Toxicities of Intravenous (IV) Pegasparaginase (ONCASPAR®) in Adults with Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2811-2811 ◽  
Author(s):  
Anjali Advani ◽  
Marc Earl ◽  
Dan Douer ◽  
Michael Rytting ◽  
Archie Bleyer
Keyword(s):  
Pediatric Patients ◽  
Liver Enzymes ◽  
Lymphoblastic Leukemia ◽  
Elevated Serum ◽  
Cleveland Clinic ◽  
Adult Patients ◽  
Cancer Center ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Chemotherapy Agents

Abstract Background: With the multiple reports of asparaginase-containing regimens used in pediatric ALL therapy achieving a greater survival rate that non-asparaginase treatment regimens used in adult patients, asparaginase therapy is now being increasingly applied in chemotherapy regimens for adults with ALL. One reason for this resurgence is the availability of a long-acting form of the enzyme, pegylated asparaginase, and more recently, flexibility in administration of pegasparaginase via either intramuscular or intravenous routes (Oncaspar®). Given an initial impression in the 1970s that adults were more vulnerable to the toxicities of asparaginase than were children, we assessed the initial experience of intravenous asparaginase in adults with ALL. Methods: The intial experience with pegylated asparaginase at the University of Southern California (USC), Cleveland Clinic, and University of Texas M.D. Anderson Cancer Center were compiled and compared between institutions and with published results in pediatric patients. Results (Table): In 76 adult patients administered 192 doses of pegasparaginase in combination with other chemotherapy agents for ALL, hepatotoxicity was most common, with grade 3–4 elevation of serum liver enzymes and grade 3–4 hyperbilirubinemia in 36% and 14% of the patients, respectively. Hyperglycemia and chemical pancreatitis were next most common, having occurred at grade 3–4 levels in 25% and 5% of patients, respectively. Grade 3–4 toxicities in the 5–10% range were thrombosis, hypofibrinogenemia, nausea/vomiting, and fatigue. Grade 3–4 allergy/hypersensitivity, neuropathy, and CNS ischemia were reported in 1–5% of patients. Conclusions: Intravenous pegasparaginase is hepatotoxic in ∼1/3 of adult patients and has a variety of other, non-hepatic toxicities in <10% of patients, of which the most common are pancreatitis, thrombosis, nausea/vomiting and fatigue. Intravenous pegasparaginase has a toxicity profile, in combination with other chemotherapy agents used in ALL therapy, in adult patients that similar to that in pediatric patients, and warrants increased use in adult patients with ALL. Grade 3–4 Toxicities of IV Pegasparaginase in Adults USC Cleveland Clinic MD Anderson Total Median Age (Years) 28 37 20 33 Age Range (Years) 17–57 20–68 14–28 17–68 No. Doses / Patients 81 / 45 41 / 18 70 / 13 192 / 76 % Patients with Grade 3–4 Toxicity Elevated liver enzymes 31% 28% 62% 36% Hyperbilirubinemia 13% 22% 15% 14% Hyperglycemia 27% 17% 31% 25% Elevated serum amylase 0% 0%R 0% 5% Fatigue 7% 0% 0% 7% Thrombosis 4% 6% 6% 0% Hypofibrinogenemia 0% 28% 28% 0% Elevated PT/INR 0% 0% 0% 7% Bleeding 0% 0% 0% 8% Nausea/vomiting 2% 17% 17% 1% Allergy/hypersensitivity 0% 0% 0% 1% Neuropathy 2% 0% 0% 4% CNS ischemia 0% 0% 15% 3%

Toxicities in Adults with Acute Lymphoblastic Leukemia (ALL) Treated with Regimens Using Pegasparaginase.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1924-1924 ◽  
Author(s):  
Michael Rytting ◽  
Marc Earl ◽  
Dan Douer ◽  
Brenda Muriera ◽  
Anjali Advani ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Cleveland Clinic ◽  
Adult Patients ◽  
Close Monitoring ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Long Acting ◽  
Age Range

