Citations

Background: Arteriovenous malformations (AVMs) are complex vascular anomalies with a high risk of hemorrhage and neurological deficits, especially when located in eloquent brain regions. The eloquence of an AVM location is a critical factor in the treatment planning, influencing both the risk of complications and long-term functional outcomes. This study aims to compare outcomes between eloquent and non-eloquent AVMs. Methods: This multicenter, retrospective study utilized data from the Multicenter International Study for Treatment of Brain AVMs (MISTA) consortium. Patients with eloquent and non-eloquent AVMs were compared on baseline characteristics, angiographic outcomes, and functional outcomes using the modified Rankin Scale (mRS). Propensity score weighting (IPTW) was applied to adjust for confounding variables. Results: The study included 1013 patients, with 498 (49.2%) AVMs located in eloquent regions and 515 (50.8%) in non-eloquent regions. In unadjusted analysis, eloquent AVMs had lower complete obliteration rates (67.6% vs 79.5%, OR: 0.53, 95% CI: 0.39–0.72, p < 0.001) and higher complication rates (24.5% vs 19.0%, OR: 1.38, 95% CI: 1.02–1.86, p = 0.03) compared to non-eloquent AVMs. After IPTW adjustment, eloquent AVMs continued to show significantly higher odds of overall complications (OR: 1.68, 95% CI: 1.12–2.52, p = 0.01) and symptomatic complications (OR: 1.77, 95% CI: 1.12–2.80, p = 0.01). Secondary analysis within the eloquent group indicated that embolization was linked to an elevated risk of complications. Surgery and radiosurgery showed comparable functional outcomes at last follow-up and complications rates with higher complete obliteration rates in surgery. Conclusion: AVMs in eloquent brain areas present higher risks of complications and lower obliteration rates, emphasizing the need for cautious, individualized treatment planning. Within the eloquent group, embolization increased the risk of complications, while surgery and radiosurgery showed comparable functional outcomes at last follow-up and complication rates with higher complete obliteration rates in surgery. These findings highlight the importance of location in AVM management and support further research focusing on comparing treatment strategies for AVMs in eloquent brain areas.

Background Brain arteriovenous malformations (AVMs) are abnormal connections between feeding arteries and draining veins, associated with significant risks of haemorrhage, seizures and other neurological deficits. Preoperative embolization is commonly used as an adjunct to microsurgical resection, with the aim of reducing intraoperative complications and improving outcomes. However, the efficacy and safety of this approach remain controversial. Methods This study is a subanalysis of the Multicenter International Study for Treatment of Brain AVMs consortium. We retrospectively analysed 486 patients with brain AVMs treated with microsurgical resection between January 2010 and December 2023. Patients were divided into two groups: those who underwent microsurgery alone (n=245) and those who received preoperative embolization, followed by microsurgery (n=241). Propensity score matching was employed, resulting in 288 matched patients (144 in each group). The primary outcomes were rates of complete AVM obliteration and functional outcomes (measured by the modified Rankin Scale (mRS)). Secondary outcomes included complication rates, mortality, hospital length of stay and postsurgical rupture. Results After matching, the complete obliteration rate was 97% with no significant difference between the microsurgery-only group and the preoperative embolization group (p=0.12). The proportion of patients with an mRS score of 0–2 at the last follow-up was similar in both groups (83% vs 84%; p=0.67). The median hospital stay was significantly longer for the embolisation group (9 days vs 7 days; p=0.017). Complication rates (24% vs 22%; p=0.57) and mortality rates (4.9% vs 2.1%; p=0.20) were comparable between the two groups. No significant differences were observed in postsurgical rupture, recurrence or retreatment rates. Conclusions In this large multicentre study, preoperative embolization did not significantly improve AVM obliteration rates, functional outcomes or reduce complications compared with microsurgery alone.

