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Hematology 2021 Leukemias

CME

Key Studies in Leukemias: Independent Conference Coverage of ASH 2021

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: April 06, 2022

Expiration: April 05, 2023

Eunice S. Wang
Eunice S. Wang, MD
CME/CE Information

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GMALL 08/2013: Background

Eunice S. Wang, MD:
Intensive chemotherapy is essential for attaining cure in adults with ALL.40,41 But toxicities, resistance, and relapsed/refractory disease are obstacles to long‑term cure in many older patients. There are debates about tailoring standard chemotherapy and incorporating targeted agents to improve treatment outcomes across biologic subsets of ALL that are difficult to treat. The use of pediatric regimens optimized for use in adolescents and young adults has improved survival and might have a role in treating adults with early-stage ALL.40-42

The GMALL 08/2013 trial is evaluating an individualized approach incorporating intensive chemotherapy but allowing for variation in backbone therapy based on the patient’s biologic subset. Results from the trial were reported at ASH 2021 by Göekbuget and colleagues.43

GMALL 08/2013: Study Design

Eunice S. Wang, MD:
This is an ongoing phase III/IV trial of patients 18‑55 years of age with newly diagnosed ALL (n = 638) or lymphoblastic leukemia (LBL) (n = 67) with severe uncontrolled complications of ALL or secondary diseases (planned N = 950).43

All patients received a pediatric‑inspired backbone therapy including dexamethasone and pegylated asparaginase for induction and consolidation. This was followed by high‑dose methotrexate, additional asparaginase, and then reinduction as needed. Following this backbone, patients were randomized to receive alterations from the standard regimen based on T-cell vs B‑cell phenotype and presence/absence of refractory disease. Patients who had T‑cell–lineage ALL received chemotherapy with nelarabine. Patients with higher‑risk disease were randomized to stem cell transplant or conventional therapy.

The primary endpoint was EFS with a timeframe of 3.5 years. The secondary endpoint was time until treatment consolidation and disease-free survival within the first year.

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GMALL 08/2013: Baseline Characteristics

Eunice S. Wang, MD:
Most patients were 18-35 years of age (51%-55%), but 15% to 22% of patients were 36-45 years of age, and 27% to 30% of patients were 46-55 years of age.43

One quarter of patients with ALL had T‑cell lineage, as we would expect, with the remaining 75% having B‑cell precursor lineage—55% Ph negative and 20% Ph positive. Among patients with LBL, 88% had T-cell lineage, and the rest had B-cell precursor lineage that was Ph negative.

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GMALL 08/2013: Response Following First Consolidation

Eunice S. Wang, MD:
Response following the first consolidation was universally high, with a >88% rate of hematologic CR across all patient subgroups.43 Early deaths were very uncommon (3%-7%), as was failure or a partial response (1%-7%).

The rates of molecular CR and molecular response also were high, with both >40% in all patient subgroups. Only approximately 10% to 15% of the patients were MRD positive following the first consolidation. The only exception was patients with T‑cell ALL whose overall hematologic CR rates and MRD rates were less favorable compared with the B‑cell phenotype.

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GMALL 08/2013: Use of Peg-Asparaginase

Eunice S. Wang, MD:
Peg‑asparaginase was initially dosed at 2000 U/m2 on Day 20 of induction I and Day 44 of induction II for Ph-negative patients; Ph-positive patients received 2000 U/m2 on Day 20 and 34 of induction.43 The first dose was reduced to 500 U/m2 if BMI was >30 kg/m2 and for preexisting liver toxicities, steatosis hepatis, or comorbidities. Of importance for the older patients, a second dose was withheld if there were relevant asparaginase-associated toxicities.

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GMALL 08/2013: Asparaginase Therapy

Eunice S. Wang, MD:
Most patients were able to receive an initial dose of asparaginase at 2000 U/m2, but only 41% to 43% of patients received this for the second dose.43 The incidence of hepatotoxicity and hyperbilirubinemia were reasonable, and dose reduction slightly reduced their incidence.

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GMALL 08/2013: Efficacy After Targeted Consolidation II

Eunice S. Wang, MD:
In total, 63 patients with standard‑risk or high‑risk disease had molecular failure and were candidates for a second consolidation followed by stem cell transplant.43 Patients with B-precursor disease received additional therapy with blinatumomab (n = 40) and had a 55% molecular response rate (MRR), a little lower than what was expected based on prior data. Patients with T-cell ALL received nelarabine (n = 11) and had an 18% MRR. Ph‑positive patients with molecular failure were individualized to receive an alternative TKI followed by stem cell transplant.

The 3-year OS in patients with ALL with MRR was impressive at 75% in Ph-negative patients and 79% in Ph-positive patients. These survival data approach the numbers we see in the pediatric, adolescent, and young adult patient population.

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GMALL 08/2013: OS

Eunice S. Wang, MD:
Patients aged 36‑45 years had a 3-year OS of 69%, and patients aged 46-55 years had a 3‑year OS of 73%.43 So it appears that this tailored salvage approach benefited survival across all patient age groups.

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GMALL 08/2013: Clinical Implications

Eunice S. Wang, MD:
I believe that this study supports the integration of targeted therapies into the frontline setting for all patients up to 55 years of age with newly diagnosed T-cell/B-cell ALL and LBL. It was especially encouraging to see a high ORR among patients of all ages and not just young adults. I think the strategy of combining a standard backbone with other drugs will become the new standard of care.

Dr. Smith, what are your thoughts?

B. Douglas Smith, MD:
I completely agree that these data are impressive, particularly for the older adults included in this trial. I think this study will change the way we go about assessing and treating patients. The strategy used in this trial really nicely pulls together data from different studies to give patients better long‑term outcomes.

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