Predictive factors of response to hypomethylating agents (HMA) in elderly acute myeloid leukemia (AML) patients remain unclear in the real-life setting and no direct comparison between azacitidine ...(AZA) and decitabine (DEC) has been carried out. We retrospectively evaluated 110 AML patients treated with HMA (78 AZA, 32 DEC) as first-line therapy outside of clinical trials. Median age was 75 years (range 58–87). The median overall survival (OS) of the entire cohort was 8.0 months (95% CI 6.1–10), without significant differences among the subgroups: AZA 8.8 months vs DEC 6.3 months (
p
= 0.291). HMA treatment yielded an overall response rate (ORR) of 40% (AZA 37% vs DEC 47%,
p
= 0.237). A stable disease (SD) after 4 HMA cycles was not associated with a worse survival outcome compared with an early optimal response. Factors independently associated with a better OS were transfusion independence during treatment (
p
= 0.049), achievement of an optimal response to treatment (
p
< 0.001), and a baseline hemoglobin level ≥ 9.25 (
p
= 0.018). A bone marrow (BM) blast count ≥ 30% (
p
< 0.001) and a therapy-related AML (
p
= 0.008) remain poor survival predictors. Of the available biologic features, an adverse risk category according to the ELN classification was significantly associated with a shorter survival over the intermediate risk category (
p
= 0.034). Disease progression remains the primary cause of death. Infectious complications were more severe (
p
= 0.036) and occurred earlier (
p
= 0.006) in the DEC group compared with that of the AZA group. In conclusion, clinical prognostic factors associated to response and survival have been identified without significant associations concerning overall outcomes between the two HMAs.
There are five tyrosine kinase inhibitors (TKIs) that are currently approved (in the European Union and the United States) for the treatment of chronic myeloid leukaemia (CML) in the chronic phase ...(CP) and each of them has its own efficacy and toxicity profile. Oral ponatinib (Iclusig®) is a third-generation TKI structurally designed to inhibit native BCR-ABL1 tyrosine kinase and several BCR-ABL1 mutants, including T315I. Ponatinib is now approved for patients with CML who are resistant or intolerant to prior TKI therapy (European Union) or for whom no other TKI therapy is indicated (United States). Despite achieving results in heavily treated patients, which led to its approval, the drug may induce cardiovascular events, requiring a careful baseline assessment of predisposing risk factors and specific management during treatment. Pharmacokinetic analysis has indicated the possibility of reducing the starting dose of ponatinib to 15 mg/day and preliminary data showed advantages in terms of safety while maintained its efficacy. This review summarizes the results achieved and drug-related side effects reported in all clinical trials and real-life experiences, testing ponatinib in patients with CP-CML. In addition, we focus on the appropriate use of ponatinib in clinical practice suggesting some useful recommendations on the proper management of this drug.
Tyrosine kinase inhibitors (TKIs), the backbone of treatment for chronic phase chronic myeloid leukemia patients (CP-CML), have changed the long-term outcome of the disease. Nonetheless, over 20% of ...patients fail front-line therapy due to intolerance or resistance. A head-to-head comparison of dasatinib and nilotinib as second-line treatment outside of sponsored clinical trials has not been reported. We retrospectively analyzed 131 CP-CML patients who, after front-line imatinib failure, switched to a second-line therapy with nilotinib (59, 45%) or dasatinib (72, 55%). Median duration of second-line treatment was 33 months (range 2–100). The reason for switching therapy was resistance in 83.2% and intolerance in 16.8% of patients. The overall survival of the entire cohort at 7 years was 78.9%, while it was 72% and 85.6% for patients treated with dasatinib and nilotinib, respectively (
p
=0.287). With regard to efficacy after 12 months of treatment, 108 patients were evaluable for molecular response: 47% achieved a major molecular response and 18.2% a deep molecular response with dasatinib, compared to 38% and 16.2% with nilotinib (
p
=ns). We observed 35% of grade 3–4 adverse events, more frequently in the dasatinib group (47%) compared to the nilotinib group (22%), without affecting molecular responses. Our study suggests that, in the real-life setting, dasatinib and nilotinib used as second-line treatment in CP-CML are equally effective, with high molecular response rates and an acceptable tolerability.
The outcome of high-risk myelodysplastic syndrome (MDS) patients treated with 5-azacitidine (5-AZA) in the real-life setting remains largely unknown. We evaluated 110 MDS patients (IPSS intermediate ...2/high) treated outside of clinical trials at a single institution between September 2003 and January 2017. Median duration of therapy was 9.5 cycles. The overall survival (OS) of the whole cohort was 66.1% at 1 year and 38.3% at 2 years. No differences in terms of OS were observed with regard to gender (
p =
0.622) and age at baseline (< 65 years, 65–75, and > 75 years,
p
= 0.075). According to the IPSS-R, the very high-risk group had an inferior 2-year OS (17%) compared with intermediate-group patients (64%,
p
< 0.001). Transfusion independency at baseline was identified as a favorable prognostic factor on 1-year (66.8%) and 2-year OS (43.4%) (
p
< 0.001). After four cycles, the persistence of bone marrow blasts > 10% identified patients with a worse outcome, with a 2-year OS of 9.4% (
p =
0.002). The occurrence of an infection during the first four cycles impacted on the 2-year OS (31.6% vs 58.3% in patients without infections,
p
= 0.032). Patients receiving at least 24 cycles of the drug have a 5-year OS of 38.2%. This analysis allowed to identify features at baseline or during treatment with 5-AZA associated with a different 2-year OS.
