COG to Assess Targeted Therapies in a Variety of NHL Clinical Trials

Birte Wistinghausen, MD

The Children's Oncology Group (COG) is currently involved in 5 studies exploring targeted therapies in non-Hodgkin lymphoma (NHL) that could eventually change the face of pediatric NHL treatment.1

Birte Wistinghausen, MD, medical director of the Division of Pediatric Hematology-Oncology, the Kravis Children's Hospital and Icahn School of Medicine at Mount Sinai, and a member of the COG Non-Hodgkin Lymphoma Committee, discussed the objectives for the 5 studies at the 2018 ASPHO Conference. The current studies are in various stages and continue beyond 2020.

First, ANHL1131 is a phase II/III trial evaluating the efficacy and safety of rituximab (Rituxan) in children or adolescents with higher-risk stages of B-cell lymphoma or B-cell leukemia. Wistinghausen said the rationale for the study was based on results showing improved outcomes for adults with diffuse large B-cell lymphoma (DLBCL) treated with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like chemotherapy versus chemotherapy alone.

In the 3-arm phase III part of the trial, patients aged <6 months to 18 years with Burkitt lymphoma and DLBCL were randomly assigned to standard chemotherapy, FAB/LMB 96 chemotherapy or FAB/LMB 96 chemotherapy with rituximab. Eighty-five percent of patients had Burkitt lymphoma, and patients had to have high-risk group B or high-risk group C disease.

There were 6 deaths due to toxicity (1.9%) and febrile neutropenia was more common in patients who received rituximab (50% vs 35%; P = .012). Overall, Wistinghausen said rituximab was well tolerated.

Moreover, patients who received rituximab had superior 2-year event-free survival (EFS; 94.2% vs 82.0%) and overall survival (OS; 96.0% vs 85.3%).

The phase II section evaluated rituximab in combination with the dose-adjusted etoposide, prednisone, vincristine (Oncovin), cyclophosphamide, doxorubicin (DA-EPOCH) regimen in patients with primary mediastinal large B-cell lymphoma. PMBCL is uncommon in children and is more difficult to cure than other types of B-cell lymphomas. However, previous results have showed a 93% EFS for adults with PMBCL.

Patients (N = 47) received 6 cycles of treatment and 85% of patients achieved complete remission (CR). At 2 years, EFS was 72% and OS was 82%. Wistinghausen called the OS results “disappointing,” adding that they were similar to the historical control.

Those findings led to the initiation of ANHL1821, a randomized phase II trial of pembrolizumab (Keytruda) in combination with R-CHOP or DA-EPOCH with rituximab (DA-EPOCH-R) for patients with newly diagnosed PMBCL.

“The rationale for pembrolizumab, which is a monoclonal anti—PD–1 antibody, lies in the fact that there is overexpression of PD-1 ligand in primary B-cell lymphomas, which arise from the thymic T cells,” Wistinghausen said. “There are already preliminary adult data using pembrolizumab as a single agent in patients with relapsed PMBCL showing an overall response of 41%.”

Wistinghausen added that physicians still do not know the optimal chemotherapy backbone for PMBCL. Investigators hypothesize that EFS and rate of radiation therapy will not be significantly different with pembrolizumab in combination with R-CHOP or DA-EPOCH-R.

All patients in ANHL1821 will receive investigational agents, and randomization will be between different chemotherapy backbones.

“This is a ‘pick the winner’ algorithm,” Wistinghausen said. “If the event-free survival is higher in [the] dose-adjusted EPOCH-R [arm], DA-EPOCH-R wins. If not, then the rate of radiation will decide who the winner is.”

COG is exploring chemotherapy in combination with brentuximab vedotin (Adcetris) or crizotinib (Xalkori) for patients with newly diagnosed stage III/IV anaplastic large cell lymphoma (ALCL) in ANHL12P1. In the phase II trial, investigators are evaluating safety and EFS for brentuximab vedotin, a monoclonal antibody-drug conjugate, in combination with standard chemotherapy versus the ALK inhibitor crizotinib plus chemotherapy. The target accrual is 140 patients with an estimated primary completion date of September 2020.

Wistinghausen said that the respective drug manufacturers would not allow investigators to compare the agents head-to-head, so each treatment arm is compared with historical controls.

Investigators found an unexpected increase in the rate of thromboembolic events in the crizotinib/chemotherapy arm, with 9 catheter-related thromboses and 4 pulmonary emboli. All patients in that arm were subsequently assigned to mandatory anticoagulation.

The brentuximab vedotin arm has completed accrual and results are expected in January 2019. Recruitment is ongoing in the crizotinib arm.

In ANHL1522, investigators are exploring the combination of rituximab and latent membrane protein (LMP)-specific T cells to treat pediatric solid organ recipients who have developed Epstein-Barr virus (EBV)-positive, CD20-positive post-transplant lymphoproliferative disorder (PTLD).

All patients will receive 3 1-week courses of rituximab, and patients who achieve CR will receive another 3 courses. All other patients are eligible for 1 course of LMP-specific T cells. Patients can receive a second course of LMP-specific T cells if they do not have a CR after the first course. Moreover, the target patient population is 90 and the study completion is set for December 2021.

Finally, Wistinghausen detailed an as-yet untitled study chaired by Carl Allen, MD, PhD, associate professor, Department of Pediatrics, Section of Hematology/Oncology, Baylor College of Medicine. That trial will explore the use of targeted BRAF inhibition or targeted MAPK inhibition to treat relapsed/refractory Langerhans cell histiocytosis.

“Results from LCH III show an overall excellent survival in patients with LCH but it also shows . . . an overall relapse rate of 30%, even in patients who do not have risk organ involvement. That leaves a lot of room for improvement,” she said.

H-9926-LCH III: Treatment Protocol of the Third International Study for Langerhans Cell Histiocytosis was an international, multicenter, prospective clinical study comparing prednisone/vinblastine/6-mercaptopuroine with leucovorin/methotrexate/vinblastine/prednisone in children with newly diagnosed LCH.2

Wistinghausen added that progression-free survival was 70% with the use of different nucleoside analogs for relapsed patients in salvage data from LCH III.

“What [Dr Allen] would like is to determine the optimal salvage therapy for patients with LCH using a combination of nucleoside analog, either cytarabine or clofarabine, with targeted therapy, a BRAF or MEK inhibitor,” she said.

References

1. Wistinghausen B. Targeted Therapies in NHL. In: Proceedings from the 2018 ASPHO Conference; May 2-5, 2018; Pittsburgh, Pennslyvania. Abstract 2014.
2. Gadner H, Minkov M, Grois N, et al. Therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis. Blood. 2013;121:5006-5014. doi: 10.1182/blood-2012-09-455774.

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