Data from the following presentations are discussed:

Minimal residual disease at end of induction and consolidation remain important prognostic indicators for newly diagnosed children and young adults with very high-risk (VHR) B-lymphoblastic leukemia (B-ALL): Children’s Oncology Group AALL1131. (Salzer, ASCO 2021 Abstract 10004)

Minimal residual disease (MRD) was examined in children and young adults with very high risk (VHR) B-acute lymphoblastic leukemia (B-ALL). Post-Induction therapy using fractionated cyclophosphamide and etoposide demonstrated significantly improved disease-free survival (DFS) (

0.0013), in MRD positive and end of consolidation (EOC)MRD negative patients compared to EOC MRD positive patients. A greater 4-year disease-free survival was noted in EOI (end of induction) MRD <0.01%, (

= 325) compared to EOI MRD >0.01 (83.3% ± 2.6% vs 72.0% ± 2.8%, respectively).

Experimental arm 2 (cyclophosphamide, etoposide, and clofarabine treatment) was discontinued in September 2014 due to disproportionate toxicities.

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Videos

Doug Smith, MD, provides context for the AALL1131: a phase III randomized trial for newly diagnosed high risk b-precursor acute lymphoblastic leukemia (ALL).

MRD as a Prognostic Indicator in Children and Young Adults with Very High-Risk ALL

Preliminary results of the GIMEMA LAL2317 sequential chemotherapy-blinatumomab front-line trial for newly diagnosed adult Ph-negative B-lineage ALL patients. (Bassan, EHA 2021 S114)

The preliminary analysis demonstrated the efficacy of blinatumomab added to chemotherapy in increasing minimal residual disease (MRD) negativity (<10-4) in CD19+ B-lineage Philadelphia Chromosome positive acute lymphoblastic leukemia, with the primary study endpoint being completely achieved. Statistically, hematological CR (complete remission) was achieved in 131 patients, equaling 90.4% where 7 were resistant, 7 died early, and 1 was not evaluable. Comparatively, within the primary study endpoint, the MRD clearance after blinatumomab course 1 resulted in 85 patients with paired MRD samples who were evaluable. Following early consolidation, 73% of these patients were classified as MRD-negative (<10-4). As a result, this increased to 96% after the first blinatumomab administration (

0.018). Moreover, there was a conversion rate from MRD positivity to MRD negativity of 87%, specifically 20 out of 23 patients.

A 12-month relapse incidence of 11% (15 relapses) was observed in patients treated with blinatumomab and was not impacted by MRD (positive, negative, or undefined). Additionally, the effect of the treatment results resulted in a lower early relapse rate, which was detectable in every risk subset.

Robin Foà, MD, discusses results from the GIMEMA LAL2317 sequential chemotherapy-blinatumomab frontline trial, where experts evaluated the efficacy of blinatumomab in increasing the early MRD (minimal residual disease) negativity rate.

GIMEMA LALl2317: Sequential Chemotherapy and Blinatumomab for Adult ALL

Updated results of the, D-ALBA trial, for newly diagnosed adults with Ph+ ALL. (Chiaretti, EHA 2021 S112)

In the updated 2-year follow-up from the GIMEMA LAL2116 trial, molecular responses to treatment with dasatinib and blinatumomab were noted in the majority of enrolled patients. An overall survival (OS) and disease-free survival (DFS) of 87.8% and was 79.8%, respectively was observed. Notably, a greater DFS rate was demonstrated in patients achieving a molecular response upon induction/consolidation treatment compared to those who did not (100% vs 75.9%, respectively; p=0.028). 

 greater DFS benefit was noted in those patients with an 

A high incidence of CNS (central nervous system) involvement wasrecorded in addition to 3 relapses. Additionally, 3 deaths in CHR (complete hematologic remission) were documented.

Robin Foà, MD, leads a discussion on the primary takeaways from the GIMEMA LAL2116, D-ALBA trial, particularly the prognostic impact of the IKZF1-plus genotype and the Ikaros mutation.

GIMEMA LAL2116, D-ALBA, Updated Results and Prognostic Impact of IKZF1 in Ph+ ALL

Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: Early results from a phase II study. (Short, ASCO 2021 Abstract 7001)

28 patients (currently 38 at the time of this interview) with either newly diagnosed (ND) or relapsed/refractory (R/R) Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) were enrolled in the phase II study. 100% of ND patients responded to treatment compared to 88% of R/R patients. A complete molecular response was noted in 86% of enrolled patients (87% in ND vs 86% in R/R patients). A greater treatment benefit was noted in the ND cohort with an estimated 1-year overall survival (OS) and event-free survival rate of 94% and 88%, respectively. This is compared to the 88% and 55% OS and event-free survival rates noted in the R/R patient cohort.

Treatment with ponatinib was well tolerated in both patient cohorts with only grade 1-2 side effects noted. Treatment with ponatinib was not discontinued due to toxicity in any patient.

Elias Jabbour, MD, highlights early findings from a phase 2 study of the combination of ponatinib and blinatumomab in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).

Phase II Results: Ponatinib + Blinatumomab in Ph+ ALL

OPTIC primary analysis: A dose-optimization study of 3 starting doses of ponatinib (PON). (Cortes, ASCO 2021 Abstract 7000)

 In this phase 2 dose optimization trial, treatment or exposure to ponatinib suggested a correlation between dose level and rates of adverse events (AEs) and measurable treatment responses. An optimal benefit/risk ratio was noted at a dose of 45 mg/d (milligrams per day), with a further dose reduction to 15 mg/d when a ≤1% BCR-ABL1IS was achieved. This benefit was noted to be most pronounced in patients with a T315I mutation.

AEs and serious AEs were noted across all treatment cohorts, with the most commonly seen grades ≥3 TEAEs leading to treatment discontinuation being thrombocytopenia (27%), neutropenia (17%) and anemia (7%).

Jorge Cortes, MD, reviews the results of the OPTIC trial: a dose-optimization study of 3 starting doses of ponatinib.

Elias Jabbour, MD, MD Anderson Cancer Center

Articles

MRD as a Prognostic Indicator in Children and Young Adults with Very High-Risk ALL

GIMEMA LALl2317: Sequential Chemotherapy and Blinatumomab for Adult ALL

GIMEMA LAL2116, D-ALBA, Updated Results and Prognostic Impact of IKZF1 in Ph+ ALL

Phase II Results: Ponatinib + Blinatumomab in Ph+ ALL

OPTIC Primary Analysis: a Dose-Optimization Study of 3 Starting Doses of Ponatinib in CML Treatment