Publications by authors named "Alex Bataller"

18 Publications

  • Page 1 of 1

Prognostic impact of DNMT3A mutation in acute myeloid leukemia with mutated NPM1.

Blood Adv 2021 Sep 13. Epub 2021 Sep 13.

Hospital Santa Creu i Sant Pau, Barcelona, Spain.

The negative prognostic impact of FLT3-ITD in patients with acute myeloid leukemia with mutated NPM1 (AML-NPM1) is restricted to patients with a higher FLT3-ITD allelic ratio (≥0.5; FLT3high) and considered negligible in wild-type (FLT3wt)/low ITD ratio (FLT3low) patients. Since the co-mutation of DNMT3A (DNMT3Amut) has been suggested to negatively influence the prognosis of AML-NPM1, we analyzed DNMT3Amut impact in FLT3-ITD subsets (absent, low and high ratio). A total of 164 patients diagnosed with AML-NPM1 who received intensive chemotherapy according to two consecutive protocols (AML-03 and AML-12) were selected: 76 harboring FLT3-ITD (46%), 79 DNMT3Amut (48%), and 39 (24%) showing both mutations. Overall, DNMT3A mutational status did not show prognostic impact with comparable OS (mut vs. wt 62±6% vs. 56±6%; p=0.2), RR (22±11% vs. 31±11%; p=0.2) and LFS (65±6 vs. 54±6, p=0.1). Prognostic stratification established by FLT3-ITD (FLT3wt= FLT3low> FLT3high) was independent of DNMT3A mutational status. Measurable residual disease (MRD) based on NPM1 quantitative-PCR kinetics was available in 94 patients. DNMT3Amut was associated with a higher number of mutated NPM1 transcripts following induction (p=0.012) and first consolidation (C1; p<0.001). All DNMT3Amut patients were MRD positive following C1 (p<0.001) and exhibit significant MRD persistence after second and third consolidations (MRD positive vs. negative p=0.027 and p=0.001). Finally, DNMT3Amut patients presented a trend to greater risk of molecular relapse (p=0.054). When molecular failure was proven, patients underwent an allogeneic transplant. In conclusion, DNMT3Amut did not modify overall prognosis exerted by FLT3-ITD in AML-NPM1 despite delayed MRD clearance, possibly due to MRD-driven pre-emptive intervention.
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http://dx.doi.org/10.1182/bloodadvances.2020004136DOI Listing
September 2021

A novel and efficient tandem CD19- and CD22-directed CAR for B cell ALL.

Mol Ther 2021 Sep 1. Epub 2021 Sep 1.

Josep Carreras Leukemia Research Institute, School of Medicine, University of Barcelona, Carrer Casanova 143, 4° floor, Barcelona 08036, Spain; RICORS-TERAV, ISCIII, Madrid, Spain; CIBER-ONC, ISCIII, Barcelona, Spain; Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona 08036, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. Electronic address:

CD19-directed chimeric antigen receptor (CAR) T cells have yielded impressive response rates in refractory/relapse B cell acute lymphoblastic leukemia (B-ALL); however, most patients ultimately relapse due to poor CAR T cell persistence or resistance of either CD19 or CD19 B-ALL clones. CD22 is a pan-B marker whose expression is maintained in both CD19 and CD19 relapses. CD22-CAR T cells have been clinically used in B-ALL patients, although relapse also occurs. T cells engineered with a tandem CAR (Tan-CAR) containing in a single construct both CD19 and CD22 scFvs may be advantageous in achieving higher remission rates and/or preventing antigen loss. We have generated and functionally validated using cutting-edge assays a 4-1BB-based CD22/CD19 Tan-CAR using in-house-developed novel CD19 and CD22 scFvs. Tan-CAR-expressing T cells showed similar in vitro expansion to CD19-CAR T cells with no increase in tonic signaling. CRISPR-Cas9-edited B-ALL cells confirmed the bispecificity of the Tan-CAR. Tan-CAR was as efficient as CD19-CAR in vitro and in vivo using B-ALL cell lines, patient samples, and patient-derived xenografts (PDXs). Strikingly, the robust antileukemic activity of the Tan-CAR was slightly more effective in controlling the disease in long-term follow-up PDX models. This Tan-CAR construct warrants a clinical appraisal to test whether simultaneous targeting of CD19 and CD22 enhances leukemia eradication and reduces/delays relapse rates and antigen loss.
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http://dx.doi.org/10.1016/j.ymthe.2021.08.033DOI Listing
September 2021

Engraftment characterization of risk-stratified AML patients in NSGS mice.

