Elderly Acute Myelogenous Leukemia Research Articles

A phase II study of sequential decitabine and rapamycin in acute myelogenous leukemia

A phase II study was conducted to ascertain whether sequential exposure to decitabine followed by rapamycin, an mTOR (mechanistic target of rapamycin) inhibitor would result in better responses than decitabine alone. Newly diagnosed acute myelogenous leukemia (AML) patients who were >65 years old and not eligible for intensive induction regimens or patients with relapsed or refractory AML received 10 days of decitabine followed by 12 days of rapamycin in cycle 1 and 5 days of decitabine followed by 17 days of rapamycin in subsequent cycles. The composite complete remission rate (CR) was 33 % (CR plus CR with incomplete count recovery). Median overall survival was 7.7 months in newly diagnosed elderly AML patients and 6.6 months in relapsed/refractory AML patients. Twenty-four evaluable patients were enrolled, and the study did not meet its primary endpoint of demonstrating a significant improvement in composite CR rate with the combination as compared to an established historical CR rate of 25 % with decitabine alone. Despite that, the survival rates in relapsed/refractory cases appear comparable to what is reported with other salvage regimens, and no significant patterns of non-hematologic toxicity were noted. 50 % of subjects in the de novo group achieved a composite CR which is significantly higher (p = 0.02) than the rate of 25 % with decitabine alone. This trial is registered at clinical trials.gov as NCT02109744.

Pilot Initiative of Fitness Testing for Treatment Selection in Elderly Acute Myelogenous Leukemia (AML)

Introduction: The optimal treatment of older patients with Acute Myeloid Leukemia (AML) is unclear. Traditional induction chemotherapy is less effective in older patients and often more toxic. Clinical trials for elderly AML patients feature inclusion/exclusion criteria based on "fitness" for chemotherapy that often include subjective assessments and variable enrollment criteria. Determining "fitness" remains controversial, and there are few validated objective markers to assist in determining whether a patient is "fit" or "unfit" for intensive induction chemotherapy. Previously published work identified a Short Physical Performance Battery (SPPB) score < 9 and a Modified Mini-Mental Status (3MS) score <77 as independent predictors of worse survival in patients treated with intensive therapy in AML (Klepin et al Blood 2013). Other data suggests using objective measures that include SPPB and 3MS scores to categorize risk in elderly AML patients as "fit", vulnerable or frail (Klepin et al Hematology 2014). Use of the geriatric assessment and quality of life measurements has been suggested to be incorporated in the initial evaluation of AML patients in order to help predict which patients will have poor outcomes with intensive therapy (Deschler et al Haematologica 2013). Based on these publications, a pilot initiative was begun to establish the feasibility of incorporating the SPPB and 3MS tests into practice as objective measures to assist in determination of "fitness" for intensive chemotherapy.Methods: Beginning December 2015, patients age ≥ 60 who presented with new or relapsed AML were evaluated using the 3MS and SPPB tests. To increase objectivity, the 3MS and SPPB tests were performed by a non-treating provider when possible. Patients who were determined to be a fall risk by history had their SPPB test performed by a specially trained physical therapist. Scores were made immediately available to the treating physician and were used as a guide to determine if the patient was "fit" for intensive therapy or "unfit". If "unfit" the patient was evaluated for a clinical trial for "unfit" patients, hypomethylating agents or best supportive care (BSC). Scores were taken into context with age and comorbidities for treatment decisions.Results: Testing was feasible using the SPPB and 3MS and easy to implement, with testing taking approximately 15 minutes. A total of 21 new or relapsed AML patients have been evaluated. The median age was 72, ranging from age 60-83. There were10 male and 11 female patients. Three patients had relapsed disease. Fifteen patients had evaluable data >60 days. Seven were determined "fit" for intensive chemotherapy. Median SPPB and 3MS scores were 9 and 95, respectively. Six achieved remission following intensive induction therapy. One patient underwent allogeneic stem cell transplant and remains in remission. Three relapses occurred at days 44, 50 and 54 from initial induction therapy. Two deaths occurred from relapsed disease at days 148 and 175 from initial induction and one death from infection at day 54 during consolidation therapy.Eight patients were determined to be "unfit" for intensive chemotherapy. Median SPPB and 3MS scores were 5 and 93, respectively. Two patients received BSC based on clinical judgement and died at days 32 and 50 from initial diagnosis. Both were the only patients of 21 evaluated to have a 3MS score < 77. Four patients were eligible for clinical trials at our institution. Two deaths occurred 95 and 52 days from initiation of clinical trial, and 2 remain on trial at 61 and 65 days from initial therapy with one in complete remission. Two patients were given decitabine. One died at 34 days from initial therapy due to infectious complications and the other remains on treatment.Conclusion: Performance of the SPPB and 3MS tests on patients age ≥ 60 is feasible and should be considered at diagnosis for elderly AML patients. Our group found that the use of objective measures was most helpful in identifying the two patients who had impaired cognition at baseline with 3MS scores < 77. The use of a second provider as an examiner allowed for thoughtful discussion regarding choice of initial therapy. Based on this pilot, further investigation and validation of SPPB and 3MS testing for "fitness" prior to determining choice of therapy in patients with new or relapsed AML age ≥ 60 should be pursued. DisclosuresNo relevant conflicts of interest to declare.

