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Cureus Jan 2024Acute lymphoblastic leukemia (ALL) during pregnancy necessitates treatment with high-dose chemotherapy, which can threaten the lives of both the mother and fetus. The...
Acute lymphoblastic leukemia (ALL) during pregnancy necessitates treatment with high-dose chemotherapy, which can threaten the lives of both the mother and fetus. The aim of the treatment not only focuses on selecting and administering optimal chemotherapy with appropriate doses to the mother but also reflects the crucial understanding of the fetal gestational age at the time of administration of chemotherapy to minimize fetal exposure. We describe the case of a 19-year-old patient diagnosed with ALL at 29 weeks gestation. She received treatment in the third trimester with the Berlin-Frankfurt-Munster (BFM) 2000 induction chemotherapy protocol consisting of a combination of daunorubicin, vincristine, pegaspargase, prednisolone, and intrathecal (IT) methotrexate and gave birth to a healthy baby girl via vaginal delivery four weeks after initiating the induction of chemotherapy.
PubMed: 38371059
DOI: 10.7759/cureus.52489 -
Pediatric Blood & Cancer Apr 2024Pegaspargase is a therapeutic enzyme that is utilized in treatment regimens targeting pediatric acute lymphoblastic leukemia. However, many patients experience...
BACKGROUND
Pegaspargase is a therapeutic enzyme that is utilized in treatment regimens targeting pediatric acute lymphoblastic leukemia. However, many patients experience hypersensitivity reactions, requiring discontinuation of the therapy. Historically, this necessitated switching to an alternative form of the drug, most commonly asparaginase Erwinia chrysanthemi; however, in recent years this was difficult due to drug shortages and eventually commercial discontinuation. We report here our experience performing pegaspargase desensitizations in patients with prior hypersensitivity reactions.
PROCEDURE
Patients with a clinical hypersensitivity reaction to pegaspargase were identified. When due for their next dose, patients were admitted to the pediatric intensive care unit, bone marrow transplant unit, or oncology unit, and underwent desensitization utilizing a rigorous premedication and multistep dilution-based protocol. Serum asparaginase activity levels were drawn after desensitization to assess for therapeutic levels of enzyme activity.
RESULTS
We identified 11 patients who underwent a total of 33 desensitizations to pegaspargase and calaspargase pegol-mknl. No patients experienced clinically significant hypersensitivity reactions necessitating stopping the infusion, nor administration of rescue medications. All serum asparaginase activity levels collected demonstrated enzyme activity levels above predefined therapeutic thresholds. Cost analysis revealed substantial savings when patients received asparaginase desensitization over the now commercially available asparaginase E. chrysanthemi (recombinant) rywn.
CONCLUSIONS
Performing desensitization to pegaspargase in the pediatric acute lymphoblastic leukemia population is feasible, safe, and effective. It is financially advantageous over available alternative approaches, and requires fewer injections and presentations to care.
Topics: Child; Humans; Asparaginase; Erwinia; Antineoplastic Agents; Drug Hypersensitivity; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hypersensitivity
PubMed: 38311802
DOI: 10.1002/pbc.30891 -
Journal of Clinical Oncology : Official... May 2024The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule.
METHODS
Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome.
RESULTS
During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions ( < .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions ( < .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 [0.032-0.653]). In addition, antibody levels were significantly lower in the continuous arm ( < .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms.
CONCLUSION
A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.
Topics: Humans; Asparaginase; Child; Child, Preschool; Polyethylene Glycols; Female; Male; Adolescent; Drug Hypersensitivity; Infant; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Drug Administration Schedule; Netherlands; Antineoplastic Agents
PubMed: 38306592
DOI: 10.1200/JCO.23.01797 -
Leukemia Apr 2024Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing...
Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1-45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.
Topics: Humans; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Hypersensitivity; Antineoplastic Agents
PubMed: 38287133
DOI: 10.1038/s41375-024-02153-6 -
BMC Health Services Research Jan 2024The high costs of innovative anticancer drugs hinder a number of cancer patients' access to these drugs in China. To address this problem, in 2018, the medical insurance...
BACKGROUND
The high costs of innovative anticancer drugs hinder a number of cancer patients' access to these drugs in China. To address this problem, in 2018, the medical insurance access negotiation (MIAN) policy was implemented, when the prices of 17 innovative anticancer drugs were successfully negotiated and they were therefore included in the reimbursement list. This study aimed to explore the impact of the MIAN policy on the utilization of innovative anticancer drugs.
METHODS
With monthly data on drug expenditures and defined daily doses (DDDs) of each innovative anticancer drug from January 2017 to December 2019, interrupted time series analysis was employed to estimate both the instant (change in the level of outcome) and long-term (change in trends of outcomes) impacts of the MIAN policy on drug utilization in terms of drug expenditures and DDDs. Our sample consists of 12 innovative anticancer drugs.
RESULTS
From January 2017 to December 2019, the monthly drug expenditures and DDDs of 12 innovative anticancer drugs increased by about 573% (from US$8,931,809.30 to US$51,138,331.09) and 1400% (from 47,785 to 668,754), respectively. Overall, the implementation of the MIAN policy led to instant substantial increases of US$8,734,414 in drug expenditures and 158,192.5 in DDDs. Moreover, a sharper upward trend over time was reported, with increases of US$2,889,078 and 38,715.3 in the monthly growth rates of drug expenditures and DDDs, respectively. Regarding individual innovative anticancer drugs, the most prominent instant change and trend change in drug utilization were found for osimertinib, crizotinib, and ibrutinib. In contrast, the utilization of pegaspargase was barely affected by the MIAN policy.
CONCLUSIONS
The MIAN policy has effectively promoted the utilization of innovative anticancer drugs. To ensure the continuity of the effects and eliminate differentiation, supplementary measures should be carried out, such as careful selection of drugs for medical insurance negotiations, a health technology assessment system and a multichannel financing mechanism.
