ALBERT

Description: Background: While immunotherapy withCD19 specific CAR T cells for relapsed/refractory (R/R) B-ALL achieves MRD negative remission in nearly all patients, relapse occurs in approximately half of patients and is frequently associated with early loss of CAR T cell persistence. Low CD19 antigen burden in the bone marrow prior to lymphodepletion and rapid contraction of CAR T cells in the blood after engraftment are predictive of early loss of CAR T cell persistence. We hypothesize that episodic antigen exposure using CD19t T cell antigen presenting cells (T-APCs) can trigger CD19 CAR T cell proliferation and re-activation in vivo, resulting in more durable CAR T cell persistence and diminished risk of CD19+ relapse. Here we report our experience to date using T-APCs following CD19 CAR T cell therapy for children and young adults with R/R B-ALL on clinical trial PLAT-03 (NCT03186118). Methods: Patient-derived T-APC products were manufactured from cryopreserved CD4/CD8 selected T cells. Cells were then activated with anti-CD3/CD28 beads, transduced with a lentiviral vector to express a truncated human CD19 (CD19t), and expanded in culture for 10 days. Subjects grade 2 among the 11 subjects, and no cytokine release syndrome or neurotoxicity has been observed. An increase in detectable CD19 CAR T cells occurred in all subjects following T-APCs, and T-APCs can be transiently detected following infusion (Figure 1). Of the 10 treated subjects with low CD19 antigen burden or rapid T cell contraction, 8/10 had CAR T cell persistence beyond Day 63, as evidenced by B cell aplasia. At last follow-up, 5/10 have ongoing B cell aplasia, with a median follow up of 8.8 months (range, 2-18.5 months). The estimated 1-year leukemia free survival (LFS) is 69.2%. Conclusion: This first-in-human study of CD19t T-APCs demonstrates the ability to successfully manufacture T-APCs from stored apheresis products collected for CAR T cell production. In 11 subjects receiving at least one T-APC dose to date, there has been one T-APC infusion reaction and no other significant associated toxicity. Early evidence of efficacy demonstrated by secondary expansion of CAR T cells suggests the potential of CD19t T-APCs to enhance durable CD19 CAR T cell persistence. Figure 1 Disclosures Gardner: Novartis: Honoraria. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding.

Description: Intraclonal heterogeneity (IH) in MM may provide a basis for the selection of resistance to therapy that occurs over time. Model systems to study IH in MM have not been defined so we focused on the expression of CD32B, the low-affinity inhibitory Fcγ-receptor that is a key participant in normal plasma cell apoptosis and a potential target for monoclonal antibody therapy. At diagnosis, CD138+ MM marrow cells are largely CD32B+ (n=72; median 94%, range 1–100) while at relapse the CD32B+ MM subpopulation is significantly smaller in both bone marrow (n=25, median 83%, (10–100), P = 0.02) and extramedullary sites (n=8, median 17% (0–78); P

Description: Background: Among many causes of thrombocytopenia acquired during hospitalization, heparin-induced thrombocytopenia (HIT), an immune complex-mediated thrombogenic state with high morbidity and mortality, is one of the most feared etiologies. The clinical '4T' score is an established method to assess risk for HIT and guide immediate management(Lo, Juhl et al. 2006). However, the 4T score is not consistently used by clinicians, leading to potential over-testing and suboptimal management of suspected HIT. Our objective in this Quality Improvement (QI) project was to implement a mandatory 4T calculator (4TC) into the electronic medical record (EMR) to improve the positive predictive value of HIT antibody (HITA) testing, decrease the incidence of testing of low-risk patients, and to improve clinical management of suspected HIT. Methods: We developed a 4TC that assisted clinicians by integrating EMR-derived data on heparin exposure and the five most recent platelet counts with a