Hematopoietic stem cell transplantation (HSCT) compared to consolidation chemotherapy (CT) to increase leukemia free survival (LFS) in acute myelogenous leukemia (AML) patients between 60 and 75 years irrespective of genetic risk: Report from the AML 2004 of the East German Study Group (OSHO).

e18501Background: HSCT has been reported to be a treatment option for elderly patients with AML. Here we analyze the outcome of CT compared to HSCT in elderly AML patients according to genetic risk...

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

A Phase 1b Study of Venetoclax (ABT-199/GDC-0199) in Combination with Decitabine or Azacitidine in Treatment-Naive Patients with Acute Myelogenous Leukemia Who Are ≥ to 65 Years and Not Eligible for Standard Induction Therapy

The Results of Chemotherapy for the Elderly Acute Myelogenous Leukemia Patients

AbstractAbstract 4346 BackgroundDespite of advances in the treatment for acute myelogenous leukemia (AML), the response of chemotherapy for the elderly is still poor and there is no definite guideline for the elderly AML patients. MethodsThe retrospective analysis with medical chart review was taken to the 82 patients over 65 years old and treated with AML from January 2003 to April 2012 at the Korea University Medical Center. The efficacy of chemotherapy for the elderly patients was evaluated and subgroup analysis was taken to determine which conditions are more effective to the chemotherapy. ResultsMedian overall survival period of 82 patients were 3.9 months. 52 patients were treated with chemotherapy (33 patients were standard dose idarubicin plus cytarabine, 19 patients were low dose cytarabine) and 30 patients received best supportive care only. Among the standard chemotherapy group, there were 16 cases of remission (48.5%) after induction chemotherapy. The treatment related mortality was 24.2% and the most common cause was pneumonia sepsis. Median overall survival period of standard chemotherapy group was 7.9 months. In a multivariate analysis, significant factors for longer overall survival were performance status, no underlying heart disease, no fever at diagnosis, high platelet count, low blast count and standard induction chemotherapy. In the subgroup analysis, the efficacy of chemotherapy was observed in the relatively younger patients group (HR 0.437, P =.022), De novo AML group (HR 0.421, P =.025), no underlying heart disease group (HR 0.421, P =.031), high WBC count group (HR 0.306, P =.026), Low platelet count group (HR 0.12, P <.001), high blast counts group (HR 0.233, P =.005), high LDH group (HR 0.21, P=.001). ConclusionThe result of chemotherapy in the elderly AML patients is poor. However the results of the chemotherapy will be better if the patients are selected appropriately through subgroup analysis. Disclosures:Choi:the korean society of hematology: Membership on an entity's Board of Directors or advisory committees.

Intensive chemotherapy for elderly patients with acute myelogeneous leukemia: a propensity score analysis by the Japan Hematology and Oncology Clinical Study Group (J-HOCS)

The prognosis of acute myelogenous leukemia (AML) in the elderly patients is extremely poor. Although several previous studies have suggested that intensive chemotherapy is associated with a better prognosis, there may have been a selection bias. Therefore, we retrospectively evaluated the impact of intensive chemotherapy for AML in the elderly by stratifying patients according to a propensity score. Eighty-one AML patients aged 70 years or more were included in this study. Patients with acute promyelocytic leukemia were not included. A propensity score for the use of intensive chemotherapy was calculated from four factors at diagnosis. Forty-five patients received intensive chemotherapy, whereas 36 received low-dose or no chemotherapy. We stratified the patients into quartiles based on the propensity score. The numbers of patients in the first, second, third, and forth quartiles who received intensive chemotherapy were 5 of 21, 10 of 20, 12 of 20, and 18 of 20, respectively. A stratified log-rank test showed significantly better overall survival in the intensive chemotherapy group (P = 0.0088). Especially, in the combined second and third quartiles, which showed an equal tendency for intensive and non-intensive strategies; overall survival at 3 years was 37.5 % for the intensive chemotherapy group and 13.0 % for the non-intensive chemotherapy group (P = 0.0022). A conventional multivariate analysis confirmed that intensive chemotherapy was beneficial (hazard ratio 0.50, 95 % confidence interval 0.27-0.93, P = 0.028). In conclusion, intensive chemotherapy may prolong overall survival in elderly AML patients who are considered to be able to tolerate such treatment based on factors at diagnosis.

