Nonmyeloablative Transplantation Research Articles

Bortezomib Consolidation after Nonmyeloablative Allogeneic Transplant Is Safe and Leads to a High Incidence of Immunophenotypic Complete Response in High-Risk or Young Myeloma Patients

▪Introduction: Allogeneic stem cell transplantation (alloSCT) is the only curative treatment for newly diagnosed multiple myeloma (NDMM) patients but is hampered by a high incidence of relapse and chronic graft-versus-host disease (cGVHD). We hypothesized that bortezomib (BTZ) in consolidation after tandem autologous stem cell transplantation (ASCT) and nonmyeloablative (NMA) alloSCT could decrease the incidence of cGVHD while improving quality of response.Method: NDMM patients ≤65 years with high-risk (HR) disease (defined as HR cytogenetics [del17p, t(4;14), t(14;16), t(14;20), del1p or gain 1q], ISS 3 or plasma cell leukemia) or ≤ 50 year regardless of risk status with an 8/8 HLA identical sibling or unrelated donor are eligible to participate in this prospective trial. After triplet BTZ-based induction chemotherapy and ASCT, outpatient NMA alloSCT is performed with either fludarabine 30 mg/m2 and cyclophosphamide 300 mg/m2 for 5 days (sibling donor) or fludarabine 30 mg/m2 for 3 days and total body irradiation 2 Gy (unrelated donor) followed by peripheral blood stem cell infusion. Acute GVHD (aGVHD) prophylaxis consists of tacrolimus and mycophenolate mofetil (MMF). BTZ is started on day +120 post-transplant at 1.3 mg/m2 every 2 weeks for 1 year. Response evaluation is based on IMWG criteria. Bone marrow minimal residual disease (MRD) evaluation is performed with highly sensitive (≥10-5) next-generation flow cytometry using 8-color Euroflow protocol before alloSCT, before BTZ, every 3 months for 2 years and at relapse. Immunophenotypic complete response (iCR) is defined as stringent CR in addition to 2 consecutive negative MRD results. aGVHD and cGVHD are evaluated according to modified Glucksberg and NIH criteria, respectively.Results: As of 07/10/2017, 33 NDMM patients (16 males) have been enrolled; median age is 55 (range: 35-64) years. ISS 3 is found in 39%, Durie-Salmon stage 3A or 3B in 85%, HR cytogenetics in 58% (12% del17p, 15% t(4;14), 33% gain 1q21, 9% del1p and 12% with >1 HR cytogenetics). Induction consisted of CyBorD (79%) or VTD (21%) for a median of 4 (range: 4-7) cycles followed by ASCT. Median times from induction to ASCT and from ASCT to alloSCT are 5.7 and 4.4 months, respectively. Sibling donor transplants were performed in 42%. With a median follow-up of 15 months after alloSCT, 23 patients have started BTZ and received 96% of planned doses. No dose reduction was needed for toxicity. Consolidation BTZ improve depth of response, increasing ≥CR rate from 55% to 80% and iCR rate from 17% to 67% (Table 1), regardless of cytogenetic abnormalities. Median progression-free survival (PFS) is not reached; 12-month PFS is 87% (CI: 66-96) (Fig. 1). The cumulative incidence of progression at 12 months is 8%. Median overall survival (OS) is also not reached and 12-month OS is 91% (CI: 68-98). In 23 patients followed ≥6 months, cumulative incidences of grade II-IV and grade III-IV aGVHD are 30% and 15%, respectively. In 18 patients followed ≥12 months, the cumulative incidence of all grade and moderate-severe cGVHD at 12 months are 58% and 40%, respectively, with mostly mouth, skin and liver involvement. There is no clear association between time of occurrence of cGVHD and improvement of response. Three patients died, one from myeloma progression and 2 from grade III aGVHD, with a non-relapse mortality at 12 months of only 5%. Observed grade ≥3 non-hematologic toxicities possibly/related to BTZ include diarrhea (n=1), viral hemorrhagic cystitis (2 adenovirus, 1BK virus) and subclinical EBV reactivations (n=4).Conclusion: Tandem ASCT-NMA alloSCT and BTZ consolidation result in a remarkably high rate of CR or better including iCR. Despite a HR NDMM population, a low relapse rate is observed. BTZ following alloSCT is safe and may contribute to decrease both the incidence of cGVHD or its severity. [Display omitted] DisclosuresSebag:Celgene, Janssen: Consultancy. Cohen:University of Montreal: Patents & Royalties: royalties.

