scholarly journals Comparison of Pegfilgrastim and Filgrastim to Prevent Neutropenic Fever during Consolidation with High Dose Cytarabine for Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1404-1404
Author(s):  
Evan Field ◽  
Paolo F Caimi ◽  
Brenda Cooper ◽  
Jane Little ◽  
Ehsan Malek ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Solid Tumors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Advisory Board ◽  
Neutropenic Fever ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract Background: Granulocyte colony stimulating factor (G-CSF) to prevent neutropenic fever is a well-accepted standard of care to minimize the risk of neutropenic fever during consolidation chemotherapy for acute myeloid leukemia (AML). Although prospective, randomized clinical trials of filgrastim versus depot pegfilgrastim demonstrated biologic equivalency, retrospective studies in patients with solid tumors suggest the use of pegfilgrastim results in reduced rates of admission for neutropenic fever. Patients undergoing AML consolidation may be at higher risk for admission, as with solid tumors. Biosimilars for filgrastim (filgrastim-sndz and tbo-filgrastim) and pegfilgrastim (pegfilgrastim-jmdb) are creating market forces that may make daily administered agents an attractive alternative to pegfilgrastim, and therefore additional observational studies to clarify of the safety of daily administered G-CSF vs depot injections. We hypothesize that the use filgrastim over pegfilgrastim may result in higher hospital admission rates in AML patients undergoing consolidation chemotherapy outside the setting of prospective trials. Methods: Patient charts from the year 2004 through early 2017 diagnosed with AML at the Seidman Cancer Center of University Hospitals Cleveland Medical Center (UHCMC) were reviewed as a retrospective cohort study. Patient were included who received at least one cycle of high dose cytarabine during 1st complete remission, and received filgrastim or pegfilgrastim were considered available for analysis. Individual cycles of chemotherapy were assessed for potential adverse outcomes with the use of different forms of GCSF. The primary outcome of interest is hospitalization during consolidation chemotherapy. The incidence of hospitalization was analyzed using longitudinal logistic regression with generalized estimating equations for statistical inference assuming exchangeable variance-covariance structure of multiple hospitalizations from the same patients. Results 436 patient charts were reviewed identifying 165 patients receiving at least one cycle of HiDAC chemotherapy. Of these, 156 patients received either filgrastim or pegfilgrastim, representing 256 cycles of high dose cytarabine chemotherapy supported with GCSF. Patients receiving filgrastims vs pegfilgrastim differed in the number of HiDAC cycles received (1.64 vs 1.97, p = 0.046), the distribution of favorable risk AML (11.9% vs 32.7%, p = 0.035). Groups did not differ based on age, sex, race, initial response to therapy, and proportion of secondary AML. After controlling the effects of age, sex, race and initial clinical response, treatment (filgrastim vs. pegfilgrastim) was significantly associated with hospitalization during consolidation therapy (p = 0.005). Specifically, the odds of having hospitalization for patients treated with Filgrastim is estimated to be 2.31 times the odds of having hospitalization for patients treated Pegfilgrastim with 95% CI (1.28, 4.17). Also, the estimated probability of having hospitalization for patients treated with filgrastim was 0.59 (95% CI: 0.43- 0.73) vs. 0.38 (95% CI: 0.27 - 0.51) for patients treated with pegfilgrastim. Conclusions: The use of filgrastim was found to be statistically significantly associated with and increased risk of hospitalization. Disclosures Caimi: Kite Pharma: Other: Advisory Board Participation; Celgene: Speakers Bureau; Genentech: Other: Advisory Board PArticipation, Research Funding; Kite Pharma: Other: Advisory Board Participation. Little:PCORI: Research Funding; Hemex: Patents & Royalties: Patent, no honoraria; Doris Duke Charitable Foundations: Research Funding; NHLBI: Research Funding. Malek:Sanofi: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau.

scholarly journals Comparison of Long-Acting G-CSF (PD-Lasta) with Short-Acting G-CSF (PD-Grastim) in Neutrophil Recovery Following Consolidation Chemotherapy with High-Dose Cytarabine in Acute Myeloid Leukemia: A Randomized Clinical Trial