Abstract Background: The current therapeutic strategy of applying pediatric-based regimens for acute lymphoblastic leukemia (ALL) to adults with ALL exposes these patients to multiple doses of asparaginase (ASP). Exposure to long-acting or pegylated ASP is particularly prominent due to dosing convenience, since pegylated ASP can be administered intravenously and requires fewer doses than shorter-acting forms. Previously, adult patients were much less likely to be treated with ASP-containing regimens due to reports from the 1970s of increased toxicity from ASP in adults compared with children. We report on the toxicities encountered in 3 protocols that include multiple doses of pegylated ASP as part of therapy for ALL in adult patients. Methods: Thus far, the 3 protocols have enrolled 92 patients between the ages of 14 and 71 years. The pegylated ASP dose ranges from 2000–2500 IU/m2. Approximately 330 doses of pegylated ASP have been given. Results: Grade 3–4 hepatic toxicity is the most prominent; grade 3–4 transaminase elevation occurred in 47 (51%) patients, and grade 3–4 hyperbilirubinemia was seen in 22 (24%) patients (Table). Hyperglycemia was grade 3–4 toxicity in 30 (33%) patients. Grade 3–4 allergic reactions to pegylated ASP occurred in 5 (5%) patients. Twelve (13%) patients developed thromboses. Of note, 3 (3%) patients have had leukoencephalopathy on magnetic resonance imaging scans with reversible stroke-like symptoms. The majority of hepatic toxicities resolve spontaneously, allowing patients to continue chemotherapy. All of the patients with stroke-like symptoms have fully recovered. Conclusions: Considerable hepatotoxicity and hyperglycemia occur in adult ALL patients treated with polychemotherapy that includes long-acting ASP. Other toxicities occur with a frequency similar to that seen in pediatric patients treated with a long-acting ASP. This toxicity profile warrants close monitoring and continued data collection from clinical trials that use pegylated ASP in adults with ALL. USC Cleveland Clinic M.D. Anderson Total *No. of patients with grade 3–4 toxicities. Median age (years) 33 46 20 33 Age range (years) 18–57 20–71 14–34 14–71 No. doses/patients 127/39 56/25 147/28 330/92 Toxicity* Elevated liver enzymes 23 7 17 47 Hyperbilirubinemia 7 6 9 22 Hyperglycemia 12 5 13 30 Clinical pancreatitis 5 N/A 3 8 Fatigue 3 1 7 11 Thrombosis 3 (SVC only) 2 7 12 Hypofibrinogenemia N/A 8 N/A 8 Elevated PT / INR N/A 1 N/A 1 Bleeding 0 N/A 0 0 Nausea / vomiting 1 4 2 7 Allergy / hypersensitivity 0 2 3 5 Neuropathy 1 1 N/A 2 CNS stroke-like syndrome 0 0 3 3

scholarly journals Thromboembolism Prophylaxis in Adult Patients with Acute Lymphoblastic Leukemia Treated in the GRAALL-2005 Study

Blood ◽  
2020 ◽  
Author(s):  
Corentin Orvain ◽  
Marie Balsat ◽  
Emmanuelle Tavernier ◽  
Jean-Pierre Marolleau ◽  
Thomas Pabst ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Fresh Frozen Plasma ◽  
Adult Patients ◽  
Bleeding Complications ◽  
Thromboembolism Prophylaxis ◽  
Prophylactic Measures ◽  
Increased Risk ◽  
Fresh Frozen ◽  
Grade 3

Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent VTE and thus might increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 16% with 69% of them occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE (8% versus 14%, OR: 0.6, p=0.1). Fibrinogen concentrates administration was associated with an increased risk of VTE (17% versus 9%, OR 2.2, p=0.02) whereas transfusion of fresh-frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE (13% versus 7%, OR 1.9, p=0.04). Prophylactic measures were not associated with an increased risk of grade 3-4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1/34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. Patients developed VTE despite extensive AT supplementation which advocates for additional prophylactic measures. While this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. NCT00327678.

Phase I Trial of Nanomolecular Liposomal Annamycin in Adult Patients with Refractory Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4098-4098
Author(s):  
Meir Wetzler ◽  
Eunice S. Wang ◽  
Robert Shepard ◽  
Deborah A. Thomas ◽  
Michael Andreeff ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Phase I ◽  
Research Funding ◽  
Cardiac Toxicity ◽  
Lymphoblastic Leukemia ◽  
Tumor Lysis Syndrome ◽  
Study Drug ◽  
Adult Patients ◽  
Grade 3 ◽  
Mdr 1