Topics: Humans; Negotiating; Interrupted Time Series Analysis; Health Expenditures; Antineoplastic Agents; Insurance; China; Drug Costs; Nitrosamines
PubMed: 38233857
DOI: 10.1186/s12913-023-10393-y -
South Asian Journal of Cancer Oct 2023Dhaarani Jayaraman Acute lymphoblastic leukemia (ALL) is a common type of leukemia in children. The innovator pegylated L-asparaginase has several advantages over...
Dhaarani Jayaraman Acute lymphoblastic leukemia (ALL) is a common type of leukemia in children. The innovator pegylated L-asparaginase has several advantages over native L-asparaginase; however, its use in India is limited due to availability and cost. Therefore, a generic pegylated L-asparaginase can be considered as an alternative to the innovator molecule. A retrospective study was conducted to assess the outcome (minimal residual disease [MRD]) and toxicity of a generic pegylated L-asparaginase (Hamsyl) at the end of induction therapy. Eighty-eight (80.7%) and 21 (19.3%) patients had received generic pegylated L-asparaginase and conventional asparaginase, respectively, as a part of their treatment protocol. Nearly 82% of patients had B-type ALL. Eight-one percent of children had a white blood cell count of fewer than 50,000/mm . At the end of induction, 80.7% (88) of children were minimal residual disease (MRD)-negative, and at the end of augmented consolidation therapy, 20.2% were MRD-negative. Ten percent of patients exhibited allergic reactions. Two children had pancreatitis, and one child had central venous thrombosis. The generic pegylated L-asparaginase (Hamsyl) was effective and safe for use in pediatric ALL.
PubMed: 38130281
DOI: 10.1055/s-0042-1759785 -
Best Practice & Research. Clinical... Dec 2023Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective... (Review)
Review
Asparaginase in various forms is a standard part of the treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. However, its use is more selective in adults. One of the key reasons is the toxicity observed from this class of agents. In a series of recent post hoc analyses of large prospective studies, obesity has emerged as a key factor that contributes to the challenges with administering regimens that include asparaginase. In this review, the most salient findings are highlighted from these latest publications, both from the pediatric and adult literature. These data are consolidated into recommendations for clinicians who treat adults with ALL, including proposals for how treatment may be modified to try to account for these complications. Lastly, avenues for future investigation are proposed in an attempt to narrow our knowledge gaps in this field, with the goal of safer and more effective treatment for adults with obesity who develop ALL.
Topics: Adult; Adolescent; Humans; Child; Asparaginase; Antineoplastic Agents; Prospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Obesity
PubMed: 38092476
DOI: 10.1016/j.beha.2023.101519 -
Leukemia Feb 2024Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected... (Randomized Controlled Trial)
Randomized Controlled Trial
Osteonecrosis is a significant toxicity of acute lymphoblastic leukemia (ALL) therapy. In retrospective analyses, superior event-free survival was noted among affected adolescents in an earlier trial. We prospectively assessed osteonecrosis incidence, characteristics, and risk factors in patients 1-30 years with newly diagnosed high-risk B-ALL on COG AALL0232. Patients were randomized to induction dexamethasone vs prednisone, and interim maintenance high-dose methotrexate vs escalating-dose Capizzi methotrexate/pegaspargase. Event-free and overall survival were compared between patients with/without imaging-confirmed osteonecrosis. Osteonecrosis developed in 322/2730 eligible, evaluable patients. The 5-year cumulative incidence was 12.2%. Risk was greater in patients ≥10 years (hazard ratio [HR], 7.23; P < 0.0001), particularly females (HR, 1.37; P = 0.0057), but lower in those with asparaginase allergy (HR, 0.60; P = 0.0077). Among rapid early responders ≥10 years, risk was greater with dexamethasone (HR, 1.84; P = 0.0003) and with prednisone/Capizzi (HR, 1.45; P = 0.044), even though neither therapy was independently associated with improved survival. Patients with osteonecrosis had higher 5-year event-free (HR, 0.51; P < 0.0001) and overall survival (HR, 0.42; P < 0.0001), and this was directly attributable to reduced relapse rates (HR, 0.57; P = 0.0014). Osteonecrosis in high-risk B-ALL patients is associated with improved survival, suggesting an important role for host factors in mediating both toxicity and enhanced efficacy of specific therapies.
Topics: Child; Female; Adolescent; Humans; Prednisone; Methotrexate; Retrospective Studies; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Osteonecrosis; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Disease-Free Survival
PubMed: 38062123
DOI: 10.1038/s41375-023-02099-1 -
IScience Nov 2023Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is... (Review)
Review
Natural killer (NK)/T cell lymphoma (NKTCL) is a rare subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma characterized by poor clinical outcomes. It is more common in East Asian and Latin American countries. Despite the introduction of asparaginase/pegaspargase-based chemotherapy, the prognosis of patients with advanced NKTCL needs to be improved, and few salvage treatment options are available for relapsed/refractory patients who fail chemotherapy. Although many unknowns remain, novel treatment strategies to further improve outcomes are urgently needed. Immunotherapy has emerged and shown favorable antitumor activity in NKTCL, including monoclonal antibodies targeting immune checkpoint inhibitors, other receptors on the cellular membrane, and cellular immunotherapy, which could enhance immune cells attack on tumor cells. In this review, we provide an overview of recent immunotherapy in NKTCL, focusing on programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), chimeric antigen receptor (CAR) T cells, EBV-specific cytotoxic T lymphocytes, immunomodulatory agents, and other targeted agents, as well as the current progress and challenges in the field.
PubMed: 38026157
DOI: 10.1016/j.isci.2023.108192