Search

Background: Older patients encompass about 75 % of patients with acute myeloid leukemia (AML). Today therapeutic options to prevent relapse in older patients who managed to achieve complete remission (CR) after intensive chemotherapy are scarce. Recent randomized controlled trials (RCTs) have aimed to reduce the risk of relapse by means of post-CR maintenance therapy., Methods: We performed a systematic review and meta-analysis of RCTs comparing the efficacy and safety of maintenance with hypomethylating agents (HMA) vs. observation, conventional care or placebo in older patients with AML who are not candidates for allogeneic hematopoietic transplantation (allo-HCT). We searched Cochrane Library, PubMed and conference proceedings up to August 2021., Results: Six trials were included. Treatment with hypomethylating agents significantly improved overall survival (HR 0.80, 95 % CI 0.70 to 0.91, I 2 = 30 %), and disease control (HR 0.80, 95 % CI 0.70 to 0.91, I 2 = 0). A significant decrease was seen in both one year mortality (Risk Ratio [RR] 0.61, 95 % CI 0.48 to 0.77, I 2 = 0) and mortality at the end of follow-up (RR 0.77, 95 % CI 0.67 to 0.88, I 2 = 0). The rate of relapse at 6 months and at one-two years was lower in the HMA arm vs. control (RR, 0.59; 95 % CI, 0.47-0.72; RR, 0.74, I 2 = 0; 95 % CI 0.69 - 0.91, I 2 = 41 %, respectively). HMA were associated with a statistically non-significant increase in the risk of serious adverse events (RR 3.44, 95 % CI 0.93-12.74, I 2 = 80 %)., Conclusions: Our meta-analysis shows that in older patients who are not candidates for allo-HCT, maintenance therapy with HMA improves OS and disease control without a statistically significant increase in adverse events., (Copyright © 2021. Published by Elsevier Ltd.)

