Risk Of Acute Myelogenous Leukemia Research Articles

Myelodysplastic Syndrome and Acute Myeloid Leukemia Incidence Following Primary Breast Cancer Treatment.

Abstract Background: Breast cancer (BC) patients receiving surgery plus radiation and/or adjuvant chemotherapy treatment are routinely monitored for incidence of myelodysplasia (MDS) and leukemia.Methods: A cohort of all breast cancer patients TNM stage 0-III treated with surgery and/or radiation or chemotherapy from 1989 to 2005 at our institution were followed for incidence of blood disorders of any type by our registry system and by linkage to the Surveillance, Epidemiology and End Results registry (SEER) for our area. Cases without surgery (n=111), with stem cell transplantation (n=98), unknown or non-standard chemotherapy regimens (n=23 + 71= 94), lost to follow up (n=66) or cancer status unknown at follow up (n=67) were excluded. The remaining 5790 cases were reviewed for incidence of leukemia including MDS and acute myelogenous leukemia (AML) post breast cancer treatment by chart review including pathology reports, SEER coding for MDS/AML, and death certificates if appropriate. Mean length of follow up was 7.17 years, range 2-18 years.Results: The mean age of MDS/AML patients was 57 years, range 33-76 years. The crude rate of MDS/AML occurrence was .29% (17/5790). 17 cases of MDS/AML (10 MDS/7 AML) occurred during the follow up period as compared with 6.22 (4.03 MDS/2.19 AML) expected on the basis of rates in the general population by age <65, ≥ 65 years calculated from SEER registry data (risk ratio (observed/expected)). The risk of MDS in women <65 was 11.68 times that expected and the risk of AML in women <65 was 9.2 times the expected rate. Risk among women over 65 was not as large (1.38 MDS, ≥ 65, 1.21 AML, ≥ 65). Average time from treatment with radiation or chemotherapy to MDS diagnosis was 5.50 years (range 1.03-12.95) and 3.42 years (range .41-6.84) for AML. The majority of MDS/AML cases occurred in the first five years post treatment (n=10) with 7 more cases observed from 5 to 12.95 years (see figure). Initial treatment of MDS/AML patients was surgery only (n=2), surgery/chemotherapy (n=1), surgery/ radiation (n=7), and surgery/chemotherapy/radiation (n=7). The two MDS patients who had initial treatment of surgery only were subsequently treated with chemotherapy and radiation for recurrence. Fifty percent of MDS patients (5/10) received surgery and radiation treatment without adjuvant chemotherapy treatment.Discussion: The incidence of MDS/AML is very small in this cohort but significantly greater than that expected in the population at large especially among women less than 65 years of age. A significant number of women who received radiation treatment without chemotherapy developed MDS post breast cancer treatment. Average time from treatment to MDS diagnosis exceeded the 2-5 year time period previously reported as an expected interval. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2082.

Phase II Study of Vorinostat in Combination with Idarubicin (Ida) and Cytarabine (ara-C) as Front Line Therapy in Acute Myelogenous Leukemia (AML) or Higher Risk Myelodysplastic Syndrome (MDS).