Long-Term Follow up of 90y-Ibritumomab Tiuxetan, Fluadarabine and TBI Based Non-Myeloablative Allogeneic Transplant Conditioning for Persistent High-Risk B-Cell Lymphoma

Purpose:Non-myeloablative allogeneic hematopoietic cell transplantation (NMA-HCT) can provide prolonged remissions in patients with advanced B-cell lymphoma (B-NHL) via the graft versus lymphoma (GVL) effect, though inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy (RIT) can safely induce responses in B-NHL with little non-hematologic toxicity. Initial results of this approach demonstrated early safety and disease control (Blood, 2011) but with short follow up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions.Patients and Methods:Eligible patients with persistent CD20+ B-NHL or CLL, with HLA-matched related or unrelated donors, and adequate organ function, underwent NMA-HCT. Patients were not excluded based on cytopenia or marrow involvement with lymphoma. Conditioning included 0.4 mCi/kg (max 32mCi) 90Y-ibritumomab tiuxetan (day-14), fludarabine (days -7 to -5) and 2 Gy total body irradiation (day 0) followed by transplantation from HLA-matched related or unrelated donors along with post-grafting immunosuppression with cyclosporine and mycophenolate mofetil. Long-term follow up was updated through July 1, 2017.Results:We accrued 40 patients to this prospective trial. Baseline features included: median age 58 years (range 29-69), median prior regimens = 6 (range 3 to 12), chemosensitive disease = 6 (15%), CR pretransplant = 0 (0%), bulk >5 cm = 17 cm (range 5.2-18.6cm, 43%), >25% bone marrow involvement with B-NHL = 10 (25%, range of marrow involvement 40-95%), comorbidity score ≥1 = 35 (85%), median comorbiditiy score 3 (range 0-10), pretransplant IPI ≥3 = 21 (53%). Histologies included: indolent (18; CLL/SLL-10, follicular lymphoma-6, hairy cell leukemia-1, and marginal zone lymphoma-1), Diffuse large B-cell (DLBCL, 14), and mantle cell lymphoma (MCL, 8). Patients received HCT from 15 matched related or from 25 matched unrelated donors.Eleven of 40 patients are alive with a median follow up of 9 years (range 5.3-10.2). There were 14 (35%) deaths due to disease progression, and 14 (35%) deaths attributed to complications from HSCT. One patient died of a Merkel cell carcinoma. The median progression-free and overall survival of the entire group was 1.1 years and 2.9 years, respectively (Figure 1). The best outcomes were observed in patients with indolent histology with an estimated 5-year PFS and OS of 44% and 67% respectively (Figure 2). Early CR/PR was achieved by 7/8 (83%) patients with indolent lymphoma, 4/1 (36%) with DLBCL, and 2/2 (50%) with MCL. Long-term PFS was observed in 7 of 15 of patients with indolent NHL and 2 of 4 MCL with early remission. None of the patients with DLBCL were long-term disease free survivors regardless of early remission status. No late complications attributable to RIT (such as secondary myeloid malignancies) were observed in any patient.Conclusions:Long-term disease control of high-risk B-NHL not in CR who underwent NMA-HCT with 90Y-ibritumomab tiuxetan conditioning varied by histology. 90Y-ibritumomab tiuxetan based allografting induced high-early response rates and favorable long-term outcomes in patients with indolent histologies likely based on both the efficacy of RIT and GVL effect in this population. Only early MCL responders to RIT had long term PFS, and none of the DLBCL patients survived regardless of response. Improved strategies are needed for these populations. Our current study escalates the dose of 90Y-ibritumomab tiuxetan prior to NMA-HCT for DLBCL for this purpose. [Display omitted] DisclosuresFlowers:Pharmacyclics: Consultancy. Maloney:Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board; Celgene: Other: Advisory board; Kite Pharmaceuticals: Other: Advisory board. Press:Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Gopal:Seattle Genetics: Consultancy, Research Funding.

