Publications by authors named "Robin Foà"

466 Publications

The complex karyotype landscape in chronic lymphocytic leukemia allows to refine the risk of Richter syndrome transformation.

Haematologica 2021 Jun 3. Epub 2021 Jun 3.

Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy; Veneto Institute of Molecular Medicine, Padua.

Complex karyotype (CK) at chronic lymphocytic leukemia (CLL) diagnosis is a negative biomarker of adverse outcome. Since the impact of CK and its subtypes, namely type-2 CK (CK with major structural abnormalities) or high-CK (CK with C5 chromosome abnormalities), on the risk of developing Richter syndrome (RS) is unknown, we carried out a multicenter reallife retrospective study to test its prognostic impact. Among 540 CLL patients, 107 harbored a CK at CLL diagnosis, 78 were classified as CK2 and 52 as high-CK. Twenty-eight patients developed RS during a median follow-up of 6.7 years. At the time of CLL diagnosis, CK2 and high-CK were more common and predicted the highest risk of RS transformation, together with advanced Binet stage, unmutated (U)-IGHV, 11q-, TP53 abnormalities. We integrated these variables into a hierarchical model: high-CK and/or CK2 patients showed a 10-year time to RS (TTRS) of 31%; U-IGHV/11q-/TP53 abnormalities/Binet stage B-C patients had a 10-year TTRS of 12%; while mutated (M)-IGHV without CK and TP53 disruption a 10-year TTRS of 3% (p<0.0001). We herein demonstrated that CK landscape at CLL diagnosis allows to refine the risk of RS transformation and we recapitulated clinico-biological variables into a prognostic model.
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http://dx.doi.org/10.3324/haematol.2021.278304DOI Listing
June 2021

Vemurafenib plus Rituximab in Refractory or Relapsed Hairy-Cell Leukemia.

N Engl J Med 2021 05;384(19):1810-1823

From the Institute of Hematology, Ospedale S. Maria della Misericordia, and the Department of Medicine, University of Perugia, Perugia (E.T., L.D.C., E.S., M.C., S.A., V.M.P., B.F.), the Department of Medicine, Section of Hematology, University of Verona, Verona (A. Ambrosetti), the Hematology Unit, Ospedale di Cosenza, Cosenza (E.L.), the Hematology Unit, Department of Transfusional Medicine-SIMMT, Maria Paternò-Arezzo Hospital, Ragusa (A. Antolino), the Hematology Unit, Department of Translational and Precision Medicine, Sapienza University of Rome (A.P., R.F.), and the Hematology and Stem Cell Transplant Unit, A.O. San Camillo Forlanini (L.R.), Rome, the Department of Hematology, Spedali Civili di Brescia, Brescia (S.F.), IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli" and Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna (P.L.Z.), the Department of Translational Medicine, Division of Hematology, Amedeo Avogadro University of Eastern Piedmont, Novara (G.G.), the Hematology Unit, Ospedale di Carrara, Carrara (R.D.S.), the Hematology Unit, Ospedale di Frosinone, Frosinone (N.F.), the Hematology Unit, Ospedale di Ronciglione, Viterbo (P.F.), the Hematology Unit, Ospedale di Pesaro, Pesaro (G.V.), and the Hematology Unit, Azienda Sanitaria Universitaria Integrata-Ospedale Maggiore, Trieste (F.Z.) - all in Italy.

Background: Hairy-cell leukemia (HCL) is a CD20+ indolent B-cell cancer in which a BRAF V600E kinase-activating mutation plays a pathogenetic role. In clinical trials involving patients with refractory or relapsed HCL, the targeting of BRAF V600E with the oral BRAF inhibitor vemurafenib led to a response in 91% of the patients; 35% of the patients had a complete response. However, the median relapse-free survival was only 9 months after treatment was stopped.

Methods: In a phase 2, single-center, academic trial involving patients with refractory or relapsed HCL, we assessed the safety and efficacy of vemurafenib (960 mg, administered twice daily for 8 weeks) plus concurrent and sequential rituximab (375 mg per square meter of body-surface area, administered for 8 doses over a period of 18 weeks). The primary end point was a complete response at the end of planned treatment.

