Dose-related mucositis with hydroxyurea for cytoreduction in acute myeloid leukemia

Hyperleukocytosis occurs in 15–20% of all newly diagnosed acute myeloid leukemia patients and requires emergent treatment with leukapheresis or hydroxyurea when accompanied by signs or symptoms of leukostasis. Currently, there is no standardized hydroxyurea dosing strategy, although usual dosing ranges from 50 to 150 mg/kg/day, and prescribing patterns vary significantly among oncologists and institutions. In addition to other hematologic and dermatologic toxicities, the use of hydroxyurea may be associated with significant mucositis and mucositis-related pain. The purpose of this study was to compare mucositis-related pain between two different hydroxyurea dosing strategies in patients who received hydroxyurea for cytoreduction during induction. A retrospective chart review of adult patients with acute myeloid leukemia treated with chemotherapy at UNC Medical Center from April 2014 to April 2016 who received at least one dose of hydroxyurea for cytoreduction was conducted. This study compared the safety and toxicity profiles of hydroxyurea in patients who received high-dose hydroxyurea (≥75 mg/kg/day) versus low-dose hydroxyurea (<75 mg/kg/day). Safety and toxicity were evaluated based on indicators of mucositis and cumulative intravenous narcotic requirements following induction chemotherapy. Data collection included baseline demographics, mucositis risk factors, baseline laboratory values, hydroxyurea dosing, mucositis indicators, and pain indicators. A total of 55 patients were included in the study, 21 patients (38.2%) received the high-dose hydroxyurea dosing strategy. The high-dose hydroxyurea dosing strategy had a significantly higher white blood cell count at diagnosis, increased duration of hydroxyurea, and received a higher cumulative dose of hydroxyurea. Additionally, the high-dose hydroxyurea dosing strategy patients were associated with significantly more grade 3 or 4 mucositis requiring a formulation change (0% versus 28.6%, p = 0.002) and significantly higher cumulative intravenous narcotic requirements during induction (p = 0.019). No significant differences in baseline demographics or mucositis risk factors between dosing strategies were identified. The high-dose hydroxyurea dosing strategy patients had a significant increase in cumulative intravenous narcotic requirements and formulation changes, both common interventions made for the treatment of mucositis. Additional studies are needed to further elucidate the safety and toxicity profiles of hydroxyurea dosing strategies and to explore the correlation between total cumulative hydroxyurea dose and total cumulative narcotic requirements.

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Results of High Dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v108.11.5438.5438 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5438-5438

Author(s):

Kenneth A. Ault ◽

Delvyn Caedren Case ◽

Marjorie A. Boyd ◽

Thomas J. Ervin ◽

Frederick Aronson ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Myelogenous Leukemia ◽

Myeloid Leukemia ◽

Medical Center ◽

Myelogenous Leukemia ◽

High Dose ◽

Transplant Program ◽

Maine Medical ◽

Acute Myelogenous ◽

Acute Myeloid

Abstract 43 patients with acute myeloid leukemia have undergone transplantation at our institution over the past 14 years. Patient selection criteria included age less than 70 years, creatinine less than 2mg/ml, no active infection, cardiac ejection fraction >40%, DLCO > 50% of predicted and no other co-morbid conditions that would jeopardize survival. 39 patients were in first remission, 4 were in second or higher remission. 3 patients had favorable cytogenetics, 40 had intermediate or unfavorable cytogenetics. After achieving remission for at least 30 days, patients were consolidated with Etoposide and AraC, followed by G-CSF. Hematopoietic stem cells were collected when the WBC rebounded to at least 10,000/μl. The target dose of CD34 positive cells was 5×106/kg. The minimum dose given was 2.3 × 106/kg). High dose therapy consisted of Busulfan 1mg/kg and Etoposide 60mg/kg. The average age at transplantation was 42 years (range 20 to 61). Days of neutropenia (AGC<500/μl) ranged from 2 to 10 (average 5.2). The median length of follow up is 4.0 years. Kaplan-Meier progression-free survival is 38% at 5 years and 35% at 10 years. Currently 26 patients are alive, and 23 are free from progression. Overall survival is 60%. Maine Medical Center Autologous HPC Transplant Program Acute Myelogenous Leukemia Maine Medical Center Autologous HPC Transplant Program Acute Myelogenous Leukemia