Establishment of A Mixed Chimeric Mouse Model of Allogeneic Bone Marrow Transplantation and Its Influencing Factors

To establish a mouse mixed chimerism (MC) model of nonmyeloablative allogeneic bone marrow transplantation(allo-BMT) and explore its affecting factors. The MC model was established by nonmyeloablative allo-BMT followed by high-dose post-transplant cyclophosphamide (PTCY). 123 mice in the experiments was retrospectively analyzed, and the factors related with the chimerism were explored with the univariate and multivariate logistic regression analysis. A multivariate linear regression was performed by R project to obtain a mathematical model for predicting the chimeric level with relevant affecting factors. The model presented mixed chimerism on day 14 after transplantation, and was characterized by a donor lymphocyte infusion (DLI) which significantly promoted donor engraftment on day 15, but transfplantation of PBS in control group was failed. Among 123 mice, 47 (38.21%) mice were MC, while 76 (61.79%) mice were non-MC in 123 mice, respectively; univariate analysis showed that the baseline body weight of mice (P=0.001, 17.84±1.19 g vs 18.50±0.94 g), total body irradiation(TBI，P=0.048) and the using of cyclophosphamide (P=0.16) were affected the chimeric state of mice, while the number of infusing cells and the time of detection showed no significant effects. Multivariate regression analysis showed that under certain conditions, the body weight of mice on day 0 was an independent factor affecting chimeric levels (OR=0.493, 95% CI 0.307-0.791, P=0.003). Through R project multiple linear regression, the math model was achieved, which was chimerism=6.09-12×weight(g)+80.03×TBI(Gy)-4.4×cell-counts (× 107) +0.38×CTX (mg/kg), R2=0.5841, P<0.001. The experiment presents a method for establishing a mixed chimeric mice model after non-myeloablative bone marrow transplantation and constructs a mathematical model with relevant factors affected chimerism status.

The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP.

Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP.Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP.Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327–277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins.Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.

Tregs and Mixed Chimerism as Approaches for Tolerance Induction in Islet Transplantation.

Pancreatic islet transplantation is a promising method for the treatment of type 1 and type 3 diabetes whereby replacement of islets may be curative. However, long-term treatment with immunosuppressive drugs (ISDs) remains essential for islet graft survival. Current ISD regimens carry significant side-effects for transplant recipients, and are also toxic to the transplanted islets. Pre-clinical efforts to induce immune tolerance to islet allografts identify ways in which the recipient immune system may be reeducated to induce a sustained transplant tolerance and even overcome autoimmune islet destruction. The goal of these efforts is to induce tolerance to transplanted islets with minimal to no long-term immunosuppression. Two most promising cell-based therapeutic strategies for inducing immune tolerance include T regulatory cells (Tregs) and donor and recipient hematopoietic mixed chimerism. Here, we review preclinical studies which utilize Tregs for tolerance induction in islet transplantation. We also review myeloablative and non-myeloablative hematopoietic stem cell transplantation (HSCT) strategies in preclinical and clinical studies to induce sustained mixed chimerism and allograft tolerance, in particular in islet transplantation. Since Tregs play a critical role in the establishment of mixed chimerism, it follows that the combination of Treg and HSCT may be synergistic. Since the success of the Edmonton protocol, the feasibility of clinical islet transplantation has been established and nascent clinical trials testing immune tolerance strategies using Tregs and/or hematopoietic mixed chimerism are underway or being formulated.

Infusion of Host-Derived Unlicensed NK Cells Improves Donor Engraftment in Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) is an efficacious and frequently the only treatment option for some hematological malignances. However, it often faces severe morbidities and/or mortalities due to graft versus host disease, and the severity of the conditioning regiment needed, that result in toxicity-related issues poorly tolerable for some patients. These shortcomings have led to the development of less aggressive alternatives like non-myeloablative (NMAC) or reduced-intensity conditioning regiments (RIC). However, these approaches tend to have an increase of cancer relapse and limited persistence of donor-specific chimerism. Thus, strategies that lead towards an accelerated and more durable donor engraftment are still needed. Here, we took advantage of the ability of host-derived unlicensed NK (UnLicNK) cells to favor donor cell engraftment during myeloablative allo-HCT, and evaluated if the adoptive transfer of this cell type can improve donor chimerism in NAMC settings. Indeed, the infusion of these cells significantly increased mixed chimerism in a sublethal allo-HCT mouse model, resulting in a more sustainable donor cell engraftment when compared to the administration of licensed NK cells or HCT controls. We observed an overall increase in the total number and proportion of donor B, NK and myeloid cells after UnLicNK cell infusion. Additionally, the extension and durability of donor chimerism was similar to the one obtained after the tolerogenic Tregs infusion. These results serve as the needed bases for the implementation of the adoptive transfer of UnLicNK cells to upgrade NMAC protocols and enhance allogeneic engraftment during HCT.