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., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Technological advances have made it possible to offer home-based chemotherapy to patients without health care professionals being present. Prior studies on effects of home-based treatment lack inclusion of patients with hematologic malignancies. We present data from a multicenter single-arm feasibility and safety study of home-based intensive chemotherapy in patients with newly diagnosed acute myeloid leukemia and their quality of life and psychological wellbeing. This national study included patients from six sites in Denmark who received intensive chemotherapy on programmed CADD Solis infusion pumps through a central venous catheter and were also managed as outpatients during treatment-induced pancytopenia. Data are presented from 104 patients, receiving 272 treatments with 1.096 (mean 4.57, SD 3.0) home infusion days out of 1.644 treatment days (67 %). Sixty-two of 168 (36.9 %) reinduction and consolidation treatment cycles ensuing pancytopenia phases were solely handled in the outpatient clinic. Patients reported high satisfaction with home-based treatment, which had a positive influence on their ability to be involved in their treatment and be socially and physically active. No unexpected events occurred during the intervention. Overall, patients improved in all quality of life outcomes over time. Home-based intensive chemotherapy treatment was feasible and safe in this population. ClinicalTrials.gov identifier: NCT04904211., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Acute myeloblastic leukemia (AML) is one of the most common types of blood malignancies that results in an AML-associated high mortality rate each year. Several causes have been reported as prognostic factors for AML in children and adults, the most important of which are cytogenetic abnormalities and environmental risk factors. Following the discovery of numerous drugs for AML treatment, leukemic cells sought a way to escape from the cytotoxic effects of chemotherapy drugs, leading to treatment failure. Nowadays, comprehensive studies have looked at the role of extracellular vesicles (EVs) secreted by AML blasts and how the microenvironment of the tumor changes in favor of cancer progression and survival to discover the mechanisms of treatment failure to choose the well-advised treatment. Reports show that malignant cells secrete EVs that transmit messages to adjacent cells and the tumor's microenvironment. By secreting EVs, containing immune-inhibiting cytokines, AML cells inactivate the immune system against malignant cells, thus ensuring their survival. Also, increased secretion of EVs in various malignancies indicates an unfavorable prognostic factor and the possibility of drug resistance. In this study, we briefly reviewed the challenges of treating AML with a glance at the EVs' role in this process. It is hoped that with a deeper understanding of EVs, new therapies will be developed to eliminate the relapse of leukemic cells., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Both inhibitory and stimulatory effect of EGCG on cancer cells have been reported, which often is linked to receptor tyrosine kinase signaling. In this study, we present evidence that green tea extract and its chemical component, Epigallocatechin-3-gallate (EGCG), inhibit growth of human myeloid leukemia cells through the regulation of pRb synthesis and formation of pRb-E2F complexes. Addition of green tea extract to the culture of TF-1a and MV4-11 myeloid leukemia cells significantly inhibited their proliferation with a substantial portion of cell death being observed. The green tea extract and EGCG had no significant effect on the expression of G1 CDKs and the CDK inhibitors but downregulated the formation of pRb-CDKs. Surprisingly, the expression of pRb was markedly upregulated while the phosphorylation of pRb downregulated. The upregulation of pRb was blocked by pre-treatment with cycloheximide, a protein synthesis inhibitor, suggesting a requirement of protein synthesis. In agreement with these results, pRb-E2F complexes were upregulated and E2F DNA binding activity decreased. Since both TF-1a and MV4-11 are factor-independent cell lines, the upregulation of pRb-E2F complexes and inhibition of DNA binding activity by green tea extract is most likely through a receptor tyrosine kinase-independent pathway. We also found that the stem/progenitor cells derived from these two leukemia cell lines are more sensitive to the inhibitory effect of green tea extract. Our result suggests that concentrated green tea extract and EGCG may have potential for clinical investigation as an inducer of cancer cell death., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Dose-intense etoposide-cyclophosphamide (D-I ECy) without stem cell transplantation has been used in salvage regimens for the treatment of resistant acute myeloid leukemia(AML). Previous D-I ECy studies classified AML according to FAB-criteria, before cytogenetic risk was found to be a major determinant of prognosis. Currently the influence of karyotype on response to D-I ECy is unknown. Thus, an observational study was conducted in thirty four patients treated with D-I ECy for resistant AML. The results show this regimen is moderately effective in achieving CR in relapsed AML patients, including those with age >60 and poor cytogenetic risk category., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Cytarabine combined with an anthracycline or an anthracenedione represents the usual intensive induction therapy for the treatment of AML. However, this protocol induces severe side effects and treatment-related mortality due to the lack of selectivity of these cytotoxic agents. In this paper, we present the study of the first galactosidase-responsive molecular "Trojan Horse" programmed for the delivery of doxorubicin exclusively inside AML blasts over-expressing the folate receptor (FR). This targeting system allows the selective killing of AML blasts without affecting normal endothelial, cardiac or hematologic cells from healthy donors suggesting that FDC could reduce adverse events usually recorded with anthracyclines., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The efficacy of azacitidine has been demonstrated in acute myeloid leukemia (AML) patients with 20-30% bone marrow (BM) blasts, but limited data is available on patients with ≥30% blasts. We analyzed 55 newly diagnosed AML patients, treated with azacitidine. The overall response rate was 42%. Median overall survival (OS) was 12.3 months. We confirmed poor-risk cytogenetics, therapy-related AML, performance score ≥2, and white blood cell count ≥15×10(9)/L as independent adverse predictors for OS. The BM blast percentage, however, had no impact on OS (P=0.55). In conclusion, administration of azacitidine is effective in AML patients with 20-30% and >30% BM blasts., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We evaluate the haematopathologic features of systemic mastocytosis associated with acute myeloid leukaemia (SM-AML) and the prognostic role of c-KIT mutation. Total 11 patients were enrolled. Cytochemistry using toluidine blue and tryptase was positive, as was immunohistochemistry for CD117 and CD25 on clustered mast cells; however, CD2 was expressed in only nine cases. In 10 cases, RUNX1-RUNX1T1 fusion gene was detected, and one patient presented with a t(5;6)(q22;q23) translocation at diagnosis. The c-KIT mutation D816V was detected in six patients. Patients with c-KIT mutations had higher relapse and death rates than those without; 4/5 (80.0%) and 5/6 (83.3%) vs. 1/5 (20%) and 2/5 (40%), respectively. Overall survival was also significantly shorter in cases with, than those without, c-KIT mutations. To identify rare cases of SM-AML, which have a dismal prognosis, c-KIT mutation study and careful examination for the presence of clustered mast cell infiltration by immunochemistry should be performed., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Daunorubicin has historically been considered the anthracycline of choice at many cancer centers for the treatment of acute myeloid leukemia (AML). Drug shortages have required the substitution of daunorubicin with idarubicin. Randomized studies have shown idarubicin (10-12mg/m(2)) to be comparable or superior to standard dose daunorubicin (45-60mg/m(2)) for achieving complete remission (CR). Whether these results can be extrapolated to dose-intense daunorubicin (90mg/m(2)), recently shown to improve CR rates when compared to standard daunorubicin doses remains uncertain. This observational study was conducted at Northwestern Memorial Hospital (NMH) to compare CR rates. The results suggest idarubicin is equivalent to daunorubicin, and for some subsets of patients, idarubicin may have superior CR rates., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Azacitidine's efficacy in therapy-related myeloid neoplasms (t-MN) has not been well-studied. In our retrospective review of 84 t-MN patients treated with azacitidine, median overall survival (OS) was 14.5 months and overall response rate was 43%, including 11% complete remission, 4% marrow complete remission, and 11% partial remission. In patients who underwent allogeneic transplant (25%), median OS was 19.2 versus 12.8 months (P=0.023) for those who did not. Response rates were comparable to those reported for de novo myelodysplastic syndrome. When we analyzed outcomes according to five scoring systems, only the Global MD Anderson Risk Model predicted survival with statistical significance., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

