Active infection at the time of CD34+ selected stem cell boost is associated with treatment failure and poor overall survival.

ABSTRACT: The use of CD34+ selected stem cell boost (SCB) after allogeneic hematopoietic cell transplant (allo-HCT) has been increasing. Predictors of treatment failure after SCB, both in the context of poor graft function (PGF) or other settings, are not well characterized. We report among the largest single-center retrospective experiences of the use of SCB and evaluate potential predictors of response and outcomes. A total of 58 patients who underwent HCT between 2015 and 2022 and who received SCB, were identified. The indication for SCB was predominantly PGF, defined as the presence of ≥2 cytopenias for at least 2 consecutive weeks beyond day +14 after allo-HCT in the presence of ≤30% bone marrow cellularity and ≥90% donor myeloid chimerism in the absence of morphologic disease. The median dose of infused CD34+ selected SCB products was 3.88 × 106 CD34+ cells per kg (range, 0.99 × 106 to 9.92 × 106). The median 2-year overall survival and nonrelapse mortality after SCB was 47% and 38%, respectively. The cumulative incidences of 6-month grade 3 to 4 acute and 2-year moderate-severe chronic graft-versus-host disease after SCB were 3.4% and 12%, respectively. Overall response (complete response + partial response) was attained in 36 of 58 patients (62%) and in 69% of patients with PGF. On multivariable analysis, an active infection at the time of SCB was the greatest predictor of poor response and survival (P = .013) after SCB. SCB can restore hematopoiesis in the majority of patients, particularly for those with PGF and in whom there is no active infection at the time of infusion.

Impact of cryopreservation and transit times of allogeneic grafts on hematopoietic and immune reconstitution.

We sought to evaluate the impact of cryopreservation of unrelated donor (URD) peripheral blood stem cell (PBSC) grafts on engraftment, chimerism, and immune reconstitution in the context of the COVID-19 pandemic. We reviewed stem cell product characteristics and clinical outcomes in 101 patients receiving cryopreserved PBSCs from URDs between January 1, 2019 and 31 December, 2020, compared with 203 patients receiving fresh URD PBSCs. We observed no differences in 6-month overall survival, progression-free survival, or nonrelapse mortality. Patients receiving cryopreserved PBSCs had delayed platelet engraftment and impaired reconstitution of white blood cells and T-cell subsets at day 30. Thirty-four percent of patients receiving cryopreserved grafts had CD3 chimerism <50% at day 30 after transplantation, compared with 14% of patients receiving fresh PBSCs (P = .0002). At day 100, this difference persisted (CD3+ chimerism <50%: 17% of cryopreserved cohort vs 6% of fresh cohort; P = .016). Greater product age at infusion was associated with increased graft failure, independent of cryopreservation. Receipt of grafts >48 hours old at time of cryopreservation or infusion significantly increased the risk of graft failure (subdistribution hazard ratio = 4.57; 95% confidence interval, 1.71-12.3; P = .0025). Our data indicate that cryopreservation is associated with similar overall short-term clinical outcomes compared with fresh PBSC. However, patients must be monitored closely for increased risk of other potentially adverse outcomes, including graft failure and poor immune recovery, particularly for grafts with older overall age at infusion. Longer-term follow-up is needed to determine impact on relapse and survival.

Lack of impact of umbilical cord blood unit processing techniques on clinical outcomes in adult double cord blood transplant recipients.