Phase II study of decitabine and gemtuzumab ozogamicin (GO) in acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

6566 Background: Antileukemic activity of GO correlates with expression of Syk, a tumor suppressor, in AML cells. Hypomethylating agents increase expression of Syk in AML cells. A phase II study of 5-azacitidine with GO in elderly untreated AML patients (pts) showed remission rate of 70%. We are investigating the efficacy and safety of the combination of GO with decitabine in AML and MDS. Methods: Induction comprises of decitabine 20 mg/m2 intravenously (IV) daily for 5 days and GO 3 mg/m2 IV X 1 on day 5. Initially an additional GO dose was allowed if pt had circulating blasts on day 14, but was revised to add 5 days of decitabine instead of GO on day 15 ± 2, if day 14 bone marrow shows > 5% blasts. Subsequent therapy allows for 5 additional cycles of decitabine and GO every 4-6 weeks. Pts with responses can continue with decitabine x 5 days every 4-6 weeks for 2 years. This report is limited to the previously untreated patients with AML or MDS. Results: We report on the 56 pts (AML = 37, MDS = 19) with previously untreated AML or MDS. The median age was 70 years (range, 42-87), 36 (58%) were male. Twenty-six (46%) pts were treated on the original schedule and 30 (54%) on the revised schedule. Responses were seen in 26 (46%) pts (10/26 [38%] in original schedule, 16/30 [53%] in revised schedule). Sixteen pts (29%) (6/26 [23%] in original schedule, 10/30 [33%] in revised schedule) achieved complete remission (CR) or CR without platelet recovery (CRp). Two pts had partial remission, 7 had clearance of marrow blasts and 1 had hematological improvement-hemoglobin. Toxicities were mostly related to infusion reactions with GO. Twelve pts had infections requiring hospitalization. Grade 3/4 nonhematologic toxicities include atrial flutter (1 pt) and 1 transient ischemic attack. There were 2 early deaths. Responding pts have continued therapy for a median day of 202 (range, 40-540). Conclusions: Decitabine plus GO is an active regimen in older pts with untreated AML or high-risk MDS, toxicities are minimal. The accrual in this study is ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Eisai

Multiple hepatocellular carcinomas developed 15 months after commencement of chemotherapy for elderly acute myelogenous leukemia

Multiple hepatocellular carcinomas developed 15 months after commencement of chemotherapy for elderly acute myelogenous leukemia

Survival after Complete Response to Treatment with Laromustine (CLORETAZINE®) in Elderly Patients with De Novo Poor Risk Acute Myelogenous Leukemia (AML).

