Untreated Acute Myeloid Leukemia Pts Research Articles

Venetoclax Plus Azacitadine for Middle Aged and Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia: Interim Analysis of a Prospective, Multicenter, Single-Arm, Phase 2 Trial

Background: “7+3” induction is the standard regimen in newly diagnosed young patients (pts) with acute myeloid leukemia (AML) fit for intensive chemotherapy with 60-80% complete remission rate. However, middle aged and elderly pts may experience more severe complications during induction therapy and overall survival is shorter than that of younger pts. Recently, venetoclax with azacitadine as induction therapy was approved as the first line therapy for pts with aged more than 75 years or unfit pts with composite complete remission (CRc) of 60-70%. We hypothesize that venetoclax with azacitadine as induction therapy in fit middle aged and elderly pts may have similar CRc rate and less complications. This study aims to evaluate the safety and efficacy of venetoclax plus azacitadine as induction therapy in fit middle aged and elderly newly diagnosed AML pts. Methods: This is an interim analysis of an ongoing phase 2 clinical trial (NCT05471700) of a planned 40 untreated AML pts aged 45-65 who were fit for intensive chemotherapy according to Ferrara Criteria. In cycle 1, pts received azacitadine 75mg/m2/day on d1-7 and venetoclax escalated from 100mg to 200mg to 400mg until 28-day cycle was finished. For pts with FLT3-ITD positive, sorafenib was optional administered at a dose of 400mg twice daily. Bone marrow assessments were performed on d28. Pts who achieved CRc (defined as complete remission[CR] and CR with incomplete hematologic recovery[CRi]) with intermediate or adverse risk groups received 1 or 2 cycles of consolidation with venetoclax plus azacitadine or center-specific cytarabine-based consolidation. Allogeneic stem cell transplantation (HSCT) was performed if a donor was available. Pts in favorable risk gruop received 3 to 4 cycles of center-specific intermediate or high dose cytarabine-base consolidation. Non-responders or pts who achieved partial remission received 1 more cycle of venetoclax plus azacitadine. Who could not get CRc after 2 cycles of induction would be withdrawn from the study. The primary objective is to determine the CRc rate. The secondary objective is safety, MRD negative rate, duration of remission (DOR), the rate of allo-HSCT, event free survival (EFS), and overall survival (OS). The endpoint is to show that venetoclax plus azacitadine is not inferior to “3+7” induction in fit pts with newly diagnosed AML aged 45-65. Results: From 10/9/2022 to 6/30/2023, a total of 32 pts was enrolled to this study, comprising 18 males and 14 females. There were 27 (84%) pts with de novo AML, 2(6%) pts were secondary AML, 3 pts (9.4%) were therapy-related AML. Median age was 58 years (range, 45-64 years). There were 2(6%), 14(44%) and 16(50%) pts were in the favorable, intermediate and adverse risk group, respectively. The baseline patient characteristics are summarized in Table 1. Outcome data were updated as of June 30, 2023, for a median follow-up of 2.2(0.2-8.8) months. Among 27 evaluable pts, 21(77.8%) achieved CRc with 11(40.8%) in CR and 10(37.0%) in CRi, 2(7.4%) achieved PR in cycle1, while 23(85.2%) achieved CRc with 14(51.9%) in CR and 9(33.3%) in CRi, 4(14.8%) got induction failure after 2 cycles(Figure 1). A total of 16 (61.5%) pts got MRD negative among the pts with CRc after cycle1, and 17 (65.4%) after cycle2. CRc rate after 2 cycles in ELN2017 favorable, intermediate, adverse risk group was 100%, 83.3% and 85.0%, respectively, and MRD negative rate was 100%, 88.9% and 55.6%, respectively. The regimen was well tolerated. No mortality occurred during induction therapy. The most common non-hematological grade 3/4 AE were febrile neutropenia (n=13, 40.6%)，followed by pneumonia (n=3, 9.4%).Sepsis occurred in 1 (3.1%) pt. With a median follow-up of 2.2(0.2-8.8) months, the median remission duration, EFS and OS have not been reached. Conclusions: Preliminary results indicate that venetoclax plus azacitadine as an induction regimen for fit middle aged and elderly pts with newly diagnosed AML is promising with high CRc and low toxicity. Recruitment of adults with newly diagnosed aged 45-65 AML pts for this trial is ongoing.

