Unrelated Donor Cord Blood Transplantation Research Articles

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning

BackgroundNo comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. MethodsWe retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. ResultsThe median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III–IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III–IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. ConclusionMMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Non-conditioned cord blood transplantation for infection control in athymic CHARGE syndrome.

CHARGE syndrome is a congenital malformation syndrome caused by heterozygous mutations in the CHD7 gene. Severe combined immunodeficiency (SCID) arises from congenital athymia called CHARGE/complete DiGeorge syndrome. While cultured thymus tissue implantation (CTTI) provides an immunological cure, hematopoietic cell transplantation (HCT) is an alternative option for immuno-reconstitution of affected infants. We aimed to clarify the clinical outcomes of patients with athymic CHARGE syndrome after HCT. We studied the immunological reconstitution and outcomes of four patients who received non-conditioned unrelated donor cord blood transplantation (CBT) at Kyushu University Hospital from 2007 to 2022. The posttransplant outcomes were compared with the outcomes of eight reported patients. Four index cases received CBT 70-144days after birth and had no higher than grade II acute graft-versus-host disease. One infant was the first newborn-screened athymic case in Japan. They achieved more than 500/μL naïve T cells with balanced repertoire 1month post transplant, and survived more than 12months with home care. Twelve patients including the index cases received HCT at a median 106days after birth (range: 70-195days). One-year overall survival rate was significantly higher in patients who underwent non-conditioned HCT than in those who received conditioned HCT (100% vs. 37.5%, p=.02). Nine patients died, and the major cause of death was cardiopulmonary failure. Athymic infants achieved a prompt reconstitution of non-skewing naïve T cells after non-conditioned CBT that led to home care in infancy without significant infections. Non-conditioned CBT is a useful bridging therapy for newborn-screened cases toward an immunological cure by CTTI.

Treatment of Omenn syndrome using multiple immunosuppressive strategies: a case series

Introduction: Omenn syndrome represents a therapeutic challenge as a state of florid immune dysregulation born out of autoreactive oligoclonal T cells due to hypomorphic variants in genes associated with severe combined immunodeficiency (SCID).Aims: To describe the therapeutic strategies used in the care of three patients with Omenn syndrome from 2013 to 2022. All had negative maternal engraftment studies and received immunosuppression to control autoreactive T cells. All patients ultimately received myeloablative conditioning with anti-thymocyte globulin (ATG), busulfan, and fludarabine for transplant. All patients are currently alive and well.Case 1: 2-month-old female with adenosine deaminase (ADA)-deficient SCID on pegylated ADA replacement developed respiratory distress, rash, and diarrhea in the setting of rising CD3+/CD4+/CD45RO+ cell count. Treated with high-dose systemic steroids. Due to continued CD3+ increase, systemic tacrolimus was added. She clinically improved and underwent matched unrelated donor cord blood transplant at 5 months of age.Case 2: A male with RAG1-SCID developed generalized erythroderma and rapidly rising CD3+/CD4+/CD45RO+ cell and absolute eosinophil counts soon after birth. Systemic steroids were given with clinical improvement. With taper of steroid, ATG 1 mg/kg was given. Initially, the absolute lymphocyte count (ALC) improved; however, within 5 days, his rash worsened and ALC rose. This necessitated re-initiation of high-dose steroids and addition of tacrolimus until matched related donor bone marrow transplant (MRD BMT) at 2 months old.Case 3: 9-day-old male with RAG1-SCID developed diffuse maculopapular rash, lymphadenopathy, and elevated memory T cells and eosinophils. Initiated high-dose systemic steroids and cyclosporine A (CSA) with quick clinical improvement. CSA discontinued due to toxicity and rising ALC and eosinophils. Given ATG 3 mg/kg/dose for 4 doses over 2 weeks with pattern of quick drop then rapid rise in ALC. Treated with steroids and tacrolimus until MRD BMT at 2 months old. ConclusionsWe describe consistent disease control with immunosuppression by systemic steroids and tacrolimus prior to transplant and suggest ATG as a potential adjunctive consideration in poorly-controlled disease. A growing body of knowledge and experience in optimal Omenn syndrome treatment strategies is imperative to improving outcomes.

HLA-B leader genotypes in a clinical population.