Abstract Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

Background: In 2015 the first B-cell acute lymphoblastic leukemia (B-ALL) patient receiving CAR T-cell therapy in Europe was reported to the EBMT registry. Today, the EBMT registry counts with more than 9000 patients treated with CAR T-cell therapies across all indications. Here, on behalf of the GoCART coalition, we present the outcomes of the largest European cohort of B-ALL patients treated with autologous, second generation, CD19-targeted CAR T-cells to date. Methods: Adult and paediatric patients with B-ALL received treatment with CAR T-cell therapy using either academic or commercially available products in 40 centres across 17 different countries. Safety was retrospectively assessed as per ASCTC 2019 consensus grading and CTCAE, and efficacy as per NCCN guidelines. Relapse incidence was defined as haematological relapse or progression after CART with non-relapse mortality as competing event. Leukemia free survival (LFS) was defined as being alive without occurrence of relapse. Follow-up includes patients treated from 2016 to Dec 2023 until data cutoff in June 2024. Results: A total of 345 patients (173 adults and 172 pediatrics) received therapy from 2016 to 2023 with tisagenlecleucel (65.2%), varnimcabtagene autoleucel (25.8%), brexucabtagene autoleucel (5.5%), and others (3.5%). Median age at infusion was 18 yrs. (range, 1.1-78.2) and 41.7% were females. High-risk features were identified including cytogenetic/genomic high-risk as per ELN guidelines (33.8%), relapse after allo-HCT (57.7%), early relapse (&lt;1 year) after prior allo-HCT (30.4%), ≥3 prior treatment lines (55.5%) including prior exposure (and refractoriness) to blinatumomab and inotuzumab in 27.3% (34%) and 28.8% (32.3%), respectively. Median time from diagnosis to CART infusion was 2.8 years (0.1-17.9). Median time from last relapse prior CART to infusion was 2 months (range, 0.9-38.4). Bridging therapy was administered in 86.4% (298) of patients based on high or low intensity chemotherapy (32.1% or 26.5%, respectively), inotuzumab-ozogamicin (13.4%), TKI (8.2%), involved-site therapy (intrathecal chemotherapy, radiotherapy, orchiectomy) (3.5%), and blinatumomab (2.6%), alone or in combination. Prior to infusion, 34.7% had more than 5% BM blast count, 16.3% had circulating blasts in PB, and 20.6% had extramedullary disease. Lymphodepletion was performed in all but one patient, based on fludarabine and cyclophosphamide regimens. The reverse Kaplan-Meier median follow-up was of 2.2 years. The incidence of any grade (and severe) CRS was 71.6% (14.5%), and for ICANS was 15.7% (7.6%). The cumulative incidence of MRD-negative CR at month +3 was 76.9% (71.9-81.1), followed by a 2-year overall survival of 64.6% (58.7-69.8), leukemia-free survival of 48% (42.1-53.7), and relapse incidence of 45.5% (39.6-51.2). Non-relapse mortality at 2 years was 6.5% (4-9.6), 2-year cumulative incidence of subsequent HSCT of 33.3% (28-38.7) and second CAR-T infusions of 12.4% (8.8-16.6). Allogeneic HSCT after CAR-T was performed in 113 cases including 67 (59.3%) HSCT-naïve patients, due to molecular or overt disease relapse (60.9%), and other non-relapse reasons including suboptimal CAR-T persistence/B-cell aplasia (19.1%), pre-CAR-T high-risk features (13.6%), second malignancies (1.8%), and others. Second CAR-T infusions were performed in 39 cases due to molecular or overt disease relapse (79.5%) or suboptimal CAR-T persistence/B-cell aplasia in the absence of relapse (20.5%). Conclusions: The results from this European study demonstrate that CD19-targeted CAR T-cell therapy is an effective treatment for patients with high-risk B-cell ALL, providing substantial leukemia-free survival and overall survival rates despite the high-risk nature of the patient population. The necessity for bridging therapies and subsequent consolidative approaches, such as HSCT and second CAR T infusions, underscores the complexity and tailored nature of managing R/R B-ALL. These findings support the continued use and further investigation of CAR T-cell therapy in diverse clinical settings, emphasizing the importance of post-infusion strategies to sustain long-term remission. This will provide deeper insights into the factors influencing outcomes and help refine treatment protocols to improve patient care.

