scholarly journals National Italian Delphi panel consensus: which measures are indicated to minimize pegylated-asparaginase associated toxicity during treatment of adult acute lymphoblastic leukemia?

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Federico Lussana ◽  
Paola Minetto ◽  
Felicetto Ferrara ◽  
Sabina Chiaretti ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Critical Evaluation ◽  
Adult Patients ◽  
Delphi Panel ◽  
Activity Levels ◽  
Treatment Protocols ◽  
Consensus Statements

Abstract Background L-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a relatively high incidence of drug-related adverse events, mainly in adult patients. In the past years the use of ASP in adult population has been mainly limited due to a poor knowledge of its safety profile and to an approximate management of ASP-related toxicity. Recently the development of pediatric-inspired treatment protocols for adult ALL has led to a wider use of ASP and since 2010 in Italy three national treatment protocols including Pegylated asparaginase (Peg-ASP) have been sequentially developed for adolescents, young adults and adults with Philadelphia-negative (Ph-) ALL. Methods With the aim to better understand the approach adopted in Italian centers for the management and prevention of Peg-ASP toxicity in adult ALL and to provide practical, consensus-based recommendations, a board of 6 Italian clinicians, with known expertise in adult ALL, designed 41 consensus statements on current challenges on the management of Peg-ASP associated toxicity. A group of 19 clinical experts in the field then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). Results The main Peg-ASP related issues identified by the board included: 1) clinician’s attitudes; 2) toxicity profile; 3) hypersensitivity reactions; 4) hepatic toxicity; 5) hepatic and/or metabolic toxicity; 6) hemorrhagic/thrombotic toxicity; 7) pancreatitis; 8) metabolic toxicity management and prevention; 9) activity levels monitoring. Overall, participants agreed on most statements, except those addressing the potential contraindications to the treatment with Peg-ASP, such as patients with a diagnosis of chronic liver disease or the subsequent administrations of the drug in patients who had previously developed chemical pancreatitis or severe metabolic toxicity. Participants agreed that adult patients with ALL should receive Peg-Asp because this drug is essential to improve treatment results. Conclusions The panel agreed that a critical evaluation of specific risk factors for each patient is crucial in order to reduce the risk of adverse events and specific advices in the management of Peg-ASP toxicities are reported.

scholarly journals Pegasperagase Toxicity in Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Experience Comparing Patients Older and Younger Than 35 Years of Age

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5067-5067
Author(s):  
Jun H Choi ◽  
Jacques Azzi ◽  
Tsivia Hochman ◽  
Mary Lynn R. Nierodzik ◽  
Shella Saint Fleur-Lominy ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Prospective Trial ◽  
Philadelphia Chromosome ◽  
Treatment Protocol ◽  
Adult Patients ◽  
Grade 3