Abstract 1055Poster Board I-77The combination of the histone deacetylase inhibitor vorinostat with Ida and ara-C has synergistic antileukemia activity in a sequence dependent fashion (Blood 2006;108:1174-82; CCR 2009;15:1698-707). The combination of high-dose vorinostat and Ida is safe and active in patients (pts) with relapsed/refractory AML (Kadia et al, submitted). Based on this, we designed a phase II study of vorinostat followed by Ida and ara-C in pts with AML or MDS. Eligibility criteria included previously untreated AML (excluding pts with APL), or int-2 or high risk MDS, age > 65 years, and adequate renal, hepatic and cardiac functions as well as performance status. Schedule for induction therapy is vorinostat 500 mg orally (po) three times a day (TID) for 3 days (days 1 to 3), Ida 12 mg/m2 IV daily x 3 (days 4 to 6) and ara-C (1.5 gm/m2 as a continuous (CI) 24 hours infusion on days 4 to 7). Five cycles of consolidation therapy are planned with same dases of vorinostat (days 1 to 3) but decreased doses of Ida (8 mg/m2 days 4 and 5) and ara-C (0.75 gm/m2 CI x 24 hours on days 4 to 6). Maintenance therapy consists of vorinostat 200 mg po TID daily x 14 days every 28 days for 12 cycles. The study is designed to stop early based on a composite endpoint and predefined stopping rules of progression free survival (PFS) (the study is to stop if a PFS of at least 7 months is not expected to be achieved), toxicity and response rates compared to standard Ida and Ara-C (IA) combination at MD Anderson. Planned interim analyses are performed every 6 months by an independent statistician to monitor the above endpoints. To test the safety of the combination, this study included a “reversed” phase 1 run-in phase starting at the maximal dose of vorinostat planned (500 mg po qd tid x 3 days). Three patients were treated at this dose with no excess toxicity and 3 of 3 pts achieved a response. After this, the phase II portion of the study started. A maximum of 75 pts are to be treated if no stopping rule is met. Currently 52 pts have been enrolled and 45, all with AML, are evaluable for response (median age 53 yeas (range 19-65), 21 (46%) female, 9 (20%) with Flt-3 mutations, 30 (66%) with abnormal cytogenetics, 24 (53%) with t-AML or antecendent MDS, median WBC was 5.5 (range 0.9-110.6). In total 43 (95%) pts had poor risk AML as defined by poor CG or Flt-3 or t-AML/MDS. Induction mortality was 2 (4%), Complete remission (CR) after was one course of therapy was achieved in 35 pts and 1 pt achieved a CRP (incomplete platelet recovery) for an overall response rate of 80%. Seven (15%) pts did not respond to therapy. CR by molecular characteristics are: diploid 13 of 15 (86%), Flt-3 9 of 9 (100%), abnormal CG (20 of 30, 66%). No excess toxicity with the addition of vorinostat has been observed compared to standard IA. Common complications were related to myelosuppresion typical of IA. No excess nausea or vomiting or diarrhea was observed. With a median follow up of 4.2 months (range 0.7 – 13 months), median OS has not been reached and median DFS was 9.5 months. The study continues to be open after two interim analysis, as the PFS is higher than 7 months (expected from standard IA). The median number of courses of consolidation therapy is 2+ (range 0-5) and 4 pts are receiving maintenance therapy without excess toxicity. Markers of induction of autophagy (LC3-II), ROS activiation and NF-Kb signaling are upregulated in pts receiving this therapy. This study indicates that the combination of vorinostat, Ida and ara-C is safe and active in AML. The role of vorinostat in Flt-3 postive leukemias needs to be further studied. A randomized study of Ida and ara-C with or without vorinostat needs to be performed to establish the role of vorinostat in front-line AML therapy. At the current accrual rate, this study will be completed by the ASH meeting. Disclosures:Garcia-Manero:Merck: Research Funding. Off Label Use: Vorinostat is not approved for use in AML or MDS.

Epigenetic Priming with Decitabine Prior to Standard Induction Chemotherapy in Less-Than-Favorable Risk Acute Myelogenous Leukemia (AML).

Abstract 3079Poster Board III-16Epigenetic silencing of tumor suppressor genes (TSGs) is among the most common acquired abnormalities observed in AML and is prototypically linked to DNA methylation. Aberrant DNA methylation is most prevalent in adverse risk AML patients (Melki, Vincent et al. 1999; Toyota, Kopecky et al. 2001). Reactivated expression of TSGs is commonly implicated in the clinical activity of DNA hypomethylating agents since these genes often have roles in cellular differentiation, apoptosis, DNA repair, and checkpoint control (Jones and Taylor 1980; Pinto, Zagonel et al. 1989; Petti, Mandelli et al. 1993; Schimmer, Pedersen et al. 2003; Schmelz, Sattler et al. 2005; Schmelz, Wagner et al. 2005; Tamm, Wagner et al. 2005). We, and others, have demonstrated that DNA hypomethylating agents can sensitize resistant cancer cells to cytotoxic agents in vitro (Avramis, Mecum et al. 1989; Anzai, Frost et al. 1992; Plumb, Strathdee et al. 2000; Fulda, Kufer et al. 2001; Niitsu, Hayashi et al. 2001; Arnold, Goel et al. 2003; Eramo, Pallini et al. 2005; Kanda, Tada et al. 2005; Qiu, Mirkin et al. 2005) yet this approach has been sparsely studied in clinical trials. We hypothesized that pre-treatment with a hypomethylating agent would increase the efficacy of standard induction chemotherapy for AML. DesignWe conducted a phase I dose-escalation study of decitabine administered just prior to a single, standard induction with infusional cytarabine (100 mg/m2 for 7 days) and daunorubicin (60 mg/m2 × 3 doses) as initial treatment for patients with less-than favorable risk AML. Three dose levels of decitabine (20 mg/m2 for 3, 5 or 7 days), delivered either as a bolus (Arm A) or by continuous infusion (Arm B), were used as priming for standard induction chemotherapy. PatientsAt current data cut-off, 25 (of 30 patients planned) were fully evaluable: median age was 56 (range 23–60); 21 (84%) patients had adverse risk AML because of karyotype (No. 15, 60%), or other adverse features (FLT3-ITD or antecedent hematologic disorder, No. 11, 44%), and the remaining 4 (16%) patients had intermediate risk AML. Toxicity was similar to that of standard induction chemotherapy alone. Two patients treated at the highest dose level had grade 3 mucositis that resolved prior to count recovery. We observed no excess hematologic toxicity and all patients had peripheral blood count recovery within 30 days or were found to have persistent AML. There was no induction mortality and no patients required ICU transfer. A maximum tolerated dose was not achieved. ResponseTwenty-one patients (84%) responded to therapy: 14 CR (56%), 7 PR (28%). Of the patients with PR to protocol treatment, 5 achieved remission with a second, standard induction bringing the overall CR rate to 76%. The final cohort of patients is currently accruing. All patients went on to receive additional AML therapy and 14 have received an allogeneic HSCT. Pharmacodynamic analyses of DNA hypomethylation prior to and immediately following priming demonstrate genome-wide DNA hypomethylation at all dose levels. Detailed analyses of DNA methylation are ongoing. ConclusionComplete remission is requisite for the cure of AML and this study demonstrates that it is safe to combine the epigenetic modifier, decitabine, with full-dose, standard, cytotoxic chemotherapy as an approach to improve remission rates. Our results suggest that epigenetic priming is potentially superior to standard induction therapy alone as initial therapy for patients with less than favorable risk AML and provide the foundation for a subsequent phase II study. DisclosuresOff Label Use: Phase I study of decitibine use in AML.

