Efficacy and Toxicity of Idarubicin Versus High-dose Daunorubicin for Induction Chemotherapy in Adult Acute Myeloid Leukemia: A Systematic Review and Meta-analysis

Background

The 2 main formulations of anthracycline used for acute myeloid leukemia (AML) induction therapy are idarubicin (IDA) and daunorubicin.

Defining Acute Myeloid Leukemia Ontogeny in Older Patients

BackgroundAcute myeloid leukemia (AML) in elderly patients is associated with poor outcomes and often arises from antecedent hematologic disorders (AHD), classified as secondary AML (sAML).Patients and MethodsTo validate the use of somatic mutations to determine AML ontogeny in the elderly population, we identified 178 elderly (> 70 years) patients with AML with NexGen Sequencing data. Patients were divided clinically into primary AML (pAML) or sAML based on prior history of AHD. Patients were then reclassified into 4 groups based on somatic mutations and cytogenetics as suggested by Lindsley et al: group 1 (pAML) with CBF rearrangements, 11q23/MLL, and NPM1 mutation (MT); group 2 (sAML) with SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 MT; group 3 with TP53 MT; and group 4 as not otherwise specified (NOS).ResultsBased on clinical criteria, 95 patients were classified as pAML and 82 patients as sAML. Based on the AML ontogeny proposed, 8 patients were classified as pAML, 72 patients as sAML, 28 patients had TP53 MT, and 70 patients were classified as NOS. The median overall survival was 22.4,14, 2.8, and 11.2 months, respectively. Clinical versus molecular classification was discordant where 25% (n = 2) of patients classified as pAML by molecular signature had a history of AHD, whereas 44% (n = 32) of patients classified molecularly as sAML had no prior AHD. In the TP53 MT and NOS categories, 37% (n = 28) and 43% (n = 70) of patients had AHD, respectively.ConclusionOur data shows that molecular annotation of elderly patients with AML reclassifies a significant proportion of patients as sAML, which may have therapeutic implications.     

Outcomes of Patients With Relapsed Core Binding Factor-Positive Acute Myeloid Leukemia

Purpose

To determine the factors associated with outcomes in patients with core binding factor acute myeloid leukemia (CBF-AML) in first relapse.

Association of SDF-1 Gene Polymorphism with Increased Risk of Acute Myeloid Leukemia Patients

Background: Acute myeloid leukemia (AML) is a heterogenous group of disorders that emerge from the malignant transformation of hematopoietic stem cells. Chemokine stromal cell-derived factor 1(SDF-1) and its receptor CXC receptor 4 (CXCR4) has an essential role in dissemination of blast cells. Study aimed to detect CXCR4 expression and the SDF-1 (rs1801157) gene polymorphisms and correlate them with prognosis and outcome in AML patients. Subjects and Methods: The study was conducted on 60 de-novo AML patients, and 60 healthy controls. SDF-1 (rs1801157) gene polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and CXCR4 expression was done using flow cytometry analysis. Results: SDF-1 dominant model (AG+AA) had higher risk AML (p 0.002). CXCR4positive cases were associated significantly with toxic manifestations (p 0.019), lower CR rates (p 0.004), and unfavorable cytogenetics (p 0.027). Multivariate analysis showed that combined CXCR4positive with dominant SDF-1 considered as independent prognostic factor for shorter overall survival (OS) in AML patients (p 0.031). Conclusion: SDF-1 dominant model had a higher risk to develop AML, and CXCR4 positive expression predicts poor prognosis in AML patients and it could represent a targeted therapy in AML. In addition, CXCR4 could be easily integrated into the initial routine diagnostic work up of AML.     

Effects of rhGM-CSF on Myeloid Clonogenic Cells in Acute Myelogenous Leukemia Patients

The effects of rhGM-CSF in vivo on the myeloid clonogenic cells present in 6 AML patients was evaluated. The relative number of clonogenic cells fell in 4 of the 6 patients. The effects of rhGM-CSF on the percentage of clonogenic cells in S phase and the sensitivity of clonogenic cells to cytosine arabinoside varied among the patients. These effects were not related to the effects of rhGM-CSF on the white blood cell count or on the proliferative rate of the leukemia cell population as a whole.     