Results: Among the 30 enrolled patients with HCL, the median number of previous therapies was 3. A complete response was observed in 26 patients (87%) in the intention-to-treat population. All the patients who had HCL that had been refractory to chemotherapy (10 patients) or rituximab (5) and all those who had previously been treated with BRAF inhibitors (7) had a complete response. Thrombocytopenia resolved after a median of 2 weeks, and neutropenia after a median of 4 weeks. Of the 26 patients with a complete response, 17 (65%) were cleared of minimal residual disease (MRD). Progression-free survival among all 30 patients was 78% at a median follow-up of 37 months; relapse-free survival among the 26 patients with a response was 85% at a median follow-up of 34 months. In post hoc analyses, MRD negativity and no previous BRAF inhibitor treatment correlated with longer relapse-free survival. Toxic effects, mostly of grade 1 or 2, were those that had previously been noted for these agents.

Conclusions: In this small study, a short, chemotherapy-free, nonmyelotoxic regimen of vemurafenib plus rituximab was associated with a durable complete response in most patients with refractory or relapsed HCL. (Funded by the European Research Council and others; HCL-PG03 EudraCT number, 2014-003046-27.).
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http://dx.doi.org/10.1056/NEJMoa2031298DOI Listing
May 2021

TH2/TH1 Shift Under Ibrutinib Treatment in Chronic Lymphocytic Leukemia.

Front Oncol 2021 15;11:637186. Epub 2021 Apr 15.

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

Ibrutinib may revert the T-helper (Th)2 polarization observed in chronic lymphocytic leukemia (CLL) by targeting the IL-2-inducible kinase, that shows a significant homology with the Bruton tyrosine kinase. In the front-line GIMEMA LLC1114 trial (ibrutinib+rituximab for 6 months, followed by ibrutinib maintenance), we investigated the modulation of T-cell cytokine production in 208 peripheral blood paired samples from 71 CLL patients: 71 samples prior to treatment (Day 0, D0) and at day +14 (D14; n=50), at month +8 (M8; 30), +12 (M12; 25), +18 (M18; 22) and +24 (M24; 10) of treatment. We documented a progressive decrease of CD3+CD4+IL-4+ T cells (Th2), that was significant at M8 and at M12 (p=0.019, p=0.002), a relative increase in the CD3+CD4+IFNγ+ T cells (Th1) and a decrease of CD3+CD4+IL-17+ (Th17) cells that was maintained up to M18 (M8 D0 p=0.003, M12 D0 p=0.003, M18 D0 p=0.004) of ibrutinib treatment. The Th2/Th1 ratio significantly decreased already after 14 days of treatment and was maintained thereafter (D14 D0 p=0.037, M8 D0 p=0.001, M12 D0 p=0.005, M18 D0 p=0.002). The Th2/Th1 modulation over time was significant only among patients with unmutated IGHV. The Th2/Th1 ratio below a cut-off of 0.088 at M8 was associated with the achievement of a complete response (CR) (p=0.016). Ibrutinib may shape the CLL T-cell profile, limiting Th2 activation and inducing a shift in the Th2/Th1 ratio. The association between the Th2/Th1 ratio decrease and the CR achievement suggests the generation of a potential host anti-tumor immune activation induced by ibrutinib.
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http://dx.doi.org/10.3389/fonc.2021.637186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082026PMC
April 2021

The current role of interferon in hairy cell leukaemia: clinical and molecular aspects.

Br J Haematol 2021 May 1. Epub 2021 May 1.

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

We investigated the current role of interferon-alpha (IFNα) in hairy cell leukaemia (HCL) in a retrospective analysis of patients with HCL. A cohort of 74 patients with HCL was divided in to three groups: (A) patients aged >65 years with first-line treatment; (B) patients with comorbidities with first-line treatment; (C) patients who were purine analogues resistant. In total, 94% achieved a response, with a complete response rate of 24%. After a median (range) follow-up of 60 (7-236) months, 55 patients (78%) are still responding. The 5-year progression-free survival was 95%, 68%, and 96% in groups A, B and C respectively. A proportion of patients were monitored through their B-Raf proto-oncogene, serine/threonine kinase (BRAF)-V600E status. IFNα remains a possible option in select patients with HCL, where minimal residual disease negativity is achievable.
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http://dx.doi.org/10.1111/bjh.17440DOI Listing
May 2021

Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group.