Abstract Abstract 4098 There continues to be no effective second line therapy for refractory acute lymphoblastic leukemia (ALL) in adult patients and the cure rate with current therapy has not significantly improved in decades. Annamycin is a highly lipophilic form of the anthracycline doxorubicin with the ability to bypass multi-drug resistance (MDR-1) mechanisms of cellular drug resistance. A novel nanomolecular liposomal entity of annamycin was recently specifically synthesized which overcomes MDR with little to no cardiac toxicity and improved anti-tumor activity when compared to the original annamycin formulation. We performed a phase I multi-center, open-label, study to determine the maximally tolerated dose (MTD) of nanomolecular liposomal annamycin in adult patients with refractory ALL. The secondary objective was to study the MDR-1 encoded (permeability glycoprotein) PgP-170 glycoprotein expression in correlation with CD34 expression and MDR-1 mRNA levels in refractory ALL patients prior to and after receiving liposomal annamycin treatment. Thirty patients were enrolled on the study. The MTD was determined to be 150 mg/m2/day for 3 days. Other than the tumor lysis syndrome, there was only 1 severe adverse event (SAE) definitely related to the study drug consisting of grade 3 mucositis. There were also 3 other SAEs of grade 3-4 mucositis probably related to the study drug which comprised the MTD determination. There was no reported cardiac toxicity in any patients. After determining the MTD, a 10-patient phase IIA was conducted. Eight of the patients completed 1 cycle of the 3 days of treatment at the MTD. Of these, 5 (62%) had an efficacy signal with complete clearing of circulating peripheral blasts. Three of these subjects also cleared bone marrow blasts with one subsequently proceeding onto successful stem cell transplantation. The other 2 developed tumor lysis syndrome and unfortunately expired prior to response assessment. Nanomolecular liposomal annamycin appears to be well-tolerated with no cardiotoxicity and evidence of clinical activity as a single agent in refractory adult ALL. Given that the likely mechanism of action is overcoming innate drug resistance via MDR, PgP-170 mRNA and protein expression will be presented. We are currently testing liposomal annamycin in a phase I study in children and young adults with refractory ALL or AML, and planning a phase 2 registration trial in adult ALL Disclosures: Wetzler: Callisto Reserach Funding: Research Funding. Off Label Use: Annamycin. Refractory relapse to ALL. Wang:Callisto : Research Funding. Shepard:Callisto: Research Funding. Thomas:Callisto: Research Funding. Andreeff:Callisto: Research Funding. Kantarjian:Callisto: Research Funding.

Childhood B-Precursor-ALL Presenting as Hepatitis - A Diagnostic and Therapeutic Challenge

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4331-4331
Author(s):  
Henriette Schneider ◽  
Ruediger Adam ◽  
Alexander Marx ◽  
Matthias Duerken
Keyword(s):  
Liver Enzymes ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Early Death ◽  
Infectious Hepatitis ◽  
Potential Hazard ◽  
Severe Hepatitis ◽  
Elevated Liver Enzymes ◽  
Piecemeal Necrosis ◽  
Clinical Dilemma

Abstract Abstract 4331 Liver involvement in childhood acute lymphoblastic leukemia (ALL) at presentation is common with hepatomegaly but severe impairment or hepatitis is rare with only 9 reported cases. The need to start anti-leukemic treatment despite the potential hazard of severe liver failure poses a clinical dilemma. We report a 6 year old girl who presented with jaundice, fever, vomiting and diarrhoea, cytopenia, hyperbilirubinemia of 5.7 mg/dl (direct 5.2), ASAT of 3389, ALAT of 2747 U/L, increased INR to 1.33, but normal ammonia. An acute common-ALL was diagnosed and serology, PCR-studies and cultures were negative for viruses causing hepatitis. Liver biopsy revealed diffuse hepatic blast infiltration, piecemeal necrosis and hepatocellular cholestasis without signs of infectious hepatitis. We treated the patient according to the ALL-BFM-2000-protocol without dose reductions and on day 8, hyperbilirubinemia had completely normalized and liver enzymes had significantly decreased. Further therapy was uneventful and the patient is alive and well 12 month after diagnosis, without any signs of hepatic dysfunction. Reviewing the literature on children with ALL presenting with hepatitis revealed 9 patients with a mean age of 8.8 years (range 4 to 15), female to male ratio of 2.0 and precursor B-cell immunophenotype in 8/9 patients. Patients had a mean bilirubin of 8.7 mg/dl (range 2 – 16.5), 3 had highly elevated transaminases above 2000 U/L, and two of them died initially. Another patient with moderately increased liver enzymes but hepatic encephalopathy needed transient hemofiltration, but survived. In none of the reported cases a viral organism has been identified and abnormal liver function normalized during chemotherapy in most of the patients. This indicates, that leukemia rather than infection was responsible for hepatitis. In conclusion, severe hepatitis in children with ALL is rare, seems to affect the older girl, and highly elevated liver enzymes are associated with early death. After infective organisms have been excluded, instant start of an effective induction therapy is required, even despite severe hepatitis, most probably caused by blast infiltration. Disclosures: No relevant conflicts of interest to declare.

