Papers by Ramón García-sanz
Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognos... more Multiple myeloma (MM) patients with t(11;14) present unique biological features and their prognosis is not well established. We report a retrospective study of 591 MM patients, 17.6% of whom had t(11;14). It was designed to determine the prognostic impact of this abnormality and the effect of novel agents on the response and outcomes. Three groups were established based on their cytogenetics: 1) t(11;14); 2) high-risk chromosomal abnormalities; and 3) standard risk (SR). After 80.1 months (1.2-273.8 months) of follow-up, no differences were observed in overall survival (OS) between the t(11;14) and SR groups (75.8 vs. 87.2 months; P = 0.438). However, in ISS-1 stage patients, MM t(11;14) individuals had shorter OS than those in the SR group (62.9 vs. 126.7 months; P = 0.004). Treatment of MM t(11;14) with novel agents did not improve their overall response rate (ORR) or complete response (CR) compared with those who received conventional therapy (ORR: 87.2% vs. 79.5%, P = 0.336; CR:...
The Lancet Oncology, 2021
In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates ... more In this Policy Review, the Bone Working Group of the International Myeloma Working Group updates its clinical practice recommendations for the management of multiple myeloma-related bone disease. After assessing the available literature and grading recommendations using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) method, experts from the working group recommend zoledronic acid as the preferred bone-targeted agent for patients with newly diagnosed multiple myeloma, with or without multiple myeloma-related bone disease. Once patients achieve a very good partial response or better, after receiving monthly zoledronic acid for at least 12 months, the treating physician can consider decreasing the frequency of or discontinuing zoledronic acid treatment. Denosumab can also be considered for the treatment of multiple myeloma-related bone disease, particularly in patients with renal impairment. Denosumab might prolong progression-free survival in patients with newly diagnosed multiple myeloma who have multiple myeloma-related bone disease and who are eligible for autologous stem-cell transplantation. Denosumab discontinuation is challenging due to the rebound effect. The Bone Working Group of the International Myeloma Working Group also found cement augmentation to be effective for painful vertebral compression fractures. Radiotherapy is recommended for uncontrolled pain, impeding or symptomatic spinal cord compression, or pathological fractures. Surgery should be used for the prevention and restoration of long-bone pathological fractures, vertebral column instability, and spinal cord compression with bone fragments within the spinal route.
Sangre, Jul 18, 2023
La leucemia linfoblástica aguda (LLA) con cromosoma Filadelfia (LLA Ph+) es una enfermedad con pa... more La leucemia linfoblástica aguda (LLA) con cromosoma Filadelfia (LLA Ph+) es una enfermedad con particularidades que le confieren un pronóstico adverso. El desarrollo de nuevas técnicas de laboratorio de aplicación diagnóstica o terapéutica y la aparición de varias generaciones de inhibidores de la tirosina cinasa han moldeado de manera notable el abordaje de esta enfermedad y han repercutido positivamente en su pronóstico. Para conocer el papel de estos nuevos avances se realizó una revisión exhaustiva de la evidencia publicada, y a continuación se elaboró un listado de recomendaciones aplicables al diagnóstico, el tratamiento y el seguimiento de los pacientes con LLA Ph+. Las recomendaciones emitidas por los autores se sometieron a valoración por parte de un panel más amplio de expertos. Este documento recoge una breve actualización del conocimiento disponible en LLA Ph+. Asimismo, se ofrece una selección de las recomendaciones consensuadas por expertos de España y Portugal, consideradas especialmente relevantes en el diagnóstico y el tratamiento de pacientes adultos con LLA Ph+ de acuerdo con los avances tecnológicos en esta área y las terapias disponibles.
Blood, Nov 5, 2021
Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular... more Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was &lt;2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1). Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy.…
Blood Advances, Sep 22, 2022
Promising results have been shown with the combination of ponatinib and chemotherapy in adults wi... more Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph 1 ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph 1 ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P 5 .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph 1 ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).
