Panizo, C. (Carlos)

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    Durable response with single-agent acalabrutinib in patients with relapsed or refractory mantle cell lymphoma
    (Springer Science and Business Media LLC, 2019) Oberic, L. (Lucie); Patel, P (Priti); Yin, M. (Ming); Dupuis, J. (Jehan); Shah, B. (Bijal); Robak, T. (Tadeusz); Le-Gouill, S. (Steven); Damaj, G. (Gandhi); Raquel; Jacobsen, E. (Eric); Jain, P. (Preetesh); Panizo, C. (Carlos); Lamy, T. (Thierry); Frigault, M.M. (Melanie M.); Rule, S. (Simon); Dlugosz-Danecka, M. (Monika); Davies, A. (Andrew); Smith, S.D. (Stephen D.); Doorduijn, J.K. (Jeanette K.); Kate, A.P. (Arnon P.); Morschhauser, F. (Franck); Casasnovas, R. O. (René Olivier); Goy, A. (Andre); Wang, M. (Michael); Eek, R. (Richard); Zinzani, P.L. (P. L.); Nguyen, D. (Dorothy)
    Bruton tyrosine kinase (BTK) inhibitors have greatly improved the spectrum of treatment options in mantle cell lymphoma (MCL) [1–4]. Acalabrutinib is a highly selective, orally administered, and potent BTK inhibitor with limited off-target activity [5]. Acalabrutinib was approved in 2017 by the US Food and Drug Administration for the treatment of relapsed/refractory MCL based on clinical data from the open-label, multicenter, phase 2 ACE-LY-004 study of acalabrutinib 100 mg twice daily [1]. Here, we present updated results from the ACE-LY-004 study after a median 26-month follow-up. Eligibility criteria and study design were published previously (Supplementary methods) [1]. Analysis of minimal residual disease (MRD) was conducted after complete response (CR) or partial response (PR) was achieved using the quantitative ClonoSEQ next-generation sequencing (5 × 10−6 ) assay (Adpative Biotechnologies, Seattle, WA, USA) in consenting patients with available paired archival tumor and whole blood samples. Data are updated as of February 12, 2018.
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    Preneoplastic somatic mutations including MYD88(L265P) in lymphoplasmacytic lymphoma
    (2022) Reinhardt, H.C. (Hans Christian); Vilas, A. (Amaia); Sanchez-Garcia, I. (Isidro); Perez, C. (Cristina); Paiva, A. (Artur); López-de-Arancibia, A. (Aitziber); Sacco, A. (Antonio); Santos, S. (S.); Celay, J. (Jon); Sarvide, S. (Sarai); García-Sanz, R. (Ramón); Goicoechea, I. (Ibai); García-Barchino, M.J. (María José); Martinez-Climent, J.A. (José Ángel); Gárate-Luzuriaga, S. (Sonia); Carrasco, Y.R. (Yolanda R.); Panizo, C. (Carlos); Larrayoz, M. (Marta); Vitoria, H. (Helena); Puig, N. (Noemí); Botta, C. (Cirino); Rodríguez-Díaz, S. (Saray); Garcés-Latre, J.J. (Juan José); Motta, M. (Marina); Geraldes, C. (Catarina); Lamo-de-Espinosa-Vázquez-de-Sola, J.M. (José María); Alignani, D. (Diego); Duarte, S. (Sara); Paiva, B. (Bruno); Larrayoz, M.J. (María J.); Prosper-Cardoso, F. (Felipe); Calasanz-Abinzano, M.J. (Maria Jose); Roccaro, A.M. (Aldo M.); Fuerte, G. (Gema); Tucci, A. (Alessandra); San-Miguel, J.F. (Jesús F.); Gentile, M. (Massimo); Jiménez, C. (Cristina)
    Normal cell counterparts of solid and myeloid tumors accumulate mutations years before disease onset; whether this occurs in B lymphocytes before lymphoma remains uncertain. We sequenced multiple stages of the B lineage in elderly individuals and patients with lymphoplasmacytic lymphoma, a singular disease for studying lymphomagenesis because of the high prevalence of mutated MYD88. We observed similar accumulation of random mutations in B lineages from both cohorts and unexpectedly found MYD88(L265P) in normal precursor and mature B lymphocytes from patients with lymphoma. We uncovered genetic and transcriptional pathways driving malignant transformation and leveraged these to model lymphoplasmacytic lymphoma in mice, based on mutated MYD88 in B cell precursors and BCL2 overexpression. Thus, MYD88(L265P) is a preneoplastic event, which challenges the current understanding of lymphomagenesis and may have implications for early detection of B cell lymphomas.
