Enthusiasm for Transplant-Free Strategies for Low-Risk Relapsed Hodgkin Lymphoma

Non-transplant salvage therapy for low-risk relapsed/refractory pediatric classical Hodgkin lymphoma (cHL) had high rates of progression-free (PFS) and overall survival (OS) at 3-5 years, three separate studies showed.

A multicenter European study resulted in a 5-year PFS of 89.7% and OS of 97.4% with PET-guided chemotherapy and radiotherapy for low-risk relapsed disease. Results were nearly identical to those of patients who underwent standard-of-care autologous stem cell transplant (ASCT).

Of two smaller studies, one showed a 3-year event-free survival and PFS of 87% and 95% without transplantation, and the other had second EFS rates of 85.0% and 78.5% at 5 and 8 years, respectively.

The studies were reported simultaneously in JAMA Oncology.

PET-guided salvage therapy without transplant achieved “excellent outcomes” in low-risk cHL suggesting ASCT might be reserved for higher-risk patients, reported Christine Mauz-Körholz, MD, of Justus Liebig University Hospital in Giessen, Germany.

“To our knowledge, this is the largest prospective risk-stratified and FDG-PET response-guided salvage study in pediatric [relapsed/refractory] cHL to date and the only trial to use FDG-PET response to de-escalate treatment to transplant-free salvage,” the authors noted in their discussion. “Risk-factor analysis in the DAL-ST-HD-86 trial showed subgroups with markedly better or poorer prognosis, and time-to-treatment failure was the dominant factor, with 10-year PFS of 41% in primary progression and 86% in late relapse, and 96% in the patients with late low-stage relapse.”

“The critical dilemma is whether nontransplant savage therapy should be considered in any patient beyond the lowest-risk relapse,” they added. “Numerous factors may be considered in addition to time-to-treatment failure … . However, there are no universally accepted prognostic criteria in children (or adults) defining risk groups in relapse.”

Collectively, the three studies provide “strong evidence to support the omission of HDC [high-dose chemotherapy]/ASCT without compromising the progression-free survival and overall survival of the treated patients,” according to the authors of an accompanying editorial.

“These studies mark significant progress and should be seen as a huge step forward in optimizing salvage therapy for relapsed low-risk Hodgkin lymphoma in children and young adults,” stated Rabi Hanna, MD, and Ilia N. Buhtoiarov, MD, of the Cleveland Clinic. “The data strongly support that the selected patients can achieve durable remission without the need for HDC and ASCT, offering less intensive, more targeted therapies with manageable adverse effects. It is key to emphasize the importance of choosing wisely who meets the low-risk relapsed cHL criteria, as well as who demonstrates the best response to benefit from HDC/ASCT.”

“However, conclusive statements about the incidence of long-term complications, including secondary malignant neoplasms, cardiovascular disease, and other treatment-related morbidities are still pending,” they noted. “Additionally, although these studies highlight promising alternatives to intensive HDC/ASCT-based therapy, they each use different criteria for defining low-risk relapse and remission, complicating the ability to generalize the findings.”

European Study Background

Pediatric patients with cHL have high cure rates with risk-adapted chemotherapy and radiotherapy, but 10-15% of patients have relapsed/refractory disease. Relapsed/refractory disease has a “fair chance of cure,” although the optimal salvage therapy has yet to be defined, Mauz-Körholz and co-authors noted.

Use of HDC and ASCT in pediatric patients came from extrapolation of randomized trials in adults. The strategy became standard of care for adults with relapsed/refractory cHL, but the clinical trials were conducted before FDG-PET imaging and use of FDG-PET response to salvage therapy to predict outcome, the authors continued. Moreover, therapeutic options have evolved to include agents such as brentuximab vedotin (BV, Adcetris) and immune checkpoint inhibitors.

In pediatric patients, nontransplant salvage therapy with chemoradiotherapy (CRT) demonstrated efficacy in several studies, showing that subsets of patients do not require HDC/ASCT. The largest of the studies, DAL-ST-HD-86, involved 176 patients, and 102 of 132 surviving patients received nontransplant salvage therapy with CRT.