American Journal of Hematology
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused high mortality ... more Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has caused high mortality in patients with hematological malignancies (HM). 1 The newly emerged omicron variants of SARS-CoV-2 harbor multiple novel spike protein mutations that raise concerns about vaccine efficiency and antiviral efficacy of the available therapeutic monoclonal antibodies. 2 The first published clinical data in immunocompetent patients have found that infection with omicron variants is associated with reduced vaccine efficiency compared to the delta variants, but decreased hospital admission and mortality. 3,4 Preliminary, prepublished, data from a large case-control study have shown that the vaccine effect against omicron in immunocompromised patients, including HM patients, is even more reduced, but data regarding clinical outcomes are lacking. 5 The aim of this study was to describe risk factors, antiviral treatment and outcomes of SARS-CoV-2 omicron variant infection in 593 HM patients included in the EPICOVIDEHA registry. EPICOVIDEHA is an international open web-based registry for patients with HM infected with SARS-CoV-2. 1,6 Both hospitalized and nonhospitalized patients are eligible for inclusion. The questionnaire includes data on the HM, SARS-CoV-2 vaccination status, risk factors for severe COVID-19 infection, SARS-CoV-2 virus variant, antiviral treatment, and outcomes including mortality (eFigure 1 and eTable 4). Classification of attributable, contributable, or nonattributable death is made by the reporting physician. All included cases are validated by experts with previous experience in research studies of hematological malignancies and infectious diseases at the
Haematologica
Next-generation sequencing (NGS) has recently been introduced to efficiently and simultaneously d... more Next-generation sequencing (NGS) has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia (AML). However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. In order to overcome this challenge, the PETHEMA group established a nationwide network of reference laboratories aimed to deliver molecular results in the clinics. We report the technical cross-validation results for NGS panel genes during the standardization process and the clinical validation in 823 samples of 751 patients with newly diagnosed or refractory/relapse AML. Two cross-validation rounds were performed in seven nationwide reference laboratories in order to reach a consensus regarding quality metrics criteria and variant reporting. In the pre-standardization cross-validation round, an overall concordance of 60.98% was obtained with a great variability in selected genes and conditi...
Blood Advances, 2021
Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell m... more Zanubrutinib is a selective Bruton tyrosine kinase (BTK) inhibitor evaluated in multiple B-cell malignancy studies. We constructed a pooled safety analysis to better understand zanubrutinib-associated treatment-emergent adverse events (TEAEs) and identify treatment-limiting toxicities. Data were pooled from 6 studies (N = 779). Assessments included type, incidence, severity, and outcome of TEAEs. Median age was 65 years; 20% were ≥75 years old. Most patients had Waldenström macroglobulinemia (33%), chronic lymphocytic leukemia/small lymphocytic lymphoma (29%), or mantle-cell lymphoma (19%). Median treatment duration was 26 months (range, 0.1-65); 16% of patients were treated for ≥3 years. Common nonhematologic TEAEs were upper respiratory tract infection (URI, 39%), rash (27%), bruising (25%), musculoskeletal pain (24%), diarrhea (23%), cough (21%), pneumonia (21%), urinary tract infection (UTI), and fatigue (15% each). Most common grade ≥3 TEAEs were pneumonia (11%), hypertension (...
Blood, 2021
Next-Generation Sequencing (NGS) has recently been introduced to efficiently and simultaneously d... more Next-Generation Sequencing (NGS) has recently been introduced to efficiently and simultaneously detect genetic variations in acute myeloid leukemia (AML). However, its implementation in the clinical routine raises new challenges focused on the diversity of assays and variant reporting criteria. To overcome this challenge, the PETHEMA group established a nationwide network of 7 reference laboratories aimed to deliver molecular results to the clinics. We report the technical cross-validation results for NGS and clinical validation in 2960 AML samples. Three cross-validation rounds (CVR) were performed to establish consensus parameters for NGS analysis and variant reporting. In the first CVR we evaluated the starting situation of the NGS studies. In the second CVR the laboratory network established minimum quality parameters and consensus recommendations to guarantee a valid NGS assay. The third CVR strengthened the established parameters and refined the clinical variant classification...
