Carfilzomib Therapy in Pediatric Acute Lymphoblastic Leukemia
Overview
In this study, the safety and tolerability of a combination of carfilzomib and vincristine, dexamethasone, asparaginase, and daunorubicin (VXLD) were assessed in children with relapsed and/or refractory acute lymphoblastic leukemia (ALL). ALL is the most common cancer diagnosed in childhood and survival for patients who have a relapse is poor.
Achieving complete remission (CR) after relapse is critical for the potential cure of the disease. Carfilzomib is a proteasome inhibitor with an acceptable safety profile and clinical activity in adults with multiple myeloma but has not been tested in children. The primary objective of this phase 1b study was to assess the safety and tolerability of the combination of carfilzomib and VXLD in children with relapsed and/or refractory ALL.
Introduction
Acute lymphoblastic leukemia (ALL)
Acute lymphoblastic leukemia (ALL) is a type of cancer that affects the blood and bone marrow. It is characterized by the overproduction of abnormal lymphocytes, a type of white blood cell. Symptoms of ALL can include fatigue, fever, easy bruising or bleeding, bone or joint pain, and swollen lymph nodes. Treatment for ALL often involves a combination of chemotherapy, radiation therapy, and stem cell transplantation. The prognosis for patients with ALL varies depending on the specific subtype of the disease and other factors.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with an annual incidence of approximately three to four cases per 100,000 children. Nearly all children with ALL achieve remission, and 80% to 90% are cured. However, about 10% to 20% will experience disease relapse, and survival for these children is poor.
The challenges of relapse are primarily related to the limited chance to achieve deep and durable remission with an acceptable toxicity profile that allows the patient to obtain definitive eradication of the leukemia clone or to bridge to additional curative therapy, typically through allogeneic hematopoietic cell transplantation (HCT). This is especially true for patients with relapsed T-cell ALL, for those experiencing multiple relapses, relapses associated with poor-risk cytogenetic or molecular abnormalities, or relapses following HCT
Carfilzomib
Carfilzomib is a tetrapeptide epoxyketone-based inhibitor of the chymotrypsin-like (CTL) activity of the 20S proteasome. It is more selective than its predecessor, bortezomib. In vitro, carfilzomib has more potent activity in ALL cell lines than bortezomib and retains activity in bortezomib-resistant cell lines.
In a pivotal head-to-head, randomized, phase 3 study comparing bortezomib plus dexamethasone to carfilzomib plus dexamethasone for the treatment of relapsed or refractory multiple myeloma (MM), carfilzomib demonstrated superiority over bortezomib. However, carfilzomib has not been studied in children.
In adults with MM, the maximum tolerated dose (MTD) of carfilzomib administered by intravenous (IV) infusion over 30 minutes on 2 consecutive days per week combined with low-dose dexamethasone was determined to be 56 mg/m2. Therefore, based on carfilzomib data in adults, the recommended phase 2 dose (RP2D) for carfilzomib combined with chemotherapy in children is unlikely to exceed 56 mg/m2 with twice-weekly dosing.
Study Design
This study was designed to assess the safety and tolerability of carfilzomib in combination with chemotherapy in children with relapsed or refractory ALL. The trial was conducted at multiple centers and followed a single-arm, phase 1b dose-escalation design. Patients were eligible if they were between 1 and 21 years old and had a diagnosis of bone marrow relapse of ALL (with at least 5% blasts) or primary induction failure, with or without the extramedullary disease.
Patients with B-cell ALL were required to have relapsed within 36 months of achieving their first complete remission. Other eligibility criteria included adequate cardiac, liver, and renal function, and a washout period of three half-lives for prior antileukemia monoclonal antibody therapy or 42 days for cellular therapies. Patients or guardians provided written informed consent, and the study protocol was approved by the relevant institutional review boards or ethics committees. An independent Data Monitoring Committee was convened to oversee the study and ensure the safety of the patients. All authors had access to the primary trial data.
Limitations of the Study
This study had the typical limitations reported in pediatric phase 1 leukemia studies: a relatively small number of patients and a diverse group with T-cell and B-cell ALL that had relapsed or were refractory and had received various prior treatments. There were not enough data for adequate interpretation of the proportion of patients achieving MRD-negative bone marrow response after induction. Despite its limitations, the combination of treatments was well tolerated in the studied population and yielded encouraging response rates (CR/CRp/CRi) of 67% or higher. Among the 17 patients treated in the first relapse, 10 had had very short first remissions, four were refractory to 1-3 regimens at enrollment, and four had prior allogeneic stem cell transplants. Retrospective studies of children with first very early relapse or first refractory relapse showed CR rates of 38% and 20%, respectively. All three of the patients with first early nonrefractory relapse without a prior transplant achieved remission.
Results
Twenty-four patients were enrolled in the study. The study included 11 patients with T-cell lymphoid disease (10 with T-cell ALL and one with T-lymphoblastic lymphoma [T-LL] with more than 25% blast bone marrow involvement) and 13 patients with B-cell ALL.
Of the patients, 16 (67%) were in their first remission for less than 18 months, 8 (33%) had relapsed after HCT, 8 (33%) were refractory to one or more re-induction attempts at the time of enrollment, and 7 (29%) were in their second or third relapse.
Final Thoughts
Children with relapsed ALL continue to have poor responses, with fewer than 50% achieving long-term survival, particularly those with T-cell disease. Proteasome inhibitors are among the novel agents being tested in these patients.
This study investigated the combination of escalating doses of the proteasome inhibitor carfilzomib with VXLD induction chemotherapy. The incidence of both hematologic and nonhematologic grade ≥3 adverse events and serious adverse events were similar across all dose levels, suggesting that increasing the dose of carfilzomib had little effect on the toxicity of the VXLD regimen.
The safety profile across the dose levels was similar to that of other contemporary relapsed regimens. The pharmacokinetic results showed that carfilzomib exposure, adjusted for body surface area, was similar between adults and children and across different age groups of children, at least for patients one year of age and older.
Limited proteasome inhibition data indicated that proteasome activity in peripheral blood was completely suppressed 2 hours after the first target dose of carfilzomib at doses of 36 mg/m2 and higher, and remained at least partially suppressed compared to baseline on day 29 of induction.
The study found that patients who achieved CRi or better had greater suppression of CTL, trypsin-like, and caspase-like activities on day 29 compared to baseline. Responses to therapy were observed at all dose levels, and a history of prior HCT, targeted immunotherapies, or second or third relapse did not seem to affect the chances of reaching CR. However, the number of patients was too small for robust statistical analysis.
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