Discussion:
This is the first report on the outcomes of a large prospective cohort of pediatric B-LBL from a refererral center in India. Pediatric B-LBL patients in the study received a modified BFM 90 protocol. While all children with advanced stage disease received re-intensification, administration of re-intensification for limited-stage disease and local radiotherapy (LRT) to primary was decided by the multidisciplinary team on a case-to-case basis. From 2014, Cranial Radiotherapy (CRT) of 18Gy was given only to CNS-3 patients. For the 21 pB-LBL patients, 5-year EFS and OS rates of 80% and 91% using the modified BFM 90 protocol were in accordance with major reported series in pB-LBL so far3,9–13. Age, gender, stage, baseline bone marrow involvement (either morphologic or by MDD/PET), and the post-phase I induction response do not seem to influence survival rates in our pB-LBL patients. This study reiterates the fact that intensive intrathecal injections in addition to high dose methotrexate (HDMTX) can safely replace prophylactic cranial irradiation (CRT) as described in major studies on childhood LBL8,14,15. Identifying prognostic factors is important due to poor prognosis at relapse, but is a challenge in childhood B-lymphoblastic lymphoma due to the rarity of the disease 4.
Delayed presentation as a cause of poor outcomes in childhood lymphoblastic lymphoma has been reported earlier16, and attributed to the diagnostic delay in developing countries. Two-third of the pB-LBL patients in our cohort with delayed presentation (4/6) had advanced-stage disease. Although there is a paucity of data on diagnostic delays in childhood lymphoblastic lymphoma and its impact on outcomes, we presume this poor outcome may be due to the development of biologic resistance with the accumulation of clonal genetic aberrations over time17,18. Elevated baseline LDH (>1ULN), an indicator of tumor bulk was also found to be significantly associated with poorer overall survival in our pB-LBL cohort (p-0.032). In high-grade NHL like Burkitt’s lymphoma and DLBCL, elevated baseline LDH (>2ULN) is a well-known predictor of overall poor outcome. Major studies on childhood lymphoblastic lymphoma were predominantly involving T-LBL and they found no direct association of baseline LDH with survival9,10. Also, childhood B-LBL is very rare which presents usually with localized stages with normal baseline LDH. Elevated baseline LDH in pB-LBL may be a potential biomarker of poor survival.
There was a trend towards poorer overall survival among advanced stage B-LBL patients presenting with osteolytic primaries compared to soft tissue lesions (p-0.08). Major pediatric co-operative groups noticed excellent outcomes of localized lymphoblastic lymphoma arising from bones10,19,20. However, 3/4 B-LBL patients with osteolytic primary had advanced-stage disease in our study, and 2 among them relapsed (1-medullary and 1-extramedullary relapse). One patient with localized iliac bone primary (patient-13) and another with Stage III disease and a tibial primary (patient-20) are alive in remission. Radiotherapy played a significant role in treatment regimens of primary bone lymphomas in the past21,22, but was associated with an increased risk of secondary malignancies such as sarcomas in the radiation field. As various studies have shown favorable survival rates without radiation, this modality is no longer included in standard treatment plans of primary bony lymphomas10. In our study, patient-1 and patient-20 with bony primaries received local radiotherapy in-view of persistent residual disease post- induction phase II.
Mussolin et al6 found flow cytometry detectable MDD in 23% of pB-LBL patients without cytological BM involvement. They also noticed a higher level of MDD (>3%) to be associated with a poorer event free survival in lymphoblastic lymphoma in children. Twenty percent (4/20) of our pB-LBL patients had baseline flow cytometry detectable MDD without cytological BM involvement (median-0.4%; Range:0.0009-0.7%). One Stage-IV B-LBL patient (patient-12) with 12% morphologic marrow involvement had 2.7% MDD by flow cytometry. We did not notice a difference in outcome in our B-LBL patients with or without baseline BM MDD which may be explained by the lower log of MDD noticed in our cohort compared to Mussolin et al. and also due to the potential use of re-intensification phase in limited-stage patients with baseline BM MDD.
Three relapses (14%) and one toxic death (5%) due to severe gram-negative septicemia remained the reason for treatment failure in our study. One patient with late testicular relapse is alive in remission post-salvage therapy and the rest 2/3 relapsed patients (1-early extramedullary relapse and 1-Late isolated medullary relapse) progressed on salvage chemotherapy and died. The EORTC reported a 15% relapse/progression rate in 8/53 B-LBL patients diagnosed between 1989 and 2008. All eight patients died, seven after allogeneic HSCT, five patients due to disease progression, and three fromTRM3. Irrespective of TRM, the best chance of cure after pB-LBL relapse is with high dose chemotherapy followed by allogeneic stem cell transplant5,23. Prospective future trials utilizing Blinatumomab or CAR-T cells in addition to chemotherapy backbone may potentially reduce failures in pB-LBL patients
Although with the limitation of retrospective single center analysis on a smaller number of pediatric B-LBL patients and lack of detailed toxicity data, our study identified a few potential clinical biomarkers which may aid in the risk stratification of pB-LBL patients in future trials.
Conclusions: Pediatric B-Lymphoblastic lymphoma is a rare entity. The modified BFM 90 protocol achieves excellent outcomes in pediatric B-LBL patients treated in the LMIC setting. pB-LBL patients presenting late (≥3months) from the first symptom onset and with elevated baseline Lactate dehydrogenase (LDH) fared poorly on this protocol.