In AML, prevention of GvHD leads to better tolerance of myeloablative therapy. 66 individuals with AML in CR underwent myeloablative conditioning and transplantation with allogeneic PBPC grafts. Median presentation age was 44.5 years. Karyotyping was intermediate in 48% and of unfavourable risk in 36%. For GvHD prophylaxis, PBPC harvests were incubated ex vivo with anti CD52 antibodies. TRM at day 100 and 1 year was 9% and 17%. At a median of 1018 days 65% are alive. Grade >1 GvHD was seen in 11%. GvHD and adverse karyotype were associated with treatment failure. In younger patients preservation of the dose intensity may improve cure rates., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Patients with normal karyotype acute myeloid leukemia (NK-AML) without the FLT3 internal tandem duplication (FLT3-ITD) mutation account for approximately 30% of all AML cases, and exhibit a heterogeneous clinical outcome. Except for NPM1 mutations, prognostic factors in this subgroup of AML are still unclear. Here we explored the impact of immunophenotypic markers along with NPM1 mutations and clinical features on the outcome of 133 FLT3-ITD negative NK-AML patients. CD34 expression was associated with poorer complete remission (CR) rate, disease-free survival (DFS), event-free survival (EFS), and overall survival (OS), whereas CD56 expression adversely affected EFS and OS. In contrast, NPM1 mutations correlated with an improved CR rate, DFS, and EFS. Moreover, males experienced shorter DFS and EFS, while older patients (≥60 years) had shorter EFS. Multivariate analysis of age, gender, NPM1, CD34, and CD56 showed NPM1 mutation was an independent predictor of better CR rate, DFS, and EFS (P<0.001, P=0.003, and P=0.006, respectively). In addition, older age was associated with shorter DFS and EFS (P=0.045 and P=0.028, respectively), and CD56 positivity predicted shorter EFS (P=0.012). Our results confirm the favorable impact of NPM1 mutations and identify the adverse prognostic relevance of CD56 expression in this subgroup of AML., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Over-expression of multidrug resistance (MDR) proteins PGP and BCRP has a negative prognostic impact in acute myeloid leukemia (AML) patients. Inclusion of fludarabine in induction chemotherapy increases remission rate in PGP over-expressing cases. We investigated the role of BCRP in 138 adult AML patients receiving induction therapy with fludarabine. None of the MDR-related proteins influenced complete remission attainment. Conversely, high levels of BCRP significantly affected disease-free survival, as higher relapse rates (48.5% vs 28.5%) and earlier relapse occurred in BCRP+ patients. Also overall survival was affected by BCRP positivity, and survival significantly worsened in case of concomitant PGP and BCRP over-expression., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Busulfan (Bu) is a DNA-alkylating drug used in myeloablative pretransplant conditioning therapy for patients with myeloid leukemia (ML). A major obstacle to successful treatment is cellular Bu-resistance. To investigate the possible contribution of DNA hypermethylation to Bu-resistance, we examined the cytotoxic activity of combined 5-aza-2'-deoxycytidine (DAC) and Bu. Exposure of Bu-resistant B5/Bu250(6) ML cells to 0.5 microM DAC resulted in G2-arrest and apoptosis. The observed G2-arrest was associated with hypomethylation and subsequent expression of epigenetically controlled genes including p16(INK4A), activation of the p53 pathway, and phosphorylation of CDC2. The DAC-mediated apoptosis was partly due to hypomethylation and up-regulation of XAF1, which resulted in down-regulation of the anti-apoptotic proteins XIAP, cIAP1 and cIAP2. The pro-apoptotic PUMA and BNIP3 proteins were up-regulated while pro-survival STAT3 and c-MYC were suppressed. Combination of 0.05 microM DAC and 5 microg/ml Bu resulted in synergistic cytotoxicity, which was associated with PARP1 cleavage and activation of caspases 3 and 8, suggesting induction of an apoptotic response. P53 inhibition in B5/Bu250(6) cells using pifithrin-alpha alleviated these effects, suggesting a role for p53 therein; this observation was supported by the relative resistance of p53-null K562 cells to [DAC+Bu] combinations and by the effects of an anti-p53 shRNA on the OCI-AML3 cell line. We conclude that the synergistic effects of [DAC+Bu] are p53-dependent and involve cell cycle arrest, apoptosis induction and down-regulation of pro-survival genes. Our results suggest that, depending on tumor p53 status, incorporation of DAC might synergistically improve the cytoreductive efficacy of Bu-based pretransplant regimen in patients with ML., (Published by Elsevier Ltd.)