A Pilot Phase II Study of the Lyn Kinase Inhibitor Bafetinib in Patients with Relapsed or Refractory B Cell Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2858-2858 ◽  
Author(s):  
Tapan Kadia ◽  
Maria L Delioukina ◽  
Hagop M. Kantarjian ◽  
Michael J Keating ◽  
William G. Wierda ◽  
...  
Keyword(s):  
B Cell ◽  
Liver Enzymes ◽  
Kinase Inhibitor ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cancer Center ◽  
Employment Equity ◽  
Lyn Kinase ◽  
Elevated Liver Enzymes ◽  
Equity Ownership

Abstract Abstract 2858 Inhibition of B cell receptor signaling is an important mechanism of controlling the proliferation and survival of B cell chronic lymphocytic leukemia (CLL) cells. Lyn, a member of the Src kinase family, couples the B cell receptor to downstream signaling and is over expressed in CLL cells relative to normal B lymphocytes. Lyn is upstream from regulatory kinases in B cells such as PI3 kinase Δ and Bruton's tyrosine kinase, which have been successfully targeted for the treatment of CLL. Addition of Lyn kinase inhibitors to CLL cell cultures accelerates apoptosis; treatment of CLL cells with drugs that induce apoptosis decreases both the activity and amount of Lyn kinase (Contri et al, J Clin Invest, 2005; 115 :369–78). These findings support a critical role for Lyn kinase in CLL pathogenesis by showing correlation between high basal Lyn activity and defects in induction of apoptosis in CLL cells. Thus bafetinib, a limited Src family kinase inhibitor targeting BCR/ABL, Lyn, and Fyn kinases, may suppress the growth of CLL cells by inhibiting Lyn kinase and thus have clinical activity. Methods and Objectives: We conducted a single arm, open-label phase 2 trial of single-agent bafetinib in patients with CLL who were relapsed or refractory to > 1course of treatment with either an alkylating agent, rituximab, or a fludaribine-based regimen. Patients were treated with oral bafetinib twice daily (BID), continuously until disease progression or unacceptable toxicity. Endpoints included response assessment by International Working Group CLL Criteria (Hallek et al, Blood, 2008) and toxicity. Results: At the time of analysis, 16 patients were administered bafetinib in the intent-to-treat population at 2 study sites (MD Anderson Cancer Center and City of Hope Cancer Center). The median age was 71 years (range 55–88 years); 13 patients were male. 13 patients were Caucasian and 3 were African-American. Of the 12 patients who were tested, 9 had del (17p;13). Patients had received a median of 3 prior treatment regimens (range 1–6). Where indicated, 5/16 (31%) patients were Rai stage I, 5/16 (31%) Rai stage II, 1/16 (6%) Rai stage III and 5/16 (31%) Rai stage IV. 14/16 patients had ECOG performance scores of 0 or 1. The median duration of treatment with bafetinib was 2 months (range 0.25 to 5 months). 11/16 patients were evaluable for response (baseline + > 1 post-baseline evaluation). There were no objective responses by IWCLL 2008 criteria. Partial nodal responses (> 50% reduction in bidimensional measurements in lymph nodes and/or > 50% shrinkage in spleen size) were observed in 7/11 evaluable patients. 2 patients had stable disease post baseline assessments and 2 patients demonstrated progressive disease at their initial evaluation post baseline. 14 patients were evaluable for toxicity. Almost all of the treatment-related adverse events were grade 1 or 2, with fatigue, nausea and elevated liver enzymes being the most common. Grade 1–2 elevated liver enzymes occurred in 9/14 patients; 1/14 patients had a grade 3 elevated liver enzymes and was removed from the study. No patients exhibited elevated bilirubin. One patient with Parkinson's disease had a worsening of his symptoms and was withdrawn from the trial. No treatment-related serious adverse events occurred. Conclusion: Bafetinib, a Lyn kinase inhibitor, shows promise in patients with relapsed/refractory B-CLL at a dose of 240 mg orally BID. No treatment-limiting toxicity was observed at this dose level. Preliminary PK analysis from a parallel solid tumor study indicated that peak bafetinib concentrations at this dose only reach 0.3–0.6 μM, which is below the concentrations that inhibit the growth of B-CLL cells in vitro (1–1.5 μM). A higher dose level of 360 mg orally BID is being investigated. Future studies involving combinations of bafetinib with monoclonal antibodies and chemotherapy are planned. Disclosures: Kadia: CytRx Corporation: Research Funding. Delioukina:CytRx Corporation: Research Funding. Wieland:CytRx Corporation: Employment, Equity Ownership. Levitt:CytRx Corporation: Employment, Equity Ownership.