The -21 dimorphism in the leader sequences of HLA-B exon 1 is associated with risk of graft-versus-host disease (GVHD), relapse and overall survival after unrelated donor hematopoietic cell transplantation (HCT), haploidentical HCT and cord blood transplantation. Consideration of the leader dimorphism in the prospective selection of allogeneic donors for HCT may help to lower risks for patients, but requires understanding of the frequencies of the leader in patients and candidate transplant donors. We defined the frequencies of the HLA-B leader, and its association to HLA-B Bw4/Bw6 and C1/C2 KIR epitopes. Sequence variants of rs1050458 of exon 1 position -21 for 11,126 haplotypes were analyzed from high resolution HLA typing of over 5500 study subjects. HLA typing was performed by TruSight/AlloSeq NGS and analyzed using TruSight/AlloSeq Assign software. HLA-B Bw4/Bw6 and C1/C2 KIR epitopes were defined based on established sequence alignments and nomenclature. Alleles at rs1050458 of HLA-B exon 1 were validated as dimorphic: rs1050458-C or -T variants encoding threonine (T) or methionine (M) at anchor position 2 (P2) of nonameric HLA-B leader peptides, respectfully. No additional variants were observed. Among study subjects, 70% of HLA-B haplotypes encoded T-leader and 30% encoded M-leader sequences. The genotype frequencies of TT, MT, and MM were consistent among patient, related, and unrelated donor groups. The associations of M/T leader, Bw4/Bw6, and C1/C2 enhanced understanding of the Class I features involved in the innate immune response. A population of patients and transplant donors confirms the rs1050458 leader dimorphism and its association with HLA-B Bw4/Bw6 and C1/C2 KIR features.

Abstract 24 Improving Cord Blood Unit Selection and Optimizing Manufacturing of a Unique Cord Blood-Derived Product (DUOC-01)

IntroductionDUOC-01 are microglia-like cells derived from umbilical cord blood CD14-positive monocytes, which have been shown to induce remyelination in murine models of demyelination. Intrathecal DUOC-01 administration is being tested clinically in two phase I studies. First, DUOC-01 is being tested as a bridging therapy for pediatric patients with inherited leukodystrophies undergoing unrelated donor cord blood transplantation. Second, DUOC-01 is being tested in a phase Ia dose escalation study in patients with primary progressive multiple sclerosis.ObjectiveDUOC-01 is manufactured from an HLA-matched cryopreserved cord blood unit (CBU). The CBU is thawed and cultured for 21 days under specific conditions, and the resulting DUOC-01 is harvested and formulated with hydrocortisone for intrathecal administration. Cell dosing per patient is limited by DUOC-01 yield, which is highly variable; therefore, there is great need to increase DUOC-01 yield and optimize manufacturing for more consistency.Methods(1) For the identification of optimal CBU selection, units are screened using small scale DUOC-01 cultures derived from CBU bag segments, which are then scored (0-4). In order to assess the value, we performed screening followed by DUOC-01 manufacturing and correlated the screening score to the DUOC-01 yield. (2) We assessed multiple variables to optimize DUOC-01 manufacturing including media volume and temperature, fetal bovine serum (FBS) lot variability, and culture container material.Results(1) 5/13 segments scored high (defined as ≥2) while the remaining 8/13 scored low (<2). All 5 high-scored CBUs resulted in high yield (defined as ≥1.64 total cells/cm2). Of the 8 low-scored segments, 4 were low yield and 4 were high yield. (2) Comparison of different FBS lots did not show a significant change in DUOC-01 yield. Furthermore, media volume and temperature did not influence product yield. The choice of container material substantially impacted culture yields and cell viability (Figure 1).Figure 1Choice of tissue culture flasks affects DUOC-01 cell yields and viabilities. (A): Average live yield comparison of harvested cells. (B): Average cell viability comparison of harvested cells. Each color/symbol represents the same source umbilical cord blood (paired, n varies from 1 to 4). Bars show means. Statistical analysis was performed by paired T test.DiscussionIn order to increase cell yield and improve product consistency, we confirmed the value of the CBU segment screening assay and discovered the potential importance of culture container material. More experiments are needed to optimize and finalize product manufacturing.

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

Review of Unrelated Donor Cord Blood Transplantation in Children over the Past 3 Decades

NK cell therapy for hematologic malignancies.

Natural killer (NK) cells are part of the innate immune system and represent the first line of defense against infections and tumors. In contrast to T cells, NK cells do not require prior antigen sensitization to induce cytotoxicity and do not cause graft-versus-host disease. These, along with other advantages, make NK cells an attractive candidate for adoptive cellular therapy. Herein, we describe the mechanisms of NK cell cytotoxicity, which is governed by an intricate balance between various activating and inhibitory receptors, including the killer cell immunoglobulin-like receptors (KIRs). We illustrate the advantages of NK alloreactivity as demonstrated in various types of hematopoietic stem cell transplants (HSCT), such as haploidentical, human leukocyte antigen-matched related or unrelated donor and umbilical cord blood transplant. We elaborate on different models used to predict NK cell alloreactivity in these studies, which are either based on the absence of the ligands for inhibitory KIRs, presence of activating NK cell receptors and KIR genes content in donors, or a combination of these. We will review clinical studies demonstrating anti-tumor efficacy of NK cells used either as a stand-alone immunotherapy or as an adjunct to HSCT and novel genetic engineering strategies to improve the anti-tumor activity of NK cells.

