Toxicities, Secondary Malignancies Loom Large Despite Modest Improvement in Outcomes for RT in Classic HL

David J. Straus, MD

Although long a mainstay of treatment in Hodgkin lymphoma, the current role of radiation remains controversial. In particular, second primary cancers and cardiovascular complications have been associated with the treatment, prompting David J. Straus, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, to state that its use should be limited or avoided in this particular population.

“We should look to reduce or limit radiation therapy or eliminate it if it’s not necessary. The major problem is the late toxicity associated with it,” Straus said in an interview prior to the eighth annual meeting of the Society of Hematologic Malignancy. During the meeting, Straus chaired the section on HL and address various treatment approaches in presentations focused on stage I/II nonbulky cHL, stage I/II bulky cHL, and advanced-stage cHL.

“Hodgkin lymphoma is different from other hematologic malignancies,” Straus said. “We’ve been curing patients for 40 years now, but radiation therapy is problematic. We see an improvement in short-term outcomes of about 5% to 10% when we add radiation therapy, but that’s relatively small. The main focus of ongoing research is to reduce the overall, particularly late, treatment-related morbidity and mortality.”

Nonbulky cHL

In the nonbulky cHL setting, recent studies suggest that the use of chemotherapy alone can achieve a high cure rate while avoiding radiation therapy. He noted the results from the RAPID trial (NCT00943423), which evaluated patients with stages IA/IIA nonbulky disease who were treated with 3 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by positron emission tomography (PET) scanning.1

In the trial, patients with negative PET findings were randomly assigned to receive involved-field RT or no further treatment. For patients with positive PET findings, a fourth cycle of ABVD was initiated, followed by RT. Of the 571 patients who underwent PET scanning, 426 were found to be negative. Among these, 209 patients were assigned to the radiotherapy group and 211 were assigned to the group receiving no further therapy.

At a median of 60 months, the investigators reported that 8 patients had progressed in the RT group and 8 had died. In the group that received no further therapy, 20 patients had progressed and 4 had died.

The 3-year progression-free survival (PFS) rate was 94.6% (95% CI, 91.5%-97.7%) in the RT group and 90.8% (95% CI, 86.9%-94.8%) in the group that received no further therapy, with an absolute risk difference of -3.8 percentage points (95% CI, -8.8 to 1.3).

Although the investigators could not demonstrate noninferiority regarding PFS in the group that got no further therapy after chemotherapy, they did show that patients with early-stage HL and negative PET findings had a very good prognosis either with or without consolidation RT after 3 cycles of ABVD.

Another trial, the phase 2 CALGB 50604 study (NCT01132807), was designed to determine if a population of patients with early-stage disease can be treated with short-course ABVD without RT on the basis of a negative interim PET/CT, thereby limiting the risks of treatment.2

This study used a less stringent criteria for PET negativity but nevertheless demonstrated that 91% of patients with nonbulky disease were interim PET-negative after just 2 cycles of ABVD. PFS for the patients who were PET-positive was 66% (HR, 3.85; 95% CI, 1.5-9.84; P = .011).

For the majority of patients with early-stage nonbulky disease and negative interim PET, 4 cycles of ABVD resulted in durable remissions without consolidative radiation therapy.

Bulky Disease

Because outcomes for bulky disease cHL are somewhat worse than for nonbulky disease, treatment focuses on regimens used in stage III/IV disease.

In the GITIL/FIL HD 0607 trial (NCT00795613), patients with advanced stage HL (IIIB-IVB) were treated with 2 cycles of ABVD and evaluated with PET.3 Patients who were PET-positive were randomly assigned to 4 cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP). This was followed by 4 cycles of standard BEACOPP with or without rituximab (Rituxan).

Patients who were PET-negative continued with ABVD. If patients were PET-negative in complete remission and also had an initial large nodal mass at diagnosis (≥ 5 cm), they were randomly assigned to RT or no further treatment. The trial’s primary end point was 3-year PFS.