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    Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma
    (American Society of Hematology, 2010) Fresquet, V. (Vicente); Rullan, A.J. (Antonio J.); Beltran, E. (E.); Roman-Gomez, J. (José); Hernandez, J.M. (J. M.); Martinez-Climent, J.A. (José Ángel); Panizo, C. (Carlos); Richter, J.A. (José Ángel); Prosper-Cardoso, F. (Felipe); Robles, E.F. (Eloy Francisco); Calasanz-Abinzano, M.J. (Maria Jose); Aguirre-Ena, X. (Xabier)
    In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL.
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    A novel gene, MDS2, is fused to ETV6/TEL in a t(1;12)(p36.1;p13) in a patient with myelodysplastic syndrome
    (Wiley-Blackwell, 2002) Zeleznik-Le, N.J. (Nancy J.); Panizo, C. (Carlos); Roman, J.P. (José P.); Novo-Villaverde, F. J. (Francisco Javier); Lahortiga, I. (Idoya); Rowley, J.D. (Janet D.); Vizmanos-Pérez, J.L. (José Luis); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores)
    ETV6/TEL is the first transcription factor identified that is specifically required for hematopoiesis within the bone marrow. This gene has been found to have multiple fusion partners of which 16 have been cloned. Fluorescence in situ hybridization (FISH) analysis in a patient with myelodysplastic syndrome (MDS) revealed a t(1;12)(p36;p13) involving ETV6, with the breakpoint in this gene between exon 2 and exon 3. We report here the cloning of a novel ETV6 partner located on 1p36.1, involved in the t(1;12). 3' RACE-PCR from RNA identified a novel sequence fused to exon 2 of ETV6. Database searches localized this sequence in a bacterial artificial chromosome (BAC) mapped to 1p36 by fingerprint analysis. This result was confirmed by FISH using this BAC as probe. 5' and 3' RACE experiments with primers from this novel sequence were carried out on RNA from a healthy donor and identified a novel full-length mRNA, which we named MDS2 (myelodysplastic syndrome 2). RT-PCR experiments were performed on a panel of human cDNAs to analyze the expression pattern of this gene and they revealed four splicing variants. RT-PCR analysis showed that ETV6-MDS2, but not the reciprocal MDS2-ETV6 fusion transcript, was expressed in the bone marrow of the patient. The product of the ETV6-MDS2 fusion transcript predicts a short ETV6 protein containing the first 54 amino acids of ETV6 plus four novel amino acids, lacking both the PTN and the DNA-binding domains. Possible mechanisms to account for the development of MDS in this patient are discussed.