Clonal Deletion and Anergy Play Dominant Role To Achieve Immune Tolerance After Reduced Intensity Unrelated Donor Cord Blood Transplantation (UCBT)

Abstract The mechanism of immune tolerance after successful hematopoietic stem cell transplantation is not fully understood. Both central (clonal deletion) and peripheral (anergy, Treg, Tr1) mechanisms are conceivable and may even coexist. In this study, we set up serial experiments to test for the presence and relative contribution of these mechanisms after HLA-mismatched UCBT in the GvH direction. Nine patients (age 1m to 9y) were transplanted and enrolled on a clinical trial (NCT01852370). Five immunocompetent patients were off immunosuppression therapy (IST) with no GVHD, while 4 had either limited or recently resolved GvHD and were still on IST when studied. Donor T cell chimerism was a median 97%. Purified T cells responses to host APCs were measured by MLR (3HTdR) and CTL reaction (Europium assay), along with cytokine secretion profiling (Bioplex). Host-reactive T cell clones were tracked with TCRVβ repertoire by ImmunoSEQ® (Adaptive Biotech). In tolerant patients, there was no significant MLR or CTL response towards host APC. Similarly, cytokine profiles revealed non-responsiveness while T cells responded vigorously to 3rd party APC by all assays. Recipient-specific T cell clones that were identified from infused UCB stimulated by host APC pre-UCBT became undetectable. There was no indication of Treg or Tr1 cell involvement in sustaining tolerance as deletion by IL-2 immunotoxin or IL-10R blockade was unable to “break” tolerance. However, low dose IL-2 (5U/mL) was able to restore some proliferation (S.I.=19; p=0.05) and IL-13, IFNγ, TNFα secretion, but in lesser degree in comparison to 3rd party responses (S.I.=112). In summary, clonal deletion and anergy contribute to immune tolerance after UCBT with deletion being dominant.

126 - Effect of cryopreservation methodology on neutrophil and platelet engraftment in unrelated donor cord blood transplantation

126 - Effect of cryopreservation methodology on neutrophil and platelet engraftment in unrelated donor cord blood transplantation

36 - Clonal Deletion Plays a Major Role to Achieve Tolerance after Reduced Intensity Unrelated Donor Cord Blood Transplantation

36 - Clonal Deletion Plays a Major Role to Achieve Tolerance after Reduced Intensity Unrelated Donor Cord Blood Transplantation

228 - Incidence, Severity, Day 100 Treatment Efficacy and Therapy Toxicity of Cytomegalovirus (CMV) Infections with Early Pre-Emptive Therapy in Adult Cord Blood (CB) Transplant Recipients

Abstract Introduction: Unrelated donor CB transplantation (CBT) is effective therapy for patients (pts) with high-risk hematologic malignancies without suitable adult donors. CBT, however, can be complicated by CMV infection in seropositive recipients with viremia rates as high as 100%. Moreover, CMV infection is associated with increased transplant-related mortality (TRM) in some reports. Therefore, our center is investigating: 1) the efficacy of pre-transplant ganciclovir (GAN) prophylaxis, 2) the efficacy of early pre-emptive therapy based on frequent serial qPCR monitoring, & 3) anti-viral therapy toxicities. The aim of this strategy is to rapidly eradicate viremia & thereby prevent disease without prohibitive toxicity. Methods: Eligible pts were adult CMV seropositive 1st allograft CB recipients transplanted 3/2013-2/2016. Pts received Cy 50/Flu 150/Thio 5-10/TBI 400 cGy myeloablative conditioning + CSA/MMF (no ATG). GAN prophylaxis (5 mg/kg IV daily) was given days -7 to -2. Viremia was evaluated by qPCR (lower detection limit 137 copies/ml) twice weekly from day +14 or earlier if indicated. Treatment for viremia was usually initiated at 1st or 2nd qPCR positivity. Foscarnet (FOS), GAN or valganciclovir (VALGAN) dosing (maintenance vs induction) was selected based on viremia level & assessment of severe infection vs toxicity risk. CMV disease was treated with induction dosing. CMV response was defined as 3 consecutive negative qPCR & no evidence of disease. Results: 42 CBT recipients [median 51 years (range 23-66), 33 acute leukemias, 6 MDS/MPD, 3 lymphomas] received double unit grafts [median donor-recipient HLA-allele match 5/8 (range 2-7/8) & infused CD34+ cell dose 1.3 (range 0.2-3.2) x 105/kg/unit]. 98% of pts engrafted (1 graft failure unrelated to CMV) & 86% (26 gr. II, 7 gr. III, 3 gr. IV) had gr. II-IV aGVHD by day 100 (median onset 29 days, range 19-35). Of the 42 pts, 35 reactivated CMV in the first 100 days [median viremia onset 33 days (range 5-74) & median viral load at 1st detection Conclusion: CMV infection is very frequent in adult seropositive CBT recipients & pre-CBT GAN is not effective prophylaxis. Early intensive monitoring permits early pre-emptive therapy which is effective in most pts. While maintenance dosing is effective in some, the development of lethal CMV pneumonia in 2 maintenance pts suggests dose escalation may be appropriate if rapid viremia eradication is not achieved. However, FOS/GAN/VALGAN toxicities are also significant. Ultimately, the optimal drug dosing to enhance efficacy but mitigate toxicity, how to predict pts at greatest risk of disease, appropriate therapy duration, & how to predict recurrence risk are not known. Improved CMV prophylaxis & therapy for allograft recipients including CBT pts are needed. Download : Download high-res image (281KB) Download : Download full-size image Download : Download high-res image (147KB) Download : Download full-size image Disclosures No relevant conflicts of interest to declare.