Hematol Oncol 2021 Mar 19. Epub 2021 Mar 19.

Department of Medical Sciences, Hematology Section, University of Ferrara, Cona - Ferrara, Italy.

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real-life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression-free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0-1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p < 0.01). Treatment breaks ≥14 days were recorded in 96% of patients and adverse events mirrored those reported in trials. In conclusion, this real-life analysis showed that IR treatment duration was longer at experienced centers, that the ECOG PS and ≥3 lines of previous therapy are strong prognostic factor and that the overall outcome with this regimen was superimposable to that reported in a randomized trial.
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http://dx.doi.org/10.1002/hon.2861DOI Listing
March 2021

Long-term follow-up of late chronic phase chronic myeloid leukemia patients treated with imatinib after interferon failure: a single center experience.

Leuk Lymphoma 2021 Mar 16:1-6. Epub 2021 Mar 16.

Hematology, Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto I, Sapienza University, Rome, Italy.

We report the long-term outcome of 139 patients treated with imatinib in late chronic phase after IFN failure. Median follow-up was 16.6 years and the estimated 18-year OS was 64.8%. 18-year EFS and PFS were 69% and 64.4%, respectively. Fifty (36%) patients stopped imatinib, 72% received a second line. b2a2 transcript was associated with a significantly inferior 18-year OS ( = 0.008), FFS ( = 0.036), PFS ( = 0.013) compared to the b3a2 type, whilst the type of transcript did not influence the time to response achievement. Failure to achieve MMR at 12 months significantly reduced the chance of reaching a DMR ( = 0.001). Imatinib discontinuation after achieving a sustained deep molecular response was attempted in 14 patients; 12 (86%) are still in treatment-free remission (TFR) at the last follow-up. Our experience confirms the long-term efficacy of imatinib after IFNα failure in real-life setting and documents the possibility of attempting a TFR in this subset of patients.
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http://dx.doi.org/10.1080/10428194.2021.1901094DOI Listing
March 2021

Real-life comparison of nilotinib versus dasatinib as second-line therapy in chronic phase chronic myeloid leukemia patients.

Ann Hematol 2021 May 7;100(5):1213-1219. Epub 2021 Mar 7.

Hematology, Department of Translational and Precision Medicine, Policlinico Umberto 1, Sapienza University, Rome, Italy.

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.
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http://dx.doi.org/10.1007/s00277-021-04477-0DOI Listing
May 2021

Droplet Digital PCR Improves IG-/TR-based MRD Risk Definition in Childhood B-cell Precursor Acute Lymphoblastic Leukemia.

Hemasphere 2021 Mar 24;5(3):e543. Epub 2021 Feb 24.

Tettamanti Research Centre, Pediatrics, University of Milano-Bicocca, Monza, Italy.

Minimal residual disease (MRD) is the most powerful prognostic factor in pediatric acute lymphoblastic leukemia (ALL). Real-time quantitative polymerase chain reaction (RQ-PCR) represents the gold standard for molecular MRD assessment and risk-based stratification of front-line treatment. In the protocols of the Italian Association of Pediatric Hematology and Oncology (AIEOP) and the Berlin-Frankfurth-Munschen (BFM) group AIEOP-BFM ALL2009 and ALL2017, B-lineage ALL patients with high RQ-PCR-MRD at day+33 and positive at day+78 are defined slow early responders (SERs). Based on results of the AIEOP-BFM ALL2000 study, these patients are treated as high-risk also when positive MRD signal at day +78 is below the lower limit of quantification of RQ-PCR ("positive not-quantifiable," POS-NQ). To assess whether droplet digital polymerase chain reaction (ddPCR) could improve patients' risk definition, we analyzed MRD in 209 pediatric B-lineage ALL cases classified by RQ-PCR as POS-NQ and/or negative (NEG) at days +33 and/or +78 in the AIEOP-BFM ALL2000 trial. ddPCR MRD analysis was performed on 45 samples collected at day +78 from SER patients, who had RQ-PCR MRD ≥ 5.0 × 10 at day+33 and POS-NQ at day+78 and were treated as medium risk (MR). The analysis identified 13 of 45 positive quantifiable cases. Most relapses occurred in this patients' subgroup, while ddPCR NEG or ddPCR-POS-NQ patients had a significantly better outcome ( < 0.001). Overall, in 112 MR cases and 52 standard-risk patients, MRD negativity and POS-NQ were confirmed by the ddPCR analysis except for a minority of cases, for whom no differences in outcome were registered. These data indicate that ddPCR is more accurate than RQ-PCR in the measurement of MRD, particularly in late follow-up time points, and may thus allow improving patients' stratification in ALL protocols.
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http://dx.doi.org/10.1097/HS9.0000000000000543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909459PMC
March 2021