BACKGROUND AIMS: Despite widespread use of umbilical cord blood (UCB) transplantation and distinct practice preferences displayed by individual UCB banks and transplant centers, little information exists on how processing variations affect patient outcomes. METHODS: We reviewed 133 adult double UCB transplants performed at a single center: 98 after reduced-intensity and 35 after myeloablative conditioning. Processing associated with contributing UCB banks and units was surveyed to identify differences in practice. We analyzed effect of selected variables on clinical outcomes of engraftment, dominance, transplant-related mortality, and survival. RESULTS: Eighty-eight percent of banks queried currently practice red blood cell (RBC) depletion before cryopreservation. This reflects a shift in practice because previously 65% of banks employed RBC-replete processing methods (i.e., cryopreservation or plasma/volume reduction). Neither neutrophil nor platelet engraftment was affected by processing conditions analyzed. RBC depletion was not associated with clinical outcomes, except in 17 recipients of 2 RBC-replete units, where survival was better than that observed in 116 recipients of ≥1 RBC-depleted units (hazard ratio 3.26, P = 0.004). When analyzed by attributes of the dominant unit, RBC depletion, time in storage, bank years in existence, and inventory size did not affect clinical outcomes. Postthaw viability and CD34 dose were factors impacting engraftment. Notably, all RBC-replete units in this cohort were washed in dextran-human serum albumin before infusion. DISCUSSION: These findings support continued utilization of the entire existing pool of cord blood units, despite recent trends in processing, and have important implications for banking resources and UCB selection practices.

Reduced-intensity conditioning stem cell transplantation: comparison of double umbilical cord blood and unrelated donor grafts.

There are little data comparing umbilical cord blood (UBC) and conventional stem cell sources for reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT). We performed a retrospective analysis of RIC HCST using double UCB (dUCB) grafts and RIC HSCT using unrelated donor (URD) grafts. The study included 64 dUCB transplantations and 221 URD transplantations performed at Dana-Farber Cancer Institute and Massachusetts General Hospital between 2004 and 2008. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 14.1% for dUCB and 20.3% for URD (P = .32). The 2-year cumulative incidence of chronic GVHD was significantly lower in dUCB compared with URD (21.9% versus 53.9%; P < .0001). The 2-year cumulative incidence of nonrelapse mortality was significantly higher in dUCB (26.9% versus 10.4%; P = .0009). In our analysis, dUCB HSCT and URD HSCT had comparable 3-year overall survival (46% in dUCB and 50% in URD; P = .49) and progression-free survival (30% in dUCB and 40% in URD; P = .47). dUCBT was associated with greater nonrelapse mortality despite less chronic GVHD. Our findings suggest that the use of 2 partially matched UCB units appears to be a suitable alternative for patients undergoing RIC HSCT without an HLA-matched donor.

Use of matched unrelated donors compared with matched related donors is associated with lower relapse and superior progression-free survival after reduced-intensity conditioning hematopoietic stem cell transplantation.

As success of reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) relies primarily on graft-versus-leukemia (GVL) activity, increased minor HLA disparity in unrelated compared to related donors could have a significant impact on transplant outcomes. To assess whether use of unrelated donors (URD) engenders more potent GVL in RIC HSCT compared to matched related donors (MRD), we retrospectively studied 433 consecutive T-replete 6/6 HLA matched URD (n = 246) and MRD (n = 187) RIC HSCT for hematologic malignancies at our institution. Diseases included: acute myelogenous leukemia (AML) (127), non-Hodgkin lymphoma (NHL) (71), chronic lymphocytic leukemia (CLL) (68), myelodysplastic syndrome (MDS) (64), Hodgkin disease (HD) (40), chronic myeloid leukemia (CML) (25), multiple myeloma (MM) (23), myeloproliferative disorder (MPD) (12), acute lymphoblastic leukemia (ALL) (7), and other leukemia (1). All received uniform fludarabine and intravenous busulfan conditioning, and GVHD prophylaxis with tacrolimus/mini-methroxate (mini-MTX) or tacrolimus/sirolimus ± mini-MTX. Unrelated donors were younger compared to MRD (median donor age: 33 years versus 52 years, P < .0001), and provided larger CD34(+) products (median CD34(+) cells infused: 8.7 × 10(6)/kg versus 7.5 × 10(6)/kg, P = .002). Distribution of diseases, disease risk, prior transplant, and cytomegalovirus (CMV) status was similar in both cohorts. Cumulative incidence of grade II-IV acute GVHD (at day +180), 2-year chronic GVHD, and 2-year nonrelapse mortality (NRM) were 20% versus 16%, 55% versus 50%, and 8% versus 6% in URD and MRD, respectively (P = NS). Cumulative incidence of relapse at 2 years was lower in URD, 52% versus 65% (P = .005). With median follow-up of 26.5 and 35.8 months, 2-year progression-free survival (PFS) was significantly better in unrelated donor transplants, 39.5% for URD, and 29% for MRD (P = .01). Overall survival (OS) at 2 years were 56% for URD versus 50% for MRD (P = .53). In multivariable analysis, URD was associated with a lower risk of relapse (hazard ratio [HR] 0.67, P = .002) and superior PFS (HR 0.69, P = .002). These results suggest that URD is associated with greater GVL activity than MRD, and could have practice changing impact on future donor selection in RIC HSCT.

