GM-CSF secreting leukemia cell vaccination for MDS/AML after allogeneic HSCT: a randomized double blinded phase 2 trial

Vaccination using irradiated, adenovirus transduced autologous myeloblasts to secrete GM-CSF (GVAX) early after allogeneic hematopoietic stem cell transplantation (HSCT) can induce potent immune responses. We conducted a randomized phase II trial of GVAX after HSCT for MDS-EB or relapsed/refractory AML. Myeloblasts were harvested before HSCT to generate the vaccine. Randomization to GVAX vs. placebo (1:1) was stratified by disease, transplant center, and conditioning. GVHD prophylaxis included tacrolimus and methotrexate. GVAX or placebo started between day +30-45 if there was engraftment and no GVHD. Vaccines were administered SC/ID weekly x 3, then q2 wks x 3. Tacrolimus taper began after vaccine completion. 123 patients enrolled, 92 proceeded to HSCT, and 57 (GVAX 30, Placebo 27) received at least 1 vaccination. No CTC grade ≥ 3 vaccine related adverse events were reported, but injection site reactions were more common after GVAX (10 vs. 1, p=0.006). With a median follow up of 39 months (range, 9-89), 18-month PFS, OS and relapse incidence were 53% vs 55% (p=0.79), 63% vs. 59% (p= 0.86), and 30% vs. 37% (p=0.51) for GVAX and placebo, respectively. NRM at 18 months was 17% vs. 7.7% (p=0.18), Grade II-IV aGVHD at 12 months 34% vs. 12% (p=0.13), and cGVHD at 3 years 49% vs. 57% for GVAX and placebo, respectively, p=0.26. Reconstitution of T, B, and NK cells were not decreased or enhanced by GVAX. There were no differences in serum MICA/B or other immune biomarkers between GVAX and placebo. GVAX does not improve survival after HSCT for MDS/AML. (Clinicaltrials.gov identifier: NCT01773395)

Impact of graft-versus-host disease prophylaxis on immune reconstitution in patients after allogeneic hematopoietic stem cell transplantation

The graft-versus-host disease (GVHD) is among the most common complications after hematopoietic stem cell transplantation (allo-HSCT). The main tools for GVHD prevention remain calcineurin inhibitors (cyclosporin A, tacrolimus), methotrexate, mycophenolate mofetil. Upon implementation of reduced-intensity conditioning regimens, antithymocyte globulin was widely introduced. However, negative effects upon reconstitution of T-cell immunity have been noted, thus increasing risk of severe infectious complications and disease relapse. With extended practice of HSCT from alternative (partially matched or haploidentical) donors, cyclophosphamide was increasingly used. Our aim was to study reconstitution of immune cell subpopulations in the patients undergoing bone marrow transplantation (BMT), when using different GVHD prophylaxis regimens, including the schedules with post-transplant CP usage. The study concerned 44 cases classified into 2 groups. The first one included patients with standard immunosuppressive therapy, antithymocyte therapy, cyclosporine A, methotrexate, mycophenolate mofetil. The second group included the patients who received CP as immunosuppressive drug combined with other treatments (cyclosporine A, methotrexate, mycophenolate mofetil). At specified control terms, (D+14, +30, +60, +90) the blood leukocyte subpopulations were assayed by means of multicolor flow cytometry. Absolute counts of CD4+ cells in HSCT recipients treated with CP post-BMT proved to be sufficiently lower at D+14 and +30, than in those treated with classical immunosuppressive therapy. However, at later terms, (D+60, +90), these differences were not observed. Moreover, in CP-treated bone marrow recipients, absolute numbers of CD8+ cells was significantly higher, compared to the patients who received conventional GVHD prophylaxis. Reconstitution of the studied lymphocyte populations in hematopoietic cell recipients did not depend on the GVHD prophylaxis regimen. Usage of CP combined with bone marrow as a source of stem cells, brings about sufficient decrease of some cell populations (CD4+; CD8+; NK cells) at early terms post-transplant. Administration of CP combined with hematopoietic stem cells as the source of hematopoietic graft seems to be more reasonable.