A deep and stable molecular response (DMR) is a prerequisite for a successful treatment-free remission (TFR) in chronic myeloid leukemia (CML). In order to better identify and analyze potential ...candidates of successful TFR, we examined the phenotypic and functional host immune compartment in DMR patients who had received TKI treatment only (TKI-only) or had been previously treated with interferon-alpha (IFNα + TKI) or had received IFNα treatment only (IFNα-only). The T/NK-cell subset distribution, NK- and T-cell cytokine production, activation and maturation markers were measured in 44 patients in DMR treated with IFNα only (9), with IFNα + TKI (11) and with TKI-only (24). IFNα + TKI and TKI-only groups were eligible to TKI discontinuation according to the NCCN and ESMO guidelines (stable MR4 for more than two years). In IFNα-treated patients, we documented an increased number of lymphocytes capable of producing IFNγ and TNFα compared to the TKI-only group. In INFα + TKI patients, the percentage of NKG2C expression and its mean fluorescence intensity were significantly higher compared to the TKI-only group and to the INFα-only group in the CD56dim/CD16+ NK cell subsets (INFα + TKI vs. TKI-only p = 0.041, p = 0.037; INFα + TKI vs. INFα-only p = 0.03, p = 0.033, respectively). Furthermore, in INFα-only treated patients, we observed an increase of NKp46 MFI in the CD56bright/CD16- NK cell subset that becomes significant compared to the INFα + TKI group (p = 0.008). Our data indicate that a previous exposure to IFNα substantially and persistently modified the immune system of CML patients in memory T lymphocytes, differentiated NKG2C+ “long-lived” NK cells responses, even years after the last IFNα contact.
Potential clinical significance of CD34 expression in acute promyelocitic leukemia (APL) has not been deeply investigated. We hereby analyzed the clinico-biological features and treatment outcome of ...APL patients in relation to CD34 expression, even when expressed in a small subpopulation: 114 APL patients homogeneously treated with the AIDA schedule were included in the study and prognostic correlation with respect to CD34 expression, both when expressed in association with CD2 and as isolated expression (cutoff ≥2 to <10 % or ≥10 %), were investigated. CD34 was associated to CD2 in 30 patients and was isolated in 19 patients. When compared to the CD34-negative population, CD34/CD2 expression identified a subgroup with characteristic features: M3 variant subtype (26 vs 7 % in the negative group,
p
= 0.02), bcr3 transcript subtype (73 vs 32 %,
p
= 0.001), high risk according to the risk of relapse (66 vs 17 %,
p
= 0.002), high incidence of differentiation syndrome (26 vs 12 %,
p
= 0.01), lower overall survival (88 vs 95 %), and a significantly higher rate of relapse (22 vs 13.8 %,
p
= 0.05). We then evaluated the prognostic value of isolated CD34 expression: it was detected in nine patients with a cutoff of expression ≥10 % and in 10 patients with a cutoff ≥2 but <10 %. Isolated CD34 positivity identified a subgroup with a classic morphology (79 %), bcr1 prevalence (53 %), higher rate of relapse (37 vs 13.8 % in the negative group,
p
= 0.002), higher incidence of differentiation syndrome (55 vs 12 %,
p
= 0.03), and lower overall survival (60 vs 95 %,
p
= 0.001). The results of our study confirm that CD34/CD2 expression characterizes a subset of APL with a high WBC count and a variant morphological subtype, associated with an unfavorable clinical course. We also show that the isolated expression of CD34, even at a low cutoff, identifies a group of classic APL with a negative prognosis. Further studies aimed at identifying other molecular signatures in CD34-positive patients are needed in order to optimize the therapeutic strategy for this subset of patients.
Abstract Limited information is available on the relationship between expression of some additional aberrant phenotypic features and outcome of acute promyelocytic leukemia (APL) patients. Here, we ...set out to assess the frequency of CD15 and CD56 expression, and their prognostic value in a large series of APL patients. One hundred and fourteen adult patients consecutively diagnosed with PML/RARα-positive APL and homogeneously treated with the AIDA induction schedule at a single institution were included in the study. Twelve (10.5%) and 9 (8%) of the 114 patients expressed CD15 and CD56, respectively. CD15 expression identified a subset of patients with a classic morphologic subtype (92%), a prevalent association with a bcr1 expression (67%) with an unexpectedly higher frequency of relapses (42% vs 20% for the CD15− patients, p = 0.03) and a low overall survival (OS) (median OS at 5 years 58% vs 85% for the CD15− patients, p = 0.01). CD56 expression was detected only in patients with a classic morphologic subtype, a prevalent bcr3 expression (67%), high incidence of differentiation syndrome (55%), higher frequency of relapse (34% vs 20% for the CD56− population, p = 0.04) and a low OS (60% vs 85% for the CD56− population p = 0.02). We hereby confirm the negative prognostic value of CD56 and we show that the same applies also to cases expressing CD15. These aberrant markers may be considered for the refinement of risk-adapted therapeutic strategies in APL patients.
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