Risk Factor Analysis for the Development of Large Granular Lymphocytosis after Allogeneic Hematopoietic Cell Transplantation: Randomized Stratification and Propensity Score Analysis
Bibliographic record
Abstract
Abstract Introduction Large granular lymphocytes (LGL) are a morphologically recognizable subpopulation of lymphocytes comprising an immunophenotypically heterogeneous population of activated CD3+ T cells and CD3- natural killer (NK) cells that mediate non-MHC-restricted cytotoxicity. Increased number of circulating LGL can be found as a response to viral infections, autoimmune disease or malignant neoplasms, as a result of chronic antigenic stimulation. Of interest, LGL lymphocytosis has been reported to occur following hematopoietic cell transplantation (HCT), with a variable incidence of up to 20%. This population display improved transplant outcomes with a lower incidence of non-relapse mortality and relapse (Kim, BMT, 2013; Nann-Rütti, BBMT, 2012). The aim of the present study is to determine the risk factors associated with the development of LGL lymphocytosis after allogeneic HCT. Methods A total of 826 patients who underwent an allogeneic HCT at Princess Margaret Cancer Centre, Toronto, Canada from 2000 to 2012 were retrospectively analyzed. LGL lymphocytosis was defined as the presence of at least two of the followings: 1) Sustained peripheral blood lymphocyte count ≥3.0 x 109/L observed in at least three consecutive determinations over a period of 2-3 months; 2) Predominance (≥30%) of LGL lymphocytes in the peripheral blood, as assessed by morphologic or immunophenotypic criteria; 3) T-cell receptor monoclonality assessed by PCR. The patient population was divided into discovery and replication sets using 2 different methods: stratified randomization and propensity score matching, using relevant baseline variables such as donor type, CMV serostatus, conditioning, T-cell depletion. Results No significant imbalances were found between the discovery and replication sets in terms of relevant baseline characteristics and clinical outcomes, for both the randomly divided patients and the propensity score matched groups. The overall incidence of LGL lymphocytosis was 14.5% at 3 years. The incidence of LGL lymphocytosis was similar across all subgroups of patients, both for the randomly divided groups and the propensity score matching (P-value not significant). A multivariable analysis of the risk factors for the development of LGL lymphocytosis was performed, including the following variables: grades 3-4 acute graft-versus-host-disease (GVHD), chronic GVHD, CMV viremia, CMV serostatus of the recipient, donor type, transplant year and T-cell depletion (TCD) for GVHD prophylaxis. In the stratified randomization analysis, the following risk factors were identified: 1) Discovery set: chronic GVHD (Hazard Ratio: 8.3, 95% CI: 3.1-22.6, P<0.001), CMV viremia (HR: 2.7, 95% CI: 1.5-4.7, P<0.001) and use of an unrelated donor (HR: 2.1, 95% CI: 1.2-3.7, P=0.01). 2) Replication set: chronic GVHD (HR: 38.9, 95% CI: 5.3-284.9, P<0.001) and CMV viremia (HR 3.8, 95% CI: 2.2-6.6, P<0.001). For the propensity score matching analysis the risk factors for the development of LGL lymphocytosis were the following: 1) Discovery set: chronic GVHD (HR: 22.9, 95% CI: 3.2-169.3, P=0.002) and CMV viremia (HR: 2.2, 95% CI: 1.1-4.2, P=0.02). 2) Replication set: chronic GVHD (HR: 28.9, 95% CI: 3.9-212.5, P<0.001), CMV viremia (HR: 3.6, 95% CI: 1.9-6.7, P<0.001). Conclusions Chronic GVHD and CMV viremia are strongly associated with the development of LGL lymphocytosis following allogeneic HCT. This may reflect a chronic antigenic stimulation in the setting of GVHD and CMV infection, leading to the expansion of LGL. However, the underlying mechanisms of LGL activation and expansion in the allogeneic HCT setting still remain unclear. Thus, further investigations are needed to elucidate these mechanisms in particular in the setting of GVHD. Disclosures Lipton: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding. Kim:Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 | 0.002 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| 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".