Background: Treatment options for patients with AML are limited. Poor outcomes are associated with increasing age, decreasing performance status, unfavorable cytogenetics, and the presence of comorbid conditions. Elderly patients ³ 65 years with AML have a short survival (median 2.4 months) (Lang 2005), and for older patients who receive treatment, 1-year survival is 5–25% (Menzin 2002, Kantarjian 2006, Burnett 2007). CR/CRp is a desired outcome from induction treatment and a requisite for meaningful survival. Laromustine (Cloretazine) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Results of two sequential Phase II multi-center studies of single agent laromustine (CLI-033 and CLI-043) conducted in elderly untreated AML patients have been reported (Giles 2007, Schiller 2008). The purpose of this analysis is to assess survival for a combined group of patients from the two studies who achieved a response to laromustine (CR/CRp by IWG criteria [Cheson 2003]).Methods: Eighty-five patients in study CLI-043 and 55 patients from a retrospectively identified de novo subset of CLI-033 who reasonably met the eligibility criteria for CLI- 043, received laromustine 600 mg/m2 as induction therapy (N=140). Poor risk was defined as the presence of at least one risk factor: age ³ 70 yrs, unfavorable cytogenetics, PS2, or pulmonary, cardiac, or hepatic comorbidity. 86% (120/140) pts had 2 or more risk factors. 16% (22/140) pts received a second induction of laromustine 600 mg/m2. 24% (34/140) patients received a consolidation cycle; per individual protocol, 15 pts received consolidation with laromustine 400 mg/m2 and 19 pts received cytarabine 400 mg/ m2. Kaplan-Meier analysis of survival was used to better understand the clinical benefit of CR/CRp.Results: 52/140 (37%) pts achieved a CR/CRp; 44/140 (31%) pts survived ³ 30 days following CR/CRp. All but one patient achieved CR/CRp following first induction. Estimated Kaplan-Meier survival from time of response for these 44 patients is shown below. Six and 12 month survival for this subset is 58% and 44%, respectively. The 30-day mortality for the entire group is 14% (20/140). [Display omitted] Conclusions: Early mortality, progressive disease, and short CR/CRp duration account for short median survival rates in leukemia studies. The 30-day mortality for this group compares favorably with published data of early death rates in older patients with multiple risk factors who receive induction chemotherapy (Appelbaum 2006, Kantarjian 2006). Relatively long survival in a subset of older patients with multiple risk factors who achieve a response to laromustine implies clinical benefit, and confirms the concept that obtaining a CR/CRp is in itself a benefit.

Lethality to leukemia cell lines of DNA interstrand cross-links generated by Cloretazine derived alkylating species

Cloretazine [1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine; VNP40101M; 101 M] is a relatively new prodrug with activity in elderly acute myelogenous leukemia (AML) patients. Its therapeutic action is due largely to the production of 1-(3-cytosinyl),2-(1-guanyl)ethane cross-links (G–C ethane cross-links) in DNA. The numbers of cross-links produced in three experimental leukemia lines (L1210, U937 and HL-60) were fewer than 10 per genome at their respective LC 50 concentrations. Only 1 in approximately 20,000 90CE molecules produces a cross-link in the AGT ( O 6-alkylguanine-DNA alkyltransferase) negative L1210 and U937 cell lines and 1 in 400,000 in the AGT positive HL-60 cell line.

In Vivo Correlates of Response for Phase I Trial of Oral Tipifarnib (T) Combined with Oral Etoposide (E) for Adults Age ≥ 70 with Newly Diagnosed Acute Myelogenous Leukemia (AML) Who Are Not Candidates for Traditional Cytotoxic Chemotherapy (TCC).

T is a farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults age ≥ 65 with poor-risk AML, T 600 mg BID for 21 out of 28–63 days induced complete remissions (CR) in 14%, median duration 7.3 mos, median survival 18.3 mos (Lancet JE, et al, Blood 109:1387–1394, 2007). In vitro, T+E exhibits synergistic anti-AML activity. In an attempt to increase CR rates in elderly AML pts, we conducted a Phase I trial of oral T+E, with escalation of both drugs and 14 vs. 21 days of T every 28–63 days (median 31 days, range 29–50). T+E resulted in a 25% CR rate (21/84 pts), duration 2 – 26+ mos, with best rates achieved with T dose ≥ 400 mg BID for 14 days (Karp JE, et al, Blood 108:130a, 2006). In the context of this trial, we have conducted longitudinal laboratory studies of changes in DNA damage and apoptosis in AML marrow blasts obtained from 84 patients prior to T+E (Day 0) and on Day 8 of T+E. Blasts were enriched by Ficoll density gradient separation and fixed in 70% ethanol. Persistent, unrepaired DNA damage was quantified by flow cytometry of cells stained with antibody to phosphorylated histone H2AX (γH2AX). Apoptosis was measured by flow cytometry of propidium iodide-stained cells with sub2n DNA content as observed in cell cycle distribution. To date, we have analyzed changes in in vivo γH2AX from 10 pts (4 CR, 6 stable disease or no response, SD/NR). CR pts had a 2-fold increase (range 1.91–2.22) in DNA damage induced by Day 8 of T+E relative to Day 0 values, while patients with SD/NR had no such increase (0–1.06) in DNA damage. Similarly, the apoptotic fraction of the cell cycle distributions of CR patients increase by 2-fold (range 1.2–5.3) for Day 8 marrow blasts. In contrast, changes in apoptosis were widely divergent for SD/NR patients (range 0.2–7.0). Taken together, these preliminary studies on AML marrow blasts obtained prior to and during T+E therapy suggest a possible linkage among induction of DNA damage, apoptotic response, and clinical outcome. Full analysis of all acquired specimens is ongoing.

