Showing papers by "Guillermo Garcia-Manero published in 2010"

Maintenance therapy with low-dose azacitidine after allogeneic hematopoietic stem cell transplantation for recurrent acute myelogenous leukemia or myelodysplastic syndrome: a dose and schedule finding study.

Abstract: BACKGROUND: Recurrence is a major cause of treatment failure after allogeneic transplantation for acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), and treatment options are very limited. Azacitidine is a DNA methyltransferase inhibitor with activity in myeloid disease. The authors hypothesized that low-dose azacitidine administered after transplant would reduce recurrence rates, and conducted a study to determine a safe dose/schedule combination. METHODS: Forty-five high-risk patients were treated. Median age was 60 years; median number of comorbidities was 3; 67% were not in remission. By using a Bayesian adaptive method to determine the best dose/schedule combination based on time to toxicity, the authors investigated combinations of 5 daily azacitidine doses, 8, 16, 24, 32, and 40 mg/m2, and 4 schedules: 1, 2, 3, or 4 cycles, each with 5 days of drug and 25 days of rest. Cycle 1 started on Day +40. RESULTS: Reversible thrombocytopenia was the dose-limiting toxicity. The optimal combination was 32 mg/m2 given for 4 cycles. Median follow-up was 20.5 months. One-year event-free and overall survival were 58% and 77%, justifying further studies to estimate long-term clinical benefit. No dose significantly affected DNA global methylation. CONCLUSIONS: Azacitidine at 32 mg/m2 given for 5 days is safe and can be administered after allogeneic transplant for at least 4 cycles to heavily pretreated AML/MDS patients. The trial also suggested that this treatment may prolong event-free and overall survival, and that more cycles may be associated with greater benefit. Cancer 2010. © 2010 American Cancer Society.

Phase I/II Study of Combination Therapy With Sorafenib, Idarubicin, and Cytarabine in Younger Patients With Acute Myeloid Leukemia

Abstract: Purpose To determine the efficacy and toxicity of the combination of sorafenib, cytarabine, and idarubicin in patients with acute myeloid leukemia (AML) younger than age 65 years. Patients and Methods In the phase I part of the study, 10 patients with relapsed AML were treated with escalating doses of sorafenib with chemotherapy to establish the feasibility of the combination. We then treated 51 patients (median age, 53 years; range, 18 to 65 years) who had previously untreated AML with cytarabine at 1.5 g/m2 by continuous intravenous (IV) infusion daily for 4 days (3 days if > 60 years of age), idarubicin at 12 mg/m2 IV daily for 3 days, and sorafenib at 400 mg orally twice daily for 7 days. Results Overall, 38 (75%) patients have achieved a complete remission (CR), including 14 (93%) of 15 patients with mutated FMS-like tyrosine kinase-3 (FLT3; the 15th patient had complete remission with incomplete platelet recovery [CRp]) and 24 (66%) of 36 patients with FLT3 wild-type (WT) disease (three additional F...

Chemoimmunotherapy With a Modified Hyper-CVAD and Rituximab Regimen Improves Outcome in De Novo Philadelphia Chromosome–Negative Precursor B-Lineage Acute Lymphoblastic Leukemia

Abstract: Purpose The adverse prognosis of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia (ALL) prompted incorporation of monoclonal antibody therapy with rituximab into the intensive chemotherapy regimen hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone). Other modifications (irrespective of CD20 expression) included early anthracycline intensification, alterations in number of risk-adapted intrathecal chemotherapy treatments for CNS prophylaxis, additional early and late intensifications, and extension of maintenance phase chemotherapy by 6 months. Patients and Methods Two hundred eighty-two adolescents and adults with de novo Philadelphia chromosome (Ph)–negative precursor B-lineage ALL were treated with standard or modified hyper-CVAD regimens. The latter incorporated standard-dose rituximab if CD20 expression ≥ 20%. Results The complete remission (CR) rate was 95% with 3-year rates of CR duration (CRD) and survival (OS) of 60% and 50%, r...

Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy

Abstract: BACKGROUND: The prognosis of patients with myelodysplastic syndrome (MDS) after decitabine failure is not known. METHODS: Data from 87 patients with MDS (n = 67) and chronic myelomonocytic leukemia (n = .20) after failure of decitabine regimens were reviewed. RESULTS: After a median follow-up of 21 months from decitabine failure, 13 (15%) patients remained alive; the median survival was 4.3 months, and the estimated 12-month survival rate was 28%. The estimated 12-month survival rates were 27%, 33%, and 33%, respectively, for patients with high-risk, intermediate-2-risk, and intermediate-1-risk disease (P = .99) by the International Prognostic Scoring System. The estimated 12-month survival rates were 100%, 54%, 41%, and 18%, respectively, for patients with low-risk, intermediate-1-risk, intermediate-2-risk, and high-risk disease according to The University of Texas M. D. Anderson Cancer Center risk model (P = .01). CONCLUSIONS: The outcome of patients after decitabine failure is poor and appears to be predictable after decitabine failure. Cancer 2010. © 2010 American Cancer Society.

Cause of death in patients with lower-risk myelodysplastic syndrome.

Abstract: The International Prognostic Scoring System is commonly used to predict survival rates and progression to acute myelogenous leukemia (AML) in patients with myelodysplastic syndrome (MDS).1 The International Prognostic Scoring System categorizes patients into lower (low/intermediate-1) versus higher (intermediate-2/high) risk groups. Approximately ⅔ of patients with MDS have lower-risk disease at the time of initial diagnosis.2,3 We studied the outcomes of patients with lower-risk MDS who presented to a cancer center. On the basis of that analysis, we developed a prognostic scoring system for lower-risk MDS3 that stratifies patient prognosis based on 7 adverse prognostic factors. Depending on the number of those factors, 4-year survival ranged from 78% to <10%. Importantly, further analysis showed that only 10% of patients had transformed to AML, but 50% had died. The cause of death (COD) among this subgroup of lower-risk patients with poor outcome is not well understood. The understanding of the natural history of disease in patients with lower-risk MDS may have significant implications for their clinical management. The median age at diagnosis of patients with MDS is approximately 75 years.4 Currently, a large fraction of MDS patients receives supportive care (such as transfusions and growth factors) only, rather than disease-specific therapy. This is likely because, until recently, no effective therapy was available for MDS. In light of the recent development of effective drugs against MDS,5-7 it is important to determine whether the COD in this elderly population is because of age-related comorbidities or directly associated with MDS. This information could be used to guide intervention in patients with lower-risk MDS who are identified as having a poor outcome and might benefit from early therapeutic intervention. The aim of the present study was to establish the COD in a cohort of MDS patients with low- or intermediate-1 risk disease at presentation and to examine whether the CODs have changed over time in this patient group.

Genome-wide DNA methylation profiling of chronic lymphocytic leukemia allows identification of epigenetically repressed molecular pathways with clinical impact

Abstract: We performed a genome-wide analysis of aberrant DNA methylation in chronic lymphocytic leukemia (CLL) using methylated CpG island amplification (MCA) coupled with a promoter microarray. We identified 280 potential targets of aberrant DNA methylation in CLL. These genes were located more frequently in chromosomes 19 (16%, p = 0.001), 16 (11%, p = 0.001), 17 (10%, p = 0.02) and 11 (9%, p = 0.02) and could be grouped in several functional networks. Methylation status was confirmed for 22 of these genes (SOX11, DLX1, FAM62C, SOX14, RSPO1, ADCY5, HAND2, SPOCK, MLL, ING1, PRIMA1, BCL11B, LTBP2, BNC1, NR2F2, SALL1, GALGT2, LHX1, DLX4, KLK10, TFAP2 and APP) in 78 CLL patients by pyrosequencing. As a proof of principle, we analyzed the expression of 2 genes, PRIMA1 and APP, in primary cells and of GALGT2, TFAP2C and PRIMA1 in leukemia cells. There was an inverse association between methylation and gene expression. This could be reversed by treatment with 5-aza-2′-deoxycytidine in cell lines. Treatment in a clinical trial with 5-azacitidine resulted in decreased methylation of LINE, DLX4 and SALL1 in the peripheral blood B-cells of patients with CLL. IgVH mutational status or ZAP-70 expression were not associated with specific methylation profiles. By multivariate analysis, methylation of LINE and APP was associated with shorter overall survival (p = 0.045 and 0.0035, respectively). This study demonstrates that aberrant DNA methylation is common and has potential prognostic and therapeutic value in CLL.

