Cytomegalovirus-Specific Immunity Recovers More Slowly after Cord Blood Transplantation Compared with Matched Sibling Donor Allogeneic Transplantation.

BACKGROUND: Rapid quantitative recovery of NK cells but slower recovery of T-cell subsets along with frequent viral infections are reported after umbilical cord blood (UCB) compared with matched sibling donor (MSD) hematopoietic cell transplantation (HCT). However, it remains unclear whether increased propensity for viral infections is also a result of slower recovery of virus-specific immunity after UCB as compared to MSD HCT. OBJECTIVES: We examined the differences in the function of virus-specific peripheral blood mononuclear cells (PBMC) after UCB (N=17) vs. MSD (N=9) using previously collected patient blood samples at various time points after HCT. METHODS: Interferon-gamma (IFN-γ) enzyme-linked immune absorbent spot (ELISpot) assay was used to quantify the PBMC frequencies that secrete IFN-γ in response to 11 immunopeptides from 5 common viruses. We included the patients who received the same reduced intensity conditioning regimen without ATG, no systemic glucocorticoids and had no relapse or acute/chronic graft-versus-host disease within 1 year after HCT. RESULTS: The CMV-reactive PBMC frequencies were higher in CMV seropositive vs. seronegative patients after HCT. Among CMV seropositive patients, the frequency of CMV-reactive PBMC was lower after UCB compared to MSD throughout one year of HCT. We observed no differences in virus-specific PBMC responses towards HHV6, EBV, BK, and adenovirus antigens between UCB and MSD. CONCLUSION: Our data demonstrate that the reconstitution of CMV-specific immunity is slower in CMV seropositive recipients of UCB vs. MSD HCT in contrast to other viruses which had similar recoveries. These study findings support implementation of more potent prophylactic strategies for preventing CMV reactivation in CMV seropositive patients receiving UCB HCT.

Improving outcomes after allogeneic hematopoietic cell transplantation for Hodgkin lymphoma in the brentuximab vedotin era.

Allogeneic hematopoietic cell transplantation (alloHCT) remains a valuable treatment alternative for relapsed/refractory (R/R) Hodgkin lymphoma (HL). Data on alloHCT outcomes in the era of new HL therapies are needed. We evaluated 72R/R HL patients who received reduced intensity conditioning alloHCT and compared the time periods 2009-2013 (n=20) with 2000-2008 (n=52). Grafts included HLA-matched sibling (35%), unrelated donor (8%) and umbilical cord blood (56%). In the recent period, patients more often received brentuximab vedotin (BV, 60% vs 2%), had fewer comorbidities (Sorror index 0: 60% vs 12%) and were in complete remission (50% vs 23%). Median follow-up was 4.4 years. Three-year PFS improved for patients treated between 2009 and 2013 (49%, 95% CI 26-68%) as compared with the earlier era (23%, 95% CI 13-35%, P=0.02). Overall survival (OS) at 3 years was 84% (95% CI 57-94%) vs 50% (95% CI 36-62%, P=0.01), reflecting lower non-relapse mortality and relapse rates. In multivariate analysis mortality was higher among those with chemoresistance (HR 3.83, 95% CI 1.38-10.57), while treatment during the recent era was associated with better OS (HR for period 2009-2013: 0.24, 95% CI 0.07-0.79) and PFS (HR 0.46, 95% CI 0.23-0.92). AlloHCT in patients with R/R HL is now a more effective treatment than previously.

Outcomes of UCB transplantation are comparable in FLT3+ AML: results of CIBMTR, EUROCORD and EBMT collaborative analysis.

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.

MDS disease characteristics, not donor source, predict hematopoietic stem cell transplant outcomes.

Myelodysplastic syndrome (MDS) is a heterogeneous group of hematological malignancies with considerably variable prognoses and curable only with hematopoietic cell transplantation (HCT). Few studies comparing MDS HCT outcomes between sibling and umbilical cord blood (UCB) donors exist. Using the University of Minnesota Blood and Marrow Transplant (BMT) database, we retrospectively analyzed HCT outcomes among 89 MDS patients undergoing either sibling or double UCB HCT in 2000-2013. We observed similar survival, relapse and non-relapse mortality between sibling and UCB donor sources. Relapse was increased in those with monosomal karyotype (P=0.04) and with reduced intensity conditioning (P<0.01). In summary, our data highlight similar MDS HCT outcomes regardless of donor source and support the use of UCB as an alternative donor when a sibling is unavailable.