The investigators reported that the 3-year PFS for patients with positive and negative PET was 60% and 87%, respectively (P < .001). For patients who received BEACOPP with or without rituximab, the 3-year PFS was 63% versus 57% (P = .53).

In 296 patients with both interim and post-ABVD-negative PET who had a large nodal mass at diagnosis, RT was randomly added after chemotherapy without a significant PFS improvement (97% vs 93%, respectively; P = .29). This demonstrated that the addition of consolidative radiation therapy did not decrease relapses and was probably unnecessary.

Advanced-Stage Disease

In advanced-stage disease, about 70% of patients are cured using the standard ABVD treatment in North America. Somewhat higher rates of PFS are associated with the more intensive but also more toxic BEACOPP regimen, which is more popular in Europe, Straus said.

Targeted therapies and immunotherapies have also emerged in the treatment landscape. The antibody-drug conjugate brentuximab vedotin (Adcetris) and immunotherapy involving PD-1 checkpoint inhibitors nivolumab (Opdivo) and pembrolizumab (Keytruda) have resulted in high response rates for patients with relapsed/ refractory cHL.4-6

Further, results from the ECHELON-1 trial (NCT01712490) demonstrated that patients who received the combination of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A + AVD) experienced a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years than patients with advanced stage HL who received ABVD.7 At a median follow-up of 24.6 months, the 2-year modified PFS rates in the A + AVD and ABVD arms were 82.1% (95% CI, 78.8%-85.0%) and 77.2% (95% CI, 73.7%- 80.4%), respectively.

Overall, Straus expects to review current approaches in newly diagnosed disease. “I’d like attendees to walk away with a concept of those options,” Straus said. “My other presentation will focus on clinical trials that are ongoing and that involve the addition of the powerful new agents to conventional chemotherapy, with the objective to improve the standard approaches.”

_References:

_{1. Radford J, Illidge T, Counsell N, et al. Results of a trial of PET-directed therapy for early-stage Hodgkin’s lymphoma. N Engl J Med. 2015;372(17):1598-1607. doi:10.1056/NEJMoa1408648}

_{2. Straus DJ, Jung SH, Pitcher B, et al. CALGB 50604: risk-adapted treatment of nonbulky early-stage Hodgkin lymphoma based on interim PET. Blood. 2018;132(10):1013-1021. doi:10.1182/blood-2018-01-827246}

_{3. Gallamini A, Tarella C, Viviani S, et al. Early chemotherapy intensification with escalated BEACOPP in patients with advanced-stage Hodgkin lymphoma with a positive interim positron emission tomography/computed tomography scan after two ABVD cycles: long-term results of the GITIL/FIL HD 0607 trial. J Clin Oncol. 2018;36(5):454-462. doi:10.1200/JCO.2017.75.2543}

_{4. Younes A, Gopal AK, Smith SE, et al. Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin’s lymphoma. J Clin Oncol. 2012;30(18):2183-2189. doi:10.1200/ JCO.2011.38.0410}

_{5. Younes A, Santoro A, Shipp M, et al. Nivolumab for classical Hodgkin’s lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial. Lancet Oncol. 2016;17(9):1283-1294. doi:10.1016/S1470-2045(16)30167-X}

_{6. Chen R, Zinzani PL, Fanale MA, et al. Phase II study of the efficacy and safety of pembrolizumab for relapsed/refractory classic Hodgkin lymphoma. J Clin Oncol. 2017;35(19):2125-2132. doi:10.1200/JCO.2016.72.1316}

_{7. Connors JM, Jurczak W, Straus DJ, et al. Brentuximab vedotin with chemotherapy for stage III or IV Hodgkin’s lymphoma N Engl J Med. 2018;378(4):331-344. doi:10.1056/NEJMoa1708984. Published correction appears in N Engl J Med. 2018;378(9):878. doi:10.1056/NEJMx180007}