Double-unit Cord Blood Transplantation Research Articles

An Analysis of the Correlation between Gastro-Intestinal (GI) Symptoms, Macroscopic Appearance, Histology & Acute Gvhd (aGVHD) Treatment Responses in Cord Blood Transplant (CBT) Recipients: Significant Implications for aGVHD Management

Background GI symptoms are common after CBT & GI aGVHD is frequent. The correlation between symptoms, macroscopic appearance (macro), histology, aGVHD severity & therapy response, however, is not established. Methods We analyzed 1st endoscopies done days +21-180 in engrafted adult double unit CBT recipients transplanted 10/2009-12/2017 with Cy 50/ Flu 150/ Thio 5-10/ TBI 400 & CSA/ MMF. All patients (pts) received fungal prophylaxis, early CMV pre-emptive therapy & C. difficile/ viral PCR stool assays (& blood for adenovirus) were routinely performed. Abnormal histology was defined as mild (grade 1-2) vs severe (grade 3-4). Results Of 156 pts, 88 pts (56%) [median 49 years (range 22-66), 65 leukemia, 5 MDS/ MPD, 18 NHL/ HL] were scoped. Their median donor-recipient HLA-allele match was 5/8 (range 3-7) & 36 (38%) pts also received haplo-CD34+ cells. Pts had 44 upper, 2 lower & 42 combined upper/ lower scopes at a median of 52 days (range 22-176) post-CBT. Of 86 pts who had upper scopes (Table 1), 67/86 (78%) were treated for upper GI aGVHD & only 3 had infection (Figure). The majority (51/67,76%) of aGVHD treated pts had normal macro appearance & the majority (49/67, 73%) had aGVHD compatible histology (typically apoptotic epithelial cells, mild in all but 2). Overall, the majority of treated pts (48/67, 72%) had a day 28 CR (37 budesonide, 11 high dose corticosteroids). Of 18 treated pts with normal macro & histology, 11 had CR & 7 PR. Nearly all (40/44, 91%) pts who had lower GI scopes (Table 2) were treated for aGVHD & none had infection (Figure). Most (33/40, 83%) were stage I-II ( Conclusions With pre-emptive CMV therapy, yeast prophylaxis, & stool PCR studies, the majority of CBT pts who required endoscopies had aGVHD & infection was very rare. This was especially true in pts with diarrhea. Normal mucosal appearance was frequent in aGVHD treated pts & nearly all pts with diarrhea & abnormal macro had aGVHD. Most had aGVHD compatible histology (usually mild). Notably, 9/23 treated pts with normal histology only had a PR supporting aGVHD is a clinical diagnosis. Moreover, pts with severe histologic abnormality were at high risk for PR/ refractory disease. This data supports early corticosteroid therapy if aGVHD compatible symptoms & not waiting for biopsy results. This is critical in pts with diarrhea. Correlation of this data with serum biomarkers & microbiota to improve the efficiency of diagnosis & risk stratification are needed.

Adult Cord Blood Transplantation (CBT) Recipients Have a High Incidence of Early Acute Kidney Injury (AKI) and AKI Increases Long-Term Chronic Kidney Disease (CKD) Risk

Introduction While adult double unit CBT (dCBT) has disease-free survival comparable to that of HLA-matched adult donor allografts, frequent patient (pt) comorbidities combined with chemotherapy/TBI & cyclosporine-A (CSA) contribute to AKI risk. Using KDIGO criteria, we analyzed renal injury incidence & risk factors in adults undergoing dCBT. Methods Adult dCBT pts transplanted 2006-2016 for hematologic malignancies using Cy/ Flu/ Thio/ TBI 400 cGy & CSA (therapeutic range 250-450)/ MMF were analyzed. Using day 0 - 100 creatinines, maximum grade (gr.) AKI [gr. 1 (1.5 - 3-fold baseline)] was calculated. If pts had multiple episodes, the highest grade was analyzed. The 2-yr CKD incidence (> 90 days of GFR Results 153 pts [median 51 years (range 23-65), 114/153 (75%) acute leukemia, 27/153 (18%) African, 88/153 (58%) CMV seropositive] were transplanted. No patient had chronic kidney disease pre-dCBT; 32/153 (21%) had hypertension & 12/153 (8%) were diabetic. Median aaHCT-CI was 3 (range 0-9) with 92/153 (60%) pts having a score > 3. 34 (22%) pts had High-Very High rDRI diagnoses. Median pre-dCBT albumin was 4 (range 2.6 - 5.2). 96% of pts engrafted, 76% had grade II-IV acute GVHD by day 100 & 90% were alive & disease-free at day 100 (11 TRM, 3 relapse). 127 pts had AKI (45 gr. 1, 60 gr. 2, & 22 gr. 3) for a day 100 grade 1-3 AKI cumulative incidence of 83% (95%CI: 77-89) (median onset 40 days, range 0-96) & 54% (95%CI: 46-62) for gr. 2-3 AKI (median onset 43 days, range 0-96) (Figure 1). The mean of the 3-day mean CSA level preceding AKI onset was high at 360 ng/ml. African ancestry, CMV seropositivity & low day -7 albumin level & post-dCBT variables of ICU admission, nephrotoxic drug exposure & bacteremia were associated with gr. 1-3 AKI (Table 1A). In multivariate analysis, low day -7 albumin, ICU admission & nephrotoxic drugs were significant (Table 1B). With a median 40 months (range 12-125) survivor follow-up, 34/109 (31%) evaluable pts had CKD at 2-yrs with 1 pt requiring long-term dialysis. Grade 2-3 AKI prior to day 100 was associated with a higher likelihood of having CKD at 2-yrs: 38% vs 25% (Figure 2). Conclusion dCBT recipients are at significant risk for AKI which increases the likelihood of long-term CKD. Early recognition of impending AKI & prompt intervention is critical to mitigate severe kidney injury & long-term impairment. Prevention strategies include adequate hydration, tight CSA level control & substitution of non-nephrotoxic medications (e.g. Letermovir CMV prophylaxis instead of pre-emptive foscarnet, non-aminoglycosides antibiotics, azoles rather than amphotericin, PO cidofovir instead of IV). Investigation of novel GVHD prophylaxis that could permit lower CSA dosing & early AKI detection using biomarkers should also be investigated.

