Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen

Hansen, M; Filipovich, Alexandra H.; Davies, Stella M.; Mehta, Parinda A.; Bleesing, Jack J.; Jodele, Sonata; Hayashi, Robert J.; Barnes, Yvonne; Shenoy, Shalini

doi:10.1038/sj.bmt.1705926

Cited by 21 publications

(18 citation statements)

References 30 publications

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“…[1][2][3][4][5][6][7] Importantly, survival has been shown to be superior for patients with higher-risk conditions such as hemophagocytic lymphohistiocytosis and combined immune deficiency compared with myeloablative regimens, mostly due to the prevention of early post-HCT regimen-related toxicities such as hepatic veno-occlusive disease and pulmonary hemorrhage. 1,2 Late effects following HCT such as gonadal dysfunction may also be decreased following RIC HCT.…”

Section: Introductionmentioning

confidence: 99%

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

Marsh

Lane

Mehta

et al. 2016

Blood

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• Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery after alemtuzumab, fludarabine, and melphalan RIC HCT.• An in vivo lytic threshold appears to lie near 0.1 to 0.16 mg/mL; targeted dose trials are warranted to optimize outcomes.Reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) with alemtuzumab, fludarabine, and melphalan is an effective approach for patients with nonmalignant disorders. Mixed chimerism and graft-versus-host-disease (GVHD) remain limitations on success. We hypothesized that higher levels of alemtuzumab at day 0 would result in a low risk of acute GVHD, a higher risk of mixed chimerism, and delayed early lymphocyte recovery and that alemtuzumab level thresholds for increased risks of these outcomes would be definable. We collected data from 105 patients to examine the influence of peritransplant alemtuzumab levels on acute GVHD, mixed chimerism, and lymphocyte recovery. The cumulative incidences of initial grades I-IV, II-IV, and III-IV acute GVHD in patients with alemtuzumab levels £0.15 vs ‡0.16 mg/mL were 68% vs 18% (P < .0001), 47% vs 13% (P 5 .0002), and 32% vs 8%, respectively (P 5 .005). The cumulative incidence of mixed chimerism in patients with an alemtuzumab level £0.15 mg/mL was 21%, vs 42% with levels of 0.16 to 4.35 mg/mL, and 100% with levels >4.35 mg/mL (P 5 .003). Patients with alemtuzumab levels £0.15 or 0.16 to 0.56 mg/mL had higher lymphocyte counts at day 130 and higher T-cell counts at day 1100 compared with patients with levels ‡0.57 mg/mL (all P < .05). We conclude that peritransplant alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following RIC HCT with alemtuzumab, fludarabine, and melphalan. Precision dosing trials are warranted. We recommend a day 0 therapeutic range of 0.2 to 0.4 mg/mL. (Blood.

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Section: Introductionmentioning

confidence: 99%

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

Marsh

Lane

Mehta

et al. 2016

Blood

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“…Одной из причин выбора данного режима кондиционирования послужил старший возраст па-циентов, медиана которого составила 28 мес. В мультицентровом исследовании, проведенном M. Aldenhoven et al [8], медиана возраста была равна 13,5 месяца, по данным M. Hansen et al [9] -18 ме-сяцев. Кроме этого, у пациентов нашего центра ме-диана времени от момента постановки диагноза до проведения алло-ТГСК была 14 мес, в то время как в работах других авторов -5,2 мес [7].…”

Section: осложненияunclassified

The results of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimen doses in patients with Hurler syndrome

Боровкова¹,

Станчева²,

Разумова³

et al. 2015

Ross. ž. det. gematol. onkol.

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“…Allogeneic stem cell transplantation for MPS I was first performed by Hobbs et al and was quickly followed by others as a life-saving measure for children with severe MPS I (Hobbs et al 1981; Peters et al 1996, 1998a, 1998b; Vellodi et al 1997; Souillet et al 2003; Hansen et al 2008). Heterozygous to normal serum levels of IDUA are routinely achieved after HCT, and the progression of this debilitating disease is arrested in most, but not all, organ systems.…”

Section: Cellular Therapymentioning

confidence: 99%

α-L-iduronidase therapy for mucopolysaccharidosis type I

Tolar

Orchard

2008

BTT

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More than 500 patients with mucopolysaccharidosis type IH (MPS IH; Hurler syndrome) have been treated with hematopoietic cell transplantation (HCT) throughout the world since the introduction of transplantation as therapy almost 30 years ago. More recently, the availability of recombinant α-L-iduronidase (IDUA) has resulted in the widespread treatment of less severe forms of MPS I with enzyme replacement therapy (ERT). In addition, over 50 MPS IH patients have been treated with a combination of ERT and HCT. The rationale for both ERT and HCT stems from the pivotal experiments performed 4 decades ago that showed α-L-iduronidase supplied in the environment can correct the accumulation of substrate in MPS I cells. Our purpose is to address the multiple applications associated with the therapeutic delivery of IDUA: intermittent delivery of recombinant protein (ERT), continuous administration through cellular therapy (HCT), the use of other stem cells or, potentially, correction of the enzyme defect itself through gene therapy approaches. Even though gene therapy and non-hematopoietic stem cell approaches, have yet to be tested in a clinical setting, it is possible that all these approaches will in the near future be a part of a paradigm shift from unimodal to multimodal therapy for MPS I.

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Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen

Cited by 21 publications

References 30 publications

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

The results of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimen doses in patients with Hurler syndrome

α-L-iduronidase therapy for mucopolysaccharidosis type I

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Allogeneic hematopoietic cell transplantation (HCT) in Hurler's syndrome using a reduced intensity preparative regimen

Cited by 21 publications

References 30 publications

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

Alemtuzumab levels impact acute GVHD, mixed chimerism, and lymphocyte recovery following alemtuzumab, fludarabine, and melphalan RIC HCT

The results of allogeneic hematopoietic stem cell transplantation with reduced-intensity conditioning regimen doses in patients with Hurler syndrome

&alpha;-L-iduronidase therapy for mucopolysaccharidosis type I

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α-L-iduronidase therapy for mucopolysaccharidosis type I