Successful Long-Term Remission in Infantile Acute Leukemia Treated With Chemotherapy and Blinatumomab: A Case Report

Introduction

Acute lymphoblastic leukemia (ALL) accounts for 80% of childhood leukemias, with the highest incidence occurring between the ages of 3 and 7 years. Diagnosis is based on bone marrow aspiration revealing 20% or more blasts and immature lymphocytes, in conjunction with a complete blood count, immunophenotyping, genetic testing (eg, chromosomal karyotyping, fusion genes), and molecular biology testing (eg, gene mutations). The treatment of pediatric ALL focuses on stratified chemotherapy combined with targeted therapy, immunotherapy, and supportive care. The complete remission rate for pediatric ALL can exceed 95%, and the rate of sustained complete remission beyond 5 years ranges from 65% to 80%. ALL in infants, defined as onset before 12 months of age, is rare, accounting for less than 5% of childhood ALL cases. Approximately 80% of cases exhibit 11q23 chromosomal abnormalities involving the KMT2A gene (formerly mixed-lineage leukemia), known as KMT2A rearrangement (KMT2A-r), while the remainder are categorized as KMT2A germline (KMT2A-g) [1]. Common symptoms include a high white blood cell count (WBC) and central nervous system involvement. ALL in infants is a rare disease with a poor prognosis. Although the disease-free survival rate of childhood ALL has improved to currently exceed 85%, infants diagnosed with ALL in the first year still have a poor prognosis, with a 6-year event-free survival rate of 46% and overall survival rate of 58% [2]. Blinatumomab is a bispecific T-cell–engaging antibody that binds CD19 on B cells and CD3 on T cells, activating endogenous T cells to induce targeted lysis of CD19-positive ALL [3]. In 2014, the U.S. Food and Drug Administration (FDA) approved blinatumomab for the treatment of adult and pediatric patients with relapsed or refractory ALL. Bartram et al similarly reported a case of infantile KMT2A-g leukemia treated with standard chemotherapy following diagnosis. One year after diagnosis, the patient experienced extramedullary relapse (central nervous system leukemia). After treatment with blinatumomab, the patient underwent bridging hematopoietic stem cell transplantation (HSCT) and achieved long-term survival [4]. In the latest study, Litzow et al report that the addition of blinatumomab to consolidation chemotherapy in adult patients who achieved minimal residual disease (MRD)-negative remission from B-cell precursor (BCP)-ALL significantly improved overall survival. They excluded adult patients who had not achieved complete remission, potentially overestimating the actual effect [5]. Further analysis is needed to determine the necessity of subsequent HSCT following blinatumomab consolidation therapy. In 2024, the FDA approved blinatumomab for the consolidation treatment of CD19-positive, Philadelphia chromosome-negative BCP-ALL in pediatric and adult patients aged 1 month and over. This report describes the case of a 10-month-old female infant with ALL who achieved sustained remission for 2 years following treatment with a chemotherapy regimen supplemented with blinatumomab.

Case Report

A 10-month-old girl weighing 10 kg was admitted to the hospital with a 1-week history of decreased alertness and 5-day history of generalized petechiae. The highest leukocyte count was 172.2×109/L (reference, 5–12×109/L). The child had hemorrhage manifestations (platelets 49×109/L; reference, 135–350×109/L), anemia (hemoglobin 76 g/L; reference, 120–140 g/L), enlarged liver and spleen, and the presence of immature cells in the peripheral blood, suggesting a diagnosis of leukemia. A bone marrow biopsy was performed, resulting in a diagnosis of ALL-L2 (primitive cells account for 78%; Figure 1). Flow cytometry revealed that 76.17% of the cells were malignant B-lineage primitive cells at the pre-B stage. Test results were negative for 56 fusion genes and the Ph-like gene. Cytogenetic analysis showed a normal female karyotype: 46, XX. The patient was diagnosed with low-risk infantile B-ALL. Informed consent was obtained from a guardian before the start of treatment. Treatment was initiated according to the Chinese Children’s Leukemia Group–ALL 2018 protocol. After diagnosis, the patient underwent 8 cycles of chemotherapy combined with an immune-targeted drug therapy. Blinatumomab was administered every 6 months until the end of the second year. The specific regimen is detailed in Table 1. Blinatumomab was administered after chemotherapy, which had suppressed the immune response; no drug-related adverse reactions, such as cytokine release syndrome (CRS) of grade 2 or higher, occurred during treatment. The patient did experience myelosuppression, abnormal liver function, and fever, all of which improved with symptomatic treatment.

