While cord blood transplantation (CBT) is an effective therapy for high-risk hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated biomarkers that could predict for aGVHD after day 28 in CBT. Day 28 samples from 113 double-unit CBT recipients transplanted for hematologic malignancies were analyzed by ELISA for ST2, TNFR1, IL-8, REG3?, IL2R?, elafin and HGF. ST2 was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels (> 33.9 ng/ml) was 30% (95%CI:18-43) versus 13% (95%CI:5-23) in patients with low levels (p = 0.024) and the adverse effect of elevated ST2 was independent of HLA-match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95%CI:13-35) versus 5% (95%CI:1-13) if levels were low (p = 0.001). GVHD was the most common cause of death in high ST2 patients. High concentrations of TNFR1, IL-8 and REG3? were also significantly associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and improve survival in CBT recipients.
Cord blood transplant (CBT) extends allograft access but is associated with a significant risk for cytomegalovirus (CMV) infection. We analyzed CMV infection in 157 CBT recipients transplanted for hematological malignancies. As compared with antigenemia testing, routine polymerase chain reaction (PCR) monitoring was associated with increased and earlier CMV infection detection (1-year incidence if seropositive 67% [median onset 41 days] vs. 100% at an earlier 33-day median [p < 0.001]) and decreased gastrointestinal disease. One-year CMV-related transplant-related mortality was 11% in CMV+ patients with 7/9 deaths associated with initial infection. Disease-free survival was lower in seropositive compared with seronegative patients (1-year: 55% vs. 73%, p = 0.02). However, in multivariate analysis adjusting for age, treatment failure risk in CMV+ patients was not significant (hazard ratio 1.52, p = 0.11). CMV infection is a major challenge in seropositive CBT recipients. While PCR surveillance permits early detection of viremia, new prophylaxis and therapeutic strategies are needed.
We investigated the unit characteristics associated with engraftment after double-unit cord blood (CB) transplantation (dCBT) and whether these could be reliably identified during unit selection. Cumulative incidence of neutrophil engraftment in 129 myeloablative dCBT recipients was 95% (95% confidence interval: 90-98%). When precryopreservation characteristics were analyzed, the dominant unit CD34(+) cell dose was the only characteristic independently associated with engraftment (hazard ratio, 1.43; P = .002). When postthaw characteristics were also included, only dominant unit infused viable CD34(+) cell dose independently predicted engraftment (hazard ratio, 1.95; P < .001). We then examined the determinants of infused viable CD34(+) cell dose (precryopreservation count, postthaw recovery, and postthaw viability) in 402 units thawed at our center. This revealed close correlation between precryopreservation and postthaw CD34(+) cell counts (r(2) = 0.73). Median CD34(+) cell recovery was 101%, although it ranged from 12% to 1480%. Notably, units from non-Netcord Foundation for the Accreditation of Cellular Therapy (Netcord-FACT)-accredited banks were more likely to have low recovery (P < .001). Furthermore, although median postthaw CD34(+) cell viability was 92%, 33 (8%) units had <75% viable CD34(+) cells. Units from non-Netcord-FACT-accredited banks and units with cryovolumes other than 24.5 to 26.0 mL were more likely to have poor postthaw viability. Precryopreservation CD34(+) cell dose and banking practices should be incorporated into CB unit selection.
Cord blood unit (CBU) transplantations to patients mismatched for only 1 HLA antigen, which is identical to the CBU noninherited maternal antigen (NIMA), are designated as having a 6/6 "virtual" NIMA-matched phenotype and have a prognosis similar to 6/6 inherited HLA-matched CBUs. Such virtual HLA phenotypes of CBUs can be created by replacing the inherited alleles with 1 or more NIMAs. Phenotypes of Dutch patients (n = 2020) were matched against the inherited and virtual HLA phenotypes of the National Cord Blood Program CBU file (with known NIMA, n = 6827). Inherited 6/6 matches were found for 11% of the patients. Including virtual phenotypes resulted in, overall, 19-fold more different phenotypes than were inherited, conferring 6/6 virtual matches for an additional 20% of the patients, whereas another 17% might benefit from CBUs with a 4/6 HLA match and 1 NIMA match (4/6 + 1NIMA or 5/6 virtual match). The elucidation of donors' maternal HLA phenotypes can provide significant numbers of 6/6 and 5/6 virtually matched CBUs to patients and is potentially cost effective.
