A Study of the Toxicity of Gemtuzumab Ozogamicin in Primary and Relapsed AML, Administered Alone or Simultaneously with Intensive Chemotherapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4512-4512
Author(s):  
Thomas Stauffer Larsen ◽  
Kai G. Schmidt
Keyword(s):  
Response Pattern ◽  
Gemtuzumab Ozogamicin ◽  
Infectious Complications ◽  
Late Relapse ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hepatic Toxicity ◽  
Allogeneic Transplant ◽  
High Dose Cytarabine ◽  
Grade 3

Abstract Introduction: Gemtuzumab Ozogamicin (Mylotarg®) is a humanized anti CD33 antibody linked to the cytotoxic drug calicheamicin, which has shown considerable antileukaemic effect in the treatment of relapsed AML. With special regard to its toxicity, we present our preliminary results of Mylotarg treatment when administered on compassionate basis as consolidating monotherapy, or combined with intensive chemotherapy. Patients and methods: A total of 86 doses, corresponding to 65 courses were administered to 49 patients. Indications for Mylotarg treatment ( mono ~ monotherapy; comb ~ combination therapy. No.of courses are shown in parentheses): Primary AML: Reinduction ( mono:1; comb:3). Cytogenetic reinduction ( mono:3; comb:1). Consolidation ( mono:24; comb:2). Relapsed AML: Induction ( mono:4; comb:11). Reinduction ( mono:1; comb:2). Cytogenetic reinduction ( mono:1). Consolidation ( mono:10; comb:2). Results: Up-front consolidation with Mylotarg as monotherapy ( 30 doses; 24 patients; mean Mylotarg dose 5.7 mg/m2). Fever: 51% of doses. Focal infections: 17%. Bacteremia 7%. Biochemical findings: Platelet nadir at day 10 ( < 20 bill./l: 25% doses). Neutrophil nadir at day 11 ( mean count = 0.12 bill./l). Hepatic toxicity ( grade 1; % of doses): Alkaline phosphatase 7%; ALAT: 13%; Bilirubin 0. A similar pattern was seen in the 10 relapsed patients consolidated with Mylotarg as monotherapy. One patient receiving an allogeneic transplant 3 months after Mylotarg treatment developed fatal VOD. Three other patients who undervent allogeneic stem cell transplantation 2, 2 and 3 months, respectively, after the administration of Mylotarg did not experience severe hepatic complications. We compared twelve courses of Mylotarg combined with DaunoXome and high dose cytarabine with ( n=10) or without ( n=2) added fludarabine and etoposide, administered to10 patients in 1st relapse with 8 similar courses but without Mylotarg, administered to 7 patients with similar characteristics regarding age, CR1 duration and cytogenetics ( mean Mylotarg dose 4.4 mg/m2). More cases of grade 3 diarrhea ( 33% vs 13%) and bacteremia ( 67% vs 38%) were seen in the Mylotarg group, in which three patients suffered hypoplastic deaths. One of these patients developed intestinal perforation following postremission treatment. The two other patients, with an early refractory relapse, and a late relapse with high risk chromosomal aberation, respectively, died from infectious complications following 20 and 36 days of profound neutropenia. These 3 patients recieved 5.9, 8.3 and 5.0 mg/m2 respectively, compared to the average Mylotarg dose of 4.4 mg/m2. Conclusion: Mylotarg seems to increase toxicity when added to intensive chemotherapy in relapsed AML. The feasibility of this approach must await further studies evaluating toxicity, appropriate dosing and response pattern. When administered as consolidating monotherapy toxicity is modest.