Background: The treatment paradigm of adult patients with acute lymphoblastic leukemia (ALL) is primarily derived from successful pediatric chemotherapy regimens. Pegasparagase (PEG) is a key component of pediatric therapy and is the backbone of cytotoxic ALL regimens. However, among the adult population the use of PEG has been limited by the difficulty in tolerating prolonged asparagine depletion. Hepatotoxicity is among the most common adverse events reported with the use of PEG, with grade 3/4 hepatotoxicity seen in 20% of young adults compared to 40-60% of older adults. Incorporating PEG into the treatment of ALL patients under 40 remains an accepted practice despite some studies that report up to 75% of patients have grade 3/4 adverse events as a result of asparagine depletion. In a study of 85 patients with ALL, 3-year overall survival (OS) was significantly different between patients older and younger than 35 (52% vs 83% p = 0.003). Whether this difference is due to PEG toxicity or to other factors remains to be determined. At NYU hospitals, PEG-containing protocols are frequently deployed to treat adult ALL. In our study, we sought to look at the difference in PEG toxicity and response rate (RR) in patients older and younger than 35 and whether these toxicities contributed to a delay in subsequent treatments and to a worse outcome. Methods: We conducted a retrospective chart review of patients older than 18 diagnosed with ALL or lymphoblastic lymphoma, who received at least 1 dose of PEG at our institution between 2014 and 2018. All patients received PEG as part of their first line treatment protocol. Our main objective was to compare the tolerability and toxicity profile of intravenous PEG in patients ≥35 years old versus <35. Our secondary objective was to investigate its effects on chemotherapy delay, RR, and relapse rate. Results: Out of a total of 50 patients, 23 were age ≥ 35 (46%). Mean age was 34.4 (Range: 18.9-63.1). The 2 groups shared similar distributions in gender, race, and Philadelphia chromosome (Ph) subtypes (Table 1). The older group received significantly less PEG, 5114.8 vs. 25353.7 units (p=0.0007) and 1.65 vs. 3.59 doses (p<0.0001) compared to the younger group. Grade 1-4 toxicity profiles were similar as both groups had high hepatotoxicity rates: transaminitis 100% vs. 89% (p=0.079) and hyperbilirubinemia 78% vs. 78% (p=0.104) in the older vs younger group, respectively. Grade 3-4 hepatotoxicity was significantly more pronounced in patients ≥35 years old (transaminitis 65% vs. 33% [p=0.0245], hyperbilirubinemia 48 vs. 15% [p=0.0111]). Coagulopathy rates evaluated with hypofibrinogenemia and thrombosis were similar between the older and the younger groups at 52% vs. 44% [p=0.104] and 17% vs. 7%, [p=0.855], respectively, and the frequency of pancreatitis and anaphylaxis were 4% vs. 18.5% (p=0.422) and 0% vs. 14.8% (p=0.115), respectively. In the older group, only 13% completed the planned PEG dosages compared to 59% in the younger group (p=0.0008), and delay in other chemotherapy by more than 30 days due to PEG hepatotoxicity occurred in 55% of older patients compared to 22% of younger patients (p=0.02). MRD negativity rate after induction was similar in the older and younger group (50% vs. 60% [p=0.491], respectively), but the 12-month relapse free survival was significantly lower in the older group (41%, [95% CI: 55.7%-89%] vs. 77%, [95% CI: 21%-61%], p=0.022) (Figure 1). Conclusions: Patients aged ≥ 35 received significantly less PEG during their treatments but were more likely to develop severe grade 3-4 hepatotoxicity compared to their younger counterparts. The response rates were similar with comparable MRD negativity rates after induction regardless of total amount of PEG administered. However, relapse occurred more frequently in the older group, possibly resulting from more frequent delays in administering other chemotherapy agents due to PEG toxicity. Incorporation of PEG is important in the treatment of ALL but should be used with caution in patients ≥35 years old, and will likely require dose and schedule modifications. A larger prospective trial investigating adequate dosing and scheduling of PEG in this age group is warranted, specifically comparing delays in chemotherapy, relapse, and survival rates in regimens with and without PEG. Disclosures No relevant conflicts of interest to declare.

scholarly journals The use of methotrexate, vincristine, L-asparaginase and dexamethasone for salvaging adult acute lymphoblastic leukemia and lymphoma: a real-life experience

2019 ◽  
Vol 6 (10) ◽  
pp. 263-267
Author(s):  
Funda Pepedil Tanrikulu ◽  
Nurhilal Buyukkurt ◽  
Mahmut Yeral ◽  
Pelin Aytan ◽  
Soner Solmaz ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Life Experience ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Real Life ◽  
Lymphoblastic Lymphoma ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Successful Transplantation

