Subject(s)
Oncogene Proteins, Fusion/genetics , Retinoic Acid Receptor alpha/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , Disease-Free Survival , Female , Humans , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/mortality , Male , Middle Aged , Survival RateABSTRACT
BACKGROUND: The ZBTB16-RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor-α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all-trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis. AIMS: The mutational profile of ZBTB16-RARA rearranged AML has not been described so far. MATERIALS AND METHODS: We performed targeted next-generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16-RARA+AML, 103 non-RARA rearranged AML, and 46 APL. The seven ZBTB16-RARA-positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4). RESULTS: ZBTB16-RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16-RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%). DISCUSSION AND CONCLUSION: Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.
Subject(s)
Leukemia, Myeloid, Acute/genetics , Oncogene Proteins, Fusion/genetics , Promyelocytic Leukemia Zinc Finger Protein/genetics , Retinoic Acid Receptor alpha/genetics , Translocation, Genetic , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/therapeutic use , Arsenic Trioxide/therapeutic use , Bone Marrow/pathology , Child , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 17 , DNA Helicases/genetics , DNA-Binding Proteins/genetics , Disseminated Intravascular Coagulation/epidemiology , Female , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Leukemia, Promyelocytic, Acute/genetics , Leukemia, Promyelocytic, Acute/pathology , Male , Middle Aged , Nuclear Proteins/genetics , Prognosis , Transcription Factors/genetics , Tretinoin/therapeutic useABSTRACT
Acute promyelocytic leukaemia (APL) represents a modern success of precision medicine. However, fatalities occurring within the first 30 days of induction treatment, in particular intracranial haemorrhage (ICH), remain the main causes of death. We studied the clinico-biological characteristics of 13 patients with APL who experienced ICH. Compared to 85 patients without this complication, patients with ICH were older and more frequently had high-risk APL. Moreover, positivity for the 'swirl' sign at neuroradiological imaging and hydrocephalus were predictors of a fatal outcome, together with lower fibrinogen, prolonged international normalized ratio (INR) and higher lactate dehydrogenase levels.
Subject(s)
Intracranial Hemorrhages/etiology , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/complications , Neuroradiography/methods , Adolescent , Adult , Aged , Aged, 80 and over , Case-Control Studies , Child , Female , Fibrinogen/analysis , Humans , Hydrocephalus/diagnosis , Hydrocephalus/epidemiology , International Normalized Ratio/methods , Intracranial Hemorrhages/diagnosis , Intracranial Hemorrhages/mortality , L-Lactate Dehydrogenase/blood , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/drug therapy , Male , Middle Aged , Mortality , Neuroradiography/statistics & numerical data , Precision Medicine/statistics & numerical data , Predictive Value of Tests , Remission Induction/methods , Risk Factors , Tomography, X-Ray Computed/methods , Young AdultABSTRACT
The results from the RATIFY trial (ClinicalTrials.gov: NCT00651261; CALGB 10603) showed that midostaurin combined with standard chemotherapy significantly improved outcomes in patients with FMS-like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML), compared with placebo. In this post hoc subgroup analysis from the trial, we evaluated the impact of midostaurin in 163 patients with FLT3-tyrosine kinase domain (TKD) mutations. At a median follow-up of 60.7 months (95% CI, 55.0-70.8), the 5-year event-free survival (EFS) rate was significantly higher in patients treated with midostaurin than in those treated with placebo (45.2% vs 30.1%; P = .044). A trend toward improved disease-free survival was also observed with midostaurin (67.3% vs 53.4%; P = .089), whereas overall survival (OS) was similar in the 2 groups. Patients with AML and NPM1mut/FLT3-TKDmut or core binding factor (CBF)-rearranged/FLT3-TKDmut genotypes had significantly prolonged OS with or without censoring at hematopoietic cell transplantation (HCT), compared with NPM1WT/CBF-negative AMLs. The multivariable model for OS and EFS adjusted for allogeneic HCT in first complete remission as a time-dependent covariable, revealed NPM1 mutations and CBF rearrangements as significant favorable factors. These data show that NPM1 mutations or CBF rearrangements identify favorable prognostic groups in patients with FLT3-TKD AMLs, independent of other factors, also in the context of midostaurin treatment.