DNA Repair Genes Polymorphisms: Impact on Acute Myeloid Leukemia Patients Outcome

Background: ATM; XRCC6 and LIG4 genes play an important role in repairing the double-strand DNA breaks and maintaining the genome stability. Single nucleotide polymorphisms (SNPs) in these genes could affect these genes expression and function. The aim of this study was to address the effect of SNP of the DNA repairing genes on corresponding  gene expression as well as AML patient’s outcome. Subjects and Methods: This is cross sectional study included 95 newly diagnosed AML patients. For all subjects included in our study SNPs  and expression of ATM (rs189037G>A), XRCC6 (rs2267437C>G) and LIG4 (rs1805388C>T) genes were evaluated by RFLP and real time PCR. Results:The following SNPs in ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of the corresponding genes (P<0.001). The lower expression of ATM and LIG4 genes are associated with shorter OS and DFS. Cox regression multivariate analysis revealed that lower expression of ATM HR : 2.02 (CI: 1.12-3.64; p=0.020. Conclusion: The following SNPs of ATM (AA); XRCC6 (GG); and LIG4 (TT) are associated with down regulation of corresponding genes expression. ATM and XRCC6 lower expression are predictors of OS while ATM is predictor of DFS and could be used for optimizing the AML therapy.     

NOTCH-1 Gene Mutations Influence Survival in Acute Myeloid Leukemia Patients

Background: Although NOTCH-1 gene mutations were reported to contributes to leukemogenesis in lymphocytic leukemias, its role in acute myeloid leukemia (AML) remains unclear. Therefor; this study was designed to determine the prevalence and clinical impact of NOTCH-1 mutations in AML patients. Materials and Methods: In the current study, NOTCH-1 gene mutations were identified in Bone Marrow samples obtained from fifty primary AML patients before start of therapy using Sanger sequencing. Results: NOTCH-1 gene mutations were detected in 6 out of 50 AML cases (12%). The three mutations were (two mutations C7318A in the Pest domain exon 34); (another 2 in the Pest domain Del 7,344, ins C7349, G7356A and the last ones in the HD-N exon-26 (Del A4609). The clinical findings in the mutant AML (mu AML) patients did not significantly different as compared to the un mutated (unmut) AML patients.  There is significant association between CD7 aberrant expression and NOTCH-1 mutations. The complete remission was significantly higher in unmut AML cases as compared to mut AML ones (P=0.024). Multivariate (Age; Gender; Bone Marrow Blast cells; NOTCH-1 mutations) Cox regression analysis revealed that NOTCH-1 mutation is an independent risk factor for AML overall survival (P<0.001). The OS in unmut AML group (21.2 months) was significantly longer as compared to mut AML one (1.2 months) (P<0.001). Conclusion: Our data indicate that NOTCH-1 gene mutations were detected in 12% of AML patients. These mutations displayed bad clinical outcome on AML patients. Therapeutic targeting of NOTCH-1 could be a potentially effective approach to combat master oncogenic drivers in AML.     

FLAG-Ida Regimen as Bridge Therapy to Allotransplantation in Refractory/Relapsed Acute Myeloid Leukemia Patients