Clonal Deletion Plays a Major Role to Achieve Immune Tolerance after Reduced Intensity Unrelated Donor Cord Blood Transplantation (UCBT)

Generation of tolerance to transplanted hematopoietic cells or organs is essential if elimination of immunosuppressive therapy (IST) is desired. Immune tolerance is the expected outcome after successful hematopoietic stem cell transplantation (HSCT). It is characterized byimmunocompetencewithout any alloreactivity (GVHD) in the absence of IST. However, the mechanism(s) required to prevent alloreactivity are not fully understood. Both central (clonal deletion) and peripheral (anergy, suppression byTreg, Tr1) mechanisms are suspected. In this study, we set up serial experiments to test for these mechanisms after unrelated donor cord blood transplant (CBT) in theGvHdirection. We also studied these mechanisms at the time of GVHD.Methods:Seven patients (age range from 1m to 9y) with non-malignant diseases were transplanted and studied for host-specific alloreactivity following reduced intensity conditioning (RIC) regimen (NCT01852370) that also utilizedAlemtuzumab(1.2mg/kg) ~ 2 weeks prior to UCBT. Five of the patients were off immunosuppression therapy when blood was drawn (6 -12 months after UCBT) while two were not and had either limited chronic GVHD or recently resolved acute GVHD. Donor T cellchimerismat the time of blood draw was a median 97% (range 87-100%). Purified T cell responses to host APC (EBV-LCL for EBV seronegative patients, or monocyte derived DC) were measured by mixed lymphocyte reaction (MLR) and cytotoxic lymphocyte (CTL) reaction after 5 or 7 days in culture, respectively. Th1/Th2/Th17 cytokines along with IL-10 secreted during MLR were quantified from day 5 supernatant by bio-plexassay. To track host-reactive T cell clones, TCRbrepertoire was monitored and quantitated using targeted amplification of rearranged TCR genes followed by high-throughput sequencing (Adaptive Biotechnologies®). The data was analyzed withImmunoSEQ® Analyzer Software. To further identify the key mechanism(s) of tolerance, we attempted to break tolerance by inhibiting or amplifying putative pathways using the following methods: Regulatory T cell (Treg) deletion was achieved byDenileukindiftitox(Ontak) treatment prior to MLR and CTL reactions. Involvement of Tr1 or anergy was examined either by blocking IL10R or by adding low dose IL2, respectively.Results and Discussion:Patients with clinical tolerance (n=5): There was no significant proliferative or cytotoxic T cell response towards recipient APC while T cells responded vigorously to 3rd party APC (Fig 1, 2). Similarly, Th1/Th2/Th17 cytokine profiles revealed recipient-specific non-responsiveness by both proliferation and cytokine secretion (Fig 1A,B) fulfilling a critical tenet of tolerance in three independent assays (MLR, CTL, cytokine secretion). In addition, tracking TCRb clonal profiles withImmunoSEQ® revealed the disappearance of recipient-specific T cell clones that were amplified from the cord blood graft itself by 7 days of stimulation with purified host APC (labeled pre-UCBT in Fig 1.C). There was no indication ofTreg or Tr1 involvement in sustaining tolerance since neither deletion ofTregs by IL-2 IT, nor IL-10R blockade had any impact on T cell hypo-reactivity in MLR, CTL, andbioplex assays. Interestingly, addition of IL-2 in MLR did enhance T cell proliferative responses in 1 out of 5 tolerant patients tested, but did not activate host-specific CTL responses. Nevertheless, here we can not exclude the possibility ofanergy playing some role in preventing host-specific alloreactivity.Patients with GvHD at time of examination: T cells isolated from patients with recently resolved or still active limited chrGVHD receiving some IST (n=2) did proliferate against recipient APC in MLR, but were not cytotoxic against host APC (Fig 3). IL-2 and IL-13 secretion towards host APC was detectable in both (data not shown).In summary, the rapid acquisition of immune tolerance in theGvH direction post-UCBT on our prospective RIC clinical trial is characterized by hypo-reactivity in all assays employed towards host APC. The proliferation, cytotoxicity, and TH1/TH2, TH17 cytokine secretion data suggest that host-specific clonal deletion is a significant mechanism of tolerance in most if not all patients. In one, there is possibility foranergy as exogenous low dose IL-2 was able to overcome absent proliferation by MLR, while having no impact on host-reactive CTL activity or TH1/TH2/Th17 cytokine secretion. DisclosuresNo relevant conflicts of interest to declare.

