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.
A phase II dose-escalation trial was conducted to ascertain low-dose thalidomide safety and response in patients with advanced myelofibrosis with myeloid metaplasia (MMM).
Thalidomide was ...administered together with current therapy to 63 patients, starting at 50 mg daily and increasing to 400 mg as tolerated.
Half of the patients sustained daily doses more than 100 mg and the drop-out rate was 51% at 6 months: the drop-out rate was lower in patients with high baseline fatigue score. At efficacy analysis, anemia was ameliorated in 22% of the patients and transfusions were eliminated in 39% of transfusion-dependent patients. Platelet count increased by 50 x 10(9)/L or more in 22% of patients with an initial count lower than 100 x 10(9)/L. Splenomegaly decreased by more than 50% of the initial size in 19% of patients. Reduction of an overall disease severity score occurred in 31% of patients and was associated with a significant reduction of fatigue. Disease severity amelioration was independently predicted by a high baseline myeloproliferative index (ie, large splenomegaly, thrombocytosis, or leukocytosis).
Low-dose thalidomide displays an acceptable toxicity profile and provides an objective and subjective advantage to a relevant portion of MMM patients.
A lthough advanced stage aggressive non-Hodgkin’slymphomas and Hodgkin’s disease are thought to be che-motherapy-responsive cancers, a considerable number of patients either relapse or never attain a ...remission. High-dose therapy(HDT) followed by autologous stem cell transplantation(ASCT) is often the only possibility of cure for most of these patients. However, many controversial issues still remain with respect to HDT/ASCT for lymphomas, including its role for, the optimal timing of transplantation, the best conditioning regimen and the potential use of localized radiotherapy or immunologic methods to decrease post-transplant recurrence. Recently, mainly due to the unavailability of carmustine, several novel conditioning protocols have been clinically developed, with the aim of improving the overall outcome by enhancing the anti-lymphoma effect and, at the same time, by reducing short and long-term toxicity. Furthermore, the better safety profiles of novel approaches would definitively allow patients aged more than 65-70 years to benefit from this therapeutic option. In this review, we will briefly discuss the most relevant and recent data available regarding HDT/ASCT in lymphomas.
A 9-year-old female received a double allogeneic stem cell transplant (SCT) from an ABO-incompatible HLA-matched sibling for β-thalassemia major, without achieving a complete donor chimerism. ...Subsequently, the patient received autologous SCT and five donor lymphocyte infusion, without increasing donor chimerism. After the double transplant failure, we performed an unrelated transplant from a full-matched umbilical cord blood (UCBT). Due to the severe immunosuppression of the patient, we did not administer any conditioning regimen nor GVHD prophylaxis. On day +40 after UCBT, trilinear engraftment was documented. Surprisingly, the hematopoietic reconstitution was related to the re-expansion of the autologous (β-thalassemic) hematopoietic stem cell, as documented by chimerism studies on both peripheral blood and bone marrow. At present, 30 months after UCBT, there is stable hematopoietic autologous reconstitution. This is the first description of the restoration of autologous hematopoiesis obtained with cord blood infusion in a thalassemia-major patient after a double transplant failure.
Summary
Limited information is available on the impact of the COVID‐19 pandemic on the management of chronic myeloid leukaemia (CML). The Campus CML network collected retrospective information on ...8 665 CML patients followed at 46 centres throughout Italy during the pandemic between February 2020 and January 2021. Within this cohort, we recorded 217 SARS‐CoV‐2‐positive patients (2·5%). Most patients (57%) were diagnosed as having SARS‐CoV‐2 infection during the second peak of the pandemic (September 2020 to January 2021). The majority (35%) was aged between 50 and 65 years with a male prevalence (73%). Fifty‐six percent of patients presented concomitant comorbidities. The median time from CML diagnosis to SARS‐CoV‐2 infection was six years (three months to 18 years). Twenty‐one patients (9·6%) required hospitalization without the need of respiratory assistance, 18 (8·2%) were hospitalized for respiratory assistance, 8 (3·6%) were admitted to an intensive care unit, while 170 (78%) were only quarantined. Twenty‐three percent of patients discontinued tyrosine kinase inhibitor (TKI) therapy during the infection. Twelve patients died due to COVID‐19 with a mortality rate of 5·5% in the positive cohort and of 0·13% in the whole cohort. We could also document sequelae caused by the SARS‐CoV‐2 infection and an impact of the pandemic on the overall management of CML patients.
