Outcomes after intensive chemotherapy for secondary and myeloid-related changes acute myeloid leukemia patients aged 60 to 75 years old: a retrospective analysis from the PETHEMA registry.

Treatment options for patients with secondary acute myeloid leukemia (sAML) and AML with myeloid-related changes (AMLMRC) aged 60 to 75 years are scarce and unsuitable. A pivotal trial showed that CPX-351 improved complete remission with/without incomplete recovery (CR/CRi) and overall survival (OS) as compared with standard "3+7" regimens. We retrospectively analyze outcomes of 765 patients with sAML and AML-MRC aged 60 to 75 years treated with intensive chemotherapy, reported to the PETHEMA registry before CPX-351 became available. The CR/CRi rate was 48%, median OS was 7.6 months (95% confidence interval [CI]: 6.7-8.5) and event-free survival (EFS) 2.7 months (95% CI: 2-3.3), without differences between intensive chemotherapy regimens and AML type. Multivariate analyses identified age ≥70 years, Eastern Cooperative Oncology Group performance status ≥1 as independent adverse prognostic factors for CR/CRi and OS, while favorable/intermediate cytogenetic risk and NPM1 were favorable prognostic factors. Patients receiving allogeneic stem cell transplant (HSCT), autologous HSCT, and those who completed more consolidation cycles showed improved OS. This large study suggests that classical intensive chemotherapy could lead to similar CR/CRi rates with slightly shorter median OS than CPX-351.

Acute leukemia arising from myeloproliferative or myelodysplastic/myeloproliferative neoplasms: A series of 372 patients from the PETHEMA AML registry.

Treatment of acute myeloid leukemia (AML) evolving from myeloproliferative (MPN) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is challenging. We evaluated disease characteristics, treatment patterns and outcomes in 372 patients diagnosed with AML after MPN or MDS/MPN over a 27-year period. Frontline treatment was intensive chemotherapy (38%), hypomethylating agents [HMAs] (17%), non-intensive chemotherapy (14%), and supportive care (31%). Median overall survival was 4.8 months, with a 5-year survival rate of 4%. Median survival was 2.8, 3.9 and 8.3 months for the 1992-2010, 2011-2015 and 2016-2019 periods, respectively (test for trend p < 0.001). Complete response (CR) rate was higher with intensive chemotherapy (43%) than with non-intensive chemotherapy (12%) or HMAs (8.5%) [p < 0.001], but responses were short-lived without allogeneic hematopoietic cell transplantation. Patients treated with intensive chemotherapy or HMAs had superior survival than those receiving non-intensive chemotherapy (median: 8.5 vs. 8.6 vs. 4.2 months, respectively). No differences in treatment response or survival were observed according to prior disease subtypes. Patients undergoing transplantation in CR had better survival than those transplanted in other response categories (3-year survival rate of 64% vs. 22%, p = 0.002). Our results support the use of intensive chemotherapy followed by transplant whenever possible, and the preferential use of HMAs over attenuated chemotherapy regimens in unfit patients. In spite of the survival improvement in recent years, this subset of AML constitutes an unmet medical need and deserves systematic incorporation in clinical trials.

Characteristics and outcome of patients with core-binding factor acute myeloid leukemia and FLT3-ITD: results from an international collaborative study.

The aim of this study was to evaluate the prognostic impact of FLT3-ITD in core-binding factor acute myeloid leukemia (CBFAML) in an international, multicenter survey of 97 patients of whom 52% had t(8;21)(q22;q22) and 48% had inv(16)(p13q22)/t(16;16)(p13;q22). The median age of the patients was 53 years (range, 19-81). Complete remission after anthracycline-based induction (n=86) and non-intensive therapy (n=11) was achieved in 97% and 36% of the patients, respectively. The median follow-up was 4.43 years (95% confidence interval [95% CI]: 3.35-7.39 years). The median survival after intensive and non-intensive treatment was not reached and 0.96 years, respectively. Among intensively treated patients, inv(16) with trisomy 22 (n=11) was associated with a favorable 4-year relapse-free survival rate of 80% (95% CI: 59-100%) as compared to 38% (95% CI: 27-54%; P=0.02) in all other patients with CBFAML/ FLT3-ITD (n=75). Overall, 24 patients underwent allogeneic hematopoietic cell transplantation (HCT), 12 in first complete remission and 12 after relapse. Allogeneic HCT in first complete remission was not beneficial (P=0.60); however, allogeneic HCT seemed to improve median survival in relapsed patients compared to that of patients treated with chemotherapy (not reached vs. 0.6 years, respectively; P=0.002). Excluding patients with inv(16) with trisomy 22, our data indicate that compathe outcome of CBF-AML patients with FLT3-ITD may be inferior to that of patients without FLT3-ITD (based on previously published data), suggesting that prognostically CBF-AML patients with FLT3-ITD should not be classified as favorable-risk. FLT3-inhibitors may improve the outcome of these patients.