Cord blood transplantation (CBT) is a known risk factor for human herpesvirus-6 (HHV-6) infection. We analyzed the nature of HHV-6 infections in 125 double-unit CBT recipients (median age, 42 years) transplanted for hematologic malignancies with calcineurin inhibitor/mycophenolate mofetil prophylaxis and no antithymocyte globulin. One hundred seventeen patients (94%) reactivated HHV-6 by quantitative plasma PCR (median peak, 7600 copies/mL; range, 100 to 160,000) at a median of 20 days (range, 10 to 59) after transplantation. HHV-6 encephalitis occurred in 2 patients (1.6%), of whom 1 died and 1 recovered with therapy. No association was found between high-level HHV-6 viremia (?10,000 or ?25,000 copies/mL) and age, diagnosis, conditioning intensity, or dominant unit characteristics or between high-level viremia and transplant outcomes (engraftment, cytomegalovirus reactivation, day 100 grades II to IV acute graft-versus-host disease, day 100 transplant-related mortality, or 1-year disease-free survival). HHV-6 therapy delayed the onset of cytomegalovirus reactivation. Interestingly, HHV-6 resolution was observed in untreated patients, and resolution of viremia correlated with absolute lymphocyte count recovery. We observed a low incidence of encephalitis and no association with CBT outcomes. Our data suggest therapy in uncomplicated viremia may not be warranted. However, further investigation of the risk-to-benefit of HHV-6 viremia treatment and standardization of PCR testing is required.
The impact of human leukocyte antigen (HLA) donor-specific antibodies (DSA) on cord blood (CB) engraftment is controversial. We evaluated the influence of pre-existing HLA-antibodies (HLA-Abs) on engraftment in 82 double-unit CB recipients (median age, 48 years) who underwent transplantation for hematologic malignancies. Of 28 patients (34%) with HLA-Abs, 12 had DSA (median mean fluorescence intensity 5255; range, 1057 to 9453). DSA patients had acute leukemia (n = 11) or myelodysplasia (n = 1) and all received either high-dose or reduced-intensity (but myeloablative) conditioning. After myeloablative CB transplantation (CBT) (n = 67), sustained donor engraftment was observed in 95% without HLA-Abs (median, 23 days), 100% with nonspecific HLA-Abs (median, 23 days), and 92% with DSA (median, 31 days, P = .48). Of 6 patients with HLA-Abs to 1 unit, 3 engrafted with that unit and 3 with the other. Of 6 patients with HLA-Abs against both units, 1 had graft failure despite being 100% donor, and 5 engrafted with 1 unit. Successful donor engraftment is possible in patients with DSA after myeloablative double-unit CBT. Our data suggest potential deleterious effects of DSA can be abrogated in patients with hematologic malignancies.
Washing cord blood (CB) grafts involves product manipulation and may result in cell loss. We investigated double-unit CB transplantation (CBT) using red blood cell (RBC) depleted units diluted with albumin-dextran in patients with hematologic malignancies. One-hundred thirty-six patients [median 43 years (range 4-71) and 69 kilograms (kg) (range 24-111)] were transplanted with a 4-6/6 HLA-matched graft. Patients < 20 kg were excluded as they only received washed units. Units were diluted a median of 8 fold to a median volume of 200 ml/unit. The median infused TNC doses were 2.7 (larger unit) and 2.0 (smaller unit) x 10(7)/kg respectively, and the median post-thaw recovery was 86%. Units were infused consecutively (median 45 minutes/unit). While only 17 patients (13%) had no infusion reactions, reactions in the remaining 119 patients were almost exclusively mild-moderate (by CTCAE v4 criteria 12 grade 1, 43 grade 2, 63 grade 3) and only 1 patient (< 1%) had a severe (grade 4) reaction. Moreover, most were easily treated. Grade 2-3 hypertension was the most common in 101 (74%) patients. The cumulative incidence of sustained donor-derived neutrophil engraftment was high: 95% in myeloablative and 94% in non-myeloablative CBT recipients. With appropriate supportive care, double-unit CBT with RBC-depleted grafts infused after albumin-dextran dilution is safe with high rates of engraftment in patients > 20 kg.
Autologous or allogeneic hematopoietic stem cell transplant (SCT) is often considered in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) but there are limited data on the use of SCT for the treatment of NHL in the pediatric setting.
