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Sequential haplo-identical conditioning transplant regimen for pediatric patients with relapsed or refractory hemophagocytic lymphohistiocytosis
Yue, Y., Fan, S., Liu, Z., Jiang, F., Chen, J., Qin, J., Sun, Y.
Bone marrow transplantation. 2024
Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) currently stands as the sole remedy for individuals afflicted with hemophagocytic lymphohistiocytosis (HLH). In this study, we retrospectively evaluated how pediatric patients with relapsed or refractory (R/R) HLH responded to our institution's cocktail conditioning regimen. The disease was diagnosed according to criteria applicable to patients with familial/genetic, relapsing, or severe/persistent HLH. All donors were HLA haplo-identical family donors. In our cohort, sixty-five patients (P-HLH), including 28 with familial/genetic HLH, 36 with secondary HLH, and 1 with an unknown cause, underwent haplo-identical family donor HSCT. The conditioning regimen consisted of intravenous administration of etoposide (VP-16), busulfan, fludarabine, rabbit anti-human thymocyte globulin (r-ATG), and cyclophosphamide (Cy). Tacrolimus and mycophenolate mofetil were used for graft-versus-host disease (GvHD) prevention. We observed that the median time for neutrophil recovery was 11 days (range, 8-24), and for platelet counts to exceed 20 × 10(9)/L, it was 14 days (range, 7-130). There were 5 patients (7.7%) who experienced grades III to IV acute GvHD, and 6 patients (9.2%) developed extensive chronic GvHD. The estimated 3- and 5-year overall survival rates were 78.1% (95% CI, 65.8-84.6%) and 74.9% (95% CI, 61.2-84.4%), respectively. The estimated 3- and 5-year event-free survival rates were 73.5% (95% CI, 60.8-82.6%) and 70.3% (95% CI, 56.4-80.5%), respectively. Our findings demonstrate that our innovative conditioning regimen is both effective and safe, offering valuable insights for healthcare professionals evaluating the merits of existing therapies.
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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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The impact of Treosulfan-based conditioning for inborn errors of immunity: Is dose monitoring crucial?
Ersoy, G. Z., Çipe, F., Fışgın, T., Aksoy, B. A., Öner Ö, B., Hashemi, N., Aydoğdu, S., Erdem, M., Dikme, G., Murat, K., et al
Clinical transplantation. 2023;:e15083
Abstract
INTRODUCTION In children with inborn errors of immunity (IEI) who will receive a hematopoietic stem cell transplant (HSCT) treosulfan-based conditioning is currently preferred. The aim of this study was to investigate early and late outcomes in pediatric IEI patients receiving pre-HSCT treosulfan and to examine the effect of treosulfan dose monitoring on outcomes. METHODS Seventy-three pediatric patients receiving this management between 2015 and 2022 were included. RESULTS Overall survival rate was 80%, and event-free survival was 67.8%. A larger treosulfan dose AUC after first application increased the rate of early toxicity (p = .034) and slowed lymphocyte engraftment (r = .290; p = .030). Underlying disease, treosulfan AUC, donor type, stem cell type, number of immunosuppressive agents, the dose of anti-thymocyte globulin, and post-transplantation cyclophosphamide did not to increase risk of acute graft-versus-host disease. The risk of mixed chimerism (MC) in patients with autoimmune lymphoproliferative syndrome and leukocyte adhesion deficiency were higher than those with severe combined immunodeficiency (p = .021 and p = .014, respectively). The risk of MC was lower in those receiving peripheral blood stem cells (SC) compared with bone marrow derived SC (OR = .204, p = .022). CONCLUSION The AUC of the treosulfan dose was not associated with poorer late outcomes. Treosulfan is an agent that can be used safely in the IEI patient group, level measurement appears essential to identify early toxicities. Prospective studies with more extended follow-up periods are needed.
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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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Conditioning regimen for allogeneic bone marrow transplantation in children with acquired bone marrow failure: fludarabine/melphalan vs. fludarabine/cyclophosphamide
Yoshida, N., Takahashi, Y., Yabe, H., Kobayashi, R., Watanabe, K., Kudo, K., Yabe, M., Miyamura, T., Koh, K., Kawaguchi, H., et al
Bone marrow transplantation. 2020
Abstract
Fludarabine/cyclophosphamide-based conditioning regimens are standard in bone marrow transplantation (BMT) for acquired bone marrow failure in children, however, graft failure may occur. Using the data from a nationwide transplantation registry, we compared the outcomes of children aged <16 years with acquired aplastic anemia and refractory cytopenia of childhood who underwent allogeneic BMT with either fludarabine/melphalan (n = 71) or fludarabine/cyclophosphamide (n = 296) between 2000 and 2016. The fludarabine/melphalan regimen provided excellent outcomes, with 3-year overall survival and failure-free survival rates of 98% and 97%, respectively. The 83% 3-year failure-free survival in the fludarabine/cyclophosphamide group was significantly inferior (P = 0.002), whereas the overall survival did not differ between the two groups. Late graft failure was the most common cause of treatment failure in the fludarabine/cyclophosphamide group, which experienced a significantly higher incidence of late graft failure than the fludarabine/melphalan group (11% vs. 3%; P = 0.035). Multivariate analyses showed that the fludarabine/melphalan regimen was associated with a better failure-free survival (hazard ratio [HR] 0.12; P = 0.005) and lower risk of late graft failure (HR 0.16; P = 0.037). Fludarabine/melphalan-based conditioning regimen can be a promising option for children with acquired bone marrow failure receiving BMT.