Successful Prevention of Acute Graft-versus-Host Disease Using Low-Dose Antithymocyte Globulin after Mismatched, Unrelated, Hematopoietic Stem Cell Transplantation for Acute Myelogenous Leukemia

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Allogeneic Stem Cell Transplantation (Allo-SCT) in Adults with Acute Myelogenous Leukemia (AML). Final Analysis of JALSG AML97 Study

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is considered to be the most intensive post remission treatment consisting of high-dose chemoradiotherapy and allo-immune mechanisms. However, the powerful anti-leukemic effects of this treatment are counterbalanced by a high incidence of treatment-related mortality (TRM), thus allo- SCT has not always been considered superior to chemotherapy. The aim of this study was to investigate the efficacy of allo-SCT as a postremission treatment in patients with intermediate/poor risk AML in first CR. Previously untreated patients aged 15 – 50 years were eligible. Patients received standard induction therapy consisting of cytarabine (100 mg/ m2 d1–7) and idarubicin (12 mg/m2 d1- 3). If the patients did not achieve remission after the first induction therapy, then the same induction therapy was given again. The patients who achieved CR were randomized into an intensified short-course postremission chemotherapy group (arm A) or conventional JALSG postremission chemotherapy group (arm B). Patients were also categorized into good, intermediate or poor risk groups by risk factors selected from previous JALSG AML trials using univariate and multivariate analyses. Intermediate or poor risk patients with living siblings were tissue typed. If an HLA matched sibling was found it was assumed that the patient would receive allo-SCT during CR1 (donor group). Those without living or HLA matched siblings were assigned to the no-donor group that continued receiving chemotherapy. The disease-free survival (DFS) rates, the relapse incidence rates (RI), TRM and the overall survival (OS) rates of the patients of the donor group were compared with those of the no-donor group on the basis of the intention to treat.Result: Of 503 patients aged 15 – 50 years old registered between December 1997 and July 2001, 397 achieved complete remission (CR). The 5-year OS rate of the CR patients with good, intermediate and poor risk was 68%, 43% and 29%, respectively (p<0.001), showing successful stratification by the JALSG scoring system. Among those who achieved CR with intermediate or poor risk, 75 with and 95 without an HLA matched sibling were assigned to the donor and no-donor groups, respectively. The actual risk of relapse at 8 years was significantly lower in the donor group than in the no-donor group (54% versus 78%, p=0.009). The TRM did not significantly differ between the donor group and the no-donor group (16% versus 17%, p= 0.948). The lower relapse rate in the donor group resulted in a significantly better DFS compared with the no-donor group (38% versus 18%, p=0.017). The significant superiority of DFS in the donor group was translated into a higher OS rate, however, the difference in OS between the two groups did not reach statistical significance (45% versus 28%, p=0.089). The OS of the patients younger than 35 years of age were comparable between the donor group and the no-donor group. However, the OS in the donor group patients older than 36 years old was significantly better than the other (47% versus 23%, p= 0.032).Conclusions: Our study showed that allo-SCT reduced the risk of relapse and contributed to the survival advantage of AML patients aged from 36 to 50 years old with intermediate or poor risk.

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.

Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies

Several genetic polymorphisms in the genes coding folate-metabolizing enzymes have been associated with susceptibility to hematology malignancies. We conducted a Korean population-based case–control study to examine the relationship between the polymorphisms of folate-metabolizing enzymes and the risk of AML (acute myelogenous leukemia), CML (chronic myelogenous leukemia), MDS (myelodyspastic syndrome), and ALL (acute lymphoblastc leukemia). The MTHFR 677TT genotype was associated with an increased risk for ALL (odds ratios (OR) = 1.77; 95% confidence intervals (CI) = 1.02–3.09, p = .044). The MTRR 66 AG genotype was associated with an increased risk for MDS (OR = 1.59; 1.06–2.38, p = .026) and the MTRR 66 GG genotype was associated with increased risk for AML (OR = 1.51; 1.03–2.23, p = .037). The TYMS 2R3R genotype was associated with a decreased risk for AML (OR = 0.76; 0.60–0.96, p = .022). The TYMS hap3 (2R-6bp) and hap4 (2R-0bp) were associated with decreased risk (OR = 0.69; 0.53–0.90, p = .006) and increased risk (OR = 1.65; 1.20–2.27, p = .002), respectively for AML. Hap C (677T-1298A) was associated with an increased risk (OR = 1.40; 1.02–1.92, p = .04) for ALL. The risk for ALL appears to be associated with the MTHFR 677 polymorphism. The results are supportive of a risk modification by folate polymorphisms in several hematologic malignancies in Korea. The pattern of results suggests that MDS was associated with the DNA methylation status and the risk for AML was associated with both the DNA synthesis and DNA methylation status.

A Phase II study of VNP40101M in elderly patients (pts) with de novo poor risk acute myelogenous leukemia (AML)

7026 Background: VNP40101M is a novel alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links and has previously shown anti-leukemic activity in clinical trials. Methods: A confirmatory Phase II study of single agent VNP40101M was conducted in elderly pts with poor risk de novo AML. Pts received induction therapy with 600 mg/m2 VNP40101M as a single 60-minute infusion on day 1. A 2nd induction cycle could be administered to pts with a PR or hematologic improvement. Pts with CR or CRp were able to receive consolidation with araC 400mg/m2/day CIV for 5 days. Pts were eligible if they were ≥ 60 yrs and had 1 poor risk factor: age ≥ 70, ECOG PS= 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Pts with a prior diagnosis of MDS or favorable cytogenetics were excluded. Results: Enrollment was completed August 14, 2007. 85 pts were treated: median age (range): 73 (61–87); male: 59%. The majority of pts (89%) had 2 or more risk factors. The most common risk factors were age ≥ 70 (76%), pulmonary dysfunction (58%), cardiac dysfunction (48%) and unfavorable cytogenetics (48%). The response rate was 35% overall (23 CR + 7 CRp); 27% in pts with unfavorable cytogenetics, 34% in pts age ≥ 70 and 37% in pts with PS= 2. 27 responders (90%) achieved remission after 1 induction cycle. 18 responders (60%) received araC consolidation per protocol. 32 VNP40101M-related serious adverse events (SAEs) have been reported in 28 of 85 pts. The most common SAEs were related to myelosuppression or infection. Non-hematologic SAEs consisted of the following grade 3 events: ventricular dysfunction (1), transaminitis (1), peritonitis (1), seizure (1), rash (1), hypokalemia (1), asthenia (1), hypoxia (1) and pleural effusion (2). 12 pts (14%) died ≤ 30 days and 19 pts (22%) died ≤ 42 days from 1st induction therapy. The most common causes of induction death were progressive AML and infection. Health resource utilization data will be presented. Conclusions: This Phase II single-agent study of VNP40101M confirms anti-leukemic activity in elderly pts with de novo AML despite additional poor risk factors such as unfavorable cytogenetics. Severe and/or serious drug-related non-hematological toxicity is uncommon. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Vion Pharmaceuticals, Inc Vion Pharmaceuticals, Inc Vion Pharmaceuticals, Inc

Association Study of hMLH1 Polymorphisms with Risk of Acute Myeloid Leukemia in Korean

Acute myelogenous leukemia (AML) is caused by dysregulation of oncogenes, tumor suppressor genes, and DNA mismatch repair genes. Accumulating evidence has shown that genetic differences in mismatch repair capacity resulting from genetic polymorphism influence the risk of environmental carcinogenesis. In AML and lymphoma, the promoter of hMLH1 is frequently hypermethylated. The purpose of this study is to investigate the association of hMLH1 gene polymorphisms with the susceptability to AML in Korean people. Allelic frequency of rs9311149, rs1800734, rs3774343, rs4647215, rs3774341, rs3774335, rs748766, D376D, V384D SNPs of hMLH1 was determined in 32 normal subjects by sequencing analysis. Haplotype frequency and linkage disequilibrium coefficiency of nine SNPs were estimated. The author selected and genotyped six SNPS for full-scale association study, they include one tagging SNP from neighboring six SNPs and five SNPs including two novel SNPs. One hundred and sixty eight AML cases and 255 unrelated healthy controls were used for the study. V384D was associated with increased risk of AML both in genotypes (OR=2.335; 95% CI: 1.056∼5.165, p=0.032) and in allele frequency (OR=2.417; 95% CI: 1.118∼5.228, p=0.021). Other SNPs except V384D were not associated with AML. The allele frequency of the SNPs between Asians, European descendants, and Africans was very significantly different (p 0.05), while that between Korean and Chinese, and that between Japanese and Chinese were significantly different (p< 0.05). The data suggests that V384D polymorphism of hMLH1 might be associated with AML.