A preparative regimen of reduced intensity that can reliably engraft cord blood (CB) and can be used as an alternative to either high-dose myeloablative or nonmyeloablative conditioning is needed. We evaluated double-unit CB transplantation in 30 patients (median age, 56 years; range, 18 to 69) with acute leukemia or myelodysplasia using a regimen of cyclophosphamide 50 mg/kg, fludarabine 150 mg/m(2), thiotepa 10 mg/kg, and 400 cGy total body irradiation with cyclosporine-A/mycophenolate mofetil immunosuppression. Ninety-seven percent of patients engrafted at a median of 26 days (range, 13 to 43), and 93% of patients had recovered platelets by day 180. Grades II to IV acute graft-versus-host disease (GVHD) incidence was 67% at day 180, and chronic GVHD was 10% at 1 year. Transplant-related mortality was 20% at day 180, and relapse was 11% at 2 years. Overall, 2-year disease-free survival (DFS) was 60% at 2 years. A hierarchy in DFS was seen according to the Sorror comorbidity score: 11 patients (median age, 55 years) with a score of 1 had a 2-year DFS of 82% compared with 62% in 9 patients (median age, 51 years) with a score of 2 to 3 and 40% in 11 patients (median age, 58 years) with a score of 4 to 5 (P = .13). This reduced-intensity regimen combined with double-unit CB transplantation reliably facilitates sustained donor engraftment without antithymocyte globulin. Although other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in patients ?50 years old who are otherwise reasonably fit. It also represents a promising alternative to high-dose conditioning in younger patients.
We evaluated HLA-compatible donor leukocyte infusions (DLIs) and HLA-compatible or HLA-disparate EBV-specific T cells (EBV-CTLs) in 49 hematopoietic cell transplantation recipients with biopsy-proven EBV-lymphoproliferative disease (EBV-LPD). DLIs and EBV-CTLs each induced durable complete or partial remissions in 73% and 68% of treated patients including 74% and 72% of patients surviving ? 8 days after infusion, respectively. Reversible acute GVHD occurred in recipients of DLIs (17%) but not EBV-CTLs. The probability of complete response was significantly lower among patients with multiorgan involvement. In responders, DLIs and EBV-CTLs regularly induced exponential increases in EBV-specific CTL precursor (EBV-CTLp) frequencies within 7-14 days, with subsequent clearance of EBV viremia and resolution of disease. In nonresponders, EBV-CTLps did not increase and EBV viremia persisted. Treatment failures were correlated with impaired T-cell recognition of tumor targets. Either donor-derived EBV-CTLs that had been sensitized with autologous BLCLs transformed by EBV strain B95.8 could not lyse spontaneous donor-derived EBV-transformed BLCLs expanded from the patients blood or biopsied tumor or they failed to lyse their targets because they were selectively restricted by HLA alleles not shared by the EBV-LPD. Therefore, either unselected DLIs or EBV-specific CTLs can eradicate both untreated and Rituxan-resistant lymphomatous EBV-LPD, with failures ascribable to impaired T-cell recognition of tumor-associated viral antigens or their presenting HLA alleles.
Thrombosis is the major risk factor for death in patients with paroxysmal nocturnal hemoglobinuria. Previous case reports indicate that venous thrombosis in patients with paroxysmal nocturnal hemoglobinuria is amenable to thrombolysis.
The development of treatment-related myelodysplastic syndrome (tMDS) or treatment-related acute myelogenous leukemia (tAML) is a complication that can occur after chemotherapy or radiation therapy. Eighteen patients with a previous malignancy treated at our institution and three patients with a nonmalignant primary tumor received an allogeneic hematopoietic stem cell transplant (HSCT) on the pediatric bone marrow (BM) transplantation service for the treatment of tMDS/tAML over a 15-year period. Five patients proceeded to HSCT without induction chemotherapy. Fourteen patients received high-dose cytarabine according to the Capizzi II regimen as first-line induction therapy with 13 of them achieving complete remission (CR) or refractory anemia (RA) with persistent cytogenetic abnormalities after this treatment. Two patients received an anthracycline-based induction therapy. Conditioning regimens were selected according to previous therapies: 11 patients received busulfan-melphalan-fludarabine (BU-MEL-FLU), which consisted of busulfan (0.8 mg/kg/dose every 6 hours ×10 doses), melphalan (70 mg/m(2)/dose × two doses), and fludarabine (25 mg/m(2)/dose × five doses) for cytoreduction; three patients received a total body irradiation (TBI)-containing regimen; seven patients received myeloablative regimens containing busulfan and/or melphalan and/or thiotepa with doses modified for