Development of the highly selective targeted tyrosine kinase inhibitors (TKIs) has expanded the therapeutic options for chronic myeloid leukemia (CML). Patients undergoing TKI therapy should be ...closely monitored to ensure that the best therapeutic response and quality of life are achieved, and to control suboptimal responses and adverse events. Despite the high rate of response using current first‐line TKIs, treatment failure may still occur, and resistance is considered a challenge in the treatment of patients with CML. The third‐generation TKI, ponatinib, is a potent orally bioavailable pan BCR‐ABL inhibitor that inhibits both wild‐type and mutant BCR‐ABL1 kinase, including the “gatekeeper” T315I mutation, which is resistant to all other currently available TKIs. This paper reviews the effectiveness, feasibility, and safety of ponatinib in the real‐life clinical management of CML. Potential prognostic factors in identifying patients most likely to benefit from ponatinib treatment will be discussed, and case presentations illustrating situations encountered in real‐life clinical practice are described. Ponatinib is effective in patients who have received prior TKIs in clinical studies as well as under real‐life conditions. Nevertheless, the risk/benefit balance must be evaluated for each patient, particularly considering disease state, mutational status, treatment line, intolerance/resistance to prior TKIs, age, frailty, and specific comorbidities.
PEG-Asparaginase (also known as Pegaspargase), along with glucocorticoids (predominantly prednisolone or dexamethasone) and other chemotherapeutic agents (such as cyclophosphamide, idarubicin, ...vincristine, cytarabine, methotrexate and 6-mercaptopurine) is the current standard treatment for acute lymphoblastic leukaemia in both children and adults. High doses of PEG-asparaginase are associated with side effects such as hepatotoxicity, pancreatitis, venous thrombosis, hypersensitivity reactions against the drug and severe hypertriglyceridemia. We report a case of a 28-year-old male who was normolipidemic at baseline and developed severe hypertriglyceridemia (triglycerides of 1793 mg/dl) following treatment with PEG-asparaginase for acute lymphoblastic leukaemia. Thorough genetic analysis was conducted to assess whether genetic variants could suggest a predisposition to this drug-induced metabolic condition. This genetic analysis showed the presence of a rare heterozygous missense variant c.11G > A-p.(Arg4Gln) in the APOC3 gene, classified as a variant of uncertain significance, as well as its association with four common single nucleotide polymorphisms (SNPs; c.*40C > G in APOC3 and c.*158T > C; c.162-43G > A; c.-3A > G in APOA5) related to increased plasma triglyceride levels. To our knowledge this is the first case that a rare genetic variant associated to SNPs has been related to the onset of severe drug-induced hypertriglyceridemia.
CML is a hematopoietic stem-cell disorder emanating from breakpoint cluster region/Abelson murine leukemia 1 (BCR/ABL) translocation. Introduction of different TKIs revolutionized treatment outcome ...in CML patients, but CML LSCs seem insensitive to TKIs and are detectable in newly diagnosed and resistant CML patients and in patients who discontinued therapy. It has been reported that CML LSCs aberrantly express some CD markers such as CD26 that can be used for the diagnosis and for targeting. In this study, we confirmed the presence of CD26+ CML LSCs in newly diagnosed and resistant CML patients. To selectively target CML LSCs/progenitor cells that express CD26 and to spare normal HSCs/progenitor cells, we designed a venetoclax-loaded immunoliposome (IL-VX). Our results showed that by using this system we could selectively target CD26+ cells while sparing CD26- cells. The efficiency of venetoclax in targeting CML LSCs has been reported and our system demonstrated a higher potency in cell death induction in comparison to free venetoclax. Meanwhile, treatment of patient samples with IL-VX significantly reduced CD26+ cells in both stem cells and progenitor cells population. In conclusion, this approach showed that selective elimination of CD26+ CML LSCs/progenitor cells can be obtained in vitro, which might allow in vivo reduction of side effects and attainment of treatment-free, long-lasting remission in CML patients.