link to an online calculator as well as clinical suggestions (Figure). As a part of this QI project, clinicians were required to enter the calculated 4T score before ordering a polyspecific HITA assay, which serves as the screening test for HIT in our institution. We reviewed laboratory records for all HITA tests performed over a six-month period, including 3 months before and after the implementation of a "hard stop" for HITA order in the EMR. We extracted data on the ordering hospital service team, 4T score documented in notes (if any), as well as quality of care indicators including rates of clinically recommended heparin cessation and initiation of alternative anticoagulation in the subgroup of patients with intermediate or high 4T score at the time of HITA order. In this QI project, we refrained from any statistical testing and summarized pre-specified outcome measures: incidence of HITA testing, positive predictive value of the HITA assay, and quality of care indicators. Results: We identified 99 (53 prior to the 4TC and 46 post) cases of HITA orders in the study period, among which there were 4 cases of confirmed HIT (either with positive IgG or positive serotonin-release assay [SRA]). Three HIT cases occurred after the 4TC was implemented. After the implementation of the 4TC, the positive predictive value for the HITA assay increased from 9% to 21%. The rate of clinically appropriate heparin order discontinuation increased from 72% to 88%, as did the initiation of alternative anticoagulation from 14% to 27%. HITA assay was most commonly ordered by the internal medicine service (35% of tests), non-cardiac intensive care service (30%), coronary care and cardiothoracic surgery services (21%), neurology (5%), and general surgery/other services (9%). Implementation of the 4TC did not significantly change this distribution, but the overall incidence of HITA orders decreased from 4.0 to 3.4 per 1000 admissions. We observed a high frequency of confirmatory SRA testing requested (18%), which is the reflex confirmatory test performed at our institution, even in cases of negative polyspecific HITA or HIT IgG. Conclusions: Addition of a 4T score calculator into the EMR which provides immediate feedback on patient's prior heparin exposure and recent platelet counts allows clinicians to consistently use the 4T score when considering HIT. Importantly, it also helps to educate non-hematologists on the proper management of HIT. Improved predictive value of the HITA assay suggests that our 4TC led to ordering HITA in a more appropriate patient population. We also demonstrated improved quality of care for suspected HIT, with increased rates of heparin cessation and initiation of alternative anticoagulation in patients with intermediate or high pre-test probability. Identifying clinical teams that order a disproportionate number of HITA assays will help us to direct education to improve clinical management. This QI project has led to other areas of improvement, particularly with regard to rational ordering of the SRA. At only three months of review since implementation of the 4TC, we have noted an improvement in the management of suspected HIT and a slight reduction in the incidence of testing. With continued review, we hope to demonstrate further improvement, as practitioners continue to use the 4TC and rely on clinical rationale rather than reflexive laboratory testing when evaluating thrombocytopenia in the hospital. Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.

