Ciceri, Fabio

Abstract “Nonclassical” myeloproliferative neoplasms (MPNs) and myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) represent a heterogeneous group of malignancies characterized by a wide range of clinical manifestations. Unlike classical MPNs, there is no standardized management approach for these conditions, particularly concerning the indications for and management of allogeneic hematopoietic cell transplantation. To address this gap, the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee and the Chronic Malignancies Working Party (CMWP) have collaborated to develop shared guidelines aimed at optimizing the selection and management of patients with these rare forms of neoplasms. A comprehensive review of the literature from the publication of the revised fourth edition of the (2016) World Health Organization classification onward was conducted. A multidisciplinary group of experts in the field convened to produce this document, which was developed through multiple rounds of draft circulation. Key recommendations include the early identification of potential transplant candidates, particularly in cases of chronic neutrophilic leukemia, chronic eosinophilic leukemia (CEL)/CEL, not otherwise specified (CEL-NOS), myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions with FGFR1, JAK2, ABL1, and FLT3 rearrangements, MDS/MPN with neutrophilia/atypical chronic myeloid leukemia, and MDS/MPN, NOS. For patients with MPN, NOS/MPN unclassifiable, standard recommendations for myelofibrosis should be applied. Similarly, in MDS/MPN with thrombocytosis, transplantation is recommended on the basis of established MDS guidelines. Given the current lack of robust evidence, this document will serve as a valuable resource to guide future research activities, providing a framework for addressing critical unanswered questions and advancing the field.

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 (<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: 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.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 ( FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202 ) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2–3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2–3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2–3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2–4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2–3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.

Abstract Background: Haploidentical allogeneic hematopoietic cell transplantation (haplo) has expanded applicability of the procedure to patients for whom a suitable HLA compatible donor was not available in the past. A small multicenter retrospective study of 185 patients with hematologic malignancies who received a nonmyeloablative preparative regimen followed by infusion of bone marrow (BM) hematopoietic cells from haploidentical donors showed no significant association between the number of HLA mismatches (HLA-A, -B, -C, and -DRB1 combined) and risk of acute grade 2-4 graft-versus-host disease (GVHD) (hazard ratio [HR]=0.89; P=0.68 for 3-4 mismatches vs fewer antigen mismatches). This haploidentical transplant platform has certainly evolved. Nowadays, G-CSF mobilized peripheral blood stem cells (PBSC) are commonly used owing to its increased convenience vis-à-vis performing a BM harvest. Study population: Here, we evaluate post transplant outcomes when using haploidentical donors with T-replete PBSC and PTCy in AML in CR1. A total of 494 patients (4/8 HLA mismatch (group 1)=360, 2-3/8 HLA mismatch (group 2)=134) underwent the procedure at an EBMT participating center. The primary endpoints were cumulative incidences of grade 2-4 acute GVHD and chronic (all grades) GVHD. Secondary endpoints included cumulative incidence of relapse (RI), non-relapse mortality (NRM), leukemia-free (LFS) and overall survival (OS) and GVHD-free relapse-free survival (GRFS). Results: Group 1 and group 2 were not statistically different in regards to median age at allografting (54.1 vs. 56.1 years, p=0.51), median year of haplo transplantation (2018 vs. 2018, p=0.36), incidence of de novo AML (86.4% vs. 88.1%, p=0.63), Karnofsky equal or more than 90 (77.5% vs. 79.1%, p=0.70), and use of myeloablative conditioning (MAC) (44.7% vs. 48.5%, p=0.45). Patients in group 1 had a longer time from diagnosis to haplo-transplantation (5.3 vs. 4.9 months, p=0.03). In multivariate analysis, group 1 and group 2 did not differ in cumulative incidence of grade 2-4 acute GVHD (Hazard ratio (HR)=0.89 (95%CI=0.62-1.26), p=0.51) but group 1 had a significantly higher incidence of chronic (all grades) GVHD (HR=1.49 (95%CI=1.02-2.16), p=0.04). There was no difference in RI (HR=0.73 (95%CI=0.47-1.14), p=0.17), NRM (HR=1.25 (95%CI=0.78-2.02), p=0.36), LFS (HR=0.95 (95%CI=0.69-1.31), p=0.76), OS (HR=1.09 (95%CI=0.76-1.55), p=0.64) and GRFS (HR=1.07 (95%CI=0.81-1.42), p=0.64) between the groups. Presence of adverse cytogenetics was independently associated with higher RI (HR=1.90 (95%CI=1.20-2.99), p=0.006), inferior LFS (HR=1.59 (95%CI=1.15-2.19), p=0.005), inferior OS (HR=1.48 (95%CI=1.05-2.08), p=0.03), and worse GRFS (HR=1.54 (95%CI=1.17-2.04), p=0.002). Conclusion: Results show that patients undergoing haplo-transplantation with 4/8 (vs. 2-3/8) HLA mismatches have a higher incidence of chronic GVHD (all grades) without adversely affecting acute grade 2-4 GVHD, RI, LFS, OS and GRFS. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Blaise: Jazz Pharmaceuticals: Honoraria. McDonald: BioCryst Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Forcade: Novartis: Other: travel grant. Ciceri: IRCCS Ospedale San Raffaele: Current Employment. Mohty: Takeda: Honoraria; Astellas: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Jazz: Honoraria, Research Funding; Pfizer: Honoraria; Amgen: Honoraria.