Tyrosine kinase inhibitors (TKIs) have radically changed the outcome of chronic myeloid leukemia (CML) patients in the last 20 years. Moreover, the advent of second generation TKIs, namely nilotinib ...and dasatinib, have largely increased the number of CML patients achieving deep and sustained molecular responses. However, the possible mechanisms capable of influencing the maintenance of the long-term molecular response are not yet fully known and understood. In this light, polymorphisms in MDR-ABC transporters may influence the efficacy and safety of TKIs. In this study, we examined seven single nucleotide polymorphisms (SNPs) in four ABC transporter genes: ABCC1 rs212090 (5463T>A), ABCC2 rs3740066 (3972C>T), ABCC2 rs4148386 G>A, ABCC2 rs1885301 (1549G>A), ABCG2 rs2231137 (34G>A), ABCG2 rs2231142 G>C, ABCB1 rs1045642 (3435C>T), to determine their effect on the achievement and/or loss of molecular response in 90 CML patients treated with nilotinib. We found that
ABCC2
rs3740066 CC and CT as well as the
ABCB1
rs1045642 TT genotypes correlated with a higher probability to achieve MR3 in a shorter time (
p
=0.02,
p
=0.004, and
p
=0.01), whereas
ABCG2
rs2231137 GG was associated with lower probability of MR3 achievement (
p
=0.005). Moreover,
ABCC2
rs3740066 CC genotype, the
ABCB1
rs1045642 CC and TT genotypes were positively correlated with MR4 achievement (
p
=0.02,
p
=0.007, and
p
=0.003). We then generated a predictive model incorporating the information of four genotypes, to evaluate the combined effect of the SNPs. The combination of SNPs present in the model affected the probability and the time to molecular response. This model had a high prognostic significance for both MR3 and MR4 (
p
=0.005 and
p
=0.008, respectively). Finally, we found
ABCG2
rs2231142 GG genotype to be associated with a decrease risk of MR3 loss. In conclusion, MDR-transporters SNPs may significantly affect the achievement and loss of molecular response in CML patients treated with nilotinib.
In chronic myeloid leukemia (CML), about half of the patients achieving a deep and stable molecular response with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease ...recurrence. As such, treatment-free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria are needed to identify CML patients suitable for efficacious discontinuation. Leukemia stem cells (LSCs) are supposed to be the reservoir of the disease. Previously, we demonstrated that residual circulating CD34+/CD38-/CD26+ LSCs were still detectable in a consistent number of CML patients during TFR.
CML LSCs could be easily identified by flow-cytometry as they express the CD34+/CD38-/CD26+ phenotype. In this study, we explored the role of these cells and their correlation with molecular response in a cohort of 109 consecutive chronic phase CML patients prospectively monitored from the time of TKI discontinuation.
After a median observation time of 33 months from TKI discontinuation, 38/109 (35%) patients failed TFR after a median time of 4 months, while 71/109 (65%) patients are still in TFR. At TKI discontinuation, peripheral blood CD26+LSCs were undetectable in 48/109 (44%) patients and detectable in 61/109 (56%). No statistically significant correlation between detectable/undetectable CD26+LSCs and the rate of TFR loss was found (
= 0.616). The incidence of TFR loss based on the type of TKI treatment was statistically significant for imatinib treatment compared to that of nilotinib (
= 0.039). Exploring the behavior of CD26+LSCs during TFR, we observed fluctuating values that were very variable between patients, and they were not predictive of TFR loss.
Up to date, our results confirm that CD26+LSCs are detectable at the time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study, the persistence of "fluctuating" values of residual CD26+LSCs does not hamper the possibility to maintain a stable TFR. On the contrary, even patients discontinuing TKI with undetectable CD26+LSCs could undergo TFR loss. Our results suggest that factors other than residual LSCs "burden" playing an active role in controlling disease recurrence. Additional studies evaluating CD26+LSCs' ability to modulate the immune system and their interaction in CML patients with very long stable TFR are ongoing.
Highlights • In CML patients, social support, psychological and subjective perceptions could influence adherence. • Based on patient's survey, high rate of adherence to TKIs has been reported. • The ...majority of patients would like to discuss more about discomfort, anxiety and fear of the future. • Fifty-five percent of patients did not take the drug for less than 3 days a month. • Forty-nine percent of patients wouldn’t interrupt the therapy due to fear of losing all the results achieved.
Abstract Dasatinib (DAS) has been l icensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients ...with CML outside clinical trials. To address this issue, we set out a “real-life” cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.
Background
Gemtuzumab‐ozogamycin (GO) is approved in combination with high‐dose chemotherapy for treatment‐naïve low‐ and intermediate‐risk acute myeloid leukemia (AML).
Aims
In this retrospective ...real‐life multicenter study, we reported efficacy and safety of GO plus high‐dose chemotherapy in newly diagnosed AML patients.
Methods and Results
A total of 31 fit low‐ and intermediate‐risk AML patients treated with GO‐based regimens were retrospectively included in this real‐life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO‐based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate‐risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02–0.89; p < .001). GO addition resulted in a survival benefit for low‐risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate‐risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO‐treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno‐occlusive disease after allogeneic transplantation were observed.
Conclusions
Our real‐life multicenter study confirmed GO‐based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate‐risk AML. However, further validation on larger prospective cohorts is required.
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