CD56dimCD57+NKG2C+ NK cell expansion is associated with reduced leukemia relapse after reduced intensity HCT.

We have recently described a specialized subset of human natural killer (NK) cells with a CD56(dim)CD57(+)NKG2C(+) phenotype that expand specifically in response to cytomegalovirus (CMV) reactivation in hematopoietic cell transplant (HCT) recipients and exhibit properties characteristic of adaptive immunity. We hypothesize that these cells mediate relapse protection and improve post-HCT outcomes. In 674 allogeneic HCT recipients, we found that those who reactivated CMV had lower leukemia relapse (26% (17-35%), P=0.05) and superior disease-free survival (DFS) (55% (45-65%) P=0.04) 1 year after reduced intensity conditioning (RIC) compared with CMV seronegative recipients who experienced higher relapse rates (35% (27-43%)) and lower DFS (46% (38-54%)). This protective effect was independent of age and graft-vs-host disease and was not observed in recipients who received myeloablative regimens. Analysis of the reconstituting NK cells demonstrated that CMV reactivation is associated with both higher frequencies and greater absolute numbers of CD56(dim)CD57(+)NKG2C(+) NK cells, particularly after RIC HCT. Furthermore, expansion of these cells at 6 months posttransplant independently trended toward a lower 2-year relapse risk. Together, our data suggest that the protective effect of CMV reactivation on posttransplant relapse is in part driven by adaptive NK cell responses.

Hemorrhagic cystitis after allogeneic hematopoietic cell transplantation: risk factors, graft source and survival.

Although hemorrhagic cystitis (HC) is a common complication of allogeneic hematopoietic cell transplantation (alloHCT), its risk factors and effects on survival are not well known. We evaluated HC in a large cohort (n=1321, 2003-2012) receiving alloHCT from all graft sources, including umbilical cord blood (UCB). We compared HC patients with non-HC (control) patients and examined clinical variables at HC onset and resolution. Of these 1321 patients, 219 (16.6%) developed HC at a median of 22 days after alloHCT. BK viruria was detected in 90% of 109 tested HC patients. Median duration of HC was 27 days. At the time of HC diagnosis, acute GVHD, fever, severe thrombocytopenia and steroid use were more frequent than at the time of HC resolution. In univariate analysis, male sex, age <20 years, myeloablative conditioning with cyclophosphamide and acute GVHD were associated with HC. In multivariate analysis, HC was significantly more common in males and HLA-mismatched UCB graft recipients. Severe grade HC (grade III-IV) was associated with increased treatment-related mortality but not with overall survival at 1 year. HC remains hazardous and therefore better prophylaxis, and early interventions to limit its severity are still needed.

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

The effect of equine antithymocyte globulin on the outcomes of reduced intensity conditioning for AML.

Whether or not the benefits of antithymocyte globulin (ATG) on engraftment and GVHD are offset by increased risk of relapse, delayed T-cell recovery and increased infections remains controversial. We retrospectively studied the effect of ATG in 144 AML patients, 34 of whom received ATG, undergoing reduced intensity conditioning (RIC) umbilical cord blood transplantation (UCB) or HLA-matched sibling PBSC. ATG patients had not received intensive chemotherapy for 3 months before transplantation for UCB, 6 months for PBSC. There were no differences in engraftment between ATG and non-ATG patients. The cumulative incidences of TRM as well as acute and chronic GVHD in ATG-treated patients were not statistically different. ATG patients had significantly more infections between 46 and 180 days post transplantation. Unexpectedly, after adjusting for donor type, relapse was lower among ATG recipients (relative risk (RR) 0.5, 95% confidence interval (CI) 0.3-1.0, P=0.04). In summary, administration of ATG to AML patients undergoing RIC had no adverse impact on major clinical outcomes. ATG may be indicated for patients at higher risk of graft failure after allogeneic hematopoietic cell transplantation (allo-HCT).

Clinical outcomes of AML patients relapsing after matched-related donor and umbilical cord blood transplantation.