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    Ibrutinib does not have clinically relevant interactions with oral contraceptives or substrates of CYP3A and CYP2B6
    (2020) Ouellet, D. (Daniele); Mitselos, A. (Anna); Panizo, C. (Carlos); Jurczak, W. (Wojciech); Dlugosz-Danecka, M. (Monika); Cordoba, R. (Raul); Hellemans, P. (Peter); Sukbuntherng, J. (Juthamas); Jong, J. (Jan) de; Wrobel, T. (Tomasz); Jiao, J. (James)
    Ibrutinib may inhibitintestinal CYP3A4 and induce CYP2B6 and/or CYP3A. Secondary to potential induction, ibrutinib may reduce the exposure and effectiveness of oral contraceptives (OCs). This phase I study evaluated the effect of ibrutinib on the pharmacokinetics of the CYP2B6 substrate bupropion, CYP3A substrate midazolam, and OCs ethinylestradiol (EE) and levonorgestrel (LN). Female patients (N = 22) with B-cell malignancies received single doses of EE/LN (30/150 μg) and bupropion/midazolam (75/2 mg) during a pretreatment phase on days 1 and 3, respectively (before starting ibrutinib on day 8), and again after ibrutinib 560 mg/day for ≥ 2 weeks. Intestinal CYP3A inhibition was assessed on day 8 (single-dose ibrutinib plus single-dose midazolam). Systemic induction was assessed at steady-state on days 22 (EE/LN plus ibrutinib) and 24 (bupropion/midazolam plus ibrutinib). The geometric mean ratios (GMRs; test/reference) for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) were derived using linear mixed-effects models (90% confidence interval within 80%-125% indicated no interaction). On day 8, the GMR for midazolam exposure with ibrutinib coadministration was ≤ 20% lower than the reference, indicating lack of intestinal CYP3A4 inhibition. At ibrutinib steady-state, the Cmax and AUC of EE were 33% higher than the reference, which was not considered clinically relevant. No substantial changes were noted for LN, midazolam, or bupropion. No unexpected safety findings were observed. A single dose of ibrutinib did not inhibit intestinal CYP3A4, and repeated administration did not induce CYP3A4/2B6, as assessed using EE, LN, midazolam, and bupropion.
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    The increase of plasminogen activator inhibitor activity is associated with graft occlusion in patients undergoing aorto-coronary bypass surgery
    (Blackwell Publishing, 1997) Paramo, J.A. (José Antonio); Rifon, J. J. (Jose J.); Rocha, E. (Eduardo); Panizo, C. (Carlos); Montes, R. (Ramón)
    Early graft occlusion is a common complication in patients undergoing aorto-coronary bypass surgery. Both mechanical and haemostatic factors play a role in the pathogenesis of thrombotic occlusion. Several studies have demonstrated a relationship between fibrinolytic activity and venous or arterial thrombosis. We undertook this study to evaluate the possible contribution of the fibrinolytic system to postoperative occlusion in patients undergoing aorto-coronary bypass graft (CABG). A venous occlusion (VO) test was performed preoperatively in 82 patients undergoing revascularization procedures. Before and after VO the euglobulin fibrinolytic activity and tissue type plasminogen activator (t-PA) activity and antigen were measured. Plasminogen activator inhibitor (PAI) activity and antigen and fibrinogen were also assessed in the preocclusion sample. An angiography performed 10d postoperatively showed graft occlusion in 23% of patients. Patients with graft occlusion had significantly higher preoperative PAI activity than patients without occlusion (P < 0.001). Reduced fibrinolytic response and t-PA capacity was also observed in the group of patients with graft occlusion (P < 0.03 and P < 0.02 respectively). We found a reduced preoperative fibrinolytic response, mainly related to high plasma PAI activity in patients with postoperative graft occlusion. These results suggest that increased PAI activity might have a predictive value for early thrombosis in patients undergoing CABG.
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    Splenic marginal zone lymphoma with Evans' syndrome, autoimmunity, and peripheral gamma/delta T cells
    (Springer Verlag, 2009) Garcia-Muñoz, R. (R.); Pegenaute, C. (Carlota); Jakes-Okampo, J. (J.); Panizo, C. (Carlos); Rodriguez-Otero, P. (Paula); Llorente, L. (Luis); Bendandi, M. (Maurizio); Merino, J. (Juana)
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    Feasibility of idiotype vaccination in relapsed B-cell malignancies
    (Ferrata Storti Foundation, 2003) Lopez-Diaz-de-Cerio, A. (Ascensión); Rocha, E. (Eduardo); Panizo, C. (Carlos); Inoges, S. (Susana); Perez-Calvo, J. (Javier); Hernandez, M. (Milagros); Cuesta, B. (Braulia); Bendandi, M. (Maurizio); Zabalegui, N. (Natalia); Rodriguez-Calvillo, M. (Mercedes)
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    Clinical benefit associated with idiotypic vaccination in patients with follicular lymphoma.
    (Oxford University Press, 2006) Garcia-Muñoz, R. (R.); Pastor, F. (Fernando); Orfao, A. (Alberto); Lopez-Diaz-de-Cerio, A. (Ascensión); Rodriguez-Caballero, A. (Arancha); Rocha, E. (Eduardo); Panizo, C. (Carlos); Inoges, S. (Susana); Perez-Calvo, J. (Javier); Villanueva, H. (Helena); Melero, I. (Ignacio); Bendandi, M. (Maurizio); Suarez, L. (Lilia); Soria, E. (Elena); Zabalegui, N. (Natalia); Rodriguez-Calvillo, M. (Mercedes)
    BACKGROUND: Follicular lymphoma is considered incurable, although cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy can induce sequential remissions. A patient's second complete response is typically shorter than that patient's first complete response. Idiotype vaccines can elicit specific immune responses and molecular remissions in patients with follicular lymphoma. However, a clinical benefit has never been formally proven. METHODS: Thirty-three consecutive follicular lymphoma patients in first relapse received six monthly cycles of CHOP-like chemotherapy. Patients who achieved a second complete response were vaccinated periodically for more than 2 years with autologous lymphoma-derived idiotype protein vaccine. Specific humoral and cellular responses were assessed, and patients were followed for disease recurrence. Statistical tests were two-sided. RESULTS: Idiotype vaccine could be produced for 25 patients who had a second complete response. In 20 patients (80%), a humoral (13/20) and/or a cellular (18/20) idiotype-specific response was detected. The median duration of the second complete response has not been reached, but it exceeds 33 months (range = 20+ to 51+ months). None of the 20 responders relapsed while undergoing active vaccination. All responders with enough follow-up for the comparison to be made experienced a second complete response that was statistically significantly (P<.0001) longer than both their first complete response (18 of 18 patients) and than the median duration of a CHOP-induced second complete response, i.e., 13 months (20 of 20 patients). The five nonresponders all had a second complete response that was shorter (median = 10 months; range = 8-13 months) than their first complete response (median = 17 months; range = 10-39 months). CONCLUSIONS: Idiotypic vaccination induced a specific immune response in the majority of patients with follicular lymphoma. Specific immune response was associated with a dramatic and highly statistically significant increase in disease-free survival. This is the first formal demonstration of clinical benefit associated with the use of a human cancer vaccine.
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    Secondary myelodysplastic syndrome after treatment for promyelocytic leukemia: clinical and genetic features of two cases
    (Elsevier, 2003) Patiño-García, A. (Ana); Rocha, E. (Eduardo); Panizo, C. (Carlos); Bendandi, M. (Maurizio); Lecumberri, R. (Ramón); Calasanz-Abinzano, M.J. (Maria Jose); Odero, M.D. (Maria Dolores)
    Acute promyelocytic leukemia (APL) represents a biologic and clinically well-defined subtype of acute nonlymphocytic leukemia with specific morphologic and karyotypic characteristics. Although secondary leukemia and myelodysplastic syndromes (MDS) are the most frequent secondary neoplasms following chemotherapy for acute leukemia, their development after complete remission in patients with APL is uncommon. We describe the clinical and genetic features of two APL patients who achieved CR after chemotherapy and all-trans retinoid acid treatment and subsequently developed a MDS. Therapy-related MDS karyotype changes such as abnormalities of chromosomes 5 and 7 were found in the cytogenetic analysis. Since TP53 alteration was detected in one case, possible implications of these findings in the onset of MDS are discussed.