Gemtuzumab Ozogamicin-Based Salvage, Followed by Allogeneic Hematopoietic Stem Cell Transplantation, Is Highly Effective in Young Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia (AML) in First Relapse

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2603-2603 ◽  
Author(s):  
Marie-Anne Hospital ◽  
Christian Recher ◽  
Xavier Thomas ◽  
Emmanuelle Tavernier ◽  
Bruno Lioure ◽  
...  
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Complete Remission ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Hematopoietic Stem ◽  
High Dose Cytarabine ◽  
First Relapse

Abstract Abstract 2603 Purpose Although CBF-AML (i.e. with t(8;21) or inv(16)/t(16;16)) represents a favorable cytogenetic AML subgroup (Döhner, Blood 2010), 35–45% of these patients still relapse after standard intensive chemotherapy. The immunoconjugate gemtuzumab ozogamicin (GO) was shown to be effective in patients with relapsed AML in non randomized studies and has been recently demonstrated in a Phase 3 trial as associated with a significant benefit in younger adults with CBF-AML (Burnett, JCO 2011). In this study, we thus investigated the impact of GO-based salvage at first relapse in this specific subgroup of patients with CBF-AML. Patients and Methods We retrospectively analysed the medical records of 84 patients aged 60 years or less with CBF-AML in first relapse after intensive chemotherapy and treated in 18 French centers. None of these patients received allogeneic (alloSCT) or autologous (autoSCT) hematopoietic stem cell transplantation in first complete remission (CR). As salvage, 27 patients received GO, combined with high-dose cytarabine in most of them; 21 patients received high-dose cytarabine and anthracycline without GO; 36 patients received conventional chemotherapy based on standard-dose cytarabine and anthracycline. Post-remission therapy was alloSCT in 49 patients, autoSCT in 17 patients, and chemotherapy alone in 11 patients. Results Among 84 patients with a median age of 39 years [16–58], 36 patients had t(8;21) AML and 48 patients had inv(16)/t(16;16) AML. Median CR1 duration was 12.9 months [2.6–55.3]. Second complete remission (CR2) rate was 92% (77/84), and early death rate was 1% (1/84). The median follow up was 4.0 years. The 5-year overall survival (5y-OS) and relapse-free survival (5y-RFS) was 52% [39–64%] and 48% [36–60%] respectively. Patients receiving alloSCT in CR2 had a better outcome (5y-OS, 56% versus 43%; p=0.05). In patients not allografted in CR2, RFS was similar after autoSCT and chemotherapy alone (5y-RFS, 44% versus 47%, respectively). Patients treated with GO had similar CR rate but a lower risk of second relapse and a better survival than other patients (5y-RFS, 89% versus 55%; p=0.05 and 5y-OS, 90% versus 45%; p=0.03). In univariate analysis, other factors associated with a better OS were younger age, longer CR1 duration, but not CBF subtype (p=0.03, 0.01, and 0.20, respectively). In multivariate analysis adjusted on age, CR1 duration, and CBF subtype, GO salvage was still associated with a significant benefit in OS (HR=0.16 [0.04–0.69], p=0.01) and RFS (HR=0.19 [0.04–0.80], p=0.02). With a median post-relapse follow-up of 2.2 years, no relapse nor death were observed in the 19 patients who received GO salvage followed by alloSCT in CR2 (p=0.007 for RFS; p=0.008 for OS). Moreover, in patients who received alloSCT, previous GO therapy significantly improved post-transplantation outcome. Conclusion Younger patients with CBF-AML in first relapse had a high second complete remission rate regardless the intensive chemotherapy salvage. More interestingly, the outcome of these patients was significantly improved by the addition of GO-based salvage, especially when followed by alloSCT. Disclosures: Off Label Use: GO is available in Europe as a compassionate treatment for relapsed AML.

Efficacy and Feasibility of High-Dose Cytarabine Plus Idarubicin and Amifostine As Induction Schedule: A Prospective Observational Study of 100 AML Elderly Fit Patients

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3621-3621
Author(s):  
Debora Capelli ◽  
Martina Chiarucci ◽  
Francesco Saraceni ◽  
Antonella Poloni ◽  
Mauro Montanari ◽  
...  
Keyword(s):  
Prospective Observational Study ◽  
Low Dose ◽  
De Novo ◽  
High Dose ◽  
Allogeneic Transplant ◽  
Free Survival ◽  
Induction Regimen ◽  
High Dose Cytarabine ◽  
De Novo Aml ◽  
Grade 3

