Unlike with ALL-type treatment regimens, the only parameter used for risk stratification of patients with T-LBL or pB-LBL is disease stage at diagnosis. Patients are classified as having limited stage (stage I and II) or advanced stage (stage III and IV) disease. The literature reports limited stage disease EFS rates of 73% to 100%. These results could be achieved with relevant dose reductions in anthracyclines and alkylators, the authors noted.

To improve treatment directed at the central nervous system (CNS), protocol modifications of methotrexate (MTX) administration have been evaluated in a growing number of studies during the past 2 decades, with varying results. In an early French study, the LSA2L2 protocol was modified by adding 10 courses of high-dose MTX, and an EFS rate of 75% was achieved.2 Another study evaluated a backbone therapy with or without the addition of high-dose MTX in patients with T-ALL or T-LBL and found that patients with T-LBL experienced no significant differences in EFS with the addition of high-dose MTX, though patients with T-ALL did.3 A recent report from the International BFM group demonstrated that in a cohort of 58 patients with LBL, escalating MTX combined with the NHL-BFM backbone treatment achieved an EFS of 90% to 98%.4

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For patients with relapsed or refractory disease, outcomes remain poor, with survival rates in the range of 10% to 30%.5 In a Japanese cohort of 260 patients who were diagnosed with LBL between 1996 and 2004, the incidence of relapse and progression was 18%.6 In this group, 19 patients underwent allogeneic hematopoietic stem cell transplant (HSCT), 6 of whom relapsed, 3 of whom died of treatment-related mortality, and 10 of whom survived without further progression. Of the 6 patients who underwent autologous HSCT, 4 relapsed and died and 2 survived.


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Another study looked at 53 pediatric patients with LBL who underwent HSCT between 1990 and 2005 and found the EFS rate for 39 patients treated with allogenic HSCT to be 40% compared with an EFS rate of 4% in the 14 patients who underwent autologous HSCT.7 Overall, the available data show that for patients who experience relapse, those who do not undergo high-dose treatment followed by autologous or allogeneic HSCT have little chance of survival.

There is ongoing discussion regarding whether autologous or allogeneic HSCT is superior. Available data suggest that allogeneic HSCT is associated with higher treatment-related mortality but also with higher probability of achieving disease-free survival compared with autologous HSCT. However, definitive conclusions cannot be drawn because of the limited evidence available in the literature.

Future Directions

New targeted drugs, as well as drugs with less toxicity, are needed for this patient population, especially because survival following relapse is so dismal. One new drug, nelarabine, received regulatory approval from the US Food and Drug Administration several years ago based on results from two phase 2 trials in pediatric and adult patients with relapsed or refractory T-ALL or T-LBL. Of 39 pediatric patients, complete remission was achieved by 5. However, there is a need for novel therapeutic agents for high-risk, refractory, or relapsed pediatric T-LBL. Potential agents of interest are targeting the NOTCH, PI3K-Akt-mTOR, JAKSTAT, and MAPK pathways in addition to cell cycle regulation, the proteasome, and epigenetic targets; still others are using approaches derived from immunotherapy.

“Despite the long list, only a limited number of substances are under investigation in T-ALL and none in T-LBL,” the authors stated. Similarly, limited patient numbers, lack of knowledge regarding prognostic molecular biomarkers, and dismal outcomes for relapsed patients have raised challenges for identifying treatment options for pB-LBL.

“I think the take home messages are that this is a highly curable disease, but the job isn’t done until we can cure every patient with minimal toxicity,” said Dr Hermiston. “Research is needed to better understand this group of diseases so that we can meet this goal.”

Reference

1.     Burkhardt B, Hermiston ML. Lymphoblastic lymphoma in children and adolescents: review of current challenges and future opportunities [February 27, 2019]. Br J Haematol. doi: 10.1111/bjh.15793

2.     Patte C, Kalifa C, Flamant F, et al. Results of LMT81 protocol, a modified LSA2L2 protocol with high dose methotrexate, on 84 children with non-B-cell (lymphoblastic) lymphoma. Med Pediatr Oncol. 1992;20(2):105-113.

3.     Asselin BL, Devidas M, Wang C, et al. Effectiveness of high-dose methotrexate in T-cell lymphoblastic leukemia and advanced-stage lymphoblastic lymphoma: a randomized study by the Children’s Oncology Group (POG 9404). Blood. 2011;118(4):874-883.

4.     Sterba J, Kovacs G, Matus M, et al. Capizzi methotrexate with BFM backbone without craniospinal irradiation is effective treatment for pediatric lymphoblastic lymphoma: results from 5 countries with I-BFM LL 09 protocol. Br J Haematol. 2015;171(Suppl. 1):33. Abstract 56.

5.     Schmidt E, Burkhardt B. Lymphoblastic lymphoma in childhood and adolescence. Pediatr Hematol Oncol. 2013;30(6):484-508.

6.     Mitsui T, Mori T, Fujita N, Inada H, Horibe K, Tsurusawa M. Retrospective analysis of relapsed or primary refractory childhood lymphoblastic lymphoma in Japan. Pediatr Blood Cancer. 2009;52(5):591-595.

7.     Gross TG, Hale GA, He W, et al. Hematopoietic stem cell transplantation for refractory or recurrent non-hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant. 2010;16(2):223-30.