A High Degree of Engrafting Unit-Recipient HLA-Allele Mismatch Is Not Associated with an Increased Risk of Transplant-Related Mortality (TRM) or Inferior Progression-Free Survival (PFS) after Double Unit Cord Blood (CB) Transplantation (dCBT) in Adults with Hematologic Malignancies

Background: While incorporation of HLA-allele matching has highlighted high degrees of CB unit-recipient HLA-disparity, the less stringent HLA-match requirements extends allograft access to many patients without matched adult donors. The extent to which HLA-mismatch can adversely affect CBT outcomes, & the maximum permitted degree of HLA-mismatch, however, are not established.Methods: We analyzed TRM, relapse & PFS after intermediate intensity myeloablative cyclophosphamide 50 mg/kg, fludarabine 150 mg/m2, thiotepa 5-10 mg/kg, 400 cGy TBI double unit CBT in adults transplanted for hematologic malignancies. Eligible patients (pts) were first allograft recipients ≤ 65 years transplanted for acute leukemia/ MDS/ MPD (≤ 10% blasts pre-CBT), B-cell or T-cell lymphomas between 1/2014 - 12/2017. TNC & CD34+ dose were typically given priority over HLA-match in unit selection.Results: 102 pts [51 (50%) non-European, 59 (58%) CMV seropositive, median age 50 years (range 21-65), median weight 80 kg (range 36-137)] were transplanted. Diagnoses included 71 acute leukemias, 17 CML/ MPD/ MDS, 14 B- or T-cell NHLs. All received double unit grafts comprised of 2 (1%) 6/6 units, 21 (10%) 5/6, 181 (89%) 4/6 HLA-match, median unit-recipient 8-allele HLA-match 5/8 (range 3-7), & median infused viable CD34+ dose 1.3 x 105/kg/unit (range 0.2-8.6). Forty-eight (47%) CB grafts were supplemented with haplo-identical CD34+ cells as a myeloid bridge. The cumulative incidence of sustained CB engraftment was 97% (95%CI 90-99) with 2 pts having graft failure. A dominant (engrafting) unit was identified in all pts but 1 who died on day +14. Day 180 incidences of grades II-IV & III-IV aGVHD were 89% (95%CI 81-94) & 23% (95%CI 15-31), respectively. 1-yr cGVHD was 4% (95%CI 1-9). Cumulative incidence of TRM was 9% (95%CI 4-15) at day 180 & 14% (95%CI 8-22) at 2 yrs. 11% (95%CI 6-19) of pts relapsed by 2 yrs. With a median survivor follow-up of 2 yrs 3 months (range 6 - 51), the 2-yr overall survival is 82% (95%CI 75-90) & PFS is 74% (95%CI 66-84). Causes of death were transplant-related in 16 pts [6 aGVHD, 4 infection (2 viral, 1 bacterial, 1 fungal), 4 organ failure, 1 graft failure, 1 unknown] & due to relapse in 4 pts. By 2-yrs post-CBT, engrafting unit-recipient HLA-allele match had no association with TRM or PFS (Figure). Univariate analysis of the association between recipient variables [age, age adjusted hematopoietic cell transplant-comorbidity index (aaHCT-CI), revised disease risk index (rDRI)] & graft variables [engrafting unit-recipient HLA-allele match & infused CD34+ cell dose] & TRM, relapse & PFS are shown (Table). Age & aaHCT-CI were associated with 2-yr TRM with the 50 younger pts (< 50 years), & the 66 pts with aaHCT-CI 0-3, having especially low 2-yr TRM of 5% & 10%, respectively. Neither engrafting unit-recipient HLA-match nor CD34+ dose were associated with TRM. No pt or graft variable was associated with relapse. The only significant variable associated with 2-yr PFS was aaHCT-CI. The 66 pts with a lower aaHCT-CI score of 0-3 had a higher 2-year PFS [82% (95%CI 73-92)] than the 36 high score 4-9 pts [60% (95%CI 46-79)]. rDRI, engrafting unit-recipient 8-allele HLA-match & CD34+ cell dose had no effect. Multivariate analysis of TRM was precluded by too few events. Multivariate analysis of PFS including aaHCT-CI, rDRI & engrafting unit-recipient HLA-match showed high aaHCT-CI was associated with worse PFS [HR 2.82 (1.28-6.25) if score 4-9 vs 0-3, p = 0.01]; neither rDRI [HR 1.21 (0.54-2.69) if high-very high vs low-intermediate, p = 0.64] nor engrafting unit-recipient HLA-match [HR 2.06 (0.89-4.74) if 5-7/8 vs 3-4/8 matched (p = 0.09] were significant.Conclusions: Our finding that a high level of HLA-allele mismatch of the engrafting unit was not significantly associated with TRM or PFS in adult dCBT for hematologic malignancies has multiple implications. It supports the use of units with a relatively high degree of HLA-mismatch in the dCBT setting if needed in these pts. This facilitates extension of allograft access to the majority of pts including minorities. Moreover, the high PFS supports our centers unit selection strategy that gives unit quality & cell dose a priority in adults with malignancies to optimize engraftment. Finally, this data support CBT in many high-risk or urgent pts even if a well-matched CB graft cannot be identified. This is especially true in younger pts or those with a low 0-3 aaHCT-CI who had high 2-yr PFS. [Display omitted] DisclosuresPerales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Abbvie: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

