Background and Aims

Background
L-asparaginase is an essential medicine for childhood ALL. The quality of generic L-asparaginase available in India is a matter of concern.

Aims
To determine the difference in asparaginase activity and the rate of development of anti-asparaginase antibodies (AAA) in patients administered generic L-asparaginase formulations

Methods

Between December 2018 to February 2020, 48 patients of childhood precursor B-ALL were randomly assigned to four generic brands of L-asparaginase i.e., Lagicad, L-aspase, Bionase and Asginase. 72-hour trough asparaginase activity was measured during induction following the first four doses of L-asparaginase administered intramuscularly at a dose of 10,000 IU/m². A colourimetric assay using L-aspartic beta hydroxamate (AHA) was developed for this purpose. AAA were measured using indirect ELISA technique. Historical patients who received L-asparaginase Medac (innovator) served as controls.

Results

A total of 168 trough samples from 42 evaluable patients were collected following the first 4 doses. Failure to achieve predefined activity threshold of 100 IU/L was observed in 9/40 samples of Lagicad (22.5%), 23/40 of Asginase (57.5%), 43/44 (98%) each of Bionase and L-aspase. All 27 samples from seven historical patients who were administered Medac had activity >100 IU/L. The average activity was significantly higher for Lagicad(181.4±20.7 IU/L) followed by Asginase(161.0±71.2), L-aspase(42.2±6.93) and Bionase(37.1±5.39) (P<0.05), while it was 704.9±400.3 IU/L for Medac. Only 6 patients had asparaginase activity >100 IU/L from all four samples (Lagicad=5; Asginase=1), and none of them developed anti-Asparaginase antibody. On the other hand, AAA was observed in 12/36 patients who had at least one level <100 IU/L (P<0.05) Lagicad 2/5; Asginase 2/9; L-aspase (4/11) and Bionase (4/11). The preparation along with antibody status affects the activity of the formulations, more the sub-therapeutic doses, the higher proportion of antibody development.

Conclusions

Lagicad and Asginase had better trough asparaginase activity compared to L-aspase and Bionase. Lower activity was associated with the development of AAA.

Background and Aims

T-ALL continues to pose unique challenges, with more aggressive presentations, high tumor burden, higher proportion of early relapses, and poorer outcomes of relapsed/refractory disease, compared to B-ALL. Evidence suggests differences in outcomes may be governed by key genetic mutations. We retrospectively studied the genetic profile of T-ALL patients at our center.

Methods

Children with T-ALL including Early T-Precursor(ETP) phenotypes, from Jan-2015-Dec-2016 treated at Tata Memorial Center, Mumbai were eligible. Those with available diagnostic bone-marrow samples from storage-facility were included. DNA was captured using a 37-gene panel comprising 1020 single-molecule molecular inversion probes technique. Response-evaluations were by 10-color flow-cytometry(FCM) for Minimal Residual Disease(MRD:<0.01%-negative) on bone-marrow. Clinical profile and events were noted from Electronic Medical Records(EMR), and outcomes correlated with genetic profiles on MedCalc®.

Results

Of 89 eligible patients, stored bone-marrow samples were available in 85, with median age 9 (range: 1.5-15 years), M:F-6:1, ETP- 5(6%), median WBC- 134(range:2.03-551.7/cmm). Treatment protocol was MCP-841 in 66(77.6%), and ICiCLe-2014 19(22.4%). BM-MRD evaluated in 75(6-induction deaths, 4-not available) patients was negative in 61(72%) post-induction and another 10 post-consolidation. Genetic profile detected FBXW7 in 19(22.3%), PTEN-17(20%), KMT2D & RPL10-15(17.6%) each, and others- USP7/BC11B-8, 11(12.9%) each, PHF6-9(10.6%), and CREBBP/NRAS, 7(8.2%) each. NOTCH1 mutations were not detected due to a technical error. Three-year relapse free and overall survival (RFS/OS) for the entire cohort were 52.3±9% and 53.5±6%, respectively. Univariate analysis showed PTEN to be an independent predictor of survival with OR 0.34[0.12 to 0.94] with 30 month RFS and OS 36.4±2 % and 23.2±1%, respectively.

Conclusions

Children with T-ALL remain curable, and most patients achieve early complete remissions, but continue to have relapse/non-relapse mortality. Genetic profiling of a selected cohort showed some role of biological factors, and PTEN mutations were especially associated with poor outcomes, suggesting the need for studying T-ALL genetic profiles in India in a systematic manner.