2021 ◽  
Author(s):  
Mohsen Esfandbod ◽  
Fatemeh Agha Bararzadeh ◽  
Mona Faraz ◽  
Fariba Zarrabi ◽  
Gholamreza Toogeh
Keyword(s):  
Clinical Trial ◽  
Acute Myeloid Leukemia ◽  
Randomized Clinical Trial ◽  
Myeloid Leukemia ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Short Acting ◽  
High Dose Cytarabine ◽  
Long Acting ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) patients are often neutropenic as a result of their disease alone or following their chemotherapy. In this randomized clinical trial the efficacy of Iranian short-acting (PD-Grastim) and long-acting G-CSF (PD-Lasta) were compared in term of time to recovery from neutropenia in de novo AML patients following the consolidation chemotherapy. Materials and Methods: Patients (n = 51) received one or two courses of Cytarabine and Daunorubicin as an induction. If complete remission was achieved, the treatment was followed by high-dose Cytarabine as consolidation chemotherapy. Twenty- four hours after the consolidation chemotherapy, patient were randomized to receive either daily short-acting G-CSF (PD-Grastim) (300 µg/kg) or single-dose long-acting G-CSF (PDLasta) (6 mg). Results: The median time to recovery of neutrophils was 11.00 and 13.00 days for short-acting G-CSF (PDGrastim) (n=22) and long-acting G-CSF (PD-Lasta) (n=29) groups, respectively (U=186.5, P>0.05 two-tailed). Incidence of adverse effects was similar in both short-acting G-CSF (PD-Grastim) and long-acting G-CSF (PDLasta) groups. Conclusion: Overall, data show that Iranian long-acting G-CSF (PD-Lasta) was not significantly different with Iranian short-acting G-CSF (PD-Grastim).

scholarly journals Condensed Versus Standard Schedule of High-Dose Cytarabine Consolidation Therapy with Pegfilgrastim Growth Factor Support in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 337-337
Author(s):  
Sonia Jaramillo ◽  
Axel Benner ◽  
Jurgen Krauter ◽  
Hans Martin ◽  
Thomas Kindler ◽  
...  
Keyword(s):  
Valproic Acid ◽  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Acute Myeloid

Abstract Background: The concept of intensive post-remission chemotherapy in acute myeloid leukemia (AML) is based on the observation that despite achievement of a first complete remission (CR) after intensive induction therapy virtually all patients relapse in the absence of further treatment. Moreover, randomized studies showed that intensive post-remission consolidation chemotherapy was superior to prolonged low-dose maintenance therapy in younger patients. With regard to consolidation therapy, the landmark study conducted by the Cancer and Leukemia Group B established the current standard for patients aged 60 years and younger with high-dose cytarabine (HDAC) 3g/m² bidaily on days days 1, 3, and 5. Aims: to compare a compressed schedule of high-dose cytarabine (HDAC) on days 1, 2, and 3 with the standard HDAC given on days 1, 3, and 5 as well as to evaluate the prophylactic use of pegfilgrastim after chemotherapy in patients in first CR receiving repetitive consolidation cycles for acute myeloid leukemia. Methods: Patients (18 to 60 years) were accrued between 2004 and 2009. They were randomized up-front 1:10 between the standard German intergroup-arm (Büchner et al. J Clin Oncol. 2012;30:3604-10) and the AMLSG 07-04 study (NCT00151242). Induction therapy in the AMLSG 07-04 study consisted of two cycles of idarubicin, cytarabine and etoposide +/- all-trans retionoic acid (ATRA) and +/- valproic acid (VPA) in a 2 by 2 factorial design. After recruitment of 392 patients the randomization for VPA was stopped due to toxicity. For consolidation therapy, patients with high-risk AML, defined either by high-risk cytogenetics or induction failure, were assigned to receive allogeneic hematopoietic cell transplantation from a matched related or unrelated donor. All other patients were assigned to 3 cycles of HDAC from 2004 to November 2006 with cytarabine 3g/m² bidaily, on days 1, 3, 5 and pegfilgrastim on day 10 (HDAC-135) and from December 2006 to 2009 patients were treated with a condensed schedule with cytarabine 3g/m², bidaily, on days 1,2,3 and pegfilgrastim on day 8 (HDAC-123). Patients randomized into the German AML intergroup arm were treated for consolidation therapy with cytarabine 3g/m² bid on days 1, 3, 5 (HDAC-135) without prophylactic growth-factor support. Results:Overall 568 patients receiving 1376 consolidation cycles were included into the study. According to up-front randomization 41 were treated with HDAC-135 without prophylactic growth factor support in the German AML Intergroup protocol, 135 with HDAC-135 and 392 with HDAC-123 with intended prophylactic pegfilgrastim at day 10 and 8, respectively, in the AMLSG 07-04 protocol. Time from start to chemotherapy until hematological recovery with leukocytes >1.0G/l and neutrophils >0.5G/l was significantly (p<0.0001, each) and in median 4 days shorter in patients receiving HDAC-123 compared to HDAC-135, and further reduced by 2 days (p<0.0001) by the addition of pegfilgrastim. Treatment with ATRA and VPA according to initial randomization had no impac on hematological recovery times. Rates of infections were significantly reduced by HDAC-123 compared to HDAC-135 (p<0.0001) and pegfilgrastim yes versus no (p=0.002). Days in hospital and platelet transfusions were also significantly reduced in patients receiving HDAC-123 compared to HDAC-135. Relapse-free and overall survival were similar with HDAC-123 and HDAC-135 (p=0.48, p=0.90, respectively). Conclusion: Data from our study suggest that consolidation therapy with a condensed schedule of HDAC-123 is superior to that of standard HDAC-135 in terms of faster hematological recovery, lower infection rate and fever days in hospital. In addition, the administration of one dose of pegfilgrastim after chemotherapy further shortened hematological recovery and reduced infection rate. Importantly, similar efficacy in terms of relapse-free and overall survival rates after HDAC-123 and HDAC-135 were observed. Disclosures Lübbert: Ratiopharm: Other: Study drug valproic acid; Janssen-Cilag: Other: Travel Funding, Research Funding; Celgene: Other: Travel Funding. Fiedler:GSO: Other: Travel; Pfizer: Research Funding; Teva: Other: Travel; Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding. Schlenk:Amgen: Research Funding; Pfizer: Honoraria, Research Funding.

