Publications by authors named "Javier López-Jiménez"

45 Publications

Secondary haemophagocytic lymphohistiocytosis in COVID-19: correlation of the autopsy findings of bone marrow haemophagocytosis with HScore.

J Clin Pathol 2021 Mar 15. Epub 2021 Mar 15.

Pathology, Hospital Ramón y Cajal, Madrid, Spain

Background: Secondary haemophagocytic lymphohistiocytosis (sHLH) is characterised by a hyper activation of immune system that leads to multiorgan failure. It is suggested that excessive immune response in patients with COVID-19 could mimic this syndrome. Some COVID-19 autopsy studies have revealed the presence of haemophagocytosis images in bone marrow, raising the possibility, along with HScore parameters, of sHLH.

Aim: Our objective is to ascertain the existence of sHLH in some patients with severe COVID-19.

Methods: We report the autopsy histological findings of 16 patients with COVID-19, focusing on the presence of haemophagocytosis in bone marrow, obtained from rib squeeze and integrating these findings with HScore parameters. CD68 immunohistochemical stains were used to highlight histiocytes and haemophagocytic cells. Clinical evolution and laboratory parameters of patients were collected from electronic clinical records.

Results: Eleven patients (68.7%) displayed moderate histiocytic hyperplasia with haemophagocytosis (HHH) in bone marrow, three patients (18.7%) displayed severe HHH and the remainder were mild. All HScore parameters were collected in 10 patients (62.5%). Among the patients in which all parameters were evaluable, eight patients (80%) had an HScore >169. sHLH was not clinically suspected in any case.

Conclusions: Our results support the recommendation of some authors to use the HScore in patients with severe COVID-19 in order to identify those who could benefit from immunosuppressive therapies. The presence of haemophagocytosis in bone marrow tissue, despite not being a specific finding, has proved to be a very useful tool in our study to identify these patients.
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http://dx.doi.org/10.1136/jclinpath-2020-207337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7970658PMC
March 2021

Risk Factors and Mortality of COVID-19 in Patients With Lymphoma: A Multicenter Study.

Hemasphere 2021 Mar 10;5(3):e538. Epub 2021 Feb 10.

Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Patients with cancer are poorly represented in coronavirus disease 2019 (COVID-19) series, and heterogeneous series concerning hematology patients have been published. This study aimed to analyze the impact of COVID-19 in patients with lymphoma. We present a multicenter retrospective study from 19 centers in Madrid, Spain, evaluating risk factors for mortality in adult patients with COVID-19 and lymphoma. About 177 patients (55.9% male) were included with a median follow-up of 27 days and a median age of 70 years. At the time of COVID-19 diagnosis, 49.7% of patients were on active treatment. The overall mortality rate was 34.5%. Age >70 years, confusion, urea concentration, respiratory rate, blood pressure, and age >65 score ≥2, heart disease, and chronic kidney disease were associated with higher mortality risk ( < 0.05). Active disease significantly increased the risk of death (hazard ratio, 2.43; 95% confidence interval, 1.23-4.77; = 0.01). However, active treatment did not modify mortality risk and no differences were found between the different therapeutic regimens. The persistence of severe acute respiratory syndrome coronavirus 2-positive polymerase chain reaction after week 6 was significantly associated with mortality (54.5% versus 1.4%; < 0.001). We confirm an increased mortality compared with the general population. In view of our results, any interruption or delay in the start of treatment should be questioned given that active treatment has not been demonstrated to increase mortality risk and that achieving disease remission could lead to better outcomes.
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http://dx.doi.org/10.1097/HS9.0000000000000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886434PMC
March 2021

May Ibrutinib Have Activity in Respiratory Complications by SARS-CoV-2? Clinical Experience in a Patient with Chronic Lymphocytic Leukemia.

Healthcare (Basel) 2021 Jan 15;9(1). Epub 2021 Jan 15.

MD Anderson Cancer Center, 28033 Madrid, Spain.

COVID-19 is affecting many countries all around the world. Unfortunately, no treatment has already been approved for the management of patients infected by SARS-CoV-2. It seems that SARS-CoV-2 can induce the activation of an exaggerated immune response against itself according to different mechanisms that are not really well known. Inflammatory interleukins, such as IL-6 among others, play a central role in this uncontrolled immune response. There is a strong rational under ibrutinib use in in the treatment of immune-based diseases, such a as GVHD or RA. Ibrutinib achieves a reduction in the production of TNFα, IL1, IL-6 and Monocyte chemo-attractant protein-1 (MCP-1) by neutrophils and macrophages, that are key players in keeping the inflammatory process. We present our clinical experience about ibrutinib use in ARDS secondary to SARS-CoV-2 in a patient with chronic lymphocytic leukemia (CLL).
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http://dx.doi.org/10.3390/healthcare9010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830068PMC
January 2021

Development and validation of a sequential two-step algorithm for the screening of individuals with potential polycythaemia vera.

Sci Rep 2021 Jan 8;11(1):209. Epub 2021 Jan 8.

Haematology Department, Hospital Universitario Ramón Y Cajal, Madrid, Spain.