Background and Aims

ABL-class gene fusions other than BCR-ABL1 have been detected in ~3% of childhood ALL, and may be targeted by tyrosine kinase inhibitors (TKIs). This large international collaborative Ponte di Legno study aimed to establish the baseline characteristics and outcome of children with ABL-class ALL treated with contemporary trials without TKIs to help identifying the potential benefit of TKIs in current and future clinical trials.

Methods

Data of 122 newly diagnosed children with ABL-class ALL were collected from 14 international study groups. Patients were treated on contemporary, minimal residual disease (MRD) based protocols without TKIs during primary therapy.

Results

Outcome of all ABL-class cases at 5 year was relatively poor with 31.0% cumulative incidence of relapse (SE 4.6), 59.0% event-free survival (EFS; SE 4.7) and 76.1% overall survival (OS; SE 4.0). ABL-class patients displayed a high frequency of poor prednisone response (49%) and deletions affecting IKZF1 (61%), but both lacked prognostic value among these patients. End of induction (EOI) MRD levels were ≥1x10^-2 in 66% of cases, and were very often detected in ABL2 fusion (86%) and PDGFRB fusion (88%) cases. EOI MRD ≥1x10^-2 predicted an unfavorable outcome among ABL-class patients (HR_EFS 3.33, 95% CI 1.46-7.56; P=0.004). The 5-year EFS was most favorable for CSF1R (80%, SE 12.6) compared to ABL1 (68.6, SE 8.0), ABL2 (37.5%, SE 17.1) and PDGFRB fusion cases (52.9%, SE 6.6; P=0.059, 3 df). Patients treated on a high-risk regimen with or without alloSCT had comparable 5-yr OS (75.0% (SE 6.9) and 75.5% (SE 7.2) respectively).

Conclusions

Children with ABL-class ALL have a poor outcome with contemporary treatment without TKIs, emphasizing the need to implement TKIs. This paper provides the baseline characteristics needed to interpret the potential benefit of upfront use of TKIs in ABL-class patients.

Background and Aims

We administered EsPhALL chemotherapy plus dasatinib 60 mg/m² (starting day 15) at COG (North America and Australia) and EsPhALL (Italy and UK) sites. Patients (>1-17.99 years) with MRD ≥0.05% following induction Ib or MRD-positive following three additional high-risk (HR) chemotherapy blocks were allocated to CR1 HSCT. The remaining patients received chemotherapy plus dasatinib for 2 years. Only CNS3 patients received cranial irradiation.

Methods

Enrollment was 109 patients (3/2012-5/2014); 3 were ineligible and received no trial therapy.

Results

All 106 treated-patients achieved CR. With database lock 6/29/19, 48/106 had events including 38 relapses (24 marrow, 4 CNS, 4 marrow+CNS, 4 other, 2 marrow+other), 9 treatment-related deaths (7 in chemotherapy-assigned patients, 2 post-HSCT), and one malignancy. Nineteen (17.9%) patients met HSCT criteria, 15 (14.2%) received CR1 HSCT with 9 remaining event-free, 2 transplant-related deaths (6 weeks, 7 months), and 4 relapses (3 alive, 1 died). Among the four not transplanted, 2 were event-free, 1 relapsed and died, and 1 had an astrocytoma. The remaining 87 patients were assigned to chemotherapy plus dasatinib, with 47 remaining event-free. Seven died in CR1, 5 on-therapy (3 in HR3, 1 reinduction 2, 1 continuation) and 2 post-therapy (21 and 31 months). Thirty-three relapsed, 3 on-therapy at 16-23 months (all alive) and 30 post-therapy (18 ≤12 months, 12 >12 months; 22 alive and 8 deceased). The primary toxicities were febrile neutropenia and infection; one chemotherapy patient discontinued dasatinib (allergy) and one discontinued post-HSCT (myelosuppression).

Conclusions

Dasatinib plus EsPhALL chemotherapy is safe and effective in pediatric Ph⁺ ALL. With only 14% of patients undergoing CR1 HSCT, as compared to 81% in the EsPhALL 2004 and 38% in the EsPhALL2010 imatinib trials, this trial demonstrates similar outcomes with 5-year EFS 54.6% (95% CI, 44.5-63.6) and OS 81.7% (95% CI, 82.8-87.9) versus 60.3%/71.5% in EsPhALL 2004, and 57%/71.8% in EsPhALL 2010.