Subject(s)
Leukemia, Myeloid, Acute , fms-Like Tyrosine Kinase 3 , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Nucleophosmin , Staurosporine/analogs & derivatives , Staurosporine/therapeutic use , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
The SLIT-ROBO axis plays an important role in normal stem-cell biology, with possible repercussions on cancer stem cell emergence. Although the Promyelocytic Leukemia (PML) protein can regulate SLIT2 expression in the central nervous system, little is known about SLIT2 in acute promyelocytic leukemia. Hence, we aimed to investigate the levels of SLIT2 in acute promyelocytic leukemia (APL) and assess its biological activity in vitro and in vivo. Our analysis indicated that blasts with SLIT2high transcript levels were associated with cell cycle arrest, while SLIT2low APL blasts displayed a more stem-cell like phenotype. In a retrospective analysis using a cohort of patients treated with all-trans retinoic acid (ATRA) and anthracyclines, high SLIT2 expression was correlated with reduced leukocyte count (p = 0.024), and independently associated with improved overall survival (hazard ratio: 0.94; 95% confidence interval: 0.92-0.97; p < 0.001). Functionally, SLIT2-knockdown in primary APL blasts and cell lines led to increased cell proliferation and resistance to arsenic trioxide induced apoptosis. Finally, in vivo transplant of Slit2-silenced primary APL blasts promoted increased leukocyte count (p = 0.001) and decreased overall survival (p = 0.002) compared with the control. In summary, our data highlight the tumor suppressive function of SLIT2 in APL and its deteriorating effects on disease progression when downregulated.
ABSTRACT
Acute myeloid leukemia (AML) with FLT3-ITD mutations (FLT3-ITDmut) remains a therapeutic challenge, with a still high relapse rate, despite targeted treatment with tyrosine kinase inhibitors. In this disease, the CD34/CD123/CD25/CD99+ leukemic precursor cells (LPCs) phenotype predicts for FLT3-ITD-positivity. The aim of this study was to characterize the distribution of FLT3-ITD mutation in different progenitor cell subsets to shed light on the subclonal architecture of FLT3-ITDmut AML. Using high-speed cell sorting, we sequentially purified LPCs and CD34+ progenitors in samples from patients with FLT3-ITDmut AML (n = 12). A higher FLT3-ITDmut load was observed within CD34/CD123/CD25/CD99+ LPCs, as compared to CD34+ progenitors (CD123+/-,CD25-,CD99low/-) (p = 0.0005) and mononuclear cells (MNCs) (p < 0.0001). This was associated with significantly increased CD99 mean fluorescence intensity in LPCs. Significantly higher FLT3-ITDmut burden was also observed in LPCs of AML patients with a small FLT3-ITDmut clones at diagnosis. On the contrary, the mutation burden of other myeloid genes was similar in MNCs, highly purified LPCs and/or CD34+ progenitors. Treatment with an anti-CD99 mAb was cytotoxic on LPCs in two patients, whereas there was no effect on CD34+ cells from healthy donors. Our study shows that FLT3-ITD mutations occur early in LPCs, which represent the leukemic reservoir. CD99 may represent a new therapeutic target in FLT3-ITDmut AML.