Active Oral Regimen for Elderly Adults with Newly Diagnosed Acute Myelogenous Leukemia (AML): Phase I Trial of Oral Tipifarnib (T) Combined with Oral Etoposide (E) for Adults ≥Age 70 Who Are Not Candidates for Traditional Cytotoxic Chemotherapy (TCC).

T is a Farnesyltransferase inhibitor with clinical activity in elderly adults with newly diagnosed AML who are not candidates for TCC. For adults ≥ age 65 with poor-risk AML, T 600 mg BID for 21 out of every 28–63 days induces complete remissions (CR) in 15%, median duration 7.3 mos, median survival 18 mos. In vitro, T+E exhibits synergistic anti-AML effects. In an attempt to increase CR rates in elderly AML pts, we are conducting a Phase I trial of oral T+E, with escalating doses of both drugs and 14 vs. 21 days of T every 28–63 days (median time to beginning cycle 2 is Day 31, range 29–43). To date, 60 adults ≥ age 70 (median 77, range 71–91) have been treated at 10 dose levels of T (300, 400 or 600 mg BID, 14 or 21 days) + E (100, 150 or 200 mg daily days 1–3 and 8–10) and have received 145 cycles (median 3, range 1–7). A total of 35 (58%) have had secondary AML and 31 (52%) have had adverse cytogenetics. Marrow blast percent was median 55% (range 20–96%), with 75% >30,000 blasts. Nonhematologic toxicities include oropharyngeal mucositis (15% ≥ grade 2), CNS (overall 30%, with 80% of those ≤ grade 2), renal (6%), hyperbilirubinemia (6%), rash (20%) and fatigue (20%). Toxicities occurred across all T+E dose levels tested to date. Documented infections occurred in 16 (27%) pts during cycle 1 and 22/145 (14%) cycles. Twenty six pts (43%) required hospitalization during cycle 1 for median 7 days (range 2–28). Overall hospitalization rate for all cycles was 28% (41/145). Ten pts (17%) died on study: 6 during cycle 1 (4 infection, 1 emphysema, 1 cerebrovascular) and 4 during cycles 2–4 (3 acute myocardial infarctions, 1 ventricular arrhythmia). For 56 evaluable pts, 12 (21%) have achieved CR and 11(20%) have achieved partial remission/hematologic improvement (PR/HI). All pts achieving CR have done so within 2 cycles (9/12 after cycle 1). Eight of 30 pts (27%) receiving T ≥ 400 mg BID have achieved CR. Median age of CR pts is 79 (range 71–86), 8 (67%) have secondary AML, and 5 (42%) have complex cytogenetics. CR durations to date range from 2+ to 13.5+ mos, with median 7+ months. Three of 12 have relapsed at 3, 10, and 11 mos, 2 have been retreated with T+E, and both have achieved 2nd CRs. In sum, the oral regimen of T+E is tolerable and feasible on an outpatient basis for elderly adults with newly diagnosed AML who are not candidates for TCC, with the suggestion of improvement of CR rates over T alone.

Acute myelogenous leukemia in elderly patients not eligible for intensive chemotherapy: the dark side of the moon

Background: Acute Myelogenous Leukemia (AML) is a common disease in people aged >60 years. About 50% of the patients are not eligible for aggressive chemotherapy (CT) and are only managed with conservative approaches. Results in this subset of patients have not been reported so far.Patients and methods: We retrospectively evaluated 244 consecutive elderly AML patients (M/F 143/101, median age 72 years, range 60–90) diagnosed at our institution from January 1989 to December 1998 and not eligible for intensive CT. Eighty-nine patients (36.5%) had evolved from previous myelodysplasia (sAML). Fifty-three out of 192 (26.4%) patients with available bone marrow (BM) analysis had oligoblastic leukaemia (blasts <40% and WBC <15×109/l).Results: Sixty-seven patients (27.5%) were managed with supportive treatment only. One hundred seventy-seven patients (72.5%), in order to control disease, received conservative CT, consisting of Hydroxyurea (HU) (127 patients, 71.7%), Cytarabine and 6-Thioguanine (39 patients, 22%) or low-dose cytarabine (11 patients, 6.3%). Median overall survival was 179 days (1–3278) with 50 patients (20.5%) surviving >12 months. Older age (>75 years), poor WHO PS (>2), lower PLT levels (<50×109/l) and higher absolute peripheral blast count (>5 × 109/l) showed a negative prognostic impact on survival in multivariate analysis.Conclusions: Our data outline the great heterogeneity of elderly AML patients not eligible for intensive CT. A simple scoring system including easily evaluable parameters, which could distinguish subjects with different prognosis, is proposed. Moreover, randomized studies in order to establish best conservative approaches are warranted.

