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.

Outcome After First Relapse In Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3084-3084
Author(s):  
Shinichi Kako ◽  
Heiwa Kanamori ◽  
Naoki Kobayashi ◽  
Akio Shigematsu ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Salvage Chemotherapy ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
First Relapse

Abstract Abstract 3084 With modern intensive chemotherapy, 78% to 93% of adult patients with acute lymphoblastic leukemia (ALL) achieve complete remission (CR). However, the disease-free survival rate is only 30% to 40% due to the high rate of relapse. A part of relapsed patients can achieve second remission (CR2) with salvage therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) in CR2 will be the only curative strategy. Prognosis after relapse in adult patients with ALL is considered to be extremely poor, but reports as to the outcome after relapse have been limited. To elucidate the outcome of relapsed patients and prognostic factors after relapse, we retrospectively collected and analyzed clinical data from 69 institutions in Japan on patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first CR (CR1) between 1998 and 2008. A total of 332 patients were included in this study. The median age of them was 35 years, and 165 patients were male. Median duration of CR1 was 290 days (range 15–7162 days), and median follow-up time after relapse was 319 days (range 3–3689 days). Fifty-eight and 4 of them relapsed after allogeneic and autologous HSCT in CR1, respectively. The overall survival (OS) rate was not significantly different between patients who relapsed after allogeneic HSCT in CR1 and those who relapsed after chemotherapy only (50.0% vs. 43.4% at 1 year and 10.6% vs. 16.3% at 5 year, respectively). Among 270 patients who relapsed after chemotherapy only, 234 patients received salvage chemotherapy after relapse, and 123 patients achieved CR2 (52.5%). Sixty-two patients out of those 123 patients underwent allogeneic HSCT in CR2. Median duration between the achievement of CR2 with salvage chemotherapy and allogeneic HSCT in CR2 was 76 days. OS rate was significantly better in patients who underwent allogeneic HSCT in CR2 following salvage chemotherapy than those who did not (74.1% vs. 55.1% at 1 year and 44.7% vs. 11.6% at 5 year, respectively) by a landmark analysis limiting patients who were surviving without disease at 76 days after the achievement of CR2. In multivariate analysis of factors that included allogeneic HSCT in CR2 following salvage chemotherapy as a time-dependent covariate, lower white blood cell count at relapse (less than 10000/μl) and allogeneic HSCT in CR2 were associated with better OS rate among patients who achieved CR2 following salvage chemotherapy. Forty-six patients underwent allogeneic HSCT in non-CR after receiving salvage chemotherapy. A part of them survived long, and 5 year OS rate was 20.9%. In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. Allogeneic HSCT after first relapse could improve the prognosis. Disclosures: No relevant conflicts of interest to declare.

Accumulation Of Gene Alterations Of TP53, Crebbp and IKZF1 Is a Prognostic Factor In Adult Acute Lymphoblastic Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1386-1386
Author(s):  
Kenji Tokunaga ◽  
Shunichro Yamaguchi ◽  
Taizo Shimomura ◽  
Hitoshi Suzushima ◽  
Yutaka Okuno ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genomic Dna ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Statistical Significance ◽  
Philadelphia Chromosome ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Adult Patients ◽  
Genomic Deletions