Crebbp HAT Domain Mutations Are Frequently Detected in Adult Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1419-1419
Author(s):  
Kenji Tokunaga ◽  
Shunichiro Yamaguchi ◽  
Eisaku Iwanaga ◽  
Tomoko Nanri ◽  
Taizo Shimomura ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
B Cell ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Prognostic Impact ◽  
Pediatric All ◽  
Crebbp Gene

Abstract Abstract 1419 Aims: Molecular pathogenesis of acute lymphoblastic leukemia (ALL) has largely been verified in pediatric patients and the identification of genetic alterations have contributed to stratifying therapeutic applications. In adult patients with ALL, cytogenetic and genetic abnormalities have not sufficiently been elucidated and therapeutic improvement has been hindered. CREB binding protein (CREBBP) is a transcriptional coactivator that interacts with a diverse range of transcription factors and regulates transcription by histone acetylation in hematopoiesis. Mutations of the CREBBP gene are recently found in approximately 2–4% of pediatric patients with ALL. Especially in relapsed cases, the mutations prevail (18–63%) and are possible markers for prediction of relapse in pediatric ALL. In adult patients with ALL, the clinical significance of CREBBP mutations remains to be determined. Here we examined adult ALL patients in an attempt to determine the incidence, clinical characteristics and prognostic impact of the CREBBP mutations. Methods: We investigated 71 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2010. Age ranged from 15 to 86 years, with a median of 54 years. CREBBP mutations are dominantly identified in histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified with RT-PCR using RNA isolated from the peripheral blood or bone marrow mononuclear cells at diagnosis and was subjected to direct sequencing. We compared clinical profiles between patients with and without CREBBPHAT domain mutations. This study was approved by the Institutional Review Boards and informed consent was obtained from each patient according to guidelines based on the revised Declaration of Helsinki. Results: CREBBP HAT domain mutations were detected in 8 of 71 (11.3%) patients: one nonsense mutation, five insertion mutations with frameshifts, and five missense mutations. Two patients harbored biallelic mutations. The mutations at diagnosis in adult patients were seen more frequently than those in pediatric patients ever reported. Such mutations were not completely identical to those detected in pediatric ALL, but were seen in the region within the HAT domain, indicating that such mutations are loss-of-function mutations. The mutations were found in both B-cell (6/53: 11.3%) and T-cell (1/9: 11.1%) ALL, and distributed in patients harboring IKZF1 alterations (3/31: 9.7%) or the BCR-ABL fusion gene (2/19: 10.5%). There were no statistical difference in age, sex, leukocyte, platelet counts and complete remission rate between patients with and without the CREBBP HAT domain mutations. Patients with the mutations had a trend with worse cumulative incidence of relapse (P=0.4637), relapse-free survival (P=0.4195) and OS (P=0.2349) compared to patients lacking the mutations, but statistical significance was not detected in this small cohort. Conclusions: CREBBP HAT domain mutations at diagnosis in adult ALL are found more frequently than in pediatric ALL. This may be one of the mechanisms that adult ALL has been associated with poor OS compared with pediatric ALL. In this study, CREBBP HAT domain mutations were observed in various subtypes of ALL: both B-cell and T-cell ALL, and both Philadelphia chromosome positive and negative ALL. In pediatric ALL, CREBBP mutations were frequently seen in relapsed patients but not in previously untreated patients. These observations suggest that CREBBP mutations play an important role in an additional late event(s) leading to the development and progression of ALL. Our study implies the possibility that mutations of the CREBBP gene are associated with the pathogenesis and prognostic marker of adult ALL and represent specific epigenetic modifiers in adult ALL, serving as potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Effect of Asparaginase on Serum Triglycerides during Therapy for Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2665-2665
Author(s):  
Emily R Finch ◽  
Colton A Smith ◽  
Wenjian Yang ◽  
Nancy M Kornegay ◽  
John C Panetta ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Elevated Serum ◽  
Remission Induction ◽  
Horizontal Line ◽  
Serum Triglycerides ◽  
Time Points ◽  
Grade 3