In 2016, the WHO included haemoglobin values within normal ranges as a diagnostic criterion for Polycythaemia Vera (PV). Since then, concerns have arisen that a large number of patients are undergoing unnecessary screening for PV. To address this issue, we estimated the prevalence of JAK2 p.V617F in individuals with elevated haemoglobin or haematocrit and developed and validated a screening algorithm for PV. A total of 15,366 blood counts performed in seven non-consecutive days were reviewed, of which 1001 were selected for subsequent JAK2 p.V617F mutation screening. Eight (0.8%) new JAK2 p.V617F-mutated cases were detected. From ROC curves, a two-step algorithm was developed based on the optimal cut-off for the detection of the JAK2 p.V617F mutation. The algorithm was prospectively validated in an independent cohort of 15,298 blood counts. A total of 1595 (10.4%) cases met the criterion for haemoglobin or haematocrit, of whom 581 passed to step 2 (3.8% of the total). The JAK2 p.V617F mutation was detected in 7 of the 501 patients tested, which accounts for 0.04% of the total cohort and 0.4% of patients with erythrocytosis. In conclusion, this data show that our two-step algorithm improves the selection of candidates for JAK2 p.V617F testing.
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http://dx.doi.org/10.1038/s41598-020-80459-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794224PMC
January 2021

Clinical outcomes of allogeneic hematopoietic stem cell transplant recipients developing Cytomegalovirus DNAemia prior to engraftment.

Bone Marrow Transplant 2020 Dec 15. Epub 2020 Dec 15.

Microbiology Service, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain.

There is limited information on the impact of CMV DNAemia episodes developing prior to engraftment (pre-CMV DNAemia) on clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). This issue was addressed in the current retrospective multicenter study including 878 patients. All participant centers used preemptive antiviral therapy strategies for prevention of CMV disease. CMV DNA load in blood was monitored by real-time PCR assays. A total of 144 patients (cumulative incidence 16.5%, 95% CI, 14%-19%) had an episode of pre-CMV DNAemia at a median of 10 days after allo-HSCT. Patients who developed pre-CMV DNAemia had a significantly higher (P = < 0.001) probability of recurrent episodes (50%) than those who experienced post-CMV DNAemia (32.9%); Nevertheless, the incidence of CMV disease was comparable (P = 0.52). Cumulative incidences of overall mortality (OM) and non-relapse mortality (NRM) at 1-year after allo-HSCT were 32% (95% CI, 29-35%) and 23% (95% CI 20-26%), respectively. The risk of OM and NRM in adjusted models appeared comparable in patients developing a single episode of CMV DNAemia, regardless of whether it occurred before or after engraftment, in patients with pre- and post-engraftment CMV DNAemia episodes or in those without CMV DNAemia.
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http://dx.doi.org/10.1038/s41409-020-01157-xDOI Listing
December 2020

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study.

J Hematol Oncol 2020 10 8;13(1):133. Epub 2020 Oct 8.

Hematology Department, CNIO-ISCIII, CIBERONC, Complutense University, Hospital 12 de Octubre, imas12, Madrid, Spain.

Background: Patients with cancer have been shown to have a higher risk of clinical severity and mortality compared to non-cancer patients with COVID-19. Patients with hematologic malignancies typically are known to have higher levels of immunosuppression and may develop more severe respiratory viral infections than patients with solid tumors. Data on COVID-19 in patients with hematologic malignancies are limited. Here we characterize disease severity and mortality and evaluate potential prognostic factors for mortality.

Methods: In this population-based registry study, we collected de-identified data on clinical characteristics, treatment and outcomes in adult patients with hematologic malignancies and confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection within the Madrid region of Spain. Our case series included all patients admitted to 22 regional health service hospitals and 5 private healthcare centers between February 28 and May 25, 2020. The primary study outcome was all-cause mortality. We assessed the association between mortality and potential prognostic factors using Cox regression analyses adjusted for age, sex, comorbidities, hematologic malignancy and recent active cancer therapy.

Results: Of 833 patients reported, 697 were included in the analyses. Median age was 72 years (IQR 60-79), 413 (60%) patients were male and 479 (69%) and 218 (31%) had lymphoid and myeloid malignancies, respectively. Clinical severity of COVID-19 was severe/critical in 429 (62%) patients. At data cutoff, 230 (33%) patients had died. Age ≥ 60 years (hazard ratios 3.17-10.1 vs < 50 years), > 2 comorbidities (1.41 vs ≤ 2), acute myeloid leukemia (2.22 vs non-Hodgkin lymphoma) and active antineoplastic treatment with monoclonal antibodies (2·02) were associated with increased mortality; conventional chemotherapy showed borderline significance (1.50 vs no active therapy). Conversely, Ph-negative myeloproliferative neoplasms (0.33) and active treatment with hypomethylating agents (0.47) were associated with lower mortality. Overall, 574 (82%) patients received antiviral therapy. Mortality with severe/critical COVID-19 was higher with no therapy vs any antiviral combination therapy (2.20).

Conclusions: In this series of patients with hematologic malignancies and COVID-19, mortality was associated with higher age, more comorbidities, type of hematological malignancy and type of antineoplastic therapy. Further studies and long-term follow-up are required to validate these criteria for risk stratification.
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http://dx.doi.org/10.1186/s13045-020-00970-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7542567PMC
October 2020

Cytomegalovirus DNAemia and risk of mortality in allogeneic hematopoietic stem cell transplantation: Analysis from the Spanish Hematopoietic Transplantation and Cell Therapy Group.

Am J Transplant 2021 01 15;21(1):258-271. Epub 2020 Jul 15.

