Philadelphia-negative ALL: A summary of hot topics presented at ASH 2022

Acute lymphoblastic leukemia (ALL) is often classified as a pediatric malignancy; however, its incidence in the older population is increasing. Compared with younger patients, patients with ALL aged >55 years have a lower clinical remission rate, higher early mortality, higher relapse rate, and poorer survival outcomes. Although progress has been made for this patient subset, there are still challenges involved in its therapeutic management; therefore, there is an urgent need for adapted regimens.¹

Below, we summarize four key topics in the treatment of Philadelphia chromosome-negative (Ph−)  ALL presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition. Boissel presented results from the GRAALL-2014/B trial (NCT02617004) on an age-adapted chemotherapy intensity and an MRD-driven transplant indication regimen²; Goekbuget presented data on outcomes in older patients prospectively treated according to pediatric-based age-adapted GMALL protocols³; Jabbour presented safety run-in results for the phase III randomized, controlled Golden Gate Study (NCT04994717) on blinatumomab alternating with low-Intensity chemotherapy in older adults⁴; and Short presented updated results from a phase II study on hyper-CVAD plus blinatumomab ± inotuzumab ogamacin (InO) in adult patients.⁵

GRAALL-2014 Trial/B: age-adapted chemotherapy intensity and MRD-driven transplant indication²

The outcomes of GRAALL-2014 trial/B study were compared to GRAALL-2005 (NCT00327678) in patients with Ph-negative B-ALL.

Results

Overall, 743 patients were evaluable in the GRAALL-2014 trial. Patient characteristics were similar between the two trials. At induction, patients aged ≥45 years achieved a higher complete remission (CR) rate due to a decreased early death rate. Hematopoietic stem cell transplant (HSCT) eligibility significantly decreased for all patients resulting in a decreased HSCT rate overall; this reduction was mostly seen in patients aged <45 years.

At a median follow-up of 3.2 years, an increased cumulative incidence of relapse was most significantly observed in patients aged ≥45 years in the GRAALL-2014 trial (Table 1). Additionally, all patients had a significant reduction in the cumulative incidence of treatment-related mortality (TRM; 48% for patients aged <45 years and 67% for patients aged >45 years). By lineage, this overall survival (OS) improvement was mostly seen in patients with B-ALL.

Table 1. Induction responses and outcomes in GRAALL-2014 vs GRAALL-2005 by age group*

Presenter’s conclusion

Age-adapted chemotherapy intensity and MRD-driven HSCT significantly reduced induction and postremission TRM in patients with Ph− ALL enrolled in the GRAALL-2014 study. This marked improvement in patients aged ≥45 years and/or those with B-ALL could be due to a reduction in early death rates, decreased TRM , and longer post-relapse survival. The combination of this study regimen with immunotherapies and small-molecule agents is likely to further improve outcomes.

Pediatric-based, age-adapted GMALL protocols in newly diagnosed Ph- ALL³

GMALL is an ongoing open-label multicenter study for the treatment of elderly patients with newly diagnosed ALL. A prospective analysis of a pediatric-based protocol, which underwent various modifications over the years, in older patients (aged 55–65 years) with Ph-ALL enrolled in the GMALL elderly trial 1/2003 (NCT00198978) and GMALL registry (NCT02872987) from 2003–2021 were presented by Gokbuget.³ Below, we report results from the standard protocol (Group 1) compared with the most recently revised protocol which consisted of asparagine in induction, increased dose-density, and an MRD-based treatment change following consolidation (Group 2).

Results

A total of 841 patients were evaluable, 593 in Group 1 and 248 in Group 2 (248).

• After induction, the overall CR rate in Group 1 and Group 2 was 72% and 75%, respectively;
• the early death rate in Group 1 and Group 2 was 15% and 9%, respectively; and
• CR rates were 76%, 73%, and 63% in three age groups (56–65, 66–75, and ≥76 years) with early death rates of 9%, 14%, and 26%, respectively (p < 0.0001).

Overall, lower MRD response rates were reported for this cohort compared with younger patients, with slight increases in molecular CR after induction, consolidation 1, and consolidation 2, (41%, 57%, and 64%, respectively %); the response rates were similar in the B-lineage subgroup. A significantly higher 3-year OS was reported in Group 2 versus Group 1 (50% vs 32%; p < 0.0001), with improvement also observed in T-lineage, B-lineage, and patients aged 56–65 years.

