Reduced Intensity Continuous Infusion Busulfan for Allogeneic Hematopoietic Cell Transplant Patients with Hematologic Disorders Who Are Ineligible or Inappropriate for Treatment with a More Intensive Therapeutic Regimen: LCCC 0306
Bibliographic record
Abstract
Abstract Background: A major advance in allogeneic stem cell transplant (SCT) has been the establishment of effective and less toxic reduced intensity regimens as alternative therapeutic approaches for patients with certain hematologic malignancies. The focus of these approaches has been to reduce treatment related mortality (TRM) while providing sufficient host immunosuppression to permit the achievement of complete donor chimerism that leads to a graft versus tumor effect, resulting in long-term disease control and cure. In this study we report overall survival (OS), relapse rate (RR), and non-relapse mortality (NRM) in patients receiving reduced intensity conditioning (RIC) with a 48 hour continuous infusion of busulfan with fludarabine followed by methotrexate (MTX) alone or with lympho-depleting anti-CD52 monoclonal antibody (mAb), alemtuzumab, or T cell depleting immunoglobulins, anti-thymocyte globulin (ATG) given as graft versus host disease (GVHD) prophylaxis. Methods: Patients with histologically confirmed hematologic malignancies, who were over the age of 55, or otherwise ineligible for more intensive busulfan-based therapy were enrolled on a Phase II protocol, LCCC 0306, at the University of North Carolina. All patients received IV fludarabine 30 mg/m2/day on days-7 through-3; busulfan 6.4 mg/kg by continuous infusion over 48 hours on days-6 through-5 and tacrolimus from day-1 plus either MTX alone, ATG or alemtuzumab alone, or a combination of these agents depending on disease risk and donor status. Results: 71 patients were enrolled. The median age was 58 (range 28 - 69). 58% were men and 42% women. 37 patients received HLA-matched related donor (MRD) stem cell grafts, and 34 patients received either matched unrelated donor (MUD) or HLA-mismatched grafts. The median HCT-Comorbidity Index (CI) score was 3 (range 0 - 8, HCT-CI score: 0 = 12 pts, 1 - 2 = 22 pts, ⪴ 3 = 36 pts). The majority of pts were intermediate risk by Disease Risk Index (DRI) score (9 low, 40 int, 19 high, 1 very high, 2 undetermined). The DRI low/int group had an estimated 18 month OS of 65% (CI 0.50 - 0.77), and DRI high/very high OS was 35% (CI 0.16 - 0.55). Estimated median survival time based on DRI for low/int was 1674 days (CI 646 - 2920) versus 375.5 days (CI 136 - 1018) (p = 0.003) for DRI high/very high pts. OS at 18 months in the MTX alone arm (n = 20) was 70% (CI 0.45 - 0.83), ATG (+/- MTX, n = 27) was 52% (CI 0.32 - 0.69), and alemtuzumab (+/- MTX, n = 24) was 46% (CI 0.26 - 0.64); (p = 0.17). The 18 month relapse rate for the MTX alone arm was 50% (CI 0.27 - 0.69), 41% in ATG (CI 0.37 - 0.76), and 41% in alemtuzumab (CI 0.36 - 0.77); (p = 0.85). The 18 month NRM in the MTX alone arm was 7% (CI 0.61 - 0.99), alemtuzumab (+/- MTX) was 32% (CI 0.42 - 0.85), and ATG (+/- MTX) was 27% (CI 0.52 - 0.86); (p = 0.05). Much of the increased NRM in the alemtuzumab and ATG arms was attributable to increased rates of fatal infectious complications: 1 in the MTX arm, 3 in the ATG arm and 8 in the alemtuzumab arm. No patients receiving MTX alone, 3 receiving alemtuzumab and 6 receiving ATG developed grade 3-4 acute GVHD. 5 of the 20 surviving patients have extensive chronic GVHD. Conclusion: Continuous infusion, reduced dose, busulfan and fludarabine can be safely administered to patients who are ineligible for myeloablative conditioning either because of age or comorbidities. The use of MTX alone with this regimen results in a median survival of over 4 years. Patients with high DRI or who received treatment with alemtuzumab or ATG had higher NRM and poorer OS irrespective of donor status. Disclosures Wood: Best Doctors: Consultancy; Inform Genomics: Consultancy.
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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 | 0.001 | 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 | 0.001 | 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".