Blood Adv 2021 Sep 1. Epub 2021 Sep 1.

Josep Carreras Leukemia Research Institute, Barcelona, Spain.

Acute myeloid leukemia (AML) is the commonest acute leukemia in adults. Disease heterogeneity is well-documented and patient stratification determines treatment decisions. Patient-derived xenografts (PDXs) of risk-stratified AMLs are crucial for studying AML biology and testing novel therapeutics. Despite recent advances in PDX modeling of AML, reproducible engraftment of human AML is mainly limited to high-risk (HR) cases, with inconsistent or very protracted engraftment observed for favorable-risk (FR) and intermediate-risk (IR) patients. We have characterized the engraftment robustness/kinetics in NSGS mice of 28 AML patients grouped according to molecular/cytogenetic classification, and have assessed whether the orthotopic co-administration of patient-matched bone marrow mesenchymal stromal cells (BM-MSCs) improves AML engraftment. PDX event-free survival correlated well with the predictable prognosis of risk-stratified AML patients. The majority (85%-94%) of the mice were engrafted in BM independently of the risk group, although HR-AML patients showed engraftment levels significantly superior to those of FR- and IR-AML patients. Importantly, the engraftment levels observed in NSGS mice by week 6 remained stable overtime. Serial transplantation and long-term culture-initiating cell (LTC-IC) assays revealed long-term engraftment limited to HR-AML patients, fitter leukemia-initiating cells (LICs) in HR- than in FR- or IR-AML samples, and the presence of AML-LICs in the CD34- leukemic fraction, regardless the risk group. Finally, orthotopic co-administration of patient-matched BM-MSCs with AML cells resulted dispensable for BM engraftment levels but favored peripheralization of engrafted AML cells. This comprehensive characterization of human AML engraftment in NSGS mice offers a valuable platform for in vivo testing of targeted therapies in risk-stratified AML patient samples.
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http://dx.doi.org/10.1182/bloodadvances.2020003958DOI Listing
September 2021

Clinicobiological Characteristics and Outcomes of Patients with T-Cell Large Granular Lymphocytic Leukemia and Chronic Lymphoproliferative Disorder of Natural Killer Cells from a Single Institution.

Cancers (Basel) 2021 Aug 2;13(15). Epub 2021 Aug 2.

Hematopathology Unit, Department of Pathology, Hospital Clínic, 08036 Barcelona, Spain.

T-cell large granular lymphocytic leukemia (T-LGLL) and chronic lymphoproliferative disorder of natural killer (NK) cells are two infrequent diseases characterized by clonal expansions of cytotoxic T lymphocytes and NK cells, respectively. Somatic mutations of are involved in the pathogenesis of these entities. We describe the clinicobiological features, mutational status of , treatment and outcome of 131 patients. Neutropenia was the most frequent finding at diagnosis, followed by anemia. Concurrent hematological disorders were diagnosed in 37% of patients and autoimmune conditions and solid tumors in 17% and 15%, respectively. All patients who needed treatment belonged to the CD8CD57 group. Remarkably, patients included in the CD4 group had a higher association with solid tumors ( = 0.037). mutations were found in 17% of patients, mainly Y640F and D661Y mutations. Patients carrying mutations more frequently presented with anemia, neutropenia, high LDH, high large granular lymphocyte counts and need for treatment ( = 0.0037). Methotrexate was the most frequently used agent (72% of cases). The overall response rate to all treatments was 50%. The 10-year overall survival of this series was 78%, with no differences according to the mutational status of . We compared the survival of these patients with the general Spanish population and no differences were found, confirming the indolent nature of these hematological malignancies. Our study further extends findings documented by others on the clinical behavior of the disease and the impact of , and for the first time analyzes survival compared to a matched general Spanish population.
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http://dx.doi.org/10.3390/cancers13153900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345581PMC
August 2021

Age and comorbidity are determining factors in the overall and relative survival of patients with follicular lymphoma.

Ann Hematol 2021 May 25;100(5):1231-1239. Epub 2021 Feb 25.

Department of Hematology, Hospital Clínic, Villarroel 170, 08036, Barcelona, Spain.