Use of a Disease-Specific Comorbidity Index To Describe Elderly Patients with Acute Myelogenous Leukemia (AML) and High Risk Myelodysplasia (MDS) Enrolled in a Phase II Study of CLORETAZINE™ (VNP40101M).

Background: Elderly patients (pts) with AML generally have an unfavorable clinical course and are under-represented in clinical studies. Comorbid conditions are common in the elderly and, for older pts with AML, may have a major influence on choice of treatment. The ability to objectively measure comorbidity in this population may help predict patients' risk for unacceptable toxicity. Comorbidity indices developed from a general medical population may underestimate the risks of cytotoxic treatment. An index developed specifically for pts with hematologic malignancies may be useful in categorizing pts by risk before selection of leukemia induction therapy. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) is an index which captures comorbidities that predict non-relapse mortality (NRM) in pts with hematologic malignancies considered for allogeneic transplant (Sorror; Blood; 2005). The HCT-CI defines low risk with a score = 0, intermediate = 1–2 and high = ≥3. We used the HCT-CI to assess baseline comorbidity in an elderly pt population (median age 72) with untreated AML or high risk MDS enrolled in a single agent phase II study of CLORETAZINE.Methods: Case report forms of 105 pts ≥ 60 years of age containing information about baseline medical history, concomitant medications, physical examination, and serum chemistries were reviewed. Using the HCT-CI definitions, pts were given scores representing the weighted sum of conditions that were active or required treatment at study entry.Results: A total of 232 comorbid conditions were scored. In order of frequency, the most common were: cardiac (28%), including congestive heart failure, myocardial infarction, arrythmias, coronary artery stenosis requiring treatment, and valve disease; psychiatric disturbances (12%); hepatic dysfunction (11%); infection (11%); and ≥ grade 2 pulmonary disease (8%). Most pts (64%) had multiple comorbid conditions. Cardiac conditions were observed in 46% of all pts, psychiatric disturbances in 27%, hepatic disease in 25%, ongoing but controlled infections in 24%, and pulmonary disease in 18%. The response rate within each risk category is similar to the overall response rate, as summarized in the table below. The 19 early deaths (≤ 30 days) occurred in pts from the intermediate and high risk categories.Risk CategoryN (%)# CR/CRp (%)# Early Deaths (%)Low (0)11 (10)4 (36)0Intermediate (1–2)32 (30)11 (34)7High (≥3)62 (59)18 (29)12Total10533 (31)19 (18)Conclusions: The HCT-CI is a helpful tool for defining comorbid conditions in elderly untreated AML pts. The majority of pts enrolled in the single agent Phase II CLORETAZINE study is at high risk for NRM as measured by HCT-CI score. Pts respond to CLORETAZINE across the HCT-CI scored risk groups.

CLORETAZINE™ (VNP40101M) Is Active in Elderly Untreated Poor Risk Patients with Acute Myelogenous Leukemia (AML) or High Risk Myelodysplasia (MDS).