Subject(s)
Leukemia, Myeloid, Acute/genetics , fms-Like Tyrosine Kinase 3/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Mutation , Prognosis , Protein Kinase Inhibitors/therapeutic use , Young AdultABSTRACT
Non-T cell activation linker (NTAL) is a lipid raft-membrane protein expressed by normal and leukemic cells and involved in cell signaling. In acute promyelocytic leukemia (APL), NTAL depletion from lipid rafts decreases cell viability through regulation of the Akt/PI3K pathway. The role of NTAL in APL cell processes, and its association with clinical outcome, has not, however, been established. Here, we show that reduced levels of NTAL were associated with increased all-trans retinoic acid (ATRA)-induced differentiation, generation of reactive oxygen species, and mitochondrial dysfunction. Additionally, NTAL-knockdown (NTAL-KD) in APL cell lines led to activation of Ras, inhibition of Akt/mTOR pathways, and increased expression of autophagy markers, leading to an increased apoptosis rate following arsenic trioxide treatment. Furthermore, NTAL-KD in NB4 cells decreased the tumor burden in (NOD scid gamma) NSG mice, suggesting its implication in tumor growth. A retrospective analysis of NTAL expression in a cohort of patients treated with ATRA and anthracyclines, revealed that NTAL overexpression was associated with a high leukocyte count (P = 0.007) and was independently associated with shorter overall survival (Hazard Ratio: 3.6; 95% Confidence Interval: 1.17-11.28; P = 0.026). Taken together, our data highlights the importance of NTAL in APL cell survival and response to treatment.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Leukemia, Promyelocytic, Acute/pathology , Adaptor Proteins, Signal Transducing/genetics , Adolescent , Adult , Aged , Animals , Anthracyclines/pharmacology , Anthracyclines/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Cell Differentiation/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Disease-Free Survival , Female , Gene Knockdown Techniques , Humans , Leukemia, Promyelocytic, Acute/blood , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/mortality , Leukocyte Count , Male , Membrane Microdomains/metabolism , Mice , Middle Aged , Retrospective Studies , Survival Analysis , Tretinoin/pharmacology , Tretinoin/therapeutic use , Xenograft Model Antitumor Assays , Young AdultSubject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/administration & dosage , Leukemia, Promyelocytic, Acute/drug therapy , Tretinoin/administration & dosage , Adolescent , Adult , Aged , Female , Follow-Up Studies , Germany , Humans , Italy , Male , Middle Aged , Prospective Studies , Treatment Outcome , Young AdultABSTRACT
Acute myeloid leukemia (AML) is often characterized by the expression of fusion or mutant proteins that cause impaired differentiation and enhanced proliferation and survival. The presence of mutant proteins prone to misfolding can render the cells sensitive to endoplasmic reticulum (ER) stress and oxidative stress that could otherwise be overcome. Here, we show that the triple combination of the differentiating agent retinoic acid (RA), the ER stress-inducing drug tunicamycin (Tm), and arsenic trioxide (ATO), able to generate oxidative stress, leads to the death of AML cell lines expressing fusion proteins involving the gene MLL and the internal tandem duplication (ITD) in the FLT3 tyrosine kinase receptor. Importantly, the combination of RA, Tm, and ATO decreased the colony-forming capacity of primary leukemic blasts bearing the FLT-ITD mutation without affecting healthy hematopoietic progenitor cells. We demonstrate in cell lines that combination of these drugs generates ER and oxidative stresses and impairs maturation and causes accumulation of FLT3 protein in the ER. Our data provide a proof of concept that low amounts of drugs that generate ER and oxidative stresses combined with RA could be an effective targeted therapy to hit AML cells characterized by MLL fusion proteins and FLT3-ITD mutation.
Subject(s)
Cell Death , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Oxidative Stress , Tandem Repeat Sequences , Tretinoin/pharmacology , Unfolded Protein Response , fms-Like Tyrosine Kinase 3/genetics , Cell Death/drug effects , Cell Line, Tumor , Endoplasmic Reticulum Stress/drug effects , Gene Duplication , Humans , Leukemia, Myeloid, Acute/pathology , Oxidative Stress/drug effects , Unfolded Protein Response/drug effects , fms-Like Tyrosine Kinase 3/metabolismABSTRACT
OBJECTIVES: We investigated the validity of the recently developed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) summary score in patients with hematologic malignancies. Specifically, we evaluated the adequacy of a single-factor measurement model for the QLQ-C30, and its known-groups validity and responsiveness to change over time. METHODS: We used confirmatory factor analysis to test the single-factor model of the QLQ-C30, using baseline QLQ-C30 data (N = 2134). The QLQ-C30 summary score was compared to the original QLQ-C30 scales using general (age, sex, Eastern Cooperative Oncology Group performance status, comorbidity) and disease-specific (red blood cell transfusion dependency) groups. Repeated measurements allowed us to investigate responsiveness to change in a subgroup of patients with acute myeloid leukemia. RESULTS: The single-factor model of the QLQ-C30 exhibited adequate fit in patients with hematologic malignancies. Known-group comparisons generally supported the construct validity of the summary score when using more general grouping variables (sociodemographics, broad clinical parameters). Nevertheless, when groups were formed on the basis of disease-specific variables (eg, transfusion dependency), the summary score performed less well the some of the original, separate scales of the QLQ-C30. CONCLUSION: Our findings provide support for the validity of the single-factor model of the EORTC QLQ-C30 in patients with hematologic malignancies. Specifically, the results suggest that the summary score can be used as an endpoint in this population when symptom- or other health domain-specific hypotheses are not available.