We analyzed the effect of (+)alpha-tocopheryl succinate (alpha-TOS) alone or associated with arsenic trioxide (ATO) or all-trans retinoid acid (ATRA) in acute promyelocytic leukemia (APL). alpha-TOS-induced apoptosis in APL clinical samples and in ATRA-sensitive (NB4) and ATRA-resistant (NB4-R2) APL cell lines. The effective dose 50% (ED-50) was calculated to be 71 and 58muM, for NB4 and NB4-R2, respectively. alpha-TOS neither induced nor modified ATRA-induced differentiation of APL cells, and did not affect the proliferation and differentiation of normal CD34(+) hematopoietic progenitors in methylcellulose assays. alpha-TOS exerted a moderate antagonistic effect to ATO-induced apoptosis when treatment was done simultaneously but when alpha-TOS was added 24h after ATO, an additive effect was observed. Our results support the concept of alpha-TOS as an anti-leukemic compound which spares normal hematopoiesis.

The aim of this study was to evaluate the efficacy and toxicity of low-dose cytarabine and aclarubicin in combination with granulocyte colony-stimulating factor (G-CSF) protocol in elderly patients with acute myeloid leukemia (AML). A total of 50 elderly patients including 8 aged over 70 years were enrolled. All patients were treated with CAG regimen including low-dose cytarabine (10mg/m(2) every 12h, days 1-14), aclarubicin (10mg every day, days 1-8), and G-CSF (200 microg/m(2) every day, days 1-14) priming. The overall response rate was 72.0%, and 29 of 50 (58.0%) patients achieved complete remission, including 23 of 35 (65.8%) with previously untreated AML, 6 of 15 (40.0%) with refractory, relapsed or secondary AML, 4 of 8 (50.0%) aged over 70 years, 4 of 10 (40.0%) with unfavorable cytogenetic aberrations. The early death rate was 7.6%. The median overall survival was 14 months. Myelosuppression was mild to moderate, severe nonhematologic toxicity was not observed. Thus CAG priming regimen as the induction therapy is well tolerated and effective in elderly patients with AML.

Gemtuzumab ozogamicin (GO) was approved for marketing in 2000 by the United States Food and Drug Administration (FDA) for older patients with relapsed acute myeloid leukemia (AML). Four months later, 14 phase II clinical trial participants who received novel GO-containing combination chemotherapy regimens developed an unexpected hepatic toxicity termed sinusoidal obstructive syndrome (SOS) or hepatic veno-occlusive disease (VOD). Investigators associated with the Research on Adverse Drug Events and Reports (RADAR) project reviewed safety reports for GO included in reports of clinical trials and observational studies, interim reports from an FDA mandated Prospective Observational Registry, and the Food and Drug Administration's Adverse Event Reporting System. Medline searches provided incidence estimates of GO-associated SOS and comparative rates of SOS without GO. SOS is characterized by hyperbilirubinemia, painful hepatomegaly, ascites, and sudden weight gain developing at a median of 10 days following GO administration for patients who did not undergo an allogeneic SCT procedure and 13 days following an allogeneic SCT for patients who had previously received GO. Among adult AML patients who received GO in clinical trials, SOS incidence was 3% at doses < or =6 mg/m(2) if administered as monotherapy or in combination with non-hepatotoxic agents versus 28% if administered with thioguanine and 15% when administered as monotherapy at a dose of 9 mg/m(2). Observational studies identified SOS rates between 15% and 40% if an SCT is performed within 3 months of GO administration. The FDA mandated Prospective Observational Registry of patients who receive care at 60 medical centers has identified GO-associated SOS rates of 14% if an SCT is performed and 9% otherwise. Caution is advised when administering GO in routine clinical practice, particularly if administered with other hepatotoxic agents, at doses and schedules more intensive than those approved by the FDA, or within 3 months of a SCT procedure.

The third-generation bisphosphonate zoledronic acid (ZOL) has recently been shown to be active against human tumour and leukemic cell lines. The purpose of this study was to evaluate the antileukemic potential of ZOL in acute myeloid leukemia (AML). We determined the lethal concentration 50% (LC 50) using the WST-1 assay of ZOL as being 287.9 microg/ml after 24 h and 108.3 microg/ml after 96 h in HL 60 cells and to be 382.4 and 43.2 microg/ml, respectively, in nine samples from patients with AML. The ZOL induced inhibition of proliferative activity of HL 60 cells could not be abrogated by the hematopetic growth factors G-CSF and GM-CSF. ZOL was found to by cytotoxic in HL 60 cells without activation of caspase 3. ZOL was not cross resistant with cytarabine as shown by the linear correlation of LC 50s. Both agents, however, exerted an additive cytotoxicity as revealed by isobologram-analysis and combination index. These data warrant further investigation of ZOL in the treatment of AML.