Microbiology Service, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain.

The net impact of cytomegalovirus (CMV) DNAemia on overall mortality (OM) and nonrelapse mortality (NRM) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a matter of debate. This was a retrospective, multicenter, noninterventional study finally including 749 patients. CMV DNA monitoring was conducted by real-time polymerase chain reaction (PCR) assays. Clinical outcomes of interest were OM and NRM through day 365 after allo-HSCT. The cumulative incidence of CMV DNAemia in this cohort was 52.6%. A total of 306 out of 382 patients with CMV DNAemia received preemptive antiviral therapy (PET). PET use for CMV DNAemia, but not the occurrence of CMV DNAemia, taken as a qualitative variable, was associated with increased OM and NRM in univariate but not in adjusted models. A subcohort analysis including patients monitored by the COBAS Ampliprep/COBAS Taqman CMV Test showed that OM and NRM were comparable in patients in whom either low or high plasma CMV DNA threshold (<500 vs ≥500 IU/mL) was used for PET initiation. In conclusion, CMV DNAemia was not associated with increased OM and NRM in allo-HSCT recipients. The potential impact of PET use on mortality was not proven but merits further research.
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http://dx.doi.org/10.1111/ajt.16147DOI Listing
January 2021

Outcomes of COVID-19 in patients with CLL: a multicenter international experience.

Blood 2020 09;136(10):1134-1143

Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Given advanced age, comorbidities, and immune dysfunction, chronic lymphocytic leukemia (CLL) patients may be at particularly high risk of infection and poor outcomes related to coronavirus disease 2019 (COVID-19). Robust analysis of outcomes for CLL patients, particularly examining effects of baseline characteristics and CLL-directed therapy, is critical to optimally manage CLL patients through this evolving pandemic. CLL patients diagnosed with symptomatic COVID-19 across 43 international centers (n = 198) were included. Hospital admission occurred in 90%. Median age at COVID-19 diagnosis was 70.5 years. Median Cumulative Illness Rating Scale score was 8 (range, 4-32). Thirty-nine percent were treatment naive ("watch and wait"), while 61% had received ≥1 CLL-directed therapy (median, 2; range, 1-8). Ninety patients (45%) were receiving active CLL therapy at COVID-19 diagnosis, most commonly Bruton tyrosine kinase inhibitors (BTKi's; n = 68/90 [76%]). At a median follow-up of 16 days, the overall case fatality rate was 33%, though 25% remain admitted. Watch-and-wait and treated cohorts had similar rates of admission (89% vs 90%), intensive care unit admission (35% vs 36%), intubation (33% vs 25%), and mortality (37% vs 32%). CLL-directed treatment with BTKi's at COVID-19 diagnosis did not impact survival (case fatality rate, 34% vs 35%), though the BTKi was held during the COVID-19 course for most patients. These data suggest that the subgroup of CLL patients admitted with COVID-19, regardless of disease phase or treatment status, are at high risk of death. Future epidemiologic studies are needed to assess severe acute respiratory syndrome coronavirus 2 infection risk, these data should be validated independently, and randomized studies of BTKi's in COVID-19 are needed to provide definitive evidence of benefit.
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http://dx.doi.org/10.1182/blood.2020006965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472711PMC
September 2020

Systemic nocardiosis in acquired aplastic anaemia: Report of 2 cases.

Enferm Infecc Microbiol Clin 2021 Jan 10;39(1):51-52. Epub 2020 Jun 10.

Servicio de Hematología y Hemoterapia, Hospital Universitario Ramón y Cajal, Madrid, España.

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http://dx.doi.org/10.1016/j.eimc.2020.05.005DOI Listing
January 2021

Diffuse follicular lymphoma variant with a typical diagnostic pattern and an unusually aggressive clinical presentation.

Int J Hematol 2020 Aug 6;112(2):136-138. Epub 2020 Jun 6.

Department of Pathology, Ramón y Cajal University Hospital, Madrid, Spain.

Diffuse follicular lymphoma (FL) variant is a rare condition that shows distinctive clinical, morphological, immunophenotypic, and molecular features that distinguish it from classical FL. Diffuse FL variant is characterized by a predominantly diffuse growth pattern, absence of the t (14;18) IGH/BCL2 translocation, CD23 expression, and presence of 1p36 deletion. Gene mutations involving STAT6 have been reported, with nuclear expression of STAT6 and phosphorylated STAT6 detected by immunohistochemistry. Patients frequently present with inguinal node involvement and low clinical stage. We describe the case of an 80-year-old female diagnosed with diffuse FL variant, presented with a classic diagnostic pattern and an unusual aggressive clinical onset.
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http://dx.doi.org/10.1007/s12185-020-02901-1DOI Listing
August 2020

Prolonged lenalidomide maintenance therapy improves the depth of response in multiple myeloma.

Blood Adv 2020 05;4(10):2163-2171

Department of Hematology, Hospital Universitario 12 de Octubre (H12O), Universidad Complutense de Madrid, Madrid, Spain.