BackgroundPatients with primary refractory or first relapse acute myeloid leukemia (AML) are considered to have worse clinical outcomes after treatment. For these patients, the achievement of complete remission appears crucial for them to be able to undergo allotransplantation, which might be the only possible treatment.Patients and MethodsWe used the FLAG-Ida (fludarabine, cytarabine [cytosine arabinoside], granulocyte colony-stimulating factor, idarubicin) regimen in patients with primary refractory/first relapse AML as a bridge to transplantation. We studied its efficacy in terms of overall response and overall survival to assess which variables (age, lactate dehydrogenase, bone marrow blast count, peripheral blood blast count, platelet count, white blood cell count, de novo or secondary AML, molecular-cytogenetic risk, duration of response, and relapsed or refractory disease) might have an effect on outcome.ResultsWe analyzed the data from 108 consecutive adult patients (52 males, 66 females; median age, 49 years; range, 17-72 years) with newly diagnosed AML refractory to standard induction regimens or relapse after first complete remission, who had received the FLAG-Ida protocol as salvage therapy from January 2005 to December 2015. An overall response was achieved in 48 patients (44%). On multivariate analysis, the variables with a positive effect on the response rate were molecular-cytogenetic risk (P = .009), duration of first response in relapsed AML (P = .003), AML status (relapsed or refractory; P = .047), and peripheral blood blast count (P = .016). On multivariate analysis, overall survival was significantly associated with FLAG-Ida response (hazard ratio, 0.343; P = .001) and receipt of allotransplantation (hazard ratio, 0.277; P < .001).ConclusionOur data seem to confirm the value of FLAG-Ida in this setting and might suggest its best usage as bridge therapy for patients awaiting allotransplantation.     

Impact of Health Care Insurance Status on Treatment Outcomes of Acute Myeloid Leukemia

IntroductionInsurance status has been found to influence treatment outcomes in various solid tumors. Limited data with conflicting results are available in patients with acute myeloid leukemia (AML). We examined the impact of health insurance at diagnosis on AML treatment outcomes.Patients and MethodsAll consecutive adult patients (≥ 18 years of age) diagnosed with AML between 2002 and 2011 and followed through August 2013 were included. Survival estimates were calculated by Kaplan-Meier survival curves. Logistic regression and multivariate Cox proportional hazards methods were used to explore the influence of multiple baseline covariates on treatment outcomes.ResultsA total of 217 patients with complete medical records were identified. Of these, 161 patients had complete cytogenetic/molecular data for risk stratification and were included in the final efficacy analyses. Most patients (45.8%) were publicly insured, 36.3% were privately insured, and 17.3% were uninsured. No significant association was found between insurance source and cytogenetic/molecular risk status. Transplantation information was available for 157 patients, with no significant association found between transplant receipt and insurance source. After adjustment for age, cytogenetic/molecular risk, and transplant receipt, we found no statistically significant association between the insurance source and either event-free or overall survival.ConclusionInsurance source at diagnosis has no impact on AML treatment outcomes. The consistency of our results with some, but not all, studies is probably driven primarily by access-to-care eligibility requirements among different states. Further efforts to better understand such disparities are warranted.     

Phase II-Trial of Double-Consolidation Following Intensive Induction Treatment for Improvement of Survival in Elderly Patients with Acute Myeloid Leukemia

Thirty-two consecutive, unselected acute myeloid leukemia (AML) patients (pts) of all FAB-subtypes with a median age of 68 years were treated with intensive induction chemotherapy consisting of one or two cycles of daunorubicin 30 mg/m² day 1-3 and Ara C 100 mg/m² as continuous infusion day 1-7. The overall CR rate was 50%, 14/24 (58%) in de novo AML, and 2/8 (25%) with preceding MDS. One patient achieved a PR of 21 months duration, 3 pts died within 7 days of the induction treatment (ED), 6 died during hypoplasia (HD), and 6 remained refractory to 2 cycles of induction. Four pts died after achieving CR. Of the remaining 12 responders, 11 pts received 2 cycles of consolidation consisting of daunorubicin 30 mg/m² day 1, and Ara C 100 mg/m² continuous IV infusion day 1-7. No deaths were observed during consolidation. DFS and survival of responders were 7 and 13 months respectively, survival of all pts, responders and non-responders, was 7 months. Large cooperative trials are necessary to identify those elderly pts who may benefit from intensified consolidation treatment.     