Defining the course and prognosis of adults with acute lymphocytic leukemia in first salvage after induction failure or short first remission duration

Abstract: Modern multiagent, dose-intensive chemotherapy regimens have resulted in cure rates of 80% to 90% in childhood acute lymphocytic leukemia (ALL).1,2 Regimens in adult ALL patterned after the pediatric programs have increased the complete response (CR) rates to 90% and have increased the long-term survival rates to 30% to 50%.3–8 Still, most adults with ALL will die from disease progression. Therefore, there is a need to discover new agents with anti-ALL activity. Approving new anti-ALL agents for front-line therapy is a daunting task, because it requires large randomized studies that compare standard regimens versus the same regimens with the addition of the new agent. Because ALL is an uncommon disease (annual US incidence, 1500–3000 cases), such endeavors are almost impossible. Therefore, the discovery and regulatory approval of new agents in ALL have relied on development in niche indications. Examples include clofarabine for pediatric ALL in second salvage,9,10 nelarabine for T-cell ALL salvage,11 and tyrosine kinase inhibitors in Philadelphia chromosome (Ph)-positive ALL.12,13 Patients with primary refractory disease or in first recurrence have CR rates of 30% to 50% with salvage therapy but have a cure rate of ≤5%.14–17 Their outcome depends on several factors, the most important of which is the duration of first complete remission (CRD). It is anticipated that adults who have primary refractory disease or a short first CRD will have a poor outcome, probably as poor as the outcome of patients in second salvage18; however, to our knowledge, no studies have investigated their outcome. Defining the precise course and prognosis of adults with ALL and primary refractory disease or with a short first CRD will help speed the development of investigations aimed at this subgroup.

Decitabine in the treatment of myelodysplastic syndromes

Abstract: Myelodysplastic syndromes (MDS) are a group of heterogeneous clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis, peripheral blood cytopenias and a propensity to transform into acute myeloid leukemia. There are few treatment options available for patients with MDS. Studies into the molecular biology of MDS have demonstrated abnormal patterns of DNA methylation that lead to silencing of tumor-suppressor genes. Hypomethylating agents are compounds that have the potential to reverse the aberrant DNA methylation and increase the expression of silenced genes, leading to cellular differentiation and/or apoptosis. Decitabine is a cytidine analogue that has activity as a hypomethylating agent and has been evaluated in the therapy of patients with high-risk MDS. Several studies have confirmed the clinical activity of low-dose decitabine in patients with high-risk MDS, leading to responses in approximately 50% of patients, with low treatment-related mortality. Responses have even been seen in patients with high-risk cytogenetic abnormalities, and some studies have demonstrated increased re-expression of genes that were previously silenced by hypermethylation, such as CDKN2B/p15INK4B. There are still some issues concerning the ideal dose and schedule of decitabine for treating patients with MDS. This article focuses on the most recent clinical studies of decitabine for therapy of MDS.

Therapy with azanucleosides for myelodysplastic syndromes

Abstract: Azanucleosides constitute the core therapy in the management of myelodysplastic syndromes (MDS), and have altered the treatment paradigm of MDS, previously dominated by supportive care strategies. DNA methylation regulates gene transcription in MDS, and it is hypothesized that azanucleoside therapy induces DNA hypomethylation and re-expression of aberrantly silenced genes in patients with these disorders. A series of clinical trials conducted over the past 5 years has demonstrated the activity of these therapies. Two agents, 5-azacitidine and decitabine, have been approved by the FDA for treatment of MDS. Recently, 5-azacitidine therapy has been shown, for the first time, to prolong survival in patients with MDS. Because the targeting of biologic pathways in MDS is best accomplished by combining agents with complementary mechanisms of action, combinations of azanucleosides with other drugs are being investigated. In this article, we critically appraise the most relevant clinical data reported on the use of azanucleosides for the treatment of patients with MDS.

Survival outcomes for clonal evolution in chronic myeloid leukemia patients on second generation tyrosine kinase inhibitor therapy