Role of Extracorporeal Photopheresis in Prevention of Graft-Versus-Host Disease in Patients Treated with Allogeneic Hematopoietic Stem Cell Transplantation: A Randomized Controlled Trial

Introduction In many patients diagnosed with a hematological malignancy, the disease cannot be totally eradicated by conventional therapeutic approaches, and for them allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option. A major complication of allo-HSCT is graft-versus-host disease (GvHD), affecting about 50% of transplant recipients. In addition to increased risk of death and long-lasting debilitating conditions, severe GvHD also impairs health-related quality of life. High-dose systemic steroids is the first line treatment for GvHD, but treatment failure is common, and steroid-refractoriness is a major cause of non-relapse mortality after allo-HSCT. While there is no established second line GvHD-treatment, extracorporeal photophoresis (ECP) has emerged as an attractive and increasingly applied alternative, partly due to its favourable safety profile. However, the use of ECP in preventing GvHD is sparse and data are inconclusive due to lack of randomized controlled trials (RCT). We therefore conducted a RCT to study if ECP given post transplantation could prevent the development of GvHD. Methods Between June 2017 and February 2020, we enrolled 157 patients (> 18 years) diagnosed with a hematological malignancy and treated with an allo-HSCT in first remission into an intention-to-treat open RCT. Ethical and IRB approvals were granted, and the RCT was registered with Clinical Trials (ID NCT03204721). The sample size (76 in intervention group and 81 controls) was calculated based on a reduction of 25% in the total number of patients diagnosed with any form of GvHD within the first year of allo-HCST (primary end-point) as clinically relevant. The patients were stratified according to whether they received myeloablative or reduced intensity conditioning (Table 1), and they were given GvHD prophylaxis as shown in Table 1. ECP (Therakos Cellex ®, Mallinckrodt Pharm., NJ) was initiated when patients had engrafted (i.e. leukocytes > 1 x 10 9/L and platelets > 20 x 10 9/L), and, according to the study protocol, we planned for ECP on two consecutive days/week for two weeks, then weekly for four weeks to a total eight treatments for each patient in the intervention group. Chi-square test was used to test differences between the two study groups. Results Table 1 shows that patient characteristics were well balanced among the two study groups. Four patients did not receive ECP while 39 received all the eight treatments. One year after allo-HCST, the proportion of GvHD was 45/76 (59%) in the intervention group and 52/81 (64%) in the controls (p=0.52). There were no significant differences between the intervention and control group regarding development of acute (45% vs. 48%) or chronic (39% vs. 40%) GvHD. Neither did we detect any statistical differences between the two study groups regarding organ involvement or severity of the GvHD manifestations (data not shown). During the one-year observation period, 16/76 (21%) and 10/81 (12%) relapsed in the intervention and control group, respectively (p=0.14). The corresponding numbers of deaths were 12/76 (16%) and 16/81 (20%), respectively (p=0.52). Six patients in the intervention group experienced mild to moderate temporary, adverse events that could possibly be related to the ECP-procedure. Conclusion In this first RCT addressing ECP as GvHD prophylaxis in allo-HSCT for hematological malignancy, we found no significant difference in the numbers, types, organ involvement, or severity of GvHD between the intervention and the control group. Thus, our study does not support the use of ECP as an adjunct to GvHD-prophylaxis based on cyclosporine and methotrexate, mycophenolate mofetil, or sirolimus. However, ECP did not seem to be harmful in this setting. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

Complex Clonal Evolution Can Occur Following Transplantation for Transfusion Dependent Thalassaemia in the Context of Mixed Myeloid Chimerism and Reduced Conditioning Regimens