Pre-existing and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs.

Blood 2021 Mar 2. Epub 2021 Mar 2.

University of Torino, Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, Torino, Italy.

Autoimmune cytopenias (AIC) affect 5-9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs - ibrutinib, idelalisib and venetoclax - have a prominent role in the treatment of CLL, but their impact on CLL-associated AIC is largely unknown. In this study, we evaluated the characteristics and outcome of pre-existing AIC, and described the incidence, quality and management of treatment-emergent AIC during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of pre-existing AIC was reported in 104/815 patients (13%). Interestingly, 80% of patients whose AIC was not resolved at the time of targeted drug start experienced an improvement or a resolution during therapy. Treatment-emergent AIC occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib and in 7% during venetoclax, with an estimated incidence rate of 5, 6 and 69 episodes per 1000 patients per year of exposure in the three treatment groups, respectively. The vast majority of patients who developed treatment-emergent AIC carried unfavorable biological features such as an unmutated IGHV, and a del(17p) and/or TP53 mutation. Notably, despite AIC, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib and venetoclax appears to have a beneficial impact on CLL-associated AIC, inducing an improvement or even a resolution of pre-existing AIC in most cases and eliciting treatment-emergent AIC in a negligible portion of patients.
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http://dx.doi.org/10.1182/blood.2020008201DOI Listing
March 2021

Safety and efficacy of obinutuzumab alone or with chemotherapy in previously untreated or relapsed/refractory chronic lymphocytic leukaemia patients: Final analysis of the Phase IIIb GREEN study.

Br J Haematol 2021 Apr 19;193(2):325-338. Epub 2021 Feb 19.

Division of Hematology, Sapienza University, Rome, Italy.

The manageable toxicity profile of obinutuzumab (GA101; G) alone or with chemotherapy in first-line (1L; fit and non-fit) and relapsed/refractory (R/R) patients with chronic lymphocytic leukaemia (CLL) was established in the primary analysis of the Phase IIIb GREEN trial (Clinicaltrials.gov: NCT01905943). The final analysis (cut-off, 31 January 2019) is reported here. Patients received G (1000 mg) alone (G-mono; fit and non-fit patients) or with chemotherapy [fludarabine and cyclophosphamide (FC; fit patients); chlorambucil (non-fit patients); bendamustine (any patient)]. Study endpoints were safety (primary) and efficacy (secondary). Subgroup analyses were performed on prognostic biomarkers in 1L CLL. Overall, 630 patients received 1L and 341 received R/R CLL treatment. At the final analysis, no new safety signals were observed [Grade ≥ 3 adverse events (AEs): 1L 82·7%, R/R 84·5%; serious AEs: 1L 58·1%, R/R 62·5%]. Neutropenia (1L 50·5%, R/R 53·4%) and thrombocytopenia (1L 14·6%, R/R 19·1%) were the most common Grade 3-5 AEs. G-mono-, G-bendamustine and G-FC-treated patients with unmutated immunoglobulin heavy chain trended towards shorter progression-free survival. Achievement of minimal residual disease negativity was greatest in 1L patients treated with G-FC. In this final analysis of the GREEN trial, the safety profile of G was consistent with current risk management strategies. Biomarker analyses supported efficacy in the specific subgroups.
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http://dx.doi.org/10.1111/bjh.17326DOI Listing
April 2021

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.

Leukemia 2021 Feb 4. Epub 2021 Feb 4.

EBMT Paris Study Office, Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Paris, France.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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http://dx.doi.org/10.1038/s41375-021-01135-2DOI Listing
February 2021

A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL1509 protocol.