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Acute Myeloid Leukemia: Longterm Outcome Predicted by Age and Genetic Groups

Blood ◽

10.1182/blood.v120.21.1509.1509 ◽

2012 ◽

Vol 120 (21) ◽

pp. 1509-1509

Author(s):

Thomas Buchner ◽

Wolfgang E. Berdel ◽

Utz Krug ◽

Claudia Haferlach ◽

Susanne Schnittger ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Standard Dose ◽

Multivariable Analysis ◽

High Dose ◽

Genetic Groups ◽

Longterm Outcome ◽

Acute Myeloid

Abstract Abstract 1509 Introduction: Both, patients' age and genetic groups are important predictors of outcome in AML while their influence remains poorly quantified and compared. Methods: In the AMLCG (Acute Myeloid Leukemia Cooperative Group) 1999 trial 1470 patients (pts) were 16–59y and 1747 pts were 60–85y of age. 95% of pts could be classified according to genetic risk groups as standardized on behalf of the ELN (Blood 2010;115:453-74). Their treatment was randomized between TAD-HAM versus HAM-HAM induction (TAD, standard dose thioguanine, cytarabine, daunorubicin 60mg/m2 × 3; HAM, high-dose cytarabine 3g/m2 × 6, mitoxantrone 10mg/m2 × 3), TAD consolidation and monthly maintenance vs TAD and autologous SCT, any chemotherapy + vs – G-CSF priming. All assignment was done upfront. Pts of <60y received routine double induction and full dose HAM while pts of 60+y preferentially received only 1 course induction and HAM at 1g instead of 3g cytarabine/m2 × 6. Results: With little difference according to randomizations, pts <60y and 60+y achieved a complete remission (CR) rate of 65% and 51% (p<.001), a 5y overall survival (OS) of 41% and 14% (p<.001), and a 5y ongoing remission duration (RD) of 47% and 21% (p<.001). We particularly focussed on pts around 60y of age and compared the 231 pts of 57–59y with the 315 pts of 60–62y. Corresponding to their similar age the two groups showed similar baseline characteristics. In contrast and due to the cutoff point for age adaption at 60y they differed considerably in treatment. Expressed by the cumulative dosage of cytarabine in induction and early consolidation, the difference between the two groups was by factor 3.9. This difference, however, did not translate into a different outcome being 60% vs 57% CR (p=0.59), 28% vs 25% 5y OS (p=0.40) and 32% vs 29% RD at 5y (p=0.46). Through focussing on patients around 60y a relevant influence of chemotherapy intensity and age adaption could thus be excluded. A multivariable analysis in the complete patients between 16 and 85y of age identified genetic groups and age (as a continuous variable) to be the only risk factors predicting CR, OS as well as RD whereas other risk factors such as secondary AML, WBC, and LDH were predictive only for subsets of endpoints. Among all treatment variables only HAM-HAM induction was associated with a slightly superior RD (p= 0.0715). Grouping by age resulted in 4 age categories (16–46y:n=683, 47–59y: n=787, 60–66y: n=815, and 67+y: n=932) with significantly different OS as well as RD. Subdividing by genetic groups (favorable: n=593, intermediate I: n=1169, intermediate II: n=526, adverse: n=780) distinguished 3 significantly different categories (favorable, intermediate, adverse), a pattern observed in all age groups. Conclusion: In a defined representative population of pts with AML the longterm outcome was mainly determined by age and genetic groups but not by treatment intensity or variables, nor by other prognostic factors. Both, age and genetic groups should thus contribute to a reliable prediction of outcome in AML. Disclosures: No relevant conflicts of interest to declare.