Background: Fc receptor-homolog 5 (FcRH5) is a type I membrane protein that is expressed exclusively in the B-cell lineage, and at a higher level on multiple myeloma (MM) cells than on normal B cells. Cevostamab is a FcRH5xCD3 bispecific antibody that facilitates T cell-mediated killing of MM cells. In an ongoing Phase I dose-escalation and dose-expansion study (GO39775; NCT03275103), cevostamab monotherapy demonstrated target dose (TD)-dependent activity and manageable safety in patients (pts) with heavily pretreated RRMM (Trudel et al. ASH 2021). We report updated efficacy and safety data from pts who received cevostamab once every 3 weeks (Q3W) at the 160mg TD level. Methods: Eligible pts were those with RRMM for which no established therapy was available or appropriate. Cevostamab was initiated with Cycle (C) 1 single-step (SS) dosing, double-step (DS) dosing (Trudel et al. ASH 2021), or triple-step (TS) dosing (step doses on D1, D2 [or D3 or D4 depending on the emergence and resolution of cytokine release syndrome [CRS] with the previous administration], and D8, TD on D9 [or D10 or D11]). Cevostamab was then continued at the TD on D1 of each subsequent 21-day cycle. Cevostamab was continued for 17 cycles, unless disease progression or unacceptable toxicity occurred. Results: As of February 23, 2024, 167 pts (median age: 66 years, range: 40-90; ECOG PS: 0, 35% or 1, 65%; median time from first MM therapy: 6.3 years, range: 0.3-21.8) had received cevostamab at the 160mg TD level (SS: n=10; DS: n=97; TS: n=60); 28% of pts had extramedullary disease and 38% of pts with a conclusive assay result (38/100) had high-risk cytogenetics (t(4;14), t(14;16), or del(17p)). The median number of prior lines of therapy was 6 (range: 2-18). Almost all pts (95.8%) were triple-class refractory and 73.7% were penta-drug refractory; 85.0% were refractory to their last prior therapy. A majority (57%) of pts had received ≥1 prior B-cell maturation antigen (BCMA)-targeted therapy. Twenty four percent of pts had received ≥1 prior bispecific antibody. Median observation time was 11.3 months (range: 0.5-42.8). The overall response rate (ORR) in all pts who received cevostamab at the 160mg TD level was 43.1% (72/167 pts); 6.6% achieved a stringent complete response (CR), 6.6% a CR, 12.6% a very good partial response (VGPR), and 17.4% a partial response (PR). The VGPR or better rate was 25.7%. Median time to first response (PR or better) was 1.4 months (range: 0.6-4.6) and to best response was 2.4 months (range: 0.7-13.4). Median duration of response was 10.4 months (95% CI: 6.8, 10.5). ORR was 30.2% (29/96) in pts with ≥1 prior BCMA-targeted therapy and 60.6% (43/71) in those without. ORR was 30.0% (12/40) in pts with ≥1 prior bispecific antibody, 33.3% (20/60) with ≥1 prior chimeric antigen receptor (CAR) T-cell, and 41.2% (14/34) with ≥1 prior antibody-drug conjugate. Common (≥20%) adverse events (AEs) included CRS (74.3%; Grade [Gr] 1: 52.7%; Gr 2: 19.8%; Gr 3: 1.2%; Gr 4: 0.6%), neutropenia (31.1%; Gr 1-2: 3.0%; Gr 3: 12.0%; Gr 4: 16.2%), cough (30.5%; Gr 1-2: 29.9%; Gr 3: 0.6%), nausea (28.1%; Gr 1-2: 27.5%; Gr 3: 0.6%), diarrhea (24.0%; all Gr 1-2), anemia (23.4%; Gr 1-2: 5.4%; Gr 3: 17.4%; Gr 4: 0.6%), and fatigue (21.0%; Gr 1-2: 19.8%; Gr 3: 1.2%). Possible immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 13.2% of pts (Gr 1: 6.0%; Gr 2: 5.4%; Gr 3: 1.8%). Infections occurred in 53.9% of pts, with serious events and Gr ≥3 events in 22.2% and 19.2%, respectively. Treatment-related AEs leading to cevostamab discontinuation occurred in 11 pts (6.6%) and treatment-related Gr 5 (fatal) AEs in 3 pts (1.8%; hemophagocytic lymphohistiocytosis, n=2; disseminated intravascular coagulation and pseudomonal sepsis, n=1). In the 0.3/1.2/3.6/160mg TS cohort, CRS occurred in 19/30 pts (63.3%) and was all Gr 1 (46.7%) or Gr 2 (16.7%). Pts with CRS were managed with tocilizumab (47.4%), steroids (21.1%), or both agents (10.5%). No pts discontinued cevostamab due to CRS and all events were resolved at cut-off. Conclusions: Cevostamab demonstrates clinically meaningful activity and manageable safety at the 160mg TD level in pts with heavily pretreated RRMM. C1 TS dosing provides effective CRS mitigation. Cevostamab combination studies may use the 0.3/1.2/3.6mg TS regimen and the Q3W 160mg TD (or similar TD exposure).

