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Pediatric Blood & Cancer Mar 2020The treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children is challenging and new treatment options are needed. Bortezomib is a proteasome...
BACKGROUND
The treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) in children is challenging and new treatment options are needed. Bortezomib is a proteasome inhibitor with activity in pediatric acute lymphoblastic leukemia. Adding bortezomib to standard reinduction chemotherapy in relapsed and refractory pediatric ALL has produced very good response rates in prior studies.
METHODS
We evaluated bortezomib in combination with reinduction therapy (ALL R3) in 10 children with relapsed or refractory ALL. Bortezomib (1.3 mg/m /dose) was administered to patients on days 1, 4, 8, and 11. In addition, patients received mitoxantrone, dexamethasone, pegaspargase, vincristine, and intrathecal methotrexate over 4 weeks.
RESULTS
Of the 10 patients, eight (80%) achieved a complete remission (CR) or complete remission with incomplete recovery (CRi). Of the patients in CR, two had undetectable minimal residual disease by flow cytometry (<0.01%). Five patients were subsequently treated with a stem cell transplant. All eight patients that achieved CR or CRi eventually relapsed. One patient remains alive following treatment with tisagenlecleucel after relapse. Grade 3 or higher infections occurred in four out of 10 patients, and other toxicities commonly associated with bortezomib were not seen.
CONCLUSIONS
In children with relapsed or refractory ALL, the addition of bortezomib to reinduction chemotherapy that includes mitoxantrone produces a complete response in the majority of cases and does not lead to excessive toxicity.
Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Bortezomib; Child; Child, Preschool; Dexamethasone; Drug Resistance, Neoplasm; Female; Follow-Up Studies; Humans; Infant; Male; Mitoxantrone; Neoplasm Recurrence, Local; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Salvage Therapy; Survival Rate; Vincristine
PubMed: 31724803
DOI: 10.1002/pbc.28062 -
Journal of Clinical Pharmacy and... Dec 2022Diabetic ketoacidosis (DKA) may occur during asparaginase use. However, limited by the study population, the association between asparaginase and DKA has not been... (Review)
Review
WHAT IS KNOWN AND OBJECTIVE
Diabetic ketoacidosis (DKA) may occur during asparaginase use. However, limited by the study population, the association between asparaginase and DKA has not been elucidated. The purpose of this study was to determine the potential association between asparaginase and DKA and analyse related clinical characteristics and possible risk factor.
METHODS
Disproportionality analysis with the reporting odd ratio (ROR) was used to detect the adverse reaction signals of asparaginase-associated DKA in Food and Drug Administration Adverse Event Reporting System (FAERS). A literature review was conducted to further analyse clinical characteristics, possible risk factor and something noteworthy in asparaginase-associated DKA.
RESULTS AND DISCUSSION
A total of 12 reports of DKA associated with l-asparaginase (l-asp) and 6 reports associated with pegaspargase (PEG-asp) were extracted in FAERS, more than 50% of the cases were classified as serious adverse events. DKA was a positive signal of l-asp (ROR = 2.397, 95% CI 1.360-4.226), while not closely related to the use of PEG-asp (ROR = 1.602, 95% CI 0.719-3.570). Searched in PubMed, Embase and Web of Science, a total of eight patients were collected. The patients were mainly adolescent patients, aged between 11 and 25 years old with a median age of 16 years. Drug dosage form distribution is unbalanced, 7 patients received l-asp and only 1 received PEG-asp.
WHAT IS NEW AND CONCLUSIONS
The ROR of KDA caused by l-asp was statistically significant, but there was not a statistical association for DKA caused by PEG-asp. Asparaginase dosage form may affect the occurrence of DKA, but further research is needed.
Topics: Adolescent; United States; Humans; Child; Young Adult; Adult; Asparaginase; Diabetic Ketoacidosis; Risk Factors; United States Food and Drug Administration; Odds Ratio; Diabetes Mellitus
PubMed: 36411584
DOI: 10.1111/jcpt.13782 -
Blood Jan 2020
Topics: Adolescent; Adult; Antineoplastic Agents; Asparaginase; Child; Child, Preschool; Desensitization, Immunologic; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Hypersensitivity; Male; Polyethylene Glycols; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prognosis; Retrospective Studies; Young Adult
PubMed: 31750901
DOI: 10.1182/blood.2019003407 -
Annals of Hematology Dec 2020Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a highly aggressive tumor with relatively poor prognosis. In this prospective study, we investigated the...
Combined gemcitabine, cisplatin, dexamethasone, methotrexate, and pegaspargase (GDP-ML) for patients with newly diagnosed extranodal natural killer/T cell lymphoma, nasal type: a single arm, single center, prospective phase 2 study.