After consolidation 2, patients with a molecular CR vs those with molecular failure achieved a higher OS in the total cohort (80% vs 52%) and the B-lineage cohort (80% vs 51%). After addition of blinatumomab, the 3-year OS improved in Group 2 vs Group 1 in patients with molecular failure (74% vs 46%). Among 48 patients analyzed, the 3-year survival rate after SCT was 56%.

Presenter’s conclusion

An age-adapted pediatric-based regimen, involving peg-asparaginase in consolidation and added blinatumomab for MRD-positive molecular failure, improved outcomes in older patients with Ph− B-ALL. Suggested further improvements to this protocol include the integration of MRD testing and immunotherapies, an earlier MRD treatment-change for patients with poor molecular responses, and a newly designed protocol based on immunotherapies for patients aged >75 years with multiple comorbidities. The importance of all patients, regardless of age, being referred to specialist centers for complete diagnostic examinations and management was also highlighted.

Golden Gate Study: blinatumomab alternating with low-Intensity chemotherapy⁴

The Golden Gate Study is a single-arm phase III study of blinatumomab alternating with low-intensity chemotherapy in newly diagnosed older adult (≥55 years) patients with Ph− B-ALL. The primary endpoints were safety and tolerability, with secondary endpoints including efficacy and pharmacokinetics (PK).

Results

Efficacy

Overall, ten patients were enrolled in the study between November 2, 2021, and April 28, 2022. All patients completed induction cycle one, with positive responses achieved after cycles one and two (Table 2). Six patients discontinued treatment, four due to SCT and two due to relapsed disease.

Table 2. Responses after induction cycles*

Safety

The most common treatment-related emergent adverse events of any grade observed in ≥20% of patients were neutropenia (70%), cytokine release syndrome (50%), pyrexia (50%), leukopenia (50%), and COVID-19 infection (50%). There were no deaths reported during induction therapy, no blinatumomab-related Grade ≥3 central nervous system/cytokine release syndrome events occurred, and only one patient had a serious blinatumomab-related adverse event (Grade 3 blood bilirubin increased).

Pharmacokinetics and pharmacodynamic profile of blinatumomab

Preliminary PK data revealed increased exposure in a dose-related manner from 9–28 μg/day in cycle one; this was consistent with previous studies. Exposures observed in cycles one and two were within predictions of previous ALL studies.

The pharmacodynamic profile was similar for blinatumomab post-chemo versus blinatumomab alone, with similar trends for the 4-day and seven-dose steps in T-cell activation and cytokine elevation.

Presenter’s conclusion

Blinatumomab alternating with low-Intensity chemotherapy was effective and well tolerated in older adult patients with Ph− B-ALL, with no deaths reported. The PK and pharmacodynamic profile was consistent with previously reported data, with the latter supporting a 7-day drug-free period and a 4-day dosing step. Overall, these data support the phase III randomized controlled trial investigating blinatumomab with alternating low-intensity chemotherapy vs standard of care regimen.

Hyper-CVAD plus blinatumomab ± InO: updated results from a phase II study⁵

This phase II study (NCT02877303) of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus blinatumomab ± InO in newly diagnosed patients with Ph− B-ALL aged ≥14 years. The primary objective was to evaluate efficacy and safety.

Results

Efficacy

A total of 62 patients were treated, 24 with InO and 38 without. About 25% of patients had a high-risk cytogenetic feature and TP53 mutations. Overall, high response rates were achieved (Table 3).

Table 3. Response rates in patients with hyper CVAD + blinatumomab ± InO*

• At a median follow-up of 41 months in patients not treated with InO, 47% were in ongoing CR without HSCT, and the 3-year OS was 81%
• At a median follow-up of 12 months in those treated with InO, 63% were in ongoing CR without HSCT, no deaths were reported, and the 1-year OS was 81%.
• For the total cohort, the 3-year continuous remission duration and OS rates were 83% and 84%, respectively.

Safety

The toxicity profile was consistent with known toxicities associated with blinatumomab and InO, with one patient discontinuing blinatumomab due to Grade 2 neurotoxicity. No patients discontinued InO and there were no cases of veno-occlusive disease reported.

Presenter’s conclusion

Hyper-CVAD plus blinatumomab with or without InO demonstrated promising efficacy and safety in newly diagnosed patients with Ph- B-ALL. The early 1-year survival data in patients treated with InO were encouraging; however, longer follow-up analyses are needed to further establish its clinical efficacy.