Abstract Abstract 3621 Acute myeloid leukemia (AML) has a dismal prognosis in elderly population because of intrinsic chemoresistance and frailty of patients. High-dose Cytarabine (HiDAC) in induction therapy did not improve the CR in younger AML patients and recent guidelines discourage this approach in elderly because of high extrahematological toxicity. Amifostine showed to selectively protect normal Hemopoietic progenitors from chemotherapy and we previously successfully tested the feasibility of an induction schedule including HiDAC (3 g/m2 days 1,2,3,4,5), Idarubicin 40mg/m2 on day 3 preceeded by Amifostine (740 mg/m2). We designed a prospective observational study including the same induction schedule, aimed to evaluate the outcome (CR rate, OS and EFS) of a larger population of fit AML elderly patients. Fit patients, selected according the Multidimensional Geriatric Assessment, received 1–2 courses and underwent PBSC mobilization after consolidation. Patients who collected ≥3×10e6CD34+/kg received ASCT, while poor mobilizers were considered for alternative regimen including Allogeneic transplantation from an HLA-matched sibling, chemotherapy (CHT) or Gemtuzumab-Ozogamicin (GO). We registered 156 consecutive patients, aged >59 yrs; 56 were unfit for intensive induction chemotherapy and received only palliative care; 100 (64%) fulfilled the inclusion criteria of our protocol: 91 received the scheduled induction regimen, while 9 received a Fludarabine regimen because of reduced cardiac function. These patients were not included in the response evaluation, but were considered for the outcome (according to the ITT criteria). Patients' characteristics are shown in table 1. CR was achieved in 73.6% of patients; multivariate analysis showed secondary disease as predictive of poor response, with a 65% CR rate (RR = 2.54; 95% CI: 1–6.45; p= 0.05) vs 83% in primary disease. Induction death rate was 5% and not influenced by any prognostic factors. The median time to achieve neutrophil>500× 106/L and platelet>20,000×106/L, were 17 and 19 days (ranges of 9–29 and 3–47 respectively). The main extrahematological toxicity were grade 3–4 mucositis (13%) and hepatic toxicity (9%). We also observed 66 grade III-IV febrile neutropenia/infectious episodes. Overall 65 patients received a first consolidation course and mobilization for PBSC harvest; we observed 6 TRD, a 3% of grade 3–4 hepatic and neurological toxicity and 6% of grade 3–4 cardiac toxicity; in 4 patients we observed rapid early leukemia relapse; overall 55 patients were eligible for post-consolidation therapy. Only 24 patients achieved a succesfull PBSC mobilization and ASCT was performed in 21 (2 relapsed and died before ASCT and 1 received Allogeneic Transplant). Thirty-one patients were poor mobilizers: 3 received Allogeneic Transplant, 3 CHT, 5 stopped treatment because of persistent aplasia and 20 received low-dose GO (3 mg/m2 monthly for 3 times and every 3 months after; median: 3, range 3–6 courses). With a median follow-up of 70 months (range 24–124) 21 patients are alive (19 in continuous CR), 6 after ASCT, 13 after GO, 1 after CHT. The 8 yrs Overall Survival (OS), Disease Free Survival (DFS) and Event Free Survival (EFS) are respectively 20.4% (median: 11.4 months), 24,3% (median 8.8 months) and 17,7% (median: 8.8 months). Secondary AML and hyperleukocytosis are factors predictive of OS at the multivariate analysis. Patients with secondary disease have a 1.59 RR to die with a 9.9% 8 yrs OS vs 27.1% of patients with primary AML. Patients with WBC ≥50,000/mcl had a 2.2 RR to die with a 0% OS at 33 months vs 23.2% 8 yrs OS in patients with WBC<50,000/mcl. In conclusion our novel intensive induction regimen for fit AML patients is safe and effective both in term of CR rate and outcome. The ASCT feasibility was confirmed to be poor in this setting (21%) while GO low-dose seems to be feasible and promising. Finally our prospective study in 156 elderly AML patients describes the real-life outcome of this setting, suggesting that two thirds of AML elderly patients are fit for intensive treatment and that long term OS can be achieved in a relevant proportion of patient with de novo AML. Table 1: Patients' characteristics N (%) Gender: Male 58 Female 42 Karyotype: Favorable 5 (5.7) Intermediate 49 (56.3) Unfavorable 33 (38) De novo AML 61 Secondary AML 39 Age: <70 yrs 55 >69 yrs 45 WBC count: <50,000/mcl 89 ≥50,000/mcl 11 PS: 0–2 96 3 4 FDI 0 60 >0 40 Sorror 0–2 62 (74.7) >2 21 (25.3) Disclosures: No relevant conflicts of interest to declare.