Description: Introduction: The optimal clinical setting and cell product characteristics for chimeric antigen receptor (CAR) T cell therapy in multiple myeloma (MM) are uncertain. In CLL patients treated with anti-CD19 CAR T cells (CART19), prevalence of an early memory (early-mem) T cell phenotype (CD27+ CD45RO- CD8+) at time of leukapheresis was predictive of clinical response independently of other patient- or disease-specific factors and was associated with enhanced capacity for in vitro T cell expansion and CD19-responsive activation (Fraietta et al. Nat Med 2018). T cell fitness is therefore a major determinant of response to CAR T cell therapy. In an accompanying abstract (Cohen et al.), we report that higher percentage of early-mem T cells and CD4/CD8 ratio within the leukapheresis product are associated with favorable clinical response to anti-BCMA CAR T cells (CART-BCMA) in relapsed/refractory MM. Here, we compare leukapheresis samples from MM patients obtained at completion of induction therapy (post-ind) with those obtained in relapsed/refractory (rel/ref) patients for frequency of early-mem T cells, CD4/CD8 ratio, and in vitro T cell expansion. Methods: Cryopreserved leukapheresis samples were analyzed for the percentage of early-mem T cells and CD4/CD8 ratio by flow cytometry and in vitro expansion kinetics during anti-CD3/anti-CD28 bead stimulation. Post-ind samples were obtained between 2007 and 2014 from previously reported MM trials in which ex-vivo-expanded autologous T cells were infused post-ASCT to facilitate immune reconstitution (NCT01245673, NCT01426828, NCT00046852); rel/ref samples were from MM patients treated in a phase-one study of CART-BCMA (NCT02546167). Results: The post-ind cohort includes 38 patients with median age 55y (range 41-68) and prior exposure to lenalidomide (22), bortezomib (21), dexamethasone (38), cyclophosphamide (8), vincristine (2), thalidomide (8), and doxorubicin (4); median time from first systemic therapy to leukapheresis was 152 days (range 53-1886) with a median of 1 prior line of therapy (range 1-4). The rel/ref cohort included 25 patients with median age 58y (range 44-75), median 7 prior lines of therapy (range 3-13), and previously exposed to lenalidomide (25), bortezomib (25), pomalidomide (23), carfilzomib/oprozomib (24), daratumumab (19), cyclophosphamide (25), autologous SCT (23), allogeneic SCT (1), and anti-PD1 (7). Median marrow plasma cell content at leukapheresis was lower in the post-ind cohort (12.5%, range 0-80, n=37) compared to the rel/ref cohort (65%, range 0-95%). Percentage of early-mem T cells was higher in the post-ind vs rel/ref cohort (median 43.9% vs 29.0%, p=0.001, left figure). Likewise, CD4/CD8 ratio was higher in the post-ind vs rel/ref cohort (median 2.6 vs 0.87, p2 lines of therapy prior to apheresis (n=3) compared to the rest of the cohort (n=35). Conclusion: In MM patients, frequency of the early-mem T cell phenotype, a functionally validated biomarker of fitness for CAR T cell manufacturing, was significantly higher in leukapheresis products obtained after induction therapy compared to the relapsed/refractory setting, as was CD4/CD8 ratio and magnitude of in vitro T cell expansion. This result suggests that CAR T cells for MM would yield better clinical responses at early points in the disease course, at periods of relatively low disease burden and before exposure to multiple lines of therapy. Figure. Figure. Disclosures Garfall: Novartis: Research Funding; Kite Pharma: Consultancy; Amgen: Research Funding; Bioinvent: Research Funding. Cohen:GlaxoSmithKline: Consultancy, Research Funding; Kite Pharma: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy; Seattle Genetics: Consultancy. Fraietta:Novartis: Patents & Royalties: WO/2015/157252, WO/2016/164580, WO/2017/049166. Davis:Novartis Institutes for Biomedical Research, Inc.: Patents & Royalties. Levine:CRC Oncology: Consultancy; Brammer Bio: Consultancy; Cure Genetics: Consultancy; Incysus: Consultancy; Novartis: Consultancy, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Research Funding. Siegel:Novartis: Research Funding. Stadtmauer:Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; AbbVie, Inc: Research Funding. Vogl:Karyopharm Therapeutics: Consultancy. Milone:Novartis: Patents & Royalties. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding. Melenhorst:Novartis: Patents & Royalties, Research Funding; Incyte: Research Funding; Tmunity: Research Funding; Shanghai UNICAR Therapy, Inc: Consultancy; CASI Pharmaceuticals: Consultancy.