Phase II Study of VNP40101M (Cloretazine®) in Elderly Patients with De Novo Poor Risk Acute Myelogenous Leukemia (AML).

VNP40101M (Cloretazine®) is a novel sulfonylhydrazine alkylating agent which preferentially targets the O6 position of guanine resulting in DNA cross-links. Data from a previously reported phase II multi-center single agent study (CLI-033) in patients ≥60 years old with newly diagnosed AML or high risk MDS showed an overall response rate of 31% after VNP40101M induction (Giles, 2007). Subgroup analysis showed significant activity in 54 elderly patients with de novo AML with 24 patients (45%) achieving a complete response (CR) or CRp (CI: 30.9;58.6). Subsequently a confirmatory phase II study of single agent VNP40101M was conducted in elderly patients with poor risk de novo AML (CLI-043). Patients received induction therapy with 600 mg/m2 VNP40101M as a 60-minute infusion on day 1. A second induction cycle could be administered to patients with a partial response or hematologic improvement. Patients with CR or CRp received consolidation with cytarabine 400mg/m2/day CIV for 5 days. Patients were eligible if they were ≥60 yrs and had one of the following poor risk factors: age ≥70 yrs, ECOG PS 2, unfavorable cytogenetics, or cardiac, pulmonary or hepatic dysfunction. Patients with a prior diagnosis of MDS or favorable cytogenetics were excluded. A 2-stage optimal minimax design was employed with a target response rate of 35%. The study proceeded to the 2nd stage when >8 responses were confirmed. At least 22 responses in 77 patients are required to accept the hypothesis of a 35% target response rate. Eighty-five patients were treated as of August 14, 2007. Median age (range): 73 yrs (61– 86 y); male: 59%. The majority of patients (79%) had 2 or more risk factors. The most common risk factors were age ≥70 (78%), unfavorable cytogenetics (45%, half with complex karyotype), ECOG PS 2 (41%) and cardiac dysfunction (38%). Thirty VNP40101M-related serious adverse events (SAE) have been reported to date in 22 of 85 patients. The most common SAEs are myelosuppression or complications thereof (pancytopenia (10%), infection (47%)). Non-hematologic SAEs consist of the following gr.3 events: left ventricular dysfunction (1), transaminitis (1), confusion (1), seizure (1), rash (1), hypokalemia (1), weakness (1) and hypoxia/pleural effusion (2). Seventy-nine patients are currently evaluable for early death analysis. Of these, 12 patients (15%) and 16 patients (20%) died at ≤30 days and ≤42 days from first induction therapy, respectively. The most common causes of induction death were progression of disease (6) and infection (6). Other causes were tumor lysis syndrome (1), acute renal failure (1), and respiratory failure (2). A confirmatory Phase II single-agent study of VNP40101M shows anti-leukemia activity in elderly patients with de novo AML and multiple poor-risk features. Major toxicities include myelosuppression. Severe drug-related non-hematological toxicity is uncommon. Patients continue in follow up, and additional safety and response data is pending.

Therapy Related Acute Myelogenous Leukemia and Myelodysplastic Syndrome in Patients with Acute Lymphoblastic Leukemia Treated with the Hyper-CVAD Regimen.

Secondary malignancies including myeloid neoplasms occur infrequently in patients with acute lymphoblastic leukemia (ALL). This has been well documented in the pediatric population but not for the adult patients. We have reviewed retrospectively 641 patients with de novo ALL, treated with the hyper-CVAD regimen or its variants, at M D Anderson Cancer Center from 1992 to 2007. Fourteen patients (2.18%, 7 female, 7 male) developed secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Six patients had AML and 8 MDS. Median age at the time of ALL diagnosis was 52 years (range, 23 – 66). Cytogenetics at ALL diagnosis was diploid in 10, pseudo-diploid with −2 in 1, t(9;22) in 1, and unavailable in 2 patients. Frontline therapy included hyper-CVAD in 7, hyper-CVAD with rituximab in 6, and hyper-CVAD with imatinib in 1 patient. Karyotype at the time of AML/MDS diagnosis was −5, −7 in 8 patients, diploid in 1, miscellaneous in 1, inv(11) in 1, t(4;11) in 1, and unavailable in 2. Secondary AML/MDS developed at a median of 31 months (range, 11 – 74) after the start of ALL therapy. Treatment for the secondary AML and MDS was varied and included cytarabine plus anthracycline based regimens for AML and high risk MDS. One patient with MDS received arsenic trioxide, 1 clofarabine, and 1 decitabine. The response rate to treatment for AML/MDS was complete remission (CR) in 2, partial remission in 6 and no response in 6 patients. Five patients (all MDS) underwent an allogeneic stem cell transplant and all but one died at a median of 3 months (range, 0.5 – 11) after the transplant. One patient is alive and in CR 14 months after a haplo-identical sibling transplant; 2 other patients are alive 3.5 and 4 months after the diagnosis of MDS. The median overall survival after the diagnosis of secondary AML and MDS is 8.3 months (range 3.5+ to 18.5+). We conclude that secondary AML and MDS occur infrequently (2.18%) in adult patients with de novo ALL treated with the hyper-CVAD regimens and response to their subsequent therapy is poor.