Double-Unit Cord Blood (CB) Transplantation with Haplo-Identical CD34+ Cells (haplo-dCBT) May Speed Neutrophil Recovery Although Successful Bridging Is Contingent on Close Haplo-Winning CB Unit HLA-Match

Background: While dCBT is associated with high rates of sustained donor engraftment, delayed neutrophil recovery in adults is frequent and can contribute to extended hospitalization and early transplant-related mortality.Methods: We investigated engraftment after myeloablative dCBT supplemented with CD34+ selected haploidentical PBSC (haploCD34+) in patients (pts) with high risk hematologic malignancies or aplastic anemia in a phase II clinical trial. The aim was to abrogate neutropenia (ANC >/= 500 within 14 days) with a haplo myeloid bridge prior to CB engraftment. Pts did not receive ATG due to the increased mortality risk reported in adult CBT. Double unit CB grafts allowed comparison to dCBT controls without haploidentical graft supplementation.Results: 78 adult pts [median age 48.5 years (range 21-68), median weight 82 kgs (range 48-138), 44 (56%) CMV+, 3 with prior allografts] underwent haplo-dCBT between 9/2012-12/2017. Diagnoses included 54 (69%) acute leukemias, 10 (13%) MDS/ MPN (all ≤ 10% blasts at work-up), 10 (17%) NHL/ HD and 1 aplastic anemia. Conditioning was myeloablative (1 Cy 120/ Flu 75/ TBI 1375, 77 intermediate intensity Cy 50/ Flu 150/ Thio 5-10/ TBI 400) with CSA/ MMF. CB units had a median infused TNC of 2.3 (range 1-5.7) x 107/kg/unit & median infused viable CD34+ cell dose of 1.1 (range 0.1-3.1) x 105/kg/unit with a median 5/8 (range 2-7) unit-recipient HLA-allele match. Haplo CD34+ grafts [procured from children (46%), siblings (31%), parents (13%) or extended family (10%)] had a median infused CD34+ dose of 5.2 x 106/kg (range 1.1-16.8) and a median infused CD3+ dose of 1.6 x 103/kg (range 0.3-13.7). Sixty-one (78%) haplos were 4/8 and 17 (22%) were 5-7/8 HLA-matched to the pt. In 77 evaluable pts (1 pt died on day 14), 4 engraftment patterns were observed (Table 1). All but 2 pts had sustained CB engraftment with either an optimal haplo-bridge (Gp. 1, 34/77, 44%), a transient bridge with a second nadir preceding CB engraftment (Gp. 2, 20/77, 26%), or no bridge (Gp. 3, 21/77, 27%). The 2 remaining pts had CB/ haplo graft failure (Gp. 4, 2/77, 3%); both were successfully re-transplanted with single CB units. While there was no difference in the day 100 TRM in the 34 optimal bridge pts vs pts with transient or no bridge [9% (95%CI 2-21) vs 15% (95%CI 6-27), p = 0.388], optimal bridge pts had faster platelet recovery [19 (range 14-41) vs 44.5 days (range 14-67)] and earlier hospital discharge [28.5 (range 20-60) vs 36 days (range 28-98)]. Similar to dCBT alone, chimerism analysis revealed sustained engraftment in haplo-dCBT is mediated by a “winning” CB unit. This was heralded by winning unit-derived T-cells seen as early as day +28. Although universal, the speed of haplo rejection varied, and a high haplo chimerism percentage early post-transplant did not guarantee successful bridging. Analysis of factors potentially predicting an optimal bridge is shown in Table 2. The median winning CB unit-haplo 8-allele HLA-match was 3/8 (range 1-7/8). In univariate analysis, higher haplo CD34+ dose/kg, > 4/8 haplo-recipient HLA-match and ≥ 3/8 winning unit-haplo HLA-match were associated with a higher likelihood of bridging. Haplo CD34+ dose and winning unit-haplo HLA-match remained significant in multivariate analysis.Conclusions: While haplo-dCBT can be associated with enhanced neutrophil recovery, this platform does not guarantee a successful myeloid bridge due to early haplo rejection by the winning CB unit. This universal haplo rejection highlights the importance of the CB graft dose and quality with this ATG-free strategy as the CB will mediate sustained engraftment. Our findings have significance for strategies that combine unmanipulated CB with any third-party or ex vivo expanded T-cell depleted product given higher product CD34+ cell dose and better HLA-match to the unmanipulated CB unit could improve the likelihood of successful myeloid bridging. The data also support alternative approaches to improve myeloid recovery after CBT such as optimized unit selection and vivo expansion. [Display omitted] DisclosuresO'Reilly:Atara Biotherapeutics: Consultancy, Patents & Royalties, Research Funding. Perales:Takeda: Other: Personal fees; Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Abbvie: Other: Personal fees. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Janssen: Research Funding; Amgen: Research Funding.