Description: Background: Immunotherapy with CD19 specific chimeric antigen receptor (CAR) T cells for relapsed/refractory acute lymphoblastic leukemia (ALL) demonstrated a minimal residual disease (MRD) negative remission rate of 93% on the phase 1 portion of Pediatric Leukemia Adoptive Therapy (PLAT)-02. However, the 1-year event free survival (EFS) was 50.8%, largely due to recurrence of disease which was frequently associated with early loss of CAR T cell persistence. Subjects on PLAT-02 with

Description: Background: The patients with multiple myeloma (MM) have an increased risk of venous thromboembolism (VTE), particularly during the induction phase of therapy. Low molecular weight heparins (LMWH) seem to be useful for thromboprophylaxis in these patients. We analyzed prophylactic efficiency of LMWH based on dose either lower or higher than 70 IU/kg of body weight. Patients and Methods: 223 patients with newly diagnosed MM were treated with induction chemotherapy consisting of vincristine, doxorubicin and dexamethasone (VAD) or vincristine, idarubicin and dexamethasone (VID) as a part of multicenter CMG 2002 trial. The first cohort of 137 patients received no systematic thromboprophylaxis. After a high incidence of thrombotic complications has been reported, the thromboprophylaxis with different doses of LMWHs was used in 86 consecutive patients for 4 months of induction therapy. Finally, 101 patients enrolled to the CMG 2002 trial in single centre were analyzed retrospectively, based on dose either lower or higher than 70 IU/kg of body weight. From this 101 patients 34% (34/101) received no systematic thromboprophylaxis, 38% (39/101) received LMWH (dalteparin) daily dose lower than 70 IU/kg, and 28% (28/101) received LMWHs daily dose higher than 70 IU/kg. The efficacy and safety of this treatment were analyzed. The chi-square test was used for statistical analysis. Results: Incidence of VTE was significantly reduced in the group of 86 patients receiving the recommended thromboprophylaxis, as compared to 137 patients without prophylaxis (1.2% vs. 12.4%, p=0.003, risk reduction 11.25%). Single centre analysis showed that no VTE was developed in the group of 28 patients receiving more than 70 IU/kg of LMWH daily. It was significantly different from the 34 patients without prophylaxis (0% vs. 15%, p=0.002). The incidence of VTE in 39 patients with LMWHs daily dose lower than 70 IU/kg was reduced to 7.6%, which is still clinicaly significant as compared to cohort of 28 patients receiving more than 70 IU/kg of LMWH daily (0% vs. 7.6%, p=0.05). No case of major bleeding was developed in any group. Conclusions: Thromboprophylaxis with LMWHs is effective in patients with newly diagnosed multiple myeloma during the induction chemotherapy only if the LMWH dose is sufficient. Our date shown that minimal sufficient dose seems to be more than 70 IU/kg of LMWH daily, as in this cohort of patients no case of VTE was developed.

Description: Background: BL is associated with a high risk of primary or secondary CNS involvement, warranting intrathecal (IT) and/or systemic therapy that penetrates the blood-brain barrier (BBB). The lower-intensity DA-EPOCH-R regimen has recently shown high survival rates in BL (Dunleavy, NEJM 2013), but it omits drugs traditionally used for CNS prophylaxis (like high-dose methotrexate [HDMTX]). The objective of this multi-institutional retrospective study was to examine treatments, risk factors, and CNS-related outcomes among patients (pts) with BL. Methods: We collected data from 26 US centers on adult BL pts diagnosed (dx) in 6/2009-6/2018. Using institutional expert pathology review and 2016 WHO criteria, we excluded other high-grade lymphomas (including BL-like/unclassifiable), or cases with inadequate clinicopathologic data. We studied factors associated with baseline CNS involvement (CNSinv) using logistic regression reporting odds ratios (OR). Progression-free (PFS), overall survival (OS), and cumulative incidence function of CNS recurrence (in a competing risk analysis) were examined in Cox or Fine-Gray models reporting hazard (HR) or subhazard ratios (SHR), respectively. All estimates report 95% confidence intervals (in square brackets). Results: Among 557 BL pts (median age, 47 years [yr], 24% women, 23% HIV+), 107 (19%) had CNSinv at dx, including 89 (16%) with leptomeningeal, and 15 (3%) with parenchymal CNS disease. In a multivariable model, factors significantly associated with CNSinv at dx included stage 3/4 (OR, 11.2 [1.47-85.9]), poor