Increased risk of acute myelogenous leukemia and multiple myeloma in a historical cohort of upstream petroleum workers exposed to crude oil

Benzene exposure has been shown to be related to acute myelogenous leukemia, while the association with multiple myeloma and non-Hodgkin lymphoma has been a much-debated issue. We performed a historical cohort study to investigate whether workers employed in Norway's upstream petroleum industry exposed to crude oil and other products containing benzene have an increased risk of developing various subtypes of hematologic neoplasms. Using the Norwegian Registry of Employers and Employees we included all 27,919 offshore workers registered from 1981 to 2003 and 366,114 referents from the general working population matched by gender, age, and community of residence. The cohort was linked to the Cancer Registry of Norway. Workers in the job category "upstream operator offshore", having the most extensive contact with crude oil, had an excess risk of hematologic neoplasms (blood and bone marrow) (rate ratio (RR) 1.90, 95% confidence interval (95% CI): 1.19-3.02). This was ascribed to an increased risk of acute myelogenous leukemia (RR 2.89, 95% CI: 1.25-6.67) and multiple myeloma (RR 2.49, 95% CI: 1.21-5.13). There were no statistical differences between the groups in respect to non-Hodgkin lymphoma. The results suggest that benzene exposure, which most probably caused the increased risk of acute myelogenous leukemia, also resulted in an increased risk of multiple myeloma.

Tobacco Use, Body Mass Index, and the Risk of Leukemia and Multiple Myeloma: A Nationwide Cohort Study in Sweden

In a prospective cohort study of more than 330,000 Swedish construction workers, we explored the effect of tobacco smoking, oral moist snuff use, and body mass index (BMI) on the risk of developing leukemia (excluding chronic lymphocytic leukemia) and multiple myeloma (MM). Study subjects were participants of a health surveillance system within the building industry. Record linkage to the nationwide Swedish cancer registry, migration registry, and cause of death registry made a comprehensive follow-up available. A total of 372 incident cases of leukemia and 520 subjects with MM was ascertained. An increase in risk of acute myelogenous leukemia (AML) was observed in current smokers (incidence rate ratio, 1.50; 95% confidence interval, 1.06-2.11). Furthermore, there was an indication of a possible association between smoking intensity and risk of acute lymphocytic leukemia. Results on snuff use as well as BMI showed no association. This study confirms the role of smoking as a risk factor for AML and gives no support to the hypothesis of a role of snuff use or BMI level on the risk of leukemia or MM.

Changes in DNA Methylation Patterns in Subjects Exposed to Low-Dose Benzene

Aberrant DNA methylation patterns, including global hypomethylation, gene-specific hypermethylation/hypomethylation, and loss of imprinting (LOI), are common in acute myelogenous leukemia (AML) and other cancer tissues. We investigated for the first time whether such epigenetic changes are induced in healthy subjects by low-level exposure to benzene, a widespread pollutant associated with AML risk. Blood DNA samples and exposure data were obtained from subjects with different levels of benzene exposure, including 78 gas station attendants, 77 traffic police officers, and 58 unexposed referents in Milan, Italy (personal airborne benzene range, < 6-478 microg/m(3)). Bisulfite-PCR pyrosequencing was used to quantitate DNA methylation in long interspersed nuclear element-1 (LINE-1) and AluI repetitive elements as a surrogate of genome-wide methylation and examine gene-specific methylation of MAGE-1 and p15. Allele-specific pyrosequencing of the H19 gene was used to detect LOI in 96 subjects heterozygous for the H19 imprinting center G/A single-nucleotide polymorphism. Airborne benzene was associated with a significant reduction in LINE-1 (-2.33% for a 10-fold increase in airborne benzene levels; P = 0.009) and AluI (-1.00%; P = 0.027) methylation. Hypermethylation in p15 (+0.35%; P = 0.018) and hypomethylation in MAGE-1 (-0.49%; P = 0.049) were associated with increasing airborne benzene levels. LOI was found only in exposed subjects (4 of 73, 5.5%) and not in referents (0 of 23, 0.0%). However, LOI was not significantly associated with airborne benzene (P > 0.20). This is the first human study to link altered DNA methylation, reproducing the aberrant epigenetic patterns found in malignant cells, to low-level carcinogen exposure.