SummaryOptimal donor choice for a second allogeneic haematopoietic cell transplant (allo‐HCT) in relapsed acute myeloid leukaemia (AML) remains unknown. We compared overall survival (OS) using registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) involving 455 adults who received a second allo‐HCT from a human leucocyte antigen (HLA)‐matched unrelated (MUD) (n = 320) or a haploidentical (n = 135) donor. Eligibility criteria required adults aged ≥18 years who received a second allo‐HCT for treating AML relapse between 2005 and 2019. The primary end‐point was OS. There was no statistically significant difference in the median (interquartile range) age between the groups, MUD 46 (35–58) versus haploidentical 44 (33–53) years (P = 0·07). The median OS was not different between the MUD and the haploidentical groups (10 vs. 11 months, P = 0·57). Similarly, the 2‐year OS was 31% for the MUD and 29% for the haploidentical donor groups. The OS was worse if the procedure was performed with active AML [hazard ratio (HR) 1·42, 95% confidence interval (CI) 1·07–1·89; P = 0·02]. Conversely, a longer time from first allo‐HCT to relapse (>13·2 months) was associated with better OS (HR 0·50, 95% CI 0·37–0·69; P < 0·0001). The results of the present analysis limit the ability to recommend one donor type over another when considering a second allo‐HCT for relapsed AML. Our findings highlight that best OS is achieved when receiving the second allo‐HCT in complete remission.

Abstract Angiogenesis has been postulated to be critical for the pathogenesis of multiple myeloma, a neoplastic disease characterized by abnormal proliferation of malignant plasma cells in the bone marrow (BM). Cleavage of the N- and C-terminal regions of circulating chromogranin A (CgA, CHGA), classically an antiangiogenic protein, can activate latent antiangiogenic and proangiogenic sites, respectively. In this study, we investigated the distribution of CgA-derived polypeptides in multiple myeloma patients and the subsequent implications for disease progression. We show that the ratio of pro/antiangiogenic forms of CgA is altered in multiple myeloma patients compared with healthy subjects and that this ratio is higher in BM plasma compared with peripheral plasma, suggesting enhanced local cleavage of the CgA C-terminal region. Enhanced cleavage correlated with increased VEGF and FGF2 BM plasma levels and BM microvascular density. Using the Vk*MYC mouse model of multiple myeloma, we further demonstrate that exogenously administered CgA was cleaved in favor of the proangiogenic form and was associated with increased microvessel density. Mechanistic studies revealed that multiple myeloma and proliferating endothelial cells can promote CgA C-terminal cleavage by activating the plasminogen activator/plasmin system. Moreover, cleaved and full-length forms could also counter balance the pro/antiangiogenic activity of each other in in vitro angiogenesis assays. These findings suggest that the CgA-angiogenic switch is activated in the BM of multiple myeloma patients and prompt further investigation of this CgA imbalance as a prognostic or therapeutic target. Cancer Res; 76(7); 1781–91. ©2016 AACR.