Abstract Introduction: Treatment for acute lymphoblastic leukemia (ALL) with asparaginase (ASP) and glucocorticoids, such as dexamethasone (DEX), can cause changes in serum triglycerides (TGs). Glucocorticoids increase the activity of lipoprotein lipase (LPL), the enzyme responsible for removing TGs from the plasma, and increase production of TG-rich particles, resulting in the mobilization and redistribution of body fat. In contrast, ASP decreases the activity of LPL. Therefore, when glucocorticoids and ASP are given together, it is likely that TG-rich particles are rapidly formed, but insufficiently cleared, resulting in elevated serum TGs. The ASP formulation, e.g., native E. coli ASP (Elspar, L-ASP) vs. PEGylated ASP (Oncaspar; PEG-ASP), may influence the magnitude of TG changes. Our aim was to compare changes in TGs, the incidence of hypertriglyceridemia (hyperTG), and associated toxicities in two front-line pediatric St. Jude ALL trials that used different formulations of ASP: Total XV (L-ASP) and Total XVI (PEG-ASP). Methods: Patients on TXV (n=392) and TXVI (n=583) were assigned to the low-risk (LR) or standard/high risk (SHR) therapeutic arms. Serum TGs were measured as research biomarkers at four time-points: consolidation day 15 ("baseline" was > 35 days after the last dose of ASP during remission induction and > 21 days after the last dose of glucocorticoid); day 1 of week 7, 8, and either week 12 (TXV) or week 17 (TXVI) of continuation. Patients received DEX for 5 days/week during weeks 1, 4, and 14, for 8 days at week 7, and for 7 days at week 9 of continuation. In TXV, SHR patients received L-ASP weekly during the observed course of continuation (25,000 U/m2/dose); LR patients received L-ASP thrice weekly during continuation weeks 7-9 (10,000 U/m2/dose). In TXVI, patients were randomized to receive PEG-ASP 2,500 or 3,500 U/m2/dose during continuation: SHR weeks 1, 3, 5, 7, 9, 11, 13, and 15; LR weeks 7 and 9. HyperTG was defined as TG > 1000 mg/dL (dotted horizontal line in Figure 1). Clinically relevant toxicities in TXV, including thrombosis (≥ grade 3), osteonecrosis (≥ grade 2) and pancreatitis (≥ grade 3) were graded according to CTCAE v2.0; in TXVI CTCAE v3.0 was used, with identical grades except for pancreatitis (≥ grade 2). Results: Similar trends in TGs were observed in both protocols for LR patients: there was a decrease in TGs from baseline to week 7, when DEX but not ASP had been given (TXV: p= 2 x 10-8, TXVI: p< 2 x 10-16); TGs increased from week 7 to 8 after both DEX and ASP (TXV: p=3 x 10-14, TXVI: p< 2 x 10-16); and the week 12/17 TG did not differ from baseline (> 16 days after last dose of DEX and ASP, TXV: p= 0.7, TXVI: p= 0.1). Among LR patients, the only difference between protocols was that the week 12/17 TG was higher on TXVI (with PEG-ASP) than TXV (with L-ASP) (p= 0.04). In contrast, among SHR patients, TGs were elevated at all time points relative to baseline (e.g. week 7 compared to baseline, TXV: p= 1 x 10-5, TXVI: p < 2 x 10-16); TGs increased from week 7 to 8 after both DEX and ASP (TXV: p= 6 x 10-16, TXVI: p < 2 x 10-16); and the week 12/17 TG remained higher than baseline (TXV: p= 9 x 10-9, TXVI: p < 2 x 10-16) at 7-16 days after last dose of DEX or ASP. Among SHR patients, TGs were higher in TXVI vs. TXV after baseline: at week 7 (p= 8 x 10-7), week 8 (p= 6 x 10-4), and at the week 12/17 TG (p= 8 x 10-4), suggesting a greater effect of PEG-ASP vs. L-ASP in increasing TGs. More patients developed hyperTG on TXVI vs TXV: 10% (59/583) vs. 5% (20/392), respectively (p= 0.007). In both protocols, only patients on SHR therapy developed hyperTG, suggesting an association with ASP. Patients with hyperTG were more likely to be diagnosed with thrombosis and osteonecrosis. However, this association was only significant after adjustment for age and risk group in TXVI: 17% of patients with vs. 4% without hyperTG developed post-induction thrombosis (p= 0.009); 39% of patients with vs. 11% without hyperTG developed osteonecrosis (p= 0.006). In TXV, associations of hyperTG with thrombosis (p= 0.2) and osteonecrosis (p= 0.08) were not significant after adjustment for age and risk group. There was no association between hyperTG and pancreatitis in either protocol. Conclusions: These data support a greater association of PEG-ASP than L-ASP with elevation of serum TGs, and a greater effect of ASP than DEX. Whether serum hyperTG contributes to toxicities such as thrombosis or osteonecrosis, or is a biomarker of greater drug exposure or sensitivity, is unclear. Figure. Figure. Disclosures Inaba: Shire: Research Funding. Relling:Shire Pharmaceuticals: Research Funding.

scholarly journals Treatment Outcomes for Adult Patients with Localized Osteosarcoma Treated with Chemotherapy without Methotrexate

2020 ◽  
Author(s):  
MRM Silva ◽  
RC Bonadio ◽  
GDR Matos ◽  
D Toloi ◽  
M Nardo ◽  
...  
Keyword(s):  
Overall Survival ◽  
Treatment Strategies ◽  
Additional Treatment ◽  
Adult Patients ◽  
Cancer Center ◽  
High Dose ◽  
High Grade ◽  
Grade 3 ◽  
High Grade Osteosarcoma ◽  
Cure Rates