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Impact of high dose cytarabine dosing strategies in obese patients with acute myeloid leukemia

Leukemia Research ◽

10.1016/j.leukres.2021.106517 ◽

2021 ◽

Vol 102 ◽

pp. 106517

Author(s):

Madeleine A. Ochs ◽

Anthony J. Perissinotti ◽

Bernard L. Marini ◽

Patrick W Burke ◽

Dale L Bixby ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

High Dose ◽

Obese Patients ◽

High Dose Cytarabine ◽

Dosing Strategies ◽

Acute Myeloid

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Risk factors for high-dose cytarabine neurotoxicity: an analysis of a cancer and leukemia group B trial in patients with acute myeloid leukemia.

Journal of Clinical Oncology ◽

10.1200/jco.1992.10.6.948 ◽

1992 ◽

Vol 10 (6) ◽

pp. 948-953 ◽

Cited By ~ 72

Author(s):

E H Rubin ◽

J W Andersen ◽

D T Berg ◽

C A Schiffer ◽

R J Mayer ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Elevated Serum ◽

High Dose ◽

Increased Risk ◽

High Dose Cytarabine ◽

Group B ◽

Leukemia Group ◽

Acute Myeloid

PURPOSE We analyzed pretreatment characteristics of patients with postremission acute myeloid leukemia (AML) treated with high-dose cytarabine (HIDAC) during a recent Cancer and Leukemia Group B (CALGB) trial to determine risk factors associated with HIDAC neurotoxicity. PATIENTS AND METHODS One hundred seventy-six patients received at least one course of HIDAC as part of a CALGB protocol designed to determine the optimal dose of cytarabine (ara-C) for postremission treatment of AML. HIDAC consisted of 3 g/m2 ara-C infused over 3 hours at 12-hour intervals on days 1, 3, and 5. The pretreatment characteristics of 170 patients were available for risk analyses. RESULTS Eighteen patients (10%) experienced neurotoxicity. Univariate analyses demonstrated associations between the occurrence of neurotoxicity and elevated serum creatinine, age, and alkaline phosphatase (AP). Multivariate analysis showed that these variables were independent risk factors. These findings were used to construct a risk model with the following parameters: creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40 years, and AP greater than or equal to 3 x normal. Seventeen of 46 (37%) patients with two or more of these criteria developed neurotoxicity compared with one of 124 (1%) patients with one or none. The sensitivity and specificity of this model were 94% and 81%, respectively. CONCLUSION We conclude that patients with two or more of the following parameters may be at increased risk for HIDAC neurotoxicity: (creatinine greater than or equal to 1.2 mg/dL, age greater than or equal to 40, and AP greater than or equal to 3 x normal). However, this model should be confirmed by analysis of additional groups of patients treated with HIDAC.

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Lower c-D-Index in Acute Myeloid Leukemia with Febrile Neutropenia during Chemotherapy

Blood ◽

10.1182/blood-2019-126721 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5190-5190

Author(s):