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

An Analysis of Maintenance Therapy and Post-Midostaurin Outcomes in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603/RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

The Addition of Midostaurin to Standard Chemotherapy Decreases Cumulative Incidence of Relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

The Addition of Midostaurin to Standard Chemotherapy Decreases Cumulative Incidence of Relapse (CIR) in the International Prospective Randomized, Placebo-Controlled, Double-Blind Trial (CALGB 10603 / RATIFY [Alliance]) for Newly Diagnosed Acute Myeloid Leukemia (AML) Patients with FLT3 Mutations

Maximal Tolerated Dose of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction in Previously Untreated Adults with Acute Myeloid Leukemia (AML)

Maximal Tolerated Dose of the BCL-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction in Previously Untreated Adults with Acute Myeloid Leukemia (AML)

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

The Impact of PHF6 Mutations in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

Phase I Trial of Escalating Doses of the Bcl-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction and High Dose Cytarabine Consolidation in Previously Untreated Adults with Acute Myeloid Leukemia ( AML)

Phase I Trial of Escalating Doses of the Bcl-2 Inhibitor Venetoclax in Combination with Daunorubicin/Cytarabine Induction and High Dose Cytarabine Consolidation in Previously Untreated Adults with Acute Myeloid Leukemia ( AML)

Interim Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with Untreated Acute Myeloid Leukemia (AML)

Interim Safety and Efficacy of Lower Intensity Induction Therapy with Intravenous Prexigebersen (BP1001) in Patients with Untreated Acute Myeloid Leukemia (AML)

Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial

Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial

The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance

The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute Myeloid Leukemia (AML) Patients (pts) Age 18-60 with FLT3 Mutations (muts): An International Prospective Randomized (rand) P-Controlled Double-Blind Trial (CALGB 10603/RATIFY [Alliance

Predicting outcome based on minimal residual disease (MRD) using multiparameter flow cytometry (FC) in acute myeloid leukemia (AML) patients (Pts).

6565 Background: Most AML pts will experience relapse caused by persistent leukemic cells during complete remission (CR). The aim of our study was to predict outcome in AML pts in CR by assessing their MRD using standard 4-colour FC panels available at our institute. Methods: We queried our AML database between 1/2004 to 10/2010 for newly diagnosed untreated AML pts >18 years of age who achieved CR after one induction regimen. Treatment included 7+3 or similar intensive approaches. The gating strategy used a series of Boolean regions that best defined the diagnostic abnormal population based on its expression patterns using three 4-colour FC panels (F7-CD38,CD10,CD19,CD34; F9-C11b,CD33,CD13,CD34; F38-CD15,CD56,CD7,CD34). The same regions were applied to post-induction samples, and the number of residual events was determined. Results: 140 AML patients with a median age of 64 (range 24-93) years, including 74 females (52.8%) were analyzed; 67 (47.8%) patients relapsed. Eighty-eight (62.8%) pts were CD34-positive (CD34+) at diagnosis. Normal karyotype was detected in 27 (30.7%): FLT-3 ITD was detected in 4/23 (17.4%) and NPM-1 mutation was detected in 1/15 (0.07%) samples. Median follow-up for CD34+ pts was 17.9 months. Forty-two (30%) pts underwent stem cell transplantation (SCT) in first CR: 31 (22.1 %) were allogeneic and 11 (7.9%) autologous. In multivariate analysis, a detectable MRD in any of the 3 panels at or beyond week 16 among CD34+ AML pts in CR was significantly associated with inferior relapse free survival (F7: P=0.035 , F9: P=0.027, F38: P=0.042). In addition, MRD ≥ week 16 using panel F9 was also significantly associated with inferior overall survival (P=0.0224). In pair-wise comparison, those who were MRD-negative ≥ week 16 did not benefit from SCT compared to the non-SCT group. Similar analyses among CD34– AML pts did not achieve statistical significance. Conclusions: MRD+ by FC in CD34+ AML is an independent prognostic factor and can identify pts who may benefit from SCT/more intensive therapy to maintain remission. However, the value of studying MRD in CD34– AML requires further consideration. More effort is needed to identify stem cells in CD34– AML.