Long-term Outcomes with Nonmyeloablative HLA-Identical Related Hematopoietic Cell Transplantation Using Tacrolimus and Mycophenolate Mofetil for Graft-versus-Host Disease Prophylaxis

Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) from HLA-identical related donors using cyclosporine (CSP) and mycophenolate mofetil (MMF) for postgrafting immunosuppression is effective therapy for hematologic cancers. However, graft-versus-host-disease (GVHD) remains a major cause of morbidity and mortality. Pilot data suggested lower acute GVHD incidence with tacrolimus/MMF compared to historical experience using CSP/MMF after nonmyeloablative HCT. In a phase II multicenter trial, we evaluated the effect of tacrolimus/MMF for GVHD prophylaxis after HLA-identical related donor peripheral blood HCT in patients with hematologic malignancies (n=150) using conditioning with 2 Gy total body irradiation (TBI) for patients with a preceding (within 6 months) planned autologous HCT (n=50) or combined with 90 mg/m2 fludarabine for those without recent autologous HCT (n=100). Oral tacrolimus was given from days -3 to 56 (tapered by day +180 if no GVHD). Oral MMF was given from days 0 to 27. Patient median age was 57 (range, 20 to 74) years. The cumulative incidences (CI) of day 100 grade II to IV and III to IV acute GVHD were 27% and 4%, respectively. With median follow-up of 10.3 (range, 3.1 to 14.5) years, the 5-year CI of chronic extensive GVHD was 48%. One-year and 5-year estimates of nonrelapse mortality, relapse/progression, survival, and progression-free survival were 9% and 13%, 35% and 50%, 73% and 53%, and 56% and 37%, respectively. GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute GVHD and compared favorably with results from a concurrent trial using CSP/MMF. A randomized phase III trial to investigate tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT is warranted.

Immune Hemolysis after a Hematopoietic Progenitor Cell Transplantation for Sickle Cell Disease: A Case Report

Background:The incidence of Delayed Hemolytic Transfusion Reaction (DHTR) is 0.04% but is higher in patients with sickle cell disease (SCD). Although it has been reported in hematopoietic progenitor cell (HPC) transplantation, its incidence in SCD following nonmyeloablative HPC transplantation remains unknown. We report a recipient with blood group O who received a nonmyeloablative HPC transplantation with blood group A three years ago. She is now typing as blood group A and developed a DHTR after receiving group A red blood cells (RBC). Case Report:A 42-year-old female was transferred from an outside hospital (OSH) for management of Acute T-Cell Lymphoblastic Leukemia. Three years prior, she received a group A+ matched sibling nonmyeloablative HPC transplantation for SCD. Her original blood group was O+, and she had a history of clinically significant RBC alloantibodies (anti-E, anti-C, anti-Goa, anti-Kell, and anti-Jkb). On admission to OSH (Day 1), the type and screen showed group A+ without ABO discrepancy. The antibody screen was negative. The OSH blood bank was unaware of her immunohematologic history, because it was not communicated to them by the OSH hematologists, and the only documented diagnosis was that of acute leukemia. Per SOP, OSH performed only immediate spin crossmatch. She was transfused three units of A+ RBC at OSH in preparation for her transfer to us on Day 3 (Fig. 1). At admission to our hospital, her laboratory parameters were suggestive of both tumor lysis syndrome and hemolysis. Her type and screen specimen was grossly hemolyzed. She typed as Group A+. The Direct Antiglobulin Test (DAT) was positive with polyspecific antisera, positive for IgG and negative for bound complement factors. Antibody screen was negative except for the anti-Goa. In the eluate, we identified anti-A or anti-A,B, which were not differentiated for lack of clinical implications. Per our request, OSH retrospectively performed a pre-transfusion DAT, which was negative, and an AHG crossmatch of the pre-transfusion sample. The results showed that the RBC transfused at OSH on Day 1 were incompatible (1+) and those transfused on Day 2 after O+ platelet transfusion were compatible (Fig. 1). This confirmed that the eluted antibodies were not passively transferred from the platelet transfusion but were rather isoagglutinins from the patient's own plasma of her original blood type O. Chimerism studies indicted the presence of only 25% donor CD3 and 30% donor myeloid cells. Further studies at our institution confirmed the hemolysis to be due to anti-A/A,B and not anti-Goa. Antibody titers of the patient's plasma with A1 and A2 cells were low (1) and negative, respectively. The titer of the eluate with A1 cells and B cells was 4 and 2, respectively. The crossmatch of the patient's plasma with A1 cells was negative at immediate spin and 37oC but positive at the IgG phase, which explains the negative crossmatch at immediate spin at OSH. We believe that the exposure of the 2 incompatible A+ RBC at OSH prompted an anamnestic response, causing the hemolysis of the transfused RBC. Subsequently, the patient required the transfusion of 3 additional RBC. Due to the presence of positive DAT developed after 24 hours of transfusion (on Day 3), the positive elution test, inadequate rise of post-transfusion Hb level and rapid fall in Hb back to the concentration pre-transfusion (Fig. 1), this reaction is best classified as a definitive DHTR in accordance with the CDC hemovigilance guidelines. Conclusion:This case is a warning for the perfect storm from the combination of HPC transplantation and SCD. Our patient had a history of transplantation for SCD and clinically significant alloantibodies. OSH blood bank was not aware of her immunohematologic history, and she received incompatible RBC units that were crossmatched at immediate spin only. She subsequently developed a DHTR which was clinically significant, requiring blood transfusion. This is a good reminder of the importance of good communication between clinicians and the transfusion services. The need for caution when using electronic crossmatch or immediate spin is also important, especially in this era of transplantation for SCD. The absence of RBC antibodies cannot be assumed when a transfusion history is lacking. Increasing awareness, prevention and early recognition and treatment are essential to avoid the potential fatal complication of hemolytic transfusion reactions. Disclosures No relevant conflicts of interest to declare.

