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Alemtuzumab and CXCL9 levels predict likelihood of sustained engraftment after reduced-intensity conditioning HCT
Geerlinks, A. V., Scull, B., Krupski, C., Fleischmann, R., Pulsipher, M. A., Eapen, M., Connelly, J. A., Bollard, C. M., Pai, S. Y., Duncan, C. N., et al
Blood advances. 2023;7(14):3725-3734
Abstract
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
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Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children
Sawada, A., Shimizu, M., Koyama-Sato, M., Higuchi, K., Okada, Y., Goto, K., Inoue, S., Yasui, M., Inoue, M.
International journal of hematology. 2021
Abstract
Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n?=?11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m(2), melphalan (MEL) 210 mg/m(2), and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n?=?10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p?=?0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.
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Reduced-intensity single-unit unrelated cord blood transplant with optional immune boost for nonmalignant disorders
Vander Lugt, M. T., Chen, X., Escolar, M. L., Carella, B. A., Barnum, J. L., Windreich, R. M., Hill, M. J., Poe, M., Marsh, R. A., Stanczak, H., et al
Blood advances. 2020;4(13):3041-3052
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Abstract
Children with many inherited nonmalignant disorders can be cured or their condition alleviated by hematopoietic stem cell transplantation (HSCT). Umbilical cord blood (UCB) units are a rapidly available stem cell source and offer great flexibility in HLA matching, allowing nearly uniform access to HSCT. Although reduced-intensity conditioning (RIC) regimens promise decreased treatment-related morbidity and mortality, graft failure and infections have limited their use in chemotherapy-naive patients. We prospectively evaluated a novel RIC regimen of alemtuzumab, hydroxyurea, fludarabine, melphalan, and thiotepa with a single-unit UCB graft in 44 consecutive patients with inborn errors of metabolism, immunity, or hematopoiesis. In addition, 5% of the UCB graft was re-cryopreserved and reserved for cord donor leukocyte infusion (cDLI) posttransplant. All patients engrafted at a median of 15 days posttransplant, and chimerism was >90% donor in the majority of patients at 1-year posttransplant with only 1 secondary graft failure. The incidence of grade II to IV graft-versus-host disease (GVHD) was 27% (95% confidence interval [CI], 17-43) with no extensive chronic GVHD. Overall survival was 95% (95% CI, 83-99) and 85% (95% CI, 64-93) at 1 and 5 years posttransplant, respectively. No significant end-organ toxicities were observed. The use of cDLI did not affect GVHD and showed signals of efficacy for infection control or donor chimerism. This RIC transplant regimen using single-unit UCB graft resulted in outstanding survival and remarkably low rates of graft failure. Implementation of the protocol not requiring pharmacokinetic monitoring would be feasible and applicable worldwide for children with inherited disorders of metabolism, immunity, or hematopoiesis. This trial was registered at www.clinicaltrials.gov as #NCT01962415.
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Reduced Toxicity (BuFlu) Conditioning Is Better Tolerated but Has Higher Second Transplant Rate Compared to Myeloablative Conditioning (BuCy) in Children with Inherited Metabolic Disorders
Gupta, A., Downey, M., Shanley, R., Jennissen, C., Miller, W. P., Lund, T. C., Orchard, P. J., Smith, A. R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
BACKGROUND Hematopoietic stem cell transplantation (HSCT) is a primary treatment for various inherited metabolic diseases (IMDs). Achieving stable and sustained engraftment while minimizing transplant related morbidity and mortality is critical in optimizing outcome for IMDs. Traditional regimens have used myeloablative approaches, primarily Busulfan and Cyclophosphamide (BuCy), which is associated with significant regimen related toxicity (RRT). Alternatively, reduced toxicity regimens, such as Busulfan and Fludarabine (BuFlu), have been proposed to offer similar efficacy with reduced toxicities. We compared transplant related outcomes with BuCy and BuFlu based conditioning in patients with IMDs. METHODS We retrospectively analyzed University of Minnesota's transplant database for patients with IMDs who underwent HSCT using BuCy (with alemtuzumab) or BuFlu (with ATG) preparative regimen from March, 2008 to September,2017. Overall survival (OS), event free survival (EFS) and incidence of neutrophil and platelet recovery was determined using standard definitions. Complications such as graft failure, sinusoidal obstruction syndrome, hemorrhagic cystitis and respiratory failure were compared. Graft failure includes primary and secondary aplastic graft failure, with and without autologous recovery. Incidence of viral infections post-transplant comparing two regimens were also determined. RESULTS Total of 99 patients underwent HSCT for IMDs during the study period. Sixty-four received BuCy conditioning and 35 received BuFlu. Hurler syndrome (46%) and adrenoleukodystrophy (43%) were most common IMDs and umbilical cord blood was the most common graft source (74%). One-year OS was similar in both groups (81.2% in BuCy vs. 85.5% in BuFlu; p=0.8) with an EFS of 75% vs 63% respectively. Similar incidence of grade 3-4 acute GVHD(9% vs. 6%; p=0.5) and chronic GVHD(9% vs. 7%; p=0.67). Neutrophil and platelet recovery were similar in both groups with significantly shorter duration of hospital stay noted in BuFlu cohort (median 21 d vs. 34 d, p=0.002). Cumulative incidence of graft failure was higher with BuFlu group (29% vs 14%, p= 0.08). Significantly higher rates of second HCT was noted following BuFlu cohort (27% vs. 3%, p= 0.001). Incidence of adenoviral infection (14% vs. 0%, p=0.02) and hemorrhagic cystitis (23% vs. 3%, p=0.01) were higher in the BuCy group. T-cell engraftment occurred significantly sooner with BuCy conditioning until 1-year post transplant, donor myeloid engraftment was similar in both groups. CONCLUSION Reduced toxicity conditioning leads to lower rates of infections and other transplant related complications, but concerning for higher rate of graft failure in patients with IMDs. Alternate immune suppressive agents and novel techniques should be considered to minimize toxicities and reduce complications.
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Successful hematopoietic stem cell transplantation for osteopetrosis using reduced intensity conditioning
Shadur, B., Zaidman, I., NaserEddin, A., Lokshin, E., Hussein, F., Oron, H. C., Avni, B., Grisariu, S., Stepensky, P.
Pediatric blood & cancer. 2018
Abstract
BACKGROUND Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin. PROCEDURES Thirty-one patients with IMO who underwent hematopoietic stem cell transplantation with fludarabine, treosulphan, thiotepa, and antithymocyte globulin at our center from 2012 to 2017 are retrospectively reviewed in this study. Twenty-six patients were transplanted from 10/10 matched donors (13 from siblings, 11 from unrelated, and two from extended family donors), four from 9/10 matched unrelated donors, and one from a 9/10 matched family donor. RESULTS Overall survival was 100% with a median follow-up of 363 days (range 74-1891). There were 12 cases of acute graft versus host disease (GvHD) (38.7%), no cases of veno-occlusive disease, and eight cases of hypercalcemia (25.8%). Almost 80% of patients suffered viral reactivations with two cases of Epstein-Barr-virus-driven post-transplant lymphoproliferative disease. All cases of GvHD and viral reactivation were successfully treated. CONCLUSIONS We conclude that transplantation in children with IMO using fludarabine, treosulphan, thiotepa, and antithymocyte globulin is safe and effective and should be performed as early as possible following diagnosis, prior to the development of severe disease sequelae.