Frailty and concurrent medical conditions are crucial factors in the management of follicular lymphoma (FL). We evaluated the impact of age and comorbidity on survival, causes of death, histological transformation (HT), and second malignancies (SM) in a large single-center series of grade 1-3A FL. We studied 414 patients diagnosed in the rituximab era, categorized into three age groups (≤60, 61-70, >70 years) and two comorbidity groups (Charlson Comorbidity Index, CCI, 0-1 and ≥2). Despite a similar cumulative incidence of relapse, older and comorbid patients had a lower 10-year overall survival (OS, 88, 65, and 41% for patients ≤60 years, 61-70 years, and >70 years, P<0.0001; and 76 vs. 51% for CCI 0-1 and ≥2, P<0.0001). In a multivariate analysis for OS, comorbidity retained its prognostic impact (HR=2.5, P=0.0003). The proportion of patients dying due to FL was higher among those ≤60 years (74%) and those with a CCI 0-1 (67%). Furthermore, 10-year excess mortality (survival reduction) was more prominent for patients >70 years (30%) and those with a CCI ≥2 (32%). Patients with a CCI ≥2 also had a higher incidence of SM. These data encourage a comprehensive pre-treatment evaluation and a tailored therapeutic approach for all FL patients.
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http://dx.doi.org/10.1007/s00277-021-04470-7DOI Listing
May 2021

Baseline correlations and prognostic impact of serum monoclonal proteins in follicular lymphoma.

Br J Haematol 2021 04 16;193(2):299-306. Epub 2020 Nov 16.

Department of Haematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The presence of a serum monoclonal component has been associated with poor outcomes in some lymphomas. However, data in follicular lymphoma (FL) are scarce. We studied 311 FL patients diagnosed at a single institution, for whom information on serum immunofixation electrophoresis (sIFE) at diagnosis was available. Baseline characteristics and outcomes were compared between patients with a positive (+sIFE) and a negative sIFE (-sIFE). sIFE was positive in 82 patients (26%). Baseline features were comparable between both groups, except for an older age and higher proportion of elevated β -microglobulin levels in the +sIFE group. With a median follow-up of 4.6 years, a +sIFE was associated with a higher risk of early relapse (POD24, 27% vs. 15%, P = 0·02), shorter progression-free survival (PFS; 42% vs. 52% at 5 years, P = 0·008), and shorter overall survival (OS; 59% vs. 77% at 10 years, P = 0·046). In patients >60 years, a +sIFE was an independent predictor of OS [hazard ratio (HR) = 2·4, 95% confidence interval (CI): 1·2-5·0; P = 0·02]. Approximately one quarter of patients with FL has a +sIFE at diagnosis, which is a predictor of poor outcome. These findings encourage further investigation of its relationship with B-cell biology and the tumour microenvironment.
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http://dx.doi.org/10.1111/bjh.17138DOI Listing
April 2021

Serum monoclonal component in chronic lymphocytic leukemia: baseline correlations and prognostic impact.

Haematologica 2021 06 1;106(6):1754-1757. Epub 2021 Jun 1.

Department of Hematology, Hospital Clínic, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid.

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http://dx.doi.org/10.3324/haematol.2020.263228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168485PMC
June 2021

A low lymphocyte-to-monocyte ratio is an independent predictor of poorer survival and higher risk of histological transformation in follicular lymphoma.

Leuk Lymphoma 2021 01 19;62(1):104-111. Epub 2020 Sep 19.

Department of Hematology, Hospital Clínic de Barcelona, Barcelona, Spain.

The lymphocyte-to-monocyte ratio (LMR) is a prognostic factor in different neoplasms, but its potential importance in follicular lymphoma (FL) is not well defined. We studied 384 FL patients for which the LMR was available at diagnosis. Baseline features and outcomes were compared between patients with an LMR ≤/>2.5. The 76 patients (20%) who had an LMR ≤2.5 were older and had a higher tumor burden. A low LMR was predictive of a lower 10-y progression-free survival (32 vs. 55%,  = .001) and overall survival (35 vs. 78%,  < .0001; HR = 2.3,  = .003 in a 6-element multivariable model). A low LMR was also an independent risk factor for histological transformation (11 vs. 6% at 10 years,  = .01). Likewise, patients with a low LMR had a higher rate of second malignancies. The potential utility of this widely available parameter and its contribution to well-established prognostic scores need to be explored in independent, prospective series.
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http://dx.doi.org/10.1080/10428194.2020.1821010DOI Listing
January 2021

Mandibular movement analisys by means of a kinematic model applied to the design of oral appliances for the treatment of obstructive sleep apnea.