DAL-ST-HD-86 identified time-to-treatment failure after first-line therapy as the dominant prognostic factor, and investigators defined three risk groups from worst to best: primary progression, early relapse, and late relapse. The dominant presalvage risk factors and FDG-PET response assessment formed the basis for the EuroNet-PHL-R1 trial, a substudy within the EuroNet-PHL-C1 nonrandomized trial that evaluated response-adapted first-line treatment strategies for pediatric patients with intermediate- and advanced-stage cHL.

Participants in EuroNet-PHL-R1 had relapsed/refractory cHL after first-line treatment. They were separated into three risk groups: progression during or within 3 months after first-line treatment (RG3), late relapse (>12 months) after first-line treatment with two cycles of chemotherapy (RG1), and patients with all other relapses (RG2).

All patients received two cycles of IEP/ABVD chemotherapy, followed by radiotherapy for patients with low-risk disease (RG1). All high-risk patients (RG3) underwent HDC/ASCT. RG2 patients with an adequate response to chemotherapy received radiotherapy, whereas patients with an inadequate response received HDC/ASCT.

Investigators enrolled 118 patients (median age 16.3 years), 24 with primary progression and 94 with relapsed disease. On the basis of risk group and early response assessment, 59 patients were categorized as having low-risk disease. Of those, 41 received nontransplant therapy and the rest received off-protocol HDC/ASCT.

After a median follow-up of 67.5 months, 5-year PFS for all 118 patients was 71.3% and OS was 82.7%. The 41 patients who received nontransplant salvage therapy had a 5-year PFS of 89.7% and OS of 97.4%. The 18 patients who received off-protocol HDC/ASCT had a 5-year PFS of 88.9% and OS of 100%. The 59 high-risk patients who underwent HDC/ASCT had a 5-year PFS of 53.3% and OS of 66.5%.

No patients discontinued treatment because of drug- or radiotherapy-related toxicity.

Multinational, U.S. Studies

The CheckMate 744 study included 28 children, adolescents, and young adults with low-risk relapsed cHL, enrolled at sites in the U.S., Canada, and Europe. Treatment began with four cycles of nivolumab (Opdivo) plus BV. Patients who achieved a complete molecular response (CMR) received two more cycles of nivolumab and BV. Patients with suboptimal response received BV and bendamustine. Patients with CMR after induction or intensification underwent involved-site radiotherapy, reported Stephen Daw, MD, of the University College London, and co-authors.

The study cohort had a median age of 17 and two-thirds of the patients were female. After a median follow-up of 31.9 months, CMR rate by independent review at any time before radiotherapy was 93% and the objective response rate (ORR) was 100%. All but five patients achieved CMR after the first four cycles of nivolumab and BV, and the ORR was 96.4%.

The estimated 3-year EFS and PFS were 87% and 95%, respectively. Treatment-related adverse events (TRAEs) occurred in 22 (79%) patients during induction, including seven grade 3/4 AEs. Two patients discontinued because of AEs.

“These promising results support further evaluation of this nontransplant treatment approach,” the authors concluded.

The AHOD0431 prospective clinical trial involved 278 patients with stage IA/IIA nonbulky cHL, treated with a standard chemotherapy regimen. The treatment led to complete responses in 175 patients, 37 of whom relapsed, including 32 patients with low-risk relapse. Subsequently, 20 of the 32 patients completed protocol-specified treatment with two additional cycles of chemotherapy plus involved-field radiotherapy, reported Bradford S. Hoppe, MD, of Mayo Clinic-Florida in Jacksonville, and co-authors.

Five of the 20 patients had second relapses, which occurred a median of 2.1 years after the initial relapse. Three of the five underwent ASCT. Taken together with studies such as CheckMate 744, the findings “support risk-directed, transplant-free, combined-modality salvage regimens.”

“Most patients avoided ASCT, and OS was not compromised by de-escalating salvage therapy,” the authors noted.

“The management of relapsed HL should risk-stratify therapy to individual patients to maintain disease control rates while minimizing toxic effects,” they added. “Transplant-free salvage approaches spare patients the risk of late effects associated with ASCT, including second cancers, cardiopulmonary disease, endocrinopathies, and infertility.”

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