Extranodal natural killer/T cell lymphoma, nasal type (ENKL) is a highly aggressive tumor with relatively poor prognosis. In this prospective study, we investigated the efficacy and toxicity of a novel GDP-ML regimen (combined gemcitabine, cisplatin, dexamethasone, methotrexate, and pegaspargase) as front-line treatment in newly diagnosed ENKL. Eligible newly diagnosed stage I/II ENKL patients received sandwich chemoradiation therapy. Patients with stage III/IV disease received an initial 4 cycles of GDP-ML regimen. After 4 cycles, responding patients continued to receive either autologous transplantation or additional two courses of GDP-ML. A total of 44 patients were enrolled with a median follow-up of 26 months. The overall response rate (ORR) were 78.6% for the whole cohort, 84.6% for stage I/II, and 66.7% for stage III/IV, and corresponding complete remission (CR) rates were 61.9%, 76.9%, and 33.3%. The 1- year and 2- year progression-free survival (PFS) rates were 69.3% and 62.9%, and 1- year and 2-year overall survival (OS) rates were 76.5% and 67.4%, respectively. Patients with stage I/II disease showed better 2-year OS rate compared with stage III/IV patients (88.1% vs. 33.2%, p < 0.001). Patients who achieved CR had significantly better 2-year OS rate compared with non-CR patients (90.8% vs. 24.5%, p < 0.001). The main adverse event was hematologic toxicity. Grade 3/4 neutropenia occurred in 59.1% of patients. These results indicate that GDP-ML is an effective and well-tolerated induction regimen with newly diagnosed ENKL patients. This clinical trial was registered on www.chictr.org.cn (ChiCTR-ONC-12002055).
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Cisplatin; Deoxycytidine; Female; Follow-Up Studies; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Methotrexate; Middle Aged; Nose Neoplasms; Polyethylene Glycols; Prospective Studies; Survival Rate; Young Adult; Gemcitabine
PubMed: 32399707
DOI: 10.1007/s00277-020-04036-z -
Oncotarget May 2016Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with...
Efficacy of combined gemcitabine, oxaliplatin and pegaspargase (P-gemox regimen) in patients with newly diagnosed advanced-stage or relapsed/refractory extranodal NK/T-cell lymphoma.
Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive neoplasm with a poor outcome. Asparaginase-based regimens are recommended for patients with advanced-stage or relapsed/refractory ENKTL. We retrospectively investigated the efficacy and toxicity of combined gemcitabine, oxaliplatin, and pegaspargase (P-gemox) in these patients. A total of 35 patients with newly diagnosed stage III-IV, relapsed or refractory ENKTL were treated with 2 to 8 cycles of P-gemox: gemcitabine (1250 mg/m2) and oxaliplatin (85 mg/m2) injected intravenously and pegaspargase (2500 IU/m2) injected intramuscularly on day 1 and repeated every 2 weeks. Upon completion of treatment, the overall response rate was 80.0%, with a complete response in 51.4% of patients. The 1-, 2- and 3- year progression-free survival rates were 45.0%, 38.6% and 38.6%, and overall survival rates were 76.8%, 64.7% and 64.7%, respectively. Patients who attained a complete response showed better progression-free survival than those without a complete response (p = 0.01). The major adverse effects were hematologic toxicity and liver dysfunction. Grade 3/4 leucopenia and neutropenia occurred in 40.0% of patients. No treatment-related deaths occurred. These results indicate the P-gemox regimen is a safe and effective treatment for patients with newly diagnosed advanced-stage or relapsed/refractory ENKTL. We anticipate future prospective trials will confirm the efficacy.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Deoxycytidine; Disease-Free Survival; Female; Humans; Kaplan-Meier Estimate; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Polyethylene Glycols; Retrospective Studies; Treatment Outcome; Young Adult; Gemcitabine
PubMed: 27093153
DOI: 10.18632/oncotarget.8647 -
Leukemia & Lymphoma Nov 2022
Topics: Humans; Asparaginase; Polyethylene Glycols; Drug Hypersensitivity; Antineoplastic Agents
PubMed: 35727258
DOI: 10.1080/10428194.2022.2086251 -
Scientific Reports Mar 2016Pegaspargase combined with gemcitabine have greatly improved the outcomes of advanced extranodal NK/T cell lymphoma (ENKL). However, patients frequently undergo...
S100A9 and ORM1 serve as predictors of therapeutic response and prognostic factors in advanced extranodal NK/T cell lymphoma patients treated with pegaspargase/gemcitabine.