Tomoya Ishida ◽

Hiroyuki Kubo ◽

Osamu Imataki ◽

Makiko Uemura ◽

Norimitsu Kadowaki

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Research Funding ◽

Febrile Episode ◽

High Dose ◽

Documented Infection ◽

The Mean ◽

Acute Myeloid

Background: The D-index is a clinical tool used to assess the total severity of a patient's neutropenia. The D-index was originally proposed by Portugal et al. as a quantitative evaluation of the severity of a patient's neutropenia. The utility of the D-index has been validated in various clinical settings. The D-index has recently been investigated as a potential predictor of febrile neutropenia (FN) and infections resulting from neutropenia. The D-index varies according to the ending period for the calculation. If the period until the onset of FN is included, this is called the cumulative D-index (c-D-index) and reflects an accumulation of neutropenia until FN. The c-D-index is thought to represent more accurate and ongoing severity of patient's neutropenia. Purpose: To examine whether the D-index/c-D-index are a useful predictor of the onset of FN or various infections in acute myeloid leukemia (AML) patients treated with chemotherapy. Methods: This study included consecutive AML patients treated in our hospital between November 1998 and December 2018, retrospectively. The inclusion criteria were age 18-74 years at the onset, Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-2, hematologic diagnosis of AML, and treatment with Japan Adult Leukemia Study Group (JALSG) 97 or JALSG 201 protocol regimens. We used the JALSG disease risk as the risk factors at the onset of AML. We extracted the cases that fulfilled all the above criteria. We collected all FN events from the start of a patient's induction chemotherapy to the end of the final consolidation therapy. We collected complete FN events during chemotherapy and evaluated associations with the severity of FN and infectious events. FN was defined as a fever ≥38°C with a neutrophil count <500 cells/μL. If a fever ≥38°C was observed again after the body temperature had decreased to <37.5°C for over 48 h, it was defined as a new febrile episode. Results: A total of 51 patients (25 women, 26 men; median age 53 years, range 18-74 years) met the eligibility criteria. These patients experienced 171 FN events (68 induction and 103 consolidation chemotherapy episodes). The JALSG prognosis score indicated good risk in 16 subjects, intermediate risk in 19, poor risk in 14, and unknown in 2. The response rate to induction chemotherapy was 56.8% (29/51), and 80.4% (41/51) of patients were alive at the end of follow-up. In the univariate analysis of the risk factors for the onset of FN, the D-index, the c-D-index, PS, remission status, diabetes mellitus, and neutrophil count at the start of chemotherapy were identified. Multivariate analysis showed the c-D-index, but not the D-index, as a risk factor for the onset of FN (P = 0.00903). The statistically significant explanatory factors for microbiologically proven infections were high-dose Ara-C (P = 0.00103) and diabetes mellitus (P = 0.0251). The most prolonged period of FN was observed in subjects in whom the site of infection was respiratory comparing to other sites; blood stream infection (P = 0.0018), oral cavity (P = 0.0026), and gastro-intestine (P = 0.047), respectively. The D-index was significantly higher in patients with FN (P = 0.0028). Conversely, the c-D-index was significantly lower in patients with FN (P = 0.0016). The mean c-D-index in patients with FN was 3842 ± 1811 (the 75% tile range is 5517), and the mean c-D-index in patients without FN was 5597 ± 4289. The median day of the onset of FN was day 14 ± 5. Among the patients with FN, c-D-index were lower in patients with documented infection compared to those whom without it (2681 vs 4295, P = 0.0006). Conclusion: The D-index did not predict the onset of infection. However, the c-D-index can predict the onset of FN. The c-D-index depict the onset of FN within the mean value of 3842 at the median day 14. Among FN events, the onset of microbiologically proven infections were significantly associated to high-dose Ara-C and diabetes mellitus. Among FN patients, the documented infection occurred in significantly lower c-D-index patients. This may suggest documented infection will be diagnosed in the earlier stage of febrile episode among patients with AML during chemotherapy. Respiratory symptoms on the onset of FN are a risk factor for the prolonged duration of FN. Future research should focus on whether comorbidity at diagnosis and the value of the D-index at the onset of FN are associated with poor treatment outcomes in AML. Disclosures Kadowaki: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Daiichi Sankyo Company Ltd.: Honoraria, Research Funding; Eisai Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Asahi Kasei Pharma Corporation: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria, Research Funding; Taiho Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria, Research Funding; Pfizer Japan Inc.: Honoraria, Research Funding; Novartis AG: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Merck & Co., Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Company Ltd.: Honoraria, Research Funding.