Lenalidomide is an immunomodulatory drug approved for maintenance treatment in newly diagnosed multiple myeloma, and it has been shown to improve progression-free survival (PFS) and, in several studies, overall survival. Nevertheless, the impact of prolonged treatment with lenalidomide on the kinetics of minimal residual disease (MRD) and its prognostic impact have not been studied in depth. To obtain better knowledge in this regard, we retrospectively analyzed 139 patients who received lenalidomide maintenance in real-world clinical practice and whose MRD levels were observed during the treatment period by multiparametric flow cytometry or next-generation sequencing with a sensitivity of at least 10-4. Lenalidomide maintenance correlated with an increased depth of the disease response, with 38.1% of patients achieving maximal response during maintenance. Moreover, 34.3% of patients who were MRD positive after induction treatment achieved MRD-negative status during maintenance and ultimately had improved PFS. Sequential MRD assessments identified patients with progressively decreasing MRD levels who also had better PFS outcomes, compared with patients not showing a decreasing pattern of MRD. These results support the role of maintenance therapy, not only to sustain, but also to increase the depth of disease response with a PFS benefit. In addition, MRD monitoring during maintenance identifies patients with better prognosis and may help in their clinical management.
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http://dx.doi.org/10.1182/bloodadvances.2020001508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7252556PMC
May 2020

Clinical and pathological characteristics of peripheral T-cell lymphomas in a Spanish population: a retrospective study.

Br J Haematol 2021 01 19;192(1):82-99. Epub 2020 May 19.

Hematology Department, Fundación Jiménez Díaz, Madrid, CIBERONC, Madrid, Spain.

We investigated the clinicopathological features and prognostic factors of patients with peripheral T-cell lymphoma (PTCL) in 13 sites across Spain. Relevant clinical antecedents, CD30 expression and staining pattern, prognostic indices using the International Prognostic Index and the Intergruppo Italiano Linfomi system, treatments, and clinical outcomes were examined. A sizeable proportion of 175 patients had a history of immune-related disorders (autoimmune 16%, viral infections 17%, chemo/radiotherapy-treated carcinomas 19%). The median progression-free survival (PFS) and overall survival (OS) were 7·9 and 15·8 months, respectively. Prognostic indices influenced PFS and OS, with a higher number of adverse factors resulting in shorter survival (P < 0·001). Complete response (CR) to treatment was associated with better PFS (62·6 vs. 4 months; P < 0·001) and longer OS (67·0 vs. 7·3 months; P < 0·001) compared to no CR. CD30 was expressed across all subtypes; >15% of cells were positive in anaplastic lymphoma kinase-positive and -negative anaplastic large-cell lymphoma and extranodal natural killer PTCL groups. We observed PTCL distribution across subtypes based on haematopathological re-evaluation. Poor prognosis, effect of specific prognostic indices, relevance of histopathological sub-classification, and response level to first-line treatment on outcomes were confirmed. Immune disorders amongst patients require further examination involving genetic studies and identification of associated immunosuppressive factors.
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http://dx.doi.org/10.1111/bjh.16741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818499PMC
January 2021

Early detection of lysosomal diseases by screening of cases of idiopathic splenomegaly and/or thrombocytopenia with a next-generation sequencing gene panel.

JIMD Rep 2020 Jan 1;51(1):53-61. Epub 2019 Dec 1.

UCA de Genómica Traslacional Hospital Universitario Ramón y Cajal, IRYCIS Madrid Spain.

Lysosomal diseases (LD) are a group of about 70 rare hereditary disorders (combined incidence 1:5000) in which diverse lysosomal functions are impaired, impacting multiple organs and systems. The first clinical signs and symptoms are usually unspecific and shared by hundreds of other disorders. Diagnosis of LD traditionally relies on performing specific enzymatic assays, if available, upon clinical suspicion of the disorder. However, the combination of the insidious onset of LD and the lack of awareness on these rare diseases among medical personnel results in undesirable diagnostic delays, with unchecked disease progression, appearance of complications and a worsened prognosis. We tested the usefulness of a next-generation sequencing-based gene panel for quick, early detection of LD among cases of idiopathic splenomegaly and/or thrombocytopenia, two of the earliest clinical signs observed in most LD. Our 73-gene panel interrogated 28 genes for LD, 1 biomarker and 44 genes underlying non-LD differential diagnoses. Among 38 unrelated patients, we elucidated eight cases (21%), five with LD (GM1 gangliosidosis, Sanfilippo disease A and B, Niemann-Pick disease B, Gaucher disease) and three with non-LD conditions. Interestingly, we identified three LD patients harboring pathogenic mutations in two LD genes each, which may result in unusual disease presentations and impact treatment. Turnaround time for panel screening and genetic validation was 1 month. Our results underline the usefulness of resequencing gene panels for quick and cost-effective screening of LDs and disorders sharing with them early clinical signs.
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http://dx.doi.org/10.1002/jmd2.12078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012743PMC
January 2020

Bone marrow infiltration by flow cytometry at diffuse large B-cell lymphoma NOS diagnosis implies worse prognosis without considering bone marrow histology.

Cytometry B Clin Cytom 2020 11 24;98(6):525-528. Epub 2019 Dec 24.

Haematology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.

Background: The significance of discrepant findings between histology (BMB) and flow cytometry (FC) in bone marrow (BM) examination at diffuse large B-cell lymphoma (DLBCL) diagnosis is uncertain.

Methods: We performed a 5-year retrospective single-center study of patients diagnosed by DLBCL not otherwise specified (n = 82), divided into three groups according to BM infiltration at diagnosis: BMB-/FC- (75.6%), BMB+/FC+ (13.4%), and BMB-/FC+ (11%).