Incidence, Severity, Day 100 Treatment Efficacy and Therapy Toxicity of Cytomegalovirus (CMV) Infections with Early Pre-Emptive Therapy in Adult Cord Blood (CB) Transplant Recipients

Introduction: Unrelated donor CB transplantation (CBT) is effective therapy for patients (pts) with high-risk hematologic malignancies without suitable adult donors. CBT, however, can be complicated by CMV infection in seropositive recipients with viremia rates as high as 100%. Moreover, CMV infection is associated with increased transplant-related mortality (TRM) in some reports. Therefore, our center is investigating: 1) the efficacy of pre-transplant ganciclovir (GAN) prophylaxis, 2) the efficacy of early pre-emptive therapy based on frequent serial qPCR monitoring, & 3) anti-viral therapy toxicities. The aim of this strategy is to rapidly eradicate viremia & thereby prevent disease without prohibitive toxicity.Methods: Eligible pts were adult CMV seropositive 1st allograft CB recipients transplanted 3/2013-2/2016. Pts received Cy 50/Flu 150/Thio 5-10/TBI 400 cGy myeloablative conditioning + CSA/MMF (no ATG). GAN prophylaxis (5 mg/kg IV daily) was given days -7 to -2. Viremia was evaluated by qPCR (lower detection limit 137 copies/ml) twice weekly from day +14 or earlier if indicated. Treatment for viremia was usually initiated at 1st or 2nd qPCR positivity. Foscarnet (FOS), GAN or valganciclovir (VALGAN) dosing (maintenance vs induction) was selected based on viremia level & assessment of severe infection vs toxicity risk. CMV disease was treated with induction dosing. CMV response was defined as 3 consecutive negative qPCR & no evidence of disease.Results: 42 CBT recipients [median 51 years (range 23-66), 33 acute leukemias, 6 MDS/MPD, 3 lymphomas] received double unit grafts [median donor-recipient HLA-allele match 5/8 (range 2-7/8) & infused CD34+ cell dose 1.3 (range 0.2-3.2) x 105/kg/unit]. 98% of pts engrafted (1 graft failure unrelated to CMV) & 86% (26 gr. II, 7 gr. III, 3 gr. IV) had gr. II-IV aGVHD by day 100 (median onset 29 days, range 19-35). Of the 42 pts, 35 reactivated CMV in the first 100 days [median viremia onset 33 days (range 5-74) & median viral load at 1st detection < 137 copies/mL (range < 137-245)] for a day 100 cumulative incidence of 83% (95%CI 67-92). Of 31 pts with both CMV & aGVHD, 15 developed viremia prior to & 16 after aGVHD onset. The median time from CMV detection to therapy initiation was 3 days (range 0-39). Treatment dosing, viremia vs disease & responses are shown (Figure). Induction dosing was given to one third of pts (n = 11). These pts started therapy later in their transplant course & predominantly received VALGAN. By day 100, just over half cleared viremia but none developed disease. Two-thirds of pts (n = 24) were started on maintenance dosing. They required therapy earlier post-CBT & most received FOS. 10 of these pts cleared viremia by day 100 although GI CMV disease developed in 1 pt after early therapy cessation. This pt was then successfully treated. Notably, half of the maintenance pts required escalation to induction due to persistent viremia in 10 or development of CMV pneumonia in 2 pts. The 2 pneumonia pts developed disease 26 & 12 days post-therapy initiation, respectively, & their peak viremias were 1,330 & 613 IU/ml, respectively. Both pts died of CMV & constituted 2/4 TRM deaths by day 100 in the study (other deaths were 1 DAH & 1 grade IV aGVHD). We then examined therapy toxicity in the first 100 days (Table). 4 pts received only FOS, 10 only GAN/ VALGAN, & 21 had courses of each. Therapy switches were due to toxicity, inadequate response, or convenience of oral VALGAN & therapy duration was highly variable according to infection severity, concurrent GVHD therapy, speed of viremia clearance & tolerance of drug toxicities. One-third of FOS pts & over half of GAN/ VALGAN pts had clinically significant toxicities.Conclusion: CMV infection is very frequent in adult seropositive CBT recipients & pre-CBT GAN is not effective prophylaxis. Early intensive monitoring permits early pre-emptive therapy which is effective in most pts. While maintenance dosing is effective in some, the development of lethal CMV pneumonia in 2 maintenance pts suggests dose escalation may be appropriate if rapid viremia eradication is not achieved. However, FOS/GAN/VALGAN toxicities are also significant. Ultimately, the optimal drug dosing to enhance efficacy but mitigate toxicity, how to predict pts at greatest risk of disease, appropriate therapy duration, & how to predict recurrence risk are not known. Improved CMV prophylaxis & therapy for allograft recipients including CBT pts are needed. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Unrelated Donor Marrow (BMT) or Cord Blood Transplantation (UCBT) for Thalassemia Major after Reduced Intensity Conditioning (URTH Trial Extension)