INTRODUCTION. Three tyrosine-kinase inhibitors (TKIs, imatinib, nilotinib NIL and dasatinib) are approved for first-line treatment of CP CML. Clinical trials, with stringent inclusion/exclusion ...criteria and management, may be not fully representative of the daily clinical practice. Thus, it is important to retrieve information on the safety and efficacy of TKIs in the real-life setting. Observational studies are particularly useful for these evaluations.
AIM. To investigate the safety and efficacy of NIL as first line treatment of newly diagnosed CP CML pts in the real-life setting
METHODS. Prospective, multicenter, observational study. Inclusion criteria: CP CML within 6 months from diagnosis; no prior treatment with TKIs; written informed consent. Comorbidities (of any kind and severity) were not exclusion criteria. NIL was used according to prescribing information (initial dose 300 mg BID). There was no formal indication for dose modifications, management of adverse events, and response monitoring.
RESULTS. Between 06/2013 and 11/2015, 123 pts were enrolled in 27 Italian Centers; median age: 51 yrs; Sokal high-risk pts: 19%; EUTOS high-risk pts: 7%. Despite Median follow-up: 18 months (updated results will be presented). At the last contact, of evaluable pts with at least 12 months of follow-up, 78% and 43% of pts were in MR3 and MR4, respectively. At the last contact, all but one pt were alive. 113 (89%) pts were still on study (on NIL treatment); in the remaining pts, NIL discontinuation occurred in: 9 pts for failure/suboptimal response, including 1 progression to blast phase; 2 pts for toxicity; 1 pt for a CML-unrelated death, 2 pts for other reasons.
CONCLUSION. These preliminary data in real-life CP CML pts treated with NIL first-line showed that: 1) despite the absence of exclusion criteria for comorbidities, the median age of enrolled pts (51 years) was similar to that reported in clinical trials, and inferior to the median age of CML pts in population based-registries; 2) NIL use was not limited to intermediate or high-risk pts; 3) efficacy was similar to that reported in clinical trials, with very low rates of progression to advanced phase and high molecular response rates.
Gugliotta:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Castagnetti:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Abruzzese:Novartis: Consultancy; Incyte: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Breccia:Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Iurlo:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Tiribelli:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Crugnola:BMS: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Bonifacio:Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Soverini:Incyte Biosciences: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Foà:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Sandoz: Consultancy, Speakers Bureau. Martinelli:PFIZER: Consultancy; JOHNSON & JOHNSON: Consultancy; CELGENE: Consultancy; ROCHE: Consultancy; ARIAD/INCYTE: Consultancy; AMGEN: Consultancy. Pane:Novartis: Honoraria, Speakers Bureau. Saglio:Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Baccarani:Novartis: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte ARIAD: Consultancy, Honoraria, Speakers Bureau. Rosti:Pfizer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau; Incyte: Research Funding, Speakers Bureau.
Background: Several studies have suggested that genetic variability related with single nucleotide polymorphisms (SNPs) of the BER system, DNA synthesis and folate-metabolizing pathway genes could ...modulate DNA repair capacity. Moreover, these genes are supposed to be related to cancer risk. However, the prognostic impact of the association of individual and/or combined genetic variants in patients with myelodysplastic syndromes (MDS) remains undetermined.
Methods: We genotyped 113 MDS patients, 54 with IPSS low/int-1 receiving only best supportive care (BSC group) and 59 with IPSS int-2/high treated with azacitidine (AZA-group), for the following polymorphisms: XRCC1 194 and 399, APE1 148, XRCC3 241, TS5'-UTR (2R/3R and G/C) and 3'-UTR (6bp+/6bp-), MTHFR 677 and 1298. Genomic DNA was analyzed by High Resolution Melting assay and restriction digests of PCR products. Overall survival (OS) was calculated using the Kaplan-Meier estimate probabilities, and differences between survival curves were analyzed by the log-rank test. Multivariate analyses were performed using the Cox method.