Results: Median infiltration by FC analysis of the BMB-/FC+ group was 0.8% and if we considered BM infiltration as positive in all cases, 4/9 would be upstaged. Median follow was 33 months. Event-free survival (EFS) after 18 months was 82, 23, and 27% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p < .001). After 18 months of observation, OS was 87, 46, and 55% for BMB-/FC-, BMB-/FC+, and BMB+/FC+, respectively (p = .001). In multivariate analysis (BM infiltration vs. cell-of-origin according to Hans algorithm and standard IPI), BM infiltration was independently associated with EFS (HR: 1.94, 95% CI: 1.3-2.9) and overall survival (HR: 1.69, 95% CI: 1.1-2.7).

Conclusion: In summary, minimal BM infiltration, detected by FC but not by BMB, has same prognostic implications than overt BM infiltration and should be considered as extranodal involvement regardless the infiltration quantity.
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http://dx.doi.org/10.1002/cyto.b.21863DOI Listing
November 2020

Autologous stem cell transplantation may be curative for patients with follicular lymphoma with early therapy failure without the need for immunotherapy.

Hematol Oncol Stem Cell Ther 2019 Dec 9;12(4):194-203. Epub 2019 Jul 9.

Hospital Universitario, 12 de Octubre, Madrid, Spain.

Objective/background: Patients with follicular lymphoma (FL) with early therapy failure (ETF) within 2 years of frontline therapy have poor overall survival (OS). We recently reported the results of autologous stem cell transplantation (ASCT) in patients from the Grupo Español de Linfomas y Trasplantes de Médula Ósea (GELTAMO) registry treated with rituximab prior to ASCT and with ETF after first-line immunochemotherapy, leading to 81% 5-year OS since ASCT. We explored whether ASCT is also an effective option in the pre-rituximab era-that is, in patients treated in induction and rescued only with chemotherapy.

Methods: ETF was defined as relapse/progression within 2 years of starting first-line therapy. We identified two groups: the ETF cohort (n = 87) and the non-ETF cohort (n = 47 patients receiving ASCT but not experiencing ETF following first-line therapy).

Results: There was a significant difference in 5-year progression-free survival between the ETF and non-ETF cohorts (43% vs. 57%, respectively; p = .048). Nevertheless, in patients with ETF with an interval from first relapse after primary treatment to ASCT of <1 year, no differences were observed in 5-year progression-free survival (48% vs. 66%, respectively; p = .44) or in 5-year OS (69% vs. 77%, p = .4). Patients in the ETF cohort transplanted in complete remission showed a plateau in the OS curves, at 56%, beyond 13.7 years of follow-up.

Conclusion: ASCT may be a curative option for ETF in patients who respond to rescue chemotherapy, without the need for immunotherapy or other therapies, and should be considered as an early consolidation, especially in patients with difficult access to rituximab.
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http://dx.doi.org/10.1016/j.hemonc.2019.06.001DOI Listing
December 2019

Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial.

JAMA 2019 07;322(2):123-133

Duke University Medical Center, Durham, North Carolina.

Importance: Herpes zoster, a frequent complication following autologous hematopoietic stem cell transplantation (HSCT), is associated with significant morbidity. A nonlive adjuvanted recombinant zoster vaccine has been developed to prevent posttransplantation zoster.

Objective: To assess the efficacy and adverse event profile of the recombinant zoster vaccine in immunocompromised autologous HSCT recipients.

Design, Setting, And Participants: Phase 3, randomized, observer-blinded study conducted in 167 centers in 28 countries between July 13, 2012, and February 1, 2017, among 1846 patients aged 18 years or older who had undergone recent autologous HSCT.

Interventions: Participants were randomized to receive 2 doses of either recombinant zoster vaccine (n = 922) or placebo (n = 924) administered into the deltoid muscle; the first dose was given 50 to 70 days after transplantation and the second dose 1 to 2 months thereafter.

Main Outcomes And Measures: The primary end point was occurrence of confirmed herpes zoster cases.

Results: Among 1846 autologous HSCT recipients (mean age, 55 years; 688 [37%] women) who received 1 vaccine or placebo dose, 1735 (94%) received a second dose and 1366 (74%) completed the study. During the 21-month median follow-up, at least 1 herpes zoster episode was confirmed in 49 vaccine and 135 placebo recipients (incidence, 30 and 94 per 1000 person-years, respectively), an incidence rate ratio (IRR) of 0.32 (95% CI, 0.22-0.44; P < .001), equivalent to 68.2% vaccine efficacy. Of 8 secondary end points, 3 showed significant reductions in incidence of postherpetic neuralgia (vaccine, n=1; placebo, n=9; IRR, 0.1; 95% CI, 0.00-0.78; P = .02) and of other prespecified herpes zoster-related complications (vaccine, n=3; placebo, n=13; IRR, 0.22; 95% CI, 0.04-0.81; P = .02) and in duration of severe worst herpes zoster-associated pain (vaccine, 892.0 days; placebo, 6275.0 days; hazard ratio, 0.62; 95% CI, 0.42-0.89; P = .01). Five secondary objectives were descriptive. Injection site reactions were recorded in 86% of vaccine and 10% of placebo recipients, of which pain was the most common, occurring in 84% of vaccine recipients (grade 3: 11%). Unsolicited and serious adverse events, potentially immune-mediated diseases, and underlying disease relapses were similar between groups at all time points.

