Hodgkin's Tx Intensity Can Be Spared With Negative PET

Nancy A. Melville

June 26, 2017

MADRID – Patients with advanced Hodgkin's lymphoma who show a rapid response to chemotherapy, as indicated by negative results on positron-emission tomography using 18F-fluorodeoxyglucose (FDG-PET), can be spared more intensive therapy – and related toxicity ― without compromising treatment efficacy. In fact, such an approach yields some improvement in overall survival (OS), according to new research.

"For patients with negative PET-2 after initial treatment with eBEACOPP therapy, only two additional cycles of eBEACOPP are very effective, very safe, very short, and affordable," said Peter Borchmann, MD, scientific secretary of the German Hodgkin Study Group (GHSG), Department of Internal Medicine, University Hospital of Cologne, Germany. He presented the findings from the phase 3 study here at the European Hematology Association (EHA) 2017 Congress.

Under the GHSG protocol, advanced Hodgkin's lymphoma is treated with the intensive regimen of eBEACOPP, consisting of dose-escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone.

It is known that some patients do not require aggressive treatment and could therefore benefit from a less toxic regimen. However, the baseline factors for identifying those patients have not been clear, he explained.

Recent studies have shown that an early response to the eBEACOPP regimen, as indicated by negative results on FDG-PET after two cycles of the therapy (PET-2), can allow for a reduction in treatment intensity.

In investigating that theory, Dr Borchmann and colleagues enrolled 2101 patients who were newly diagnosed with advanced-stage Hodgkin's lymphoma in the international, phase 3 HD18 trial. The cohort included 1005 patients with negative FDG-PET assessments.

Those with negative FDG-PET assessments were randomly assigned to receive either standard therapy with 8/6 cycles (n = 504; the standard therapy of eight cycles was reduced to six cycles in 2011 on the basis of emerging GHSG research) or just two additional cycles (n = 501) following the initial two cycles.

The median age of the patients was about 32 years in each group. Cancer stages were similar for each group (stage IIIA/B, 57% in the 8/6-cycle group and 55% in the 4-cycle group; stage IVA/B, 35%, and 36%, respectively).

At a median follow-up of 55 months, the estimated 3-year survival rate was 92.3% in the 8/6 eBEACOPP group and 94.8% in the 4-cycle group; 5-year progression-free survival (PFS) rates were 91.2% and 91.8%, respectively, with a hazard ratio of .88 for the 5-year estimate.

One patient in the 8/6-cycle group and three patients in the 4-cycle group experienced disease progression (0.2%, 0.6%, respectively); seven patients in the 8/6 group experienced early relapse (1.4%) compared to 12 (2.4%) in the 4-cycle group; 17 patients in the 8/6 group experienced late relapse (3.4%) vs 20 patients (4.0%) in the 4-cycle group.

The total rate of any disease progression or relapse was 5% in the 8/6 group and 7% in 4-cycle group.

Organ toxicities of grade 3-4 were higher in the 8-cycle (22%) and 6-cycle (13%) arms compared to the 4-cycle arm (8%). For the patients who received standard treatment, rates of anemia, thrombopenia, or infection of grade IV were higher (59% and 53%) compared to the patients in the 4-cycle arm (38%; P < .001).

Second neoplasias were reported among 3.6% of standard-care 8/6-cycle patients and 2.6% in the 4-cycle group.

Deaths occurred among 25 patients (5%) in the standard group and nine patients (2%) in the 4-cycle group. The most frequent cause of death was secondary malignancies, which occurred in 11 patients in the standard group and one patient in the 4-cycle group.

Six patients (1.2%) in the standard treatment group and none in the 4-cycle group died as a result of toxicity of the study treatment.

With a median observation time of 56 months, the OS rate in a 3-year estimate was 95.9% in the standard treatment group and 98.7% in the 4-cycle group. In a 5-year estimate, the OS rate was 95.4% vs 97.6% (P = .006).

"The results showed a significant reduction of severe acute hematological and nonhematological toxicities," Dr Borchmann said.

"There was a relevant reduction of mortality for reasons other than Hodgkin's lymphoma and an elimination of Hodgkin's lymphoma as a relevant cause of death [in the 4-cycle group].

"Furthermore, the overall survival was significantly superior with four cycles of eBEACOPP over 8/6 cycles," he added.

