Page 176 - Haematologica May 2020

A. Lazaryan et al.
major ALL cytogenetic risk schemes, only the modified MRC-ECOG classification could be validated in our dataset for its association with post-transplant outcomes. The association of the modified MRC-ECOG classifica- tion was largely explained by favorable outcomes for patients with high hyperdiploidy, a factor known to be associated with better outcomes.12,13 While a few individ- ual high-risk cytogenetic abnormalities maintained their prognostic relevance for recipients of allogeneic HCT, many others had no significant prognostic influence on the transplant outcomes. Thus, the aggregate effects of previously established high or very high risk cytogenetic groups defined by MRC-ECOG, SWOG, NILG-ALL, North UK, and GIMEMA 0496 were overcome by allo- geneic HCT and did not predict the outcomes of the trans- plant recipients. High-risk cytogenetic abnormalities including trisomy 8, low hypodiploidy, t(1;19), del(6q) could be overcome, in part, by the graft-versus-leukemia effect of allogeneic HCT, and thus, were not unfavorable in this analysis. In contrast to findings in acute myeloid leukemia14,15 and recently reported cases of ALL,4,16 in our dataset and elsewhere,17 monosomal karyotype did not predict poor post-transplant outcomes for Ph– ALL. Similarly, our analysis did not confirm the adverse effect of t(4;11) on relapse or leukemia-free survival among all carriers of this well-known cytogenetic risk, but uncov- ered a differential effect of t(4;11) on transplant outcomes which was modified by pre-transplant disease status. Nevertheless, given the relatively small subset of patients with t(4;11) in CR2, the results of our post-hoc analysis should be interpreted with caution. Moreover, the infre- quency of CR2 allografts in patients with t(4;11) may reflect intrinsic difficulty for those patients to effectively maintain maintain subsequent remissions. A recent com- parison of allograft recipients with t(4;11) and normal karyotype in CR1 demonstrated relatively favorable sur- vival of patients with t(4;11) and especially those with undetectable pretransplant minimal residual disease.18 Allogeneic HCT in CR1 for adult ALL patients with t(4;11) remains valuable.19
High-risk cytogenetic abnormalities found in this study included t(8;14), complex karyotype, and monosomy 7, previously known poor-risk categories in major classifica- tion schemes, excluding GIMEMA 0496 (Table 1). Patients with these high-risk cytogenetic abnormalities were predominantly young adults, most of whom received myeloablative conditioning and still had poor
outcomes, thus confirming the high-risk nature of cytoge- netic abnormalities.
The t(8;14) is a rare recurrent abnormality among patients with ALL20-23 and has been associated with a poor outcome.7 It was observed in ten allogeneic HCT recipi- ents (median age, 21) who had a nearly 3-fold significantly lower leukemia-free survival in our cohort. In addition to the IGH-MYC fusion resulting from the t(8;14), other IGH translocations involving BCL2 (when present together
Table 4. Multivariable model of prognostic factors for post-transplant treatment failure.
Factors
N
HR (95% CI)
1.0
1.21 (1.04-1.41) 1.42 (1.07-1.88)
1.0
1.53 (1.34-1.74)
1.0
1.4 (1.18-1.66) 1.0
1.26 (0.97-1.64)
1.0
1.32 (1.15-1.52)
1.0
1.06 (0.9-1.24) 1.43 (1.21-1.68) 1.36 (1.02-1.81)
1.0
1.11 (0.96-1.28) 1.39 (1.1-1.75)
2.85 (1.35-6.02)
1.97 (1.2-3.24)
P-value
0.02 0.01
<0.001
<0.001 0.09
<0.001
0.49 <0.001 0.03
0.15 0.006
0.006
0.007
Age, years
16-39 1270 40-55 363 55+ 86
Remission status pre-alloHCT
CR1
CR2
Conditioningregimens MAC (+TBI)
MAC (-TBI)
MAC (+TBI) RIC/NMA
986
733
1334 253 1334 96
Performance status
KPS≥90 1234
KPS<90
Donor type MSD
Matched URD Mismatched URD Other RD/URD
GvHD prophylaxis Tac-based CsA-based Other
Cytogenetics t(8;14)
Monosomy 7*
423
818 464 351 86
569 996 134
10
33
Table 5. Novel Center for International Blood and Marrow Transplant Research risk scheme for post-transplant Philadelphia-negative acute lym- phoblastic leukemia outcomes
N: number; HR: hazard ratio; 95% CI: 95% confidence interval; alloHCT: allogeneic hematopoietic cell transplantation; CR1: first complete remission; CR2: second com- plete remission; MAC: myeloablative conditioning; TBI: total body irradiation; RIC: reduced-intensity conditioning; NMA: non-myeloablative; KPS: Karnofsky Performance Status; MSD: matched sibling donor; RD: related donor; URD: unrelated donor; GvHD: graft-versus-host disease; CSA: cyclosporine. *Adjusted for monosomal karyotype.
Cytogenetic risk groups N
Favorable (high hyperdiploidy) 28
Intermediate (normal karyotype 1578
and all other abnormalities§)
Adverse (monosomy 7, complex karyotype, 125 del(7q), t(8;14), t(11;19), del(11q),
tetraploidy/near triploidy)
Adverse vs. favorable -
Treatment failure(1-LFS)
0.6 (0.35-1.02)
1.0 (Reference)
1.26 (1.01-1.57) 2.1 (1.19-3.7)
HR (95% CI)* Relapse
0.39 (0.15-1.05)
1.0 (Reference)
1.48 (1.09-2.0) 3.78 (1.36-1.76)
Overall mortality (1-OS)
0.64 (0.37-1.08)
1.0 (Reference)
1.22 (0.97-1.53) 1.91 (1.08-3.38)
HR: hazard ratio; 95% CI: 95% confidence interval; LFS: leukemia-free survival; OS: overall survival. *Adjusted for conditioning intensity, disease status prior to transplantation, recipient age, Karnofsky Performance Status, donor type, graft-versus-host disease prophylaxis, as applicable based on the individual models. §Except for those included in the adverse and favorable groups
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haematologica | 2020; 105(5)