Haemopoietic stem cell transplantation (HSCT) is a well-established treatment modality for the cure of transfusion dependent thalassaemia (TDT) and sickle cell disease (SCD). Clonal evolution has recently been identified as a concerning event in the setting of mixed chimerism and/or ineffective haemopoiesis following conventional bone marrow transplantation and gene therapy for haemoglobinopathies. This has so far been restricted to SCD only, with the presumption that despite both conditions sharing an ineffective erythropoietic marrow compartment, there may be inflammatory and hypoxic differences enabling clonal evolution, in addition to the different exposure to hydroxycarbamide as a therapeutic agent. However, there is a need to investigate whether this may also be an occurrence in TDT. From 2011 to 2021, over a ten-year period, sixty-five consecutive paediatric patients received a sibling HSCT (n=55) or a haploidentical HSCT (n=10) for TDT in our institution. Conditioning intensity was minimised at the start of this cohort in order to limit toxicity and late effects, abandoning the use of Bu/Cy, which resulted in approximately 50% of the patients having stable mixed chimerism long-term. Sibling HSCT was conditioned with fludarabine 160 mg/m 2, treosulfan 42 g/m 2, thiotepa 10 mg/kg and ATG (Thymoglobulin) or alemtuzumab, and received GvHD prophylaxis with ciclosporin and MMF. Haploidentical HSCT was conditioned with fludarabine 150 mg/m 2, cyclophosphamide 30 mg/kg, TBI 2 or 4 Gy, and ATG 4.5 mg/kg (thiotepa 10 mg/kg added if TBI 2 Gy only) with GvHD prophylaxis provided by two doses of post-transplantation cyclophosphamide 50 mg/kg, sirolimus and MMF. All patients had pre-transplantation endogenous haemopoiesis was suppressed pre-transplantation with hypertransfusions for a minimum of 8 weeks, and/or the use of hydroxycarbamide and azathioprine. GvHD prophylaxis was provided with ciclosporin and MMF. All patients were Pesaro class I or II at the time of transplantation. The median age was 5 years (2 - 19). The median survival was 26.8 months (2.6-101.8). The OS was 93.8% and DFS was 89.2%. Three patients in this cohort developed clonal evolution in the context of myeloid mixed chimerism identified due to the development of cytopenias and transfusion dependence. All patients had a complex karyotype and it involved deletion of chromosome 7: Patient 1 had a sibling BMT at 3 years and 2 months. Day +28 chimerism was >95% in whole blood and 95% in T cells. The myeloid fraction had a progressive reduction from day +60 onwards. At 15 months post-transplantation clonal evolution was identified [18% ring sideroblasts, 46;XY, del (7) (q22 q34) [5]/46;XY [5], chimerism 13% donor in whole marrow and 41% marrow T cells. Two months later he became red cell transfusion dependence. A second BMT with busulfan based conditioning resulted in long-term cure. Patient 2 had a sibling BMT at 3 years and 8 months of age. Day +28 chimerism was 99% donor in whole blood and 99% donor in T cells. Day +161 post-transplantation he started requiring erythropoietin support to maintain him transfusion independent and on day +217 we first identified in the bone marrow the appearance of myeloid mixed chimerism (75% donor in whole marrow and 91% marrow T cells) and complex clonal evolution involving -7 and FISH identified deletion of one copy of KMT2E (7q22) and MET (7q31) detected [16/200]. The patient is under monitoring at present with a progressive reduction of the size of the abnormal clones. Patient 3 had a haplo BMT at 5 years and 8 months. Day +28 chimerism was 97% donor in whole blood and 99% donor in T cells. She developed mixed myeloid chimerism following cessation of immunosuppression on day +206: 86% donor whole blood and 99% donor in T cells. At 22 months post-BMT she started to require transfusion and a complex clonal evolution involving deletion 7 in her bone marrow when the chimerism was 42% donor whole blood and 81% donor marrow T cells. FISH identified deletion of one copy of KMT2E(7q22) and MET(7q31) detected[22/100]. She is being prepared for a second bone marrow transplant. In conclusion, complex clonal evolution also occurs post HSCT in TDT, at least in the context of reduction of conditioning intensity and development of mixed myeloid chimerism. This finding warrants further investigation and may have significant implications for the design of both conventional HSCT and gene therapy strategies. Disclosures No relevant conflicts of interest to declare.

