Publications by authors named "Lara Aprile"

11 Publications

  • Page 1 of 1

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

Cancer Med 2021 Mar 16;10(5):1726-1737. Epub 2021 Feb 16.

University of Bologna, Bologna, Italy.

Background: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong.

Methods: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR ) and to improve Health Related Quality of Life (HRQoL).

Results: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR /MR completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR was 81% and 23.5% of the patients who lost the molecular response regained the MR after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001).

Conclusions: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR /MR in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR regained the MR and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.
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http://dx.doi.org/10.1002/cam4.3778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940223PMC
March 2021

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T-cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study.

Am J Hematol 2020 12 31;95(12):1466-1472. Epub 2020 Aug 31.

Ematologia, Dipartimento di Medicina Traslazionale e di Precisione, "Sapienza" Università di Roma, Rome, Italy.

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74 years), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log-rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE.
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http://dx.doi.org/10.1002/ajh.25957DOI Listing
December 2020

Erythropoietin treatment in chronic phase chronic myeloid leukemia patients treated with frontline imatinib who developed late anemia.

Eur J Haematol 2020 Sep 22;105(3):286-291. Epub 2020 May 22.

Department of Translational and Precision Medicine, University "La Sapienza" of Rome, Rome, Italy.

Background: Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined.

Methods: Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated.

Results: Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed.

Conclusions: Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.
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http://dx.doi.org/10.1111/ejh.13436DOI Listing
September 2020

Residual Peripheral Blood CD26 Leukemic Stem Cells in Chronic Myeloid Leukemia Patients During TKI Therapy and During Treatment-Free Remission.

Front Oncol 2018 30;8:194. Epub 2018 May 30.

Hematology Unit, Ospedale Oncologico A. Businco, Cagliari, Italy.

Chronic myeloid leukemia (CML) patients in sustained "deep molecular response" may stop TKI treatment without disease recurrence; however, half of them lose molecular response shortly after TKI withdrawing. Well-defined eligibility criteria to predict a safe discontinuation up-front are still missing. Relapse is probably due to residual quiescent TKI-resistant leukemic stem cells (LSCs) supposedly transcriptionally low/silent and not easily detectable by BCR-ABL1 qRT-PCR. Bone marrow Ph+ CML CD34/CD38 LSCs were found to specifically co-express CD26 (dipeptidylpeptidase-IV). We explored feasibility of detecting and quantifying CD26 LSCs by flow cytometry in peripheral blood (PB). Over 400 CML patients (at diagnosis and during/after therapy) entered this cross-sectional study in which CD26 expression was evaluated by a standardized multiparametric flow cytometry analysis on PB CD45/CD34/CD38 stem cell population. All 120 CP-CML patients at diagnosis showed measurable PB CD26 LSCs (median 19.20/μL, range 0.27-698.6). PB CD26 LSCs were also detectable in 169/236 (71.6%) CP-CML patients in first-line TKI treatment (median 0.014 cells/μL; range 0.0012-0.66) and in 74/112 (66%), additional patients studied on treatment-free remission (TFR) (median 0.015/μL; range 0.006-0.76). Notably, no correlation between BCR-ABL/ABL ratio and number of residual LSCs was found both in patients on or off TKIs. This is the first evidence that "circulating" CML LSCs persist in the majority of CML patients in molecular response while on TKI treatment and even after TKI discontinuation. Prospective studies evaluating the dynamics of PB CD26 LSCs during TKI treatment and the role of a "stem cell response" threshold to achieve and maintain TFR are ongoing.
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http://dx.doi.org/10.3389/fonc.2018.00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988870PMC
May 2018

The and polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia.

Oncotarget 2017 Oct 30;8(50):88021-88033. Epub 2017 Sep 30.

Department of Clinical and Experimental Medicine, Section of Hematology, University of Pisa, Pisa, Italy.

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of (rs683369 [c.480C>G]) and (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, and polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, n contrast to data obtained in patients treated with imatinib, and polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.
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http://dx.doi.org/10.18632/oncotarget.21406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675690PMC
October 2017

Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients.

Oncotarget 2016 Nov;7(44):72311-72321

Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Siena, Italy.

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced "inflammatory/oxidative status", together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.
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http://dx.doi.org/10.18632/oncotarget.11100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342164PMC
November 2016

Peptide vaccines for hematological malignancies: a missed promise?

Int J Hematol 2014 Feb 8;99(2):107-16. Epub 2014 Jan 8.

Department of Hematology, University of Siena, Azienda Ospedaliera Universitaria Senese, Viale Bracci 16, 53100, Siena, Italy,

Despite the crucial aid that newly developed target therapies are providing to chemotherapy and stem cell transplant, the cure for many hematological malignancies is still an unmet need. Although available therapies are able to induce an effective debulking of the tumor, most of the time, an insidious minimal residual disease survives current treatments and it is responsible for an immediate or delayed relapse. Peptide-derived antitumor vaccines have been developed with the idea that an artificially "educated" immune system may exert an active specific antitumor response able to control and ultimately eradicate underlying post-treatment residual disease. This review will summarize current knowledge of peptide vaccines for hematological malignancies, trying to analyze promises and pitfalls of a safe and intelligent tool that after many years from its first appearance has not yet established its potential role as alternative immune mediated therapeutic approach for hematopoietic tumors.
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http://dx.doi.org/10.1007/s12185-013-1497-3DOI Listing
February 2014

Identification of a novel p190-derived breakpoint Peptide suitable for Peptide vaccine therapeutic approach in ph+ acute lymphoblastic leukemia patients.