AML relapse remains the leading cause of transplant failure among Allo-SCT recipients. A single institution study was conducted on 348 patients with AML who received an Allo-SCT from an umbilical cord blood (UCB, 222) or HLA-matched-related (RD, 126) donor between 2000-2011. Relapse after Allo-SCT occurred in 72 UCB and 32 RD transplant recipients. Three patients achieved CR after withdrawal of immune suppression with no further therapy. Fifty-two patients received intensive post-relapse therapy, defined as systemic chemotherapy (22 UCB, 7 RD), second Allo-SCT (nine UCB, two RD), or DLI±systemic chemotherapy (0 UCB, 12 RD); of these, 25% achieved CR (21% UCB vs 35% RD, P=0.16). Survival at 1 year after relapse was 22% for all patients (19% UCB vs 28% RD, P=0.36). In multivariable analysis, post-relapse mortality was lower in patients receiving intensive therapy for relapse (hazard ratio (HR)=0.4; 95% confidence interval (CI) 0.2-0.6, P<0.01) and higher in patients with peripheral blood blasts above the median (HR=3.8; 95% CI 2.2-6.6, P<0.01), active infection (HR=1.9; 95% CI 1.0-3.5, P=0.05) and non-infectious medical complications (HR=2.0; 95% CI 1.2-3.5, P=0.01). In conclusion, patients with AML relapsing after Allo-SCT who were in good-enough clinical condition to receive intensive therapy had superior short-term survival.

Higher therapeutic CsA levels early post transplantation reduce risk of acute GVHD and improves survival.

We studied whether early CsA trough levels were associated with the risk of acute GVHD in 337 patients after either sibling PBSC or double umbilical cord blood transplantation. All patients, regardless of donor type, started CsA at a dose of 5 mg/kg i.v. divided twice daily, targeting trough concentrations 200-400 ng/mL. The CsA level was studied by a weighted average method calculated by giving 70% of the weight to the level that was measured just before the onset of the event or day +30. We found that higher weighted average CsA trough levels early post transplantation contributed to lower risk of acute GVHD, and lower non-relapse and overall mortality. Thus, our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels in the first weeks of allo-HCT. In patients who are near or even modestly above the CsA target trough level, in the absence of CsA-related toxicity, dose reduction should be cautious to avoid subtherapeutic drug levels resulting in higher risk of acute GVHD.

Impact of ABO-mismatch on risk of GVHD after umbilical cord blood transplantation.

Recent advances in allogeneic hematopoietic cell transplant (allo-HCT) have led to an increasing use of alternative donors, including banked umbilical cord blood (UCB). Despite these advances, acute GVHD (aGVHD) and chronic GVHD (cGVHD) continue to be the leading causes of early and late transplant-related mortality. ABO-mismatch has been frequently reported as a risk factor for GVHD, however, data in the UCB recipients are limited. We hypothesized that as the lymphocytes in the cord blood are thought to be naive, they will therefore be less likely to mediate GVHD. Therefore, we analyzed the impact of ABO-mismatch on aGVHD and cGVHD in recipients of single and double UCB-HCT. In both univariate and multivariate analyses, presence of ABO-mismatch did not have an impact on aGVHD or cGVHD. Whereas ABO-compatible donors are preferred in recipients of URD-HCT, ABO compatibility generally need not be considered in recipients of UCB-HCT.

Factors predicting single-unit predominance after double umbilical cord blood transplantation.

Double umbilical cord blood transplantation (dUCBT), developed as a strategy to treat large number of patients with hematologic malignancies, frequently leads to the long-term establishment of a new hematopoietic system maintained by cells derived from a single umbilical cord blood unit. However, predicting which unit will predominate has remained elusive. This retrospective study examined the risk factor associated with unit predominance in 262 patients with hematologic malignancies who underwent dUCBT with subsequent hematopoietic recovery and complete chimerism between 2001 and 2009. Dual chimerism was detected at day 21-28, with subsequent single chimerism in 97% of the cases by day +100 and beyond. Risk factors included nucleated cell dose, CD34+ and CD3+ cell dose, colony-forming units-granulocyte macrophage dose, donor-recipient HLA match, sex and ABO match, order of infusion and cell viability. In the myeloablative setting, CD3+ cell dose was the only factor associated with unit predominance (odds ratio (OR) 4.4, 95% confidence interval (CI) 1.8-10.6; P<0.01), but in the non-myeloablative setting, CD3+ cell dose (OR 2.1, 95%CI 1.0-4.2; P=0.05) and HLA match (OR 3.4, 95%CI 1.0-11.4; P=0.05) were independent factors associated with unit predominance. Taken together, these findings suggest that immune reactivity has a role in unit predominance, and should be considered during graft selection and graft manipulation.