Sleep Med 2020 09 30;73:29-37. Epub 2020 Apr 30.

Master Program of Dental Sleep Medicine, Catholic University of Murcia, Spain.

Background: Mandibular advancement devices (MADs) are one of the treatment options used for the obstructive sleep apnea syndrome (OSAS). At present, MADs are designed with standard titration systems, without considering each patient's anatomical characteristics of the temporomandibular joint and mandible shape. The main objective of this study is to evaluate if a variability in mandibular morphology will influence the displacement of the jaw with a MAD. Such knowledge will be of help to find optimal mandibular positions with MAD even when opening the mouth.

Methods: By using a mandibular movement model, the movement patterns of different points on the chin have been analyzed. The influence of different skeletal mandibular shapes on these movements have also been studied. The results show differences in the movement patterns of the lower front teeth depending on its distance to the center of the condyle, with a more horizontal direction in those in which there is a greater distance.

Results: Variations in mandibular morphology imply differences in movement patterns of the analyzed points of the mandible. Consequently, MADs should be designed according to each patient's anatomy to avoid mandibular retrusion in those areas that may narrow the upper airways.

Conclusions: This study may help to understand why not all patients move their lower jaws forwards equally with the same degree of mandibular protrusion measured in relation to the teeth. These results might also partially explain why airway obstruction is more severe in certain untreated sleep apnea subjects than in others when opening their mouth during sleep.
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http://dx.doi.org/10.1016/j.sleep.2020.04.016DOI Listing
September 2020

41BB-based and CD28-based CD123-redirected T-cells ablate human normal hematopoiesis in vivo.

J Immunother Cancer 2020 06;8(1)

Biomedicine, Research Institute Against Leukemia Josep Carreras, Barcelona, Catalunya, Spain

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy which is biologically, phenotypically and genetically very heterogeneous. Outcome of patients with AML remains dismal, highlighting the need for improved, less toxic therapies. Chimeric antigen receptor T-cell (CART) immunotherapies for patients with refractory or relapse (R/R) AML are challenging because of the absence of a universal pan-AML target antigen and the shared expression of target antigens with normal hematopoietic stem/progenitor cells (HSPCs), which may lead to life-threating on-target/off-tumor cytotoxicity. CD33-redirected and CD123-redirected CARTs for AML are in advanced preclinical and clinical development, and they exhibit robust antileukemic activity. However, preclinical and clinical controversy exists on whether such CARTs are myeloablative.

Methods: We set out to comparatively characterize in vitro and in vivo the efficacy and safety of 41BB-based and CD28-based CARCD123. We analyzed 97 diagnostic and relapse AML primary samples to investigate whether CD123 is a suitable immunotherapeutic target, and we used several xenograft models and in vitro assays to assess the myeloablative potential of our second-generation CD123 CARTs.

Results: Here, we show that CD123 represents a bona fide target for AML and show that both 41BB-based and CD28-based CD123 CARTs are very efficient in eliminating both AML cell lines and primary cells in vitro and in vivo. However, both 41BB-based and CD28-based CD123 CARTs ablate normal human hematopoiesis and prevent the establishment of de novo hematopoietic reconstitution by targeting both immature and myeloid HSPCs.

Conclusions: This study calls for caution when clinically implementing CD123 CARTs, encouraging its preferential use as a bridge to allo-HSCT in patients with R/R AML.
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http://dx.doi.org/10.1136/jitc-2020-000845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292050PMC
June 2020

Acute myeloid leukemia with NPM1 mutation and favorable European LeukemiaNet category: outcome after preemptive intervention based on measurable residual disease.

Br J Haematol 2020 10 8;191(1):52-61. Epub 2020 Jun 8.

Hematology Department, Hospital Clínic de Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain.