Leukemia & Lymphoma, 2021
In the midst of the COVID-19 pandemic, different vaccines in front of SARS-CoV-2 have been approv... more In the midst of the COVID-19 pandemic, different vaccines in front of SARS-CoV-2 have been approved and administered in different vulnerable populations. As patients with cancer were excluded from pivotal trials of vaccination, little is known on their immunogenic response to these vaccines, particularly in patients with severely impaired immune system. In response to that uncertainty, the Spanish Society of Hematology and Hemotherapy launched an initiative aimed to provide recommendations for vaccination of the main hematological conditions. This document is based on the available information on COVID-19 outcomes, prior knowledge on vaccination in hematological patients, recent published data on serological response in oncohematological patients and expert opinions. New information about SARS-CoV-2 vaccination will be gathered in the near future, providing new scientific grounds to delineate the most adequate management of vaccination in patients with hematological diseases. The current limited data on SARS-CoV-2 vaccines in hematological patients represents a major limitation of this expert consensus opinion. In fact, the speed in which this field evolves may reduce their validity in the near future.
Blood, 2021
Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CA... more Patients with multiple myeloma (MM) carrying standard- or high-risk cytogenetic abnormalities (CAs) achieve similar complete response (CR) rates, but the later have inferior progression-free survival (PFS). This questions the legitimacy of CR as a treatment endpoint and represents a biological conundrum regarding the nature of tumor reservoirs that persist after therapy in high-risk MM. We used next-generation flow (NGF) cytometry to evaluate measurable residual disease (MRD) in MM patients with standard- vs high-risk CAs (n = 300 and 90, respectively) enrolled in the PETHEMA/GEM2012MENOS65 trial, and to identify mechanisms that determine MRD resistance in both patient subgroups (n = 40). The 36-month PFS rates were higher than 90% in patients with standard- or high-risk CAs achieving undetectable MRD. Persistent MRD resulted in a median PFS of ∼3 and 2 years in patients with standard- and high-risk CAs, respectively. Further use of NGF to isolate MRD, followed by whole-exome sequen...
Blood, 2020
Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple mye... more Risk of developing myelodysplastic syndrome (MDS) is significantly increased in both multiple myeloma (MM) and monoclonal gammopathy of undetermined significance, suggesting that it is therapy independent. However, the incidence and sequelae of dysplastic hematopoiesis at diagnosis are unknown. Here, we used multidimensional flow cytometry (MFC) to prospectively screen for the presence of MDS-associated phenotypic alterations (MDS-PA) in the bone marrow of 285 patients with MM enrolled in the PETHEMA/GEM2012MENOS65 trial (#NCT01916252). We investigated the clinical significance of monocytic MDS-PA in a larger series of 1252 patients enrolled in 4 PETHEMA/GEM protocols. At diagnosis, 33 (11.6%) of 285 cases displayed MDS-PA. Bulk and single-cell–targeted sequencing of MDS recurrently mutated genes in CD34+ progenitors (and dysplastic lineages) from 67 patients revealed clonal hematopoiesis in 13 (50%) of 26 cases with MDS-PA vs 9 (22%) of 41 without MDS-PA; TET2 and NRAS were the mos...
Blood Advances, 2020
Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (... more Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enro...
Blood, 2020
Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Wald... more Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, r...
Blood Cancer Journal, 2020
Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated... more Multiple myeloma is a heterogeneous disease whose pathogenesis has not been completely elucidated. Although B-cell receptors play a crucial role in myeloma pathogenesis, the impact of clonal immunoglobulin heavy-chain features in the outcome has not been extensively explored. Here we present the characterization of complete heavy-chain gene rearrangements in 413 myeloma patients treated in Spanish trials, including 113 patients characterized by next-generation sequencing. Compared to the normal B-cell repertoire, gene selection was biased in myeloma, with significant overrepresentation ofIGHV3,IGHD2andIGHD3, as well asIGHJ4gene groups. Hypermutation was high in our patients (median: 8.8%). Interestingly, regarding patients who are not candidates for transplantation, a high hypermutation rate (≥7%) and the use ofIGHD2andIGHD3groups were associated with improved prognostic features and longer survival rates in the univariate analyses. Multivariate analysis revealed prolonged progressi...
Journal of Clinical Oncology, 2019
PURPOSE Assessing measurable residual disease (MRD) has become standard with many tumors, but the... more PURPOSE Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG). PATIENTS AND METHODS In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10−6. Patients received maintenance (lenalidomide ± ixazomib) accordi...
Blood, 2019
Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (i... more Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy and first or second generation tyrosine kinase inhibitors (TKI) (Jabbour, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducts the phase 2 PONALFIL trial, that incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019. doi:10.1002/cncr.32156). The preliminary results of this trial are herein reported. Patients and method. The PONALFIL trial (NCT02776605) combines ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, merc...