performance status (PS; OR, 2.12 [1.22-3.69]), ≥2 extranodal sites (OR, 3.77 [2.02-7.03]), or marrow involvement (OR, 2.44 [1.35-4.39]), whereas intestinal involvement conferred low risk of CNSinv (OR, 0.27 [0.11-0.65]). CNSinv at dx was not significantly associated with use of specific chemotherapy regimens (Fig. A,P=.75) or receipt of IT chemotherapy (91% vs 84%, P=.065). Pts with CNSinv were less likely to achieve a complete response (62% vs 76%, P=.005), had worse 3 yr PFS (47% vs 69%; P3x]; see Evens AM et al, ASH 2019 for further details). With median follow up of 3.6 yrs, 33 pts (6%) experienced a CNS recurrence (82% within 1 yr from dx; 79% purely in CNS, and 21% with concurrent systemic BL). The cumulative risk of CNS recurrence was 6% [4-8%] at 3y (Fig. D). Univariate significant predictors of CNS recurrence included baseline CNSinv, HIV+ status, stage 3/4, poor PS, LDH〉3x, involvement of ≥2 extranodal sites, marrow, or testis. However, in a multivariate model only baseline CNSinv (SHR, 3.35 [1.53-7.31]) and poor PS (SHR, 2.24 [1.03-4.90]) retained significance. The 3 yr risk of CNS recurrence varied from 3% for pts with no risk factor, to 10% with one, and 17% with both factors (Fig. E). In addition, the risk of CNS recurrence differed according to chemotherapy regimen, and was significantly higher for pts treated with DA-EPOCH (12% at 3y [8-18%]; Fig. F) compared with CODOX-M/IVAC (4% [2-8%]) or hyperCVAD/MA (3% [1-6%]; SHR for DA-EPOCH vs. others, 3.50 [1.69-7.22]). All pts recurring after DA-EPOCH had received IT chemotherapy. Higher risk of CNS recurrence persisted with DA-EPOCH regardless of baseline CNSinv (Pinteraction=.70), poor PS (Pint=.14), or HIV status (Pint=.89). Baseline CNSinv was the strongest factor associated with CNS recurrence after DA-EPOCH (3 yr risk, 30% vs 8%, P

Description: Despite advances in therapy, many patients with systemic light-chain amyloidosis (AL) die within 3 years from diagnosis. The humanized 2B6 monoclonal antibody (MoAb) is specific for the low-affinity IgG Fc receptor CD32B and effective in a human CD32B+ B-cell lymphoma murine xenograft model. Because MoAb therapy could improve outcomes in AL, we studied CD32B expression by clonal plasma cells obtained from 48 patients with AL. Transcript profiling showed that expression of CD32B was significantly higher than expression of all other Fc receptor family members. Reverse-transcriptase polymerase chain reaction (RT-PCR) using double-enriched CD138+ plasma cells showed uniform expression of the stable cell surface CD32B1 isoform at diagnosis and relapse, and flow cytometry showed intense CD32B cell surface staining on 99% of CD138+ plasma cells at diagnosis and relapse. These data provide a rationale for the novel therapeutic targeting of CD32B using the humanized 2B6 MoAb in patients with systemic AL-amyloidosis.

Description: Overactivated complement is a high-risk feature in HSCT recipients with transplant associated thrombotic microangiopathy (TA-TMA), and untreated patients have dismal outcomes. We present our experience of 64 pediatric HSCT recipients with high risk TA-TMA and multi-organ injury treated with the complement blocker eculizumab. We demonstrate significant improvement in 1y post-HSCT survival to 66% in treated patients from our previously reported untreated cohort with same high-risk TA-TMA features that had 1y post-HSCT survival of 16.7%. Responding patients benefited from a brief but intensive eculizumab therapy course using PK/PD guided dosing, requiring a median of 11 doses of eculizumab (IQR 7-20). Therapy was discontinued due to resolution of TA-TMA at a median of 66 days (IQR 41-110). Subjects with higher complement activation measured by elevated blood sC5b-9 at the start of therapy were less likely to respond to treatment (OR =0.15, p-value 0.0014), and required more doses of eculizumab [r = 0.43, p-value = 0.0004]. Patients with intestinal bleeding had the fastest eculizumab clearance, required the highest number of eculizumab doses (20 vs 9, p=0.0015), and had lower 1y survival (44% vs 78%, p=0.01). Over 70% of survivors had proteinuria on long term follow up. The best GFR recovery in survivors was a median 20% lower (IQR 7.3-40.3%) than their pre-HSCT GFR. In summary, complement blockade with eculizumab is an effective therapeutic strategy for high risk TA-TMA, but some patients with severe disease lack a complete response, prompting us to propose early intervention strategies and search for additional targetable endothelial injury pathways.