Haematologica 2021 Feb 4. Epub 2021 Feb 4.

Hematology, Department of Translational and Precision Medicine, Sapienza University.

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39.
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http://dx.doi.org/10.3324/haematol.2020.260935DOI Listing
February 2021

Dasatinib-Blinatumomab for Ph-Positive ALL. Reply.

N Engl J Med 2021 01;384(4):384

Sapienza University, Rome, Italy

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http://dx.doi.org/10.1056/NEJMc2033785DOI Listing
January 2021

Low-density lipoprotein (LDL) levels and risk of arterial occlusive events in chronic myeloid leukemia patients treated with nilotinib.

Ann Hematol 2021 Jan 3. Epub 2021 Jan 3.

Hematology Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

Recommendations for dyslipidemia management aimed at reducing arterial occlusive events (AOEs) have been recently published. So far, no data have been reported on the management of dyslipidemia in chronic myeloid leukemia (CML) patients treated with nilotinib. We investigated 369 CML adult patients, stratified according to the new Systematic Coronary Risk Evaluation (SCORE) scoring system. Plasma levels of cholesterol, HDL, LDL, and triglycerides were measured prior to the start of nilotinib and after 3, 6, and 12 months. The 5-year cumulative incidence of AOEs was 15.9%. Patients with cholesterol levels > 200 mg/dL and LDL > 70 mg/dL 3 months after treatment showed a significantly higher incidence of AOEs (21.9 ± 4.6% vs 6.2 ± 2.5, P = 0.003). Patients belonging to the high and very high SCORE risk group showed a significant increase of AOEs (34.4 ± 6% vs 10 ± 2.1%, P < 0.001). In multivariate analysis, both high cholesterol and LDL levels and a high and very high SCORE risk remained significantly associated with the risk of AOEs (P = 0.008; HR = 3.5; 95% CI = 1.4-8.7 and P < 0.001; HR = 4.4; 95% CI = 2-9.8, respectively). Overall, 78 patients (21.1%) presented dyslipidemia at the time of CML diagnosis and 88 (23.3%) after starting nilotinib, but only 26 of them (29.5%) were treated with statins.Low LDL and cholesterol plasma levels are associated with a significant lower risk of AOEs in CML patients treated with nilotinib in the real life.
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http://dx.doi.org/10.1007/s00277-020-04392-wDOI Listing
January 2021

Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases.

Eur J Haematol 2021 Apr 28;106(4):493-499. Epub 2021 Jan 28.

UOSD Ematologia ASL Roma 1, Roma, Italy.

Objectives: To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only.

Methods: A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study.

Results: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P = .04) independent of potential confounders.

Conclusions: Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.
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http://dx.doi.org/10.1111/ejh.13573DOI Listing
April 2021

Relapsed/refractory diffuse large B-cell lymphoma patients. A multicenter retrospective analysis of eligibility criteria for car-T cell therapy.

Leuk Lymphoma 2021 04 4;62(4):828-836. Epub 2020 Dec 4.

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

Anti-CD19 chimeric antigen receptor (CAR) T cells represent the first approved third-line therapy associated with long-term remissions in patients with refractory/relapsed (R/R) diffuse large B-cell lymphoma (DLBCL). Eligibility criteria to identify patients who can successfully receive CAR-T are still debated. For this reason, the aim of this study was to identify factors influencing eligibility and define a realistic patient estimate. Of 1100 DLBCL patients, 137 were included. Based on the Juliet trial inclusion criteria, only 64 patients (46.7%) would be eligible. Median overall survival (OS) was 8.04 months in eligible 3.23 in non-eligible patients ( < 0.001). Multivariate analysis identified stage III-IV ( 0.017) and ECOG 2 ( < 0.001) as significant independent prognostic factors for OS. Moreover, only 64/1100 (5.8%) DLBCL patients would be truly eligible for CAR-T. Our real-life data confirm that with a longer waiting time patients with advanced stage and poor ECOG are less likely to be eligible for CAR-T cell infusion.
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http://dx.doi.org/10.1080/10428194.2020.1849676DOI Listing
April 2021

Digital droplet PCR as a predictive tool for successful discontinuation outcome in chronic myeloid leukemia: Is it time to introduce it in the clinical practice?