Abstract: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that typically evolves through 3 clinical phases: chronic phase, accelerated phase (AP), and blastic phase The hallmark of CML, the Philadelphia (Ph) chromosome, is an abnormally short chromosome 22 that results from a balanced translocation t(9;22) (q34;q112) The translocation leads to the formation of a hybrid gene BCR-ABL that encodes for the fusion protein Bcr-Abl with its characteristic deregulated tyrosine kinase activity1 Clonal evolution in CML denotes the presence of a variety of additional, nonrandom chromosomal abnormalities besides the Ph chromosome Clonal evolution occurs in approximately 30% of patients in AP and about 80% patients in blastic phase2,3 Although clonal evolution may involve any abnormality within any chromosome, the most commonly reported abnormalities include double Ph, chromosome 17 abnormalities, and trisomy 8 Clonal evolution has been considered a criterion for AP of CML, particularly when it appears during the course of therapy In this setting, clonal evolution is associated with a poor prognosis3–11 The prognostic significance of clonal evolution may vary with different therapeutic modalities The outcome after allogeneic stem cell transplant may not be adversely affected by clonal evolution, with a reported long-term survival rate of 60% if clonal evolution was the only feature of AP12,13 Interferon (IFN)-α therapy caused complete resolution of clonal evolution in 46% patients, with a better response rate if clonal evolution was not associated with other features of AP, although patients with abnormalities of chromosome 17 had a worse outcome compared with those with other abnormalities8 In patients treated with IFN-α and low-dose Ara-C, 3-year survival rates of 67% were observed if clonal evolution was the only feature of AP disease, compared with 22% if other features of AP were present (P < 01)14 With imatinib, the outcome of patients with clonal evolution is significantly inferior compared with those without clonal evolution7 Patients who develop resistance to imatinib frequently develop clonal evolution as a mechanism of resistance (or associated with resistance)15–17 The second generation tyrosine kinase inhibitors dasatinib and nilotinib are effective in patients with CML after failure of imatinib18,19 The significance of different chromosomal abnormalities associated with clonal evolution for the outcome after therapy with second generation tyrosine kinase inhibitors is unknown Herein, we analyzed the response to therapy and long-term outcome after second generation tyrosine kinase inhibitor therapy in patients with CML with clonal evolution after imatinib failure

The combination of a histone deacetylase inhibitor with the Bcl-2 homology domain-3 mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.

Abstract: Purpose: Single-agent histone deacetylase inhibitors (HDACi) have limited clinical activity in human leukemia. Although the way HDACi exert their antileukemia effect is not fully understood, it is accepted that induction of apoptosis is important. We hypothesized, therefore, that combination of an HDACi with a proapoptotic agent, such as the Bcl-2 homology domain-3 mimetic GX15-070, could result in enhanced antileukemia activity. Experimental Design: We analyzed the cellular and molecular effects of two different HDACi (MGCD0103 and vorinostat) in combination with GX15-070 in leukemia cell lines and primary acute myelogenous leukemia cells. Results: We showed that the combination had synergistic antileukemia effect both in leukemia cell lines and in primary acute myelogenous leukemia cells. Using molecular markers and electron microscopy, we observed that in addition to apoptosis, autophagy accounts for the nonapoptotic decrease in cell viability, an effect that could be inhibited by chloroquine, an inhibitor of autophagy. Finally, we established a role for calpain activity in the induction of both autophagy and apoptosis by this combination. Conclusions: The combination of an HDACi and GX15-070 has synergistic antileukemia activity, and the effect is mediated by induction of apoptosis and autophagy. The combination should be studied in clinical trials of leukemia and the role of autophagy in leukemia therapy needs to be better understood. Clin Cancer Res; 16(15); 3923–32. ©2010 AACR.

Acute myeloid leukemia outcome: Role of nucleotide excision repair polymorphisms in intermediate risk patients

Abstract: In acute myeloid leukemia (AML), cytogenetics predicts treatment outcome for the favorable and poor subgroups but not for the intermediate subgroup. Polymorphisms within the nucleotide excision repair (NER) pathway may lead to interindividual differences in DNA repair capacity, influencing outcome. We studied the role of six polymorphisms (ERCC1 Gln504Lys, XPD Lys751Gln, XPC Ala499Val, XPC Lys939Gln, XPG Asp1104His, and CCNH Val270Ala) in overall and disease-free survival among 170 adult de novo patients with intermediate cytogenetics (diploid [n = 117]; non-diploid [n = 53]), treated with induction chemotherapy. Kaplan-Meier and Cox proportional hazards models were performed. Diploid patients with the XPD AC/CC genotype survived shorter than those with the wild-type genotype (median survival 22 vs. 40 months, p = 0.03). Diploid patients with XPC CT/TT genotype survived shorter than those with the wild-type genotype (median survival 15 vs. 30 months, p = 0.02). After adjusting for clinical and sociodemographic variables, patients carrying both XPD AC/CC and XPC CT/TT had a greater than two-fold increased risk of dying, compared to those with the wild-type genotypes (HR = 2.49; 95% CI: 1.06-5.85). No associations were observed for disease-free survival. This combined genotype may modulate treatment effect, decreasing overall survival. These findings could in the future help select treatments for patients with normal cytogenetics.

