Rebeca Rodríguez-Veiga

Central nervous system involvement at first relapse in patients with acute myeloid leukemia

The risk factors for and incidence of central nervous system involvement at first relapse in adult patients with acute myeloid leukemia have not been established. This single-center study analyzed the prognostic factors for and cumulative incidence of meningeal relapse in 458 adult patients achieving complete remission. Before 1990, patients received old chemotherapy approaches without stem cell transplantation that often included prophylactic intrathecal chemotherapy. Since 1990, modern protocols included stem cell transplantation without intrathecal prophylaxis. Meningeal relapse occurred in 6 patients (overall 5-year cumulative incidence 1.3%). The 5-year cumulative incidence of meningeal relapse in patients treated with old and modern protocols were 3.9% and 0.3%, respectively. Univariate and multivariate analyses showed that the chemotherapy approach was the main prognostic factor for central nervous system relapse (P=0.02). This study shows an extremely low incidence of meningeal relapse in adult patients with acute myeloid leukemia treated with modern protocols including stem cell transplantation without intrathecal prophylaxis.

Incidence and risk factors of post-engraftment invasive fungal disease in adult allogeneic hematopoietic stem cell transplant recipients receiving oral azoles prophylaxis

Studies that analyze the epidemiology and risk factors for invasive fungal disease (IFD) after engraftment in alloSCT are few in number. This single-center retrospective study included 404 alloSCT adult recipients surviving >40 days who engrafted and were discharged without prior IFD. All patients who received ⩾20 mg/day of prednisone were assigned to primary oral prophylaxis (itraconazole or low-dose voriconazole). The primary end point was the cumulative incidence (CI) of probable/proven IFD using the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. The independent prognostic factors after multivariate analyses were used to construct a post-engraftment IFD risk score. The 1-year CI of IFD was 11%. The non-relapse mortality was 40% in those developing IFD and 16% in those who did not. The intent-to-treat analysis showed that 17% of patients abandoned the assigned prophylaxis. Age >40 years, ⩾1 previous SCT, pre-engraftment neutropenia >15 days, extensive chronic GVHD and CMV reactivation were independent risk factors. The post-engraftment IFD score stratified patients into low risk (0–1 factor, CI 0.7%), intermediate risk (2 factors, CI 9.9%) and high risk (3–5 factors, CI 24.7%) (P<0.0001). The antifungal prophylaxis strategy failed to prevent post-engraftment IFD in 11% of alloSCT. Our risk score could be useful to implement risk-adapted strategies using antifungal prophylaxis after engraftment.

A prognostic model for survival after salvage treatment with FLAG-Ida +/− gemtuzumab-ozogamicine in adult patients with refractory/relapsed acute myeloid leukaemia

The combination of fludarabine, cytarabine, idarubicin, and granulocyte colony‐stimulating factor (FLAG‐Ida) is widely used in relapsed/refractory acute myeloid leukaemia (AML). We retrospectively analysed the results of 259 adult AML patients treated as first salvage with FLAG‐Ida or FLAG‐Ida plus Gentuzumab‐Ozogamicin (FLAGO‐Ida) of the Programa Español de Tratamientos en Hematología (PETHEMA) database, developing a prognostic score system of survival in this setting (SALFLAGE score). Overall, 221 patients received FLAG‐Ida and 38 FLAGO‐Ida; 92 were older than 60 years. The complete remission (CR)/CR with incomplete blood count recovery (CRi) rate was 51%, with 9% of induction deaths. Three covariates were associated with lower CR/CRi: high‐risk cytogenetics and t(8;21) at diagnosis, no previous allogeneic stem cell transplantation (allo‐SCT) and relapse‐free interval <1 year. Allo‐SCT was performed in second CR in 60 patients (23%). The median overall survival (OS) of the entire cohort was 0·7 years, with 22% OS at 5‐years. Four independent variables were used to construct the score: cytogenetics, FLT3‐internal tandem duplication, length of relapse‐free interval and previous allo‐SCT. Using this stratification system, three groups were defined: favourable (26% of patients), intermediate (29%) and poor‐risk (45%), with an expected 5‐year OS of 52%, 26% and 7%, respectively. The SALFLAGE score discriminated a subset of patients with an acceptable long‐term outcome using FLAG‐Ida/FLAGO‐Ida regimen. The results of this retrospective analysis should be validated in independent external cohorts.