The frequency of acute myeloid leukemia (AML) with balanced chromosomal translocations arising after anticancer therapy with DNA-damaging agents such as DNA topoisomerase II inhibitors has increased over the last two decades. However, factors that predispose to these therapy-related disorders are still poorly defined. It has been reported that DNA double-strand break (DSB) repair by the non-homologous end-joining (NHEJ) pathway is impaired in myeloid leukemia cells. This led us to hypothesize that therapy-related AML (t-AML) may result from individual differences in the repair of DSBs generated by the treatment. We show here that DSB repair is accurate, in vivo, in non-tumoral cells derived from patients who developed t-AML with t(9;11) or t(15;17) translocation after treatment for a first cancer with DNA topoisomerase II inhibitors. These results indicate that a major constitutive defect in the NHEJ pathway is unlikely to predispose to t-AML with balanced chromosomal translocations.

For patients with acute myeloid leukemia refractory to intensive chemotherapy prognosis is very poor and treatment options are limited. 5-Azacytidine, a demethylating drug, is effective in the treatment of myelodysplastic syndromes when administered at a low-dose, subcutaneously. We report a case of a patient with AML refractory to induction chemotherapy as well as to two high-dose salvage regimens. The patient achieved CR through monotherapy with low-dose azacytidine.

UM384 cells, derived from the human myeloid leukemia U937 cell line, fail to differentiate in response to 12-O-tetradecanoylphorbol-13-acetate (TPA). Using cDNA microarray and real-time quantitative PCR (RT-QPCR) approaches, we observed a difference in the response to TPA treatment: all the genes from U937 cells were continuously modulated from 2 to 24h. In UM384 cells, 60% of the genes were transiently modulated at 2h, then returned to control levels at 24h. Moreover, HuR, an AU-rich element-binding protein (ARE-BP), was differentially located in the two cell lines. Therefore, a defect of mRNA stabilization could be responsible for the resistance of UM384 cells to TPA-induced differentiation, suggesting a possible role for the post-transcriptional regulation in the leukemogenesis.

The anti-epileptic drug valproic acid harbors anti-tumoral activity in solid and leukemic tumor cell models and is currently evaluated in clinical trials. However, the plasma trough concentrations obtained in patients by common anti-epileptic dose regimens are below concentrations required for exerting anti-tumor effects in vitro. Here, we describe the identification of three novel valproic acid derivatives with superior differentiation-inducing and anti-proliferative activities in K562 bcr/abl-positive chronic myeloid leukemia cells and HL60 promyelocytic leukemia cells at achievable therapeutic VPA concentrations. These compounds reveal potent inhibition of histone deacetylase activity, induction of p21Cip/Waf expression as well as low toxicity on CD34+ bone marrow cells.

Granulocytic sarcoma (GS) is a rare extra-medullary tumor and usually involves the skin, soft tissue, and lymph nodes. GS is found in 8% of acute myeloid leukemia (AML) patients, especially patients with t(8;21)AML. It has been suggested that GS is a poor prognostic factor in t(8;21)AML. Compared to t(8;21)AML, GS is rare in cases of inv(16)AML. Thus, the characteristics of inv(16) with GS are not well understood. Here, we describe a patient with AML and mesentery GS. The chromosomal analysis was normal, but molecular analysis detected the CBFB/MYH11 fusion gene in the blasts. A complete remission was achieved with standard induction therapy followed by high-dose cytarabine consolidation. We have also summarized 12 reported cases of inv(16)AML with GS and found that GS was commonly found in abdominal lesions. These observations suggest that when abdominal GS is diagnosed, an analysis of the CBFB/MYH11 fusion gene is necessary to make an appropriate decision regarding treatment options, even if no chromosomal abnormalities are found.

HIV-1 protease inhibitor, ritonavir (RTV) is a potent inhibitor of cytochrome p450 (CYPs) enzymes. This study explored the effects of RTV on CYP24 which converts 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] to its inactive form 1,24,25,(OH)(3). Real-time RT-PCR showed that exposure of HL-60 cells to 1,25(OH)(2)D(3) induced expression of CYP24, and pre-incubation of these cells with RTV decreased this transcripts, resulting in increased intracellular levels of 1,25(OH)(2)D(3) and potentiation of the ability of 1,25(OH)(2)D(3) to induce growth arrest and differentiation of these cells. Taken together, inhibition of CYP24 might open a new paradigm for therapy using Vitamin D compounds.