Leuk Res Treatment 2012 15;2012:150651. Epub 2012 Feb 15.

Department of Hematology, University of Siena, 53100 Siena, Italy.

Ph+ acute lymphoblastic leukemia (Ph+ ALL) is a high-risk acute leukemia with poor prognosis, in which the specific t(9;22)(q34;q11) translocation results in a chimeric bcr-abl (e1a2 breakpoint) and in a 190 KD protein (p190) with constitutive tyrosine kinase activity. The advent of first- and second-generation tyrosine kinase inhibitors (TKIs) improved the short-term outcome of Ph+ ALL patients not eligible for allo-SCT; yet disease recurrence is almost inevitable. Peptides derived from p190-breakpoint area are leukemia-specific antigens that may mediate an antitumor response toward p190+ leukemia cells. We identified one peptide named p190-13 able to induce in vitro peptide-specific CD4+ T cell proliferation in Ph+ ALL patients in complete remission during TKIs. Thus this peptide appears a good candidate for developing an immune target vaccine strategy possibly synergizing with TKIs for remission maintenance.
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http://dx.doi.org/10.1155/2012/150651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505930PMC
December 2012

Evaluation of residual CD34(+) Ph(+) progenitor cells in chronic myeloid leukemia patients who have complete cytogenetic response during first-line nilotinib therapy.

Cancer 2012 Nov 19;118(21):5265-9. Epub 2012 Apr 19.

Department of Hematology, University of Siena, Siena, Italy.

Background: Compared with imatinib, nilotinib is a potent breakpoint cluster region/v-abl Abelson murine leukemia viral oncogene (bcr-abl) kinase inhibitor, and it induces higher rate and rapid complete cytogenetic response (CCyR), yet no clinical data are available regarding its efficacy against chronic myeloid leukemia (CML) stem cells. Earlier studies demonstrated that clusters of differentiation 34-positive, Philadelphia chromosome-positive (CD34(+) Ph(+) ) cells are detectable in about 45% of patients with CML, despite being on long-term imatinib therapy and having achieved sustained CCyR.

Methods: CD34(+) cells from bone marrow of de novo CML patients in the chronic phase (n = 24) treated with nilotinib (median duration of therapy, 22 months) were isolated and scored for BCR-ABL by fluorescent in situ hybridization (FISH) analysis. Similar analysis was also performed in 5 de novo CML chronic phase patients who achieved CCyR within 3 months of nilotinib therapy.

Results: FISH evaluation of a median of 100 CD34(+) nuclei per patient revealed that only 1 of 20 (5%) evaluable patients showed residual Ph(+) progenitor cells. In this patient, just 1 of 140 (0.7%) CD34(+) interphase nuclei was found to be positive for BCR-ABL. Surprisingly, no CD34(+) Ph(+) cells were found even in those 5 patients evaluated after 3 months of nilotinib treatment.

Conclusions: This study assessed for the first time the persistence of CD34(+) Ph(+) cells during nilotinib first-line treatment. Preliminary results showed that in patients in CCyR, even after short-term nilotinib therapy, residual leukemic progenitors are very rarely detected compared with imatinib-treated CCyR patients. It is yet to be determined if these findings will have an impact in the path to a cure of CML with tyrosine kinase inhibitors.
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http://dx.doi.org/10.1002/cncr.27506DOI Listing
November 2012

Complete molecular response in CML after p210 BCR-ABL1-derived peptide vaccination.

Nat Rev Clin Oncol 2010 Oct 31;7(10):600-3. Epub 2010 Aug 31.

Hematology and Transplants, University of Siena and AOUS, Viale Bracci 16, 53100 Siena, Italy.

Background: A 63-year-old woman with chronic myeloid leukemia (CML) received treatment with interferon (IFN)-α for 6 years. After achieving a complete cytogenetic response that was repetitively documented, IFN-α treatment was stopped. Despite maintenance of a complete cytogenetic response, a progressive rise of the BCR-ABL1 transcript was detected and loss of major molecular response occurred about 2 years after stopping IFN-α therapy. Disease remained at molecular level.

Investigations: Peripheral blood quantitative real-time PCR every 3 months and periodical bone marrow aspirate were performed to monitor disease.

Diagnosis: Chronic-phase, Philadelphia-positive CML that was still detectable after complete cytogenic response 2 years after cessation of IFN-α therapy.

Management: The patient was treated with a target immune approach receiving a therapeutic vaccine that consisted of an immunogenic 25-mer b2a2 breakpoint-derived peptide (CMLb2a2-25) with binding properties for several HLA-DR molecules. After nine boosts of vaccine the patient developed an adequate b2a2-25 peptide-specific CD4(+) T-cell response and BCR-ABL1 transcript started to decline in peripheral blood. No hematological or extrahematological effects were documented during therapy. At the last evaluation, 39 months since vaccinations commenced, the patient is in complete molecular response with an undetectable level of BCR-ABL1 transcript both in peripheral blood and in bone marrow and she continues to receive boosts of vaccine every 3 months as the only treatment.
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http://dx.doi.org/10.1038/nrclinonc.2010.141DOI Listing
October 2010