A phase I window, dose escalating and safety trial of metformin in combination with induction chemotherapy in relapsed refractory acute lymphoblastic leukemia: Metformin with induction chemotherapy of vincristine, dexamethasone, PEG‐asparaginase, and doxorubicin
Acute lymphoblastic leukemia (ALL) remains a major cause of death in children. AMP-activated protein kinase (AMPK) affects the unfolded protein response (UPR), leading to increased vulnerability to endoplasmic reticulum (ER) stress in ALL cells. In vitro, metformin causes ALL cell death via AMPK-mediated inhibition of the UPR. It was evaluated whether ER stress could be induced in relapsed ALL through a phase I study investigating the safety and feasibility of metformin in combination with relapse induction chemotherapy.
Metformin was administered twice daily for 28 days in addition to vincristine, dexamethasone, PEG-asparaginase and doxorubicin (VXLD). Dose escalation of metformin was evaluated using a 3+3 design. Pharmacokinetics (PK), pharmacodynamic (PD) evaluation of the AMPK and ER stress/UPR pathways, and treatment response were assessed.
Fourteen patients were enrolled; all were evaluable for toxicity. The recommended phase 2 dose (RP2D) was Dose level 2, 1,000 mg/m2 /day. A single dose-limiting toxicity (DLT), hypoglycemia with acidosis, was observed at the RP2D and two DLTs, diarrhea and acidosis, were observed at Dose Level 3. Nine patients were evaluable for response as defined by the protocol, receiving at least 85% of planned metformin doses. Five complete remissions, one partial response, and one stable disease were observed. PD evaluation showed induction of ER stress, activation of AMPK, and inhibition of the UPR.
The VXLD with metformin was tolerable with a RP2D for metformin of 1,000 mg/m2 /day and yielded responses in a heavily pretreated population. ER stress was induced and toxicities attributable to metformin occurred in all dose levels.
Pharmacology, Toxicology and Pharmaceutical Science
4
4%
Business, Management and Accounting
2
2%
Nursing and Health Professions
2
2%
Other
7
8%
Unknown
52
58%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 8. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 14 October 2021.
All research outputs
#6,646,795
of 34,411,289 outputs
Outputs from Pediatric Blood and Cancer
#786
of 6,901 outputs
Outputs of similar age
#90,338
of 373,848 outputs
Outputs of similar age from Pediatric Blood and Cancer
#12
of 96 outputs
Altmetric has tracked 34,411,289 research outputs across all sources so far. Compared to these this one has done well and is in the 80th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 6,901 research outputs from this source. They receive a mean Attention Score of 4.2. This one has done well, scoring higher than 88% of its peers.
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We're also able to compare this research output to 96 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 87% of its contemporaries.