A Prospective Phase 2 Study Testing High Dose Post-Transplant Cyclophosphamide As Sole Ghvd Prophylaxis after Matched Allotransplant Using Baltimore-Based Reduced-Intensity Conditioning Regimens and PBSC As Source of Graft

Introduction: The use of high-dose post-transplant cyclophosphamide (PTCY) has revolutionized graft-versus-host disease (GVHD) prophylaxis and allowed to successfully reconsider haplotransplant in recent years. As this strategy significantly reduces the incidence of both acute and chronic GVHD, PTCY has been thereafter considered not only in matched settings but also as sole GVHD prophylaxis, at least when considering myeloablative allotransplant using matched sibling (MSD) or unrelated (MUD) donors and bone marrow as source of graft. Here, PTCY, as a sole GVHD prophylaxis, was tested in a reduced-intensity conditioning (RIC) setting, using peripheral blood stem cells (PBSC) as source of graft considering that this platform is currently broadly used worldwide in adults. Methods: This prospective monocentric phase 2 study was designed with the main objective to demonstrate the feasibility and safety of using only PTCY (without cyclosporine A nor mycophenolate mofetyl after transplant) in adults (18-70 years old) eligible for a RIC PBSC transplant with MSD or MUD. The Baltimore platform with 2 days of PTCY 50mg/kg/day on days 3 and 4 post infusion was considered as conditioning regimen, using fludarabine for lymphoid disease or clofarabine for myeloid disease. The primary objective was to appreciate the incidence of corticosteroid-resistant acute grade 3-4 GVHD (CR 3-4 GVHD) within 100 days post-transplant. According to statistical rules, patients have to be included in a step by step fashion (3, 3, 6, 15, 15 and 17 patients) for a total of 59 evaluable patients (meaning having received PTCY), in order to stop the protocol soon enough in case of excessive rate of deleterious severe acute GVHD (graded according to Mount Sinai International Consortium). Thus, the trial had to be stopped in case of documentation of > 2 CR 3-4 GVHD for the first 3 patients, >3 CR 3-4 GVHD for the first 6 patients, > 4 CR 3-4 GVHD for the first 12 patients, > 6 3-4 CR GVHD for the first 27 patients, > 8 CR 3-4 GVHD for the first 42 patients and finally as soon as > 9 CR 3-4 GVHD for the last included patients. All patients gave informed consent. The trial was registered at ClinicalTrials.gov Identifier: NCT03263767. Results: The results of the first 27 first patients (males n=17 and female n=10; median age: 59 years old (yo), range: 26-70) are reported here. They were included between February 2018 and November 2020. Diagnoses were AML (N=8), MDS (N=5), CMML (N=2), myelofibrosis (N=5), CML (N=1), DLBCL (N=1), T-cell lymphoma (N=1), Philadelphia positive B-ALL (N=1), CLL (N=1), lymphoblastic lymphoma (N=1) and mixed phenotype acute leukemia (N=1). Donors were MSD in 10 cases and MUD in 17. Only one primary graft failure was documented in a 61 yo MDS patient with active disease at transplant. He is however still alive in response after autologous reconstitution. With a median follow-up of 17.6 months (range: 10-42) for alive patients at the time of analysis (July 2021), 1-year and 2-year survivals were 80.9+7% and 74.7+9%, respectively, for both OS et DFS. GVHD-free/relapse-free survival (GRFS) at 1-year and 2-year was 58.7+9% and 52.2+10%, respectively. Three relapses (11%) and 6 deaths occurred. Deaths were due to acute GVHD in 4 patients (including 1 with sepsis and 1 with SARS-COVID 19 infection) and relapse in 2. Grade 2, 3 and 4 acute GVHD occurred in 11, 1 and 4 patients, respectively, for a total of 59% of grade 2-4 acute GVHD. CR 3-4 GVHD was observed in all of 5 patients with acute grade 3-4 GVHD and 4 died related to GVHD. Moderate/severe chronic GVHD occurred in 5/22 (22.7%) evaluable patients, including 4 still on immunosuppressive therapy at 40, 28, 25 and 16 months post-transplant. Overall non-relapse mortality (NRM) was 14.8% and related to acute GVHD. However, the number of cases conducting to stop the protocol was not reached. Conclusion: PTCY as a sole GVHD prophylaxis is here demonstrated as possible and relatively safe for adults receiving a matched PBSC Baltimore-based RIC allograft. The very good survivals reported here may be related to a strong GVL effect associated with the high incidence of acute GVHD. However, because of this high incidence and the fact that NRM was related to GVHD after this first analysis, we have now made an amendment to test the addition to PTCY of one day of anti-thymoglobulin (ATG) 2.5 mg/kg on day-2 for the next 32 patients to be included. This second cohort receiving PTCY+ATG as a sole prophylaxis is ongoing. Disclosures Moreau: Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Oncopeptides: Honoraria.

