Novel treatment in Philadelphia negative ALL: Key updates from EHA 2023

The treatment landscape for patients with Philadelphia chromosome negative (Ph−) acute lymphoblastic leukemia (ALL) has expanded with the introduction of targeted therapies; therefore, combining these agents with chemotherapy is a key treatment of interest. Below, we summarize three key presentations on novel therapies for the treatment of Ph− ALL, presented at the European Hematology Association (EHA) 2023 Congress.

Haddad presented overall survival (OS) and relapse-free survival (RFS) data for venetoclax in combination with mini-hyper-cyclophosphamide, vincristine, and dexamethasone (CVD) in relapsed/refractory (R/R) Ph− ALL, and a study of inotuzumab ozogamicin (InO) with or without blinatumomab in older patients with newly diagnosed Ph- ALL^1,2; Short presented response rates of hyper-CVAD (cyclophosphamide, vincristine doxorubicin, and dexamethasone) with blinatumomab and InO in de novo Ph− ALL.³

Mini-hyper-CVD with venetoclax in R/R Ph− ALL¹

This open-label, phase II trial (NCT03808610) investigated the combination of venetoclax with low intensity mini-hyper-CVD in patients with R/R Ph− B-cell or T-cell ALL (B-ALL; T-ALL). The study endpoints included RFS and OS, other endpoints included complete response (CR), overall response rate (ORR), and median time to platelet and neutrophil recovery.

• Overall, 23 patients were enrolled with a median age of 45 years, 52% were male, 78% had B-cell ALL and 22% had T-cell ALL; the median number of prior treatments was two and 57% of the patients had prior allogeneic stem cell transplant.
• Median 1-year OS and RFS was 8.1 months and 6.4 months, respectively, with a 1-year RFS rate of 15% and OS rate of 37%; survival was worse in patients with adverse cytogenetics compared with those without (median OS, 6 months vs 12 months).
• In total, 55% of patients responded to therapy and 41% achieved a CR (n = 9); ORR was 67% among patients who underwent a bone marrow transplant after Cycle 1 (n = 18); median time to platelet and neutrophil recovery was 27 days and 21 days, respectively, after Cycle 1.
• Mortality rates were 0% and 13% after 30 days and 60 days, respectively.

Presenter’s conclusions

Mini-hyper CVD in combination with venetoclax was effective with a favorable safety profile in patients with R/R Ph− B-cell or T-cell ALL.

Mini-hyper-CVD-InO with or without blinatumomab in newly diagnosed Ph− ALL³

Haddad presented another open-label, phase II trial (NCT01371630) investigating InO plus mini-hyper-CVD in combination with blinatumomab in newly diagnosed patients aged ≥60 years with Ph− pre-B ALL. The study endpoints were the duration of complete remission and OS. Other endpoints included CR, ORR, and minimal residual disease (MRD) negativity rate.¹

• The study included 83 patients with a median age of 68 years, 34% were ≥70 years old, 13% had an Eastern Cooperative Oncology Group Performance Status of ≥2, 39% had a TP53 mutation, and 5% had central nervous system disease at diagnosis.
• ORR was 99%, of which 90% achieved CR. The MRD negativity rate was 79% at Cycle 1 and 94% overall.
• Five-year duration of complete remission was 78% and OS was 48%; patients aged 60–69 without poor-risk cytogenetics had better survival than patients aged ≥70 years (72% vs 38%).
• Three patients developed veno-occlusive disease (VOD), two after subsequent stem cell transplantation.

Presenter’s conclusions

Mini-hyper-CVD plus InO plus blinatumomab was effective with a tolerable safety profile in this subgroup of older patients with newly diagnosed Ph− ALL.¹ Patients aged 60–69 years without poor-risk cytogenetics and had significantly improved 5-year OS (72%).

Hyper-CVAD with blinatumomab and InO in newly diagnosed Ph- ALL²

Short presented an open-label, phase II study (NCT02877303) examining the efficacy and safety of hyper-CVAD in combination with sequential blinatumomab with or without InO in patients with newly diagnosed Ph− B-cell ALL. The study endpoints were CR, RFS, and OS. Other endpoints included flow MRD negativity rate and 30-day mortality.

• Overall, 72 patients were enrolled with a median age was 34 years, 85% had an Eastern Cooperative Oncology Group Performance Status of 0–1, 8% had central nervous system involvement at diagnosis, and 18% had a TP53 mutation.
• RFS at 1-year in the hyper-CVAD + blinatumomab + InO and hyper-CVAD + blinatumomab groups was 97% and 82%, respectively (p = 0.07).
• OS at 1 year in the hyper-CVAD + blinatumomab + InO and hyper-CVAD + blinatumomab groups was 100% and 87%, respectively (p = 0.04).
• Response rates were higher in patients treated with InO and blinatumomab compared with blinatumomab alone, with CR after induction and at any time achieved by 84% and 100%; 69% were flow MRD negative after induction and 95% were at any time (Figure 1).
• There were no cases of mortality at Day 30 posttreatment and no cases of VOD/sinusoidal obstruction syndrome or discontinuations were observed in patients treated with InO; one patient discontinued blinatumomab due to a Grade 2 neurotoxicity event.

Figure 1. Response rates* 

CR, complete response; blina, blinatumomab; HCVAD, hyper-cyclophosphamide, vincristine doxorubicin, and dexamethasone; InO, inotuzumab ozogamicin; MRD, minimal residual disease.
Data from Short.³

Presenter’s conclusions

Hyper-CVAD combined with sequential blinatumomab ± InO is an effective first-line therapy for patients with newly diagnosed Ph− B-cell ALL.³ The addition of InO improves response and safety outcomes compared with blinatumomab alone.