Abstract 119: AR42, a histone deacetylase inhibitor (HDACI), increases microRNA (miR)-29b and sensitizes cells to decitabine (DAC) treatment: A novel epigenetic-targeting approach in acute myeloid leukemia (AML)

Abstract The outcome of the majority of older AML patients (pts) remains poor despite advances made in both pathogenesis and prognostication. Epigenetic gene silencing by DNA hypermethylation contributes to AML pathogenesis. Recently we reported promising results in older previously untreated AML pts receiving low-dose of hypomethylating agent DAC alone. However these results can be improved upon. In our study pts with higher miR-29b expression were more likely to respond to DAC therapy (P=.02). MiR-29b directly or indirectly targets and downregulates the DNA methyltransferases (i.e. DNMT1, DNMT3A and DNMT3B) and has hypomethylating and tumor suppressor activity in AML. We recently showed that miR-29b is repressed by a Sp1/NFkB/HDAC1 complex, and that the HDACI AR42 can increase miR-29b expression by disrupting this complex in AML. Thus we hypothesized that priming AML cells with AR42 would result in miR-29b upregulation and increased response to DAC in AML pts. Here we showed first that in three AML cell lines i.e. THP-1, NB4 & Kasumi-1, miR-29b is upregulated (1.7, 2.4 & 1.6, fold respectively) as early as 1h after 1 µM AR42 vs DMSO control treatment. Confirming the upregulation of miR-29b by AR42, we next tested if this would sensitize the cells to DAC treatment. Priming THP-1 cells with 1 µM AR42 (for 12h) followed by 2.5 µM DAC treatment (for 24h) decreased the cell viability (measured by MTS assays) by 7-fold when compared to cells that were treated with the reverse drug sequence i.e., 2.5 µM DAC (for 12h) followed by 1 µM AR42 (for 24h). The decrease of cell viability was also higher than for each drug alone; 1 µM AR42 (for 12h) followed by 2.5 µM DAC treatment (for 24h) decreased the cell viability by 5-fold compared to 1 µM AR42 alone (for 36h) and 2-fold compared to 2.5 µM DAC therapy alone (for 36h). To test this effect in vivo we utilized an AML model constituted by FDCP1 cells expressing mutant KIT (KITmut) that we engrafted in NOD/SCID mice. Mice developed AML at 4 weeks from inoculation. The sequential administration of AR42 followed by DAC resulted in longer overall survival (P<.001) of FDCP1-KITmut mice (60% alive at day 120) compared to mice treated with DAC followed by AR42 or either drug alone (0% alive at day 120 in each group). The sequence of “HDACIs followed by DAC” is novel as to our knowledge only the sequence of “hypomethylating agents followed by HDACIs” has been explored in the clinic. These preclinical results support AR42 as an effective compound to upregulate miR-29b and in turn the approach of priming AML blasts with HIDACIs in order to sensitize them to treatment with hypomethylating agents. Phase I trials with microRNA priming with AR42 prior to DAC treatment are presently underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 119. doi:1538-7445.AM2012-119

A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML)