Crit Rev Oncol Hematol 2021 Jan 12;157:103163. Epub 2020 Nov 12.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Azienda Policlinico Umberto 1, Rome, Italy. Electronic address:

Tyrosine kinase inhibitors (TKIs) have drastically changed the outcome of chronic myeloid leukemia (CML) patients. A sustained and deep molecular response achieved over time paves the way to therapy discontinuation, and is a pre-requisite to attempt treatment-free remission. Monitoring of the molecular response during treatment discontinuation is routinely carried out by RQ-PCR, but it may not be the optimal tool to monitor minimal residual disease at the time of stopping treatment and during treatment discontinuation. Different digital PCR platforms (such as droplet dPCR) are available, a method based on water-emulsion droplet technology in which the sample is partitioned into 20,000 droplets and PCR amplification of the template subsequently occurs in each individual droplet. The consequent high sensitivity and precision with a very reliable quantification without the need of a calibration curve and the exquisite reproducibility makes this procedure as an ideal alternative method for the detection of very low levels of disease. Aim of this review is to describe and discuss the recent use of dPCR/ddPCR in CML, focusing in particular on its role in TKI treatment discontinuation strategies.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103163DOI Listing
January 2021

Tyrosine kinase inhibitor discontinuation in the management of chronic myeloid leukemia: a critical review of the current practice.

Expert Rev Hematol 2020 12 1;13(12):1311-1318. Epub 2020 Dec 1.

Hematology, Department of Translational and Precision Medicine, Azienda Policlinico Umberto I, Sapienza University , Rome, Italy.

: Tyrosine kinase inhibitors (TKIs), which target BCR-ABL1 kinase activity, have significantly prolonged the overall survival of patients affected by chronic myeloid leukemia (CML) and changed drastically the outcome. Evidences from several studies suggest that in patients who have achieved a sustained, stable and deep molecular response, TKI treatment can be safely discontinued with a close subsequent monitoring. Thus, a stable deep molecular response (DMR) has become a feasible treatment goal in CML. : In this review, the main findings extrapolated from sponsored and real-life evidences regarding TKI discontinuation were discussed, through a broad research on Medline, Embase and archives from EHA and ASH congresses (including words such as discontinuation, treatment-free remission, TFR, etc). Moreover, suggestions emerged from international guidelines about treatment-free remission (TFR) are presented. : With the growing availability of clinical trials and real-life data on TFR, in recent years the possibility of offering to CML patients a safe, informed and shorter path to TFR, through the achievement of a stable deep molecular response (DMR), has become an increasing option. However, many controversial aspects remain regarding treatment choices and timings, predictive factors, patient communication and optimal strategies aimed at achieving a successful TFR.
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http://dx.doi.org/10.1080/17474086.2021.1852924DOI Listing
December 2020

Ponatinib for the treatment of Ph-like acute lymphoblastic leukemia.

Leuk Lymphoma 2021 03 5;62(3):755-757. Epub 2020 Nov 5.

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

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http://dx.doi.org/10.1080/10428194.2020.1842401DOI Listing
March 2021

Dasatinib-Blinatumomab for Ph-Positive Acute Lymphoblastic Leukemia in Adults.

N Engl J Med 2020 10;383(17):1613-1623

From the Division of Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome (R.F., A.V., L.E., M.-C.P., M.C., M.-S.D.P., M.V., S.C.), Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Data Center, Fondazione GIMEMA Franco Mandelli Onlus (A.P., M.V.), and the Department of Molecular Medicine, Sapienza University of Rome (A.G.), Rome, the Hematology Unit, Ospedale dell'Angelo and Ospedale SS Giovanni e Paolo, Venice (R.B., P.V., A.M.), the Division of Hematology, Cardarelli Hospital, Naples (F. Ferrara), the Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara (M.L.), Division of Hematology and Bone Marrow Transplantation, Ospedali Riuniti Villa Sofia Cervello, Palermo (F. Fabbiano), the Department of Medicine, Section of Hematology, University of Verona, Verona (M.B.), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Università degli Studi di Milano (N.F.), and the Department of Oncology-Hematology, University of Milan (A.R.), Milan, the Department of Hematology, Ospedale Civile, Pescara (P.D.B.), and Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo (A.R.) - all in Italy.

