Intrabone Infusion of Umbilical Cord Blood Stem Cells to Improve Hematopoietic Recovery after Allogeneic Umbilical Cord Blood Transplantation in Children
Bibliographic record
Abstract
Abstract Umbilical cord blood transplantation (UCBT) has been used to treat malignant and non-malignant diseases. UCBT offers the advantages of easy procurement, immediate availability, and acceptable partial HLA mismatches. Still, patients treated with UCBT show delayed hematopoietic and immunological recoveries, and have higher rates of infection. The problem of slower hematopoietic recovery post-UCBT has been addressed using different approaches: infusion of two CB units, ex-vivo expansion of CB, transplantation of a UCB combined with a selected CD34+ peripheral stem cell unit from an haplo-identical donor. Intrabone (IB) injection is a known emergency access route for infusion of fluids and drugs in children. Frassoni et al published a study on the IB injection of a single unit of CB into 32 adult patients (Frassoni F, et al. Lancet Oncol. 2008) and showed a neutrophil (0.5x10^9/L) and platelet (20x10^9/L) recoveries with a median of 23 and 36 days, respectively, with a median nucleated cell dose of only 2.6 x 10^7 cells/kg. These results have been confirmed in a retrospective study comparing IB infusion of CB with infusion of two units of CB in adult patients (Rocha V, et al. Transplantation. 2013). The only data of IB infusion in pediatric patients is a case report of 5 patients (Saglio F, et al. J Pediatr Hematol Oncol. 2012). In order to confirm the role of IB infusion of CB to improve hematopoietic reconstitution after UCBT in pediatric patients, we started a Phase II single arm, exploratory clinical trial (NCT01711788). Our primary hypothesis is that use of IB infusion of CB reduces stem cell trapping seen with IV infusion, maximizing the number of stem cells and providing a faster short- and robust long-term engraftment. Inclusion criteria includes age up to 21 years, diagnosis of hematopoietic disorders (malignant or not), availability of a single CB with at least 3 x 10^7 nucleated cells (NCs)/kg at freezing (use of two CB units is allowed provided a single CB unit fulfilling the above criteria is not available), and use of a myeloablative-conditioning regimen. On the day of UCBT, frozen CB unit is thawed, washed and re-suspended in 20 ml of a saline/albumin solution and aliquoted into four 5-ml syringes. Patient is sedated with propofol and ketamine according to the current protocol for sedation in children. After sedation, a first aliquot of CB stem cell suspension is injected into the bone marrow, followed by a of 0.5-1 ml saline solution rinse. This procedure is repeated for all remaining aliquots at different places and can be performed in one or both iliac crests, depending on patient size. Each injection is performed within a 2-minute timeframe. If patient requires two CB units, one unit is infused IB while the second unit is infused IV after recovery from sedation. G-CSF is given from D+7. A total of 12 patients has been included since Nov/2012. Eight were male, and median age was 7 (2 - 15) years. Diagnosis were AML (n=6), ALL (n=4) and sickle cell anemia (n=2). Most UCB were unrelated (n=10) and 6/6, 5/6 and 4/6 HLA matching comprised four, five and three UCBT. Busulfan-based conditioning was used in eight patients. Ten patients received a single unit UCB. Median NC infused was 3.4 (2.17-8.4) x 10^7/kg. There was no toxicity related to IB infusion. Engraftment occurred in 10 out of 12 patients and median time to engraftment (neutrophil ≥ 0.5x10^9/L) was 14.5 days. Platelet recovery (≥ 50x10^9/L) occurred in just 6/12 patients (due mainly to early relapse) and median time to recovery was 41 (28-77) days. Three patients presented a grade II aGVHD. There were three relapses. Ten out of twelve patients are alive, one patient died from UCBT complication (ARDS) and other from relapse. In conclusion, IB infusion of UCB is feasible in pediatric patients without any particular toxicity and there is a positive impact on neutrophil recovery. Inclusion of more patients are needed to confirm the impact of IB-UCBT on platelet recovery, duration of hospitalisation, and survival. IB-UCBT might be a more affordable alternative to improve hematopoietic recovery comparing to other methods of UCB expansion. Disclosures No relevant conflicts of interest to declare.
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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) | 0.001 | 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) | 0.001 | 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".