Thiotepa-Based Intensified Reduced-Intensity Conditioning Adult Double-Unit Cord Blood Hematopoietic Stem Cell Transplantation Results in Decreased Relapse Rate and Improved Survival Compared with Transplantation Following Standard Reduced-Intensity Conditioning: A Retrospective Cohort Comparison

The “Minnesota” reduced-intensity conditioning (RIC) cord blood transplantation (CBT) regimen (standard RIC) of fludarabine (Flu) (200 mg/m2), cyclophosphamide (Cy) (50 mg/kg), and 200- or 300-cGy total body irradiation (TBI) is the most published RIC CBT regimen. Though well tolerated, high relapse rates remain a concern with this regimen. Intensification of conditioning may reduce relapse without increasing transplant-related mortality (TRM). We performed a retrospective cohort comparison of outcomes in adult patients who underwent first double-unit CBT with standard RIC as compared with the intensified regimen of Flu 150 mg/m2, Cy 50 mg/kg, thiotepa 10 mg/kg, and 400-cGy TBI (intensified RIC). Of the 99 patients studied, 47 received intensified RIC. Acute myelogenous leukemia was the major indication for transplant. The median age at transplant was 67 years (range, 24 to 74 years) and 54 years (range, 25 to 67 years) in standard RIC and intensified RIC, respectively. Median hematopoietic stem cell transplantation comorbidity index was 3 (range, 0 to 5) and 1 (range, 0 to 6) in the standard RIC and intensified RIC groups, respectively. Median follow-up among survivors was 22 months (range, 3.7 to 79 months) following standard RIC and 15 months (range, 2.8 to 36 months) following intensified RIC. The cumulative incidence (CI) of relapse was significantly lower following intensified RIC compared with standard RIC (P = .0013); this finding maintained significance in multivariate analysis (P = .045). TRM was comparable between the 2 groups (P = .99). Overall survival (OS) was significantly improved following intensified RIC as compared with standard RIC (P = .03). Median OS was 17 months following standard RIC versus not reached followed intensified RIC. The CI of grade II to IV acute graft-versus-host disease (GVHD) was significantly higher in the intensified RIC cohort than the standard RIC-cohort (P = .007), while CI of grade III to IV acute GVHD, any chronic GVHD, and moderate-to-severe chronic GVHD was comparable in each cohort (P = .20, P = .21, and P = .61, respectively). This retrospective analysis shows an improvement in OS and decreased relapse without increase in TRM in patients receiving intensified RIC as compared with standard RIC. Our data suggest that consideration of thiotepa-based intensified RIC may improve outcomes in fit, older patients undergoing double-unit CBT.