Phase I study of dose dense induction and consolidation with gemtuzumab ozogamicin and high dose cytarabine in older adults with AML

2012 ◽  
Vol 3 (3) ◽  
pp. 220-227
Author(s):  
Arati V. Rao ◽  
David A. Rizzieri ◽  
Carlos M. DeCastro ◽  
Louis F. Diehl ◽  
Anand S. Lagoo ◽  
...  
Keyword(s):  
Older Adults ◽  
Phase I ◽  
Phase I Study ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Dose Dense

Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4565-4565
Author(s):  
Bayard L. Powell ◽  
James Lovato ◽  
Claire Kimbrough ◽  
Susan Lyerly ◽  
Sonya Galloway-Daniels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Skin Toxicity ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.

All-Trans Retinoic Acid and Gemtuzumab Ozogamicin as Adjunct to High-Dose Cytarabine-Based Salvage Therapy in Primary Refractory Acute Myeloid Leukemia: Results of AMLSG 05-04 Trial.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1837-1837
Author(s):  
Richard F. Schlenk ◽  
Konstanze Döhner ◽  
Jürgen Krauter ◽  
Daniela Späth ◽  
Francesco de Valle ◽  
...  
Keyword(s):  
Salvage Therapy ◽  
Myeloid Leukemia ◽  
Liver Toxicity ◽  
Gemtuzumab Ozogamicin ◽  
High Dose ◽  
Significant Variable ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
High Dose Cytarabine ◽  
Refractory Acute Myeloid Leukemia

Abstract Background: Patients with primary refractory acute myeloid leukemia (AML) have a dismal outcome. Only allogeneic stem cell transplantion (SCT) currently offers the chance of cure to these patients. In order to improve outcome after allogeneic SCT, one important prerequisite is to increase response rates prior to SCT. Aims: To evaluate the impact of all-trans retinoic acid (ATRA) and gemtuzumab ozogamicin (GO) given as adjunct to high-dose cytarabine-based salvage therapy in younger adult patients with primary refractory AML on achievement of response. Consecutive allogeneic SCT was intended in all patients. Methods: Main inclusion criteria of the AMLSG 05-04 trial (NCT00143975) were refractory AML following one cycle of ICE (idarubicin, cytarabine, etoposide); and age 18 to 60 years. Dose and schedule of the GO-A-HAM regimen were as follows: GO 3mg/m2, day 1; cytarabine 3g/m2 bid., days 1–3; mitoxantrone 12mg/m2, days 2,3; ATRA 45mg/m2, days 3–5, 15mg/m2 days 6–28. Primary endpoint of the study was CR rate. Safety endpoints comprised early / hypoplastic (ED/HD) death rate, liver toxicity CTC grade 3–5, and rate of veno occlusive disease (VOD) after allogeneic SCT. Results: Between September 2004 and June 2007, 94 patients (median age, 48 yrs; range, 22 to 62) were enrolled. Distribution of cytogenetics was as follows: adverse, n=29 [abn(3q), −5/5q-, −7/7q-, abn(12p), abn(17p), complex]; other n=57 [core binding factor (n=3), cytogenetically normal AML (n=37), various aberrations (n=18)]. FLT3-ITD was present in 18 (22%) of 82 analyzed patients. Response to GO-A-HAM was as follows: CR, n=28 (30%); CRi, n=19 (20%); PR, n=11 (12%); refractory disease (RD), n= 34 (36%); and ED/HD, n=2 (2%). In a logistic regression analysis for achievement of CR, the only significant variable was adverse cytogenetics (OR 0.34, p=0.02). The rate of severe liver toxicity was 0%, the incidence of neutropenic fever was 52%, platelet and neutrophil recovery times from start of treatment were 21 and 22 days, respectively. Following GO-A-HAM, allogeneic SCT was actually performed in 60 patients (64%): matched related (n=14) or unrelated donor (n=42); haploidentical related donor, n=4. All SCT were performed within 3 months after GO-A-HAM, intermediate/severe VOD developed in 5 patients after SCT (9%, 95%-confidence interval (CI) 4–19%), mild VOD in 3 patients. Survival analyses revealed that patients with adverse cytogenetics and/or FLT3-ITD (n=45) had a significantly (p=0.001) inferior overall survival after one year of 38% compared to all other patients (n=39) of 81%. The proportions of patients receiving an allogeneic SCT were similar in both groups (68% and 66%, respectively). Conclusions: The GO-A-HAM regimen is feasible and effective as salvage therapy. However, cytogenetics still remains the most significant variable for achievement of response. Allogeneic SCT after GO-A-HAM was not associated with an increased VOD-rate.

