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Annals of Hematology Feb 2024We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient...
Liver failure after treatment with inotuzumab and polychemotherapy including PEG-asparaginase in a patient with relapsed Philadelphia chromosome-negative acute lymphoblastic leukemia.
We present the case of a 58-year-old female patient who presented with an extramedullary B-ALL relapse after prior allogenic HSCT and blinatumomab therapy. The patient died from complications of a drug-induced acute liver failure after a salvage therapy combining inotuzumab ozogamicin (InO)-based induction followed by consolidation with high dose MTX and pegaspargase based on the GMALL protocol for older ALL patients. After a diagnosis of the extramedullary relapse in the form of a retro vesical chloroma, the patient received an individualized multi-agent chemotherapy based on induction chemotherapy for older patients in combination with InO. After four administrations of InO, in combination with vincristine, dexamethasone, cytarabine, and cyclophosphamide, CT-imaging showed a reduction in volume of the chloroma and response to therapy. Consolidation with high-dose methotrexate and pegaspargase was administered. The patient developed toxic liver damage manifested by hyperbilirubinemia and progressive hepatic encephalopathy. The diagnostic criteria for VOD were met, and therapy with defibrotide was initiated. Liver biopsy revealed no histological signs of VOD but instead steatohepatitis indicative of drug-induced toxicity. The patient ultimately died of hemorrhagic shock through postinterventional hemorrhage after liver biopsy. In conclusion, although InO shows promising results in the therapy of r/r ALL with and without additional chemotherapy, the combination with MTX and pegaspargase in an intensively pretreated patient with relapse after HCST may impart an increased risk for liver-related toxicity. Special caution is required when assessing fitness for further liver toxic regimens. A key takeaway is also the reminder that InO can cause liver damage not only in the form of VOD but also through direct hepatocellular toxicity.
Topics: Female; Humans; Middle Aged; Philadelphia Chromosome; Sarcoma, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Inotuzumab Ozogamicin; Antineoplastic Combined Chemotherapy Protocols; Liver Failure; Recurrence; Asparaginase; Polyethylene Glycols
PubMed: 37999763
DOI: 10.1007/s00277-023-05495-w -
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 -
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 -
Zhonghua Xue Ye Xue Za Zhi = Zhonghua... Aug 2023To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. The clinical data of 656 ENKTL patients... (Randomized Controlled Trial)
Randomized Controlled Trial
To explore the prognostic factors of extracellular NK/T cell lymphoma (ENKTL) treated with pegaspargase/L-asparaginase. The clinical data of 656 ENKTL patients diagnosed at 11 medical centers in the Huaihai Lymphoma Working Group from March 2014 to April 2021 were retrospectively analyzed. The patients were randomly divided into two groups: a training set (460 cases) and a validation set (196 cases) at 7∶3, and the prognostic factors of the patients were analyzed. A prognostic scoring system was established, and the predictive performance of different models was compared. Patients' median age was 46 (34, 57) years, with 456 males (69.5% ) and 561 nasal involvement (85.5% ). 203 patients (30.9% ) received a chemotherapy regimen based on L-asparaginase combined with anthracyclines, and the 5-year overall survival rate of patients treated with P-GEMOX regimen (pegaspargase+gemcitabine+oxaliplatin) was better than those treated with SMILE regimen (methotrexate+dexamethasone+cyclophosphamide+L-asparaginase+etoposide) (85.9% 63.8% ; =0.004). The results of multivariate analysis showed that gender, CA stage, the Eastern Cooperative Oncology Group performance status (ECOG PS) score, HGB, and EB virus DNA were independent influencing factors for the prognosis of ENKTL patients (<0.05). In this study, the predictive performance of the prognostic factors is superior to the international prognostic index, Korean prognostic index, and prognostic index of natural killer lymphoma. Gender, CA stage, ECOG PS score, HGB, and EB virus DNA are prognostic factors for ENKTL patients treated with pegaspargase/L-asparaginase.
Topics: Male; Humans; Middle Aged; Asparaginase; Prognosis; Retrospective Studies; Lymphoma, Extranodal NK-T-Cell; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Cyclophosphamide; Methotrexate; DNA; Treatment Outcome
PubMed: 37803837
DOI: 10.3760/cma.j.issn.0253-2727.2023.08.005 -
Annals of Hematology Nov 2023Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment...
Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 10 copies/ml (range, 0.44 to 21.1 × 10copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.
Topics: Male; Female; Humans; Child; Adolescent; Lymphoma, Extranodal NK-T-Cell; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Combined Modality Therapy; Methotrexate; DNA; Treatment Outcome; Multicenter Studies as Topic
PubMed: 37486391
DOI: 10.1007/s00277-023-05375-3 -
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 -
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