Results: For all the target genes, the distribution of genotypes was consistent with the Hardy-Weinberg equilibrium. Among the baseline characteristics analyzed (age, sex, diagnosis according to WHO, hemoglobin) there was no statistically significant difference in the genotype distribution of studied polymorphisms. In the BSC group, the variants XRCC1 399 GG Hazard ratio (HR)=7.07; p=0.02, -6/-6 of TS3'-UTR (HR=4.65; p=0.05), 2R/3G, 3C/3G, 3G/3G of TS5'-UTR (HR=11.44; p=0.02) and TT of MTHFR 677 (HR=67.12; p<0.001), were associated with a statistically significant adverse clinical outcome compared to variant alleles (Table 1). This is consistent with the enzymatic activity reduction attributed to these genetic variants. Multivariable regression model analysis was also performed in the AZA group for the same genetic variants. We found similar results for the association between XRCC1 399 GG(HR=5.71 p=0.002), TS3'-UTR +6/+6(HR=0.097 p=0.004), MTHFR 677 TT (HR=8.58 p<0.001) and survival, but not for SNPs in TS5'-UTR (Table 2). Finally, we performed an exploratory analysis to investigate the combined effect of the unfavorable genotypes on survival. In the BSC group, the 3-year OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles. The predictive role of the adverse genotypes combination on survival was confirmed also in the AZA group, suggesting that patients with a higher number of genetic variants had a shorter survival. Interestingly, when we compared survival of patients with adverse genotypes between BSC and AZA groups, we did not find any statistically significant difference between the 2 groups (Kaplan-Meyer and Log-rank test). Therefore, we speculated that azacitidine could give a survival advantage to patients with unfavorable genetic variants, independently from IPSS at diagnosis.
Conclusion: Our study reveals, for the first time, an associations between genetic variants in TS, MTHFR and XRCC1 genes, BSC, azacitidine and survival in MDS patients. If confirmed, they could represent new prognostic markers able to provide guidance for clinical management of MDS patients. In particular, the presence of adverse genotypes could represent a biomarker to treat patients with low-risk IPSS with azacitidine, if confirmed on larger series. Further studies with larger population are needed to validate these associations, especially in SNPs with low variant allele frequency.
Table 1GeneGenotypeHazard risk95,0% CI forHazard Risk Lower95,0% CI forHazard Risk Upperp valueXRCC1 399G/GversusA/G-A/A7,0721,29538,6190,024TS5'-UTR3G/3G, 3G/3C, 2R/3Gversus2R/2R, 2R/3C, 3C/3C11,4471,33098,5440,026TS3'-UTRDel/DelversusDel/Ins, Ins/Ins4,6530,94622,8740,058MTHFR 677T/TversusC/T-C/C67,1256,409703,081<0,001
Table 2GeneGenotypeHazard risk95,0% CI forHazard Risk Lower95,0% CI forHazard Risk Upperp valueXRCC1 399G/GversusA/G-A/A5,7131,90417,1420,002TS3'-UTRIns/InsversusIns6/del6, del6/del60,0970,0190,4790,004MTHFR 677T/TversusC/T-C/C8,5872,74926,828<0,001
Finelli:Celgene: Other: Speaker, Research Funding; Novartis: Other: Speaker; Janssen: Other: Speaker.
Despite the prediction of a fairly benign clinical course, a subset of patients with low-risk myelodysplastic syndromes (MDS) have a more aggressive disease and shorter overall survival. The DNA ...repair and folate pathway genes play an important role in prognosis and progression in both solid and hematological cancers, and their expression has been known to be associated with polymorphism of genes. However, the impact of polymorphisms of these genes on MDS patients outcome has not yet been demonstrated. The aim of this study was to investigate the association between the polymorphisms of genes encoding main proteins of BER system (XRCC1, XRCC3 and APE1) and folate-metabolizing enzymes (TS, MTHFR) and survival in IPSS low-intermediate1 MDS patients.
the study was designed according to the Schoenfeld design for biomarkers, assuming the presence of an unfavorable pharmacogenetic profile (one or more adverse genotypes) in at least one-third of the study population. Accordingly, 10 events in 54 patients would allow the detection of an Hazard Ratio (HR) >6 associated with the group having unfavorable genotypes (80% power and 5% type I error for a two-tailed test). We thus prospectively genotyped 54 MDS patients (median age 75 years) with IPSS low (n=23) or intermediate-1 (n=31) treated with best supportive care only. Genomic DNA was isolated from 1ml of peripheral blood by means of commercially available kits. Polymorphisms were determined by PCR-HRM (High Resolution Melting) assay and restriction digests of PCR products. All samples were analyzed for the following polymorphisms: XRCC1 194 (rs1799782 C/T, Arg/Trp) and 399 (rs25487 G/A, Arg/Gln), XRCC3 241 (rs861539 C/T, Thr/Met), TS5'-UTR (2R/3R and rs183205964 G/C) and 3'-UTR Ins/Del (rs11280056 6bp+/6bp-), MTHFR 677 (rs1801133 C/T, Ala/Val) and 1298 (rs801131 A/C, Gln/Ala), APE1 148 (rs1130409 T/G, Asp/Glu). The characteristics and laboratory features of MDS patients with each polymorphisms were compared using Х2-test and Mann-Whitney test. The associations between polymorphisms status and survival were assessed using Kaplan-Meier method and Log-rank test. For the multivariate survival analysis, Cox proportional hazard models, was used to identify the genotypes fitted as indicator variables. Before performing clinical correlations, genotype frequencies were checked for agreement with those expected under the Hardy-Weinberg equilibrium.