Donor-derived second hematologic malignancies after cord blood transplantation.

Double umbilical cord blood transplantation (UCBT) with a reduced-intensity conditioning regimen is an effective strategy for adult patients without a matched donor. The risk of second malignancies in these patients has not yet been established, however. In the present study, 98 adults with a hematologic malignancy underwent double UCBT. Seventy patients received a reduced-intensity conditioning regimen of fludarabine 30 mg/m(2)/day for 6 days, melphalan 100 mg/m(2)/day for 1 day, and rabbit antithymocyte globulin 1.5 mg/kg/day for 4 days, and 28 patients received a myeloablative total body radiation-containing conditioning regimen. Sixty-three patients received sirolimus-based graft-versus-host disease (GVHD) prophylaxis, and 35 patients received non-sirolimus-based GVHD prophylaxis. The median patient age was 48 years (range, 19-67 years). Eighteen patients developed a second malignancy at a median of 134 days after transplantation. Sixteen patients had lymphoma, and 2 patients had myelodysplasic syndrome/myeloproliferative disorder (MDS/MPD). Sixteen of these second malignancies (both cases of MDS/MPD and 14 of the lymphomas) were donor-derived; the origins of the others were not determined. GVHD prophylaxis, HLA matching, primary disease, age, total nucleated cell dose, and CD34(+) cell dose were not associated with a higher rate of second malignancy. Second myelogenous malignancies of donor origin occur after double UCBT, suggesting that a search for donor origin should be performed in all patients with suspected relapse.

Clearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis.

Umbilical cord blood grafts are increasingly used as sources of hematopoietic stem cells in adults. Data regarding the outcome of this approach in adults are consistent with delayed and insufficient immune reconstitution resulting in high infection-related morbidity and mortality. Using cytomegalovirus (CMV)-specific immunity as a paradigm, we evaluated the status, mechanism, and clinical implications of immune reconstitution in adults with hematologic malignancies undergoing unrelated double unit cord blood transplantation. Our data indicate that CD8(+) T cells capable of secreting interferon-gamma (IFN-gamma) in a CMV-specific enzyme-linked immunosorbent spot (ELISpot) assay are detectable at 8 weeks after transplantation, before reconstitution of thymopoiesis, but fail to clear CMV viremia. Clearance of CMV viremia occurs later and depends on the recovery of CD4(+)CD45RA(+) T cells, reconstitution of thymopoiesis, and attainment of T-cell receptor rearrangement excision circle (TREC) levels of 2000 or more copies/mug DNA. In addition, overall survival was significantly higher in patients who displayed thymic regeneration and attainment of TREC levels of 2000 or more copies/mug DNA (P = .005). These results indicate that reconstitution of thymopoiesis is critical for long-term clinical outcome in adult recipients of umbilical cord blood transplant. The trial was prospectively registered at http://www.clinicaltrials.gov (NCT00133367).

High-resolution HLA matching in double-umbilical-cord-blood reduced-intensity transplantation in adults.