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Outcome after a cord blood transplantation using busulfan pharmacokinetic targeted myeloablative conditioning for Hurler syndrome
Lum, S. H., Orchard, P. J., Lund, T. C., Miller, W. P., Boelens, J. J., Wynn, R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
We report cord blood transplantation (CBT) outcomes of 97 children with Hurler syndrome (HS) after a busulfan pharmacokinetic targeted myeloablative conditioning regimens from 2004 to 2016. The median age at transplant was 10.8 months (range 0.23 - 63.2 months). The median follow-up for surviving patients was 4.2 years (range, 1.0 to 12.8 years). 5-year overall survival (OS) and engrafted survival (ES) were 88% and 79%. OS was 95% after Busulfan-Fludarabine-ATG, 90% after Busulfan-Cyclophosphamide-ATG and 74% after Busulfan-Cyclophosphamide-Alemtuzumab (p=0.02). ES was 84% for Busulfan-Fludarabine-ATG, 83% for Busulfan-Cyclophosphamide-ATG and 65% for Busulfan-Cyclophosphamide-Alemtuzumab (p=0.34). Washed CB unit (p=0.03) and HLA = 6/10 (p=0.02) were associated with significantly lower ES. The one-year cumulative incidence of graft-failure was 11% (95% CI, 6-21%). Five (5%) had grade III-IV acute GvHD. Five had limited chronic GvHD and one had extensive GvHD. The incidence of veno-occlusive disease was higher in patients conditioned with Busulfan-Cyclophosphamide (n=10, 19%) compared to Busulfan-Fludarabine (n=2, 5%) (p=0.03). Of the 11 patients with graft failure, 8 (73%) were aplastic and 3 (27%) autologous reconstitution. Of 11 patients with graft failure, 9 received a second transplant, and 8 (89%) survived. 89% after first CBT and all after second transplant had full donor chimerism. Survival after CBT for HS has improved but better strategies are needed to improve graft outcome.
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What is the best first-line treatment for POEMS syndrome: autologous transplantation, melphalan and dexamethasone, or lenalidomide and dexamethasone?
Zhao, H., Huang, X. F., Gao, X. M., Cai, H., Zhang, L., Feng, J., Cao, X. X., Zhou, D. B., Li, J.
Leukemia. 2019
Abstract
POEMS syndrome is a rare plasma cell dyscrasia. This study compared the responses to and survival of 347 POEMS syndrome patients given three first-line treatment regimens: autologous stem cell transplantation (ASCT, N = 165) and melphalan + dexamethasone (MDex, N = 79), or lenalidomide + dexamethasone (LDex, N = 103). After a median 45-month follow-up, overall hematologic complete remission (CRH) was 46.4%, vascular endothelial growth factor complete remission (CRV) was 55.1%, and neurological remission (RN) was 93.8%. CRH was better with ASCT (49.7%) than with MDex (37.7%, p = 0.001). CRV was better with ASCT (66.2%) than with MDex (38.5%, p = 0.001) or LDex (47.7%, p = 0.008). Differences in RN achieved by three regimens (91.5% vs. 100% vs. 93.8%, p = 0.234) were not significant. Overall 3-year progression-free survival (PFS) was 80.5% and overall 3-year overall survival (OS) was 90.8%. PFS was 87.6% with ASCT and 64.9% with LDex (p = 0.003). OS in the three regimens did not differ (p = 0.079). In medium-high risk patients, ASCT had better CRH and CRV than MDex, and better PFS than LDex. Therefore, although all three treatments had reasonable responses and survivals, patients with higher risk may benefit more from ASCT treatment.
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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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Hematopoietic Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria in the Age of Eculizumab
Cooper, J. P., Farah, R. J., Stevenson, P. A., Gooley, T. A., Storb, R., Scott, B. L.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by destruction of hematopoietic cells through the activation of the complement system with manifestations that can be life threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the only cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement mediated hemolysis in PNH since its FDA approval in 2007. We examined outcomes of HCT in PNH patients to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre- or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least one HCT, and 4 patients required a second HCT for graft failure. Median age at time of first HCT was 30.0 years (range 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH while the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of patients, myeloid malignancy (MDS, MPN, or AML) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of first HCTs, 26 were performed with myeloablative conditioning, 27 with reduced-intensity conditioning, and two sets of identical twins underwent HCT without any conditioning. Donor sources included HLA-matched related (38.2%), HLA-matched unrelated (34.5%), single HLA-allele mismatched unrelated (16.4%), umbilical cord blood (5.5%), syngeneic (3.6%), and HLA-haploidentical (1.8%). Median follow-up for surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. Median time to neutrophil and platelet engraftment was 17 and 19 days, respectively; all but two patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH sub-type affected survival. Nineteen patients died during follow-up, including 12 patients before day 365. Six patients received treatment with eculizumab prior to HCT and two were treated after HCT. All patients treated with eculizumab pre- or peri-HCT remain alive with a median follow-up of 2.3 years (range, 0.2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (grade I skin in one patient and no acute GVHD in the other patient) and no chronic GVHD at 2.1 and 4.1 years post-HCT. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in our two patients who received eculizumab after HCT.