Efficacy of Mitoxantrone and Etoposide in Patients with Acute Myeloid Leukemia Refractory to Initial Standard Induction Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4385-4385 ◽  
Author(s):  
Rajesh Sehgal ◽  
Wassim McHayleh ◽  
James Natale ◽  
Anastasios Raptis ◽  
Mounzer Agha ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Infectious Complications ◽  
High Dose ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
Grade 3 ◽  
Acute Myeloid

Abstract The most effective reinduction regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after one cycle of cytarabine combined with an anthracycline is not well established. In an effort to search for new synergistic and non-cross resistant antileukemic regimens different chemotherapeutic combinations have been investigated in refractory AML patients. Multiple regimens including high dose cytarabine, anthracyclines, fludarabine and etoposide have been used with CR rates up to 40%. Mitoxantrone and etoposide have activity in AML as induction agents but their role in reinduction in patients not responding to first line therapy has not been fully established. In the current retrospective study we evaluated the efficacy and toxicity of mitoxantrone and etoposide in AML patients treated at our institution who did not respond to first induction therapy with cytarabine and an anthracycline. A total of fifty seven AML patients were treated with mitoxantrone and etoposide (mean age 55 years, range 18–75 years). Twenty four patients were treated with mitoxantrone 10 mg/m2/d and etoposide 100 mg/m2/d both administered intravenously, days 1 to 5 (regimen 5+5) and thirty three patients were treated with mitoxantrone 10 mg/m2/d administered intravenously days 1 to 3 and etoposide 100 mg/m2/d administered intravenously, days 1 to 5 (regimen 3+5). Twenty six of fifty seven patients (46%) achieved CR. CR was achieved in 38% of patients (9/24) treated with the 5+5 regimen and 52% of patients (17/33) treated with the 3+5 regimen. Mean blast percentage before treatment with mitoxantrone and etoposide was 25% in patients who achieved CR vs 40% in patients who did not achieve CR (p < 0.03). Grade 3/4 hepatic toxicities were seen in 5% (3/57) of patients and there were no grade 3 or 4 renal toxicities. The median duration of neutropenia in patients achieving CR was 29 days after reinduction. 10% (6/57) of the patients died from infectious complications. Cytogenetic analyses were performed prior to first-line therapy in all patients. Patients with favorable cytogenetics treated with etoposide and mitoxantorne had 100% CR (3/3), patients with standard cytogenetics had 58% CR (19/33) and patients with unfavorable cytogenetics had 19% CR (4/21). Overall CR was achieved in 61% (22/36) of patients with favorable and standard cytogenetics. Our data suggest that the combination of etoposide and mitoxantorne is an active and well tolerated regimen, especially in patients with favorable and standard cytogenetics, and warrants further studies in prospective trials.