A Prospective Randomized Comparison of Idarubicin and High-Dose Daunorubicin in the Induction Chemotherapy for Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2535-2535 ◽  
Author(s):  
Je-Hwan Lee ◽  
Hawk Kim ◽  
Young-Don Joo ◽  
Won Sik Lee ◽  
Sung Hwa Bae ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
High Dose ◽  
Event Free Survival ◽  
Consolidation Chemotherapy ◽  
Free Survival ◽  
Acute Myeloid

Abstract Introduction: We conducted a randomized trial comparing two different doses of daunorubicin as induction chemotherapy in young adults with acute myeloid leukemia (AML) and showed intensification of induction therapy using a high daily dose of daunorubicin (90 mg/m2/d x 3d) improved both complete remission (CR) rate and survival duration compared to standard daunorubicin dose (45 mg/m2/d x 3d) (Lee JH et al. Blood 2011;118:3832). As it is necessary to compare the effects of high-dose daunorubicin with that of other agents, especially idarubicin, we performed another randomized trial comparing two induction regimens in young adults with AML: idarubicin vs. high-dose daunorubicin (ClinicalTrials.gov #NCT01145846). Here, we present final results of the study. Methods: Between May 2010 and March 2014, a total of 316 patients (65 years or younger) with newly diagnosed AML except acute promyelocytic leukemia were registered in this study. Seventeen patients were removed from the study (change of diagnosis in 11, patient's refusal to be randomized in 3 and other in 3) and the remaining 299 patients were analyzed. After random assignments, 149 patients received idarubicin (AI, 12 mg/m2/d x 3d) and 150 patients received high-dose daunorubicin (AD, 90 mg/m2/d x 3d) in addition to cytarabine (200 mg/m2/d x 7d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of idarubicin (AI, 12 mg/m2/d x 2d) or daunorubicin (AD, 45 mg/m2/d x 2d) plus cytarabine (5d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 x 6 doses) in patients with good- or intermediate-risk cytogenetics and 4 cycles of cytarabine (1 g/m2 x 6d) plus etoposide (150 mg/m2 x 3d) in those with high-risk cytogenetics. Hematopoietic cell transplantation (HCT) was performed according to attending physician's discretion after one or two cycles of consolidation chemotherapy in most transplant cases. Results: CR was induced in 232 (77.6%) of 299 patients. Reasons for induction failure were resistant disease in 50, hypoplastic death in 5, and indeterminate cause in 12. As postremission therapy, 3 patients received no further treatment, 71 received consolidation chemotherapy without HCT, 137 underwent allogeneic HCT, and 21 underwent autologous HCT. The CR rates were not significantly different between two arms: 80.5% (120 of 149, AI) vs. 74.7% (112 of 150, AD) (P=0.224). With a median follow-up of 1046 days, overall survival probabilities at 4 years were 51.1% in AI vs. 54.7% in AD (P=0.756). The probabilities at 4 years for relapse-free survival were 63.5% in AI vs. 74.2% in AD (P=0.181) and those for event-free survival were 44.8% in AI vs. 50.7% in AD (P=0.738). Toxicity profiles were similar between two arms. Interestingly, overall and event-free survivals of 44 patients with FLT-ITD mutants (27 in AI and 17 in AD) were significantly different according to the induction regimens (AI vs AD; overall survival, 30.8% vs. 61.9%, P=0.030; event-free survival, 31.4% vs. 61.9%, P=0.025). Conclusions: The results of this phase 3 trial, which compared idarubicin (12 mg/m2/d x 3d) with high-dose daunorubicin (90 mg/m2/d x 3d), did not show significant differences between two arms in the outcomes of patients in terms of CR rates and overall, relapse-free or event-free survivals. In subset analysis, high-dose daunorubicin seems to be more effective than idarubicin in patients with FLT-ITD mutants. Disclosures Kim: Celgene: Research Funding; Alexion Pharmaceuticals: Research Funding; Il-Yang: Research Funding; Novartis: Research Funding.