organ toxicity. Sixteen patients received T cell-depleted (TCD) grafts; four patients received unmodified grafts; one patient received a double-unit cord blood transplantation (DUCBT). Donors included HLA-matched (n = 9), or mismatched (n = 3) related donors, or HLA-matched (n = 4), or mismatched (n = 4) unrelated donors, or DUCBT (n = 1). Disease status at the time of HSCT was: morphologic and cytogenetic CR (n = 12); RA with positive cytogenetics (n = 6); and refractory disease (n = 3). With a median follow-up of 5.9 years (2.2-15.7 years), the 5-year overall survival (OS) and disease-free survival (DFS) rates for the entire group were 61.1% with 12 patients alive without evidence of either primary disease or tMDS/tAML. The OS and DFS rate for the 11 patients who received the BU-MEL-FLU cytoreduction with TCD grafts was 54.5%. DFS was 65.7% for patients in RA or CR at HSCT compared with 0% for patients with >5% residual marrow blasts (P = .015). Nine patients died; the cause of death was relapse of MDS/AML (n = 4) or primary disease (n = 2), graft-versus-host disease (GVHD; n = 2), and infection (n = 1). Four patients developed grade II to IV acute GVHD. One patient developed localized chronic GVHD. Our results suggest that the strategy of induction with high-dose cytarabine therapy followed by allogeneic stem cell transplantation improves the overall outcome for patients with tMDS/tAML. In addition, the use of a TCD transplantation with BU-MEL-FLU as cytoreduction may decrease the toxicity of transplantation in heavily pretreated patients without an increase in relapse rate.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease in children. The most significant clinical features of PNH include: bone marrow failure, intravascular hemolysis, and thrombosis. To further characterize the clinical presentation and outcome to treatment we performed a retrospective analysis of pediatric patients with PNH.
Donor-recipient human leukocyte antigen mismatch level affects the outcome of unrelated cord blood (CB) transplantation. To identify possible "permissive" mismatches, we examined the relationship between direction of human leukocyte antigen mismatch ("vector") and transplantation outcomes in 1202 recipients of single CB units from the New York Blood Center National Cord Blood Program treated in United States Centers from 1993-2006. Altogether, 98 donor/patient pairs had only unidirectional mismatches: 58 in the graft-versus-host (GVH) direction only (GVH-O) and 40 in the host-versus-graft or rejection direction only (R-O). Engraftment was faster in patients with GVH-O mismatches compared with those with 1 bidirectional mismatch (hazard ratio [HR] = 1.6, P = .003). In addition, patients with hematologic malignancies given GVH-O grafts had lower transplantation-related mortality (HR = 0.5, P = .062), overall mortality (HR = 0.5, P = .019), and treatment failure (HR = 0.5, P = .016), resulting in outcomes similar to those of matched CB grafts. In contrast, R-O mismatches had slower engraftment, higher graft failure, and higher relapse rates (HR = 2.4, P = .010). Based on our findings, CB search algorithms should be modified to identify unidirectional mismatches. We recommend that transplant centers give priority to GVH-O-mismatched units over other mismatches and avoid selecting R-O mismatches, if possible.
There are limited studies assessing the live attenuated varicella vaccine following allogeneic hematopoietic cell transplantation (alloHCT). Because of the morbidity of varicella acquired after childhood, we immunized and retrospectively analyzed the safety and immunogenicity of this vaccine in 46 varicella zoster virus (VZV) seronegative patients <20 years old at HCT who achieved a CD4 cell count ?200/?L, were off immunosuppression, and responded to ?1 post-HCT vaccines. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-matched sibling (n = 18) or an alternative (HLA mismatched related or unrelated) donor (n = 26). Median time to vaccination was 4 years. Sixty-four percent of patients seroconverted following 1 immunization. There was no significant difference in response between recipients of a matched related or alternative donor graft (P = .2) or between those given a T cell-depleted or T-replete alternative donor graft (P = .27). Three of 44 patients developed a self-limited varicella-like rash within 2.5 weeks of immunization. With a median follow-up of 29.1 (range: 6.9-167.1) months, there were no subsequent cases of varicella-like rashes. No patient developed shingles. This study suggests that this vaccine is safe and immunogenic when given according to preset clinical and immunologic milestones, warranting larger prospective studies in patients ?24 months following HCT as outlined in current post-HCT vaccine guidelines.