Outcomes of Non-Myeloablative HLA-Haploidentical Bone Marrow Transplant with Thiotepa and Post-Transplant Cyclophosphamide in Children and Adults with Severe Sickle Cell Disease, a Phase II Trial: Vanderbilt Global Haploidentical Transplant Learning Collaborative (VGC2)

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to &amp;gt; 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants. Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules. Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as &amp;lt;5% donor myeloid chimerism or &amp;lt; 5% donor cells by whole blood chimerism by day +42 posttransplant. Secondary graft rejection was defined &amp;lt;5% donor myeloid chimerism or &amp;lt; 5% donor cells by whole blood chimerism with prior documentation of &amp;gt; 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD. Results: We enrolled 41 consecutive participants from 8/14/2014 - 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were &amp;lt;18 years of age. Donors included siblings (14/41, 34%), parents (27/41, 61%), and 88% (36/41) had sickle cell trait. Median TNC dose was 5.8 x 108 /kg (4.2, 8.0), and median CD34+ and CD3+ cell doses were 3.9 x 106/kg (2.6, 6.1) and 32.3 x 108/kg (27.1, 50.8), respectively. A total of 93% of participants engrafted. Median times to neutrophil (&amp;gt; 500/mcL) and platelet (&amp;gt;50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants &amp;lt;18 years of age, and all had autologous reconstitution (Table). Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (&amp;lt; 18 years), and all older participants (&amp;gt; 18 years) engrafted. The trial will add new stopping rules by age strata (&amp;lt;18, &amp;gt; or = to 18 years) and will modify the conditioning regimen in pediatric stratum. Disclosures Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

Nonmyeloablative Allogeneic Stem Cell Transplantation with or without Inotuzumab Ozogamicin for Lymphoid Malignancies

Nonmyeloablative Allogeneic Stem Cell Transplantation with or without Inotuzumab Ozogamicin for Lymphoid Malignancies

CXXC5 variant in an immunodeficient patient with a progressive loss of hematopoietic cells

Partial loss of function variant in CXXC5 identified in an immunodeficient patient with progressive bone marrow failure, corrected by bone marrow transplant.