A retrospective safety analysis of adult patients treated with high-dose methotrexate for osteosarcoma in Stockholm, Sweden.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10083-10083 ◽  
Author(s):  
Daniel Alm ◽  
Christina Linder Stragliotto ◽  
Annika Folin ◽  
Jonas Bergh ◽  
Theodoros Foukakis
Keyword(s):  
Oral Mucositis ◽  
Blood Concentration ◽  
Renal Toxicity ◽  
Adult Patients ◽  
Bleeding Complications ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Hepatic Toxicity ◽  
Dose Methotrexate ◽  
Grade 3

10083 Background: Patients with osteosarcoma are routinely treated with pre- and post-operative chemotherapy that includes high-dose methotrexate. The treatment is associated with a risk of severe renal and hepatic toxicity. Methods: All patients with osteosarcoma that had received at least one cycle of high-dose methotrexate at the adult oncology department, Karolinska University Hospital were retrospectively identified. Treatment toxicity, including hematologic, renal, hepatic toxicity, infections and oral mucositis were registered and graded according to CTCAE v 4.0. A possible relationship between methotrexate blood concentration and toxicity was investigated. Results: Sixteen eligible patients that had received a total of 103 cycles of high-dose methotrexate were identified. Ten patients experienced a severe hepatic toxicity, (Grade 3, n=5 and Grade 4, n=5). Grade 3 renal toxicity was seen in one patient and although reversible, it led to treatment interruption. Reversible, grade 2 elavation of serum creatinine occured in 5 cases. Four grade 3 infections were seen in 2 patients and 8 patients had at least one occurrence of Grade 3 oral mucositis. Thrombocytopenia was a common event (Grade 3, n=5 and Grade 4, n=2) but no severe bleeding complications were observed. One patient died as a result of multi-organ failure two days after methotrexate administration. Methotrexate blood concentration at 24 hours from administration could predict for renal toxicity (p<0.005, by chi-square test), but not for other toxicity. Conclusions: High-dose methotrexate in adult patients with osteosarcoma was frequently associated with severe, however reversible toxicity.

scholarly journals Second induction with high-dose cytarabine and mitoxantrone: different impact on pediatric AML patients with t(8;21) and with inv(16)

Blood ◽  
2011 ◽  
Vol 118 (20) ◽  
pp. 5409-5415 ◽  
Author(s):  
Ursula Creutzig ◽  
Martin Zimmermann ◽  
Jean-Pierre Bourquin ◽  
Michael N. Dworzak ◽  
Christine von Neuhoff ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Independent Predictor ◽  
High Dose ◽  
Intensive Chemotherapy ◽  
Event Free Survival ◽  
Core Binding Factor ◽  
Free Survival ◽  
Binding Factor ◽  
High Dose Cytarabine ◽  
Pediatric Aml

Abstract Patients with core binding factor acute myeloid leukemia (CBF-AML) benefit from more intensive chemotherapy, but whether both the t(8;21) and inv(16)/t (16;16) subtypes requires intensification remained to be determined. In the 2 successive studies (AML-BFM-1998 and AML-BFM-2004), 220 CBF-AML patients were treated using the same chemotherapy backbone, whereby reinduction with high-dose cytarabine and mitoxantrone (HAM) was scheduled for these cohorts only in study AML-BFM-1998 but not in AML-BFM-2004 against the background to minimize overtreatment. Five-year overall survival (OS) and event-free survival (EFS) were significantly higher and the cumulative incidence of relapse (CIR) lower in t(8;21) patients treated with HAM (n = 78) compared with without HAM (n = 53): OS 92% ± 3% versus 80% ± 6%, plogrank0.047, EFS 84% ± 4% versus 59% ± 7%, plogrank0.001, and CIR 14% ± 4% versus 34% ± 7%, p(gray)0.006. These differences were not seen for inv(16) (n = 43 and 46, respectively): OS 93% ± 4% versus 94% ± 4%, EFS 75% ± 7% versus 71% ± 9% and CIR 15% ± 6% versus 23% ± 8% (not significant). The subtype t(8;21), but not inv(16), was an independent predictor of worse outcome without HAM reinduction. Based on our data, a 5-year OS of > 90% can be expected for CBF-AML, when stratifying t(8;21), but not inv(16), patients to high-risk chemotherapy, including HAM reinduction.