Cohort-Controlled Comparison of Umbilical Cord Blood Transplantation Using Carlecortemcel-L, a Single Progenitor–Enriched Cord Blood, to Double Cord Blood Unit Transplantation

Umbilical cord blood (UCB) transplantation has a high early mortality rate primarily related to transplanted stem cell dose. To decrease early mortality and enhance engraftment, a portion of selected cord blood units (20% to 50%) was expanded with cytokines and the copper chelator tetraethylenepentamine (carlecortemcel-L) and transplanted with the unmanipulated fraction after myeloablative conditioning. The primary endpoint was 100-day survival, which was compared with a contemporaneous double-unit cord blood transplantation (DUCBT) group. We enrolled 101 patients at 25 sites; the DUCBT comparison (n = 295) was selected from international registries using study eligibility criteria. Baseline carlecortemcel-L study group unit nucleated cell (NC) and CD34+ were 3.06 × 107 cell dose/kg and 1.64 × 105 cell dose/kg. Median NC and CD34+ fold expansion were 400 and 77, with a mean total CD34 infused of 9.7 × 105/kg. The 100-day survival was 84.2% for the carlecortemcel-L study group versus 74.6% for the DUCBT group (odds ratio, .50; 95% CI, .26 to .95; P = .035). Survival at day 180 was similar for the 2 groups; the major cause of death after day 100 was opportunistic infections. Faster median neutrophil (21 days versus 28 days; P < .0001), and platelet (54 days versus 105 days; P = .008) engraftment was seen in the carlecortemcel-L study group; acute and chronic graft-versus-host disease rates were similar. In this multinational comparative study, transplanting expanded CD34+ stem cells from a portion of a single UCB unit, with the remaining unmanipulated fraction improved 100-day survival compared with DUCBT control patients while facilitating myeloid and platelet engraftment. This trial was registered at www.clinicaltrials.gov as #NCT00469729.

197 - Long-Term Follow-Up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen

197 - Long-Term Follow-Up of Adult Double Unit Cord Blood (CB) Transplantation (dCBT) Recipients Reveals High Rates of Progression-Free Survival after a Novel Cy/ Flu/ Thio/ TBI 400 Intermediate Intensity Conditioning Regimen

Chronic graft-versus-host disease features in double unit cord blood transplantation according to National Institutes of Health 2005 cGVHD Consensus criteria.

Chronic graft-versus-host disease features in double unit cord blood transplantation according to National Institutes of Health 2005 cGVHD Consensus criteria.

Double vs. single cord blood transplantation in adolescent and adult hematological malignancies with heavier body weight (≥50 kg)

ABSTRACTBackground: Double-unit cord blood transplantation (CBT) can be used to overcome the limitation of single-unit CBT with low cell content for adults and larger adolescents. However, whether double-unit CBT is superior to single-unit CBT remains controversial.Methods: We reviewed the medical records of 228 consecutive hematological malignancies who received CBT between November 2005 and December 2013. Ninety-seven eligible patients met the criteria (age ≥14 years and body weight ≥50kg) and were enrolled in this study.Results: The incidence of myeloid engraftment in the double-unit CBT group was significantly lower that in the single-unit CBT group (89.2 vs. 96.7%) (p = 0.026), and the incidence of platelet engraftment in the double-unit CBT group was slightly lower (70.3 vs. 86.7%) (p = 0.057). The 5-year transplant-related mortality rate was significantly higher in the double-unit CBT group when compared with that of the single-unit CBT group [54.1 vs. 33.3%, p = 0.026]. The 5-year probabilities of overall survival, disease-free survival and graft-versus-host disease (GVHD) -free/relapse-free survival in the double-unit CBT group were significantly lower than that of the single-unit CBT group (37.8 vs. 56.7%, p = 0.037; 32.4 vs. 55.0%, p = 0.017; 24.3 vs. 50.0%, p = 0.006). The incidences of GVHD and relapse were similar.Conclusions: For adolescent and adult hematological malignancies with heavier body weight (≥50kg), double-unit CBT has an inferior clinical outcome when compared with single-unit CBT having a sufficient cell dose. Double-unit CBT should only reserve for patients who need an urgent transplant but lacking of a related or unrelated donor and without an adequately dosed single CB.

Real Time Immunophenotyping of Leukocyte Subsets Early after Double Cord Blood Transplantation Predicts Graft Function

Cord blood transplantation (CBT) recipients are at increased risk for delayed engraftment and primary graft failure, complications that are often indistinguishable early post-transplantation. Current assays fail to accurately identify recipients with slow hematopoietic recovery and distinguish them from those with pending graft failure. To address this, we prospectively examined the kinetics of immune cell subset recovery in the peripheral blood of 39 patients on days +7 and +14 after double-unit CBT (dCBT) by multiparametric flow cytometry analysis, which we term real-time immunophenotyping (RTIP). RTIP analysis at day +14 revealed distinctive patterns of reconstitution and, importantly, identified patients with slow hematopoietic recovery who went on to engraft. Strikingly, higher absolute numbers of circulating monocytes and natural killer cells at day +14 were predictive of engraftment, but only the absolute number of circulating monocytes was significantly correlated with time to engraftment. This is the first evidence that RTIP on patient peripheral blood mononuclear cells early after dCBT is technically feasible and can be used as a “signature” for predicting the kinetics of hematopoietic recovery. Furthermore, RTIP is a time- and cost-efficient methodology that has the potential to become a clinically feasible diagnostic tool to guide therapeutic interventions in high-risk patients; therefore, its utility should be evaluated in a large cohort of patients.

