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Introduction: FLT3 inhibitors (FLT3i) are drugs in which there is limited experience and not yet enough information on the mechanisms of absorption, transport, and elimination; but especially on the potential drug-drug interactions (DDIs). There are therefore risks in the management of FLT3i DDIs (i.e. sorafenib, ponatinib, crenolanib, midostaurin, quizartinib, and gilteritinib) and ignoring them can compromise therapeutic success in acute myeloid leukemia (AML) treatment, in complex patients and secondary pathologies., Areas Covered: This review summarizes the DDIs of FLT3i with P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting (OAT), organic cationic transporting (OCT), cytochrome P450 (CYP) subunits, and other minor metabolic/transport pathways. EMBASE, PubMed, the Cochrane Central Register and the Web of Science were searched. The last literature search was performed on the 14 February 2022., Expert Opinion: FLT3i will be combined with other therapeutic agents (supportive care, doublet, or triplet therapy) and in different clinical settings, which means a greater chance of controlling and even eradicating the disease effectively, but also an increased risk to patients due to potential DDIs. Healthcare professionals should be aware of the potential interactions that may occur and be vigilant in monitoring those patients who are receiving any potentially interacting drug.

Introduction: The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib., Areas Covered: In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML., Expert Opinion: Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.

We have analyzed treatment patterns and outcomes of relapsed/refractory(R/R) FLT3mut AML adult patients registered in our institutional data base between 1998 and 2018. Overall, 147 patients were evaluable: 34 from 1998 to 2009, 113 from 2010 to 2018. Salvage treatments were intensive chemotherapy ( n  = 25, 74%), and supportive care ( n  = 9, 26%) in the 1998-2009 period, and intensive chemotherapy ( n  = 63, 56%), hypomethylating agent ( n  = 7, 6%), low-dose cytarabine-based ( n  = 8, 7%), clinical trial ( n  = 16, 14%) and supportive care ( n  = 19, 17%) in the 2010-2018 period. Complete remission (CR) or with incomplete recovery (CRi) rate was 44%, 49% among patients treated intensively (vs 30% with non-intensive p  = 0.005). Median overall survival since first R/R was 5.8 months, and 16.3 months in subjects receiving an allo-HSCT in CR/CRi after first salvage (vs 3.8 in the remaining patients p  < 0.0001). Clinical outcomes of R/R FLT3mut AML remain unsatisfactory. Inclusion in clinical trials and expanding options could lead to improved outcomes.

Anthracycline uptake could be affected by influx and efflux transporters in acute myeloid leukemia (AML). Combinations of single-nucleotide polymorphisms (SNPs) of wild-type genotype of influx transporters ( SLC22A16, SLCO1B1 ) and homozygous variant genotypes of ABC polymorphisms ( ABCB1, ABCC1 , ABCC2 , ABCG2 ) were evaluated in 225 adult de novo AML patients. No differences in complete remission were reported, but higher induction death was observed with combinations of SLCO1B1 rs4149056 and ABCB1 (triple variant haplotype, rs1128503), previously associated with ABCB1 and SLCO1B1 SNPs. Several combinations of SLCO1B1 and SLC22A16 with ABCB1 SNPs were associated with higher toxicities, including nephrotoxicity and hepatotoxicity, neutropenia, previously related to ABCB1 , and a novel correlation with mucositis. Combination of SLC22A16 rs714368 and ABCG2 rs2231142 was related to cardiac toxicity, reproducing previous correlations with ABCG2 . This study shows the impact of transporter polymorphisms in AML chemotherapy safety. Further prospective studies with larger populations are needed to validate these associations.

Acute promyelocytic leukemia is infrequent among patients aged ≥75 years old, a population that is rarely eligible for clinical protocols. This study aims to analyze the treatment strategies and clinical outcomes of very old APL patients reported to the international PETHEMA registry. Between 1997 and 2017, among 2501 APL cases registered 120 were ≥75 years old. Treatment approaches were: AIDA regimen, 79 patients; ATRA alone, 23; 16, supportive care (SC) and 2, other strategies. Patients treated with AIDA were younger, had better ECOG and lower leukocytes. Complete remission (CR) was achieved in 65% of AIDA-group vs. 45% in the ATRA-group, being infections followed by bleeding the most frequent causes of induction death. Patients in CR after AIDA showed 3-year DFS of 73%. Our real-life series of very old APL patients provides a reference basis for future treatment strategies aiming to improve clinical outcomes in this challenging population.

Introduction: Induction chemotherapy based on anthracyclines and cytarabine (Ara-C) combination remains the standard of care for acute myeloid leukemia (AML) patients who are considered candidate for intensive and curative approaches. However, the toxicity of this regimen is high, with disappointing clinical outcomes among the so-called poor-prognosis AML subsets, which generally refer to patients with adverse cytogenetic risk, secondary AML including therapy-related AML, poor-prognosis mutations, especially FLT3-ITD, and relapse/refractory AML. Areas covered: To the best of our knowledge, the role and efficacy of 7 + 3 schedules containing daunorubicin (DNR) and Ara-C for certain types of poor-prognosis AML has not been systematically assessed. A critical approach to the role of DNR and Ara-C induction could be relevant to establish which patients should be enrolled in clinical trials using novel therapies. Expert commentary: In this regard, a recent randomized clinical trial (RCT) showed improved results in older patients with sAML or high-risk cytogenetics who received CPX-351 compared with standard 7 + 3 combination. We perform a systematic literature review to analyze the clinical outcomes reported with DNR plus Ara-C regimens in adult patients with poor-prognosis AML, the use of liposomal formulations of DNR and Ara-C and the RCTs which compared standard 7 + 3 with the addition of a third drug.

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.

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.