Alternative Effective and Safe Induction Regimens for Newly Diagnosed Acute Myeloid Leukemia in Patients With Cardiac Contraindication to Anthracyclines

IntroductionThe standard first-line treatment for acute myeloid leukemia (AML) is a combination of cytarabine and anthracyclines. To date, there is no commonly agreed-on regimen for patients who are ineligible for this therapy because of cardiac comorbidities or prior exposure to anthracyclines. We compared 3 anthracycline-free regimens currently used in France.Patients and MethodsTwo patients with newly diagnosed or relapsed/refractory AML were treated intensively in 3 French centers. All patients had at least one contraindication to the receipt of anthracyclines. Three regimen types were used: fludarabine, cytarabine, and granulocyte-colony stimulating factor (FLAG); clofarabine and cytarabine (CLARA); and topotecan plus cytarabine (TA).ResultsThirty patients (58%) had de novo AML. The European LeukemiaNet 2013 risk categories were favorable, intermediate, and adverse in 4 (8%), 27 (52%), and 20 (39%) patients, respectively. Twenty-four patients received TA and 28 FLAG/CLARA regimens. Fifty percent of patients had cardiac dysfunction, and 50% had prior anthracycline exposure above the maximum tolerated dose. The rate of cardiac events was similar after TA (17%) and FLAG/CLARA (25%) (P = .78). The 5-year nonrelapse mortality was 17.9% and 12.5% in the TA and FLAG/CLARA groups, respectively (P = .59). In patients with previously untreated AML, complete response occurred in 18 (72%) of 25, but median overall survival was only 9.7 months.ConclusionTA, FLAG, and CLARA regimens are efficient and are associated with acceptable toxicity in AML patients ineligible for the 3 + 7 regimen as a result of cardiac comorbidities. However, long-term outcome remains disappointing, thereby highlighting the need for the development of less toxic regimens.     

High Remission Rate in Acute Myeloblastic Leukemia with Only Two Days of Chemotherapy

Twenty five patients with AML who had neither a history of toxic exposure or myelodysplasia were treated with a remission induction regimen consisting of two pulses of chemotherapy separated by 96 hrs. Each pulse consisted of cytarabine 2gm/m² (at t=0 and t=12 hrs) with mitoxantrone [30mg/m²] administered immediately after the second cytarabine administration. Amifostine was administered three times a week [on Monday, Wednesday, and Friday] until the outcome of therapy was known. This regimen induced complete remissions in 15 of 17 patients less than 70 years of age and in 5 of 8 patients older than 70 years.     

Adding Oral Pioglitazone to Standard Induction Chemotherapy of Acute Myeloid Leukemia: A Randomized Clinical Trial

BackgroundThe hypothesis of an effect by thiazolidinedione on leukemia cells was proposed 2 decades ago, but there is little clinical evidence regarding its efficacy. We evaluated the safety and efficacy of adding pioglitazone to standard induction chemotherapy in patients with acute myeloid leukemia (AML).Patients and MethodsIn this randomized clinical trial, newly diagnosed AML patients were randomized to 1 of 2 groups. Patients in both groups received cytarabine (100 mg/m² per day for 7 days) and daunorubicin (60 mg/m² per day for 3 days). Patients in the pioglitazone group additionally received oral pioglitazone (45 mg per day). The 2 groups were compared according to remission rate, laboratory findings, and adverse events during treatment.ResultsForty patients were evaluated, 20 patients in each group. The complete remission rate was 20% more in the pioglitazone group compared to the control group (P = .202). Complications due to pioglitazone discontinuation were observed in 2 cases. The mean serum alanine aminotransferase in the fourth treatment week was significantly more in pioglitazone group compared to the control group (65.5 vs. 33.6 mg/dL, P = .039). The mean serum creatinine in all treatment phases was significantly higher in the pioglitazone group compared to the control group (P < .05). There were no significant differences between the 2 groups regarding other laboratory findings (P > .05).ConclusionAdding pioglitazone to cytarabine and daunorubicin increased the remission rate in AML patients compared to control subjects. Although this difference in remission rate between the 2 groups was not statistically significant, it could be important in the clinical setting. Pioglitazone may provide benefits as an adjuvant therapy for AML patients without causing serious adverse events.     

Neurocysticercosis Coincident with Acute Myeloid Leukemia: A Case Report

We describe the unusual coincidence in a 25 year old Mexican immigrant who presented with neurocysticercosis and acute myeloid leukemia. Treatment for the acute leukemia was initiated after corticosteroids were administered to decrease cerebral edema caused by the neurocysticercosis. Complete remission of the leukemia was eventually achieved and specific antibiotic therapy for neurocysticercosis was initiated with praziquantel. We discuss our approach to the treatment of these two diseases, the complications that arose, and briefly review the literature on the current treatment of neurocysticercosis.     