Nonmyeloablative allogeneic transplantation achieves clinical and molecular remission in cutaneous T-cell lymphoma

AbstractThe majority of patients with refractory, advanced-stage mycosis fungoides (MF) or Sézary syndrome (SS) have a life expectancy of <5 years. Here, we report a phase 2 study of a novel nonmyeloablative allogeneic transplantation strategy tailored for this patient population. This study has completed the enrollment, and 35 patients (13 MF, 22 SS) have undergone transplant as planned. The majority (80%) of the patients had stage IV disease and received multiple previous systemic therapies. All patients had active disease at the time of conditioning using total skin electron beam therapy, total lymphoid irradiation, and antithymocyte globulin, and received allograft infusion as outpatients. Cyclosporine or tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GVHD) prophylaxis. Patients tolerated the transplant well, with 1- and 2-year nonrelapse mortality of 3% and 14%, respectively. The day +180 cumulative incidence of grade 2 to 4 acute GVHD was 16%, and the 2-year incidence of moderate/severe chronic GVHD was 32%. With a median posttransplant follow-up of 5.4 years, the 2-, 3-, and 5-year overall survival rates were 68%, 62%, and 56%. Using high-throughput sequencing of the T-cell receptor for minimal residual disease monitoring, we observed that 43% achieved molecular remission, which was associated with a lower incidence of disease progression or relapse (9% vs 87%; P = .02). Our study also showed that patients who were aged ≥65 years at the time of allotransplant had similar clinical outcomes compared with younger patients. Thus, we have developed an alternative and potentially curative nonmyeloablative allogeneic transplant regimen for patients with advanced stage MF/SS. This trial was registered at www.clinicaltrials.gov as #NCT00896493.

Effects of heterochronic, non-myeloablative bone marrow transplantation on age-related behavioural changes in mice

Experiments using heterochronic parabionts, i.e. young and old animals connected surgically and hence developing a shared circulation, have shown that blood-borne factors, transferred from young to old mice and vice versa, play a role in influencing a range of health outcomes associated with advanced age. Previous work has explored the contributory role of plasma-derived factors in mediating such parabiotic effects, including those on aging-associated neural and behavioural impairments. Here, we wanted to identify possible influences that blood-borne cellular factors may have on age-related behavioural phenotypes. Towards this end, we subjected old BALB/c H-2d mice to repetitive non-myeloablative bone marrow transplants (BMT) from young donor animals and assessed effects on behaviour and cognition. We detected expected age-related alterations in our behavioural assays but did not discern any obvious differences between old BMT mice and old control animals. Our study represents the first to look at possible behavioural and cognitive effects of heterochronic, non-myeloablative BMT. Future work should extend this study by including additional behavioural tests in the analysis, addressing whether beneficial effects of BMT may be detectable on other genetic backgrounds and reconciling our findings with those achieved by myeloablative BMT.

Prospective phase 2 trial of ixazomib after nonmyeloablative haploidentical peripheral blood stem cell transplant

AbstractProteasome inhibition results in extensive immunomodulatory effects that augment natural killer cell cytotoxicity and inhibit aspects of T-cell, B-cell, and dendritic cell function. We performed a phase 2 study that examined the effects of ixazomib for graft-versus-host disease (GVHD) prophylaxis (up to 12 cycles) with posttransplant cyclophosphamide and tacrolimus after standard nonmyeloablative haploidentical donor transplantation (HIDT). Ixazomib was started on day +5 (4 mg on days 1, 8, and 15 of a 28-day cycle), with dose reductions allowed in future cycles for toxicity. All patients received peripheral blood stem cells. Twenty-five patients were enrolled with a median age of 62 years (range, 35-77 years) who had acute leukemia (4), myelodysplastic syndrome (7), non-Hodgkin lymphoma/Hodgkin lymphoma/chronic lymphocytic leukemia (8), and myeloma (6). The hematopoietic cell transplant comorbidity index was ≥3 in 68% of the patients. After a median follow-up of 33.5 months, the cumulative incidence of relapse/progression at 1 year was 24% and 44% at 3 years, which failed to meet the statistically predefined goal of decreasing 1-year risk of relapse. Engraftment occurred in all patients with no secondary graft failure, and 3-year nonrelapse mortality (NRM) was 12%. Cumulative incidence of grade 3 to 4 acute GVHD was 8%, whereas moderate-to-severe chronic GVHD occurred in 19%. Nineteen patients survive with an estimated 1-year overall survival (OS) of 84% and 3-year OS of 74%. Hematologic and cutaneous toxicities were common but manageable. The substitution of ixazomib for mycophenolate mofetil (MMF) post-HIDT results in reliable engraftment, comparable rates of clinically significant GVHD, relapse and NRM, and favorable OS. This trial was registered at www.clinicaltrials.gov as # NCT02169791.

Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America

ObjectiveTo estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS). MethodsWe collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients’ wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively. ResultsOutside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were $85,184 (range $70,635 to $120,260). Mean revenue collected was $95,268 (range $16,544 to $173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged from $80,000 to $100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life. LimitationsCosts of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates. ConclusionCosts of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.

Stable renal function in children and adolescents with sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation.

Sickle cell disease (SCD) is associated with renal complications starting as early as infancy. Allogeneic hematopoietic stem cell transplant (HSCT) treatments using newer nonmyeloablative (NMA) conditioning regimens show promising results in treating SCD in the pediatric population, but renal outcome parameters after transplantation have not been described. To describe baseline renal parameters as well as short- and long-term renal outcomes in pediatric patients with SCD who underwent NMA-HSCT. A retrospective chart review of pediatric patients who received NMA-HSCT in Alberta, Canada. Short-term renal outcomes evaluated were: (1) acute kidney injury (AKI), (2) fluid overload (FO), and (3) hypertension. Long-term outcomes evaluated were: (1) estimated glomerular filtration rate (eGFR) development and at last follow-up with hyperfiltration defined as eGFR≥150mL/min/1.73 m2 , (2) proteinuria, and (3) hypertension. The mean follow-up time was 128.6weeks (standard deviations, 69.3). No posttransplant AKI events or FO were observed. eGFR remained>90mL/min/1.73 m2 at last follow-up in all patients, whereas hyperfiltration was present in eight (44.4%) and four (22.2%) patients pre- and post-HSCT, respectively, which are significantly different (P<0.0001). Consequently, median GFR was significantly higher pre-HSCT compared with 24 months HSCT (P<0.009). Long-term hypertension post-HSCT was present in six patients (33.3%). This study describes stable kidney function in children with SCD after NMA-HSCT without evidence of AKI or FO episodes. Rates of hyperfiltration decreased post-HSCT, which signifies that NMA-HSCT could potentially preserve long-term renal function in this population at risk of progressive chronic kidney disease. Further prospective studies are needed to confirm these novel findings.

Non-myeloablative matched sibling stem cell transplantation with the optional reinforced stem cell infusion for patients with hemoglobinopathies.

The NIH protocol for non-myeloablative (NMA) conditioning allogeneic stem cell transplantation (alloSCT) with alemtuzumab and low-dose total body irradiation corrected the abnormal sickle cell disease (SCD) phenotype without the risk of graft-versus-host disease. However, alloSCT using NMA conditioning had been rarely applied to β-thalassemia major (β-TM) patients. To avoid prolonged immunosuppression, we developed a two-stage strategy. Mixed donor chimerism was initially achieved using the protocol developed by the NIH protocol. Thereafter, we facilitated donor chimerism using the optional reinforced stem cell (SC) infusion in cases requiring protracted immunosuppression or experiencing impending graft failure. In this study, β-TM (n=9) and SCD (n=4) patients were equally effectively treated with eradicating the abnormal hemoglobin phenotype. Five patients, including four β-TM, achieved stable mixed chimerism without receiving optional reinforced SC infusion. All patients that received optional reinforced infusion achieved complete (n=4) or mixed chimerism (n=1). The overall survival rate and event-free survival at 4years were 91.7% (95% CI; 53.9-98.8) in both groups, with a thalassemia-free survival rate in β-TM patients of 87.5% (95% CI; 38.7-98.1). This study is the first to report successful NMA conditioning alloSCT to achieve stable mixed chimerism correcting the abnormal hemoglobin phenotype in adult β-TM patients.

The impact of pre-existing HLA and red blood cell antibodies on transfusion support and engraftment in sickle cell disease after nonmyeloablative hematopoietic stem cell transplantation from HLA-matched sibling donors: A prospective, single-center, observational study.