Background: The majority of patients (pts) with AML and high risk MDS are ≥ 60 years of age at diagnosis (median age 70), and have a poor prognosis due to age-related risk factors and disease biology. Commonly accepted risk factors in this population include age ≥ 60 yrs, ECOG PS ≥2, secondary AML, unfavorable cytogenetics, and organ dysfunction. The response rate with induction treatment for these pts is lower than that of their younger counterparts, and additional risk factors worsen prognosis. Hepatic, pulmonary, and/or cardiac compromise is likely to determine both selection and tolerance of the induction regimen, and these pts are often not considered for aggressive chemotherapy such as “3+7”. In the US, up to 70% of elderly AML/MDS pts do not receive induction treatment (Menzin, et al; Arch Int Med ; 2002; 162:1597). CLORETAZINE, a novel sulfonylhydrazine alkylating agent, has significant activity in AML/MDS with a favorable safety profile. In an ongoing Phase II trial, pts with AML or high risk MDS, age ≥60 years, and no prior cytotoxic treatment, receive CLORETAZINE 600mg/m2 for remission induction, re-induction, and consolidation.Methods: This elderly pt population was analyzed for the presence of risk factors and underlying organ dysfunction. Pts were assessed according to the commonly accepted risk factors described above and categorized by number of factors present. Organ dysfunction was defined as hepatic abnormalities (elevated liver function tests), moderate/severe pulmonary compromise (grade 2–4 dyspnea by NCI-CTC Version 3.0 or dependence on oxygen), and/or a history of significant cardiac disease. Data was obtained from case report forms of baseline demographics, medical history, physical exam, and concomitant medications.Results: 105 pts with age ≥60 were enrolled as of April 21, 2005. Specific risk factors were as follows: 31 pts (30%) were PS 2; 36 pts (34%) had unfavorable cytogenetics; 43 pts (41%) had secondary AML. Forty-eight pts (46%) had cardiac dysfunction; 26 pts (25%) had hepatic disease; and 19 pts (18%) had pulmonary dysfunction. The response rate (CR+CRp) for the group as a whole was 31% (N=33). Non-hematologic toxicity was minimal, and the early death rate of 18% is within the range expected for cytotoxic induction regimens in the elderly AML population. The table below describes the risk categories for all patients, early deaths, and responders:# Risk FactorsN [%]# CR/CRp (%)# Early Deaths (%)Age + 012 (11)7 (58)2Age + 124 (23)9 (38)4Age + 239 (37)8 (21)7Age ≥3+30 (29)9 (30)6Total10533 (31)19 (18)Conclusions: According to risk assessment on the basis of age-related risk factors, the majority of the study pt population had multiple risk factors and represents a group for whom standard AML induction therapy may not be an option. In this elderly patient population with limited therapeutic options, CLORETAZINE is tolerable and results in a response rate of 31%.

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documented aplastic bone marrows. The overall response rate was 49%; 33% with CR and 16% with PR. Median duration of CR was 251 days (range 36–842). The CR for secondary AML was 18%, for de novo AML 38%, and for MDS 67%. None of the patients developed mucositis or alopecia, and no patient had greater than grade I nausea and vomiting. The most common adverse effects were neutropenic fever (68%), atrial fibrillation (7%) and congestive heart failure (5%). Five patients died of treatment related toxicity (sepsis). The median survival for all patients was 150 days, for patients achieving CR was 290 days, and the 1 year survival rate was 24%. Conclusions: GM-CSF priming can enhance the cytoreductive effects of low doses of cytarabine. This combination therapy is well tolerated, and should be explored as an alternative regimen for high risk and elderly AML and advanced MDS patients. No significant financial relationships to disclose.

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documen...

Malignancy of hematopoetic system in the elderly--acute myelogenous leukemia

高齢者急性骨髄性白血病を中心に述べる. 発症以前に骨髄異形成症候群を始めなんらかの血液異常を指摘されている例が約40%と多い. 白血病細胞の形態では, FAB分類のM3が少ない以外一般成人とほぼ同一であるが, 3系統に形態異常を認める割合が高い. 染色体異常では, 予後良好とされる異常は3～5%と少なく, 二次性悪性腫瘍に多い5番, 7番の異常や複雑な染色体異常が30～40%を占める. 多剤耐性遺伝子のMDR1陽性率も高い. その上, 加齢に伴う各臓器の機能低下があり, 合併症も多いことから, 高齢者の白血病はいまだに予後不良である. 治療を開始するにあっては, 全身状態, 高齢者の包括的機能評価 (CGA), 白血病の性質を総合して, 強力な多剤併用, マイルドな治療, 対症療法のみのいずれかを選択する. 二次性白血病, 予後不良染色体は, 寛解に関する予後因子として重要であるが, 全身状態が良好であれば通常の多剤併用療法を試みる. AraC 7日間とダウノルビシン3日間の療法が基準であり, ダウノルビシンの代わりにイダルビシンやミトキサントロンなどが検討されているが, いずれも完全寛解率は40～60%, 平均生存期間は1年以内であり, 特に優れた治療法は今のところない. 白血球を増加させるCSFは顆粒球減少期間を短縮できたが, 寛解率の向上や入院期間の短縮は認められないという報告が多い. 一方, 近年多剤耐性を取り除く薬剤や新抗がん剤が開発され難治性白血病に試みられるようになってきている. また, ターゲット療法である抗CD33抗体も特に高齢者の急性白血病に使用可能になってきている. 骨髄抑制が少ないことから, 全身状態の不良な高齢者への使用も期待できる. 造血幹細胞移植とくにミニ移植も60代以上の高齢者に試みられており, 次第に成績も向上してきている. 血管新生抑制剤, インターロイキンなど新しい考え方の治療法が開発されており, 今後高齢者の治療成績も向上するものと期待される.

