Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors

Mazzi, Benedetta; Clerici, Thomas; Zanussi, Monica; Stanghellini, Maria Teresa Lupo; Vago, Luca; Sironi, Elisabetta; Peccatori, Jacopo; Bernardi, Massimo; Carrera, Paola; Palini, Alessio; Rossini, Silvano; Bordignon, Claudio; Bonini, Chiara; Ferrari, Maurizio; Ciceri, Fabio; Fleischhauer, Katharina

doi:10.1038/leu.2008.98

Cited by 16 publications

(10 citation statements)

References 5 publications

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“…The DNA yield ranged from 4 to 2925 ng/µL. We used polymerase chain reaction sequence‐specific priming (PCR‐SSP) for HLA typing using commercially available reagents (Olerup, Stockholm, Sweden) . HLA typing was performed on HLA‐A, ‐B or ‐DRB1 since only those data were available on the donor‐recipient pairs.…”

Section: Methodsmentioning

confidence: 99%

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

Kinch

Cavelier

Bengtsson

et al. 2014

American Journal of Transplantation

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Previous studies of donor or recipient origin of posttransplant lymphoproliferative disorders (PTLDs) following solid organ transplantation (SOT) have either been small or with selected patient groups. We studied tumor origin in a population‐based cohort of 93 patients with PTLD following SOT. Tumor origin of PTLD tissue was analyzed by fluorescence in situ hybridization of the sex chromosomes in cases of sex mismatch between donor and recipient (n = 41), or HLA genotyping in cases of identical sex but different HLA type (n = 52). Tumor origin of PTLD could be determined in 67 of the 93 cases. All 67 PTLDs were of recipient origin. They were found in recipients of kidney (n = 38), liver (n = 12), heart (n = 10) and lung (n = 7). The most common recipient‐derived lymphomas were monomorphic B‐cell PTLDs (n = 45), monomorphic T cell PTLDs (n = 9), indolent lymphomas (n = 6), and polymorphic PTLD (n = 4). Half of the recipient‐derived PTLDs were Epstein–Barr virus‐positive. Twelve of the recipient‐derived PTLDs were located in the grafts: in four cases exclusively and in eight cases in combination with disseminated disease outside the graft. Tumor origin was indeterminable in 26 cases, probably due to low DNA quality. We conclude that the vast majority of PTLDs after SOT was of recipient origin.

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Section: Methodsmentioning

confidence: 99%

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

Kinch

Cavelier

Bengtsson

et al. 2014

American Journal of Transplantation

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“…Neutrophil engraftment was defined as the first of 3 consecutive days with neutrophil counts ≥ 0.5 × 10 9 /L after transplantation, and platelet engraftment was defined as platelet counts ≥ 20 × In case of relapse, defined as the presence of >5% of leukemic blasts in the bone marrow aspirate, eventual genomic loss of the mismatched HLA was performed either by low-resolution typing or by allele-specific qPCR, as previously described 42,43 . In case of suspected HLA-loss relapse in the presence of low blast burden (<20%), leukemic cells were FACS-purified and confirmatory genomic HLA typing was performed on sorted cells.…”

Section: Engraftment Chimerism and Relapse Detectionmentioning

confidence: 99%

Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells

Cieri

Greco²,

Crucitti

et al. 2015

Biology of Blood and Marrow Transplantation

133

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Haploidentical hematopoietic stem cell transplantation (HSCT) performed using bone marrow (BM) grafts and post-transplantation cyclophosphamide (PTCy) has gained much interest for the excellent toxicity profile after both reduced-intensity and myeloablative conditioning. We investigated, in a cohort of 40 high-risk hematological patients, the feasibility of peripheral blood stem cells grafts after a treosulfan-melphalan myeloablative conditioning, followed by a PTCy and sirolimus-based graft-versus-host disease (GVHD) prophylaxis (Sir-PTCy). Donor engraftment occurred in all patients, with full donor chimerism achieved by day 30. Post-HSCT recovery of lymphocyte subsets was broad and fast, with a median time to CD4 > 200/μL of 41 days. Cumulative incidences of grade II to IV and III-IV acute GVHD were 15% and 7.5%, respectively, and were associated with a significant early increase in circulating regulatory T cells at day 15 after HSCT, with values < 5% being predictive of subsequent GVHD occurrence. The 1-year cumulative incidence of chronic GVHD was 20%. Nonrelapse mortality (NRM) at 100 days and 1 year were 12% and 17%, respectively. With a median follow-up for living patients of 15 months, the estimated 1-year overall and disease-free survival (DFS) was 56% and 48%, respectively. Outcomes were more favorable in patients who underwent transplantation in complete remission (1-year DFS 71%) versus patients who underwent transplantation with active disease (DFS, 34%; P = .01). Overall, myeloablative haploidentical HSCT with peripheral blood stem cells (PBSC) and Sir-PTCy is a feasible treatment option: the low rates of GVHD and NRM as well as the favorable immune reconstitution profile pave the way for a prospective comparative trial comparing BM and PBSC in this specific transplantation setting.

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“…Hematopoietic chimerism was assessed on bone marrow aspirate samples by performing in parallel short-tandem repeats analysis (AmpFISTR Profiler Plus PCR Kit; Applied Biosystem, Foster City, CA, USA) and genomic HLA typing. 26 Immune reconstitution Immune reconstitution was evaluated by fluorescence-activated cell sorting (FACS) (Beckman Coulter, Brea, CA, USA; FC500) and analyzed with the FCS Express software (De Novo Software, Los Angeles, CA, USA). Absolute cell counts were determined on the CD45 bright /SSC low population with fluorochrome-conjugated monoclonal antibodies to CD3, CD4, CD8, CD16 and CD56, and TrueCount beads (Beckman Coulter).…”

Section: Engraftment and Chimerismmentioning

confidence: 99%

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

et al. 2014

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Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

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Genomic typing for patient-specific human leukocyte antigen-alleles is an efficient tool for relapse detection of high-risk hematopoietic malignancies after stem cell transplantation from alternative donors

Cited by 16 publications

References 5 publications

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

Donor or Recipient Origin of Posttransplant Lymphoproliferative Disorders Following Solid Organ Transplantation

Post-transplantation Cyclophosphamide and Sirolimus after Haploidentical Hematopoietic Stem Cell Transplantation Using a Treosulfan-based Myeloablative Conditioning and Peripheral Blood Stem Cells

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors

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