Abstract Aims Mutations of the genes associating with cell differentiation or proliferation are recognized as factors of tumorigenesis or prognosis in hematological malignancies. In pediatric acute lymphoblastic leukemia (ALL), alterations of IKZF1 (a factor of lymphocyte differentiation), TP53 (a cell cycle regulator) and CREBBP (a histone modifier) are found as possible prognostic markers for stratification of treatments. On the other hand, in adult ALL, clinical significance of such alterations remains to be determined. In the present work, we examined whether the mutations in those genes affected the incidence and prognosis in adult ALL patients. Methods We investigated 87 adult patients with newly diagnosed ALL treated with JALSG protocols between 1986 and 2011. Age ranged from 15 to 86 years, with a median of 51 years. We obtained cDNA and genomic DNA from the peripheral blood or bone marrow mononuclear cells at diagnosis. CREBBP mutations are dominantly identified in the histone acetyltransferase (HAT) domain. HAT domain in the CREBBP gene was amplified by PCR using cDNA and was subjected to direct sequencing. Additionally other histone modifiers, EZH2, EED, and UTX, were sequenced as the same as in CREBBP. TP53 exons 5 – 8 and 10, in which mutations were commonly reported, were sequenced using genomic DNA. We amplified IKZF1 using RT-PCR for detecting aberrant dominant negative isoforms: Ik6 and Ik10. Genomic deletions of IKZF1 were assessed with RQ-PCR or genomic DNA PCR. We compared clinical profiles between patients with and without such gene mutations. The present 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 In 87 adult patients with ALL, alterations of CREBBP, EED, TP53 and IKZF1 were detected in 7 (9.5%), 3 (4.8%), 6 (6.9%) and 42 (50%), respectively. None of EZH2 and UTX mutation was found. The alterations of CREBBP and IKZF1 at diagnosis in adult patients were more frequent than those in pediatric patients ever reported. Some gene mutations were not found frequently. Each gene mutation per se did not significantly affect prognosis. We tried to predict the prognosis by scoring gene mutations and chromosomal abnormalities. Philadelphia chromosome (Ph) has great impact to prognosis of patients with ALL. We scored the number of mutated genes and Ph for each patient. As the score was higher, adult patients with ALL had poorer relapse-free survival (P=0.0439) and OS (P=0.4819), but statistical significance was not detected in this small cohort. Conclusions and Discussion Single gene mutations, such as IKZF1, can predict the prognosis in pediatric ALL. In adult ALL, however, only few gene mutations are reported to be promising prognostic factors which have impacts to treatment outcomes. Scoring system may be a useful method for predicting prognosis and stratifying treatment in adult ALL. Our study implies the possibility that a variety and heterogeneity of genetic alterations in adult ALL are associated with the pathogenesis for treatment resistance and prognostic marker of adult ALL. Disclosures: No relevant conflicts of interest to declare.

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 Venetoclax-Ponatinib for T315I/Compound-Mutated Ph+Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3395-3395
Author(s):  
Huafeng Wang ◽  
Jiejing Qian ◽  
Chang Yang ◽  
Yi Zhang ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Group ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Tumor Lysis Syndrome ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Molecular Remission ◽  
Grade 3

Abstract The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have greatly improved in tyrosine kinase inhibitors (TKIs) era and is just moving to a chemo-free era using dasatinib and blinatumomab (Foà R, N Engl J Med. 2020; Ravandi F, Blood. 2019). However, the outcome of T315I/compound-mutated Ph+ ALL patients is dismal (Cortes JE, N Engl J Med. 2013), representing an unmet need. Recently, Scherr et al reported the curative potential of venetoclax-TKIs-dexamethasone in a BCR-ABL+ mouse model (Scherr M, Leukemia. 2019). Here, we firstly reported outcome of 19 T315I/compound-mutated relapsed/refractory （R/R）Ph+ ALL patients treated with venetoclax(100mg d1, 200mg d2, 400mg d3-28), ponatinib (45mg d1-28) and dexamethasone (0.15mg/kg d1-21,0.075mg/kg d22-28）(VPD regimen) (Figure 1A) between January 2020 and May 2021. They had already received a median of 3 lines of salvage therapy. After one cycle, 17 patients (89.5%) achieved CR/CRi [13 minimal residual disease (MRD)--negative by flow cytometry;11 major molecular remission (MMR);8 complete molecular remission (CMR)] (Figure 1B). Subsequently relapse occurred in 1/6 [allogeneic hematopoietic cell transplantation (allo-HSCT) group)] and 7/11 (VDP consolidation group). At a median follow-up of 259 days, the median EFS and OS of patients from the starting VPD treatment was 242 and 400 days. Adverse events of VPD regimen were listed in Figure 1C. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 73.7%,36.8% and 52.6% patients. 5.3% and 16% patients have grade 3-4 rash and infection separately. No tumor lysis syndrome or death occurred. 7/19 patients were treated safety outpatient. Moreover, venetoclax had a strong synergistic effect with ponatinib and dexamethasone on inducing apoptosis of primary blast cells and BaF3 cells expressing p190 BCR/ABL with T315I-mutation in vitro, with a combination index of 0.019 when the suppressing rate is 0.05, while the effect was significant decreased when ponatinib was replaced by dasatinib (Figure 1D-F), a prominent change of mitochondrial membrane potential as well as the cleavage of PARP were also observed in triple-combination treatment group (Figure 1G-H). For T315I/compound-mutated Ph+ ALL, VPD regimen exhibited 89.5% CR/CRi rate, with deep molecular remission (57.9% MMR), while ponatinib alone showed 41% hematologic response (Cortes JE, N Engl J Med. 2013), which supported by the preclinical data suggesting TKIs and venetoclax are highly synergistic in BCR-ABL + cells in vitro (Scherr M, Leukemia. 2019). 7/11 and 1/6 patients subsequently relapsed in continuous VPD and allo-HSCT postremission treatment group separately, suggested bridging to allo-HSCT after remission is warranted. Moreover, novel compounds such as blinatumomab showed a preliminary efficacy (Couturier MA, Leuk Lymphoma. 2021). In summary, VPD regimen provides a novel treatment for T315I/compound-mutated R/R Ph+ALL under a complete oral and chemo-free model. A clinical trial also using similar VPD regimen for treatment of R/R Ph+ ALL is ongoing now (Short NJ, Am J Hematol. 2021). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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.