Factors contributing to infection risk after cord blood transplantation (CBT) include the use of anti-thymocyte globulin (ATG), prolonged neutropenia, and failure to transfer immunity. In the present study, we investigated the potential of double-unit CBT without ATG to reduce the risk of infection and evaluated the nature of serious infections in the first year after CBT using this approach. Seventy-two predominantly adult patients underwent CBT for hematologic malignancies; of these, 52 patients received myeloablative conditioning, and 20 received nonmyeloablative conditioning. The peak incidences of bacterial infections (32%), fungal infections (14%), and bacterial/fungal pneumonias (10%) occurred in the first 30 days posttransplantation. Three such infections contributed to early mortality. The peak incidence of viral infections was 31-60 days posttransplantation, affecting 30% of patients. Cytomegalovirus (CMV) was the most common viral infection. CMV infections occurring before day 120 (n = 23) had no relationship with graft-versus-host disease (GVHD), whereas CMV infections occurring after day 120 (n = 5), along with all cases of Epstein-Barr virus viremia (n = 5) and adenoviral enteritis (n = 2), occurred exclusively in the context of GVHD therapy or corticosteroid use for another indication. Viral infections had the highest lethality: 2 were a direct cause of death, and 3 contributed to death. Patients exhibited steady immune recovery, achieving a median CD3(+)4(+) T cell count >200 cells/?L by day 120 post-CBT, and no infection-related deaths occurred after day 120. Our results suggest that double-unit CBT without ATG is associated with prompt T cell recovery, and, unlike in CBT incorporating ATG, infection is rarely a primary cause of death. However, CBT without ATG is associated with a significant risk of GVHD, and serious infections remain a challenge, especially in the setting of GVHD. New strategies are needed to further reduce infectious complications after CBT; these will require earlier neutrophil recovery and more effective prevention of GVHD, ideally without the profound T cell depletion associated with ATG therapy.
Cord blood transplantation (CB-T) is increasingly used as a treatment alternative for hematologic malignancies. However, how CB-T compares to related (RD-T) and unrelated donor transplantation (URD-T) is not established. We compared survival of 75 double-unit CB-T, 108 RD-T, and 184 URD-T recipients who received transplants over the same period for the treatment of hematologic malignancies. Patients had similar ages and disease risk, and a similar percentage had acute leukemia. The incidence of day 180 transplant-related mortality (TRM) of 21% (95% confidence interval [CI]: 12-31) after CB-T was higher than that of RD-T recipients. However, this was compensated for by a low risk of TRM after day 180, and a relatively low incidence of relapse. Hence, the 2-year progression-free survival (PFS) of 55% (95% CI: 45-68) after CB-T was similar to that after RD-T or URD-T (P = .573). In multivariate analysis, donor source had no influence on PFS, with the only significant factors being recipient age and disease risk. In a subanalysis of 201 patients with acute leukemia, CB-T, RD-T, and URD-T recipients also had similar 2-year disease-free survival (P = .482). These data provide strong support for the further investigation of double-unit CB grafts as an alternative hematopoietic stem cell source.
Use of unrelated donor cord blood (CB) as an alternative stem cell source is increasing, and yet there is little information to guide transplant centers in the unique aspects of the search and selection of CB grafts. There is no mechanism to easily access the global inventory of CB units, nor is the product information provided by all banks standardized. To address these challenges, this manuscript reviews the logistics of the search, selection process, and acquisition of CB grafts as practiced by our center. Topics include who should be considered for a CB search, how to access the global CB inventory, and how to balance total nucleated cell dose and human leukocyte antigen match in unit selection. We discuss aspects of unit quality and other graft characteristics (processing methods, unit age, availability of attached segments, infectious disease, and hemoglobinopathy screening) to be considered. We incorporate these considerations into a unit selection algorithm, including how to select double-unit grafts. We also describe how we plan for unit shipment and the role of backup grafts. This review aims to provide a framework for CB unit selection and help transplantation centers perform efficient CB searches.
The influence of cell dose and human leukocyte antigen (HLA) match on double-unit cord blood (CB) engraftment is not established. Therefore, we analyzed the impact of cell dose and high-resolution HLA match on neutrophil engraftment in 84 double-unit CB transplant recipients. The 94% sustained engraftment rate was accounted for by 1 unit in nearly all patients. Higher CD3(+) cell doses (P = .04) and percentage of CD34(+) cell viability (P = .008) were associated with unit dominance. After myeloablative conditioning, higher dominant unit total nucleated cell (TNC), CD34(+) cell, and colony-forming unit doses were associated with higher sustained engraftment and faster neutrophil recovery (P = .07, P = .0008, and P < .0001, respectively). Total infused TNC (P = .0007) and CD3(+) cell doses (P = .001) also significantly influenced engraftment. At high-resolution extensive donor-recipient HLA disparity was frequent, but had no influence on engraftment (P = .66), or unit dominance (P = .13). Although the unit-unit HLA match also did not affect sustained engraftment (P = 1.0), recipients of units closely (7-10 to 10-10) HLA-matched to each other were more likely to demonstrate initial engraftment of both units (P < .0001). Our findings have important implications for unit selection and provide further insight into double-unit biology.