A phase I study of vorinostat in combination with idarubicin in relapsed or refractory leukaemia

Abstract: Histone deacetylase inhibitors (HDACi) affect chromatin remodelling and modulate the expression of aberrantly silenced genes. HDACi have single-agent clinical activity in haematological malignancies and have synergistic anti-leukaemia activity when combined with anthracyclines in vitro. We conducted a two-arm, parallel Phase I trial to investigate two schedules of escalating doses of vorinostat (Schedule A: thrice daily (TID) for 14 d; B: TID for 3 d) in combination with a fixed dose of idarubicin in patients with refractory leukaemia. Of the 41 patients enrolled, 90% had acute myeloid leukaemia, with a median of 3 prior therapies. Seven responses (17%) were documented (two complete response (5%), one complete response without platelet recovery (2.5%), and four marrow responses). The 3-d schedule of vorinostat was better tolerated than the 14-d schedule. The maximum tolerated dose for vorinostat was defined as 400 mg TID for 3 d. The most common grade 3 and 4 toxicities included mucositis, fatigue and diarrhoea. Correlative studies demonstrated histone acetylation in patients on therapy and modulation of CDKN1A and TOP2A (topoisomerase II) gene expression. Pharmacokinetic analysis confirmed a dose-related elevation in plasma vorinostat concentrations. The combination of vorinostat and idarubicin is generally tolerable and active in patients with advanced leukaemia and should be studied in the front-line setting.

Characteristics of pericardial effusions in patients with leukemia

Abstract: BACKGROUND: Little information exists regarding the prevalence and natural history of pericardial disease in patients with leukemia. Recently, it has been reported that the use of histone deacetylase inhibitors is associated with an increased incidence of pericardial effusions (PEs). To study the characteristics and treatment relationships of PEs in patients with leukemia, the authors retrospectively analyzed a cohort of patients with leukemia evaluated at a single center. METHODS: The authors reviewed 2592 patients with acute myeloid leukemia (AML, n = 1282, 49%), acute lymphocytic leukemia (ALL, n = 336, 13%), or myelodysplastic syndrome (MDS, n = 974, 38%), who were evaluated from August 2003 to July 2008. Electronic medical records were reviewed to select patients who had undergone at least 1 echocardiographic evaluation. Data regarding diagnosis, timing, effusion size, survival, and prior therapy were collected for the patients who had echocardiographic evidence of PEs. RESULTS: PEs were detected in 325 (20%) of the patients who had echocardiograms: 21% in AML, 23% in ALL, and 18% in MDS patients. Only a small portion of PEs were detected before the initiation of therapy: 26% in AML, 25% ALL, and 15% in MDS patients. Most PEs were of minimal size (70%) overall. No significant differences in effusion characteristics, including severity, were observed among different types of therapies. The presence of PEs had no impact on the survival of the patients evaluated. CONCLUSIONS: PEs are relatively common in patients with leukemia and do not appear to be related to specific types of therapy or to survival. Cancer 2010. © 2010 American Cancer Society.

Clinical impact of dose reductions and interruptions of second-generation tyrosine kinase inhibitors in patients with chronic myeloid leukaemia.

Abstract: Second (2nd)-generation tyrosine kinase inhibitors (TKI) (dasatinib, nilotinib) are effective in patients with all phases of chronic myeloid leukaemia (CML). Dose reductions and treatment interruptions are frequently required due to toxicity, but their significance is unknown. We analysed the impact of dose reductions/interruptions and dose intensity of 2nd-generation TKI on response and survival. A total of 280 patients with CML (all phases) were analysed. Dose reductions were considered when the daily dose was below the standard dose. Dose intensity was determined based on the percentage of the ideal dose intensity. Overall, 176 patients (63%) required treatment interruptions and/or dose reduction at least once during therapy. Dose reductions/interruptions, analysed as a time-dependent covariate, were associated with worse failure-free survival only in patients with untreated CML. Dose intensity analysis did not reveal a worse response or survival in patients who received a lower dose intensity (<100%) during therapy or during the first 6 months. In conclusion, dose reductions and treatment interruptions of 2nd generation TKI in patients with CML have a minimal impact in the response rate and survival of these patients. Further studies are required to determine whether there might be a minimum adequate dose of these agents.

Acute myeloid leukemia with t(9;11)(p21-22;q23): common properties of dysregulated ras pathway signaling and genomic progression characterize de novo and therapy-related cases.