Background and Aims

AALL1331 established blinatumomab as standard-of-care for post-reinduction consolidation for high-risk first relapse of B-lymphoblastic leukemia (B-ALL), improving survival by 20%. However, only patients progressing through UKALLR3-based chemotherapy reinduction to randomization were included in this analysis. Here, we critically examine the efficacy and tolerability of UKALLR3 chemotherapy reinduction in early (<36 months from diagnosis) bone marrow (BM) relapses.

Methods

AALL1331 early BM relapse patients (1-30 years) received UKALLR3 reinduction (vincristine, dexamethasone, pegaspargase, mitoxantrone and intrathecal chemotherapy) followed by randomization to two blocks of post-induction chemotherapy or blinatumomab. Outcomes included adverse events (AEs), morphologic response, flow-based minimal residual disease (MRD) and survival.

Results

Of 206 (n=176 ages 1-17; n=30 ages 18-30) early BM relapses that began reinduction, only 118 (57%) proceeded to randomization, with 88 (43%) dropping out prior to randomization. Drop-out reasons included toxic death (n=11; 5%), severe AEs (n=6; 3%), treatment failure (M3 BM, n=34; 17%) and family/physician preference (n=37; 18%; nearly all due to high MRD and/or significant residual AEs). The 2-year overall survival was: 44+/-4% for all 206 patients; 25+/-6% for n=88 reinduction dropouts; 70+/-7% for n=59 randomized to post-reinduction blinatumomab; and 38+/-8% for n=59 randomized to post-reinduction chemotherapy. Life-threatening/fatal (grade 4/5) AEs occurred in 68/206 (33%) patients. Of 155 patients completing reinduction with M1/M2 marrows, only 52 (34%) achieved <0.01% MRD, and 37 (24%) had MRD >1%.

Conclusions

UKALLR3 reinduction chemotherapy demonstrated poor efficacy and tolerability in early first BM relapse of B-ALL, resulting in high rates of severe AEs, toxic death and M3 induction failure, high MRD levels among those who responded, high dropout rates, and poor survival. While post-reinduction blinatumomab improves survival for the subset of patients able to be randomized, the failure of intensive reinduction chemotherapy translates into unacceptably low survival rates from the time of relapse. New approaches to reinduction are needed.

Background and Aims

Background and Aims
Collaborative study in Chinese Children Cancer Group (CCCG) which involves 12 centers in China to study the efficacy and safety of adding rituximab in CD20+ve relapsed ALL and the efficacy and safety of adding bortezomib in high risk patients with early or very early relapse ALL.

Methods

Methods
Open label single arm phase 2/3 study with newly diagnosed first relapse of ALL. Patients were classified as Standard Risk (SR), Intermediate Risk (IR) and High Risk (HR) based on stratification criteria. All CD20 +ve relapse ALL will be given rituximab at induction and consolidation phases. All HR patients (all patients with MRD > or equal 0.01% at week 5 or those with early and very early bone marrow relapse), bortezomib is added in consolidation therapy and all will proceed to haematopoietic stem cell transplantation (HSCT) after consolidative therapy.

Results

Results
From Jan 2018 to Feb 2020, a total of 115 patients enrolled in 12 sites in China (SR : 6 ; IR 52 , HR 54; 3 cases unknown ); Lineage classification (B-cell 93; T-cell 10; Unknown 12). Very early relapse 22 (diagnosed < 18 months from diagnosis); early relapse 34 (diagnosed at >18months but less than 36 months); late relapse 59 at > 36 months from initial diagnosis.Overall, 84.3% achieved CR after induction (B-cell 83.8%; T-cell 88.9%). Non-remission rate for B-cell was 11.3% and T cell was 11.1%. For relapsed B-ALL, 1-year OS and EFS was 86.7% and 81.0% respectively whereas relapsed T cell ALL was 52.5% and 48.2% respectively. One-year EFS for non-HR and HR with induction remission was 93.2% and 73.3% respectively. Treatment-related mortality accounted for 4.3%.

Conclusions

Conclusions

The remission rate was similar to other published studies and the treatment toxicity was acceptable in this study. Longer follow up is required to assess the efficacy of additional agents.