AbstractAbstract 3288 Introduction:The elderly constitute the majority of patients (pts) with AML. Effective and tolerable therapeutic alternatives are necessary for these pts, in whom outcomes with standard induction therapy are poor. Azacitidine (AZA), a DNA methyltransferase inhibitor, decreases methylation of tumor suppressor gene (TSG) promoters, which correlates with clinical responses. Lenalidomide (LEN), an immunomodulatory and anti-angiogenic agent, has anti-leukemic activity when used as a single agent. We hypothesized that combining these two agents would decrease promoter methylation and upregulate TSG expression. We present the Phase I results of a Phase I/II clinical trial that sequentially combines AZA with LEN in elderly, previously untreated AML pts. Methods:Eligible pts were ≥ 60 years, had a World Health Organization-confirmed diagnosis of non-M3 AML, a performance status (PS) ≤ 2, adequate organ function, no prior leukemia therapy and were not candidates for standard induction. All pts had a white blood cell count ≤ 10,000/mm3 at the time of study entry; the use of hydroxyurea to attain this was permitted. Pts were enrolled into 4 cohorts using a 3+3 dose escalation design. In cohort 1, pts received 75 mg/m2 AZA SC/IV on d 1–7, followed by 21 days of observation for a 28-day cycle. At the completion of this “cycle 0,” pts were escalated to cycle 1, in which they received the same dose and schedule of AZA followed by LEN 5 mg PO daily on d 8–28, and then observation on d 29–42. Cohorts 2, 3 and 4 received the same dose and schedule of AZA with LEN doses of 10, 25 and 50 mg respectively, at the same schedule described for cycle 1. Intra-cohort dose escalation after cycle 0 was not permitted. Baseline bone marrow biopsies were compared to biopsies obtained after cycles 0, 1, 3, 6 and 12, and response assessments were based on International Working Group criteria. Adverse events (AEs) were graded according to the NCI CTCAE v 3.0. Pts were eligible for a maximum of 12 cycles, provided they tolerated therapy and achieved a response (defined as a complete response [CR], a CR with incomplete recovery of blood counts [CRi] or a partial response [PR]). Result:Eighteen pts were enrolled between April 2009 and July 2010. The median age was 72 years (64-86), 67% were male and 94% were Caucasian. The median PS was 1 (0-2) and the median hematopoietic cell transplant comorbidity index score was 0.5 (0-4). Six of 18 (33%) required hydroxyurea prior to enrollment. Seven of 18 (39%) had de novo AML and 11/18 (61%) had secondary AML (1 therapy-related, 1 evolved from primary myelofibrosis and 9 with myelodysplasia-related changes). The median bone marrow blast percentage was 63.5% (21-91%). Three of 18 (17%) pts had adverse cytogenetics, while 15/18 (83%) pts exhibited intermediate grade cytogenetics (11/15 with normal karyotype). Grade 3 serious AEs with a suspected relationship to treatment included neutropenic fever (NF) (n=5), fatigue (n=3), renal insufficiency (n=2), hyponatremia (n=1) and bleeding (n=1). In Cohort 4, 1/6 pts experienced grade 4 NF; however, 5/6 did not experience DLT, and therefore, the MTD was not reached. Pts have completed a median of 2 treatment cycles (0-6), with a median follow up of 94 days (21-275). Presently, of the 17 evaluable pts, 9/17 (53%) are alive. The overall response rate (ORR; defined as CR+CRi+PR) is 8/17 (47%) and the CR+CRi rate is 4/17 (24%). Thirty-day mortality was 12% (2/17); both deaths occurred in the first cohort in pts who had not received the drug combination, and were related to disease progression. Of the 5 pts enrolled in cohort 1, none responded, and all ultimately died of disease progression. However, among those in cohorts 2–4, 9 of 12 (75%) evaluable pts are alive with an ORR of 67% (CR+CRi= 4/12 [33%]), a median of 104 days after initiation of treatment (42-275). No responder has relapsed to date. Of the 3 post-cohort 1 deaths, 1 was from disease progression and 2 were from infectious complications. Conclusion:The sequential combination of AZA and LEN was well tolerated in elderly, untreated AML pts. The MTD was not reached at the highest dosing cohort, and the Phase II dose and schedule is AZA 75 mg/m2 d 1–7 and LEN 50 mg d 8–28, on a 6-week cycle schedule. The preliminary ORR of 47% is encouraging, as is the 67% ORR in pts who received ≥10 mg of LEN. Six month follow up will be presented. This trial was registered at ClinicalTrials.gov as NCT00890929. Disclosures:Off Label Use: Azacitidine and lenalidomide for AML. Liedtke:Celgene: Lecture Fee, Research Funding.

Preliminary Results of a Phase II Study of Low Dose Decitabine as a Single Agent in Older Patients (age≥60) with Previously Untreated Acute Myeloid Leukemia (AML)