BackgroundHematopoietic stem cell transplantation (HSCT) is curative for patients with sickle cell disease (SCD). Prior to HSCT, patients with SCD commonly receive RBC transfusions with some becoming RBC or HLA alloimmunized. This alloimmunization may impact post-HSCT transfusion requirements and donor engraftment.MethodsThe study population included patients with SCD transplanted on a single-center nonmyeloablative, HLA-matched sibling HSCT trial at the National Heart, Lung, and Blood Institute (NHLBI) who had a pre-HSCT sample available for HLA class I antibody testing. We evaluated transfusion requirements and engraftment outcomes comparing patients with and without pre-existing HLA and RBC antibodies.FindingsOf 36 patients studied, 10 (28%) had HLA class I antibodies and 11 (31%) had a history of RBC alloantibodies. Up to day +45 post-HSCT, patients with HLA antibodies received more platelet transfusions (median 2.5 vs 1, p = 0.042) and those with RBC alloantibodies received more RBC units (median 7 vs 4, p = 0.0059) compared to respective non-alloimmunized patients. HLA alloimmunization was not associated with neutrophil engraftment, donor chimerism, or graft rejection. However, RBC alloimmunization correlated with a decreased donor T cell chimerism at 1 year (median 24% vs 55%, p = 0.035).InterpretationPre-existing HLA and RBC alloantibodies are clinically significant for patients undergoing HLA-matched nonmyeloablative HSCT. Testing for both HLA and RBC antibodies is important to help estimate transfusion needs peri‑HSCT. The association of lower donor T cell chimerism and pre-existing RBC alloantibodies needs further investigation.FundingNIH Clinical Center and NHLBI Intramural Research Program (Z99 CL999999, HL006007–11) and the Thrasher Research Fund.

Non-Myeloablative Allogeneic Transplantation with Post-Transplant Cyclophosphamide after Immune Checkpoint Inhibition for Classic Hodgkin Lymphoma: A Retrospective Cohort Study.

: Immune checkpoint inhibitors (ICIs) are approved in relapsed classic Hodgkin lymphoma (cHL). The safety and effectiveness of allogeneic blood or marrow transplantation (alloBMT) in ICI-pretreated patients with cHL remain unclear. The aim of this study is to assess outcomes of patients with cHL receiving ICIs before alloBMT using post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis. : We performed a retrospective study of relapsed/refractory patients with cHL undergoing alloBMT with PTCy at Johns Hopkins between November 2004 and September 2019. Engraftment, GVHD incidence, nonrelapse mortality, progression-free survival (PFS), and overall survival (OS) were compared between patients receiving pre-alloBMT ICI or standard salvage chemotherapy. : We identified 105 consecutive relapsed/refractory patients with cHL, of whom 37 (35.2%) received ICIs and 68 (64.7%) received chemotherapy without ICIs (no-ICI) before alloBMT. ICI and no-ICI patients experienced a 3-year estimated OS of 94% versus 78% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.08 to 1.56; P=.17) and a 3-year estimated PFS of 90% and 65% (HR, 0.3; 95% CI, 0.09 to 1; P=.05), respectively. We observed no statically significant difference in the 12-month cumulative incidence of acute grade II to IV GVHD or in the 24-month incidence of chronic GVHD. : ICIs do not increase acute or chronic GVHD incidence compared with salvage chemotherapy. Patients with cHL receiving ICIs prior to alloBMT experienced outstanding PFS and OS. Thus, ICI therapy is safe in patients with cHL when undergoing alloBMT with PTCy and may improve post-alloBMT disease progression and survival.

Hodgkin lymphoma: A 2020 update on diagnosis, risk-stratification, and management.

Hodgkin lymphoma (HL) is an uncommon B-cell lymphoid malignancy affecting 8480 new patients annually and representing approximately 10% of all lymphomas in the United States. Hodgkin lymphoma is composed of two distinct disease entities: classical HL and nodular lymphocyte predominant HL. Nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich HL are subgroups of classical HL. An accurate assessment of the stage of disease in patients with HL is critical for the selection of the appropriate therapy. Prognostic models that identify patients at low or high risk for recurrence, as well as the response to therapy as determined by positron emission tomography (PET) scan, are used to optimize therapy. Initial therapy for HL patients is based on the histology of the disease, the anatomical stage and the presence of poor prognostic features. Patients with early stage disease are typically treated with combined modality strategies utilizing abbreviated courses of combination chemotherapy, followed by involved-field radiation therapy. Patients with advanced stage disease receive a longer course of chemotherapy, often without radiation therapy. However, newer agents including brentuximab vedotin and anti-PD-1 antibodies are now being incorporated into frontline therapy. High-dose chemotherapy (HDCT) followed by an autologous stem cell transplant (ASCT) is the standard of care for most patients who relapse following initial therapy. For patients who fail HDCT with ASCT, brentuximab vedotin, PD-1 blockade, non-myeloablative allogeneic transplant or participation in a clinical trial should be considered.