Erratum: Molecular genetic features of myelodysplastic syndromes (MDS)

Recent developments in molecular genetics have provided insights on the molecular mechanisms that lead to myelodysplasias (MDS), secondary acute myelogenous leukemia (AML), therapy-induced AML, and elderly AML. These disorders are characterized by dysregulation of growth and differentiation of multilineage stem cells, a genetic profile characterized by unbalanced abnormalities that result in "unfavorable cytogenetics," and an increased frequency of intrinsic multidrug resistance. The unfavorable cytogenetics associated with this group of disorders include chromosome 5 and 7 monosomy, deletions of the long arm of chromosomes 5 and 7, inversions of chromosome 3, translocations, deletions and trisomies involving several other chromosomes. Presumably, these unbalanced chromosomal aberrations result in hemizygosity and unmasking of oncogenes or inactivation of tumor suppressor genes. In addition, polymorphisms in genes encoding metabolic detoxification enzymes, defective DNA repair mechanisms, and intrinsic chromosomal instability have been implicated in the etiology of the myelodysplastic syndromes. It is evident that the cytogenetics associated with MDS are highly complex and heterogeneous. This review summarizes the most recent developments in the understanding of the molecular changes associated with the development of myelodysplasias and related leukemic disorders.

73 P - Oral idarubicin (OIDA) in elderly patients (pts) with acute myelogenous Leukemia (AML): An opportunity?

IDA, besides Its unique peculiarity of oral as well as I.v. administration, exhibits Intriguing potentials for (partially) reverting Pgp/mar -l –related MutiDrug Resistance (MDR), especially relevant in hematological malignancies, as well as for killing noncyling/testing bone narrow precursors, possibly via simulation of apoptosis. Compared to I.v. IDA, oiDA yields a twofold amount of its uniquely affective OH-13 metabolite, IDAOL, equally active and myelotoxic as the parent IDA. Thus, although oiDA cannot be meaningfully introduced in intensive chemotherapy (CT), it was proposed for elderly pts with AML conventionally, Pts over 60 are considered as elderly, and over all they had lower CR and higher toxic death rates compared to younger adults, even if recent report emphasize the need for Risk-adjusted treatment, tallored to the biological rather than chronological age of the individual pts. Based on data from published trials in elderly AML patients. Table Author/Year Patient Population Regimen(mg/m 2 ) CR CR/pts % CR median, duration, wks % Deafts on induction MST, wks Harousseau, 1989 >65 yrs, untreated oiDA 30×3d 8/20 40 21+ 25 20 Harousseau, 1991 >65 yrs, untreated oiDA 20×3d, LD Ara-C s.c. 13/32 41 15 19 23 Ruutu, 1994 >65 yrs, untreated ETI * vs TAD * 15/25 60 6/26 23 30 12 4 23 40 15 Pagano, 1991 65 yrs, untreated/pretreated oiDA 25×3d Ara-c s.c. 8/17 47 22 23 49(in responders) Helg, 1990 >65 yrs, untreated/pretreated oiDA 30×3d LD Ara-C s.c. 14/26 53 20 19 not available Total 58/120 48% CR TAD: 6-TG p.p. 200 mg/m 2 dialy × 5 d; Am- cC i.v. 200 mg/m 2 daily × 5 d; Denorubicin i.v, 60 mg/m 2 × 1d. * TI: VP-16 p.a. 180 mg/m 2 daily × 5 d; 6-TG p.a. 200 mg/m 2 daily × 5 d; oiDA 15 mg/m 2 daily × 5d. oiDA, both as a single-agent and as a component of fully or partially oral combinations with cytosine arobinoside (Ara-c), etopside (VP-16), or 6-thioguanine (6-TG), proved effective. However it should not be understood as attenuated CT, on account of significant myelotoxicity anyway preciuding outpatient treatment (especially at doses > 15 mg/m 2 dally × 3). Indeed, cumulated evidence appears to suggest use of hematopoietic support. Other, strictly investigational approaches are:1) Induction with chronic low-dose oiDA in poor risk pts, unit for aggressive/intensive CT, and 2)use of an oral regimen as postremission treatment following a standard “intensive” L.v, CT.