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Safety, Feasibility, and Cost-Effectiveness with Outpatient Administration of High-Dose Cytarabine Consolidation in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v112.11.2405.2405 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2405-2405 ◽

Cited By ~ 2

Author(s):

Gene A. Wetzstein ◽

Jeffrey E. Lancet ◽

Jennifer E. Kallner ◽

Jeffrey M. Sivik ◽

Viet Q. Ho ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

High Dose ◽

Inpatient Setting ◽

Institutional Review ◽

High Dose Cytarabine ◽

Inpatient Group ◽

Grade Iii ◽

Acute Myeloid

Abstract Introduction: High-dose cytarabine (HiDAC) consolidation chemotherapy is frequently used in acute myeloid leukemia (AML) patients less than 60 years of age. Traditionally, the potential risk for neurotoxicity, which has been reported to occur in 8–26% of patients, has limited its administration to the inpatient setting with a median length of stay of 5 days. Institutional retrospective data revealed the incidence to be much lower than previously reported with grade III/IV neurotoxicity in only 0.7% of cycles (N=267). As a result, we developed a comprehensive outpatient (OP) approach for the administration of HiDAC utilizing a pre-printed order and monitoring forms, pre-defined eligibility criteria/risk factors, administration/screening checklist, standard ancillary medications, designated scheduling, patient counseling, and written instructions for follow up. The benefits of OP administration may include improved patient satisfaction and decreased institutional costs and constraints on inpatient resources. However, there does not appear to be any published literature to date describing the OP administration of HiDAC. We report herein on the safety, feasibility, and outcomes of 43 patients receiving HiDAC consolidation therapy (n=88 cycles) between September 2006 and July 2008. Methods: Patients < 60 yo received 3 g/m2 over 1 hour every 12 hours on days 1, 3, and 5 and the dose was reduced to 1.5 g/m2 for pts ≥ 60 yo. All cycles of HiDAC were dosed based on age, renal, and hepatic function. There were no empiric dosage adjustments based on renal function alone. Post-treatment, patients received antibiotic prophylaxis and growth-factor support. Patients returned twice weekly for blood work until neutrophil and count recovery. Results: Forty-three patients received 88 cycles of HiDAC as an OP. The median patient age was 49 yrs (23–74) with 16% being over 60. Patient baseline characteristics of the OP group were similar to the inpatient group from our institutional review with respect to age, body surface area, gender, and race. Diagnosis, history of CNS radiation/disease, intrathecal chemotherapy, alcohol abuse, cumulative cytarabine dosage, and concurrent medications were also similar between the two groups. Only 1 patient was ineligible to receive OP therapy which was the result of both renal (estCL < 60mL/min) and hepatic (alk phos > 3X ULN) risk factors. Two patients with moderate renal insufficiency (est CL 30–60 mL/min) received full dose HiDAC without adverse event. All 43 patients successfully completed their full course of therapy. During the 88 cycles, there were no cases of clinically significant neurotoxicity (≥ grade III). There were 3 instances of grade I nystagmus. In all cases, therapy was completed without interruption. Rates of admission to the hospital post HiDAC OP consolidation for neutropenic fever (NF) was comparable to the inpatient group from our institutional review, occurring in 26% and 37% (p=0.07), respectively. All admissions post HiDAC OP was secondary to NF with the exception of one patient who was admitted for mucosal bleeding. Conclusions: In the present analysis, we confirm the safety and feasibility of OP-based HiDAC chemotherapy for the management of AML patients in remission. If patients are dosed and monitored properly, HiDAC can be successfully transitioned to the OP setting. With the implementation of this approach, we have improved patient convenience and satisfaction, decreased pressure on inpatient resources (nearly 450 days of hospital bed use), while maintaining similar rates of hospital re-admission. With proper patient selection, dosing, and education of both providers and patients, HiDAC can be safely administered in the OP setting and has become our standard of care.

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KIT Mutation Versus MRD, Which Is More Important To Predict Relapse Of Acute Myeloid Leukemia With t (8; 21)?