359: Outcome of matched sibling donor hematopoietic stem cell transplantation for standard risk pediatric acute myelogenous leukemia in first complete remission

In recent years there has been a significant improvement in the outcome of children with standard risk acute myelogenous leukemia (AML) treated with chemotherapy only. In the MRC-UK trials 10 and 12, standard risk AML children were allowed to proceed to hematopoietic stem cell transplantation (HSCT) if there is a full matched family donor. However, with the excellent results of chemotherapy and the known risks and long term effects of HSCT, this decision remains controversial. Herein, our objective was to review the outcome of all children between 1995-2005 with standard risk AML who received a matched sibling donor (MSD) in CR1 in our institution and compare their outcome with the published MRC-UK results.

MTHFR 677CC/1298CC genotypes are highly associated with chronic myelogenous leukemia: A case-control study in Korea

Methylenetetrahydrofolate reductase (MTHFR) is an enzyme involved in folate metabolism and DNA methylation. Studies on MTHFR polymorphism in leukemia have largely focused on the protective role of MTHFR polymorphism in acute lymphoblastic leukemia (ALL). We evaluated the C677T and A1298C polymorphisms using the TaqMan ® allelic discrimination assay in various malignancies. The study population included 115 subjects with chronic myelogenous leukemia (CML), 200 with acute myelogenous leukemia (AML), 196 with multiple myeloma (MM) and 434 healthy control subjects. The frequency of 1298CC was statistically significantly higher in subjects with CML than that of the controls (OR = 5.12, 95% CI: 1.75–14.9, P-value = .003). Of note, the frequencies of 677CC/1298CC genotype were statistically significantly higher in subjects with CML, AML and MM than that of the controls (OR = 8.8, 3.5, 3.83, P-value = .002, 0.036, 0.023, respectively). Our results demonstrate that the MTHFR 1298CC homozygote variant is strongly associated with an increased risk of CML, while MTHFR C677T does not significantly affect the risk of CML. Moreover, we demonstrated that MTHFR 677CC and 1298CC genotype might have combined effect on risk of CML, AML and MM and it is inferred that the A1298C may play a different role in carcinogenesis, depending on the types of organs involved, the types of disease entities and the genotype of C677T.

Treatment with Homoharringtonine and Cytarabine in Patients with High Risk Acute Myelogenous Leukemia (AML).

Objective: To evaluate response of homoharringtonine in patients with high risk AML or as a second-line therapy in patients with AML refractory to anthracycline based chemotherapy.Patients and methods: From Jan 1998-Jan 2006, there were 66 patients enrolled in this regimen. Male:female=40:26. Median age was 47 (17–69). There were 48 newly diagnosed AML, 5 relapsed AML and 13 secondary AML (secondary to MDS) in this group. Among these patients, there were 40 patients untreated previously — 20 patients had unfavourable chromasomal abmormalities, 10 patients had pgp positive, 10 patients had normal chromasome but high CD34 expression on leukemic cells. The remaining 26 patients were previously treated with daunorubincin or mitoxantrane combined with cytarabine at least two cycles and failed to achieve response. Homoharringtonine was given at dose of 4mg/m2/d(2.5mg/m2/d for age≥60 years) intraveniously for 7 days. Cytarabine was given at dose of 100mg/m2/d at same time. The therapy was repeated every 21 days.Post remission therapy was divided into two cohot —same regimen maintainance in 20 cases and cytarabine 1g/m2/d q12h for 4 days at least 4 cycles in 20 cases.Results: 40/66 patients achieved complete remission. 3/66 achieved partial remission. In patients refactory to anthracycline based regimen, the CR rate was 57.7%(15/26). In previously untreated high risk AML patients,the CR rate was 62.5%(25/40). Median disease free survival were 4.25 months (2–30) in cohot 1 and 18 months (12–47) in cohot 2 (P<0.05). CD95(APO-1/Fas) was tested by flow cytometry during treatment. APO-1/Fas (CD95) increased from (9.56±5.58)% to (25.64±0.70)% after induction chemotherapy. Main toxicities were marrow suppression and infection. There were 7 early deaths, 5 patients died of cerebral hemorrage and 2 cardiovascular events.Conclusions: Homoharringtonine is effective in patients with high risk AML. It is also a choice of second line therapy in patients refractory to anthracycline based chemotherapy. Intensive post remission therapy is superior to conventional dose maintainance therapy in high risk AML. One of the ways for homoharringtonine to induce leukemic cell apoptosis is probably through Fas pathway.

