Background: Several cytogenetic risk stratifications have been developed and used as prognostic tools at diagnosis of acute lymphoblastic leukemia (ALL). However, most prior studies on the prognostic significance of ALL karyotyping were influenced by inclusion of Philadelphia-positive (Ph+) patients and those treated predominantly with conventional chemotherapies. The application of existing cytogenetic risk schemas to recipients of allogeneic hematopoietic cell transplantation (alloHCT) with Ph-negative (Ph-) ALL remains elusive because of the relatively low frequencies of individual Ph- abnormalities and modest population samples of prior studies.
Patients and Methods: In this large international cohort (N=1731; 256 transplant centers from 38 countries) of adult Ph- ALL recipients of alloHCT (1995-2011), we examined the prognostic impact of individual cytogenetic abnormalities together with major established cytogenetic risk classifications (MRC-ECOG, modified MRC, SWOG, NILG-ALL, North UK, and GIMEMA 0496) on clinical outcomes after alloHCT. Abnormal cytogenetic profiles were validated via review of original reports (54%) from participating centers or from the CIBMTR database (46%); normal cytogenetics were reviewed and confirmed for 27% of reports (>95% accuracy). Leukemia-free survival (LFS) was the primary study endpoint. We included allograft recipients of both myeloablative (92.3%; 78% TBI-based) and reduced intensity/non-myeloablative (7.7%) conditioning using matched related (50%) and unrelated donor (27% 8/8 MUD; 21% mismatched UD), peripheral blood (46%) or bone marrow (54%) grafts.
Results: A total of 632 patients (36.5%) had abnormal and 1099 (63.5%) had normal cytogenetics (Table). Young adults (<45 years) accounted for 82% of the entire cohort (63% males; 69% with B-cell ALL; 23% with high-risk hyperleukocytosis at diagnosis). Fifty-seven percent of patients underwent alloHCT in CR1 and 43% in CR2. Patients with abnormal cytogenetics had 40% LFS and 42% OS at 5-years post-transplant; which was similar to those with normal karyotype (both p>0.6). As opposed to all other cytogenetic schemas, only the modified MRC-ECOG stratification of patients into standard (n=24 with better outcomes) vs. intermediate (n=1447), high (n=160), and very high (n=78) groups was prognostic for LFS (overall p=0.03) in the multivariable analysis adjusted for recipient age, pre-HCT remission status, conditioning regimen, KPS, donor type, and GVHD prophylaxis (all co-variates were prognostic for LFS, p<0.01). Individual cytogenetic abnormalities that were consistent in their prognostic significance with modified MRC-ECOG but also associated independently with LFS in our cohort included unfavorable t(8;14) (HR=2.9; 95%CI, 1.4-6.0), del7q/-7 (HR=1.4; 95%CI, 1.0-2.1), and favorable high hyperdiploidy (HR=0.6; 95%CI, 0.4-1.0). Complex cytogenetics, monosomal karyotype, t(4;11), -17/i17q/del17p, +8, or t(1;19) were not associated with post-transplant LFS or OS in individual adjusted models.
Conclusions: In this large analysis of adult Ph- ALL recipients of alloHCT with screened and validated cytogenetic profiles, we show that previously established high-risk ALL cytogenetics can be overcome by alloHCT. Although modified MRC-ECOG risk stratification appeared to be most prognostic for post-transplant LFS, its effect was largely driven by only few and relatively infrequent cytogenetic abnormalities. Our data argue that factors other than cytogenetic risk have greater impact on post-transplant survival of Ph- ALL.
Bachanova: Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees. De Lima: Celgene Corporation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees.
Asterisk with author names denotes non-ASH members.
This icon denotes a clinically relevant abstract