Haploidentical Vs. Matched Unrelated Donor Transplants Using Post-Transplant Cyclophosphamide for Lymphoma: A Joint CIBMTR/EBMT Study

Introduction: Post-transplant cyclophosphamide (PTCy) is a standard GVHD prophylactic approach for haploidentical hematopoietic cell transplantation (haploHCT). Retrospective studies in patients with lymphoma showed lower chronic GVHD in haploHCT with PTCy-based GVHD prophylaxis compared to matched unrelated donor (MUD) HCT with calcineurin-based GVHD prophylaxis (+/- ATG). Recent retrospective studies showed that using MUD donors was better than haplo donors when PTCy and reduced-intensity conditioning are used for ALL, AML or MDS. However, no studies to date have compared haploHCT and MUD HCT when PTCy is used in the setting of lymphomas. Methods: 2155 adults (730 CIBMTR, 1425 EBMT) aged =/>18 years who received their first haploHCT or MUD HCT (8/8 match at HLA-loci A, B, C and DRB1) using PTCy from 2010-2019 for lymphoma were included. The majority of both MUD (n=312; 14%) and haplo (n=1843; 86%) HCTs received reduced intensity/non-myeloablative conditioning (n=1655; 77%) using a peripheral blood stem cell graft (n=1379; 64%) and a three-drug GVHD prophylaxis (PTCy + calcineurin inhibitor + MMF, n=1805; 84%). Hodgkin's lymphoma was the most common indication (n=899; 42%) followed by diffuse large B-cell lymphoma (n=525; 24%), T-cell lymphomas (n=328; 15%), mantle cell lymphoma (n=234; 11%) and follicular lymphoma (n=169; 8%). Most had chemosensitive disease at transplant (n=1781; 83%). Some main characteristics of the two cohorts are shown in Figure 1. Median follow-up among survivors was longer for haplo-HCT (36 and 31 months for the CIBMTR and EBMT cohort, respectively) than MUD-HCT (24 and 17 months, respectively). Cox proportional hazards models were built using stepwise forward and backward selection with a selection/retention threshold of 0.05. Any clinical variables that did not meet the proportional hazard assumption were adjusted for by stratification, and regression models were built to compare outcomes between donor types. Center effect was adjusted in all the models. Results: Figures 2 and 3 show the multivariate analysis results. Overall survival was 73% (71-75%) at 1 year and 65% (63-67%) at 2 years. Relapse was 21% (20-23%) at 1 year and 26% (24-28%) at 2 years. All outcomes favored MUD over haplo donors with the use of PTCy-based GVHD prophylaxis for both. Conclusions: Patients with lymphoma receiving PTCy HCT from MUDs demonstrated better outcomes than those with haplo donors in this retrospective study of CIBMTR and EBMT data Future prospective studies are needed to confirm and clarify the reasons for these differences. Figure 1 Figure 1. Disclosures Mussetti: GILEAD: Other: Clinical trials participation, Research Funding; TAKEDA: Honoraria; NOVARTIS: Honoraria, Other: Clinical trials participation. Hamadani: Janssen, Incyte, ADC Therapeutics, Omeros, Morphosys, Kite: Consultancy; Sanofi, Genzyme, AstraZeneca, BeiGene: Speakers Bureau; Takeda, Spectrum Pharmaceuticals and Astellas Pharma: Research Funding. Glass: Novartis: Consultancy; Riemser: Research Funding; Helios Klinik Berlin-Buch: Current Employment; Kite: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Dreger: Novartis: Consultancy, Speakers Bureau; Riemser: Consultancy, Research Funding, Speakers Bureau; BMS: Consultancy; Bluebird Bio: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Gilead Sciences: Consultancy, Speakers Bureau; Janssen: Consultancy; AbbVie: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau. Lee: AstraZeneca: Research Funding; Incyte: Research Funding; Janssen: Other; Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Sureda: BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Bluebird: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Mundipharma: Consultancy; Roche: Other: Support for attending meetings and/or travel; GSK: Consultancy, Honoraria, Speakers Bureau.