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Although acute lymphoblastic leukemia (ALL) is the most common neoplasm in children, with survival rates of 80–90%, the landscape is different for adult patients.1 ALL is rare in adults and survival outcomes are unfavorable in comparison with pediatric ALL. With the advancement of therapies, such as T-cell engagers and immunotherapies, results are progressively improving for this cohort of patients for both Philadelphia chromosome-negative (Ph−) and Philadelphia chromosome-positive (Ph+) ALL.1
Here, we summarize five key studies discussing novel treatment approaches for adult patients with ALL presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition.
Chiaretti presented results from GIMEMA LAL2317 (NCT03367299), a phase II trial investigating sequential chemotherapy and blinatumomab for improving the rate of early minimal residual disease (MRD) negativity in adult patients with Ph− CD19+ B-cell ALL. The primary objective was the rate of early MRD negativity at the end of Week 14 (Timepoint 3 [TP3]). Median follow-up was 38.1 months, Timepoint 2 (TP2) was after the 1st cycle of consolidation, and timepoint 3 (TP3) was after the 1st cycle of blinatumomab.
In total, 98 patients experienced Grade ≥3 adverse events (AEs), of which 33 were blinatumomab related and 32 were pegylated asparaginase related (Table 1).
Table 1. Most commonly reported Grade ≥3 AEs related to blinatumomab treatment.*
Adverse event, % |
|
CNS |
67 |
Hematologic |
23 |
Hepatic |
5 |
CRS |
2 |
Hypogammaglobulinemia |
2 |
AE, adverse event; CRS, cytokine release syndrome; CNS, central nervous system. |
The primary objective was reached, with 93% of patients experiencing MRD negativity at TP3 and 77% of MRD-positive cases at TP2 achieving MRD negativity after blinatumomab. Blinatumomab was effective across all age groups, with a significant survival improvement in patients aged 40–55 years, and relapses were improved in comparison with historical controls.
Boissel presented results from the T ATRIALL trial investigating the impact of nelarabine in patients with newly diagnosed T-cell ALL (T-ALL) from the GRAALL-2014 study (2014-002146-44), including 325 participants in total; 112 patients had high-risk features, were in continuous complete remission from the ATRIALL substudy, were assigned to nelarabine plus chlorpheniramine and etoposide, and results were compared with a control cohort (n = 33). The baseline characteristics were comparable between the two cohorts.
The safety profile was considered manageable, with 37 patients experiencing Grade ≥3 serious AEs and no association of occurrence of AEs across treatment stages (Figure 1).
Figure 1. Serious AEs in all patients included in the substudy according to treatment phase*†
AE, adverse event; HSCT, hematopoietic stem cell transplantation; DI, delayed intensification.
*Adapted from Boissel.2
†N = 120.
Nelarabine was well tolerated in adult patients with high-risk T-ALL and MRD was improved compared with standard chemotherapy. Further studies are warranted to reveal the specific patient subgroups that might benefit from nelarabine treatment.
This phase I multicenter trial (NCT02881086) investigated venetoclax and blinatumomab in combination for adults with relapsed/refractory (R/R) or MRD-positive Ph− B-precursor ALL. The primary endpoint was determination of the maximum tolerated dose ahead of the phase II expansion trial, and the secondary endpoint was efficacy.
Venetoclax in combination with blinatumomab was well tolerated, with five serious adverse events reported (Figure 2). No treatment-related mortality and no dose-limiting toxicities were reported.
Figure 2. Serious adverse events reported in patients with R/R or MRD-positive Ph− precursor B-cell ALL treated with venetoclax plus blinatumomab*
ALL, acute lymphoblastic leukemia; ICANS, immune effector cell-associated neurotoxicity syndrome; MRD, minimal residual disease; Ph−, Philadelphia-chromosome negative; R/R, relapsed/refractory.
*Adapted from Fransecky.3
Venetoclax plus blinatumomab was well tolerated in patients with R/R or MRD-positive Ph− precursor B-cell ALL and the maximum tolerated dose was not reached. This treatment showed encouraging efficacy, with 56% achieving molecular CR and the recommended phase II dose of 800 mg once daily. Despite limited patient numbers, the expansion trial currently ongoing in 18 centers will provide further understanding of these results.
BLISSPHALL (NCT04329325) is a multicenter, phase II study investigating dasatinib plus corticosteroid induction followed by a tyrosine kinase inhibitor (dasatinib [n = 13]; bosutinib [n = 2]; ponatinib [n = 2]) plus blinatumomab consolidation and maintenance therapy in adults with newly diagnosed Ph+ ALL. The primary objective was complete molecular response (CMR) by the end of consolidation (N = 17). Secondary objectives included the safety of blinatumomab + dasatinib, duration of CMR, incidence of relapse, and event-free survival (EFS)/OS.
At a median follow-up of 14.5 months:
AEs were well tolerated, with 42% Grade 3 AEs reported but no Grade 4 or 5 AEs (Table 2).
Table 2. Grade 3 AEs reported in patients with newly diagnosed Ph+ ALL related to treatment with blinatumomab or dasatinib therapy*
Most common Grade 3 AE, % |
|
Alanine aminotransferase increase |
12 |
Aspartate aminotransferase increase |
6 |
Nausea |
6 |
AE, adverse event. |
High rates of deep molecular response and low rates of severe toxicities can be achieved in patients with newly diagnosed Ph+ ALL through initial treatment with dasatinib plus corticosteroid induction followed by blinatumomab plus a tyrosine kinase inhibitor. Follow-up studies are required to confirm the durability of responses to blinatumomab consolidation and maintenance in the absence of allo-HSCT.
Similarly, to the trial summarized by Geyer.4 above, Haddad presents this phase II trial specifically investigating ponatinib plus blinatumomab in adult patients with Ph+ ALL. The primary endpoint was CMR rate (N=62), and the secondary endpoints included EFS, OS, and safety. In total:
There were seven relapses in total and four deaths (Table 3).
Table 3. Causes of death in patients enrolled in the phase II trial investigating blinatumomab plus ponatinib*
Cause of death, n |
|
Early death pre CR |
|
Intracranial hemorrhage from prior chemotherapy |
1 |
In CR |
|
Post-procedural bleeding and hypovolemic shock |
1 |
Brain aneurysm |
1 |
Post relapse |
1 |
CR, complete response. |
Ponatinib and blinatumomab were shown to have deep and rapid responses with durable remissions; the safety profile was manageable. It was concluded that this combination treatment is a promising, chemotherapy-free, HSCT-sparing regimen for patients with newly diagnosed Ph+ ALL.
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