Conclusions And Relevance: Among adults who had undergone autologous HSCT, a 2-dose course of recombinant zoster vaccine compared with placebo significantly reduced the incidence of herpes zoster over a median follow-up of 21 months.

Trial Registration: ClinicalTrials.gov Identifier: NCT01610414.
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http://dx.doi.org/10.1001/jama.2019.9053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6618796PMC
July 2019

Imaging and bone marrow assessments improve minimal residual disease prediction in multiple myeloma.

Am J Hematol 2019 08 9;94(8):853-861. Epub 2019 Jun 9.

Department of Hematology , Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Departamento de Medicina, H12O CNIO Clinical Research Hematology Unit; CIBERONC, Madrid, Spain.

The value of minimal residual disease (MRD) status by bone marrow and imaging analysis as independent prognostic factors has been well established in multiple myeloma (MM). Nevertheless data about their potential complementarity for a more accurate assessment are limited. With this aim, we retrospectively analyzed the prediction of outcome with the combination of PET-CT and MRD, assessed by multiparameter flow cytometry (MFC) in 103 patients with newly diagnosed MM. We confirmed the benefit in terms of progression-free survival (PFS), linked to the achievement of negativity by MFC (hazard ratio [HR] 0.53; 95% confidence interval [CI]: 0.28-0.98), and PET-CT (HR 0.18; 95% CI: 0.09-0.36) individually. By combining both techniques, patients who became MRD-/PET-, with a median of PFS 92 months, had significant prolonged median PFS (P < .001). This is compared with MRD+/PET- and PET+ patients (median PFS of 45 and 28 months, respectively). We observed a significant difference (P = .003) in overall survival (OS) outcomes between MRD-/PET- and MRD+/PET- patients (4-year OS 94.2% and 100%, respectively), vs PET+ patients (4-year OS 73.8%). All survival results were confirmed in a conditional landmark analysis. These findings support the potential complementarity between PET-CT and MFC, and highlight their better predictive capability when improving sensitivity.
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http://dx.doi.org/10.1002/ajh.25507DOI Listing
August 2019

High prognostic value of measurable residual disease detection by flow cytometry in chronic lymphocytic leukemia patients treated with front-line fludarabine, cyclophosphamide, and rituximab, followed by three years of rituximab maintenance.

Haematologica 2019 11 19;104(11):2249-2257. Epub 2019 Mar 19.

Hematology, Hospital Universitario de Getafe, Madrid, Spain.

It has been postulated that monitoring measurable residual disease (MRD) could be used as a surrogate marker of progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) patients after treatment with immunochemotherapy regimens. In this study, we analyzed the outcome of 84 patients at 3 years of follow-up after first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) induction followed by 36 months of rituximab maintenance thearpy. MRD was assessed by a quantitative four-color flow cytometry panel with a sensitivity level of 10 Eighty out of 84 evaluable patients (95.2%) achieved at least a partial response or better at the end of induction. After clinical evaluation, 74 patients went into rituximab maintenance and the primary endpoint was assessed in the final analysis at 3 years of follow-up. Bone marrow (BM) MRD analysis was performed after the last planned induction course and every 6 months in cases with detectable residual disease during the 36 months of maintenance therapy. Thirty-seven patients (44%) did not have detectable residual disease in the BM prior to maintenance therapy. Interestingly, 29 patients with detectable residual disease in the BM after induction no longer had detectable disease in the BM following maintenance therapy. After a median followup of 6.30 years, the median overall survival (OS) and PFS had not been reached in patients with either undetectable or detectable residual disease in the BM, who had achieved a complete response at the time of starting maintenance therapy. Interestingly, univariate analysis showed that after rituximab maintenance OS was not affected by IGHV status (mutated unmutated OS: 85.7% alive at 7.2 years 79.6% alive at 7.3 years, respectively). As per protocol, 15 patients (17.8%), who achieved a complete response and undetectable peripheral blood and BM residual disease after four courses of induction, were allowed to stop fludarabine and cyclophosphamide and complete two additional courses of rituximab and continue with maintenance therapy for 18 cycles. Surprisingly, the outcome in this population was similar to that observed in patients who received the full six cycles of the induction regimen. These data show that, compared to historic controls, patients treated with FCR followed by rituximab maintenance have high-quality responses with fewer relapses and improved OS. The tolerability of this regime is favorable. Furthermore, attaining an early undetectable residual disease status could shorten the duration of chemoimmunotherapy, reducing toxicities and preventing long-term side effects. The analysis of BM MRD after fludarabine-based induction could be a powerful predictor of post-maintenance outcomes in patients with CLL undergoing rituximab maintenance and could be a valuable tool to identify patients at high risk of relapse, influencing further treatment strategies. This trial is registered with EudraCT n. 2007-002733-36 and ClinicalTrials.gov Identifier: NCT00545714.
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http://dx.doi.org/10.3324/haematol.2018.204891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821631PMC
November 2019

Bendamustine as part of conditioning of autologous stem cell transplantation in patients with aggressive lymphoma: a phase 2 study from the GELTAMO group.

Br J Haematol 2019 03 12;184(5):797-807. Epub 2018 Dec 12.

Department of Haematology, Hospital Universitario de Salamanca - IBSAL, CIBERONC, Salamanca, Spain.

