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.