Allogeneic transplant access can be severely limited for patients of racial and ethnic minorities without suitable sibling donors. Whether cord blood (CB) transplantation can extend transplant access because of the reduced stringency of required HLA-match is not proven. We prospectively evaluated availability of unrelated donors (URD) and CB according to patient ancestry in 553 patients without suitable sibling donors. URDs had priority if adequate donors were available. Otherwise ?4/6 HLA-matched CB grafts were chosen utilizing double units to augment graft dose. Patients had highly diverse ancestries including 35% non-Europeans. In 525 patients undergoing combined searches, 10/10 HLA-matched URDs were identified in 53% of those with European ancestry, but only 21% of patients with non-European origins (P < .001). However, the majority of both groups had 5-6/6 CB units. The 269 URD transplant recipients were predominantly European, with non-European patients accounting for only 23%. By contrast, 56% of CB transplant recipients had non-European ancestries (P < .001). Of 26 patients without any suitable stem cell source, 73% had non-European ancestries (P < .001). Their median weight was significantly higher than CB transplant recipients (P <.001), partially accounting for their lack of a CB graft. Availability of CB significantly extends allo-transplant access, especially in non-European patients, and has the greatest potential to provide a suitable stem cell source regardless of race or ethnicity. Minority patients in need of allografts, but without suitable matched sibling donors, should be referred for combined URD and CB searches to optimize transplant access.
Umbilical-cord blood (UCB) is increasingly considered as an alternative to peripheral blood progenitor cells (PBPCs) or bone marrow, especially when an HLA-matched adult unrelated donor is not available. We aimed to determine the optimal role of UCB grafts in transplantation for adults with acute leukaemia, and to establish whether current graft-selection practices are appropriate.
The aims of this review are to summarize the relevant published literature regarding cord blood (CB) graft characteristics and their impact on transplantation outcomes, to present new analyses from patients transplanted with CB units from the New York Blood Centers National Cord Blood Program, and to propose new guidelines for prioritizing CB unit selection.
Both total nucleated cell (TNC) dose and human leukocyte antigen (HLA)-match affect the outcome of cord blood (CB) transplantation. However, how to prioritize these characteristics in unit selection is not established. Therefore, we analyzed the outcomes of 1061 patients who received single-unit myeloablative CB transplantation for leukemia or myelodysplasia. TNC dose and HLA-match each affected survival via their effect on transplant-related mortality (TRM); neither was associated with relapse. Therefore, TRM was the focus of multivariate analyses combining dose and HLA-match. Compared with our 1 HLA-mismatch (MM) reference group with TNC 2.5 to 4.9 x 10(7)/kg, recipients of 0 MM units had the lowest TRM regardless of dose (relative risk [RR] = 0.4, P = .019). TRM for recipients of 1- or 2-MM units with TNC 5.0 x 10(7)/kg or greater was similar to the reference group (RR = 0.8, P = .391 and RR = 1.0, P = .847) despite their greater dose. Recipients of 2 MM units with TNC 2.5 to 4.9 x 10(7)/kg had a greater TRM (RR = 1.5, P = .014), and those with 1 or 2 MM and TNC less than 2.5 x 10(7)/kg or 3 MM did substantially worse. These findings support new unit selection criteria that take into account both TNC dose and HLA-match and have important implications for the size of the global CB inventory needed to find an optimum CB graft.
Cord blood (CB) hematopoietic stem cell transplantation can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result from tolerance-inducing events during pregnancy but to date this concept has not been tested in CB transplantation. Hence we analyzed the impact of fetal exposure to noninherited maternal antigens (NIMA) of the HLA-A, -B antigens, or -DRB1 alleles on the outcome of CB transplants. The 1,121 patients studied were transplanted for hematological malignancy with a single CB unit: 1,059 received grafts mismatched for one or two HLA antigens. Of these patients, 79 patients had a mismatched antigen that was identical to a donor NIMA, 25 with one HLA mismatch (MM), and 54 with two. If there was a NIMA match, transplant-related mortality (TRM) was improved, especially in patients >or=10 years (P = 0.012) as were overall mortality and treatment failure (P = 0.022 and 0.020, respectively, in the older subset), perhaps related to improved neutrophil recovery, especially in patients who received a low total nucleated cell (TNC) dose (P = 0.031). Posttransplant relapse rate also tended to be reduced, especially in patients with myelogenous malignancies given units with a single HLA mismatch (P = 0.074). These findings represent unique evidence that donor exposure to NIMA can improve survival in unrelated CB transplantation and might reduce relapse, indicating that cord blood cells can mount an antileukemic effect. By matching for donor NIMAs in search algorithms of CB inventories, the probability of selecting a graft with an optimal outcome will increase significantly.