AbstractBackgroundStandard treatment for pediatric patients with localized osteosarcoma include high-dose methotrexate (HDMTX) and cure rates greater than 60% are observed. In adult patients, however, the toxicity profile limits the use of HDMTX and it is usually excluded from chemotherapy protocols for this group. We aimed to evaluate the outcomes of adult patients with localized osteosarcoma treated with chemotherapy without methotrexate.MethodsIn this retrospective cohort, we evaluated adult patients with high-grade osteosarcoma who received treatment with chemotherapy without methotrexate in a reference cancer center from 2007 to 2018. Outcomes analyzed were recurrence-free survival (RFS), overall survival (OS), and prognostic factors associated with overall survival.ResultsA total of 48 patients had localized disease and received treatment with chemotherapy without methotrexate. The majority of them received chemotherapy with a combination of cisplatin and doxorubicin (N=42, 87.5%). Median age was 27 years. (range 16.8 – 66.7) With a median follow-up of 29.2 months, median RFS was 29.9 months. Median OS was not reached. 5-year RFS and OS rates were 35.1% (95% CI 20.3 – 50.2%) and 71.6% (95% CI 52.3 – 84.2%), respectively. Patients who received cumulative doses of doxorubicin ≥ 375 mg/m2 had better OS than those who received lower doses (HR 0.26, 95% CI 0.07 – 0.94, P = 0.041). Similarly, patients who received ≥ 6 cycles of neoadjuvant/ adjuvant cisplatin tended to have better OS than those who received < 6 cycles (HR 0.30, 95% CI 0.08 – 1.09, P = 0.069).Nineteen patients received less than 6 cycles of cisplatin and doxorubicin mainly because of grade 3 or 4 toxicities (11), disease progression (6),patient refusal(1), physician choice(1).ConclusionIn our study, adult patients with localized high-grade osteosarcoma who were treated with chemotherapy without methotrexate had unfavorable outcomes. The cumulative doxorubicin dose and the number of cisplatin/doxorubicin cycles were associated with improved OS. The investigation of additional treatment strategies is of utmost importance to improve adult patients outcomes.

Gemcitabine and carboplatin in the treatment of metastatic cholangiocarcinoma and gallbladder cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15102-15102
Author(s):  
R. Suresh ◽  
J. Picus ◽  
S. Sorscher ◽  
C. Fournier ◽  
B. R. Tan
Keyword(s):  
Gallbladder Cancer ◽  
Phase Ii ◽  
Stable Disease ◽  
Liver Enzymes ◽  
Phase Ii Study ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Elevated Liver Enzymes ◽  
Grade 3 ◽  
Electrolyte Abnormalities

15102 Background: There is currently no standard therapy for patients with unresectable or metastatic biliary tract cancers. Gemcitabine has been shown to be active against these tumors with a 20–30% response in various phase II studies. Gemcitabine is also synergistic with platinum compounds. Aim: We conducted a Phase II study of gemcitabine plus carboplatin in patients with unresectable or metastatic choloangiocarcinoma or gallbladder cancer to assess the regimen’s safety and efficacy. Methods: Since 3/2002, 49 (48 evaluable) patients were treated with gemcitabine at 1000 mg/m2 IV over 30 minutes days 1 and 8 with carboplatin at AUC 5 IV on day 1 of a 21 day cycle. There were 34 women and 15 men enrolled. Ages ranged from 34 to 87 with a median age of 65 years. Results: Best radiologic responses - 5CR, 9 PR, 24 stable disease and 10 progression. CR+PR 14/48 (29.2%) and stable disease 24/48 (50%). Toxicity: Hematological toxicities: Grade 3 neutropenia 33%, febrile neutropenia 0.02%, anemia 12.5% and thrombocytopenia 14.6%. Grade 4 hematological toxicites were rare - neutropenia 0.04%, and thrombocytopenia 0.06%. Non-hematologic toxicities were generally mild (fatigue, edema, nausea, vomiting, elevated liver enzymes, electrolyte abnormalities). Except for one patient who had depression there were no grade 4 non-hematological toxicity. Grade 3 non- hematological toxicites were also rare occurring only in 1 to 3 patients. Conclusions: Gemcitabine and carboplatin is active against biliary cancer and is highly tolerable. This study is being supported by Eli Lilly & Co. No significant financial relationships to disclose.

