Haploidentical Stem Cell Transplantation: High Doses of Alloreactive-T Cell Depleted Donor Lymphocytes Administered Post-Transplant Decrease Infections and Improve Survival without Causing Severe Gvhd.
Bibliographic record
Abstract
Abstract Abstract 512 Delayed immune reconstitution following intensive T cell depletion of the stem cell graft is the main complication limiting broad utilization of haplo-mismatched donors for stem cell transplantion (SCT). Indeed, it results in frequent and rapidly lethal infectious events. The ability to accelerate immune reconstitution following haplo-SCT would provide a unique opportunity to transplant the large number of patients who cannot find an HLA-matched donor. We present results of our Phase I clinical trial of haploidentical allogeneic SCT followed by an “add-back of donor T cells to accelerate immune reconstitution” (ATIR). This donor lymphocyte infusion (DLI) underwent photodynamic depletion (PD) of host-reactive T cells using dibromorhodamine as photosensitizer (Kiadis Pharma). Nineteen patients (11 M, 8 F) with very high-risk hematologic malignancies (mostly refractory or relapsed acute myeloid leukemia (10) and myelodysplastic syndromes (4), and refractory ALL (1), CLL (2), CML (1) and NHL (1)) entered the trial. Median age at SCT was 54 years (range: 19-62). HLA compatibility was 3/6 in 6 pts, 4/6 in 12 pts and 5/6 (DR mismatch) in 1 pt. Increasing doses of PD-treated donor cells (ATIR: 1×104 to 5.0 ×106 CD3+ cells/kg) were administered on day 34±6 after transplant. In the ATIR, greater than 95% of CD4+CD25+ and CD8+CD25+ T cells as well as anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection (Miltenyi). The myeloablative regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (200 mg/m2). No GVHD prophylaxis was administered. All patients showed complete donor chimerism and durable hematologic engraftment. Five patients developed grade II GVHD affecting skin (n = 5 pts), liver (2 pts) and gastrointestinal tract (1 pt) at a median of 101 days post-SCT. No patient developed grade III-IV acute GVHD. Chronic GVHD developed in 9 pts, mostly in those receiving higher T cell doses. Treatment of acute and chronic GVHD involved steroids, tacrolimus and mycophenolate mofetil in 3 patients, steroids and tacrolimus in 3 pts, and steroids only in 3 pts. GVHD responded rapidly to treatment since the median duration of total immunosuppressive therapy in each patient was 187 days (range: 61-319 d). All 7 patients in cohorts 1-3, who received 1.3×105 or less CD3+ cells/kg, developed infectious complications (100% of pts), with 5 lethal episodes in these 7 pts. In sharp contrast, only 6 (50%) of the following 12 patients (cohorts 4-7) receiving ATIR with the highest CD3+ cell doses (3.2×105 to 5.0×106 CD3+ cells/kg) developed infections (p <0.05), none resulting in a fatal event (p<0.001). Interestingly, CD3 lymphocytes recovered earlier in the last 2 cohorts (6 and 7) receiving 2-5×106 CD3+ cells/kg than in the first 5 cohorts (7.9×105 or less CD3+ cells/kg) (p<0.01). Eight patients died: 4 of relapsed leukemia (3 AML; 1 ALL) and 4 of infections. Overall treatment related mortality (TRM) is 27% at 2 years post-SCT, with a TRM of 0% in patients receiving the highest CD3+ cell doses (cohorts 4-7). The overall survival is 60% at 2 years (median f-up: 12.1 mo; 95% confidence interval at 2 years: 37-83%). The 12 patients in cohorts 4-7 receiving the higher CD3+ cell doses had an improved survival (82% at 2 yrs) over the 7 patients in cohorts 1-3 administered a lower CD3+ cell dose (14% at 2 yrs) (p<0.05). Our results indicate that the post-transplant infusion of an ATIR-PD treated DLI is feasible, results in accelerated T cell reconstitution, and decreases the incidence and severity of infections without inducing severe GVHD. These results suggest a clinical benefit for patients receiving the highest ATIR doses and form the basis of an international pivotal clinical trial to decrease TRM in patients undergoing haploidentical stem cell transplantation. Disclosures: Roy: Kiadis Pharma: Research Funding. Egeler:Kiadis Pharma: Employment.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".