Despite recent improvements in the treatment options, adult relapsed/refractory Acute Lymphoblastic Leukaemia (ALL) and lymphoblastic lymphoma (LBL) exhibit poorer cure rates than in childhood. Since, the mainstay difference of childhood multidrug regimens is L-Asparaginase, we sought to salvage adult patients with a protocol containing methotrexate, vincristine, conventional L-asparaginase, and dexamethasone (MOAD). In this study, we aimed to summarize our experience. Methods: Adult patients with relapsed/refractory ALL and LBL followed-up in our institution between 2017 and 2018 were reviewed and those treated with MOAD protocol were retrospectively included in the study. Clinical data, treatment responses, and adverse events were summarised. The protocol featured 28-day cycles of methotrexate 200 mg/m2 intravenously (IV) on days 1 and 15; vincristine 1.4 mg/m2 IV on days 1, 8, and 15; L-asparaginase 10,000 IU/m2 IV twice weekly; and dexamethasone 40 mg IV or orally on days 1–4 and 15–18. Results: A total of eight patients were enrolled, of median age 37 years (range: 21–58 years). Four patients were recovered after transplantation. Complete remission was evident in 38%. Two such patients underwent allogeneic hematopoietic stem cell transplantation after the protocol. Another patient with lymphomatous disease achieved partial remission and underwent successful transplantation. L-asparaginase did not trigger any clinically evident hypersensitivity reaction; the most common adverse events associated with the protocol were hypofibrinogenemia, anemia, and febrile neutropenia. Conclusions: The MOAD protocol was effective and tolerable, enabling to salvage before and after transplantation, particularly in patients with relapsed/refractory T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma.

The ABCs of Immunotherapy for Adult Patients With B-Cell Acute Lymphoblastic Leukemia

2017 ◽  
Vol 52 (3) ◽  
pp. 268-276 ◽  
Author(s):  
Troy Z. Horvat ◽  
Amanda N. Seddon ◽  
Adebayo Ogunniyi ◽  
Amber C. King ◽  
Larry W. Buie ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Data Extraction ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Efficacy And Safety ◽  
Car T Cells ◽  
Car T ◽  
American Society

Objective: To review the pharmacology, efficacy, and safety of Food and Drug Administration approved and promising immunotherapy agents used in the treatment of acute lymphoblastic leukemia (ALL). Data Sources: A literature search was performed of PubMed and MEDLINE databases (1950 to July 2017) and of abstracts from the American Society of Hematology and the American Society of Clinical Oncology. Searches were performed utilizing the following key terms: rituximab, blinatumomab, inotuzumab, ofatumumab, obinutuzumab, Blincyto, Rituxan, Gazyva, Arzerra, CAR T-cell, and chimeric antigen receptor (CAR). Study Selection/Data Extraction: Studies of pharmacology, clinical efficacy, and safety of rituximab, ofatumumab, obinutuzumab, inotuzumab, blinatumomab, and CAR T-cells in the treatment of adult patients with ALL were identified. Data Synthesis: Conventional chemotherapy has been the mainstay in the treatment of ALL, producing cure rates of approximately 90% in pediatrics, but it remains suboptimal in adult patients. As such, more effective consolidative modalities and novel therapies for relapsed/refractory disease are needed for adult patients with ALL. In recent years, anti-CD20 antibodies, blinatumomab, inotuzumab, and CD19-targeted CAR T-cells have drastically changed the treatment landscape of B-cell ALL. Conclusion: Outcomes of patients with relapsed disease are improving thanks to new therapies such as blinatumomab, inotuzumab, and CAR T-cells. Although the efficacy of these therapies is impressive, they are not without toxicity, both physical and financial. The optimal sequencing of these therapies still remains a question.

Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison

Blood ◽  
2009 ◽  
Vol 113 (6) ◽  
pp. 1375-1382 ◽  
Author(s):  
Jan J. Cornelissen ◽  
Bronno van der Holt ◽  
Gregor E. G. Verhoef ◽  
Mars B. van 't Veer ◽  
Marinus H. J. van Oers ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Donor Group ◽  
No Donor ◽  
Sibling Donor ◽  
Standard Risk