Description: Background Historically diagnosis and prognosis of myeloid disorders including acute myeloid leukemia (AML) have been determined using a combination of morphology, immunophenotype, cytogenetic and more recently single gene, if not single mutation, analysis. The introduction of NGS technology has resulted in an explosion in the quantity of mutation data available. However, the feasibility and utility of NGS technology with regards to decision-making in routine clinical practice of myeloid disorders is currently unknown. We therefore developed an advanced NGS tool for simultaneous assessment of multiple myeloid candidate genes from low amounts of input DNA and present clinical utility analysis below. Methods We designed a targeted resequencing assay using a TruSeq Custom Amplicon panel with the MiSeq platform (both Illumina) consisting of 341 amplicons (~56 kb) designed around exons of genes frequently mutated in myeloid malignancies (ASXL1, ATRX, CBL, CBLB, CBLC, CEBPA, CSF3R, DNMT3a, ETV6, EZH2, FLT3, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, NPM1, NRAS, PDGFRA, PHF6, PTEN, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1 & ZRSR2). Filtering, variant calling and annotation were performed using Basespace and Variant Studio (Illumina) with additional indel detection achieved using Pindel. A cohort of samples previously characterised with conventional techniques was used for validation and the lower limit of detection established using qPCR. Post-validation, DNA from 152 diagnostic blood or bone marrow samples from patients with confirmed or suspected myeloid disorders; both AML (n=46) and disorders with the potential to transform to AML i.e. myelodysplasia (confirmed n=54, suspected n=10) and myeloproliferative neoplasms (n=42), were analysed using this assay. To gather clinical utility data we developed a reporting algorithm to feed back information to clinicians; only those variants with a variant allele frequency (VAF) of 〉10% and described as acquired in publically available databases were reported with the exception of novel mutations predicted to result in a truncated protein. Further utility data was obtained using published mutation algorithms to determine the proportion of patients in whom mutation data altered prognosis. Results In the validation cohort, initial concordance for detection of clinically significant mutations was 88% rising to 100% once Pindel was used to identify FLT3 ITDs. The lower limit of detection was 3% VAF, and mean amplicon coverage was 390 reads. Using our reporting algorithm 66% of patients in the post-validation cohort had a suspected pathogenic mutation relevant to a myeloid disorder, rising to 74% in patients with confirmed diagnoses. The median number of reported variants per sample for all diagnoses was one (range 0-6). When mutation data for patients with AML with intermediate risk cytogenetics was analysed using the algorithm of Patel et al (N Engl J Med. 2012;366:1079-1089), 4/22 (18%) moved into another risk category. A further two patients had double CEBPA mutations, improving their prognosis. Identification of complex mutations in KIT exon 8 in 2/6 patients with core binding factor AML resulted in more intensive MRD monitoring due to the increased risk of relapse. Interpretation of mutation data for patients with confirmed myelodysplasia using the work of Bejar et al (N Engl J Med. 2011;364:2496-2506) revealed 13/54 (24%) had a high risk mutation independently associated with poor overall survival. 2/8 (25%) patients with chronic myelomonocytic leukemia and 1/12 (8.3%) patients with primary myelofibrosis had high risk ASXL1 exon 12 mutations, independently associated with a poor prognosis. Among suspected diagnoses confirmatory mutations were found in 2/19 (11%), while the absence of mutations reduced the probability of myeloid disease in 11/19 (58%), in some cases sparing elderly patients invasive bone marrow sampling. A further 20 patients had clinically relevant mutations. Conclusions The NGS Myeloid Gene Panel provided extra information to clinicians in 57/152 patients (38%) helping inform diagnosis, individualize disease monitoring schedules and support treatment decisions. The targeted panel approach requires rigorous validation and standardisation in particular of bio-informatics pipelines, but can be adapted to incorporate new genes as their relevance is described and will become central to treatment decisions. Disclosures No relevant conflicts of interest to declare.