Sustained and Prolonged Asparagine Depletion by Multiple Doses of Intravenous Pegylated Asparaginase in the Treatment of Adults with Newly Diagnosed Acute Lymphoblastic Leukemia.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1928-1928
Author(s):  
Dan Douer ◽  
Kristy Watkins ◽  
Lisa Mark ◽  
Mohrbacher Ann ◽  
Allen S Yang ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Liver Enzymes ◽  
Induction Phase ◽  
Multiple Doses ◽  
Elevated Liver Enzymes ◽  
Pediatric All ◽  
Multi Agent ◽  
Asparaginase Activity ◽  
Grade 3

Abstract The better outcome in pediatric ALL may not be solely related to the biology of the disease. Adult regimens are less intensive than used in children and include less, shorter or no use of asparaginase; the drug is often considered more toxic than in children. However, adequate serum asparagine depletion was shown to be associated with improved overall outcome. Further in several, multi-agent, large pediatric randomized trials, longer administration of asparaginase in the post remission phase and more sustained asparagine depletion resulted in better outcome. PEG-asparaginase (PEG-ASP) is a modified E.coli ASP, with less hypersensitivity reactions and longer half-life. In adults a single IV dose of PEG-ASP during induction produces long duration of asparagine depletion of up to 4 weeks, t½ = 7 days, with similar toxicity to equivalent multiple doses of E.coli ASP (Douer et al Blood 19:2744,2007). We now report the use of multiple doses of PEGASP, given during induction and throughout the post-remission phases in order to produce prolonged and sustained asparagine depletion in the context of an intensified pediatric protocol, in newly diagnosed, treatment naïve, adult ALL. Sustained asparaginase activity after the short acting E.coli ASP, can be impaired by development of neutralizing anti – asparaginase antibodies. We therefore measured the asparaginase enzymatic activity in a cohort of our patients who received PEG-ASP which in children was shown to be associated with less antibody formation (Avramis et al Blood2002;99:1986). Methods: The backbone of our protocol is an augmented BFM pediatric ALL regimen consisting of 8 cycles of multi-agent chemotherapy, followed by maintenance. PEG-ASP (2000 U/m2/dose) is given IV once on day 15 of the following cycles (total 6 doses): induction phase I (cycle 1), induction phase II (cycle 2), two cycles of consolidation (cycles 3 and 6), and two cycles of delayed re-induction (cycles 5 and 8). Since December 2006, Ph+ patients receive imatinib 600mg/daily. Asparaginase enzymatic activity was measured in samples obtained before and after PEG-ASP doses in cycles 1, 5 and 8. Results: 41 patients, aged 19–57 (median 33) years, with precursor B cell – 36, T cell-5, Ph+ 9, were studied. Median WBC at diagnosis - 15,900/cumm (range 1,900–512,000). CR rate: 37 (95%) pts. all after induction phase I. To date 15 patients received all 6 doses of PEG-ASP, having completed all consolidation cycles. The other patients are still being treated. So far the number of PEG-ASP doses given is: 6(15pts), 3(6 pts), 2(7 pts), 1(13 pts) Fifteen patients could not continue the protocol for: allogeneic stem-cell transplantation (8), refusal (1), pancreatitis (5), grade 3 DVT(1). Two additional patients died in CR from neutropenic sepsis. Patients with elevated liver enzymes, high bilirubin, or hyperglycemia continued on the study. Total number of PEG-ASP doses was 135. No pt had an allergic reaction. The number of pts with grade 3/4 toxicities during PEG-ASP cycles were: elevated liver enzymes 24 (59%), hyperbilrubinema 8 (20%), hyperglycemia 12 (29 %), pancreatitis 6(15%), fatigue 4(10%), hypertriglyceridemia 3 (7%), catheter thrombosis- 4 (10%), neuropathy-1. All toxicities were reversible. With a median follow up of 18 months, EFS at 3 and 4 yrs is 68 % (Ph- patients 74%) and CIR is 23%. Asparaginase enzymatic activity after each dose was very long in a cohort of 19 pts with a population average of t½ = 10.99 days (peak concentration 0.88 IU/ml). All 74 specimens analyzed from this cohort of patients had significant asparaginase activity after each PEG-ASP dose, highly suggesting that none of the patients analyzed had developed neutralizing anti asparaginase antibodies. Additional patients with enzymatic measurements will be presented Conclusions: Multiple doses of PEG-ASP IV in adults (ages 19–57 years) provide prolonged and sustained asparagine depletion and no apparent drug inactivating by antibody formation. In combination with an intensified BFM-based protocol this pediatriclike strategy is feasible, without allergic reactions, and with acceptable toxicity. Although the follow up is relatively short the EFS appears to be high. Such approach may benefit adults with ALL

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