Abstract
Abstract 2488
Hairy cell leukemia (HCL) is a B-cell malignancy which is thought to originate in most patients after the B-cell contacts antigen. To determine whether certain HLA types are preferentially expressed in HCL, HLA class I and class II allele frequencies at low resolution were collected from 247 HCL patients including 233 Caucasian, 5 Black, 5 Hispanic, 2 Asian and 2 Hawaiian/Pacific Islanders. Out of 494 total alleles from the 247 patients, the most frequent were HLA-A*02 (145, 29%), HLA-B*07 (58, 12%), HLA-C*07 (141, 29%), and HLA-DRB1*11 (76, 15%). In comparison with normal donors, only HLA-DRB1*11 was preferentially expressed in HCL, with a population frequency among the 233 Caucasians of 70 (30%), compared to 17% of a database of USA Caucasians (n=61655, p<0.0001) and 12–21% in 8 other smaller USA Caucasian databases (n=194–8525, p=0.01, 0.005, p<0.0001 for 6 others).
Because it was recently reported that HLA-DRB1*11 is a strong risk factor for acquired ADAMTS13 deficiency-related thrombotic microangiopathy, HCL patients who had hemolytic uremic syndrome (HUS) after anti-CD22 recombinant immunotoxin BL22 were examined for HLA expression at the DRB1 locus. BL22 was previously reported to be associated in HCL with a 12% risk of completely reversible grade 3–4 HUS mainly during the 2nd or 3rd retreatment cycle. We found that of 49 HCL patients treated with at least 2 cycles of BL22, most (71%) of 7 HCL patients with HUS expressed HLA-DRB1*11, compared to only 21% of 42 without HUS (p=0.015). Even when considering all 66 evaluable HCL patients who received BL22, including the 17 who received just 1 cycle, expression of HLA-DRB1*11 was more frequent in those with compared to without HUS (63% of 8 vs 24% of 58 patients, p=0.038).
In the poor-prognosis variant of HCL, termed HCLv, we found that the most common HLA-DRB1 gene expressed was HLA-DRB1*04, found in 19 (56%) of 34 patients, compared to 30% of the normal USA Caucasian database (n=61655, p=0.002) and 27–37% in the 8 smaller databases mentioned above (p values 0.016 and 0.001–0.01). HLA-DRB1*04 expression was recently reported to be significantly reduced in patients with idiopathic thrombotic microangiopathy. In BL22-associated HUS in HCL, DRB1*04 expression was not increased and none had HCLv.
Moxetumomab pasudotox, an affinity-matured version of BL22, binds with 14-fold higher affinity to CD22 due to mutations in the CDR3 domain of the heavy chain, and was recently reported in 28 HCL patients to be associated with only 2 cases of transient grade 2 HUS, defined as grade 1 creatinine and platelet abnormalities. No HUS was observed in 20 additional HCL patients treated. Despite the similarity in the population incidences of HLA-DRB1*11 in those receiving moxetumomab pasudotox and BL22 (35% vs 29%), the grade 3–4 HUS risk was significantly lower with moxetumomab pasudotox than with BL22 (p=0.02). We conclude that 1) HLA-DRB1*11 is preferentially expressed in HCL, 2) HLA-DRB1*04 is preferentially expressed in HCLv, and 3) HLA-DRB1*11 constitutes a potential marker in HCL for susceptibility to HUS from BL22, but not from moxetumomab pasudotox, possibly because the latter molecule binds more specifically to CD22 and avoids HUS.
Disclosures:
Off Label Use: BL22 and Moxetumomab Pasudotox are experimental agents for CD22+ malignancies. Pastan:NIH: Coinventor on NIH patents for BL22 and Moxetumomab, Coinventor on NIH patents for BL22 and Moxetumomab Patents & Royalties. Kreitman:NIH: Coinventor on NIH patents for BL22 and Moxetumomab, Coinventor on NIH patents for BL22 and Moxetumomab Patents & Royalties.
Phase II Trial of Recombinant Immunotoxin RFB4(dsFv)-PE38 (BL22) in Patients With Hairy Cell Leukemia