Impact of Pegfilgrastim on Hematological Reconstitution and Incidence of Neutropenic Fever after Consolidation Therapy with High-Dose Cytarabine in Acute Myeloid Leukemia: Comparative Analysis between AMLSG 07-04 and the German AML Intergroup Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2020-2020 ◽  
Author(s):  
Richard F. Schlenk ◽  
Konstanze Dohner ◽  
Silia Groner ◽  
Peer C. Hartmann ◽  
Jürgen Krauter ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Serum Levels ◽  
Neutropenic Fever ◽  
Total Leukocyte Count ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Intergroup Trial ◽  
Acute Myeloid

Abstract Therapy using high-dose cytarabine (HiDAC) according to the CALGB scheme (3g/m2 bid. days 1,3,5) is recognized as a standard consolidation treatment for younger adult patients with acute myeloid leukemia (AML). Pegfilgrastim has been shown to be effective in reducing the duration of neutropenia in the treatment of solid tumors and it seems to be even more effective than Filgrastim in reducing the incidence of neutropenic fever. The objective of the current study is to investigate the effect of pegfilgrastim given after HiDAC consolidation within our AMLSG 07-04 clinical trial. The AMLSG 07-04 trial was initiated in September 2004 (age 18–60 yrs). Consolidation therapy consists of 3 cycles of HiDAC (3g/m2 bid. days 1,3,5) with pegfilgrastim 6mg given at day 10 after start of chemotherapy. As a control group, patients randomized from AMLSG into the German AML Intergroup protocol using the same scheme for consolidation therapy with permitted interventional application of G-CSF were used. Data from 127 patients and a total of 285 cycles are available, including 104 patients of the AMLSG 07-04 trial and 23 patients of the German AML Intergroup trial. Data from all three cycles were pooled for the comparison between AMLSG 07-04 (prophylactic pegfilgrastim) and German AML Intergroup (interventional G-CSF) trials. The duration of leukopenia and neutropenia was significantly shorter in patients receiving prophylactic pegfilgrastim (p=0.01 and p=0.008, respectively) compared to patients with interventional G-CSF, which was given in 16% of the pts. This was paralleled by a lower incidence of neutropenic fever with 53% in patients receiving prophylactic pegfilgrastim compared to 77% in patients with interventional G-CSF (p=0.0004). Data from 12 patients and 23 cycles were available for pharmocokinetics of pegfilgrastim. The median peak G-CSF serum level was 221 ng/ml (range 57–553 ng/ml) measured between 24 and 48 hours after the administration of pegfilgrastim and median terminal half-life was 5 days (range 3–7 days). G-CSF serum levels returned to normal in all patients after neutrophil reconstitution. Multivariable regression analysis for longitudinal data on G-CSF serum levels revealed total leukocyte count (p=0.02) and presence of neutropenic fever (p=0.03) as statistically significant variables. In conclusion, the administration of pegfilgrastim shortened the duration of leuko- as well as neutropenia and reduced the rate of neutropenic fever in pts. with AML receiving consolidation therapy with high-dose cytarabine.

scholarly journals A Phase I Dose Finding Trial of Eltrombopag during Consolidation Therapy in Adults with Acute Myeloid Leukemia Employing a Unique Dosing Design: PrE0901, a Precog Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4053-4053
Author(s):  
Stephen A. Strickland ◽  
Hillard M. Lazarus ◽  
Xin Victoria Wang ◽  
Jan Cerny ◽  
Witold B. Rybka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
High Dose ◽  
Consolidation Therapy ◽  
High Dose Cytarabine ◽  
Dose Levels ◽  
Kinetics Of ◽  
Acute Myeloid