Abstract: We compared pathogenetic features of 32 de novo and 29 therapy-related (t) t(9;11)(p21-22;q23)/MLLT3-MLL acute myeloid leukemia (AML) cases to identify progression factors and to assess whether distinction between these manifestations is warranted. MLLT3-MLL rearrangement was commonly the sole karyotypic abnormality at diagnosis, with many secondary chromosomal changes emerging at relapse in both subgroups. Ras point mutations were common in both groups (overall, 18/50 [36%]) and associated with monocytic phenotype and aneuploid progression. Expression patterns of 675 microRNAs profiled in 7 cases were also similar, with let-7 species linked to Ras down-modulation expressed at low levels. Outcome for both groups was poor (relapsed or refractory in 49/61 [80%] cases); however, patients with t-AML were generally older and female, with worse outcome (P = .03), likely secondary to t-AML mostly arising in patients with breast cancer following topoisomerase inhibitor-containing chemotherapy. Ras activation seems to complement the MLLT3-MLL oncogene in transformation with features of de novo and t-AML with MLLT3-MLL being similar.

Safety and efficacy of azacitidine in myelodysplastic syndromes

Abstract: Purpose: The clinical efficacy, different dosages, treatment schedules, and safety of azacitidine are reviewed.

Prognosis of myelodysplastic syndromes.

Abstract: The myelodysplastic syndromes (MDS) are a very complex group of hematopoietic disorders. The degree of complexity relates not only to the intrinsic pathobiological characteristics of the disease, but also to the group of patients whom it affects most frequently: older individuals or those who have been exposed to prior forms of chemotherapy. It is therefore crucial to develop clinical tools to predict with a certain degree of precision the prognosis and outcome for patients with specific subtypes of MDS in specific clinical situations. At the present time, patients with MDS are diagnosed using a set of well-established histopathological criteria. Prognosis is established using classifications that include morphological features, percentage of blasts, and clinical and molecular characteristics such as peripheral cytopenias and cytogenetics. The International Prognostic Scoring System (IPSS) is a classic example of this type of classification. Over the last 5 years, there has been an intense effort to develop new prognostic systems for MDS, and new molecular alterations with potential prognostic value have been discovered. Over the same period of time, several new therapeutic interventions have been developed for patients with MDS. Biomarkers of response to these agents, in particular for the hypomethylating agents, are needed to predict clinical benefit. This review summarizes current prognostic models of MDS and new molecular alterations with potential prognostic potential.

The combination of a histone deacetylase inhibitor with the BH3-mimetic GX15-070 has synergistic antileukemia activity by activating both apoptosis and autophagy.

Abstract: We analyzed the cellular and molecular effects of two different histone deacetylase inhibitors (HDACi), MGCD0103 and vorinostat, in combination with GX15-070, a BH3-mimetic, in acute myeloid leukemia (AML) cell lines and primary AML cells, and demonstrated that the combination has a synergistic antileukemia effect. We observed that in addition to apoptosis, autophagy also accounts for the observed nonapoptotic decrease of cell viability. Mechanistically, we established a role for calpain activity and ER-located caspase signaling in the induction of both autophagy and apoptosis following this combination of drugs. These findings reveal that for this specific combination, autophagy plays a positive role in inducing cytotoxicity, and that the involved ER signaling networks, as well as their clinical relevance, should be further studied in both preclinical and clinical trials of leukemia and other malignancies.

Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome

Abstract: Background Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS.

Feasibility of Therapy With Hypomethylating Agents in Patients With Renal Insufficiency

Abstract: Background To our knowledge, the feasibility of therapy with hypomethylating agents (HAs) in patients with renal insufficiency (RI) has not been examined. Patients and Methods We reviewed 41 patients with a diagnosis of acute myeloid leukemia (n = 17), myelodysplastic syndromes (n = 15), and chronic myelomonocytic leukemia (n = 9) who had RI and were receiving therapy with azacitidine or decitabine. The median number of administered cycles was 3. Most patients (39; 95%) received a standard dose of the drugs at the initiation of therapy. Nine patients (22%) required treatment interruptions or discontinuation, and 10 patients (24%) required dose reductions. Results: The overall response rate was 63%, and 4 patients (10%) achieved a complete response. Twenty patients (51%) experienced grade 3 or 4 myelosuppression-related toxicities. Hospitalization was required in 68% of the patients. Among 12 patients with an estimated glomerular filtration rate of 29 mL per minute or less, 6 required dose reductions attributable to myelosuppression (n = 3) or to worsening renal function (n = 3). The overall survival (OS) at 18 months was 12%, and the median OS was 8.6 months. Conclusion The use of HA in patients with RI is feasible, but is associated with a higher incidence of toxicity. Dose adjustments and the use of growth factor may be necessary for some patients.