In the European LeukemiaNet favourable risk category, allogeneic haematopoietic stem cell transplantation (alloSCT) is not indicated in first complete remission for patients with acute myeloid leukaemia (AML) with NPM1 mutations (ELNfav NPM1 AML), although a proportion of these patients will relapse. Given the prognostic importance of measurable residual disease (MRD), CETLAM-12 considered a pre-emptive intervention in patients with molecular failure (MF). We analyzed 110 ELNfav NPM1 AML patients achieving complete remission (CR) after induction chemotherapy. Two-year cumulative incidence of relapse (CIR), overall survival (OS) and leukaemia-free survival (LFS) were 17%, 81·5% and 82%, respectively. Forty-six patients required additional therapy for MF (n = 33) or haematological relapse (HemR; n = 13), resulting in a molecular LFS (molLFS) and a cumulative incidence of MF at two years of 61% and 38% respectively. Two-year OS for these 46 patients was 66%, with a different outcome between patients with MF (86%) and HemR (42%) (P = 0·002). Quantitative NPM1 detection at different timepoints was predictive of molLFS; an MRD ratio (NPM1mut/ABL1 × 100) cut-off of 0·05 after first consolidation identified two cohorts with a two-year molLFS of 77% and 40% for patients below and above 0·05, respectively. In conclusion, MRD-based pre-emptive intervention resulted in a favourable outcome for ELNfav NPM1 AML patients.
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http://dx.doi.org/10.1111/bjh.16857DOI Listing
October 2020

The role of TGFβ in hematopoiesis and myeloid disorders.

Leukemia 2019 05 28;33(5):1076-1089. Epub 2019 Feb 28.

Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The role of transforming growth factor-β (TGFβ) signaling in embryological development and tissue homeostasis has been thoroughly characterized. Its canonical downstream cascade is well known, even though its true complexity and other non-canonical pathways are still being explored. TGFβ signaling has been described as an important pathway involved in carcinogenesis and cancer progression. In the hematopoietic compartment, the TGFβ pathway is an important regulator of proliferation and differentiation of different cell types and has been implicated in the pathogenesis of a diverse variety of bone marrow disorders. Due to its importance in hematological diseases, novel inhibitors of this pathway are being developed against a number of hematopoietic disorders, including myelodysplastic syndromes (MDS). In this review, we provide an overview of the TGFβ pathway, focusing on its role in hematopoiesis and impact on myeloid disorders. We will discuss therapeutic interventions with promising results against MDS.
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http://dx.doi.org/10.1038/s41375-019-0420-1DOI Listing
May 2019

Improving security of autologous hematopoietic stem cell transplant in patients with light-chain amyloidosis.

Bone Marrow Transplant 2019 08 21;54(8):1295-1303. Epub 2019 Jan 21.

Amyloidosis and Multiple Myeloma Unit, Department of Hematology, Hospital Clínic of Barcelona, Barcelona, Spain.

Autologous stem cell transplant (ASCT) has demonstrated to be an effective treatment for patients with light-chain (AL) amyloidosis. However, a high transplant-related mortality (TRM) rate was reported in previous series of patients and questioned the role of transplant in this disease. Recently, experienced groups have shown a significant TRM decrease that has been attributed to an accurate selection of patients. Moreover, application of several supportive measures has decreased toxicity over amyloid-involved organs. We analyzed a series of 66 patients with AL amyloidosis, who underwent ASCT at a single institution and evaluated the impact of these measures beyond patient selection. Four temporary groups were established: group-A (non-selection plus post-transplant G-CSF use) with 29 patients, group-B (selection) with 13, group-C (selection and G-CSF avoidance) with 14, and group-D (selection, G-CSF avoidance and corticosteroid's prophylaxis) with 10. A decreasing TRM was observed over time from group-A (38%), to group-D (0%); p = 0.02. We also observed a progressive increase of three-year OS from 62% in group-A to 100% in group-D; p = 0.049. On the multivariate analysis, cardiac involvement was the only independent predictor of survival. Therefore, tailored selection policy together with transplant supportive measures have allowed ASCT to be a safe procedure in AL amyloidosis.
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http://dx.doi.org/10.1038/s41409-019-0447-yDOI Listing
August 2019

Isolated cutaneous lymphomatous form of adult T-cell leukaemia/lymphoma.

Br J Haematol 2019 04 6;185(2):205. Epub 2019 Jan 6.

Department of Haematology, Hospital Clinic de Barcelona, IDIBAPS, Barcelona, Spain.

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http://dx.doi.org/10.1111/bjh.15744DOI Listing
April 2019

Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation.

Bone Marrow Transplant 2018 12 29;53(12):1541-1547. Epub 2018 Apr 29.

Bone Marrow Transplant Unit, Department of Hematology, Hospital Clínic of Barcelona, Barcelona, Spain.

Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro-inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids' prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid's prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P < 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P = 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P = 0.001). The most important variables related to ES were HCT-CI >2 (p < 0.0001; HR 8.5) and risk groups (p < 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid's prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs.
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http://dx.doi.org/10.1038/s41409-018-0189-2DOI Listing
December 2018
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