Introduction Monoclonal antibodies (MoAbs) directed against CD38 are a mainstay in multiple myeloma (MM). Downregulation of CD38 expression is a resistance mechanism of antigenic escape, however, cell surface expression may return. While this tumor cell plasticity is likely driven by epigenetic mechanisms, it is unknown if MM cells can develop permanent resistance to anti-CD38 MoAb by acquiring genomic events leading to biallelic disruption of CD38 thus precluding re-treatment. Here, we report biallelic loss of CD38 as a recurrent mechanism of resistance, often via convergent evolution where distinct subclones are advantaged towards the same selective pressure. Methods We interrogated two sets of patients (Mayo Clinic; n = 31, Calgary University; n =19) with relapse following anti-CD38 MoAbs. Two additional cases of interest were selected from Heidelberg University. Whole genome sequencing (WGS, 60-100x) or whole exome sequencing (WXS), flow cytometry (flow), and bulk RNAseq were used to validate the effect of genomic events on CD38. Missense mutations predicted to affect CD38 MoAb binding were validated with site-directed mutagenesis of a CD38 plasmid, transduction into K562 MM cells, and CD38 MoAb binding assays. Results The prevalence of biallelic inactivation of CD38 at anti-CD38 MoAb relapse was 6% (3/50). An additional selected biallelic event was noted in the Heidelberg set. Each case is described in detail: MM-19 (Calgary) received daratumumab (Dara), lenalidomide, and dexamethasone (Dex), and then had a second exposure to Dara, following relapse. At this second relapse, WGS was performed on two independent extramedullary disease localizations in the liver. Both samples had unique, large deletions (&gt;3 Mb) on chromosome 4 coupled with additional unique focal deletions involving CD38. Flow confirmed the presence of CD138+/CD38- plasma cell populations in both sites. A second case of convergent evolution was seen in a patient (Mayo) after seventh-line Dara/Len/Dex. WGS revealed a common deletion encompassing CD38. On the remaining allele, one subclone had a structural variation-mediated loss of CD38(cancer cell fraction; CCF 40%) while another harbored an L153H missense mutation (CCF 60%). Flow confirmed presence of two CD138+ clones; one with diminished CD38 expression. L153H was functionally validated to abrogate Dara binding, while maintaining CD38 expression. The third sample was collected after fifth-line Dara and sixth-line Dara/Bortezomib/Dex (Heidelberg) and represents another case of convergent evolution with a common loss of chromosome 4 and two subclones detected by WGS (P98Lfs*12, CCF 39% resulting in biallelic inactivation; R140G, CCF 61%). Bulk RNAseq revealed, in comparison to NDMM from CoMMpass, CD38 expression below the first decile. Notably, the R140G variant reduced binding affinity to Dara but not to Isatuximab (Isa). A fourth case (Mayo) relapsing after 6 months of Dara-based therapy similarly had a focal deletion of CD38 with an L18Sfs*16 frameshift deletion on the remaining allele associated with a 4.35-fold reduction in CD38 expression by RNAseq compared to pre-treatment. Interestingly, in 3/4 cases the CD38-negative clone emerged after a second exposure to anti-CD38 MoAb, suggesting emergence with the first exposure and then selection during the second. One other monoallelic event (C275Y; Heidelberg) was detected post-Isa. Copy number of the alternate allele is not known given targeted sequencing methodology, but the variant was seen to reduce binding affinity to both Dara and Isa. The prevalence of monoallelic loss of CD38 in newly diagnosed MM from MMRF CoMMpass was 7% (50/701) and two patients had mutations in CD38, but there were no cases of biallelic loss suggesting these events are driven by treatment pressure. Conclusion Distinction of the mode of CD38 loss is valuable for predicting outcome of re-challenge to anti-CD38 MoAbs. We see here an estimated 5-10% of anti-CD38 MoAb relapses are characterized by genomic antigen escape. Results here are in line with antigen escape to BCMA- and GPRC5D-directed immunotherapies (Lee et al, Nat Med 2023), suggesting that acquired antigen escape resulting from prolonged exposure to the selective pressures of immunotherapy is a recurrent mechanism of resistance in MM. Moreover, in select cases, non-overlapping resistance mutations provide rationale for switching agents at second exposure.