Outcome of Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome According to Health Insurance Status

BackgroundAge, cytogenetic status, and molecular features are the most important prognostic factors in acute myeloid leukemia (AML). This study aimed to analyze the outcomes of patients with AML or high-risk myelodysplastic syndrome (MDS) according to insurance status.Patients and MethodsA retrospective chart review was performed, covering all patients with AML and high-risk MDS evaluated and treated at Akron General Medical Center between 2002 and 2012. A Cox regression model was analyzed to account for survival over time, adjusted for insurance type, while controlling for patient age at diagnosis and patient risk of mortality.ResultsA total of 130 adult patients (age ≥ 18 years) were identified. Insurance information was available for 97 patients enrolled in the study; 3 were excluded because of self-pay status. Cox regression analysis with insurance type as the predictor found that overall survival declines over time and that the rate of decline may be influenced by insurance type (χ²(2) = 6.4; P = .044). The likelihood of survival in patients with Medicaid or Medicare without supplemental insurance was .552 (95% CI, .338-.903; P = .018) times the likelihood in patients who had Medicare with supplemental insurance. To explain the difference, variables of age, gender, and risk of mortality were added to the model. Age and risk of mortality were found to be significant predictors of survival. The addition of insurance type to the model did not significantly contribute (χ²(3) = 3.83; P = .147).ConclusionNo significant difference in overall survival was observed when patients with AML or high-risk MDS were analyzed according to their health insurance status. The overall survival was low in this study compared with the national average. Early referral to a specialized center or possible clinical trial enrollment may be a good alternative to improve outcome.     

Rapid Remission Induction and Improved Disease Free Survival in Acute Myeloid Leukaemia Using Daunorubicin, ARA-C, and CCNU

Thirty-four patients with acute myeloblastic leukaemia were treated with DAC, a schedule containing the nitrosourea CCNU (lomustine) 200 mg/m2 given on day one of treatment, together with a standard “3 + 7” remission induction schedule of daunorubicin (DR) and cytosine arabinoside (Ara-C). The results were compared with an historical control group of 24 patients who received 3 + 7 remission induction (DA). The DAC patients were older (median age 55 years) compared with the DA patients (median age 42 years), and had a higher frequency of poor prognosis features including secondary AML and prior myelodysplasia (11/34 DAC patients versus 1/24 patients receiving DA). Overall remission induction was the same for both groups (79%), but 89% of DAC patients who achieved remission did so with one course, compared with 37% of DA patients. The cytopenic phase following a single course of DAC was only slightly longer than that of a single course of DA (26 days vs. 19.5 days). DAC also gave a higher three year actuarial survival than DA (34% vs. 11%), and a lower relapse probability (44% vs. 74%).

These results support the hypothesis that chemotherapy for AML may be favoured by including agents such as CCNU, which are active against both non-cycling and cycling leukaemic stem cells, in remission induction schedules.     

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) in Acute Myeloid Leukemia Patients

Backgrounds: Toll-like receptors 2; 4 (TLR2;4) are an essential component of the innate immunity and play an important role in immune-surveillance and immune response to various microorganisms. This study aimed to investigate the association between TLR2 and TLR4 polymorphism and the risk of acquiring severe infections, and impact on AML patient’s outcome. Subjects and methods: Using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP); we analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) in 120 AML patients and 100 healthy control subjects. Results: No significant differences in genotype or alleles frequency between healthy controls and AML patients regarding TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms (P>0.05 for all). Neutropenic fever was detected in 110 out of 120 (91.7%) of the studied AML patients. The sepsis and pneumonia were identified in 20 out of 120 patients (16.7%). The incidence of sepsis was associated with TLR2 Arg753Gln: AG genotypes, A allele and TLR4 Asp299Gly: CT genotype and C allele as compared to other genotypes and alleles. Moreover; TLR2 (Arg753Gln) GG polymorphisms significantly associated with shortest overall survival (OS) and shortest disease-free survival (DFS); while TLR4 polymorphisms affect the DSF only but not OS. In AML patients TLR2 Arg753Gln gene polymorphism is associated with high susceptibility to sepsis and TLR4 (Asp299Gly and Thr399Ile) gene polymorphism is associated with high susceptibility for both pneumonia; and sepsis. Conclusion: TLR2 Arg753Gln (AG; GG genotype) polymorphisms are associated with shortest OS and DFS. Moreover; significant association between TLR2 polymorphisms, TLR4 Arg753Gln polymorphisms and risk of severe infections in AML patients was documented.     