Autoimmune hemolysis and immune thrombocytopenic purpura after cord blood transplantation may be life-threatening and warrants early therapy with rituximab.

Autoimmune hemolysis (AH) and immune thrombocytopenic purpura (ITP) are recognized complications after cord blood transplantation (CBT). We evaluated the incidence and characteristics of AH/ITP after double-unit CBT in a day 100 landmark analysis of 152 patients (median age 36 years, range 0.9-70 years) transplanted for hematologic malignancies with myeloablative or nonmyeloablative conditioning and calcineurin inhibitor (CNI)/mycophenolate mofetil. With a median 5.2-year (range 1.6-9.7 years) survivor follow-up, 10 patients developed autoimmune cytopenias (8 AH, 1 ITP, 1 both) at a median of 10.4 months (range 5.8-24.5) post CBT for a 7% cumulative incidence 3 years after the day 100 landmark. Six patients presented with severe disease (hemoglobin ⩽6 g/dL and/or platelets <20 × 109/L). All AH patients were direct antiglobulin test positive. All 10 cases developed during immunosuppression taper with 8 having prior acute GVHD. All 10 patients received rituximab 2-18 days after diagnosis, and corticosteroids combined with rituximab within <7 days was the most effective. No patient died of AH/ITP. AH/ITP occurs infrequently after CBT but may be life-threatening requiring emergency therapy. Rituximab combined with corticosteroids at diagnosis is warranted in patients with severe disease.

Single- vs double-unit cord blood transplantation for children and young adults with acute leukemia or myelodysplastic syndrome

AbstractTransplantation of 2 unrelated cord blood (UCB) units instead of 1 has been proposed to increase the cell dose. We report a prospective randomized study, designed to compare single- vs double-UCB transplantation in children and young adults with acute leukemia in remission or myelodysplasia. Eligible patients had at least two 4-6 HLA-identical UCBs with >3 × 107 nucleated cells/kg for the first and >1.5 × 107 for the second. The primary end point was the 2-year cumulative incidence of transplantation strategy failure, a composite end point including transplant-related mortality (TRM), engraftment failure, and autologous recovery. Randomized patients who did not proceed to transplantation due to refractory disease were considered transplantation failures. A total of 151 patients were randomized and included in the intent-to-treat analysis; 137 were transplanted. Double-UCB transplantation did not decrease transplantation strategy failure (23.4% ± 4.9% vs 14.9% ± 4.2%). Two-year posttransplant survival, disease-free survival, and TRM were 68.8% ± 6.0%, 67.6% ± 6.0%, and 5.9% ± 2.9% after single-unit transplantation compared with 74.8% ± 5.5%, 68.1% ± 6.0%, and 11.6% ± 3.9% after double-unit transplantation. The final relapse risk did not significantly differ, but relapses were delayed after double-unit transplantation. Overall incidences of graft-versus-host disease (GVHD) were similar, but chronic GVHD was more frequently extensive after double-UCB transplantation (31.9% ± 5.7% vs 14.7% ± 4.3%, P = .02). In an exploratory subgroup analysis, we found a significantly lower relapse risk after double-unit transplantation in patients receiving total body irradiation without antithymocyte globulin (ATG), whereas the relapse risk was similar in the group treated with busulfan, cyclophosphamide, and ATG. Single-UCB transplantation with adequate cell dose remains the standard of care and leads to low TRM. Double-unit transplantation should be reserved for patients who lack such units. This trial was registered at www.clinicaltrials.gov as #NCT01067300.