We conducted a phase 2 trial to evaluate the safety and efficacy of bendamustine instead of BCNU (carmustine) in the BEAM (BCNU, etoposide, cytarabine and melphalan) regimen (BendaEAM) as conditioning for autologous stem-cell transplantation (ASCT) in patients with aggressive lymphomas. The primary endpoint was 3-year progression-free survival (PFS). Sixty patients (median age 55 [28-71] years) were included. All patients (except one who died early) engrafted after a median of 11 (9-72) and 14 (4-53) days to achieve neutrophil and platelet counts of >0.5 × 10 /l and >20 × 10 /l, respectively. Non-relapse mortality at 100 days and 1 year were 3.3% and 6.7%, respectively. With a median follow-up of 67 (40-77) months, the estimated 3-year PFS and overall survival (OS) were 58% and 75%, respectively. Patients in partial response at study entry had significantly worse PFS and OS than patients who underwent ASCT in complete metabolic remission, and this was the only prognostic factor associated with both PFS (Relative risk [RR], 0.27 [95% confidence interval {CI} [0.12-0.56]) and OS (RR, 0.40 [95% CI 0.17-0.97]) in the multivariate analysis. BendaEAM conditioning is therefore a feasible and effective regimen in patients with aggressive lymphomas. However, patients not in complete metabolic remission at the time of transplant had poorer survival and so should be considered for alternative treatment strategies.
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http://dx.doi.org/10.1111/bjh.15713DOI Listing
March 2019

PD-1 genotype of the donor is associated with acute graft-versus-host disease after HLA-identical sibling donor stem cell transplantation.

Ann Hematol 2018 Nov 17;97(11):2217-2224. Epub 2018 Jul 17.

Clinical Hematology Department, Institut Català d'Oncologia (ICO Girona), IDIBGi, Avda França s/n, 17007, Girona, Spain.

Programmed death 1 (PD-1) activation triggers an immune checkpoint resulting in inhibition of T cells that leads to peripheral tolerance. Some PD-1 polymorphisms have been described and associated with the development of autoimmune diseases or cancer predisposition, but there are few data concerning the relevance of such polymorphisms on the clinical outcome after allogeneic hematopoietic stem cell transplant (alloHSCT). We analyzed the distribution of the SNPs PD-1.1G/A (rs36084323) and PD-1.3G/A (rs11568821) genotypes of the donor in a cohort of 1485 alloHSCT from HLA-identical sibling donors. We found an increased risk of grades II to IV graft-versus-host disease (GvHD) in patients receiving grafts from donors homozygous for the G allele at the rs36084323 SNP (P = 0.033; hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.1 to 4.8) and also from donors homozygous for the A allele at the rs11568821 position (P < 0.001; HR 4.5, 95%CI 2.0 to 10.1). In contrast, the PD-1 genotype of the donor did not show association with overall survival or relapse incidence. These results suggest that the PD-1 genotype of the donor plays an important role for the development of acute GvHD after alloHSCT from HLA-identical sibling donors.
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http://dx.doi.org/10.1007/s00277-018-3438-yDOI Listing
November 2018

Progression-free survival at 2 years post-autologous transplant: a surrogate end point for overall survival in follicular lymphoma.

Cancer Med 2017 Dec 26;6(12):2766-2774. Epub 2017 Oct 26.

Hospital Universitario, 12 de Octubre, Madrid, Spain.

Overall survival (OS) is the gold-standard end point for studies evaluating autologous stem cell transplantation (ASCT) in follicular lymphoma (FL), but assessment may be elusive due to the lengthy disease course. We analyzed the validity of two earlier end points, proposed in the setting of first-line chemo-/immunotherapy, as surrogates for OS-progression-free survival (PFS) status at 24 months (PFS24) and complete response at 30 months (CR30) post-ASCT. We also have investigated the clinical features of patients with early progression after ASCT. Data were available for 626 chemosensitive FL patients who received ASCT between 1989 and 2007. Median follow-up was 12.2 years from ASCT. In the PFS24 analysis, 153 (24%) patients progressed within 24 months and 447 were alive and progression-free at 24 months post-ASCT (26 who died without disease progressions within 24 months were excluded). Early progression was associated with shorter OS (hazard ratio [HR], 6.8; P = 0.00001). In the subgroup of patients who received an ASCT in the setting or relapse after being exposed to rituximab, the HR was 11.3 (95% CI, 3.9-30.2; P < 0.00001). In the CR30 analysis, 183 of 596 (31%) response-evaluable patients progressed/died with 30 months post-ASCT. The absence of CR30 was associated with shorter OS (HR, 7.8; P < 0.00001), including in patients with prior rituximab (HR, 8.2). PFS24 and CR30 post-ASCT are associated with poor outcomes and should be primary end points. Further research is needed to identify this population to be offered alternative treatments.
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http://dx.doi.org/10.1002/cam4.1217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727300PMC
December 2017

Bone marrow biopsy superiority over PET/CT in predicting progression-free survival in a homogeneously-treated cohort of diffuse large B-cell lymphoma.

Cancer Med 2017 Nov 27;6(11):2507-2514. Epub 2017 Sep 27.

Servicio de Hematología y Oncología Médica. H.J.M. Morales Meseguer, IMIB-Arrixaca, Murcia, Spain.