Blood, 2005
It is assumed that patients with primary refractory myeloma are the most likely to benefit from e... more It is assumed that patients with primary refractory myeloma are the most likely to benefit from early HDT. In four series the CR rate was between 8 and 40% and the overall survival ranged from 4 to 6 years. However‚ the number of patients with progressive disease vs those with “stable disease” was not given in published series. The aim of our study was to investigate the efficacy in terms of response up-grading and survival of early HDT in patients with primary refractory myeloma. From October 1999 to December 2003 patients with MM younger than 70 years were given 6 courses of VBMCP/VBAD chemotherapy. Patients with refractory disease were scheduled to receive a tandem transplant‚ the first procedure intensified with busulphan-12 mg/kg-/melphalan-140 or melphalan-200 and the second with the CVB -cyclophosphamide‚ etoposide and BCNU- or with a dose-reduced intensity “allo” conditioned with fludarabine/melphalan-140‚ depending on sibling donor availability. Response and progression wer...
Hematological Oncology, 2019
Introduction: Patient-derived data and reported outcomes (PROs) can increase breadth of knowledge... more Introduction: Patient-derived data and reported outcomes (PROs) can increase breadth of knowledge in rare cancers like Waldenström's Macroglobulinemia (WM). This study utilised www.cart-wheel.org, an ethically approved online rare cancer database for patient-derived data, to develop a continuously expanding dataset for hypothesis generation around WM. Methods: An ethically approved WM-specific extension to the www. cart-wheel.org questionnaire was developed by clinician and patient investigators. Patients complete consent online and enter their symptom, pathology and treatment data. Recruitment strategies driven by the International Waldenström's Macroglobulinemia Foundation investigators utilised multiple social media platforms. Inclusion of the EORTC QLQ C30 quality of life (QoL) questionnaire went live in October 2018, with targeted recruitment messaging sent out in February 2019. Results: 355 patients from 17 countries have been recruited, predominantly from USA (48%) and male (62%). Median age at diagnosis was 61 years (24-83), median IgM 27.4 g/L (IQR 13.1-40.3 g/L, n = 130) and median hemoglobin 112 g/L (IQR 97-128 g/L, n = 134). Fatigue was the most common symptom listed at diagnosis (44%). Using the Impact of Event Scale for symptoms of posttraumatic stress disorder (PTSD) related to cancer, the mean score was 5.8 (no stress = 0, maximal stress = 24, n = 305), with 29 (10%) scoring >13 (PPV 94% for PTSD, Thoresen et al, 2010). 41 unique first line therapeutic combinations were documented by 238 patients. Median time from diagnosis to first treatment for USA patients was 50 days (IQR 15-423, n = 104) vs Rest of World (ROW) 170 days (IQR 22-775, n = 120) (p = 0.06). Of the 213 therapies listed by USA patients (n = 108), 59 (28%) were reported as accessed by government or public program and 8 (4%) via clinical trials, whereas among ROW patients (n = 113), 122/225 (54%) were government/public program accessed and 31/225 (14%) via clinical trials (p = 0.0001 and p = 0.0002, respectively). 156 patients responded to the QoL questions within 3 weeks from targeted messaging. Raw scores for overall health (Q29) and overall quality of life (Q30), ranging from 1: very poor to 7: excellent, demonstrated means of 5.1 and 5.8, respectively. Respondents who received BTK inhibitors (BTKi, n = 33) had comparable Q29 and Q30 scores compared to those who received non-BTKi treatment (n = 84): Q29 means 5.8 vs 5.5, Q30 6.1 vs 5.7 (p = 0.2 and p = 0.13, respectively). This was despite median 2 (IQR 1-4) lines of treatment in the BTKi group compared to median 1 (IQR 1-2) in the non-BTKi group. Conclusions: WhiMSICAL is a robust global patient-derived data platform providing insight into patient symptoms, diversity of therapies and QoL. Further recruitment (Project 1000) and ongoing data entry will increase its utility. As it grows, WhiMSICAL has the potential to map real-world PROs to treatments and provide a scientific and ethically approved portal for patients' voices globally.
Blood Cancer Journal, 2017
Transformation of Waldenström’s macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) o... more Transformation of Waldenström’s macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene ...
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Papers by Ramón García-sanz