Unrelated Donor Marrow (BMT) or Cord Blood Transplantation (UCBT) for Thalassemia Major after Reduced Intensity Conditioning (URTH Trial Extension)

Outcomes of Second Unrelated Donor Cord Blood Transplants (UCBT) Performed in Children with Graft Failure of Autologous Recovery Following the First UCBT

Outcomes of Second Unrelated Donor Cord Blood Transplants (UCBT) Performed in Children with Graft Failure of Autologous Recovery Following the First UCBT

Unrelated donor cord blood transplantation for non‐malignant disorders in children and adolescents

This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant diseases. Sixty-five patients were evaluated in this study: SAA (n = 24), iBMFS, (n = 16), and primary immune deficiency/inherited metabolic disorder (n = 25). The CI of neutrophil recovery was 73.3% on day 42. By day 100, the CI of acute grade II-IV graft-versus-host disease was 32.3%. At a median follow-up of 71 months, five-yr OS was 50.7%. The survival rate (37.5%) and CI of neutrophil engraftment (37.5%) were lowest in patients with iBMFS. Deaths were mainly due to infection, pulmonary complications, and hemorrhage. In a multivariate analysis, the presence of >3.91 × 10(5) /kg of infused CD34 + cells was the only factor consistently identified as significantly associated with neutrophil engraftment (p = 0.04) and OS (p = 0.03). UCBT using optimal cell doses appears to be a feasible therapy for non-malignant diseases in children and adolescents for whom there is no appropriate HLA-matched related donor. Strategies to reduce transplant-related toxicities would improve the outcomes of UCBT in non-malignant diseases.

Higher Mycophenolic Acid (MPA) Trough Levels Result In Lower Day 100 Severe Acute GVHD Without Increased Toxicity In Double-Unit Cord Blood Transplantation (CBT) Recipients