Subject(s)
Hematologic Neoplasms/psychology , Quality of Life , Surveys and Questionnaires/standards , Adult , Aged , Europe , Factor Analysis, Statistical , Female , Health Status , Humans , Interpersonal Relations , Male , Mental Health , Middle Aged , Physical Functional Performance , Reproducibility of ResultsABSTRACT
Myelodysplastic syndromes (MDS) are highly heterogeneous myeloid diseases, characterized by frequent genetic/chromosomal aberrations. Olaparib is a potent, orally bioavailable poly(ADP-ribose) polymerase 1 (PARP1) inhibitor with acceptable toxicity profile, designed as targeted therapy for DNA repair defective tumors. Here, we investigated olaparib activity in primary cultures of bone marrow mononuclear cells collected from patients with MDS (n = 28). A single treatment with olaparib induced cytotoxic effects in most samples, with median IC50 of 5.4 µM (2.0-24.8 µM), lower than plasma peak concentration reached in vivo. In addition, olaparib induced DNA damage as shown by a high proportion of γH2AX positive cells in samples with low IC50s. Olaparib preferentially killed myeloid cells causing a significant reduction of blasts and promyelocytes, paralleled by an increase in metamyelocytes and mature granulocytes while sparing lymphocytes that are not part of the MDS clone. Consistently, flow cytometry analysis revealed a decrease of CD117+/CD123+ immature progenitors (p < 0.001) and induction of CD11b+/CD16+ (p < 0.001) and CD10+/CD15+ (p < 0.01) neutrophils. Morphological and immunophenotypic changes were associated with a dose-dependent increase of PU.1 and CEBPA transcription factors, which are drivers of granulocytic and monocytic differentiation. Moreover, the combination of olaparib with decitabine resulted in augmented cytotoxic and differentiating effects. Our data suggest that olaparib may have therapeutic potential in MDS patients.
ABSTRACT
We designed a trial in which postremission therapy of young patients with de novo acute myeloid leukemia (AML) was decided combining cytogenetics/genetics and postconsolidation levels of minimal residual disease (MRD). After induction and consolidation, favorable-risk patients (FR) were to receive autologous stem cell transplant (AuSCT) and poor-risk patients (PR) allogeneic stem cell transplant (AlloSCT). Intermediate-risk patients (IR) were to receive AuSCT or AlloSCT depending on the postconsolidation levels of MRD. Three hundred sixty-one of 500 patients (72%) achieved a complete remission, 342/361 completed the consolidation phase and were treatment allocated: 165 (48%) to AlloSCT (122 PR, 43 IR MRD-positive) plus 23 rescued after salvage therapy, for a total of 188 candidates; 150 (44%) to AuSCT (115 FR, 35 IR MRD-negative) plus 27 IR patients (8%) with no leukemia-associated phenotype, for a total of 177 candidates. Overall, 110/177 (62%) and 130/188 (71%) AuSCT or AlloSCT candidates received it, respectively. Two-year overall (OS) and disease-free survival (DFS) of the whole series was 56% and 54%, respectively. Two-year OS and DFS were 74% and 61% in the FR category, 42% and 45% in the PR category, 79% and 61% in the IR MRD-negative category, and 70% and 67% in the IR MRD-positive category. In conclusion, AuSCT may still have a role in FR and IR MRD-negative categories. In the IR MRD-positive category, AlloSCT prolongs OS and DFS to equal those of the FR category. Using all the available sources of stem cells, AlloSCT was delivered to 71% of the candidates.This trial was registered at www.clinicaltrials.gov as #NCT01452646 and EudraCT as #2010-023809-36.
