprets these data. I would not be surprised if more and more experts feel comfortable reducing the intensity of their therapy and dropping radiation therapy for younger patients who have evidence of early response to treatment.
The other interesting thing was the increase in PET-negative patients on this trial by including patients with a Deauville criteria score of 3. Without compromising efficacy at all, researchers spared a significant number of people from radiation therapy (91%). Even though this is a small study, that’s a big difference (16%) from the patients with Deauville 1 to 2 (75%).
This study also included patients who were high-risk (75% were unfavorable). If you look at younger people with favorable-risk Hodgkin’s lymphoma, Deauville 1 to 3 will probably stick as a standard of care.
References:
Meyer RM, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111961.
Radford J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1408648.
Perspective
Back to TopStephen Douglas Smith, MD
This early-stage non-bulky Hodgkin’s lymphoma trial is really a combination of two phase 2 trials, using interim PET results to assign the treatment after two initial cycles of ABVD.
In one arm, patients with a negative interim PET scan with a Deauville score of 1 to 3 proceed to receive only two additional cycles of ABVD without involved-field radiotherapy. In the other arm, patients with a positive interim PET proceed to dose-escalated BEACOPP for 2 cycles plus involved field radiotherapy.
This creates two very different arms to test different hypotheses. Overall, this study attempts to strike a balance between over- and undertreatment of early-stage Hodgkin’s lymphoma based on early chemosensitivity. Researchers test the approach of avoiding radiotherapy — given known late cardiac and second malignancy risks — in low-risk chemosensitive patients, and escalating treatment in high-risk patients.
There’s no randomization, and follow-up is limited, but two main conclusions can be made.
The first — which is primarily confirmatory — shows that patients with a negative interim PET achieve excellent outcomes, with disease control rates of over 90%.
Because this is a validation of two recent studies from the United Kingdom and EORTC, in a sense, this study does not provide new insight or change the calculus for making clinical decisions. But, it is notable that interim PET is considered negative with a Deauville score of 1 to 3, which is a higher threshold than in the European studies.
Even when including Deauville 3 patients, the interim PET-negative group still had a very good outcome. For many early-stage patients with Hodgkin’s lymphoma, especially younger patients or those with disease in the chest, avoiding radiation when the interim PET is negative seems to be a very reasonable option.
In the other study arm, a secondary endpoint was evaluated — whether escalated BEACOPP and radiotherapy would significantly improve outcomes among PET-positive patients with Deauville 4 to 5 disease at the interim scan.
We do not yet know the final results, but preliminarily, it appears the study will not reach its specified endpoint in that group, meaning that intensified chemotherapy and radiation may not be the answer for high-risk patients.
This leaves the door open to novel strategies to improve upon first-line therapy for some early-stage patients, such as with brentuximab vedotin (Adcetris, Seattle Genetics), other antibodies or small molecules.
My hope is that the results in the PET-positive arm will prompt regulatory and grant-funding bodies to fully support novel clinical research in this subgroup. Although incredible advances have been made in Hodgkin’s lymphoma with chemotherapy and radiation, it may be time to truly think outside of the box for patients with early chemoresistance as defined by PET.
References:
Meyer RM, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1111961.
Radford J, et al. N Engl J Med. 2015;doi:10.1056/NEJMoa1408648.
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