Double unit cord blood (CB) transplantation (CBT) appears to augment engraftment despite only one unit engrafting in most patients. We hypothesized that superior unit quality, as measured by a higher percentage of viable cells postthaw, would determine the engrafting unit. Therefore, we prospectively analyzed 46 double-unit transplants postthaw using flow cytometry with modified gating that included all dead cells. Using a 75% threshold (mean viability minus 2 SD), 20% of units had low CD34+ cell viability, with viability varying according to the bank of origin. Further, in the 44 patients with single unit engraftment, CD34+ cell viability was higher in engrafting units (P=.0016). Although either unit engrafted if both had high CD34+ viability, units with <75% viability were very unlikely to engraft: in 16 patients who received one high and one low CD34+ viability unit, only 1 of 16 units with viability <75% engrafted (P=.0006). Further, in the single patient without engraftment of either unit, both had CD34+ viability <75%. Finally, poor CD34+ viability correlated with lower colony forming units (CFUs) (P=.02). Our data suggests one mechanism by which double unit CBT can improve engraftment is by increasing the probability of transplanting at least one unit with adequate viability and the potential to engraft.
Pre-engraftment syndrome (PES) occurring after cord blood transplantation (CBT) is poorly characterized. We reviewed 52 consecutive double-unit CBT recipients treated for high-risk hematologic malignancies. PES was defined as unexplained fever >38.3 degrees C (101 degrees F) not associated with infection and unresponsive to antimicrobials, and/or unexplained rash occurring before or at neutrophil recovery. CBT recipients (median age, 38 years; range, 3-66 years) received either myeloablative (MA; n=36) or nonmyeloablative (NMA; n=16) conditioning. Sixteen patients (31%) fulfilled PES criteria: 15 with fever (median at onset, 39 degrees C [102.2 degrees F]), 13 of whom also had rash, and 1 with rash alone. The median onset was 9 days (range, 5-12 days) posttransplantation (a median of 14 days before neutrophil recovery). Sixteen patients (14 with PES and 2 with infection and possible PES) received intravenous methylprednisolone (median dose, 1mg/kg; median duration, 3 days); 15 (94%) experienced resolution of fever within 24 hours. Recurrent PES (n=3) resolved with retreatment. There was no association between the development of PES and the likelihood of sustained donor engraftment, speed of neutrophil recovery, grade II-IV acute graft-versus-host disease (aGVHD), day-180 treatment-related mortality (TRM), or survival. PES is common after CBT, precedes neutrophil recovery, is distinct from and does not predict for aGVHD, and responds promptly to short-course corticosteroid therapy.
Preparation of cord blood (CB) units for infusion by albumin-dextran dilution without centrifugation may be advantageous for adult patients to minimize cell loss and, unlike a bedside thaw, is still conducted in the controlled laboratory environment. Therefore, we studied CB transplantation (CBT) using this technique in 54 consecutive CBT recipients >20 kg. Patients (median age=42 years [range: 7-66 years]; median weight=71 kg [range: 24-109]) were transplanted for high-risk hematologic malignancies with myeloablative (n=35) or nonmyeloablative (n=19) conditioning and 4-6/6 human leukocyte antigen (HLA)-matched double-unit grafts. One hundred seven units were thawed with dilution, whereas 1 red blood cell (RBC)-replete unit was washed. A 5:1 dextran 40%/25% albumin solution was used. RBC-depleted units (n=104) were diluted >or=5.5-fold (median final volume 200 mL [range: 200-500]), whereas RBC-replete units (n=3) were diluted >or=4-fold (median final volume 400 mL [range: 400-535]). Total nucleated cell (TNC) recovery was 86%; the median infused TNC dose was 2.17x10(7)/kg/unit. Although 35 patients (65%) had a total of 45 infusion reactions (6 nausea, 31 hypertension, 3 pain, 1 rigors/fever, 2 transient hypoxia, 2 renal impairment) requiring additional therapy, there were no infusion-related serious adverse events, and reactions were not related to dimethyl sulfoxide (DMSO) dose/kg. Cumulative incidence of sustained donor engraftment was 94% (95% cumulative incidence [CI]: 87-100) with neutrophil recovery occurring at a median of 25 days (range: 13-43) in myeloablative and 10 days (range: 7-36) in nonmyeloablative recipients. CB thaw with albumin-dextran dilution reduces unit manipulation, and minimizes cell loss, speeds time to infusion, is associated with a tolerable infusion reaction profile, and a high rate of sustained engraftment in CBT recipients >or=20 kg.