BackgroundMycophenolate mofetil (MMF) is frequently combined with cyclosporine-A (CSA) as immunosuppression in unrelated donor CBT. Recent evidence suggests that therapeutic drug monitoring of mycophenolic acid (MPA), the active metabolite of MMF, is advisable based on intra- and inter-patient variability of MMF pharmacokinetics. Moreover, an increased incidence of acute graft-versus-host disease (aGVHD) has been associated with low unbound MPA AUCs in hematopoietic stem cell transplantation. This is highly relevant in cord blood transplantation (CBT) as aGVHD is a leading cause of transplant-related morbidity and mortality. However, as AUCs are cumbersome, a limited pharmacokinetic parameter such as MPA troughs would be ideal. Additionally, the toxicity associated with MPA trough levels is not established and is of concern in CBT especially due to the theoretical risk of myelosuppression from high MPA levels. MethodsWe evaluated the association between serial (weeks 1-6) total MPA serum trough levels and transplant outcomes in pediatric and adult recipients of double-unit CB grafts. Patients were transplanted between 8/2009 and 11/2012 for hematologic malignancies with 4-6/6 HLA-A,-B antigen, -DRB1 allele donor-recipient matched units and intravenous CSA/MMF was commenced on day -3. To evaluate the association between trough levels and outcomes, the trough levels were dichotomized into < 2 mcg/mL and ≥ 2 mcg/mL for toxicity (neutrophil and platelet engraftment, gastro-intestinal toxicity as measured by TPN duration, and CMV infection) at each time point. For the efficacy (aGVHD prevention) analysis, mean week 1 and 2 trough levels were split at < 0.5 versus ≥ 0.5 mcg/mL. ResultsEighty-three patients (median age 44 years, range 1-71) had MPA serum trough levels drawn weekly for the first 6 weeks after CBT. Sixty-nine (83%) received myeloablative (MA) conditioning and 45 (54%) were CMV seropositive. Diagnoses included acute leukemia (n = 51), myeloproliferative disorders/MDS (n = 7), or lymphoma (n = 25). Median trough levels by week were 0.9, 0.9, 0.6, 0.6, 0.9 and 1.3 mcg/mL. The increase in trough levels over time reached significance (p = 0.03). Recipients of MA conditioning had lower MPA troughs than those who received non-myeloablative conditioning (p = 0.02). Younger age (0-15 years old) was associated with lower trough levels (p = 0.002). By time dependent Cox regression analysis, there was no association between trough levels and toxicity as measured by speed and success of neutrophil engraftment, duration of TPN in myeloablative CBT recipients, or time to CMV viremia in seropositive patients. However, MA CBT recipients with a MPA trough ≥ 2 mcg/mL had enhanced platelet recovery (p = 0.005). In a competing risk 2-week landmark efficacy analysis, there were no differences in rates of grade II-IV aGVHD (61% vs 57%, p = 0.52) according to trough level. However, patients with a low MPA trough early post-CBT had nearly triple the incidence of severe (grade III-IV) aGVHD (27.8% vs 9.5%, p = 0.06, Figure 1). ConclusionsThis analysis suggests that higher total MPA serum trough levels are safe from the standpoint of toxicity and may protect against severe aGVHD. The beneficial effect on platelet engraftment was unexpected but may be explained by a lower incidence of severe aGVHD. Prospective investigation of the utility of MPA trough measurements, and ultimately intervention based on drug monitoring in a larger CBT series is warranted.▪ Disclosures:No relevant conflicts of interest to declare.

Alternative Donor Hematopoietic Transplantation For Patients Older Than 50 Years With AML In First Complete Remission: Unrelated Donor and Umbilical Cord Blood Transplantation Outcomes

Post-remission allogeneic transplantation is increasingly used for treatment of the high-risk acute myeloid leukemia (AML) affecting older adults. We analyzed 740 adults over age 50 with AML in first complete remission (CR1) to compare the effectiveness of volunteer unrelated donor (URD) and umbilical cord blood (UCB) graft sources in providing a successful transplant. For prospective cases reported (2005-2010) to the Center for International Blood and Marrow Transplant Research and Eurocord, we evaluated 8/8 HLA allele matched (at HLA-A, -B, -C, -DRB1) n=441; 7/8 matched URD n=94 and UCB n=205 for the outcomes of engraftment, treatment related (non-relapse) mortality (TRM), relapse, leukemia free survival (LFS) and overall survival (OS) using the cumulative incidence and Kaplan-Meier estimators and multivariate Cox regression modeling. Patient age (median 58, range 50-75), gender and CMV serostatus were similar across the treatment groups. However, UCB recipients were less likely to achieve CR within 8 weeks, more likely to report Intermediate and unfavorable risk cytogenetics, more likely to receive reduced-intensity conditioning compared to myeloablative conditioning regimens, and receive cyclosporin rather than tacrolimus-based GVHD prophylaxis.After a median follow-up of 50, 61 and 37 months in 8/8 URD, 7/8 URD and UCB grafts, neutrophil and platelet recovery was slower in UCB compared to URD recipients; the day-42 incidence of neutrophil recovery in UCB recipients was 85% compared to 98% and 92% in 8/8 and 7/8 URD recipients. While there were no significant differences in rates of grade II to IV acute GVHD (35%, 36% and 44% in UCB, 8/8 URD and 7/8 URD recipients respectively), the 3-year incidence of chronic GVHD was significantly lower in UCB recipients (28% compared to 53% and 59% in 8/8 and 7/8 URD recipients. Compared to 8/8 URD transplants, multivariate analysis confirmed higher TRM after transplantation of UCB grafts, but only in the first 3 months (HR 2.83, p<0.0001) with similar risks thereafter (HR 1.00, p=0.99). Compared to 8/8 URD transplants, TRM was higher after 7/8 URD transplants (HR 1.73, p=0.005). There were no significant differences in relapse risks between the three groups; compared to 8/8 URD transplants, relapse risks after UCB and 7/8 URD transplants were HR 1.15, p=0.36 and HR 0.86, p=0.47, respectively. These hazards yielded higher adjusted 3-year LFS after 8/8 URD (39% [95% CI 34%-43%]) compared to 7/8 URD (34% [95% CI 24%-43%]) and UCB transplants (28% [95% CI 22%-35%]), p=0.015) and adjusted 3-year OS of 43% (95% CI 38%-48%), 37% (95% CI 27%-46%) and 30% (95% CI 23%-37%), respectively (p=0.003). Relapse risks were greater in patients with intermediate or unfavorable risk cytogenetics, independent of graft type and leukemia-free and overall survival were also worse in patients with unfavorable risk cytogenetics and in patients over age 60. For the older population with AML, allotransplantation in CR1 can provide extended leukemia-free survival for 30%-43% of patients using any of these graft sources. While 8/8 URD transplants are preferred for patients who can promptly obtain a well-matched URD, for ethnic or racial minorities, UCB grafts provide a meaningful chance of extended LFS, even though nearly all UCB grafts are HLA mismatched.Additionally, the rapid availability of UCB provides effective therapy for older patients with expected short initial remissions: settings where ongoing consolidation therapy has not been effective in limiting risks of relapse. Later TRM and relapse rates were similar, lower risks of chronic GVHD and the need for long-term immunosuppression and its morbidities may be of particular value for these older patients. These encouraging results suggest that allotransplantation need not be withheld from older patients and for clinically suitable AML patients, can produce extended and even curative long-term survival. Disclosures: GluckmanCord use: Honoraria; gamida: Honoraria.