Chemotherapy-Phased Imatinib Pulses Improve Long-Term Outcome of Adult Patients With Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Northern Italy Leukemia Group Protocol 09/00

2010 ◽  
Vol 28 (22) ◽  
pp. 3644-3652 ◽  
Author(s):  
Renato Bassan ◽  
Giuseppe Rossi ◽  
Enrico M. Pogliani ◽  
Eros Di Bona ◽  
Emanuele Angelucci ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Adult Patients ◽  
Negative Group ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Positive Group ◽  
Disease Free

Purpose Short imatinib pulses were added to chemotherapy to improve the long-term survival of adult patients with Philadelphia chromosome (Ph) –positive acute lymphoblastic leukemia (ALL), to optimize complete remission (CR) and stem-cell transplantation (SCT) rates. Patients and Methods Of 94 total patients (age range, 19 to 66 years), 35 represented the control cohort (ie, imatinib-negative [IM-negative] group), and 59 received imatinib 600 mg/d orally for 7 consecutive days (ie, imatinib-positive [IM-positive] group), starting from day 15 of chemotherapy course 1 and from 3 days before chemotherapy during courses 2 to 8. Patients in CR were eligible for allogeneic SCT or, alternatively, for high-dose therapy with autologous SCT followed by long-term maintenance with intermittent imatinib. Results CR and SCT rates were greater in the IM-positive group (CR: 92% v 80.5%; P = .08; allogeneic SCT: 63% v 39%; P = .041). At a median observation time of 5 years (range, 0.6 to 9.2 years), 22 patients in the IM-positive group versus five patients in the IM-negative group were alive in first CR (P = .037). Patients in the IM-positive group had significantly greater overall and disease-free survival probabilities (overall: 0.38 v 0.23; P = .009; disease free: 0.39 v 0.25; P = .044) and a lower incidence of relapse (P = .005). SCT-related mortality was 28% (ie, 15 of 54 patients), and postgraft survival probability was 0.46 overall. Conclusion This imatinib-based protocol improved long-term outcome of adult patients with Ph-positive ALL. With SCT, post-transplantation mortality and relapse remain the major hindrance to additional therapeutic improvement. Additional intensification of imatinib therapy should warrant a better molecular response and clinical outcome, both in patients selected for SCT and in those unable to undergo this procedure.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Herve Dombret ◽  
O.G. Ottmann ◽  
G. Rosti ◽  
B. Simonsson ◽  
R.A. Larson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
Hematologic Response ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

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

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