Human cord blood (CB) units donated for transplantation require testing for various markers in blood and plasma aliquots. Although the identity link between the CB unit and the labeled aliquots with the same identifiers can be confirmed by HLA-DNA assays, these methods have not been used for CB plasma. We have previously reported that viral DNA sequences are present in the CB plasma of carrier babies and now hypothesize that human genomic DNA may also be present in CB plasma.
In contrast to the very high transplant-related mortality (TRM) associated with the early experience of cord blood (CB) transplantation (CBT), recent transplant series have been associated with comparable survival to that of human leucocyte antigen (HLA)-matched unrelated donor transplantation in children with similarly promising results in adults. Consequently, the use of CB as an alternative stem cell source and the global inventory of units in public banks are rapidly increasing although challenges remain. This review will address efforts to optimize CBT from 3 different perspectives: that of the transplant center, the CBT registry, and the CB bank.
Cell dose is a major limitation for umbilical cord blood (UCB) transplantation because units containing a minimum of 2.5 x 10(7) total nucleated cells (TNC)/kilogram patient body weight are frequently not available. The transplantation of 2 partially HLA-matched UCB units has been adopted as a simple approach for increasing the TNC.We sought to determine whether the relative safety and efficacy of this approach was comparable with a single UCB transplantation. Included are adults with acute leukemia who received transplants with 1 (n =106) or 2 (n =303) UCB units. All UCB units for single UCB transplantations contained TNC ? 2.5 x 10(7)/kg. For double UCB transplantations, the total TNC for units 1 and 2 were > 2.5 x 10(7)/kg but in approximately half of these transplantations, 1 of the 2 units contained < 2.5 x 10(7) TNC/kg. Adjusting for factors associated with outcomes, risks of neutrophil recovery (odds ratio 0.83, P =.59), transplantation-related mortality (hazard ratio [HR] 0.91, P= .63), relapse (HR 0.90, P= .64), and overall mortality (HR 0.93, P= .62) was similar after double UCB and adequate dose single UCB transplantations. These data support double UCB unit transplantation for acute leukemia when an adequately dosed single UCB unit is not available thereby extending access to nearly all patients.
The inability to obtain additional stem cells is a disadvantage of unrelated donor cord blood transplantation (CBT). Moreover, in the event of problems with unit shipment, compromised unit quality, thaw mishaps, or graft failure, the time to secure a back-up graft could be unacceptable. Emergent shipment of 1 to 2 back-up units that have been previously typed and reserved could overcome this limitation. However, the advantages of this approach are not established. Therefore, we present our use of back-up units over a 5.5-year period. Six of 121 CBT recipients (5%) required back-up unit infusion. Indications included shipment mishaps (n = 2), poor unit viability (n = 2), significant infusion reaction (n = 1), and graft failure (n = 1). Lack of back-up units would have caused transplantation delay or infusion of inferior-quality units. Five of the 6 patients achieved sustained donor engraftment. We demonstrate that back-up units are emergently required in a significant minority of patients, supporting the incorporation of at least 1 back-up unit in cord blood (CB) selection algorithms to enhance CBT safety.
During pregnancy women can develop B- and T-cell immunity against the inherited paternal antigens (IPAs) of the fetus, such as HLA, peptides of minor histocompatibilty antigens, and possibly onco-fetal antigens. The biological and pathological role of these pregnancy-induced immunological events is only understood in part. However, anti-IPA immunity in the mother persists for many decades after delivery and may reduce relapse in offspring with leukemia after HLA-haploidentical transplantation of maternal hematopoietic stem cells (HSC). We hypothesized that maternal anti-IPA immune elements cross the placenta and might confer a potent graft-versus-leukemia effect when cord blood (CB) is used in unrelated HSC transplantation. In a retrospective study of single-unit CB recipients with all grafts provided by the New York Blood Center, we show that patients with acute myeloid or lymphoblastic leukemia (n = 845) who shared one or more HLA-A, -B, or -DRB1 antigens with their CB donors IPAs had a significant decrease in leukemic relapse posttransplantation [hazard ratio (HR) = 0.38, P < 0.001] compared with those that did not. Remarkably, relapse reduction in patients receiving CB with one HLA mismatch (HR = 0.15, P < 0.001) was not associated with an increased risk of severe acute graft-versus-host disease (HR = 1.43, P = 0.730). Our findings may explain the unexpected low relapse rate after CB transplantation, open new avenues in the study of leukemic relapse after HSC transplantation (possibly of malignancies in general), and have practical implications for CB unit selection.
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