Abstract Introduction: High-dose cytarabine consolidation chemotherapy for acute myeloid leukemia (AML) induces profound transient myelosuppression. Thrombocytopenia is a limiting factor in chemotherapy administration for maintaining dose intensity and schedule as thrombocytopenic-related hemorrhage may contribute to significant morbidity and mortality. Therapeutic and prophylactic platelet (plt) transfusions remain the treatment of choice but the benefits typically last only 3-7 days, are expensive, time consuming, and may induce alloimmunization and transmit infection. PrE0901 was a phase I multi-center study to evaluate the safety and toxicity of eltrombopag, an orally bioavailable thrombopoietin (TPO) receptor agonist, for plt recovery in AML patients (pts) receiving consolidation therapy. Methods: The primary objectives were to determine the safety, tolerability, and optimal dosing of eltrombopag while describing the kinetics of plt recovery in AML pts receiving intensive consolidation. Plt recovery was defined as a sustained plt count of ≥ 20 x 109/L following the nadir with no plt transfusions in prior 7 days or a continued upward trend in plt count for at least 2 successive measurements despite no plt transfusions in 48 hours. We used a standard 3+3 design utilizing a novel dose escalation/de-escalation strategy for pts in either first or second complete remission, ≥18 and ≤70 years of age, who had an ECOG performance status of 0-2. Cytarabine was administered at 3 g/m2 (1.5 g/m2 for pts >60 years) IV over 3 hours twice daily on days 1,3,5. Eltrombopag at assigned dose was administered with a first cycle of cytarabine only. Planned eltrombopag dose levels -2, -1, 1, 2, 3, 4, and 5 were 50, 100, 150, 150, 150, 200, and 300 mg, respectively (Table 1). Eltrombopag was to start on days X, X, 3, -1, -5, -5, and -5 relative to day of cytarabine start and levels -2, -1, 1, 2, 3, 4, and 5, respectively, with day X being variable depending on timing of observed dose limiting toxicities (DLTs). The eltrombopag was continued until plt recovery or for up to 35 consecutive days, whichever occurred first. An exploratory objective was to determine if eltrombopag had an effect on TPO and EPO blood concentrations in this setting. Results: Accrual began on July 31, 2012 and the trial closed on January 8, 2016 upon recommendation after an independent Data and Monitoring Committee reviewed a separate trial of eltrombopag therapy in MDS which demonstrated futility. 104 pts were screened. 54 declined participation and 35 were deemed medically ineligible. A total of 15 eligible pts were enrolled; 14 were treated on study with one pt being withdrawn prior to starting treatment due to infection. Three pts were treated at each of dose levels 1-4 and two were treated on dose level 5. No DLTs were observed. Median time to plt recovery of all pts treated on study was 22.5 (range 16-43) days. Pts in cohort 1 dosed with eltrombopag 150 mg daily starting on day 3 of consolidation demonstrated the fastest plt recovery (median =19 days; range 19, 19, 19) compared to cohort 2 who received 150 mg daily starting on day -1 of consolidation and recovered the slowest (median 23 days; range 16, 23, 43). Dose escalation in terms of starting eltrombopag further in advance of chemotherapy exposure as within cohort 3 (150 mg starting day -5) was associated with a median plt recovery of 27 (range 22, 27, 27) days. Eltrombopag dose intensification with cohort 4 at 200 mg daily and cohort 5 at 300 mg daily was associated with median plt recoveries of 24 (range 18, 24, 26) and 23 (range 19, 27) days, respectively. Kinetics of plt recovery for all cohorts are represented in Figure 1 and duration of eltrombopag exposure for each individual patient is represented in Table 2. Conclusions: Endogenous cytokine (TPO and EPO) levels varied inversely with plt and hematocrit values and did not appear to be affected by eltrombopag dose / schedule (details to be provided at ASH Annual Mtg). Unusually high screen fail numbers warrant examination to guide future trial design in the post-remission setting. The addition of eltrombopag to high-dose cytarabine consolidation therapy was well-tolerated and no DLTs were observed. The results for cohort 1 [eltrombopag 150 mg daily starting on day 3 of consolidation] demonstrated the fastest plt recovery. Further investigation is needed to define the optimal role, dose, and schedule of eltrombopag in the treatment of chemotherapy associated myelosuppression. Disclosures Strickland: Alexion Pharmaceuticals: Consultancy; Ambit: Consultancy; Baxalta: Consultancy; Boehringer Ingelheim: Consultancy, Research Funding; CTI Biopharma: Consultancy; Daiichi Sankyo: Consultancy; Sunesis Pharmaceuticals: Consultancy, Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Celator: Research Funding; Cyclacel: Research Funding; GlaxoSmithKline: Research Funding; Karyopharm Therapeutica: Research Funding; Sanofi: Research Funding.

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