Pegaspargase combined with gemcitabine have greatly improved the outcomes of advanced extranodal NK/T cell lymphoma (ENKL). However, patients frequently undergo recurrent disease due to chemoresistance, and few predictive parameters are available. The present study explored potential biomarkers to predict the therapeutic response of advanced ENKL treated with pegaspargase/gemcitabine and evaluate the prognostic significance. Through serum proteomic analysis, we identified 61 upregulated and 22 downregulated proteins in nonresponders compared with responders. We further validated that patients with unfavourable treatment outcomes displayed higher levels of S100A9 and ORM1 via enzyme-linked immunosorbent assay (ELISA). Moreover, the sensitivity and specificity for detecting refractory patients were 81.5% and 71.4% for S100A9 > 62 ng/ml, 85.2% and 77.1% for ORM1 > 1436 ug/ml, 100% and 57.1% for S100A9 combined with ORM1. Furthermore, in multivariate analysis elevated levels of S100A9 were associated with poor 2-year OS (40.2% vs. 76.6%, RR = 2.92, p = 0.005) and 2-year PFS (33.1% vs. 61.1%, RR = 2.61 p = 0.011). High ORM1 also predicted inferior 2-year OS (38.7% vs.76.1, RR = 2.46, p = 0.023) and 2-year PFS (18.4% vs. 73.2%, RR = 2.86, p = 0.009). Our results indicated that S100A9 and ORM1 could serve as reliable predictors of therapeutic response and independent prognostic factors of survival in advanced ENKL patients treated with pegaspargase/gemcitabine.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Biomarkers, Tumor; Blood Proteins; Calgranulin B; Deoxycytidine; Disease-Free Survival; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Multivariate Analysis; Orosomucoid; Outcome Assessment, Health Care; Polyethylene Glycols; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proteome; Proteomics; Young Adult; Gemcitabine
PubMed: 27021626
DOI: 10.1038/srep23695 -
Blood Advances Jan 2023Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to...
Asparaginase is a key component of pediatric-inspired regimens in young adults with acute lymphoblastic leukemia (ALL). Truncation of asparaginase therapy is linked to inferior outcomes in children with ALL. However, a similar correlation in adults is lacking. Here, we studied the prevalence and risk factors associated with pegylated (PEG)-asparaginase discontinuation in young adults with ALL treated on the US intergroup Cancer and Leukemia Group B (CALGB) 10403 study and examined the prognostic impact of early discontinuation (ED) (defined as <4 of 5 or 6 planned doses) on survival outcomes. The analysis included 176 patients who achieved complete remission and initiated the delayed intensification (DI) cycle. The median number of PEG-asparaginase doses administered before DI was 5 (range, 1-6), with 57 (32%) patients with ED. The ED patients were older (median, 26 vs 23 years; P = .023). Survival was apparently lower for ED patients compared with those receiving ≥4 doses, but this finding was not statistically significant (hazard ratio [HR], 1.82; 95% confidence interval [CI], 0.97-3.43; P = .06), with corresponding 5-year overall survival (OS) rates of 66% and 80%, respectively. In patients with standard-risk ALL, the ED of PEG-asparaginase adversely influenced OS (HR, 2.3; 95% CI, 1.02-5.22; P = .04) with a trend toward inferior event-free survival (EFS) (HR, 1.84; 95% CI, 0.92-3.67; P = .08). In contrast, there was no impact of early PEG-asparaginase discontinuation on OS (P = .64) or EFS (P = .32) in patients with high-risk disease based on the presence of high-risk cytogenetics, Ph-like genotype, and/or high white blood cell count at presentation. In conclusion, early PEG-asparaginase discontinuation is common in young adults with ALL and may adversely impact survival of patients with standard-risk ALL.
Topics: Child; Humans; Young Adult; Asparaginase; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Polyethylene Glycols; Remission Induction
PubMed: 36269846
DOI: 10.1182/bloodadvances.2022007791 -
American Journal of Hematology Nov 2021Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease....
Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95% CI 1.820-7.359, p < 0.001; OS, HR 3.825, 95% CI 1.442-10.148, p = 0.007) and Eastern Cooperative Oncology Group performance status ≥ 2 (PFS, 3.042, 95% CI 1.468-6.306, p = 0.003; OS, HR 3.983, 95% CI 1.678-9.457, p = 0.02) were independent prognostic factors for survival outcomes. Among the established prognostic models for ENKTL, the nomogram-revised risk index model had optimal prognostic risk stratification ability (PFS, p < 0.001; OS, p < 0.001) and relatively balanced population distribution. The adverse events of this CMT were well-tolerated and manageable. In conclusion, sequential P-GEMOX and radiotherapy showed favorable efficacy with acceptable toxicity, and could be an effective treatment option for early-stage ENKTL patients.
Topics: Adult; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Asparaginase; Deoxycytidine; Female; Humans; Lymphoma, Extranodal NK-T-Cell; Male; Middle Aged; Organoplatinum Compounds; Polyethylene Glycols; Prognosis; Survival Analysis; Treatment Outcome; Young Adult
PubMed: 34449095
DOI: 10.1002/ajh.26335 -
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