scholarly journals Phase I Dose-Finding Study of Eltrombopag Following High Dose Cytarabine and Mitoxantrone Chemotherapy in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4426-4426
Author(s):  
Mahesh Swaminathan ◽  
Amanda Przespolewski ◽  
Elizabeth A. Griffiths ◽  
James E. Thompson ◽  
Amro Elshoury ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Dose Finding ◽  
High Dose ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
Finding Study ◽  
Dose Finding Study ◽  
Grade 3

Abstract Background: Thrombocytopenia is prevalent at presentation and following induction chemotherapy (chemo) regimens in patients (pts) with newly diagnosed and relapsed/refractory (R/R) acute myeloid leukemia (AML). Eltrombopag (EPAG), oral, nonpeptide thrombopoietin (TPO)-receptor agonist, is currently approved for treatment of chronic immune thrombocytopenia, hepatitis-associated thrombocytopenia, and aplastic anemia. It has also been evaluated as a strategy to mitigate chemo-induced thrombocytopenia in pts with solid tumors, myelodysplastic syndrome, and following allotransplant. Prior studies have demonstrated that EPAG can directly inhibit the proliferation of human AML cells in vitro. Although EPAG has been studied following induction and consolidation chemo in the frontline AML setting, to date, the tolerability and efficacy of EPAG in pts receiving salvage chemo for R/R AML is not known. Objectives: This study's objectives were to (a) estimate the maximum tolerated dose (MTD) and tolerability of EPAG, (b) examine platelet (plt) response (defined as plt count ≥ 100 x 10 9/L), and (c) anti-leukemic activity of EPAG in pts receiving high dose cytarabine (HiDAC) and mitoxantrone (Mito) for R/R AML. Methods: In this phase I open-label study, adult pts (³ 18 yrs) with R/R AML with adequate organ functions and grade 4 thrombocytopenia following HiDAC (given every 12 hrs (3 g/m 2 for age &lt; 50; 1.5 g/m 2 for age ≥50) for 12 doses) and Mito (dosed at 12 mg/m 2 x 3 doses every other day) were eligible. All pts must have had marrow hypoplasia demonstrated on Day 14 ± 3 days from the initiation of HiDAC. EPAG was started daily on Day 14 ± 3 days with dose determined using a standard '3+3' dose-escalation design. EPAG was discontinued if an adequate plt response was achieved or following 9 weeks of therapy. The dose-limiting toxicity (DLT) window was defined as the first 15 days of EPAG dosing. Results: Nine pts with R/R AML were enrolled (Table 1). Median age was 64 yrs (range, 33-80), and 5 pts were men. All pts had intermediate (6/9, 67%), adverse (2/9, 22%), or unknown (1/9, 11%) cytogenetic risk disease. One (1/9) pt had NPM1+FLT3-ITD+ disease. Five pts (56%) had relapsed disease (2pts had prior allotransplant). All pts received HiDAC+Mito chemo and started on EPAG on Day 14 ± 3 days. Three received EPAG 150 mg, and 6 pts received 200 mg daily. The median duration on EPAG was 26 days (range, 11-82). One pt experienced a DLT of grade 3 myocardial ischemia while receiving EPAG 200 mg/day and was taken off study. No other DLTs were reported, and no MTD was determined. The most frequent grade ³3 adverse events (AEs, Table 2): were bacteremia (56%), neutropenic fever (44%), and hyperbilirubinemia (33%). Similarly, common grade 1-2 AEs consisted of hyperbilirubinemia, tachycardia, and confusion (33% each, respectively). At a median follow-up of 30.3 months (mo), all 9 pts had discontinued EPAG. Six pts (67%) achieved plt response (3 each in 150 mg and 200 mg/day dose level). The median time to achieve plt response and the duration of plt response was 27 days (range, 14-41) and 40.5 mo (range, 2-49.6), respectively. Three other pts discontinued EPAG therapy: 1 each due to cardiac ischemia, donor lymphocyte infusion, and patient choice, respectively (Table 3). Of note, 7/9 pts (78%) had clinical response: CR in 5 (56%), CRc (CR+CRp) in 6 (67%), MLFS in 1 (11%, Table 4). Two (2/7 responders) went on to subsequent allotransplant, and 6 died; 2-progressive disease, one each from pneumonia, failure to thrive, encephalopathy, and unknown cause, respectively. Among the 6 pts who achieved plt recovery on EPAG, 5 achieved CR and 1-MLFS following HiDAC+Mito. Conclusion: This phase 1 dose-finding study demonstrated that EPAG 150-200 mg daily following HiDAC+Mito chemo for R/R AML was well tolerated with one DLT of cardiac ischemia (200 mg dose). Two-thirds (67%) of pts achieved plt recovery on EPAG after a median of 27 days (range, 14-41). In these small number of pts (n=9), addition of EPAG therapy did not seem to adversely affect clinical outcomes (CRc 67%) and may have contributed to long-term platelet recovery. Further studies are required to determine the optimal schedule and potential benefit of EPAG added to chemo regimens for R/R AML. Figure 1 Figure 1. Disclosures Przespolewski: Jazz: Research Funding. Griffiths: Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Apellis Pharmaceuticals: Research Funding; Alexion Pharmaceuticals: Consultancy, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; Genentech: Research Funding; Taiho Oncology: Consultancy, Honoraria; Boston Biomedical: Consultancy; Takeda Oncology: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Elshoury: Bristol Meyers Squibb: Other: advisory board. Wang: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Other: Advisory Board; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Mana Therapeutics: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; DAVA Oncology: Consultancy, Speakers Bureau; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy.