Abstract While commonly accepted in poor-risk acute lymphoblastic leukemia (ALL), the role of allogeneic hematopoietic stem cell transplantation (allo-SCT) is still disputed in adult patients with standard-risk ALL. We evaluated outcome of patients with ALL in first complete remission (CR1), according to a sibling donor versus no-donor comparison. Eligible patients (433) were entered in 2 consecutive, prospective studies, of whom 288 (67%) were younger than 55 years, in CR1, and eligible to receive consolidation by either an autologous SCT or an allo-SCT. Allo-SCT was performed in 91 of 96 patients with a compatible sibling donor. Cumulative incidences of relapse at 5 years were, respectively, 24 and 55% for patients with a donor versus those without a donor (hazard ratio [HR], 0.37; 0.23-0.60; P < .001). Nonrelapse mortality estimated 16% (± 4) at 5 years after allo-SCT. As a result, disease-free survival (DFS) at 5 years was significantly better in the donor group: 60 versus 42% in the no-donor group (HR: 0.60; 0.41-0.89; P = .01). After risk-group analysis, improved outcome was more pronounced in standard-risk patients with a donor, who experienced an overall survival of 69% at 5 years (P = .05). In conclusion, standard-risk ALL patients with a sibling donor may show favorable survival following SCT, due to both a strong reduction of relapse and a modest nonrelapse mortality. This trial is registered with http://www.trialregister.nl under trial ID NTR228.

A prognostic scoring system for adult patients less than 60 years of age with acute lymphoblastic leukemia in first relapse

2009 ◽  
Vol 50 (7) ◽  
pp. 1126-1131 ◽  
Author(s):  
Anjali Advani ◽  
Tao Jin ◽  
Brian Bolwell ◽  
Edward Copelan ◽  
Mikkael Sekeres ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Scoring System ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
First Relapse

scholarly journals Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study Group

Haematologica ◽  
2010 ◽  
Vol 95 (4) ◽  
pp. 589-596 ◽  
Author(s):  
A. Oriol ◽  
S. Vives ◽  
J. M. Hernandez-Rivas ◽  
M. Tormo ◽  
I. Heras ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Adult Patients ◽  
Study Group

scholarly journals Blinatumomab In pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis

2022 ◽  
Author(s):  
Franco Locatelli ◽  
Gerhard Zugmaier ◽  
Noemi Mergen ◽  
Peter Bader ◽  
Sima Jeha ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Expanded Access ◽  
Molecular Abnormalities

The safety and efficacy of blinatumomab, a CD3/CD19-directed bispecific T-cell engager molecule, for treatment of pediatric relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL) were examined in an open-label, single-arm, expanded access study (RIALTO). Children (&gt;28 days, &lt;18 years) with CD19+ R/R B-ALL received up to five cycles of blinatumomab by continuous infusion (cycle: 4 weeks on/2 weeks off). The primary endpoint was incidence of adverse events. Secondary endpoints included complete response (CR) and measurable residual disease (MRD) response within the first two cycles, relapse-free survival (RFS), overall survival (OS) and allogeneic hematopoietic stem cell transplant (alloHSCT) after treatment. At final data cutoff (1/10/20), 110 patients were enrolled (median age, 8.5 years; 88% ≥5% blasts at baseline). Blinatumomab treatment resulted in a low incidence of grade 3-4 cytokine release syndrome (n=2 [1.8%]) and neurologic events (n=4 [3.6%]). No blinatumomab-related fatal adverse events were reported. The probability of response was not affected by the presence of cytogenetic/molecular abnormalities. Median OS was 14.6 months (95%CI: 11.0─not estimable) and was significantly greater for MRD responders versus MRD non-responders (not estimable vs 9.3; HR 0.18, 95%CI: 0.08─0.39). One-year OS probability was higher for patients who received alloHSCT versus without alloHSCT post-blinatumomab (87% versus 29%). Median RFS for MRD responders (n=57) was 8.0 months (95%CI:3.4─10.1) versus 2.8 months (95%CI: 0.3─9.2) for MRD non-responders (n=10). Of patients achieving CR after 2 cycles, 73.5% (95%CI: 61.4%-83.5%) proceeded to alloHSCT. These findings support the use of blinatumomab as a safe and efficacious treatment for pediatric R/R B-ALL. (ClinicalTrials.gov identifier NCT02187354)

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