Chemotherapy Plus Inotuzuamb Ozogamicin Elicits Promising Responses in B-Cell ALL

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The addition of inotuzumab ozogamicin (Besponsa), with or without blinatumomab (Blinctyto), to low-intensity chemotherapy in the treatment of older patients with B-cell acute lymphocytic leukemia (ALL) showed promising efficacy signs while an adjustment of the chemotherapy may be needed to increase tolerability, according to a long-term follow up in a phase 2 trial (NCT01371630).¹

In this open-label, single-center, phase 2 study, 80 patients were enrolled from 2011 to 2022, with a median age of 68 years, and found that at a median follow up of 92.8 months (range, 42.0-106.7) the 2-year progression-free survival (PFS) rate was 58.2% (95% CI, 46.7%-68.2%) and the 5-year PFS rate was 44.0% (95% CI, 31.2%-54.3%).

These patients were initially given an induction therapy of mini-hyper-CVD with inotuzumab ozogamicin given intravenously (IV) on day 3 of the first 4 cycles at 1.3–1.8 mg/m² in cycle 1, then 1.0–1.3 mg/m² doses in cycles 2 through 4. A maintenance therapy of dose reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was then given for 3 years. However, from the 50th patient enrolled and onward the protocol was amended to giving the patient a max dose of 2.7 mg/m² of inotuzumab ozogamicin at 0.9 mg/m² during cycle 1 fractionated into 0.6 mg/m2 on day 2 and 0.3 mg/m² on day 8 of cycle 1. Then, 0.6 mg/m² of the anti-CD22 antibody­–drug conjugate was given in cycles 2 through 4 and fractionated into 0.3 mg/m² on day 2 and 0.3 mg/m² on day 8. This was followed by the same amount of blinatumomab for 4 cycles, but POMP maintenance was shortened to 12 cycles with 1 cycle of the blinatumomab given continuously after every 3 cycles of POMP.

Ultimately, 31 of the 80 patients were enrolled and treated after the protocol was amended and were followed up with at a median of 29.7 months (range, 12.8-59.6) compared with 104.4 months (range, 92.8-110.4) for those who started treatment before the amendment. When comparing these two groups of patients, however, there was no significant difference between their median PFS of 34.7 months (95% CI, 15.0-68.3) and 56.4 months (95% CI, 11.3-69.7), respectively (P =.77).

Overall survival (OS) was also seen to be promising among these patients at 2-year OS rate of 63.6% (95 CI, 51.9%-73.3%) and a 5-year OS rate of 46.0% (95% CI, 33.6%-58.0%). When not including patients that died during disease remission a median continuous remission duration was still not reached but at 2-years had a rate of 84.0% (95% CI, 72.0%-91.5%), which lowered to 80.2% (95% CI, 65.7%-88.0%) at 5 years.

According to the researchers, the combination of inotuzumab ozogamicin and low-intensity chemotherapy with and without blinatumomab produced an overall response rate of 99% and a flow minimal residual disease (MRD) negative response rate of 94%. Seventy-nine of the 80 patients were eligible for MRD evaluation and 4 of the 5 patients who enrolled with MRD-positive remission had MRD negativity in the end. Further, 84% of the patients who were in remission after the first cycle of treatment had MRD negativity then and in 72 patients evaluated for an early MRD response 85% were MRD negative.

Looking at 74 patients for response outcomes, 6 already had complete remission when they started the trial hence, they were not eligible for the response assessment, 66 of these patients had a complete response (CR) and six of these patients had a CR without platelet recovery. Looking at patients with certain biomarkers, just 1 patient with tetraploidy but harboring no TP53 mutation in their disease and not positive for CRLF2 did not respond. Looking at these patients with cytogenetic data, the median PFS for patients with CTG-HR vs without was 14.7 months (95% CI, 6.5-50.2) vs 60.4 months (95% CI, 27.3-109.6), respectively (P = 0.010). Median PFS and OS for those 24 patients harboring a TP53 mutation in their disease were both 33.2 months (95% CI, 10.5-61.5) and among those with a wild-type TP53 mutation, both the median OS and PFS was 46.6 months (95% CI, 16.2-70).

Patients on the study were also divided into 3 groups based on age; 60-64 years of age (n = 25), 65-69 years of age (n = 27), and those 70 years of age or older (n = 28). In the 60-64 group median PFS was 70.2 months (95% CI, 16.3-Not reached [NR]) compared with 46.6 months (95% CI, 8.2–109.5) in the 65-69 group, and 34.2 months (95% CI, 13.6-56.2) in the 70 and older group (P =.11). Median OS reflected these trends in the 60-64 group compared with the 65-69 group and 70 and older group at 75.2 months (95% CI 31·5–NR), 46·6 months (10.7–109.5), and 34.7 months (20·0–56·3), respectively (P =.048). Further, when the researchers combined the under 70 years of age groups and compared them with patients 70 years older or older the median PFS was better in the younger group at 60.4 months (95% CI, 14.7-109.6) vs 34.2 months (95% CI, 14.7-109.6) in the older group (P =.27). Median OS also reflected this at 69.0 months (95% CI, 16.3-109.7) in the younger group compared with 34.7 months (95% CI, 20.0-56.3) in the older group (P =.17).

When looking at older patients, safety and development of another malignancy, 9 patients at a median age of 71 years (range, 64-87) developed a second hematologic neoplasm after a median of 32.6 months (range, 2.7-65.8) after treatment initiation. Further, 5 patients developed myelodysplastic syndrome, 3 patients developed ALL, and 1 patient developed mixed-phenotype ALL.

All patients were assessed for safety, with the most common treatment-emergent adverse event (TEAEs) being constipation (58%), nausea (54%), diarrhea (34%), mucositis (26%), abdominal pain (24%), thrombocytopenia (80%), neutropenia (70%), ALT elevation (59%), hyperbilirubinemia (55%), febrile neutropenia (33%), hyperglycemia (56%), hypokalemia (44%), fatigue (55%), headache (46%), neuropathy (45%), and limb oedema (39%). While the treatment was not considered to be associated with any of these there was an increase of deaths during remission most commonly due to infections (n = 8) along with the development of a second disorder (n = 9). While the use of chemotherapy was low intensity, the researchers also noted that cytopenia and immunosuppression was still a problem for patients 70 or older. Suggesting a dose reduction may be needed for elderly patient.

_Reference:

_{Jabbour E, Short NJ, Senapati J, et al. Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukemia: long-term results of an open-label phase 2 trial. Lancet Haematol. 2023;10(6):e433-e444. doi:10.1016/S2352-3026(23)00073-X}