Inotuzumab ozogamicin and blinatumomab in older adults with newly diagnosed B-ALL: ALLIANCE trial

Older patients (≥60 years) with newly diagnosed Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL) have poor survival with conventional chemotherapy. The phase II ALLIANCE A042001 (NCT05303792) trial investigated induction with inotuzumab ozogamicin (InO) and consolidation with blinatumomab in older adult patients with relapse/refractory (R/R) ALL. The study hypothesized that this regimen would improve 1-year event-free survival (EFS) compared with historical outcomes with conventional chemotherapy (1-year EFS, 10%). The aim was to provide an alternative treatment to conventional chemotherapy as first-line therapy in older patients (≥60 years old) who may experience multiagent chemotherapy regimens as toxic and only modestly effective.

Study design

This phase II, interventional clinical trial enrolled patients who were previously untreated for CD22⁺ Ph-negative ALL. Patients eligible for this study had Ph-negative B-ALL and were

• ≥60 years of age;
• had an Eastern Cooperative Oncology Group Performance Status of 0 to 2;
• had no planned allogeneic or autologous hematopoietic cell transplant (HCT);
• had no active central nervous system or testicular leukemia or additional malignancy active within the previous 2 years; and
• had no history of chronic liver disease, veno-occlusive disease/sinusoidal obstruction syndrome, significant cardiac disease, or clinically relevant neurologic disorder.

The study consisted of a treatment schema involving two courses of InO given at an induction dose on a weekly basis before a response assessment. Patients who showed response after the first assessment went on to receive a second dose of InO and those who did not went straight onto consolidation therapy (Figure 1).

The primary endpoint was estimated 1-year EFS (event = progression of disease prior to the end of cycle 2 of consolidation blinatumomab, relapse, or death from any cause). Secondary endpoints included overall survival, relapse-free survival, complete response rate, minimum residual disease (MRD) negativity rate, treatment-related mortality, and safety and tolerability.

ALL, acute lymphoblastic leukemia; CIV, continuous intravenous infusion; CNS, central nervous system; CR, complete remission; CRi, complete remission with incomplete hematologic recovery; InO, inotuzumab ozogamicin; IT MTX, intrathecal methotrexate; R/R, relapsed/refractory.
*Adapted from Wieduwilt, et al.¹

Results

A total of 33 patients aged between 60–84 years were treated. At baseline, 24% had prior malignancy and chemo/radiotherapy and 18% had multiple myeloma. Additionally, 92% had CD22 expression. Baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

ECOG, Eastern Cooperative Oncology Group; WBC, white blood count; RXT, radiotherapy. *Adapted from Wieduwilt, et al.1
Characteristic, % (unless otherwise stated)	Total (N = 33)
Age
Median, years (range)	71 (60-84)
≥70 years	52
Race
White	85
Asian	3
Not reported / unknown	12
Ethnicity
Not Hispanic or Latino	82
Hispanic or Latino	9
Unspecified	9
Gender
Male	58
ECOG performance status
0	24
1	58
2	18
Prior malignancy and chemo-RXT
Any	24
Multiple Myeloma	18
Presenting WBC (range), median ×1000/mcl	3.2 (0.6–38)
Median CD22 expression (range)	92 (21–100)

Hematologic response and efficacy

The study met its primary endpoint and overall survival after one year was promising, with median overall survival not been reached (95% confidence interval [CI], 31 months–not reached) (Figure 2). In total, 12 events were recorded in all patients, with nine patients relapsing from the systemic central nervous system, CD19 or CD22 negative.

Composite complete remission was achieved by 96% of patients in both treatment groups, with 60% of this group achieving complete responses. Complete response/complete remission with partial hematologic recovery/complete remission with incomplete hematologic recovery was achieved by 85% of patients on the course of treatment IA/IB/IC and CR was achieved by 58% of patients by the end of the second course of treatment.

EFS, event-free survival; OS, overall survival
*Adapted from Wieduwilt, et al.¹

Safety

The most common ≥Grade 3 adverse events reported in over 30% of patients were decreased neutrophil count (87.9%), platelet count decrease (72.7%), anemia (42.4%), and white blood cell decrease (39.4%). Overall, there were nine deaths, six due to relapsed ALL and three due to adverse events.

Conclusion

The ALLIANCE A042001 trial reached its primary endpoint. The author concluded that a conventional chemotherapy-free regimen of InO induction and blinatumomab consolidation was highly effective and safe in older patients with newly diagnosed Ph-negative CD22+ B-ALL. Further study is required to establish the significance of these results; however, this trial shows InO plus blinatumomab may be a more suitable alternative to conventional chemotherapy in this population of patients.