Sent Liver Grafts Do Not Have a Detrimental Impact on Post-transplant Outcome

Abstract RIC regimens followed by allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated in patients with hematologic malignancies who were not candidates for conventional transplantation because of age or medical co-morbidities. In this kind of transplantation, the analysis of chimerism kinetics remains fundamental. The main aims of this study were to evaluate and compare the impact of pre- and post-transplant variables and chimerism on transplantation outcome. Chimerism status was evaluated in total blood (TB) and in purified CD3+ cells using quantitative PCR (STR/SNP) for all. We analysed donor type and kinetics chimerism of 52 patients (32 M - 20 F) who had undergone allogeneic HSCT after RIC for hematological malignancies. Median age was 40 years (range 25–67 years). Diagnosis were multiple myeloma: 16, acute myeloid leukemia: 13, myelodysplasia: 6, chronic lymphocytic leukemia: 5, Non Hodgkin’s lymphoma: 5, acute lymphoblastic leukemia: 1, chronic myeloid leukemia: 2 and primitive myelofibrosis: 4. Conditioning regimens were Fludarabine + Busulfan in 33 patients, Fludarabine + 2 Gys total body irradiation 15, Cyclophasphamide 3 (2 alone/one with Busulfan) and one other chemotherapy. Stem cell source was PB in all except one who received cord blood. Fourty-eight were identical sibling and 4 unrelated donor transplantations. At transplant, 17 patients were in CR, 21 PR and 14 in evolutive diseases. All patients except one engrafted. Twenty-five developed aGVHD ≥ Grade II (16 Grade III-IV). At the last follow-up 22 patients died (9 disease progression and 13 of transplant related mortality, 30 were alive (18 developed chronic graft vs Host disease (cGVHD) 12 extensive/6 limited cGHVD). Among 52 patients, only 49 had a long-term chimerism documentation of CD3 subpopulation (43 TB and CD3+ cells): 15 (14 TB) were full donor chimerism (FDC) throughout the follow-up, and 34 remained mixed chimerism (MC). Among these 34 (29 TB) MC patients at the latest follow-up, 7 (5 TB) remained in MC, 2 (5 TB) converted to recipient profile and 25 (19 TB) converted to donor profile. Univariate analysis demonstrated the close correlation between chimerism status evaluated on PB CD3+ cells only at any time post-transplant and the onset of aGVHD (p = 0.0391) but not cGVHD. Multivariate analysis according to linear regression method did not find any impact of the following variables on chimerism kinetics after RIC transplant: disease status before transplant, age, sex, type of RIC regimen, number of days of ATG, aGVHD (p ≥ 0.11). In conclusion, this study underlines the tight correlation that exists between chimerism status and kinetics on CD3+ PB subpopulations after RIC transplant and acute GVHD development that impacts on transplant outcome.

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Co-Infusion of Allogeneic Cord Blood with Haploidentical CD34+ Cells Improved Transplant Outcome for Patients with Severe Aplastic Anemia Undergoing Cord Blood Transplantation

Blood ◽

10.1182/blood.v118.21.654.654 ◽

2011 ◽

Vol 118 (21) ◽

pp. 654-654 ◽

Cited By ~ 6

Author(s):

Nicole J. Gormley ◽

Jennifer Wilder ◽

Hahn Khuu ◽

Jeremy Pantin ◽

Theresa Donohue ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cord Blood ◽

Aplastic Anemia ◽

Severe Aplastic Anemia ◽

Transplant Outcome ◽

Neutrophil Recovery ◽

Post Transplant ◽

Cd34 Cells ◽

Matched Donor

Abstract Abstract 654 Unrelated cord blood (UCB) transplantation is a useful alternative for patients with hematological malignancies or non-malignant hematological disorders lacking an HLA matched donor. However, outcomes for patients with severe aplastic anemia (SAA) undergoing either a single or dual UCB transplant have been disappointing. A recent EBMT/ Eurocord study reported engraftment and 3 year survival rates of only 51% and 38% respectively (Perrault de Latour, Biol Blood Marrow Transplant 2011). We investigated whether co-infusion of a single UCB unit with CD34+ selected cells from a haploidentical relative following a highly immunosuppressive conditioning regimen could improve transplant outcome for patients with SAA refractory to immunosuppressive therapy that lack an HLA matched donor. Subjects with SAA and life-threatening neutropenia (ANC <500) refractory to 2 or more immunosuppressive agents were eligible for enrollment if they lacked an HLA matched related or unrelated donor. Conditioning consisted of cyclophosphamide (120 mg/kg), fludarabine (125 mg/m2), equine ATG (160 mg/kg) and one dose of 200 cGy of total body irradiation. Patients received a G-CSF mobilized, T-cell depleted CD34+ selected stem cell product prepared from a haplo-identical donor using the Miltenyi CliniMacs system combined with a single ≥ 4/6 HLA antigen matched UCB unit. Eight patients with treatment refractory SAA (median age 18 years; range 9–20), including 1 patient with SAA evolved to MDS, have been transplanted. All patients were platelet and RBC transfusion-dependent with severe neutropenia (median ANC 60 neutrophils/ul; range 0–260). Patients were at high risk for graft rejection, being heavily transfused, having failed a median 3 (range 2–4) immunosuppressive regimens, and 4 (50%) were HLA alloimmunized. Six patients received a single 4/6 HLA matched UCB unit and 2 received a 5/6 HLA-matched unit. Transplanted allografts contained a median 2.9 × 107 CB TNCs/kg (range 2.6–7.3), 1.5 × 105 CB CD34+cells /kg (range 0.4–3.2), and 3.3 ×106 CD34+cells/kg (range 2.6–3.6) from the haploidentical relative. All patients achieved the primary study endpoint of donor engraftment with an ANC of >500 by day 42, 7 of 8 achieving a UCB-derived ANC >500 cells/μl. The median time to neutrophil recovery was 10 days (range 10–18 days). One patient failed to engraft with the cord unit, but has had sustained engraftment from the haploidentical donor, and is transfusion independent with a normal neutrophil count >25 months post transplant. Acute GVHD grade II developed in 2 patients and one developed limited chronic GVHD. Early T-cell engraftment was predominantly UCB in 7 cases; on day 21, T-cell chimerism was a median 100% cord in origin (range 0–100%). In contrast, myeloid chimerism at engraftment was predominantly haplo-donor in origin and showed 3 phases of engraftment: 1) early myeloid engraftment from the haplo-CD34+ cell donor 2) delayed myeloid engraftment from the cord unit resulting in dual myeloid chimerism and 3) disappearance of the haplo-donor cells with transition towards full cord donor myeloid chimerism (see figure). Mixed lymphocyte reactivity assays performed on post transplant PBMCs showed increasing alloreactivity of cord blood T-cells against the haploidentical donor during the period when myeloid chimerism transitioned towards cord, indicating that the disappearance of haplo-donor myeloid cells occurred as a consequence of rejection by engrafting cord blood T-cells. At a median follow-up of 9 months (range 75 days to 3 years), 7 patients survive, and all are transfusion–independent. One patient died 14 months after transplantation from complications related to CMV pneumonitis. In conclusion, transplantation of haploidentical CD34+ cells can shorten the time to neutrophil recovery in SAA pts undergoing a single UCB transplant. Furthermore, durable full engraftment from donor haploidentical CD34+ cells can occur in the context of cord graft failure. These data suggest co-infusion of allogeneic cord blood with haploidentical CD34+ cells can improve the outcome of UCB transplantation for SAA. Disclosures: Wilder: NCI: Funded in part by NCI contract No. HHSN261200800001E.

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