Tailored strategy for AML patients receiving allogeneic peripheral blood stem cell transplantation

Considering the heterogeneity of acute myelogenous leukemia (AML), along with the pros and cons of allogeneic peripheral blood stem cell transplantation (PBSCT), a tailored strategy is needed to minimize the transplant-related mortality and maximize the transplant outcomes in AML patients exhibiting certain factors that have an impact on the post-transplant quality of life and outcomes. The factors that need to be considered when tailoring a strategy in an allogeneic PBSCT setting include the recipient's performance status and co-morbid disease include AML risk stratification, disease status, expected severity of graft-versus-host disease, and the necessity of a graft-versus-leukemia effect. Accordingly, this review article describes a possible tailoring strategy for AML patients receiving allogeneic PBSCT based on certain factors influencing the transplant outcome.

Poor risk assessment in the elderly receiving cloretazine induction for AML or MDS

18562 Background: Elderly patients (pts) ≥60 years with acute myelogenous leukemia (AML) have lower response rates, and higher morbidity and mortality than younger pts when treated with cytotoxic induction therapy. Common disease-related factors that predict poor response in the elderly are adverse cytogenetics and secondary leukemia (following antecedent hematologic disorder or exposure to chemotherapy). Pt-related factors such as ECOG performance status (PS) and organ dysfunction affect treatment decisions due to poor tolerability and early death. Cloretazine, a novel alkylating agent has significant activity in AML and MDS with a favorable safety profile. A Phase II study of monotherapy induction was conducted in elderly pts with AML or high risk MDS (N = 105, median age 72, range 60–88), with a 31% complete response rate and minimal non-hematologic toxicity. To describe the pts in this study considered “unfit” for 7+3 induction, disease-related and pt-related information was obtained. The Hematopoietic Cell Transplantation Comorbidity Index (Sorrer et al, 2005) (HCT-CI) is a modification of the Charlson Comorbidity Index (Charlson et al.1987), for pts considered for stem cell transplant. Seventeen medical conditions are included with weighted values predicting non-relapse mortality (NRM). Methods: Baseline demographic and pt-related data was obtained from case report forms. In addition to disease-related prognostic indicators, pt-related data was scored by the HCT-CI. Pts were grouped in risk categories for NRM by HCT-CI scores (low = 0, intermediate = 1 or 2; high ≥3). Results: Either or both disease-related poor risk factors were present in 68 pts (65%): 42 pts (40%) had unfavorable cytogenetics and 45 pts (43%) had secondary AML. No pt had favorable cytogenetics. Ninety-four (89%) pts had at least one HCT-CI comorbidity. The most common were cardiac (46%), psychiatric (28%); hepatic (25%) and controlled infection (24%). By HCT-CI, the risk for NRM was low in 10%, intermediate in 32%, and high in 57% of pts. Conclusions: The majority of these elderly pts were poor-risk by disease-related criteria or comorbidities measured by the HCT-CI. This index warrants further testing for determining NRM risk of induction regimens for elderly pts with AML. [Table: see text]

Case report: hydroquinone and/or glutaraldehyde induced acute myeloid leukaemia?

BackgroundExposures to high doses of irradiation, to chemotherapy, benzene, petroleum products, paints, embalming fluids, ethylene oxide, herbicides, pesticides, and smoking have been associated with an increased risk of acute myelogenous leukemia (AML). Although there in no epidemiological evidence of relation between X-ray developer, fixer and replenisher liquids and AML, these included glutaraldehyde which has weakly associated with lymphocytic leukemia in rats and hydroquinone has been increasingly implicated in producing leukemia, causing DNA and chromosomal damage, inhibits topo-isomerase II, alter hematopoiesis and inhibit apoptosis of neoplastic cells.Case presentationTwo white females (A and B) hired in 1985 as medical radiation technologists in a primary care center, in Greece. In July 2001, woman A, 38-years-old, was diagnosed as having acute monocytic leukaemia (FAB M5). The patient did not respond to therapy and died threeweeks later. In August 2001, woman B, 35-year-old, was diagnosed with acute promyelocytic leukaemia (FAB M3). Since discharge, she is in continuous complete remission. Both women were non smokers without any medical history. Shortly after these incidents official inspectors and experts inspected workplace, examined equipment, archives of repairs, notes, interviewed and monitored employees. They concluded that shielding was inadequate for balcony's door but personal monitoring did not show any exceeding of TLV of 20 mSv yearly and cytogenetics analysis did not reveal findings considered to be characteristics of ionizing exposure. Equipment for developing photos had a long list of repairs, mainly leakages of liquids and increases of temperature. On several occasions the floor has been flooded especially during 1987–1993 and 1997–2001. Inspection confirmed a complete lack of ventilation and many spoiled medical x-ray films. Employees reported that an "osmic" level was continuously evident and frequently developed symptoms of respiratory irritation and dizziness.ConclusionThe findings support the hypothesis that the specific AML cases might have originated from exposure to chemicals, especially hydroquinone and/or glutaraldehyde. The report also emphasises the crucial role of inspection of facilities and enforcement of compliance with regulations in order to prevent similar incidents.