A randomized controlled trial of an intensive insulin regimen in patients with hyperglycemic acute lymphoblastic leukemia.
Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL). To examine whether intensive insulin therapy could improve outcomes, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy. Intensive insulin did not improve ALL clinical outcomes despite improved glycemic control. Secondary analysis suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes.


BACKGROUND
Hyperglycemia during hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine, with methylprednisolone premedication) chemotherapy is associated with poor outcomes of acute lymphoblastic leukemia (ALL).


METHODS
To examine whether an intensive insulin regimen could improve outcomes compared with conventional antidiabetic pharmacotherapy, a randomized trial was conducted that compared glargine plus aspart vs. conventional therapy (control). Between April 2004 and July 2008, 52 patients newly diagnosed with ALL, Burkitt lymphoma, or lymphoblastic lymphoma who were on hyper-CVAD in the inpatient setting and had a random serum glucose level >180 mg/dL on ≥2 occasions during chemotherapy were enrolled.


RESULTS
The trial was terminated early due to futility regarding ALL clinical outcomes despite improved glycemic control. Secondary analysis revealed that molar insulin-to-C-peptide ratio (I/C) > 0.175 (a surrogate measure of exogenous insulin usage) was associated with decreased overall survival, complete remission duration and progression-free survival (PFS), whereas metformin and/or thiazolidinedione usage were associated with increased PFS. In multivariate analyses, factors that significantly predicted short overall survival included age ≥ 60 years (P = .0002), I/C ≥ 0.175 (P = .0016), and average glucose level ≥ 180 mg/dL (P = .0236). Factors that significantly predicted short PFS included age ≥ 60 years (P = .0008), I/C ≥ 0.175 (P = .0002), high systemic risk (P = .0173) and average glucose level ≥ 180 mg/dL (P = .0249). I/C ≥ 0.175 was the only significant (P = .0042) factor that predicted short complete remission duration.


CONCLUSIONS
A glargine-plus-aspart intensive insulin regimen did not improve ALL outcomes in patients with hyperglycemia. Exogenous insulin may be associated with poor outcomes, whereas metformin and thiazolidinediones may be associated with improved outcomes. Analysis of these results suggests that the choice of antidiabetic pharmacotherapy may influence ALL outcomes.
Department of General Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Khanh
K
Vu
Naifa
N
Busaidy
Maria E
ME
Cabanillas
Marina
M
Konopleva
Stefan
S
Faderl
Deborah A
DA
Thomas
Susan
S
O'Brien
Kristine
K
Broglio
Joe
J
Ensor
Carmen
C
Escalante
Michael
M
Andreeff
Hagop
H
Kantarjian
Victor
V
Lavis
Sai-Ching Jim
SC
Yeung
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D001786:Blood Glucose / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000097:blood / Q000188:drug therapy; D002096:C-Peptide / Q000378:metabolism; D003520:Cyclophosphamide / Q000008:administration & dosage; D003907:Dexamethasone / Q000008:administration & dosage; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use*; D000069036:Insulin Glargine; D049528:Insulin, Long-Acting / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood / Q000188:drug therapy*; D011379:Prognosis; D011446:Prospective Studies; D045162:Thiazolidinediones / Q000627:therapeutic use; D016896:Treatment Outcome; D014750:Vincristine / Q000008:administration & dosage; D055815:Young Adult
D001786:Blood Glucose; D002096:C-Peptide; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D045162:Thiazolidinediones; D000069036:Insulin Glargine; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide; D008687:Metformin