Dr Borchmann noted that a caveat of the approach is that FDG-PET negativity is not always clear. Therefore, the researchers took a conservative approach in their definition of negativity for the study.

"When we started this trial, our primary objective was to maintain high efficacy ― we want to cure the patient and not put them at risk for treatment failure, so we wanted to be very cautious with the definition of PET negativity," he told Medscape Medical News.

"In most other trials, a score of 3 on the Deauville (5-point) grading scale is PET-negative, but we used a Deauville scale of 2 to define PET negativity to be on the safer side."

The conservative approach resulted in a relatively low-risk population, which in part could have explained the good responses, Dr Borchmann said.

"After we looked at the results, we thought we may have been almost too conservative, so we have concluded that we can use Deauville 3 as PET-negative, and that's what we are going to do in the future."

Practice-Changing Implications

Experts here at the meeting said the findings have "practice-changing" implications in the treatment of Hodgkin's lymphoma.

Shai Izraeli, MD, professor and head of functional genomics and the Childhood Leukemia Research Center at the Sheba Medical Center, in Tel Aviv, Israel, said the findings suggest an encouraging alternative for treatment that can sometimes be toxic.

"Hodgkin's lymphoma is a highly curable disease even when diagnosed at advanced stages, but the therapy for advanced Hodgkin's is very intensive and very toxic," he told Medscape Medical News.

"Given that this is a disease of young people, lowering immediate and especially late toxicity is essential."

Whereas the lower toxicity with the treatment was not surprising, the evidence of its efficacy is welcome, Dr Izraeli said.

"It was very rewarding to see that this hypothesis is correct in a randomized trial. This trial will change the practice of treating patients with advanced Hodgkin's lymphoma," Dr Izraeli predicted.

These results "have significant implications for the treatment of patients with advanced Hodgkin lymphoma," commented Michael Crump, MD, Division of Medical Oncology and Hematology, the Princess Margaret Cancer Center, Toronto, Ontario, Canada.

Previous results from this group and from several other cooperative groups have shown consistent, significant improvement in PFS using six to eight cycles of escalated BEACOPP chemotherapy compared to other doxorubicin-containing regimens, with smaller improvements noted in OS, Dr Crump told Medscape Medical News. However, universal adoption of this regimen has been tempered by concerns over acute toxicity (myelosuppression, febrile neutropenia) and the possibility of a small but higher risk for secondary myeloid neoplasms when compared to ABVD (doxorubicin [Adriamycin], bleomycin, vinblastine, dacarbazine).

Dr Borchmann and colleagues have now reported excellent PFS and OS at 5 years using a reduced number of cycles of eBEACOPP (four vs six or eight cycles) in patients with a negative results on FDG-PET scanning performed after the second cycle of chemotherapy. The PFS results are in line with the excellent PFS and OS reported in their previous trials using more intensive chemotherapy and are superior to those obtained with ABVD or other combinations in patients with advanced-stage disease. Notably, acute hematologic and organ toxicities are significantly less with fewer cycles of eBEACOPP, and efficacy is not compromised.

"These results should have implications for clinical practice and allow more patients and their physicians to consider four cycles of eBEACOPP to be the optimum treatment regimen and duration of chemotherapy after a negative PET-2 scan in this setting," Dr Crump commented.

In addition, because of the very large number of patients with negative PET-2 scans who received the shorter therapy, this trial also shows a small improvement in OS in the reduced-duration therapy arm. This is unlike other trials by this group in advanced Hodgkin's lymphoma that compared BEACOPP treatments of different durations and intensities, Dr Crump noted. Further follow-up is needed for complete data on late toxicities arising after six or eight cycles of eBEACOPP to be certain of the magnitude of this survival difference, but at present, excellent OS at 5 years (approximately 95% or higher) can be anticipated with only four cycles of therapy in patients meeting the eligibility criteria for this trial.

The study received funding from Deutsche Krebshilfe (German Cancer Aid), the Swiss State Secretariat for Education, Research and Innovation (SERI), and Roche Pharma AG. Dr Borchmann and Dr Izraeli have disclosed no relevant financial relationships.

European Hematology Association (EHA) 2017 Congress. Abstract S150, presented June 23, 2017.

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