Day 14 Bone Marrow Evaluation During Acute Myeloid Leukemia Induction in a Real-world Canadian Cohort

IntroductionThe 2017 National Comprehensive Cancer Network guidelines for acute myeloid leukemia have recommended performing bone marrow (BM) aspiration and BM trephine biopsy (BMTB) 14 to 21 days after starting induction therapy (commonly referred to as “day 14 [D14] marrow”). Those who do not achieve a hypoplastic marrow, with cellularity < 20% and blasts < 5%, are recommended to undergo 2-cycle induction (2CI). We performed a retrospective analysis to determine the impact of D14 BM characteristics in predicting for remission, association with overall survival (OS), and the effect of 2CI according to the D14 BM results.Patients and MethodsPatients aged 18 to 70 years undergoing induction therapy with standard “7 + 3” regimens were included. D14 cellularity was determined from BMTB samples and the blast percentage was assessed by morphology on BM aspiration and BMTB samples. The outcomes evaluated included the rates of complete remission (CR) and OS.ResultsA total of 486 patients with results from D14 BM evaluation were included in the present study. On multivariate analysis, cytogenetic risk and D14 blasts < 5% were predictive of CR/CR with incomplete count recovery (P < .001). Cytogenetic risk (P < .001), age < 60 years (P = .001), and D14 blasts < 5% (P = .045) predicted for OS. 2CI was performed in 131 patients (27%). Patients with hypocellular D14 BM but residual blasts (n = 106) underwent 2CI in 46% of cases, with improved remission rates (43.9% vs. 72.0%; P = .004) but no difference in OS.ConclusionsThe results from D14 BM evaluations are predictive of subsequent remission and OS. Our findings did not show a survival benefit with D14 BM-driven 2CI.     

Sepsis and Acute Myeloid Leukemia: A Population-Level Study of Comparative Outcomes of Patients Discharged From Texas Hospitals

BackgroundIn the United States, approximately 750,000 cases of sepsis occur annually, and 28% to 50% of affected people die. Treatment is costly, often involving admission to the intensive care unit and prolonged hospitalization. We evaluated outcomes of patients with acute myeloid leukemia (AML) and sepsis in Texas.Patients and MethodsWe conducted a population-based cohort study of adults discharged from Texas hospitals during 2011, using ICD-9-CM codes and the Texas Inpatient Data Collection.ResultsA total of 2,173,776 adults were discharged from hospitals in Texas, and 5501 (0.25%) had a diagnosis of AML. Among patients with AML, 40% were ≥ 65 years old, and 52% were men. The rate of sepsis for AML patients was 16% compared to 4% for non-AML patients. Among patients with AML, sepsis was associated with pneumonia, acute renal failure, and hematologic dysfunctions in 34%, 32%, and 29% of discharges, respectively. Median length of stay, intensive care unit admission rate, and median hospital charges per stay for patients with AML and sepsis were 13 days (range, 1-133 days), 72%, and $122,333, respectively. Among in-hospital deaths due to sepsis, mortality was 30% in AML patients compared to 21% in non-AML patients.ConclusionPatients with AML had a higher sepsis incidence and higher mortality rates overall, especially in relation to stem-cell transplant recipients and those with other types of cancer. Clinical trials are needed to determine whether early intervention or treatment in specialized centers could improve outcomes and reduce costs of care, particularly in the management of serious complications such as sepsis.