Subject(s)
Consolidation Chemotherapy/methods , Hematopoietic Stem Cell Transplantation/methods , Leukemia, Myeloid, Acute/therapy , Precision Medicine/methods , Adolescent , Adult , Age Factors , Combined Modality Therapy , Cytogenetics , Female , Humans , Induction Chemotherapy/methods , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Molecular Targeted Therapy/methods , Neoplasm, Residual , Prognosis , Remission Induction/methods , Risk Assessment , Young AdultABSTRACT
In the context of precision medicine, assessment of minimal residual disease (MRD) has been used in acute myeloid leukemia (AML) to direct individual treatment programs, including allogeneic stem cell transplantation in patients at high-risk of relapse. One of the limits of this approach has been in the past the paucity of AML markers suitable for MRD assessment. Recently, the number of biomarkers has increased, due to the identification of highly specific leukemia-associated immunophenotypes by multicolor flow-cytometry, and of rare mutated gene sequences by digital droplet PCR, or next-generation sequencing (NGS). In addition, NGS allowed unraveling of clonal heterogeneity, present in AML at initial diagnosis or developing during treatment, which influences reliability of specific biomarkers, that may be unstable during the disease course. The technological advances have increased the application of MRD-based strategies to a significantly higher number of AML patients, and the information deriving from MRD assessment has been used to design individual post-remission protocols and pre-emptive treatments in patients with sub-clinical relapse. This led to the definition of MRD-negative complete remission as outcome definition in the recently published European Leukemianet MRD guidelines. In this review, we summarized the principles of modern technologies and their clinical applications for MRD detection in AML patients, according to the specific leukemic markers.
ABSTRACT
The hypomethylating agent azacitidine (AZA) is used to treat higher-risk myelodysplastic syndromes (HR-MDS) and elderly patients with low-blast count acute myeloid leukemia (LBC-AML). Platelet recovery is an early predictor of AZA response. We prospectively studied the expression profile of transcription factors, critical for late megakaryopoiesis and changes in their expression after AZA treatment in patients with HR-MDS and LBC-AML enrolled in the BMT-AZA trial (EudraCT number 2010-019673-15). Twenty-five additional patients with low-risk (LR)-MDS were also studied. At the time of diagnosis, GATA2 mRNA levels were significantly higher in MDS as compared to controls, with increasing levels from LR- to HR-MDS/AML. RUNX1 expression was also significantly higher in MDS, as compared to controls, but no differences were found between LR- and HR-MDS. Looking at biomarkers of response, we found that patients AZA responsive had higher basal GATA1 and lower FLI1 expression, compared to those with stable or progressive disease after treatment. Univariate analysis showed that increased GATA2 mRNA expression was associated with a worse overall survival. Our findings suggest that high GATA2 expression is a poor prognostic marker for survival in patients with HR-MDS and LBC-AML treated with azacitidine. Moreover, GATA1 and FLI1 mRNA expression may predict response to AZA treatment.
Subject(s)
Azacitidine/therapeutic use , Hematopoietic Stem Cell Transplantation , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/therapy , Thrombopoiesis/genetics , Transcription Factors/genetics , Adult , Aged , Cell Differentiation/genetics , Combined Modality Therapy , Female , GATA1 Transcription Factor/genetics , GATA1 Transcription Factor/metabolism , GATA2 Transcription Factor/genetics , GATA2 Transcription Factor/metabolism , Gene Expression , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/methods , Humans , Male , Middle Aged , Myelodysplastic Syndromes/diagnosis , Transcription Factors/metabolism , Transplantation, Homologous , Treatment OutcomeABSTRACT
Despite the high probability of cure of patients with acute promyelocytic leukemia (APL), mechanisms of relapse are still largely unclear. Mutational profiling at diagnosis and/or relapse may help to identify APL patients needing frequent molecular monitoring and early treatment intervention. Using an NGS approach including a 31 myeloid gene-panel, we tested BM samples of 44 APLs at the time of diagnosis, and of 31 at relapse. Mutations in PML and RARA genes were studied using a customized-NGS-RNA panel. Patients relapsing after ATRA-chemotherapy rarely had additional mutations (P = .009). In patients relapsing after ATRA/ATO, the PML gene was a preferential mutation target. We then evaluated the predictive value of mutations at APL diagnosis. A median of two mutations was detectable in 9/11 patients who later relapsed, vs one mutation in 21/33 patients who remained in CCR (P = .0032). This corresponded to a significantly lower risk of relapse in patients with one or less mutations (HR 0.046; 95% CI 0.011-0.197; P < .0001). NGS-analysis at the time of APL diagnosis may inform treatment decisions, including alternative treatments for cases with an unfavorable mutation profile.