Several studies have reported uneven results when evaluating the prognostic value of bone marrow biopsy (BMB) and PET/CT as part of the staging of diffuse large B-cell lymphoma (DLBCL). The heterogeneity of the inclusion criteria and not taking into account selection and collinearity biases in the analysis models might explain part of these discrepancies. To address this issue we have carried a retrospective multicenter study including 268 DLBCL patients with a BMB and a PET/CT available at diagnosis where we estimated both the prognosis impact and the diagnostic accuracy of each technique. Only patients treated with R-CHOP/21 as first line (n = 203) were included in the survival analysis. With a median follow-up of 25 months the estimated 3-year progression-free survival (PFS) and overall survival (OS) were 76.3% and 82.7% respectively. In a multivariate analysis designed to avoid a collinearity bias with IPI categories, BMB-BMI [bone marrow involvement](+) (HR: 3.6) and ECOG PS > 1 (HR: 2.9) were independently associated with a shorter PFS and three factors, age >60 years old (HR: 2.4), ECOG PS >1 (HR: 2.4), and abnormally elevated B2-microglobulin levels (HR: 2.2) were independently associated with a shorter OS. In our DLBCL cohort, treated with a uniform first-line chemotherapy regimen, BMI by BMB complemented performance status in predicting those patients with a higher risk for relapse or progression. In this cohort BMI by PET/CT could not independently predict a shorter PFS and/or OS.
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http://dx.doi.org/10.1002/cam4.1205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673915PMC
November 2017

Donor CTLA-4 Genotype Modulates the Immune Response to Minor Histocompatibility Antigen Mismatches.

Biol Blood Marrow Transplant 2017 Dec 4;23(12):2042-2047. Epub 2017 Aug 4.

Hematology Department, Hospital Gregorio Marañón, Madrid, Spain.

Minor histocompatibility antigen (miHA) mismatches have been related to graft-versus-host disease (GVHD) after allogeneic stem cell transplantation, but this association remains controversial due to the lack of consistency in the results obtained by different groups. The CTLA-4 genotype of the donor has been reported to be relevant in the appearance of acute GVHD. We explored the effect of the donor's CTLA-4 genotype in the incidence of acute GVHD associated with HA-1, HA-8, or H-Y miHA mismatches in a large cohort of 1295 patients receiving an allogeneic transplant from an HLA-identical sibling donor. The incidence of acute GVHD was higher if the donor and recipient were mismatched for HA-1, HA-8, or H-Y, but only when the donor had the CTLA-4 rs231775 AA genotype (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.27 to 3.75; P = .005; HR, 2.11, 95% CI, 1.06 to 4.18; P = .033; and HR, 1.50; 95% CI, 1.05 to 2.15; P = .025, respectively). In contrast, this increased risk of developing acute GVHD was not found when the donor presented the CTLA-4 rs231775 AG or GG genotypes. We conclude that the immune response to specific miHA mismatches is modulated by the CTLA-4 genotype of the donor.
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http://dx.doi.org/10.1016/j.bbmt.2017.08.003DOI Listing
December 2017

Autologous Stem Cell Transplantation for Follicular Lymphoma: Favorable Long-Term Survival Irrespective of Pretransplantation Rituximab Exposure.

Biol Blood Marrow Transplant 2017 Oct 19;23(10):1631-1640. Epub 2017 May 19.

Hospital Universitario 12 de Octubre, Madrid, Spain.

High-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) has contributed to modify the natural history of follicular lymphoma (FL); however, an overall survival (OS) benefit has been demonstrated at relapse only after a rituximab-free chemotherapy regimen. A total of 655 patients with FL were reported to the Spanish GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) registry and underwent first ASCT between 1989 and 2007. A total of 203 patients underwent ASCT in first complete response (CR1), 174 in second complete response (CR2), 28 in third complete response (CR3), 140 in first partial response (PR1), 81 in subsequent PR, and 29 with resistant/refractory disease; 184 patients received rituximab before ASCT. With a median follow-up of 12 years from ASCT, median progression-free survival (PFS) and overall survival (OS) were 9.7 and 21.3 years, respectively. Actuarial 12-year PFS and OS were 63% (95% confidence interval [CI], 58%-68%) and 73% (95% CI, 68%-78%), respectively, for patients in CR (with a plateau in the curve beyond 15.9 years), 25% (95% CI, 19%-28%) and 49% (95% CI 42%-56%), respectively, for patients in PR, and 23% (95% CI, 8%-48%) and 28% (95% CI, 9%-45%), respectively, for patients with resistant/refractory disease (P < .001). In patients who received rituximab before ASCT, the estimated 9-year PFS and OS from ASCT were 59.5% (95% CI, 51%-67%) and 75% (95% CI, 68%-83%), respectively. Interestingly, for patients who underwent transplantation in CR ≥2 or PR ≥2 who had received rituximab before ASCT (n = 90), 9-year PFS and OS were 61% (95% CI, 51%-73%) and 75% (95% CI, 65%-80%), respectively, with no relapses occurring beyond 5.1 years after ASCT. The cumulative incidence of second malignancies in the global series was 6.7% at 5 years and 12.8% at 10 years. This analysis strongly suggests that ASCT is a potentially curative option for eligible patients with FL. In the setting of relapse, it is of especial interest in pretransplantation rituximab-sensitive patients with FL.
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http://dx.doi.org/10.1016/j.bbmt.2017.05.021DOI Listing
October 2017