Triapine, an iron chelator and a potent inhibitor of ribonucleotide reductase, has significant anti-leukemia activity. A phase I study of Triapine in combination with ara-C was conducted in 32 patients with refractory acute leukemia and high-risk MDS. Triapine (105 mg/m2/day 6-h infusion) was followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8)mg/m2/day] as an 18-h infusion for 5 consecutive days. Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (one patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/day, no DLTs occurred in seven patients treated at this dose level. Mean Triapine C(max) and AUC were 1.13 microg/mL and 251.5 minmicrog/mL. Of 31 evaluable patients, 4 (13%) (3 AML, 1 Ph+ALL) achieved a CR (1 at a dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200mg/m2). The recommended phase II regimen is Triapine 105 mg/m2/day followed by ara-C 600 mg/m2/day for 5 consecutive days every 3-6 weeks.

AG-013736 is an oral anti-angiogenesis agent with activity against a variety of receptor tyrosine kinases, including VEGFR-1, VEGFR-2, VEGFR-3, c-kit, and PDGFR-beta. A phase 2 study was conducted in patients with poor prognosis AML or MDS. Twelve patients (six AML; six MDS) were treated with AG-013736 at a dose of 10mg orally daily for a median of 56 days (range, 1-248 days). Median age was 80 years (range, 58-88 years). Grade 3 or 4 drug-related toxicities included hypertension (42%), mucositis (8%) and deep venous thrombosis (8%). No objective responses occurred; two patients with MDS had stable disease for 8.3 and 6.2 months, respectively. Bone marrow expression of VEGFR-1 and VEGFR-2 was observed in 11% and 0% of patients, respectively. Sustained decreases in soluble VEGFR-2 plasma levels with concomitant elevation in plasma VEGF and placental growth factor levels were obtained during the course of therapy with AG-013736. AG-01736 had minimal biologic or clinical activity in this elderly patient population.

Randomized trials of substituting high-dose cytarabine (HiDAC) for standard dose cytarabine (SDAC) during induction therapy for newly diagnosed AML have not demonstrated an improvement in the complete remission (CR) rate. Phase II trials of the scheduled administration of HiDAC after SDAC suggest an improved outcome. The hematological complications of intensification are considerable. GM-CSF after chemotherapy improved the survival of older patients in a randomized trial. Recombinant human interleukin 11, a thrombopoietic cytokine, reduced the incidence of chemotherapy-induced thrombocytopenia in patients with solid tumors. Therefore, 34 patients were treated, with newly diagnosed AML less than 56 years of age, with daunorubicin 45 mg/m2 on days 1-3, cytarabine 100mg/m2 days 1-7 and cytarabine 2g/m2 for 12 h on days 8-10 (7+3+3). rhIL-11 (50 microg/kg/day,) and GM-CSF (250 microg/kg/day) were administered subcutaneously from day 11 until recovery. The complete remission rate was 59% (90% C.I. 43-73%). The median time to recovery of neutrophils to >500 and platelets to > or =20,000 microl(-1) was 27 days (95% C.I. 27-30 days) and 25 days (95% C.I. 24-29 days), respectively. The trial does not confirm the high CR rate observed in phase II trials, despite optimal supportive care.

Oblimersen selectively targets Bcl-2 mRNA and has been shown to enhance the apoptotic activity of various antileukemic agents, including gemtuzumab ozogamicin (GO), in preclinical studies. We evaluated the efficacy and safety of oblimersen combined with GO in patients > or =60 years of age in first relapse with CD33+ acute myeloid leukemia. Oblimersen 7 mg/kg/day was given as a continuous intravenous infusion on days 1-7 and 15-21. GO 9 mg/m2 was given intravenously on days 4 and 18. Twelve of 48 patients (25%) achieved a major response (five, complete response and seven, complete response without platelet recovery). Ten of the 12 patients who achieved a major response survived >6 months compared with six of 36 non-responders. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone. Oblimersen can be safely combined with GO. Assessment of incremental benefit will require a randomized trial.

We assessed remission rates and toxicity in 24 consecutive elderly (age>or=60) patients with untreated Acute myeloid leukemia (AML) who received the anthracycline-free combination of fludarabine, cytosine arabinoside and G-CSF (FLAG) as initial induction chemotherapy at our center. CR was achieved following one cycle of FLAG in 14 patients (58%). Another four patients cleared blasts from their bone marrow by day 30 without complete platelet recovery. Three patients died from infections prior to neutrophil recovery (12%). No other grade 3/4 toxicities and no clinically significant mucositis were seen. No significant association was found between age, WBC and cytogenetic risk group with likelihood of achieving CR. Fifteen patients proceeded to consolidation therapy and seven patients received a stem cell transplant (six autologous, one allogeneic). Primary induction with FLAG in elderly AML patients achieves a high remission rate without prohibitive mucosal or cardiac toxicity and may thus be considered as an alternative to standard anthracycline-based regimens in this setting.