Background: The prognosis of patients (pts) with relapsed or refractory B ALL (r/r B-ALL) treated with CAR T-cells and receive a 2nd CART infusion is unknown. Few reports with limited numbers of patients suggest that 2nd CART infusion is feasible with questionable efficacy. This GoCART coalition registry study aimed at compiling data to investigate the indications, efficacy, and toxicity of CART2 infusion in pts with r/r B-ALL. Methods: This is a multicenter, retrospective registry study that included pediatric and adult patients with r/r B-ALL who received autologous CD19-targeted CAR T-cell therapy (CART1) and subsequently were treated with a second administration of CD19 and/or CD22-targeted CAR-T cell therapy (CART2) from 2017 to 2023. Baseline features, prior stem cell transplant (SCT), indications for CART2 and outcomes were collected. Relapse incidence (RI) was defined as overt recurrence, non-relapse mortality (NRM) as death without relapse occurrence, leukemia free survival (LFS) as being alive without occurrence of relapse and overall survival (OS) as being alive. RI and NRM were estimated using cumulative incidence function and OS and LFS Kaplan-Meier estimation. Results: Out of 345 pts who received CART1, 39 (2y cumulative incidence of second CART: 12.4% (95%CI: 8.8-16.6)) received CART2. Reasons for CART2 were overt relapse (n= 26; 66.7%), molecular relapse by measurable residual disease (MRD+) (n=5; 12.8%), and B-cell recovery (BCR) in the absence of relapse (n=8; 20.5%). Seventeen pts (43.6%) were female and median age at CART2 infusion was 19 yrs (range: 6.9-67.1), including 19 children and 20 adults. 74.4% of the pts had received a prior SCT, 25 pts (64%) before CART1, 2 (5.1%) only between CART1 and CART2, and 2 (5.1%) before CART1 and between CART1 and CART2. Among the 31 pts who received CART2 for relapse, this was CD19+ in 24 (92.3%), CD19- in 2 (7.7%), and unknown in 5. CART1 products were varnimcabtagene autoleucel (ARI-0001) (23), tisagenlecleucel (13), brexucabtagene autoleucel (1), and other experimental (2). All CART2 products targeted CD19 except 2 (1 CD22 and 1 dual CD19-CD22). Median time between CART1 and CART2 was 11.0 months. For patients who received CART2 for BCR, median time between CART1 and CART2 was shorter than for those who received it for relapse: 2.4 (IQR: 2.3-3.3) months vs. 12.4 (IQR:6.4-19.3) months. Regarding leukemic burden at the time of CART2 infusion, 19 pts (48.8%) were in overt relapse (14/19 with extramedullary disease, including 7 in CNS), 12 (30.1%) were in complete remission (CR) MRD+ and 8 (20.5%) CR MRD-. With a median follow-up time of 2.3 yrs [95% CI: 1.2-3.4], the 2-yr OS and LFS after CART2 were 47.1% [95% CI: 27.8-64.3] and 39.9% [95% CI: 24-55.3], respectively. 2-yr RI was 54.5% (95% CI: 36.5-69.4) and NRM was 5.6% (95% CI 1-16.8). 2-yr OS, LFS and RI for pts in CR at CART2 infusion irrespective to MRD were 76.1%, 63.3% and 25.6% while for those not in CR these outcomes were 17.7%, 15% and 85%, respectively (p= 0.007, 0.006 and 0.002). 2-yr LFS (71.4% [95% CI 25.8-92]) and RI (0%) was significantly better for pts receiving CART2 for BCR than in those who received it for relapse (31.6% [15.6-48.9] and 68.4% [46.7-82.8]; p= 0.036, p=0.002). Conclusion: This is a large registry study describing indications and outcome of CART2 in patients with r/r B-ALL. At 2-yrs after CART2, the LFS was of 39.9% and for patients receiving CART2 due to B-cell recovery was of 71.4%. These results show that CART2 is associated with low NRM and might be a bridge to SCT or other additional therapies. Updated results with data about subsequent therapies after CART2 will be presented at ASH meeting.