Effects of the anticancer dehydrotarplatin on cytochrome P450 and antioxidant enzymes in male rat tissues.

The effect of dehydrotarplatin (DTP), a new antineoplastic drug analogous to cisplatin, and its metabolite (Triacid) on the hepatic, renal and testicular CYP and antioxidant enzymes of male rats was investigated. The rats were treated i.p. with a single dose of DTP (25 mg kg(-1) day(-1)) or Triacid (17.5 mg kg(-1) day(-1)) and analysed 3 or 7 days post treatment. Three days after treatment, both drugs reduced body and liver weights, which partially recovered the control level after 7 days. DTP and, to a less extent, Triacid caused a depletion of plasmatic testosterone content and a down regulation in the liver of androgen dependent male specific CYP 2C11, but not of CYP 1A and 2E1, as determined by a significant decrease of 2alpha- and 16alpha-testosterone hydroxylase activities (markers for CYP 2C11) and of apoprotein immunoreactive with anti-rat CYP 2C11 antibodies. However, the activity of testicular 17alpha-progesterone hydroxylase, a key reaction in steroidogenesis, was not altered by these drugs. The DTP and Triacid administration did not cause any alteration of the plasmatic urea nitrogen and creatinine, known as markers of kidney toxicity. However, treatment with DTP, not Triacid, either 3 and 7 days post treatment, caused in the kidney microsomes a significant increase of the total CYP content, the CYP 4A-dependent (omega)- and (omega - 1)-lauric acid hydroxylase activities and apoprotein immunoreactive with anti-rat CYP 4A1. The present study also examined the enzymatic antioxidant status of kidney and liver. Neither DTP nor Triacid administration induced, with respect to control values, any alteration of hepatic and renal glutathione reductase, glutathione S-transferase, catalase, superoxide dismutase activities, hepatic GSH level and renal microsomal lipid peroxidation level. Among the antioxidant enzymes assayed, only the renal activity of glutathione peroxidase was significantly increased after DTP but not Triacid treatment. These results indicate that DTP at a dose of 25 mg/kg and Triacid cause a feminization of the CYP enzymes in male rat liver similar to that reported for cisplatin when administered at a low dose (5 mg/kg). However, unlike cisplatin, DTP and its metabolite were unable to enhance BUN and creatinine and cause any depression of CYP activities and antioxidant enzymes in the kidney, suggesting that DTP may have low or even no potential in inducing nephrotoxicity.

CAR and PXR expression and inducibility of CYP2B and CYP3A activities in rat and rabbit lungs.

Several CYP enzymes are expressed in the lung of mammals but studies on their regulation have been rather neglected. In this study, the CAR and PXR expression and the inducibility of CYP 2B and CYP 3A isoforms in the lung rats and rabbits were investigated. Rats were treated with phenobarbital, clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile, whereas rabbits were treated with phenobarbital or rifampicin. A low constitutive expression of CAR mRNA was demonstrated by RT-PCR analysis in the lung of rat but not in rabbit. Phenobarbital treatment did not change the CAR expression profiles and did not induce in either rats and rabbits the pulmonary CYP 2B isoforms, as judged by western blot analysis and the marker pentoxyresorufin O-dealkylase and 7-ethoxy-4-trifluoroethylcoumarin O-deethylase activities. On the contrary, these marker activities were strongly induced by phenobarbital in the liver of both species. A low constitutive level of PXR mRNA was also detected by RT-PCR in the lung of rabbit but not in rat. However, also in this case, their expressions were not altered by the administration of strong CYP 3A inducers such as clotrimazole or a mixture of dexametasone plus pregnenolone 16alpha-carbonitrile for the rat and rifampicin or phenobarbital for the rabbit. For the first time, it was demonstrated by RT-PCR that rat lung expresses CYP 3A2, 3A9, 3A18 and 3A23 whereas the rabbit lung expresses the CYP 3A6, the only CYP 3A isoform identified in the rabbit so far. However, notwithstanding the differences observed in the constitutive presence of PXR and CYP 3A transcripts in both species, the above mentioned treatments did not affect in their lungs, unlike their livers, neither the anti-rat 3A immunoreactive proteins nor the CYP 3A marker 7-benzyloxyquinoline O-debenzylase and the 6beta-testosterone hydroxylase activities. The results obtained indicate that the role of CAR and PXR in the lung of rat and rabbit is different from that observed in the liver or other extrahepatic tissues where the induction of the CYP 2B and CYP 3A isoforms is regulated by these receptors.