12-O-Tetradecanoylphorbol-13-acetate (TPA) is being developed as a therapeutic agent by virtue of its being a potent modulator of signal transduction in pre-clinical models of AML [Strair RK, Schaar D, Goodell L, Aisner J, Chin KV, Eid J, et al. Administration of a phorbol ester to patients with hematological malignancies: preliminary results from a phase I clinical trial of 12-O-tetradecanoylphorbol-13-acetate. Clin Cancer Res 2002;8:2512-8]. In this report, we identify a subset of primary AML samples that undergoes apoptosis after exposure to TPA and demonstrate that TPA-induced cytotoxicity is associated with modulation of the ERK signaling pathway. Analysis of mitogen-activated protein kinase (MAPK) dual-specificity phosphatases (DUSP), as potential regulators of AML cell signaling, indicates that these genes are coordinately regulated and rapidly induced by TPA in primary AML cells. Therefore, TPA-induced primary AML cytotoxicity is associated with modulation of ERK signaling which may be partially mediated by regulation of phosphatase expression.

The correlation between drug sensitivity in vitro and the mutation status of the FLT3 receptor gene was evaluated in tumour cells from 17 previously untreated AML patients. Tumour cells with internal tandem duplication (ITD) in the FLT3 receptor gene were significantly more sensitive to the FLT3 inhibitor SU5614 than tumour cells with wild type FLT3. Combinations of SU5614 with etoposide and amsacrine showed better effect (p<0.05) compared with the respective single drugs. Our results suggest that the FLT3 inhibitor SU5614 may have a therapeutic potential, especially in combination with other cytotoxic agents, in patients with FLT3-ITD positive AML.

We have used the dose of 9 mg/m(2) of mylotarg 4 days after the beginning of a chemotherapy including intermediate-dose aracytin and mitoxantrone (MIDAM) in 17 patients with refractory (n=4) or relapsed (n=13) AML. Thirteen patients (76%) achieved CR (n=12) or partial CR (n=1). All four refractory patients and all four patients with poor risk cytogenetic achieved CR or CRp. Although the dose of mylotarg given in combination with chemotherapy was not reduced, the toxicity profile was acceptable (1VOD/17 patients). The MIDAM protocol appears to be highly effective especially in patients with poor risk cytogenetic and/or refractory disease.

The prognosis of acute myeloid leukemia (AML) in older adults is generally poor. Standard cytotoxic chemotherapy is usually poorly tolerated and provides dismal results in this patient population. Gemtuzumab ozogamicin (GO) is an immunoconjugate that has activity in the relapsed and refractory setting. We hypothesized that administering this agent, as an initial treatment in AML patients over the age of 65 would have, at least, similar efficacy to standard therapy, but at much less toxicity. We report on the first 12 patients that were treated solely with GO as induction, consolidation, and maintenance therapy as part of a single institution clinical trial. The treatment was well tolerated, with a response rate of 27%. Toxicities were acceptable, although five patients (41%) developed cardiac toxicity three of which had grade 3 and/or 4. Responses were present regardless of the karyotype, and lasted for a median of 7.6 months. These early results suggest that the option of single agent monoclonal antibody therapy is viable in this patient population and that additional studies are warranted with this agent either alone or in combination as initial therapy.

CD44 is a cell surface antigen that expresses on leukemia blasts from most acute myeloid leukemia (AML) patients. It has been reported that ligation of CD44 with some specific anti-CD44 monoclonal antibodies can reverse the differentiation blockage of leukemia cell lines. In this study, the differentiation and apoptosis-inducing effects of HI44a, another anti-CD44 monoclonal antibody (IgG2a), were investigated on leukemia cells obtained from 31 patients with AML-M2, AML-M3, AML-M4 or AML-M5. When the AML cells were treated with HI44a, the percentage of nitroblue tetrazolium (NBT)+ cells was significantly increased. The expression of CD11b, CD14 and CD15 on treated AML cells was also increased compared to control AML cells. In addition, HI44a was found to induce apoptosis of leukemia cells, as evidenced by an annexin-V assay. The mean percentage of apoptotic cells in HI44a-treated AML cells was significantly increased compared to that in control AML cells. Moreover, the level of c-myc transcript expression on AML cells was found to be obviously decreased in all detected patients. These results indicate that HI44a effectively induces both differentiation and apoptosis of AML cells and suggest that this activity of the anti-CD44 antibody may be associated with its inhibitory effect on c-myc transcript expression.