BACKGROUND: Double-cord-blood transplantation (DCBT) offers an option for patients receiving reduced-intensity transplants. These unique transplants have two donors, both of whom are usually HLA mismatched at one to two loci. STUDY DESIGN AND METHODS: Fifty-three patients were recipients of a reduced-intensity DCBT. Cords were at least 4/6 allele-level HLA-A, -B, and -DR match with the patient and each other with a minimum combined cell dose of more than 3.7 x 10(7) total nucleated cells per kg. Twenty-one patients received cyclosporine/mycophenolate mofetil and 32 patients received sirolimus/tacrolimus (SIR/TAC) for graft-versus-host disease prophylaxis. The effect of allele level HLA typing on clinical endpoints of overall survival (OS), disease-free survival (DFS), engraftment, and acute graft-versus-host disease (aGVHD) were assessed. RESULTS: Neutrophil (p = 0.001) engraftment and platelet engraftment (p = 0.027) were significantly faster in patients who have closer Class I (HLA-A, -B, -C) matching. Neutrophil engraftment was faster in patients who had closer HLA-B matching to their combined cords (p = 0.007). There was a low incidence of aGVHD overall, especially in the SIR/TAC group. Class I HLA matching had no effect on aGVHD. HLA-DR and -DQ had no effect on engraftment or aGVHD. CONCLUSION: Class I allele matching, and HLA-B matching specifically, were associated with faster neutrophil engraftment. High-resolution HLA matching did not affect OS or DFS.

Double unrelated reduced-intensity umbilical cord blood transplantation in adults.

Umbilical cord blood (UBC) stem cells are a useful stem cell source for patients without matched related or unrelated donors. Adult transplantation with single UBC units is associated with high transplantation-related mortality (TRM). In most cases, mortality is due to infection related to slow engraftment and immunoincompetence. In this study, we used a reduced-intensity conditioning regimen of fludarabine, melphalan, and antithymocyte globulin followed by 2 partially matched UBC units. The UBC units were a 4/6 HLA match or better with each other and with the patient and achieved a minimum precryopreservation cell dose of 3.7 x 10(7) nucleated cells/kg. A total of 21 patients (median age, 49 years) were treated. The median time to an absolute neutrophil count > 0.5 x 10(9)/L was 20 days, and the median time to an unsupported platelet count > 20 x 10(9)/L was 41 days. Two patients experienced primary graft failure and underwent a second UBC transplantation. One patient had a late graft failure. Acute graft-versus-host disease (GVHD) grade II-IV occurred in 40% of patients. The 100-day TRM was 14%, and the 1-year disease-free survival was 67%. Mixed chimerism was associated with a higher risk of chronic GVHD. Our findings indicate that adult patients can tolerate double UBC transplantation well and achieve sustained antitumor responses using this reduced-intensity conditioning regimen.

Comparable outcome with T-cell-depleted unrelated-donor versus related-donor allogeneic bone marrow transplantation.

To assess the effect of related versus unrelated donors on outcomes in patients following T-cell-depleted (TCD) allogeneic BMT, we compared engraftment, GVHD, relapse rates, and survival in BMT patients who received CD6+ TCD marrow from HLA-matched related donors (MRD) with those in patients who received CD6+ TCD marrow from unrelated donors (URD). A total of 170 consecutive patients (120 with related donors, 50 with unrelated donors) were analyzed. The 2 groups were similar in age, sex, prior cytomegalovirus exposure, and stage of disease at the time of transplantation. GVHD prophylaxis was identical in the 2 groups, with TCD as the only method of GVHD prophylaxis. The total number of nucleated, CD34+, CD33+, and CD6+ cells infused did not significantly differ between the 2 groups. The median day to reach 500 x 10(6) neutrophils/L was 12 days for both related (range, 8-22 days) and unrelated (range, 9-23 days) graft recipients (P = .92). Incidence of grades 2 through 4 acute GVHD was higher in URD than in MRD recipients (42% versus 20%, P = .004). According to multivariable analysis results, donor source was the single most important factor influencing GVHD (P = .01). The 2-year estimated risk of relapse was 45.9% in MRD recipients compared to 25.7% in URD recipients (P = .06). Multivariable analysis revealed that the 2 most pertinent factors adversely affecting overall survival were advanced disease stage (P = .0002) and age greater than 50 years (P = .0003) at transplantation. There was no difference in relapse-free survival in URD and MRD recipients. We conclude that for patients undergoing TCD-BMT, use of unrelated marrow is associated with a higher risk of GVHD and other transplantation-related complications. However, these adverse events do not lead to inferior probability of relapse-free survival because they are accompanied by a reduction in relapse rates.