Discussion

In the present case, low-dose chemotherapy administered during induction therapy reduced the leukocyte burden, allowing subsequent treatment with blinatumomab to achieve complete remission. Subsequent bridging chemotherapy was then administered together with intermittent blinatumomab therapy over 3 cycles, maintaining persistent MRD negativity. No significant adverse reactions were observed during treatment. This approach offers a favorable initial treatment option for infants with acute leukemia, reducing complications during the induction phase. The Interfant-99 regimen was the first international collaborative combination-therapy trial to show improved outcomes compared with historical studies; however, despite the use of potent combination chemotherapy, it did not significantly improve the prognosis of infants with KMT2A-r. The associated treatment had a high risk of death and relapse, with a survival rate after relapse of just under 20%. The Interfant-06 program subsequently divided patients into 3 groups based on gene rearrangement, age, WBC count, and early prednisone response. Low-risk patients were those without KMT2A rearrangements (KMT2A-g), including some with a poor prednisolone response. High-risk patients included those with KMT2A-r, age younger than 6 months, a WBC count of 300×109/L or higher, and/or a poor prednisolone response. Intermediate-risk patients included all remaining patients. The primary objective of Interfant-06 was aimed at evaluating whether the 2 acute myeloid leukemia regimens (ADE: cytarabine, daunorubicin, and etoposide; and MAE: mitoxantrone, cytarabine, and etoposide) were more effective than standard Berlin-Frankfurt-Münster consolidation therapy in patients with intermediate or high risk [2]. Among 651 patients, 74% had KMT2A-r. Treatment with acute myeloid leukemia regimens did not reduce the risk of relapse and was associated with excess toxicity, with a 37% incidence of serious adverse events. The 6-year event-free survival was 73.9% for low-risk patients, compared with 44.5% for intermediate-risk patients and 20.9% for high-risk patients. Most importantly, event-free and overall survival did not improve, with a high treatment-related mortality of 7.1%, compared with Interfant-99 [6]. Intermediate-risk patients were elected to undergo stem cell transplantation if they were still MRD-positive (>0.01%) at the time of delayed intensification of therapy (OCTADAD: consisting of vincristine, dexamethasone, asparaginase, daunorubicin, thioguanine, cytarabine, and cyclophosphamide). Overall 40% of relapses occurred less than 6 months after the start of treatment, and 90% occurred within 1 year. Despite intensive ADE/MAE treatment, 45% of high-risk patients in the experimental group relapsed, and the overall relapse rate did not differ from that of the control group [2]. Thus, more intensive treatment was both less effective and more toxic. The addition of blinatumomab to standard chemotherapy in infants with KMT2A-r ALL has been studied for higher antileukemic activity, favorable MRD response, and improved short-term survival, compared with that of the Interfant-06 regimen. Blinatumomab added immediately after induction therapy resulted in a 2-year disease-free survival rate of 81.6% in the current study, compared with the rate of 49.6% in the Interfant-06 trial. Despite the need for longer follow-up, disease-free survival was significantly improved; thus, 90% of recurrences in this group occurred within 2 years of diagnosis. ALL of the 8 high-risk patients underwent HSCT, compared with 46% of high-risk patients in Interfant-06, who developed complications prior to HSCT. Four of 21 intermediate-risk patients underwent HSCT due to persistently high levels of MRD. In addition, none of the 3 patients with M2 marrow (5% to 25% blasts) experienced any adverse events at the end of induction. In contrast, all patients with M2 or M3 (≥25% blasts) in the Interfant-06 trial died at the end of induction [7].