The frequencies of genotypes of studied gene polymorphisms in patients with low/Int-1 risk are listed in Table 1. At univariate analysis, a significantly shorter survival was associated with XRCC1 399 GG, TS3'-UTR -6/-6, TS5'-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR 677 TT variant alleles. In multivariate analysis, using a stepwise logistic regression model, patients with TS3'-UTR -6/-6, XRCC1-399 GG, TS5'-UTR 2R/3G, 3C/3G, 3G/3G and MTHFR- 677 TT unfavorable genotypes presented with an Hazard Ratios of 4.65, 7.07, 11.44 and 67.12, respectively, if compared to the reference group of variant alleles (P=.058, P=.024, P=.026 and P=.000). Accordingly, we performed an exploratory analysis to investigate the effect on survival arising from the combination of the unfavorable genotypes to each other. As a fact, 3-years OS was 33% for those patients with ≥2 variant alleles, as compared to 62.5%, and 100%, respectively, for those with 2 or 0/1 variant alleles, suggesting that patients with a higher number of variant alleles had a shorter survival.
Table 1Genotypes frequenciesXRCC1 194XRCC1 399XRCC3 241TS5'-UTRTS3'-UTRMTHFR 677MTHFR 1298APE 1 148CC91%GG46%TT39%2R/3G,3C/3G 3G/3G49%+6/+626%CC30%CC48%GG13%CT9%AG43%CT22%2R/2R,2R/3C 3C/3C49%+6/-650%CT46%CA52%GT50%AA11%TC22%Unknow18%-6/-624%TT24%TT37%CC13%Unknow4%
The mutational status of BER, TS and MTHFR genes predicts the overall survival of patients with low-Int-1 IPSS MDS treated with best supportive care only. If confirmed on larger series, these polymorphisms could help to identify a subset of low-risk MDS patients with shorter survival, who might benefit from an early therapy with hypometilating agents.
The study was supported in part by AIL Pesaro Onlus.
No relevant conflicts of interest to declare.
Outcome for older patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. In this phase II study we tested, for the first time, the ...efficacy of a novel combination therapy with low-dose lenalidomide plus low-dose cytarabine. Further, based on the hypothesis that genetic features might influence treatment response, we aimed at identifying a possible biomarker by studying the global gene expression profiles (GEP).
We designed a prospective phase II study to assess the efficacy of the concomitant administration of low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged more than 70 years.
Forty-five patients (median age 76 years, range: 70-85) ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10 mg/day orally, days 1-21) plus low-dose cytarabine (10mg/m2 twice daily, subcutaneously, days 1-15) every six weeks, up to 6 cycles.
Median white blood cell count at diagnosis was 3.2x109/l (range: 0,4-46,8x109/l), whereas median hemoglobin was 8,9 g/dl and median platelet count was 31x109/l. Twenty-three out of 45 patients had an intermediate karyotype (18/23 normal), 18/45 an unfavorable karyotype and 4/45 were not evaluable. Nineteen patients had a de novo AML, whereas 26 patients had a secondary AML (18 after MDS, 3 after a CMPD, 2 after myelofibrosis, 3 after chemo-radiotherapy for a breast cancer). To identify possible biomarkers associated to sensitivity/resistance, global gene and miRNA expression profiling (Affymetrix Transciptome 2.0) was performed on purified AML cells.
Induction-period mortality was 17%, with 8 deaths occurring during cycle 1. Thirty-seven patients completed at least one cycle of therapy and are evaluable for response. Overall CR rate was 43% among evaluable patients. Nine out of 16 responding patients are still in CR after a median follow-up of 12 months (range: 2-39). Statistical analysis showed that responding patients had a longer median overall survival than non-responders (428 vs. 74 days, P = .000).
Conversely, by studying the global miRNA and gene expression profile we identified a molecular signature, including 114 genes and 18 miRNA associated with the clinical response (CR vs. no CR). Of note, the involved genes belonged to relevant functional categories such as angiogenesis, cell cycle regulation and immune response. Of note, based on the expression of 5 genes, we developed an algorithm to predict treatment response that was successfully validated by showing an 87% overall accuracy.
In conclusion, low-dose lenalidomide plus low-dose cytarabine has high clinical activity, predictable by GEP, in elderly AML patients with poor prognosis.
The study was registered at EMA (EUDRA-CT 2008-006790-33).
Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus.
No relevant conflicts of interest to declare.
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