An Intermediate Alemtuzumab Schedule Reduces the Incidence of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis

Marsh, Rebecca; Kim, Miok; Liu, Chunyan; Bellman, Denise; Hart, Laura K.; Grimley, Michael; Kumar, Ashish; Jodele, Sonata; Myers, Kasiani C.; Chandra, Sharat; Leemhuis, Tom; Mehta, Parinda A.; Bleesing, Jack J.; Davies, Stella M.; Jordan, Michael B.; Filipovich, Alexandra H.

doi:10.1016/j.bbmt.2013.09.001

Cited by 70 publications

(84 citation statements)

References 25 publications

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“…This underscores the need to optimize HSCT to prevent low-level DC (ie, timing, conditioning regimen, donor choice, GVHD, and rejection prophylaxis). 6,7,17 The analysis of the current management approaches in patients with declining DC showed that weaning of immune suppression was started at a median DC of 85% and DLI were applied at a median DC of 45%. As expected, interventions were more frequent in the group of patients in which the lowest DC was #30%.…”

Section: Discussionmentioning

confidence: 99%

“…Forty-three of these patients have been previously reported in articles with a focus on HLH and HSCT, but not on mixed chimerism. 4,[6][7][8]12,[17][18][19] The genetic defects represent the full spectrum of hereditary forms of HLH, including FHL2-5, GS2, XLP 1 and 2, and CHS (Table 1). Most patients had been diagnosed with HLH and received HSCT in the first 2 years of life; however, age at onset and at HSCT ranged until young adulthood.…”

Section: Patient Cohortmentioning

confidence: 99%

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The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Hartz

Marsh

Rao

et al. 2016

Blood

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Key Points• Donor chimerism .20%-30% usually protects against late disease reactivation after day 180 post stem cell transplantation for primary HLH.• Lower levels do not inevitably result in reactivations. The risks of intervention must be weighed against the risk of reactivation.Reduced-intensity conditioning has improved survival after hematopoietic stem cell transplantation (HSCT) for hemophagocytic lymphohistiocytosis (HLH) at the cost of more frequent mixed chimerism. The minimum level of donor chimerism (DC) required to prevent HLH reactivation in humans remains to be determined. In a multicenter retrospective study, 103 patients transplanted for hereditary HLH (2000HLH ( -2013 and DC permanently or transiently <75% (overall, CD3 1 , CD56 1 ) were analyzed regarding DC, specific immunologic function, occurrence of systemic reactivations ( ‡5/8 HLH criteria), partial systemic flares (<5 criteria and HLH-directed treatment), isolated central nervous system reactivations, and management. Recurrence was reported in 18 patients (systemic reactivation n 5 11, partial flare n 5 3, isolated central nervous system reactivation n 5 4). Ten events occurred during profound immune suppression before day 180 (median DC, 10%; range, 1-100%; CD3 1 if available, otherwise overall DC), which renders a differentiation between secondary post-HSCT HLH and HLH related to the genetic defect difficult. Eight events occurred between 0.5 and 6.7 years post-HSCT (median DC, 13%; range, 0-30%). In 5 patients, overall and lineage-specific DC were £10% for >6 months (median, 5.1; range, 1.1-10 years) without reactivation. A second HSCT was performed in 18 patients (median, DC 4%; range, 0-19%). Death from reactivation occurred in 4 patients (22% of recurrences). Six patients died of transplant complications following a second HSCT (33% of second HSCT). We conclude that a DC >20%-30% is protective against late reactivation. Lower levels do not, however, inescapably result in recurrences. The decision for or against second HSCT must be based on a thorough risk assessment. (Blood. 2016;127(25):3281-3290)

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Section: Discussionmentioning

confidence: 99%

Section: Patient Cohortmentioning

confidence: 99%

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

Hartz

Marsh

Rao

et al. 2016

Blood

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“…All patients were treated with an RIC regimen consisting of alemtuzumab, fludarabine, and melphalan as previously described 1,21,22 and received a stem cell graft from a bone marrow (n 5 101) or peripheral blood stem cell (n 5 4) donor. Patients received fludarabine 150 mg/m 2 (1 mg/kg in those weighing ,10 kg) divided over days 28 to 24 or over days 27 to 23 and melphalan 140 mg/m 2 (4.7 mg/kg in those weighing ,10 kg) on day 23 or 22.…”