Primary research on unrelated double umbilical cord blood transplantation and implantation kinetics

ObjectiveThis study sought to examine implantation and implantation kinetics in double umbilical cord blood transplantation (DUCBT).MethodsTwenty-nine patients who underwent a two-unit unrelated donor cord blood transplantation were included in this study. After transplantation, hematopoietic chimerism of the peripheral blood was evaluated based on the results of short tandem repeat polymerase chain reaction. Using these results, we were able to judge whether the transplanted cells implanted, determine which donor's cells implanted, and further examine the kinetics of implantation in DUCBT. The numbers of total nucleated cells (TNCs), CD34+ cells, colony forming units (CFUs), colony forming unit-granulocytes and macrophages (CFU-GMs), and CD3+ cells were compared between the dominant units and the non-dominant units in an attempt to understand the discipline and implantation kinetics of DUCBT.ResultsNeither the TNC counts nor the counts of CD34+ cells, CFU, CFU-GM, or CD3+ cells were significantly different between the dominant units and the non-dominant units (P values of 0.584, 0.322, 0.842, 0.534, and 0.082, respectively).ConclusionsWe were able to determine the engraftment status at 14 days after DUCBT, although the implantation kinetics of DUCBT remain uncharacterized and require further research.

Similar Overall Survival Using Sibling, Unrelated Donor, and Cord Blood Grafts after Reduced-Intensity Conditioning for Older Patients with Acute Myelogenous Leukemia

For older patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) provides the best chance of long-term survival. A formal comparison between matched sibling (SIB), unrelated donor (URD), or umbilical cord blood (UCB) transplantation has not yet been reported in this setting. We compared reduced-intensity conditioning HCT in 197 consecutive patients 50 years and older with AML in complete remission from SIB (n = 82), URD (n = 35), or UCB (n = 80) transplantation. The 3-year cumulative incidences of transplantation-related mortality were 18%, 14%, and 24% with SIB, URD, and UCB transplantation, respectively (P = .22). The 3-year leukemia-free survival rates were 48%, 57%, and 33% with SIB, URD, and UCB transplantation, respectively (P = .009). In multivariate analysis, poor-risk cytogenetics was associated with relapse (hazard ratio, 1.7 [95% confidence interval, 1.0 to 3.0]; P = .04) and worse leukemia-free survival (hazard ratio, 1.6 [95% confidence interval, 1.0 to 2.5]; P = .03), whereas donor choice had no significant impact on overall survival (P = .73). Adjusted 3-year overall survival rates were 55% with SIB, 45% with URD, and 43% with UCB transplantation (P = .26). Until prospective studies are completed, this study supports the recommendation to consider SIB donor, URD, or UCB for HCT for older patients with AML in complete remission.