Isatuximab Treatment in Refractory T-Acute Lymphoblastic Leukemia
The difficulty of making an accurate prognosis of acute T- cell lymphoblastic leukemia (T- ALL) and T- cell lymphoblastic lymphoma (T- LBL) in seniors and patients with relapsed illness has always been an issue in the medical field. Since there is no specified standard of care and only limited treatment options.
Around 40% to 50% of adult patients with T-ALL or T- LBL on treatment will relapse and overall survival in adults over the age of 50 years is poor, with less than 25% of patients who had relapsed still alive five years after diagnosis.
Abnormal levels of CD38 expression in T- ALL and T- LBL are linked with tumor expansion and disease development, making CD38 a potential target for anti-T- ALL and T- LBL treatment. Isatuximab is a monoclonal antibody that binds to a specific epitope on CD38.
The Study
The research seeks to understand the efficacy and safety of isatuximab monotherapy in phase 2 open-label study in patients with relapsed or refractory T- ALL or T- LBL. The study had a total of 19 patients that were initially scheduled, but only 14 showed up and became subjects in the study. The study was conducted in six countries: Finland, France, Italy, Lithuania, the Russian Federation, and the United States. It used Simon’s optimal two-stage design.
There was an interim analysis after stage 1 based on efficacy and safety of isatuximab in the first 19 patients (note that only 14 patients were enrolled) and the study was to proceed to stage 2 if >3/19 patients showed a clinical response to treatment. in the first 19 patients enrolled was scheduled, however, only 14 patients were enrolled in the study.
Before the researchers proceeded with the study, they first made sure that the protocol was approved by ethics committees and review boards of all participating institutions. Participants then gave their written informed consent.
The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice.
Participants were accepted in the study if they were above 16 years of age at the time of signing the consent form. They should also have a confirmed diagnosis of relapsed ALL (T- or B-cell origin) including lymphoblastic lymphoma or relapsed AML. All participants must have been previously treated for their disease and have relapsed or were refractory to their most recent treatment.
The demographic and baseline characteristics of the 14 enrolled patients are the following: The median age was 33.0 years with three patients aged between 65 and 75 years. The majority of patients were male. At baseline, all 14 patients had an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤2, with 11 (78.6%) patients having an ECOG score of <2.
At initial diagnosis, most patients had T- ALL (11 patients, 78.6%), with the remaining patients having T- LBL. Among the 14 patients enrolled in the study, all had been given at least one prior leukemia/lymphoma treatment regimen, and 5 (35.7%)
Results
There were no patients who achieved complete response (CR) or CR with incomplete peripheral recovery. Most of the patients in the study developed progressive disease and had progressive disease as their best response. A total of 10 patients had treatment-emergent adverse events considered treatment-related, with infusion reactions as the most frequent drug-related TEAE, occurring in 8 patients. A total of 11 patients died during the study. Six of them died within 30 days from the last dose of treatment. Five patients died due to disease progression. One patient died due to an acute myocardial infarction.
Despite the disappointing results of the efficacy of isatuximab in the current study, it is likely that the use of immunotherapy medication in T- ALL will be expanded through logically targeted approaches. This will be done with advances in the design of T- cell therapy and clinical experience and will provide restorative options beyond chemotherapy and targeted treatments.
Discussion
Natural killer cells are considered in the observation and cytotoxic eradication of malignant leukemic cells. In fact, the stimulation of these natural killer cells to eliminate major tumor blasts is critical for the success of the therapy and long-term remission of patients.
Isatuximab promotes NK cell-mediated ADCC and ADCP in tumor cells in MM by crosslinking CD38 and CD16. Furthermore, preclinical studies have shown that isatuximab has significant activity against ALL cell lines with a robust ADCC and ADCP effect, with a clear association between the expression of CD38 and isatuximab activity in both T- ALL and B- ALL. CD38 is uniformly manifested across leukemic blasts of patients with T-ALL at all stages of the disease.
Furthermore, cytotoxic chemotherapy for the treatment of ALL does not reduce the manifestation of CD38 at numerous time points during the course of treatment. Even though there is a high expression of CD38 in T-ALL, the expression is not as high as observed in MM, which may have contributed to the poor outcome observed in the current study.
Limitations of the Study
The major limitation of the study was that it included heavily pretreated patients that had received multiple previous lines of therapy. Overall, 14 patients were treated but the study was stopped due to the lack of efficacy of isatuximab in adult patients with relapsed/refractory T-ALL or T- LBL. Most patients had progressive disease during the treatment period, making it unlikely to achieve the responses required to continue the study.
Two patients discontinued the study due to adverse events. Most patients, eight patients had mild infusion reactions and one patient developed a cytokine release syndrome.
T-ALL is an aggressive disease and the expression of CD38 is not sufficient to allow a biologic agent to be effective as monotherapy in heavily pretreated patients.
Combination therapy with chemotherapy may be more effective in patients who have not received previous rounds of intensive treatment. Most patients in the study discontinued treatment before optimal blood levels of isatuximab could be reached.
The poor response and safety profile of isatuximab monotherapy in this study led to an unsatisfactory risk/benefit ratio for this cohort of patients.
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