Studies have shown that adding blinatumomab to combination chemotherapy significantly improves disease-free survival in children with newly diagnosed standard-risk B-ALL, including those with standard or high relapse risk. Grade 3 or higher CRS, seizures, and sepsis are infrequent following cycles of blinatumomab treatment. However, in patients at intermediate risk of relapse receiving blinatumomab with chemotherapy, the rates of nonfatal sepsis and catheter-associated infections were significantly higher than in the chemotherapy group [8]. Targeted drug therapy–associated adverse reactions, including CRS and immune effector cell–associated neurotoxicity syndrome, were also observed. These toxicities, along with infections, are serious adverse events that can lead to drug discontinuation [9]. CRS is an acute systemic inflammatory syndrome characterized by fever and multiorgan dysfunction mediated by elevated levels of cytokines and other markers of inflammation and is thought to be associated with blinatumomab immunotherapy [10]. Specific symptoms of CRS can manifest as fever, headache, nausea, malaise, syncope, rash, dyspnea, fatigue, weakness, hypotension, elevated alanine aminotransferase levels, elevated aspartate aminotransferase levels, elevated total bilirubin levels, and disseminated intravascular coagulation. Manifestations of CRS after receiving immunotherapy can overlap with those of infusion reactions, infection-related symptoms, capillary leakage syndrome, and phagocytic histiocytosis/macrophage activation syndrome, which need to be differentiated. Studies have shown that risk factors for CRS include tumor load and the starting dose of blinatumomab administered [11]. Therefore, to prevent or reduce the severity of CRS, prophylactic doses of dexamethasone (5 mg/m2, with a maximum dose of 20 mg) are recommended for children with high tumor load, dose escalation, or dose interruptions of more than 4 hours [12], and for the first dose in the induction phase. A dose-escalation regimen (low dose for the first 7 days, full dose on day 8) or an adjustment of the infusion rate is recommended for the first administration during the induction phase.

In the present case, the child underwent a low-dose chemotherapy of vincristine, cyclophosphamide, and prednisone (VCP) or cyclophosphamide, vincristine, cytarabine and dexamethasone (COAD) prior to blinatumomab infusion as a pretreatment. She experienced febrile reactions during the infusion, primarily during the dose-escalation phase. Laboratory testing subsequently showed transient transaminase elevation in blood biochemistry. She developed a respiratory infection during the first infusion. The infectious symptoms improved substantially following gammaglobulin transfusion and subsequent therapeutic management. The child received 28 days of chemotherapy combined with blinatumomab, followed by 14-day blinatumomab treatments administered every 6 months. The child remains in sustained remission. During the treatment period, regular follow-up treatment was given in the form of intrathecal injections to prevent and control central nervous system leukemia. The child is now in continuous remission and is being followed up regularly. As previously described, the case lacked the KMT2A gene, but had a mutation in the NUTM1 fusion gene. After remission was achieved through conventional chemotherapy, the patient received treatment with blinatumomab as a bridge to transplantation following extramedullary relapse, ultimately resulting in long-term remission. Approximately 20% to 30% of cases without KMT2A gene rearrangements have recently been found to exhibit a high rate of fusion genes and may be more physiologically analogous to childhood ALL [13]. Overall, outcomes for KMT2A-g are significantly better than those for KMT2A-r counterparts.

Conclusions

We present a case of sustained MRD negativity in an infant with B-ALL following the administration of blinatumomab in combination with chemotherapy. At present, there is insufficient data on infantile ALL to support the conclusion that blinatumomab can replace conventional chemotherapy. However, recent data suggest that blinatumomab can replace intensive treatment regimens for consolidated ALL [14] and recurrent pediatric ALL [15]. The efficacy of targeted immunotherapy in reducing chemotherapy-related toxicity and its capacity to enhance the clearance of MRD have been well documented. In our patient, no genealogical transition occurred. There were no instances of serious infections, organ injuries, or other adverse reactions observed during individualized treatment. The occurrence of tumor lysis and grade 3 or higher CRS were not detected, and the child underwent long-term follow-up monitoring due to persistently negative MRD. This patient underwent chemotherapy prior to targeted therapy, to reduce adverse reactions such as tumor burden and CRS severity. During a 2.5-year follow-up period, no adverse events, including severe infection, neurological symptoms, or allergic reactions, have occurred. The patient is currently growing and developing well and remains under observation. As this is an individual case report, long-term follow-up is required to assess the efficacy of the treatment.