Rapid Screening of ASXL1, IDH1, IDH2, and c-CBL Mutations in de Novo Acute Myeloid Leukemia by High-Resolution Melting

Recently, many novel molecular abnormalities were found to be distinctly associated with acute myeloid leukemia (AML). However, their clinical relevance and prognostic implications are not well established. We developed a new combination of high-resolution melting assays on a LightCycler 480 and direct sequencing to detect somatic mutations of ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), and c-CBL (exons 8 and 9) genes to know their incidence and prognostic effect in a cohort of 175 patients with de novo AML: 16 patients (9%) carried ASXL1 mutations, 16 patients had IDH variations (3% with IDH1(R132) and 6% with IDH2(R140)), and none had c-CBL mutations. Patients with ASXL1 mutations did not harbor IDH1, [corrected] or CEBPA mutations, and a combination of ASXL1 and IDH2 mutations was found only in one patient. In addition, we did not find IDH1 and FLT3 or CEBPA mutations concurrently or IDH2 with CEBPA. IDH1 and IDH2 mutations were mutually exclusive. Alternatively, NPM1 mutations were concurrently found with ASXL1, IDH1, or IDH2 with a variable incidence. Mutations were not significantly correlated with any of the clinical and biological features studied. High-resolution melting is a reliable, rapid, and efficient screening technique for mutation detection in AML. The incidence for the studied genes was in the range of those previously reported. We were unable to find an effect on the outcome.

Influence of cytarabine metabolic pathway polymorphisms in acute myeloid leukemia induction treatment

Abstract Cytarabine is considered the most effective chemotherapeutic option in acute myeloid leukemia (AML). The impact of 10 polymorphisms in cytarabine metabolic pathway genes were evaluated in 225 adult de novo AML patients. Variant alleles of DCK rs2306744 and CDA rs602950 showed higher complete remission (p = .024, p = .045), with lower survival rates for variant alleles of CDA rs2072671 (p = .015, p = .045, p = .032), rs3215400 (p = .033) and wild-type genotype of rs602950 (p = .039, .014). Induction death (p = .033) and lower survival rates (p = .021, p = .047) were correlated to RRM1 rs9937 variant allele. In addition, variant alleles of CDA rs532545 and rs602950 were related to skin toxicity (p = .031, p = .049) and mucositis to DCK rs2306744 minor allele (p = .046). Other toxicities associated to variant alleles were hepatotoxicity to NT5C2 rs11598702 (p = .032), lung toxicity (p = .031) and thrombocytopenia to DCK rs4694362 (p = .046). This study supports the interest of cytarabine pathway polymorphisms regarding efficacy and toxicity of AML therapy in a coherent integrated manner.

Impact of ABC single nucleotide polymorphisms upon the efficacy and toxicity of induction chemotherapy in acute myeloid leukemia

Abstract Anthracycline uptake could be affected by efflux pumps of the ABC family. The influence of 7 SNPs of ABC genes was evaluated in 225 adult de novo acute myeloid leukemia (AML) patients. After multivariate logistic regression there were no significant differences in complete remission, though induction death was associated to ABCB1 triple variant haplotype (p = .020). The ABCB1 triple variant haplotype was related to higher nephrotoxicity (p = .016), as well as this haplotype and the variant allele of ABCB1 rs1128503, rs2032582 to hepatotoxicity (p = .001; p = .049; p < .001). Furthermore, the variant allele of ABCC1 rs4148350 was related to severe hepatotoxicity (p = .044), and the variant allele of ABCG2 rs2231142 was associated to greater cardiac (p = .004) and lung toxicities (p = .038). Delayed time to neutropenia recovery was observed with ABCB1 rs2032582 variant (p = .047). This study shows the impact of ABC polymorphisms in AML chemotherapy safety. Further prospective studies with larger population are needed to validate these associations.