Introduction: Despite the success of anti-CD19 Chimeric Antigen Receptor T cells (CART19) in patients with B-cell acute lymphoblastic leukemia (B-ALL), an allogeneic haematopoietic stem cell transplantation (HSCT) might rescue patients with disease recurrence. However, in patients at high risk of relapse, indication and timing of HSCT are challenging. Whether waiting for detectable disease or proceeding to consolidative HSCT in remission, is still controversial. This GoCART Coalition registry study aimed at investigating the outcome of patients who received HSCT after CART19. Methods: We retrieved data from the EBMT registry on adults and children with B-ALL who received autologous CART19 from 2016 and 2023. Baseline, previous treatment, bridging therapy, CART19 therapy, B cell aplasia duration, outcome, disease status at follow-up were collected. Kaplan Meier estimates were used for overall survival (OS), leukemia-free survival (LFS) and non-relapse mortality (NRM) from date of HSCT, whereas cumulative incidence was used for relapse after HSCT. The relapse was defined as molecular or hematologic recurrence of the disease. Relapse and NRM were mutually competing events. Results: Of 345 patients (173 adults and 172 children) infused with CART19 (Tisagenlecleucel in 65.2%, Varnimcabtagene autoleucel 25.8%, brexucabtagene autoleucel 5.5%, and others 3.5%), 113 subsequently received an HSCT (37 adults and 76 children; median age 13.5 years, IQR 8.2-22.2) at a median of 6.2 months (3.7-11.8) after CART19 infusion. Median follow-up was 1.6 years (95%CI 1.1-1.9). Overall, 67/113 (59.3%) patients were transplant-naive (17 adults; 50 children). 78.2% received a myeloablative conditioning, 36.8% were grafted from a mismatched related donor. Most of the patients (64.2%) were transplanted in CR3 or more. Disease status at HSCT was relapsed disease for 9% of the patients, whereas among patients in CR with reported MRD 26/95 (27%) received HSCT with MRD positivity (MRD+). Among the patients with disease recurrence after CART19, 19/60 (32%) detected a CD19-negative clone. Indication for the subsequent HSCT was reported for 110 patients, as follow: (I) Rescue HSCT in 68 (62%) patients with molecular/morphological disease after CAR-T (including one patient with MDS post CAR-T); (II) Pre-emptive HSCT in 22 (20%) patients with B-cell aplasia loss with no signs of disease recurrence; (III) ConsolidativeHSCT in the 20 patients (18%) who were transplanted for the high risk of relapse, despite ongoing B cell aplasia and no disease recurrence. Median time elapsed between CART19 and HSCT was 9.5, 4.4 and 3.4 months in the three groups, respectively. The 2-yr OS was 71.1% (95%CI 59.8-79.7) and 2-yr LFS was 53.5% (41.9- 63.8), relapse incidence was 32.7% (22.4-43.5), while NRM was 11.6% (6.1-19.1). The 2-years LFS was 59.6% (45.2-71.4) vs 42% (19.2-63.4), for patients transplanted with negative or positive MRD, respectively. 5/11 patients transplanted with overt disease (including one with MDS) relapsed or died, the 6 survivors free of disease had follow-up inferior to 2 years. Children compared with adults showed better OS (76.8%, 62.1-86.4; 59.9%; 40.8-74.6; p=0.02), and better LFS (64.3%, vs. 36.4%; p= 0.02). Patients receiving a rescue HSCT for MRD+ or overt relapse had a significant lower LFS (43.6% and 33.2%), as compared to pre-emptive (77.3%) and consolidative HSCT (83.6%, p= 0.001). In univariate analysis, no significant differences in OS (74.5% vs 65.6%, p=0.32), LFS (54.3% vs 52.4%, p=0.75) and NRM (10.7% vs 12.9%, p=0.68) were reported for those patients having a previous HSCT before CART19. Conclusion: To the best of our knowledge this is the largest cohort of transplanted patients after CART19. In this “real-world” registry-based study we found that patients transplanted without disease recurrence had a better LFS, also accounting for MRD. For those who experienced molecular or overt relapse, achieving MRD negativity appeared to be relevant for a better outcome. The low NRM, with no differences between pre-transplanted and transplant naive patients, suggest that HSCT after CART19 is well tolerated, and represent a valid strategy to reduce the risk of relapse. As it remains unclear for which patients autologous CART19 cells remains a stand-alone treatment, future studies should focus on strategies for early identification of patients at higher risk of treatment failure.

Introduction: Adults older than 60 years constitute 20-25% of newly diagnosed classic Hodgkin lymphoma (cHL) and have inferior outcomes compared to younger patients (pts). Salvage therapy followed by an autologous stem cell transplant (ASCT) is a potentially curative option for pts with relapsed/refractory (R/R cHL). There is limited data regarding outcomes of older adults with R/R cHL who undergo ASCT in the current era where novel agents are employed in the R/R setting, in comparison with younger patients. Methods: This multicenter, international, retrospective study of 18 participating institutions included adults with R/R cHL who underwent ASCT from January 1, 2010 through December 31 2020. Retrospective chart review was performed to collect data on patient and disease characteristics at relapse, including lines and type of salvage therapy, pre-ASCT response by PET, and use of brentuximab vedotin (BV) as consolidation post-ASCT. Study objectives were to assess progression-free survival (PFS), overall survival (OS), and the probability of non-relapse mortality (NRM) with relapse as a competing event. NRM was defined as death without preceding relapse. Results: Of the total 1172 adults with R/R cHL enrolled in the parent cohort, 96 (8.1%) were age 60 years or older at the time of ASCT. In this older cohort, the median age was 66 years (range: 60-72). 54 (56%) were age 60-64, 31 (32%) were of age 65-69 and 11 (11%) were of age 70-72. 59 (61%) were male, 63 (66%) had advanced stage disease, 17 (18%) had bulky disease, 37 (39%) had B symptoms and 38 (40%) had extranodal disease. All patients (pts) received ABVD or ABVD-like frontline therapy. The median time to relapse was 6 months (range: 0-174). 48 pts (50%) relapsed within a year after completion of frontline treatment and 25 (26%) had primary refractory disease. Salvage therapy prior to ASCT included platinum-based chemotherapy (65%), BV-based regimen (34%), and PD-1 inhibitor-based regimens (3%). 16 pts (16%) underwent ASCT after &gt;1 line of salvage therapy and 75 (78%) underwent ASCT after achieving a complete metabolic response (CMR). 14 pts (14.6%) received BV consolidation. Median follow-up for entire population was 53.4 months (range: 0.3-199.0). In older adults, the 5-year PFS was 54.2% (CI95: 43.4-67.6) not statistically different compared to pts &lt;60 years (67.7% (CI95: 64.3-71.3), p=0.2). However, 5-year OS was inferior in older adults: 71.9% (CI95: 43.4-67.6) vs. 82.6% (CI95: 43.4-67.6) in pts &lt;60 years (p &lt;0.0001)). In pts ≥60, 26 (27%) died including 12 (12.5%) without preceding relapse. Older adults had 3-month, 1-year and 5-year probability of NRM of 5.2% (CI95: 2.2-12.2), 7.5% (CI95: 3.6-15.3), and 10.9% (CI95: 5.8-20.8), respectively. NRM was significantly higher in older adults compared to pts &lt;60 who had 3-month, 1-year and 5-year probability of NRM of 0.3% (CI95: 0.1-1.0), 0.9% (CI95: 0.5-1.7), and 2.5% (CI95: 1.6-3.9), respectively (p&lt;0.0001). Older adults had 3-month, 1-year and 5-year probability of relapse of 1% (CI95: 0.2-7.3), 7.5% (CI95: 