Background: Outcomes in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) have improved with the use of tyrosine kinase inhibitors. Molecular remission is a primary goal of treatment.

Methods: We conducted a phase 2 single-group trial of first-line therapy in adults with newly diagnosed Ph-positive ALL (with no upper age limit). Dasatinib plus glucocorticoids were administered, followed by two cycles of blinatumomab. The primary end point was a sustained molecular response in the bone marrow after this treatment.

Results: Of the 63 patients (median age, 54 years; range, 24 to 82) who were enrolled, a complete remission was observed in 98%. At the end of dasatinib induction therapy (day 85), 29% of the patients had a molecular response, and this percentage increased to 60% after two cycles of blinatumomab; the percentage of patients with a molecular response increased further after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival was 95% and disease-free survival was 88%; disease-free survival was lower among patients who had an deletion plus additional genetic aberrations ( or , , or both [i.e., ]). mutations were detected in 6 patients who had increased minimal residual disease during induction therapy, and all these mutations were cleared by blinatumomab. Six relapses occurred. Overall, 21 adverse events of grade 3 or higher were recorded. A total of 24 patients received a stem-cell allograft, and 1 death was related to transplantation (4%).

Conclusions: A chemotherapy-free induction and consolidation first-line treatment with dasatinib and blinatumomab that was based on a targeted and immunotherapeutic strategy was associated with high incidences of molecular response and survival and few toxic effects of grade 3 or higher in adults with Ph-positive ALL. (Funded by Associazione Italiana per la Ricerca sul Cancro and others; GIMEMA LAL2116 D-ALBA EudraCT number, 2016-001083-11; ClinicalTrials.gov number, NCT02744768.).
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http://dx.doi.org/10.1056/NEJMoa2016272DOI Listing
October 2020

Efficacy of bendamustine and rituximab in unfit patients with previously untreated chronic lymphocytic leukemia. Indirect comparison with ibrutinib in a real-world setting. A GIMEMA-ERIC and US study.

Cancer Med 2020 11 24;9(22):8468-8479. Epub 2020 Sep 24.

Hematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy.

Limited information is available on the efficacy of front-line bendamustine and rituximab (BR) in chronic lymphocytic leukemia (CLL) with reduced renal function or coexisting conditions. We therefore analyzed a cohort of real-world patients and performed a matched adjusted indirect comparison with a cohort of patients treated with ibrutinib. One hundred and fifty-seven patients with creatinine clearance (CrCl) <70 mL/min and/or CIRS score >6 were treated with BR. The median age was 72 years; 69% of patients had ≥2 comorbidities and the median CrCl was 59.8 mL/min. 17.6% of patients carried TP53 disruption. The median progression-free survival (PFS) was 45 months; TP53 disruption was associated with a shorter PFS (P = 0.05). The overall survival (OS) at 12, 24, and 36 months was 96.2%, 90.1%, and 79.5%, respectively. TP53 disruption was associated with an increased risk of death (P = 0.01). Data on 162 patients ≥65 years treated with ibrutinib were analyzed and compared with 165 patients ≥65 years treated with BR. Factors predicting for a longer PFS at multivariable analysis in the total patient population treated with BR and ibrutinib were age (HR 1.06, 95% CI 1.02-1.10, P < 0.01) and treatment with ibrutinib (HR 0.55, 95% CI 0.33-0.93, P = 0.03). In a post hoc analysis of patients in advanced stage, a significant PFS advantage was observed in patient who had received ibrutinib (P = 0.03), who showed a trend for OS advantage (P = 0.08). We arrived at the following conclusions: (a) BR is a relatively effective first-line regimen in a real-world population of unfit patients without TP53 disruption, (b) ibrutinib provided longer disease control than BR in patients with advanced disease stage.
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http://dx.doi.org/10.1002/cam4.3470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666748PMC
November 2020

COVID-19 in Patients with Hematologic Disorders Undergoing Therapy: Perspective of a Large Referral Hematology Center in Rome.

Acta Haematol 2020 15;143(6):574-582. Epub 2020 Sep 15.

Hematology, Department of Hematology, Oncology and Dermatology, AOU Policlinico Umberto I, Sapienza University of Rome, Rome, Italy.