Blood ◽

10.1182/blood.v122.21.1309.1309 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1309-1309 ◽

Cited By ~ 1

Author(s):

Hong-Hu Zhu ◽

Daihong Liu ◽

Hao Jiang ◽

Ya-Zhen Qin ◽

Lan-Ping Xu ◽

...

Keyword(s):

Risk Factors ◽

Acute Myeloid Leukemia ◽

Relapse Rate ◽

Subgroup Analysis ◽

Myeloid Leukemia ◽

High Dose ◽

Hematopoietic Stem ◽

Kit Mutation ◽

Very High ◽

Acute Myeloid

Abstract Background Although acute myeloid leukemia (AML) with t (8; 21) translocation generally belongs to the favorable-risk AML subtypes, relapse occurs in about 40% of cases and long-term (>5years) survival less than 50%. KIT-mutation (KIT+) and minimal residual disease (MRD) levels have been demonstrated as two most important risk factors in several retrospective studies. Until now, only two prospective studies (Our AML05 trial; French CBF-2006 trial) have assessed their respective prognostic values (Zhu HH, et al. Blood 2013; 121:4056; Jourdan E, et al. Blood 2013; 121:2213). We found both KIT+ and MRD were independent risk factors for relapse, but Joundan et al found only MRD rather than KIT+ was sole prognostic factor for relapse in multivariate anaysis. Both studies did not perform a comprehensive subgroup analysis combining the two factors, and risk-adopt postremission treatment might also affect this assessment. Therefore, we performed a subgroup analysis combining KIT mutation and MRD in a prospective protocol AML05 to answer which is more important to predict outcomes of t(8;21)AML. Methods From July, 2005, to Jan, 2013, 114 patients with t (8; 21) AML after achieving complete remission were included in this analysis. KIT mutations in exons 17 and 8 were screened using the direct sequencing method. MRD was detected using quantitative PCR to detect the RUNX1/RUNX1T1 transcript. MRD-positive (MRD+) was defined as < 3 log reduction of RUNX1/RUNX1T1 transcript from baseline after second consolidation therapy. Sixty-two patients received high-dose cytarabine-based consolidation chemotherapy (CT) or autologous hematopoietic stem-cell transplantation (auto-HSCT), and 52 patients received allogeneic HSCT (allo-HSCT). Results When receiving CT/auto-HSCT as postremission treatment, KIT+ patients (n=19) had a higher 3 year cumulative incidence of relapse (CIR) than KIT-patients (n=43) (94.4% vs. 38.2%, p<0.0001). Similar results also found in MRD+ (n=19) and MRD- (n=43) patients (CIR 92.9% vs. 46.6%, p<0.0001). Among KIT+ patients, a very high relapse rate was found in both MRD+ and MRD-patients (CIR, 100% vs.88.9%). However, among KIT-patients, MRD+ patients had a significant higher relapse rate than MRD-patients (CIR, 84.4% vs.26.3%, p=0.0006). When pooling KIT+ and or MRD+ into one group (KIT+/MRD+), this group had a significant higher relapse rate than KIT-MRD- group ( 94.4% vs. 26.3%, p<0.0001), However, the prognostic values of KIT and MRD was lost when patients received allo-HSCT (CIR of KIT+/MRD+ and KIT-MRD-, 23.8% vs. 15.6%, p=0.47). Similar results were also been found in disease-free survival (DFS) and overall-survival (OS). Multivariate analysis revealed that KIT+, MRD+, and treatment (allo-HSCT or CT/auto-HSCT) were three independent prognostic factors for relapse (all p<0.0001), DFS (all p<0.0001) and OS (p<0.0001, p<0.0001, p=0.007). Conclusions Both KIT status and MRD level were important to predict relapse of t (8;21) AML. KIT+ patients hold a very high relapse risk. Disclosures: No relevant conflicts of interest to declare.

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