Subject(s)
Leukemia, Promyelocytic, Acute/genetics , Mutation , Oncogene Proteins, Fusion/genetics , Promyelocytic Leukemia Protein/genetics , RNA, Messenger/genetics , RNA, Neoplasm/genetics , Retinoic Acid Receptor alpha/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arsenic Trioxide/administration & dosage , Arsenic Trioxide/pharmacology , Bone Marrow/pathology , Clone Cells , Disease Progression , Drug Resistance, Neoplasm , High-Throughput Nucleotide Sequencing , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Neoplasm Proteins/genetics , Neoplastic Stem Cells , Protein Domains/genetics , Recurrence , Remission Induction , Reproducibility of Results , Tretinoin/administration & dosageABSTRACT
By combining the analysis of mutations with aberrant expression of genes previously related to poorer prognosis in both acute promyelocytic leukemia (APL) and acute myeloid leukemia, we arrived at an integrative score in APL (ISAPL) and demonstrated its relationship with clinical outcomes of patients treated with all-trans retinoic acid (ATRA) in combination with anthracycline-based chemotherapy. Based on fms-like tyrosine kinase-3-internal tandem duplication mutational status; the ΔNp73/TAp73 expression ratio; and ID1, BAALC, ERG, and KMT2E gene expression levels, we modeled ISAPL in 159 patients (median ISAPL score, 3; range, 0-10). ISAPL modeling identified 2 distinct groups of patients, with significant differences in early mortality (P < .001), remission (P = .004), overall survival (P < .001), cumulative incidence of relapse (P = .028), disease-free survival (P = .03), and event-free survival (P < .001). These data were internally validated by using a bootstrap resampling procedure. At least for patients treated with ATRA and anthracycline-based chemotherapy, ISAPL modeling may identify those who need to be treated differently to maximize their chances for a cure.
Subject(s)
Biomarkers, Tumor/genetics , DNA Mutational Analysis , Gene Expression Profiling , Leukemia, Promyelocytic, Acute/diagnosis , Leukemia, Promyelocytic, Acute/genetics , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Pharmacological/analysis , Biomarkers, Tumor/analysis , Cohort Studies , DNA Mutational Analysis/methods , Female , Gene Expression Profiling/methods , Gene Expression Regulation, Leukemic/drug effects , Humans , Leukemia, Promyelocytic, Acute/drug therapy , Leukemia, Promyelocytic, Acute/pathology , Male , Middle Aged , Molecular Diagnostic Techniques/methods , Mutation , Prognosis , Tandem Repeat Sequences/genetics , Transcriptome , Treatment Outcome , Tretinoin/administration & dosage , Young Adult , fms-Like Tyrosine Kinase 3/geneticsABSTRACT
We present a case report of a patient with acute myeloid leukemia (AML) characterized by the simultaneous presence of nucleophosmin 1 (NPM1) mutation and the breakpoint cluster region-Abelson (BCR-ABL) fusion oncogene. Our findings emphasize the importance of routinely including BCR-ABL in the diagnostic workup of AML in order to offer to the patients the most appropriate risk category and treatment options.
ABSTRACT
Arsenic trioxide and all-trans retinoic acid have become the frontline treatments for patients with acute promyelocytic leukemia (APL). Despite the long wait for an oral arsenic drug, a commercially available agent, realgar-indigo naturalis formula (RIF), was not launched in China until 2009. Since then, over 5000 APL patients have been treated with oral RIF in China. Oral arsenic not only shows a clinical efficacy comparable to that of IV formulations but also displays a better safety profile, improved quality of life, and lower medical costs for patients. The promising results promote incorporating an outpatient postremission therapy model into clinical practice for both low-risk and high-risk APL patients in China. In this review, we discuss the evolution of oral arsenic RIF in the treatment of APL, with a special focus on how to address the related complications during induction therapy.