Section: Transplant Proceduresmentioning

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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“…11 Our patient received a fludarabine-based RIC with both transplants; the rejection observed after first transplant, prepared with alemtuzumab (Table 1, Figure 1), confirmed that DC can result in high risk of engraftment failure. As suggested previously, 12 alemtuzumab administration more distant from graft infusion could allow sufficient T-cell depletion in recipients with less in vivo T-cell depletion of the graft, reducing the risk of rejection and preserving an effective GVHD prophylaxis. In the second transplant, our patient received a higher dose of fludarabine in combination with cyclophosphamide, a single-dose total body irradiation (300 cGy), and antilymphocyte serum (antithymocyte globulin) ( Figure 1B), which may have provided the needed immunosuppression to obtain full donor engraftment without fatal toxicity.…”

Section: Discussionmentioning

confidence: 76%

Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection

Giardino¹,

Faraci²,

Lanino³

et al. 2023

Exp Clin Transplant

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Dyskeratosis congenita is a rare congenital telomeropathy characterized by cutaneous and nail dystrophy, oral leukoplakia, and bone marrow failure. Pulmonary fibrosis and cancers are late manifestations. Allogeneic hematopoietic stem cell transplant represents the only cure for those with bone marrow failure with this disease, but outcomes reported are overall poor, with organ toxicities, graft failure, and graft-versus-host disease as main issues. Although reduced intensity conditioning regimens seem to be related to better outcomes, a standard regimen for dyskeratosis congenita has never been defined. Here, we report a successful long-term outcome of an 8-year-old girl with dyskeratosis congenita who received 2 consecutive allogeneic hematopoietic stem cell transplants from different unrelated donors, because of rejection after the first one, both conditioned with fludarabine-based reduced intensity conditioning regimen. The second transplant was complicated by severe hemorrhagic cystitis and acute grade IV graft-versus-host disease in the early phase and mild chronic graft-versus-host disease and ureteral stenosis in the late phase. This experience confirms that dyskeratosis congenita is at high risk for transplant-related morbidity but that a fludarabine-based reduced intensity conditioning regimen is a safe and feasible option as a preparative regimen, as shown here in a second transplant after first graft rejection. To reduce the risk of graft-versushost disease, more effective prophylaxis schedules should be chosen in cases of unrelated donor, and haploidentical hematopoietic stem cell transplant with in vitro α/β+ and CD19+ depletion should be considered. Key words: Allogeneic hematopoietic stem cell transplant, Bone marrow failure, Reduced intensity conditioning regimen IntroductionDyskeratosis congenita (DC) is a rare heterogeneous inherited disorder, characterized by abnormal skin pigmentation, oral leukoplakia, nail dystrophy, and bone marrow failure. 1,2 Cancer predisposition with increased risk of squamous cell carcinoma and hepatolymphoid neoplasms and pulmonary fibrosis represent typical severe features of the disease. 3 About 60% to 70% of affected patients carry a mutation in telomerase genes (DKC1, TERC, TERT, NOP10, and NHP2), which are required to synthesize the tandem repeats of the TTAGGG sequencing or of the telosome/shelterin complex proteins (TINF2) acting at chromosome ends. 4 Their defect leads to telomere shortness and consequent chromosomal instability, with premature stem cell exhaustion, tissue failure, and high tissue sensitivity to toxic damage. 5 Moreover, high sensibility to oxidative stress has been demonstrated in DC-cultured cells. 6 Androgen therapy has been reported to improve bone marrow function 7 ; however, allogeneic hematopoietic stem cell transplant (HSCT) still represents the only curative option for DC-related bone marrow failure.Few reports on HSCT for DC have been published so far. Although overall survival has progressively improved over the years with ...

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An Intermediate Alemtuzumab Schedule Reduces the Incidence of Mixed Chimerism Following Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Hemophagocytic Lymphohistiocytosis

Cited by 70 publications

References 25 publications

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

The minimum required level of donor chimerism in hereditary hemophagocytic lymphohistiocytosis

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

Successful Second Unrelated Donor Hematopoietic Stem Cell Transplant in a Patient With Dyskeratosis Congenital After First Graft Rejection

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