Correction to: A phase I–II study of plerixafor in combination with fludarabine, idarubicin, cytarabine, and G-CSF (PLERIFLAG regimen) for the treatment of patients with the first early-relapsed or refractory acute myeloid leukemia

The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández in the original article.The original version of this article was revised: The name of Pau Montesinos was inadvertently presented as Pau Montesinos Fernández.

Treatment of invasive fungal disease using anidulafungin alone or in combination for hematologic patients with concomitant hepatic or renal impairment.

BACKGROUND Invasive fungal disease (IFD) treatment is challenging in hematologic patients due to drug interactions and toxicities that limit the use of the antifungal agents. AIMS To analyze retrospectively in terms of safety and potential efficacy anidulafungin therapy, alone or in combination. METHODS Our institutional guidelines recommended anidulafungin treatment in hematologic patients with suspected IFD and concomitant renal or liver impairment (to avoid drug interactions and preserve organ function). RESULTS From 2008 to 2013, 24 episodes of IFD occurring in 21 patients were classified as proven (4 cases), probable (15 cases) and possible (5 cases). Anidulafungin was administered alone (13%) or in combination (88%). Eight (33%) episodes were resolved, using monotherapy (1 out of 3, 33%) or a combined therapy (7 out of 21, 33%). Twelve cases (50%) were registered as failure (death due to IFD progression in 4 patients, and treatment change due to lack of efficacy in 8), and 4 cases (17%) were not evaluable (death unrelated to the IFD). Anidulafungin was not withdrawn in any case due to toxicity. CONCLUSIONS Anidulafungin therapy, alone or in combination, could be considered in hematologic patients with IFD and concomitant liver or renal impairment. Due to the low number of patients, we cannot draw any conclusion about efficacy.

Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy

Efficacy and toxicity of anthracycline treatment in acute myeloid leukemia (AML) is mediated by reactive oxygen species (ROS). NADPH oxidase is the major endogenous source of ROS and a key mediator of oxidative cardiac damage. The impact of NADPH oxidase polymorphisms (CYBA:rs4673, NCF4:rs1883112, RAC2:rs13058338) was evaluated in 225 adult de novo AML patients. Variant alleles of NCF4 and RAC2 were related to higher complete remission (P=0.035, P=0.016), and CYBA homozygous variant showed lower overall survival with recessive model (P=0.045). Anthracycline-induced cardiotoxicity was associated to NCF4 homozygous variant (P=0.012) and CYBA heterozygous genotype (P=0.027). Novel associations were found between variant allele of CYBA and lower lung and gastrointestinal toxicities, and a protective effect in nephrotoxicity and RAC2 homozygous variant. Moreover, RAC2 homozygous variant was related to delayed thrombocytopenia recovery. This study supports the interest of NADPH oxidase polymorphisms regarding efficacy and toxicity of AML induction therapy, in a coherent integrated manner.

Anti-D Alloimmunization after RhD-Positive Platelet Transfusion in RhD-Negative Women under 55 Years Diagnosed with Acute Leukemia: Results of a Retrospective Study

Background: Anti-D alloimmunization can occur when platelets from RhD-positive donors are transfused to RhD-negative patients, due to red blood cell residues in the platelet concentrates. Methods: Our objective was to analyze the anti-D alloimmunization rate in a selected group of women under 55 years of age diagnosed with acute leukemia over an 18-year period. We focused the analysis on RhD-negative patients who received RhD-positive platelet transfusions. Results: From January 1998 to October 2016, 382 women under 55 years were diagnosed with acute leukemia. A total of 56 patients were RhD-negative, and 48 (85.7%) received RhD-positive platelets. The median number of platelet concentrates transfused per patient was 23, and 48% of all platelet transfusions were RhD-positive. The 48 RhD-negative patients received a total of 949 RhD-positive platelet concentrates. Two patients developed anti-D: a 36-year-old woman with M3 acute myeloblastic leukemia and a 52-year-old patient with a secondary acute myeloblastic leukemia. Conclusion: We conclude that there is a need for agreement in the transfusion guidelines on the recommendation of anti-D alloimmunization prophylaxis. We suggest a possible benefit in favor of anti-D prophylaxis in childbearing women with acute leukemia.