Introduction: Patients with cancer may be more susceptible to and have higher morbidity and mortality rates from COVID-19 than the general population, while epidemiologic data specifically addressed to hematologic patients are limited. To investigate whether patients with hematologic diseases undergoing therapy are at increased risk for acquiring SARS CoV-2 infection compared to the general population, a retrospective study was carried out at a referral hematologic center in Rome, Italy, during the period of the greatest epidemic spread (March 8 to May 14, 2020).

Methods: All adult and pediatric patients with a diagnosis of a neoplastic or a nonneoplastic hematologic disease who underwent treatment (chemotherapy or immunosuppressive or supportive therapy) during the study period or in the previous 6 months were considered. The prevalence of COVID-19 in the overall outpatient and inpatient population undergoing hematologic treatment compared to that of the general population was analyzed. The measures taken to manage patients during the epidemic period are described.

Results: Overall, 2,513 patients with hematological diseases were considered. Out of 243 (9.7%) patients who were screened for SARS CoV-2, three of 119 (2.5%) outpatients with fever or respiratory symptoms and none of 124 asymptomatic patients were diagnosed with COVID-19. Three further patients were diagnosed with COVID-19 and managed in other hospitals in Rome. As of May 14, 2020, the prevalence of COVID-19 in our hematologic population accounted for 0.24% (95% CI 0.23-0.25; 6 of 2,513 patients: 1 case in every 419 patients) as compared to 0.12% (7,280 of 5,879,082 residents; 1 case in every 807 residents) in the general population (p = 0.14). Three of 6 patients diagnosed with COVID-19 required critical care and 2 died while still positive for SARS CoV-2. Out of 225 healthcare providers on duty at our Institution during the study period, 2 (0.9%) symptomatic cases were diagnosed with COVID-19.

Conclusion: In our experience, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. Definition of adapted strategies for healthcare services, while continuing to administer the standard hematologic treatments, represents the crucial challenge for the management of hematologic diseases in the COVID-19 era.
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http://dx.doi.org/10.1159/000510769DOI Listing
December 2020

The advantages and risks of ruxolitinib for the treatment of polycythemia vera.

Expert Rev Hematol 2020 10 11;13(10):1067-1072. Epub 2020 Sep 11.

Hematology, Department of Translational and Precision Medicine, Sapienza University Azienda Policlinico Umberto 1 , Rome, Italy.

Introduction: Polycythemia vera is a myeloproliferative neoplasm characterized by an increased red blood cell mass, risk of thromboembolic events, and of transformation into secondary myelofibrosis and acute leukemia. The goal of treatment is to reduce the risk of fatal cardiovascular events reducing the hematocrit level with phlebotomies and low-dose aspirin. In high-risk patients (age >60 years or previous thromboembolic events) cytoreductive therapy is indicated. In this setting, resistance and/or intolerance is common.

Areas Covered: Authors searched Medline, Embase, archives from the EHA and the ASH annual congresses from 2014 onward about ruxolitinib treatment in PV patients. Two trials (RESPONSE and RESPONSE2) have documented the efficacy and safety of ruxolitinib. The drug is able to persistently control the hematocrit level and symptoms (due to increased cytokine levels, increased viscosity, and increased splenomegaly), to reduce WBC counts and the rate of thromboembolic events, to increase the quality of life.

Expert Opinion: Although ruxolitinib has entered into the clinical practice, the real-life incidence of resistant/intolerant patients, the long-term safety, and the activity on thromboembolic events (associated or not to a reduction of the molecular burden) remains to be conclusively determined. More information extrapolated by registries are required to shed light on the missing information.
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http://dx.doi.org/10.1080/17474086.2020.1816819DOI Listing
October 2020

Management of myelofibrosis and concomitant advanced cutaneous squamous cell carcinoma with ruxolitinib associated with cemiplimab.

Ann Hematol 2020 Aug 27. Epub 2020 Aug 27.

Hematology, Department of Translational and Precision Medicine, Azienda Ospedaliera Policlinico Umberto 1, Sapienza University, Via Benevento 6, 00161, Rome, Italy.

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http://dx.doi.org/10.1007/s00277-020-04236-7DOI Listing
August 2020