Cyclosporin A (CsA) inhibits the P-gp pump that can be responsible for failure of cytostatic treatment in acute myeloid leukaemia (AML). Eighty patients with relapsing/refractory AML were randomly assigned to mitoxantrone (M) and etoposide (VP) (MVP) in unmitigated antileukaemic doses with or without CsA, to investigate if toxicity was manageable and if antileukaemic therapy could be improved. CsA did not delay haematological recovery, but fewer CsA patients received post-induction therapy because of haematological and non-haematological toxicity. CR rate was 43% for MVP and 53% for CsA; DFS was 9 and 8 months, and OS 8 and 9 months, respectively. Seventeen of 38 CR patients proceeded to stem cell transplantation (SCT). After a median follow-up of 66 months, six patients were still alive. Addition of CsA did not improve treatment outcome, possibly due to inadequate post-induction therapy as a result of increased toxicity.

Gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody conjugated to calicheamicin, is effective as single agent in the treatment of poor risk acute myeloid leukaemia (AML) patients. We treated with GO in combination with cytarabine as continuous perfusion nine elderly AML patients, either untreated (five cases), or with relapsed/refractory disease (four cases). Five patients achieved a complete remission (CR), four were resistant. One patient died while in CR due to CNS haemorrhage, two relapsed and two are still in CR. The median CR duration was 10 months. The median overall survival was 6 months (1-19 months). The most common adverse event was myelosuppression, as expected. No hepatic veno-occlusive disease was recorded. Notably, in four cases we observed a grade III/IV bleeding, including gasto-intestinal bleeding, epistaxis, CNS haemorrhage, and ocular bleeding. Larger prospective studies are now warranted in order to better define the possible role of this regimen in the treatment of elderly AML patients.

The prognosis for patients with relapsed/refractory AML, secondary leukemia and AML in older adults is extremely poor. An appealing alternative approach to intensive cytotoxic chemotherapy is to induce apoptosis with a novel agent. There is in vitro evidence that arsenic trioxide (ATO) has anti-proliferative and pro-apoptotic effects on myeloid leukemia cell lines. To evaluate efficacy and toxicities of ATO, we conducted a phase II trial including subjects with relapsed/refractory or secondary AML or age > or = 65 years with de novo disease. Eleven subjects were entered with a median age of 77 years (56-90) and a median total dose of ATO of 415.55 mg (91.5-793) with a daily dose of 0.25 mg/kg. Median survival following the first dose of ATO was 2.25 months (0.4-19). Myelosuppression was the major adverse effect, most likely due to disease progression rather than drug-related. All subjects had progressive disease. There was no direct treatment-related mortality. Based on this study, we do not recommend single agent ATO as a treatment option for AML.

Acute myeloid leukemia (AML) is associated with dysregulated hematopoietic cell proliferation and increased bone marrow angiogenesis, each regulated by signaling through receptor tyrosine kinases (RTKs). SU5416 is a small molecule inhibitor of VEGF receptors, c-kit and FLT3 and therefore provides a novel opportunity to target both angiogenesis and proliferation in AML. SU5416 was assessed in a phase II hematological malignancy trial in the US, where partial responses were observed in two of 33 patients. Since AML provides a unique platform to evaluate mechanism of action of small molecule inhibitors, investigation of the effect of SU5416 on FLT3 expression and phosphorylation in blood and bone marrow was an additional focus of this trial. Phosphorylated FLT3 was detected by immunoprecipitation/Western analysis in peripheral blood samples from 17 of 22 patients, and seven exhibited strong inhibition of phosphorylation immediately following a 1h SU5416 infusion, demonstrating that SU5416 can modulate RTK phosphorylation in humans. Although no clear correlation with clinical response was observed, analysis of patient plasma drug levels suggested that a threshold SU5416 concentration of 15 microM was associated with FLT3 inhibition. This observation was supported by data from an ex vivo model where AML cells were spiked into human blood, established to mimic the clinical setting and enable more rigorous analysis of effect of SU5416. In addition, FLT3 protein levels were downregulated in patient bone marrow samples, analyzed by an RIA assay. To identify putative predictors of response, patient plasma was analyzed for levels of secreted ligands of SU5416 targets; SCF and FLT3 ligand. Baseline levels of SCF in patients with stable or progressive disease were significantly higher than those in normal donors, whereas FLT3 ligand levels in patients who exhibited progressive disease were significantly lower than those in normal donors. The translational and clinical analyses described in this report provide some insights into the mechanism and duration of action of SU5416.