Reduced-intensity hematopoietic cell transplantation in older patients with AML/MDS: umbilical cord blood is a feasible option for patients without HLA-matched sibling donors.

Umbilical cord blood (UCB) has increased access to hematopoietic cell transplantation (HCT) for patients without HLA-matched sibling donors (MSD). We compared outcomes of HCT using MSD (N=38) or UCB (N=60) among older patients (age ≥ 55 years) with AML or myelodysplastic syndromes (MDS). All patients received a reduced intensity regimen consisting of CY, fludarabine and 200 cGy TBI. Median age at HCT was 63 years for MSD and 61 years for UCB recipients. Among UCB recipients, 95% received two UCB units and 88% received 1-2 locus HLA-mismatched units to optimize cell dose. OS at 3-years was 37% for MSD and 31% for UCB recipients (P=0.21). On multivariate analysis, donor source (MSD vs UCB) did not impact risks of OS, leukemia-free survival and relapse or treatment-related mortality. UCB is feasible as an alternative donor source for reduced-intensity conditioning HCT among older patients with AML and MDS who do not have a suitable MSD.

Umbilical cord blood: current status and future directions.

Once considered biological waste, umbilical cord blood (UCB) has become an accepted source of haematopoietic stem cells (HSCs). With initial success in the pediatric setting, UCB transplantation continues to gain favor in the adult patient population. Novel approaches to UCB transplantation include use of two units and a variety of graft manipulations. Additional uses for UCB are currently being explored and include applications in regenerative medicine and immunotherapy.

High fludarabine exposure and relationship with treatment-related mortality after nonmyeloablative hematopoietic cell transplantation.

Despite its common use in nonmyeloablative preparative regimens, the pharmacokinetics of fludarabine are poorly characterized in hematopoietic cell transplantation (HCT) recipients and exposure-response relationships remain undefined. The objective of this study was to evaluate the association between plasma F-ara-A exposure, the systemically circulating moiety of fludarabine, and engraftment, acute GVHD, TRM and OS after HCT. The preparative regimen consisted of CY 50 mg/kg/day i.v. day -6; plus fludarabine 30-40 mg/m²/day i.v. on days -6 to -2 and TBI 200 cGy on day -1. F-ara-A pharmacokinetics were carried out with the first dose of fludarabine in 87 adult patients. Median (range) F-ara-A area-under-the-curve (AUC((0-∞))) was 5.0 µg h/mL (2.0-11.0), clearance 15.3 L/h (6.2-36.6), C(min) 55 ng/mL (17-166) and concentration on day(zero) 16.0 ng/mL (0.1-144.1). Despite dose reductions, patients with renal insufficiency had higher F-ara-A exposures. There was strong association between high plasma concentrations of F-ara-A and increased risk of TRM and reduced OS. Patients with an AUC((0-∞)) greater than 6.5 µg h/mL had 4.56 greater risk of TRM and significantly lower OS. These data suggest that clinical strategies are needed to optimize dosing of fludarabine to prevent overexposure and toxicity in HCT.

Delayed platelet recovery after allogeneic transplantation: a predictor of increased treatment-related mortality and poorer survival.

Delayed platelet recovery (DPR) is common after allo-SCT. Insufficient data on risk factors and association with OS and TRM are available. We conducted a retrospective analysis of all allografts at the University of Minnesota between 2000 and 2005 to characterize the frequency of DPR (platelets <50 000/µL by day 60), risk factors and related complications. A total of 850 patients with hematological malignancies and benign disorders were included. Myeloablative (MA) conditioning was used in 65% of the patients and 45% received umbilical cord blood (UCB) grafts. The 60-day cumulative incidence of platelet recovery was 40% in UCB, 57% in unrelated donor (URD) and 74% in sibling donor. Multivariate analysis confirmed that the variables associated with DPR were MA (versus reduced intensity) conditioning, graft source other than sibling donor, ABO major mismatch, recipient CMV-positive serostatus, the presence of grade II-IV acute GVHD and slower neutrophil recovery. These data demonstrate that DPR is frequent after allogeneic hematopoietic cell transplantation, especially after UCB. DPR is a significant independent risk factor for increased TRM and poorer OS along with HLA-mismatched URD, but not UCB, grade II-IV acute GVHD, old age and advanced disease stage.