3.6-15.3), and 28.6% (CI95: 19.1-42.1), respectively, which did not differ significantly from younger pts (p=0.3) who had 3-month, 1-year and 5-year probability of relapse of 0.6% (CI95: 0.3-1.3), 5.1% (CI95: 3.8-6.6), and 29.9% (CI95: 26.6-33.5), respectively. Conclusions: Although older adults with cHL are more likely to relapse after frontline treatment, only a minority of pts (&lt;10%) in this large multicenter cohort underwent ASCT at age ≥60. In select older adults who underwent ASCT, the risk of relapse was similar to younger pts, but NRM was significantly higher, especially in the early post-ASCT period. Detailed assessment of comorbidity scores, toxicities of salvage therapies, and prognostic factors will be presented at the conference.

Background New therapies for myelofibrosis (MF) are being developed but how these compare with current therapies is limited to analyzing single outcome measures such as spleen volume reduction or quality-of-life (QoL). However, these outcome trajectories might diverge and some endpoints may not be clinically relevant. To remedy this an ELN (European LeukemiaNet) taskforce developed a composite endpoint using the Desirability-Of-Outcome-Ranking (DOOR) method which allows multiple outcomes to be simultaneously considered and therapies achieving diverging endpoints compared. Methods An Expert Panel used DOOR to divide outcome relevancy into 8 dimensions: clinical meaningfulness, modifiability, reliability, feasibility, decisional value, acceptability, frequency, and cost. Next, a weight was assigned to each dimension using the mean Likert score assigned by the panelists. Next, the panel validated which dimensions were met by each of 30 outcomes most frequently listed by clinical trials. A weighted score (WS) for each outcome was calculated based on weights assigned to a dimension and accomplishment rates assigned to outcomes. Outcomes were then distributed into quartiles. Next, operational definitions of outcomes were tested in Delphi consensus method requiring &gt; 75% agreement. Last, a literature review indicated correlations of the outcomes ranked in the 1st 2 quartiles with survival. Results Three composite endpoints were developed and named DEMYOs (DEsirability-of-MYelofibrosis-Outcomes). DEMYO-1, the proportion of people alive and free of severe vascular events, blast transformation, severe anaemia and thrombocytopenia and very-severe symptom burden, encompassed outcomes in the 1st quartile (WS &gt; 29.5) and is the proposed composite endpoint for trials of people with advanced JAK-inhibitor refractory MF. DEMYO-2, defined as the proportion of people alive and free of accelerated or blast phase, severe or worsening anaemia, severe and major vascular events, severe or symptomatic splenomegaly, severe or worsening symptoms and any emergent adverse genetic abnormality, included the outcomes ranked in the 1st 2 quartiles (WS &gt; 26.5) and is proposed for trials of people with a sub-optimal response to JAK-inhibitors. DEMYO-3, defined as the proportion of people alive and free of blast transformation, vascular events, severe, symptomatic or worsening clinical features and of worsening prognostic co-variates, included outcomes in the 1st 3 quartiles (WS &gt; 23.5) and is proposed for trials of people not yet receiving JAK-inhibitors. Interpretation DEMYO composite endpoints capture relevant clinical features of MF and represent endpoints important to patients, physicians and other stakeholders. DEMYO validation is feasible by available trial data and, once validated, the composite endpoints can be endorsed by medicines regulatory agencies. DOOR proved feasible and robust in this 1st-in-haematology application and we encourage further use. No funding