Chemosensitization and Mobilization Of AML/ALL/MDS With Plerixafor (AMD 3100), a CXCR4 Antagonist: A Phase I Study Of Plerixafor + Cytarabine and Etoposide In Pediatric Patients With Acute Leukemia and MDS
Bibliographic record
Abstract
Abstract Background The protection afforded to leukemic blasts by the bone marrow microenvironment has been identified as an important mechanism of chemoresistance. Interaction between stroma-derived growth factor-1 alpha (SDF-1α) and its receptor, CXC chemoreceptor 4 (CXCR4) are implicated in chemotaxis, homing, and survival/apoptosis of normal and malignant hematopoietic cells in the bone marrow. Preclinical data demonstrates that plerixafor (AMD3100), a CXCR4 antagonist, disrupts tumor-stroma interactions and mobilizes leukemia cells from their protective stromal environment. Combinations of CXCR4 antagonists with chemotherapy have demonstrated preclinical synergy. Chemosensitization using plerixafor prior to cytotoxic chemotherapy has been tested in adults with acute leukemia. We report the first Phase I study of plerixafor (NCT01319864) delivered prior to chemotherapy in children with relapsed/refractory acute leukemia and MDS. Study Design Patients > 3 and < 30 years of age with relapsed or refractory AML, ALL, MDS or mixed phenotype acute leukemia were eligible for enrollment. Plerixafor was administered intravenously (IV) once daily followed 4 hours later by cytarabine (1 gm/m2 every 12 hours) and IV etoposide (150 mg/m2 daily) for a total of 5 days of therapy. Plerixafor pharmacokinetic studies were performed on days 1 and 5. Correlative biology studies included measurement of peripheral blood mobilization of leukemic blasts by flow cytometry, quantitative expression of CXCR4 on leukemic blasts, and the change in surface expression of CXCR4 on residual blasts after course 1 of therapy. Results Eighteen evaluable patients (11 AML, 6 ALL, 1 MDS) were treated at 4 dose levels of plerixafor (6, 9, 12, and 15 mg/m2/dose) utilizing a Rolling 6 design. The median number of prior regimens was 2.8 (range 1-7) for ALL and 2.1 (range 1-4) for AML. Six patients had high risk cytogenetics (3 ALL, 2 AML, 1 MDS). Three patients with ALL and 4 with AML had prior hematopoietic stem cell transplant (HSCT). Toxicities were consistent with intensive relapsed leukemia regimens. The most common Grade 1 and 2 toxicities attributed to plerixafor occurring in >10% of patients were anorexia, nausea, vomiting, diarrhea, fatigue, and dizziness. There were no dose limiting toxicities and no delay in count recovery attributable to plerixafor. There were responses in 3 (2 complete response (CR), 1 complete response with incomplete hematologic recovery (CRi)) of 11 AML patients (27%) and no responses in those with ALL or MDS. Peripheral leukemia-specific blast counts (measured by flow cytometry before and 4 hours after the first dose of plerixafor) demonstrated mobilization of leukemic blasts in 14 of 16 patients with samples available, with median fold increase of 3.4 (range 1.3 to 17). The degree of leukemic blast mobilization correlated positively with quantitative leukemia blast surface CXCR4 protein expression (expressed as median fluorescence index relative to isotype control), with a Pearson’s correlation co-efficient of 0.56, p=0.02. Mean ± SD plerixafor AUC values at 12 and 15 mg/m2 were 5074 ± 380 and 5732 ± 573 ng*h/mL, respectively. Drug clearance was similar between days 1 and 5 (p=0.195). Conclusion The favorable safety profile of plerixafor and biologic rationale demonstrated in this clinical trial support further clinical study of chemosensitization using CXCR4 antagonists in overcoming chemoresistance. Disclosures: Off Label Use: Plerixafor is not approved for chemosensitization in the treatment of acute leukemia.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
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".