The hypomethylating agent decitabine inhibits DNA methyltransferase (DNMT) enzymatic activity and is approved by the FDA for treatment of myelodysplastic syndromes. We previously performed a phase I trial in AML of decitabine (with or without the histone deacetylase inhibitor valproic acid); the trial was designed to establish a biologically effective dose (BED) of decitabine based on drug-induced re-expression of methylated and silenced genes. With the derived BED of 20mg/m2/day given for 10 days, every 4 weeks, clinical activity was observed in previously untreated older AML patients (pts, CR in 4/12); clinical response correlated with gene re-expression (Blum, JCO 2007). The addition of tolerable doses of valproic acid did not appear to improve clinical results or increase gene re-expression compared to decitabine alone. Therefore, we designed a phase II study of single agent decitabine for previously untreated AML pts of age≥60 who were not candidates for intensive chemotherapy (or who refused it). Performance status was ECOG <3. All pts received induction with decitabine at 20mg/m2 IV over 1 hour on days 1–10 of a 28 day cycle. The schedule for subsequent cycles was customized for each patient based on clinical response and/or toxicity (e.g., myelosuppression). Pts with persistent AML at the end of a cycle received a repeat of the 10 day treatment. In contrast, pts with <5% blasts received decitabine as consolidation for only 5 days/cycle (every 4 weeks for 1 year). For CR/CRi patients, the decitabine schedule could be reduced further to 4 or 3 days/cycle for Grade 4 neutropenia lasting more than 2 weeks, if applicable. 33 pts were enrolled; accrual was completed in 13 months. Pts had a median age of 74 years (range, 60–83); 24 pts were age≥70. 18 pts had de novo AML; 15 had secondary or t-AML. Pts had a median presenting white blood cell count of 2,400/uL (range, 400–58,800/uL) with median marrow blasts of 44% (range, 21–92%). 13 pts had complex karyotype (≥3 abnormalities); 12 had normal karyotype; one patient had t(8;21), and the rest had other abnormalities (with one unknown). This was a high risk group by any comorbidity measure. Scoring was as follows on four high-risk factors of age ≥70, antecedent hematologic disorder, unfavorable karyotype, and ECOG 2: 16 pts had 3+ risk factors; 15 had two, and the other 2 pts had one risk factor. Using the transplant comorbidity index for older AML pts (HCT-CI; Giles, BJH 2007), pts had scores of 3+ (N=18), 1–2 (N=10), or 0 (N=5). The median number of cycles received to date is 3 (range, 1–10); 17 pts continue to receive study therapy. 10 pts have received 4+ cycles. Of the first 22 consecutive pts enrolled, 11 achieved CR (50%); 4 more have achieved CRi by IWG criteria for response (Cheson, JCO 2003). 11 pts are <3 months since entry onto the study, with response evaluations ongoing. The response rate was similar between cytogenetic risk subgroups and in both de novo and secondary AML. 4 pts who achieved CR subsequently relapsed, with CR duration of 9, 6, 6, or 2 months, respectively. The other CR pts have maintained ongoing responses for 2–11+ months. 9/11 pts who achieved CR required only 1 cycle of induction therapy (10 day course) before initial response was achieved (CR, N=2; CRi, N=7). For pts who had CRi as initial response, the median number of additional cycles to achievement of full CR was 1 (range, 1–3). In this high risk group, death within 8 weeks of any cause occurred in 4 pts and was related to infection in each case. Though therapy was often administered in the outpatient clinic, febrile neutropenia and infections in the setting of drug and/or disease-related myelosuppression requiring hospitalization during the induction courses were frequent, occurring in nearly all pts. Post-CR therapy, however, was very well tolerated with no hospitalizations for complications during consolidation courses. In conclusion, decitabine in this novel schedule of induction with outcome-adapted modification of consolidation therapy was highly active and well tolerated by most in this poor risk cohort of older AML pts. Clinical results compare favorably to those seen in this population with low dose clofarabine (Erba, ASCO 2008a) or decitabine-5 day schedule (Cashen, ASH 2006a). Correlative studies including re-expression of epigenetically silenced genes, target gene promoter methylation, and global DNA methylation are ongoing.

An Analysis of Treatment Choices for Acute Myeloid Leukemia in Patients 60 Years and Older from the University of Duesseldorf AML/MDS Database.

Treatment choices for elderly patients (pts) with acute myeloid leukemia (AML) were assessed through a retrospective analysis of 705 pts aged ≥ 60 years (yrs), diagnosed between January 1986 and December 2005. The treatments administered to pts were grouped into three categories: best supportive care (BSC), combination induction chemotherapies including high dose ara-C (HDT), and low-intensity single-agent therapies (LDT; approx. 50% were low-dose ara-C, others included valproic acid, thalidomide, lenalidomide, decitabine, 5-azacytadine, gemcitabine and etoposide). The reviewed AML population consisted of 57% of pts aged 60–69 yrs, 17% 70–74 yrs and 26% ≥75 yrs; median age at baseline was 70 yrs. Overall, 41% of pts had antecedent MDS, and 75% had a bone marrow (BM) blast count of 20–30% at baseline. Of the 705 pts 56.5% who received BSC, 33.2% were treated with HDT and 10.4% with LDT. Age was shown to strongly influence the choice of treatment. The use of HDT dropped significantly from 57.6% for pts <65 yrs old to 24.2% for patient 70 to 74 yrs. At ≥75 yrs, 89.2% of the pts received BSC, only 4.3% received HDT, and 6.5% received LDT. Antecedent MDS was another important factor influencing treatment choices. In the age group 60 to 69 yrs, HDT treatments dropped from 67.1% in pts with no prior history of MDS to 28.9% in pts with a history of MDS. For pts ≥70 yrs, there was a clear drop in administration of HDT from 21.8% to 2.1% respectively. A third factor impacting on treatment choice was BM blast percentage. The majority of pts with a baseline BM blast count of over 30% were treated with HDT regardless of age, but the proportion decreased from 86.4% in pts <70 yrs of age to 54.2% in the age group ≥70 yrs, with a corresponding increase in BSC treatment. In contrast, 84.2% of pts 70 yrs and older with a blast count of 20–30% were treated with BSC. An unfavorable karyotype is also considered to be an adverse prognostic variable. However, karyotype exhibited an influence on treatment choice only in the group of pts 70 yrs and older, where 41.3% of pts with not unfavourable karyotype vs 19.6% with unfavourable karyotype received intensive chemotherapy. The median overall survival based upon treatment type, age or prior MDS shows that pts receiving either HDT(<70 yrs 9.93 month (mth); ≥70 yrs 7.9 mth; prior MDS 5.54 mth) or LDT (<70 yrs 10.62 mth; ≥70 yrs 6.39 mth; prior MDS 6.1 mth) survived significantly longer than those treated with BSC only (<70 yrs 4.03 mth; ≥70 yrs 2.56 mth; prior MDS 1.21 mth). Interestingly the analysis showed not much difference in median overall survival for pts treated with HDT (9.67 mth) vs LDT (9.54 mth). However, the number of pts for LDT is too small to make statistically relevant conclusions. One reason for the extremely poor outcome in pts treated with BSC might be a worse performance status compared with pts treated with chemotherapies. In summary, treatment choices are affected by age, BM blast count and a history of prior MDS. In the future, according to newer data from several groups, karyotype will presumably gain more importance for the selection of treatment. The analysis indicated that BSC was a major treatment option for elderly AML pts. However results show very poor overall survival for untreated AML pts, justifying the use of new agents to improve outcome in this subgroup.

Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age &gt;18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.

Circulating Endothelial Cells Are an Indicator of Response to Treatment in Acute Myeloid Leukemia Patients.

Introduction. The circulating endothelial cells (CEC) are proposed to be a noninvasive marker of angiogenesis. The number of CEC in peripheral blood of patients (pts) with acute myeloid leukemia (AML) has not been investigated so far.Patients and Methods. We evaluated the count of resting (rCEC) and activated (aCEC) CEC and circulating endothelial progenitor cells (CEPC) as well as apoptotic CEC (CECAnnV+) in 62 AML pts at the time of diagnosis and 30 healthy controls. Additionally in 26 pts measurements were performed at the time of response evaluation and in 15 pts also 24 h after the first and last dose of chemotherapy. The levels of CEC were correlated with known prognostic factors and response to treatment. CEC were evaluated by the four colour flow cytometry using a panel of previously described monoclonal antibodies and an appropriate analysis gate. CEPC were defined as negative for hematopoietic marker CD45 and positive for endothelial cells markers CD34, CD31 and the endothelial progenitor marker CD133. Resting CEC were defined as CD45−, CD133−, CD31+, CD34+, CD146+ and negative for activation markers (CD105, CD106). CD105 or CD106 positive mature endothelial cells were classified as activated CEC. Apoptotic CEC were CD146 and Annexin V positive.Results. In untreated AML pts we observed 10-fold higher CEC level (median 29,3/μL) than in the control group (2,95/μL) p<0,0001. The numbers of aCEC (12,7/μL), rCEC (12,3/μL) and CEPC (1,7/μL) were significantly higher in AML pts at diagnosis when compared to healthy controls (aCEC 0,9/μL, rCEC 1,6/μL and 0,1/μL; p<0,0001). CECAnnV+ count was also 10-fold higher in AML (1,5/μL) than in controls (0,15/μL; p<0,0001). Both CEC and CECAnnV+ counts did not correlate with WBC, hemoglobin and platelets count as well as percentage of blasts in bone marrow and absolute blast count. The positive correlations between CEC number and CEPC count (r=0,435; p<0,001), CECAnnV+ count (r=0,502; p<0,01) as well as LDH activity (r=0,328; p<0,02) were found. The significant decrease of aCEC and rCEC numbers 24 hours after the first dose of chemotherapy was noted in patients who achieved complete remission (CR)(p<0,04) but not in pts refractory to treatment. Moreover aCEC, rCEC, CEPC and CECAnnV+ counts determined at the time of response's evaluation were significantly lower then at the time of diagnosis in pts who achieved CR (p<0,01) and did not differ in refractory AML. There was no difference between levels of both viable and apoptotic CEC in AML pts in CR and in the control group (p>0,05).Conclusions. The CEC and CECAnnV+ levels are significantly higher in AML patients than in healthy subjects and correlate with response to treatment. Further investigation should be undertaken to better determine their prognostic and therapeutic value.