Relapsed acute megakaryoblastic leukemia in Down syndrome (AMKL-DS) may be cured with chemotherapy alone, without stem cell transplantation (HSCT)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 17543-17543
Author(s):  
S. Jayabose ◽  
C. Sandoval ◽  
O. Levendoglu-Tugal ◽  
M. F. Ozkaynak
Keyword(s):  
Down Syndrome ◽  
Good Health ◽  
Lung Lesion ◽  
High Dose ◽  
Unrelated Donor ◽  
Intensive Chemotherapy ◽  
Megakaryoblastic Leukemia ◽  
Transient Leukemia ◽  
High Dose Cytarabine ◽  
Disease Free

17543 Background: Children with recurrent AMKL -DS have an extremely poor prognosis without HSCT. Methods: We report a case of a relapsed AMKL-DS cured with intensive chemotherapy alone, without HSCT. Results: A 19 month old boy with Down syndrome, who had transient leukemia as a newborn, developed AMKL-DS (GATA1 positive) and was treated with four cycles of CI-TAD: continuous infusion of cytarabine and daunorubicin, and oral thioguanine for four days, and intrathecal cytarabine; followed by two cycles of high dose cytarabine plus L-Asparaginase; and three weekly doses of intrathecal cytarabine. Although he achieved remission at the completion of first cycle of the induction chemotherapy, he relapsed within 6 weeks after the completion of therapy. He then received the following chemotherapy over the next six months: Cycle 1 and 2. High dose Ara-C ( 33. 3 mg/kg q 12 hours x 8 doses) on days 0 to 3 plus mitoxantrone 0. 4 mg/kg/day x 4 on days 3 to 6 Cycle 3. High dose Ara-C 33. 3 mg/kg q 12 hours x 8 doses Cycle 4 and 5 (FLAG): Fludarabine 0. 8 mg/kg/day x 4 plus Ara-C 67 mg/kg/d x 4 and G-CSF 10 mcg/kg/day x 4 all on days 0 to 3. He achieved complete remission after the 1st cycle of chemotherapy, and underwent further cycles of chemotherapy while waiting for HSCT from an unrelated donor. But after the 5th cycle of chemotherapy, he developed a pulmonary lesion of fungal etiology for which he received three months of therapy with liposomal amphotericin. Because of a persistent lung lesion on imaging, he was considered ineligible for HSCT, and no further therapy was given. His bone marrow aspirate after the 3rd cycle of therapy was negative for GATA1. He has been disease-free for 59 months after the completion of his last cycle of chemotherapy, and he is currently in good health without any evidence of pulmonary or cardiac dysfunction. Conclusions: Intensive chemotherapy alone, without HSCT, may be curative for relapsed AMKL- DS. No significant financial relationships to disclose.

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