Double Unit Cord Blood Transplantation (dCBT) Progression-Free Survival (PFS) is Unaffected by Grade III-IV Acute Graft-Versus-Host Disease (aGVHD) and Survivors Are Likely to Discontinue Immunosuppression (IS) and Reconstitute T-Cells

Double Unit Cord Blood Transplantation (dCBT) Progression-Free Survival (PFS) is Unaffected by Grade III-IV Acute Graft-Versus-Host Disease (aGVHD) and Survivors Are Likely to Discontinue Immunosuppression (IS) and Reconstitute T-Cells

High Progression-Free Survival (PFS) in Adult Double Unit Cord Blood (dCB) Transplant Recipients with High Risk Disease after a Novel Intermediate Intensity Conditioning Regimen

High Progression-Free Survival (PFS) in Adult Double Unit Cord Blood (dCB) Transplant Recipients with High Risk Disease after a Novel Intermediate Intensity Conditioning Regimen

Analysis of Cyclosporine-a (CSA) Levels Supports New Dosing Guidelines in Adult Double Unit Cord Blood Transplant (dCBT) Recipients to Optimize Immunosuppression Early Post-Transplant

Analysis of Cyclosporine-a (CSA) Levels Supports New Dosing Guidelines in Adult Double Unit Cord Blood Transplant (dCBT) Recipients to Optimize Immunosuppression Early Post-Transplant

Prospective Evaluation of Cord Blood (CB) & Haplo-Identical Donor Availability Reveals Compromised Donor Access for Both Graft Types in Minorities and High Rates of Failure to Clear Haplo Donors in Adult Patients

Background: Many patients in need of hematopoietic allografts without matched siblings do not have any 8/8 HLA-matched unrelated volunteer donors (URD). This is especially true in patients of non-European & mixed ancestries & this applies to 50% of patients undergoing URD searches at our center. While unrelated donor CB & haploidentical (haplo) related donors offer alternative graft sources their availability in all patient populations is not established.Methods: We prospectively evaluated the availability of CB & haplo grafts 9/2012 - 7/2015 in a phase II clinical trial of double unit CBT (dCBT) supplemented by haplo CD34+ cells in patients with hematologic malignancies lacking an 8/8 HLA-matched URD. CB units required a cryopreserved TNC dose ≥ 1.5 x 107 /kg/unit, were ≥ 4/6 HLA-A,-B antigen, -DRB1 allele matched, & high resolution 8 HLA-allele match & CD34+ cell dose were also considered. Standard criteria were used to define donor eligibility for haplo PBSC collection. Reasons for failure of haplo donor clearance were classified as either medical ineligibility or psychosocial (including financial inability to relocate to our transplant center, international donors unable to come to the US, donor refusal or withdrawal of consent during workup, donor imprisonment, or patient refusal to approach the donor for collection).Results: 89 patients [median age 50 years (range 15-68)] were evaluated. Diagnoses included 58 acute leukemias, 10 MDS/ myeloproliferative disorders, & 21 NHL/ Hodgkins lymphomas. Evaluation of CB graft &/or haplo donor availability revealed 3 patient groups. Group 1 (59/89, 66% of the total) had both suitable CB grafts & haplo donors and underwent dCBT-haplo CD34+ transplants. 33% were non-European & their median weight was 78 kg (range 33-133). The CB grafts had a median infused TNC of 2.4 (larger unit) & 1.9 (smaller unit) x 107/kg with a median 5/8 (range 2-7/8) donor-recipient HLA-match whereas the 59 haplos (median age 36 years, range 15-71) included 17 siblings, 9 parents, 27 children, & 6 extended family. In Group 1, the first haplo chosen was cleared for donation in 52/59 (88%) patients whereas 6/59 (10%) required work-up of 2-4 haplos/ patient for a total of 16 donors who failed clearance for medical or psychosocial reasons. The remaining patient had pan-donor specific HLA antibodies to 5 haplos & subsequently a 7/8 HLA-matched nephew was secured. Group 2 (17/89, 19% of the total) received only dCB grafts due to failure to identify a suitable haplo donor. Group 2 patients were more likely to be non-European (65%) but had a similar weight (median 78 kg, range 55-118) as Group 1. The CB grafts were also similar to Group 1 (median infused TNC 2.2 & 1.5 x 107/kg & median donor-recipient HLA-match 5/8, range 3-8/8). Of these 17 dCBT only patients, 6 had no eligible haplos identified within their extended family whereas in 8 patients 1-4 haplos/ patient failed to clear for medical reasons, combinations of medical & psychosocial reasons, or pursuit of haplos failed due to a combination of medical failure & subsequent transplant urgency. Of the remaining patients, 2 had haplos who failed for purely psychosocial reasons, & in 1 the transplant was too urgent to delay to complete donor clearance. In this group a total of 19 haplos failed to clear. Finally, Group 3 (13/89, 15% of the total) had no dCB grafts + no haplo grafts. They were nearly all (85%) non-European including 7 patients of African ancestry & they had a higher weight (median 95 kg, range 52-143). One of these patients received a haplo transplant, 3 had no haplos identified, & in 9 patients clearance of potential haplos was not determined to date, or they pursued alternative therapy, were lost to follow-up, or their disease progressed.Conclusions: In this study, 15% of patients had no CB grafts & these patients were predominantly non-European with a high weight. Additionally, over 20% of patients had no haplo grafts & compromised haplo donor availability was common especially in minority patients. This data demonstrates that even in patients with identified haplos, donor clearance cannot be assumed & the need for workup of multiple haplos/ patient can delay admission & substantially add to transplant costs. These observations support continued investment in public CB inventories to provide a readily available graft especially for minority patients who are at increased risk for inability to identify a CB &/or haplo donor. DisclosuresPerales:National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Scaradavou:National Cord Blood Program- New York Blood Center: Employment.

