Study Highlights Challenges in Treating Young Patients With Lymphoid Malignancies

In the EURO-LB02 trial, children and adolescents with lymphoma received the Non-Hodgkin Lymphoma-Berlin-Frankfurt-Münster (NHL-BFM90) protocol without prophylactic cranial radiotherapy, to determine whether replacing prednisone with dexamethasone during induction could prolong event-free survival (EFS). However, the trial was closed early because of a substantial number of toxic deaths in the dexamethasone arm.

In an updated analysis of the EURO-LB02 trial published in Haematologica, Eva Landmann, MD, from the Department of Pediatric Hematology and Oncology at Justus-Liebig-University in Giessen, Germany, and co-authors reported results from the secondary aims of the study, including testing whether the “outstanding results” seen in patients with T-cell lymphoma seen in previous studies were reproducible and identifying predictors of response to either prednisone, dexamethasone, or treatment re-intensification.

Though the NHL-BFM90 is “the backbone of [acute lymphocytic leukemia] treatment in many countries,” the authors wrote, based on the results from this trial, “improving the outcome for pediatric and adolescent patients with lymphoma remains a challenge.”

EURO-LB02 included patients younger than age 22 who were newly diagnosed with lymphoma; patients were excluded if they had a previous malignancy, preexisting disease prohibiting chemotherapy outlined in the NHL-BFM90 protocol, or previously received systemic corticosteroid treatment within two months before the start of therapy.

A total of 319 patients were enrolled in the trial (median age = 8.76 years; range = 0.3-18.8 years): 233 with T-cell lymphoma, 66 with precursor B-cell lymphoma, 12 with mixed phenotype, and eight with unclassifiable disease.

Patients were treated according to the NHL-BFM90 protocol:

  • cytoreductive phase: prednisone, methotrexate
  • induction phase Ia: vincristine, daunorubicin, asparaginase, methotrexate, either prednisone or dexamethasone
  • induction phase Ib: cyclophosphamide, cytarabine, 6-mercaptopurine, methotrexate
  • consolidation phase M: 6-mercaptopurine, methotrexate

Patients with stage III/IV disease underwent re-intensification with dexamethasone, vincristine, doxorubicin, asparaginase (phase IIa) and cyclophosphamide, cytarabine, methotrexate, 6-thioguanine (phase IIb).

Thirty-five of 40 patients with stage I/II disease completed all of the treatment protocol; 270 patients with stage III, IV, or unknown-stage disease received additional re-intensification therapy. During the induction phase, 215 patients received prednisone (standard group) and 104 patients received dexamethasone (experimental group).

With a median follow-up period of 6.8 years (range = 3.0-10.3 years), the five-year EFS was 82 percent; all patients with mixed phenotype lymphoma were alive at five years, and rates for precursor B-cell and T-cell lymphoma were 80 percent and 82 percent, respectively.

“The outstanding result of a five-year EFS of 90 percent for patients with T-cell lymphoma reported in [an earlier trial evaluating NHL-BFM90] could not be replicated in [the present study],” the authors noted, primarily due to higher rates of toxic deaths and central nervous system (CNS) relapses.

Twelve patients (3.8%) died because of toxicity during study follow-up. By day 33 of induction therapy, 39 patients relapsed and five developed secondary malignancies.

In the subgroup of patients with T-cell lymphoma, the median time from diagnosis to relapse was 12 months (range = 1-77 months). “CNS relapses occurred early (median = 12 months from diagnosis; range = 3-27 months),” the authors reported. “All nine patients suffering from CNS relapse received prednisone during induction.”

While results suggest that “dexamethasone in induction may prevent CNS relapse more effectively than prednisone … [dexamethasone] produces a higher burden of toxicity,” the researchers noted. Patients who received dexamethasone experienced significantly more grade 3/4 toxicities, including anemia (2.2% with prednisone vs. 7.4% with dexamethasone; p<0.001), thrombocytopenia (1.1% vs. 7.4%; p<0.001), leukopenia (12.4% vs. 25.5%; p=0.034), and infection (0% vs. 3.2%; p=0.041).

“A shorter duration of dexamethasone treatment might be another reasonable option for taking advantage of the efficacy of dexamethasone at a tolerable toxicity,” they wrote.

While treatment optimization relies on identifying highly predictive markers that can distinguish which patients could benefit from additional therapy and those who could be spared from treatment intensification, the only variable associated with shorter EFS was poor performance status at diagnosis (for <5 vs. 5 = hazard ratio = 3.0; 95% CI 1.3-6.9; p=0.01). “This parameter is not very useful for risk stratification,” the authors acknowledged, but it may “alert physicians to pay special attention to these patients.”

The study was limited by its premature closure and the use of EFS as a primary endpoint to evaluate a frontline treatment. Researchers also noted that a lack of familiarity with the NHL-BFM90 treatment protocol at certain participating centers may have confounded patient outcomes.

The authors report no relevant financial conflicts.


Reference

Landmann E, Burkhardt B, Zimmermann M, et al. Results and conclusions of the European Intergroup EURO-LB02 trial in children and adolescents with lymphoblastic lymphoma. Haematologica. 2017 October 5. [Epub ahead of print]

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