Robust Vaccine Responses in Adult and Pediatric Cord Blood Transplantation Recipients Treated for Hematologic Malignancies.

Because cord blood (CB) lacks memory T and B cells and recent decreases in herd immunity to vaccine-preventable diseases in many developed countries have been documented, vaccine responses in CB transplantation (CBT) survivors are of great interest. We analyzed vaccine responses in double-unit CBT recipients transplanted for hematologic malignancies. In 103 vaccine-eligible patients, graft-versus-host disease (GVHD) most commonly precluded vaccination. Sixty-five patients (63%; engrafting units median HLA-allele match 5/8; range, 2 to 7/8) received protein conjugated vaccines, and 63 patients (median age, 34 years; range, .9 to 64) were evaluated for responses. Median vaccination time was 17 months (range, 7 to 45) post-CBT. GVHD (n = 42) and prior rituximab (n = 13) delayed vaccination. Responses to Prevnar 7 and/or 13 vaccines (serotypes 14, 19F, 23F) were seen in children and adults (60% versus 49%, P = .555). Responses to tetanus, diphtheria, pertussis, Haemophilus influenzae, and polio were observed in children (86% to 100%) and adults (53% to 89%) even if patients had prior GVHD or rituximab. CD4(+)CD45RA(+) and CD19(+) cell recovery significantly influenced tetanus and polio responses. In a smaller cohort responses were seen to measles (65%), mumps (50%), and rubella (100%) vaccines. No vaccine side effects were identified, and all vaccinated patients survived (median follow-up, 57 months). Although GVHD and rituximab can delay vaccination, CBT recipients (including adults and those with prior GVHD) have similar vaccine response rates to adult donor allograft recipients supporting vaccination in CBT recipients.

Association between Nondominant Unit Total Nucleated Cell Dose and Engraftment in Myeloablative Double-Unit Cord Blood Transplantation

Sustained hematopoiesis after double-unit cord blood transplantation (dCBT) is mediated by 1 unit in nearly all patients. To investigate the associations between nondominant unit characteristics and neutrophil engraftment, we studied 129 consecutive myeloablative dCBT recipients. Ninety-five percent (95% confidence interval, 90 to 98) of patients engrafted. Detection of the nondominant unit 21 to 28 days after dCBT was not associated with improved neutrophil engraftment. In univariate analyses, nondominant unit characteristics (infused total nucleated cell [TNC] and viable CD3+ cell doses) were significantly associated with speed and success of neutrophil engraftment as were dominant unit characteristics (infused TNC; viable CD34+, viable CD3+, and viable CD3-56+16+ cell doses; and post-thaw CD34+ cell viability). In multivariate analysis, higher infused TNC dose of the nondominant unit was independently associated with improved neutrophil engraftment, even when this unit did not contribute to donor hematopoiesis. In further subgroup analysis, this association was only evident when the infused viable CD34+ cell dose of the dominant unit was low (<1.20 × 105/kg). These findings suggest nondominant units mediate a dose-dependent facilitation of engraftment in myeloablative dCBT and support continued investigation of dCBT biology and the clinical practice of dCBT in adults in whom low cell dose grafts are common.

Evaluation of Initial Telomere Length and Changes after Transplantation in Adult Double-Unit Cord Blood Transplant Recipients

Cord blood (CB) leukocytes have inherent telomere length (TL) variation, and CB hematopoietic stem cells (HSC) can maintain high telomerase levels preventing telomere attrition in vitro. We evaluated TL changes in 13 adult double-unit CB transplant (CBT) recipients. In the 26 units, we observed a marked variation in CB TL at thaw (median, 9.99 kilobases [kb]; range, 6.85 to 13.5). All 13 patients engrafted. Of 11 engrafting with 1 unit, there was no correlation between unit dominance and TL (mean dominant unit TL, 8.84 kb ± 1.76; mean nonengrafting unit TL, 10.3 kb ± 1.81; P = .77). Serial measurements of TL up to 1 year after CBT demonstrated an overall mean 3.04 kb ± .16 TL decrease with only 1 patient exhibiting telomere maintenance. In summary, initial TL does not predict CB unit dominance. Moreover, our analysis suggests neonatal hematopoiesis makes a transition to an HSC characterized by changes in average TL and potentially low telomerase asymmetric cell division in adult CBT recipients. Further investigation of alterations in telomere length and its clinical implications after transplantation of this observation are indicated.

General and Virus-Specific Immune Cell Reconstitution after Double Cord Blood Transplantation

Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin–containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT.