The impact of additional cytogenetic abnormalities and complex karyotype on outcomes of adult patients with Philadelphia-positive acute lymphoblastic leukemia undergoing allogeneic stem cell transplantation in first complete remission: A study from the ALWP/EBMT

Abstract

Abstract Background: (Ph+) is the most common cytogenetic abnormality in adults with ALL. Additional chromosomal abnormalities (ACA) are found in about 60%-70% of patients (pts) with Ph+ ALL. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment paradigm in Ph+ ALL. Allogeneic transplantation (HSCT) is still the standard of care in Ph+ ALL-eligible pts in CR1. Data are conflicting regarding the impact of ACA and complex karyotype (CK) on outcomes of Ph+ ALL pts undergoing HSCT while in CR1 in the TKI era. Methods:The study aimed to assess the impact of ACA and CK on HSCT outcomes of Ph+ ALL pts that received a TKI and underwent first HSCT while in CR1 between 2010-2022. Pts needed to have full karyotyping data, including Ph as an abnormality. Outcomes were LFS, OS, GVHD-free relapse-free survival (GRFS), RI, and NRM. The impact of ACA was evaluated by comparing the presence of ACA (1 ACA, 2-3 ACA, or ≥4 ACA) to the referent group with no ACA (noACA). Results: 514 Ph+ pts were included: with ACA (n=345); without ACA (n=169). Of the 345 pts with ACA, 109 had 1 ACA, 100 had 2-3 ACA, and 136 had > 4 ACA. 210 pts had at least one monosomy, most frequently monosomy 7 (n=63). 101 pts had at least one trisomy. Twelve pts had 11q23 translocations. IKZF1 mutations were observed in 8.7% and 7.7% of pts with and without ACA, respectively. The presence of ACA was associated with a higher rate of MRD-negativity pre HSCT (56.2% vs. 46.5%, p=0.04). Median follow-up was 4.2 years (95% CI, 3.9-4.7). Median year of transplant was 2018 IQR, 2015-2020), with no significant difference between the groups (p=0.27). Median age was 42.6 years (IQR, 31.7-53.5), and 54.5% were male. The groups (ACA vs. noACA) did not differ significantly in terms of age, gender, and interval from diagnosis to HSCT. In the ACA and noACA groups, donors were matched siblings in 32.5% vs. 28.4%, unrelated in 37.1% vs. 27.2%, or haploidentical in 28.7% vs. 40.2%, respectively. More pts with ACA received PB grafts compared to the noACA group (86.4% vs. 78.1%, p=0.03). Pt CMV seropositivity was more frequent in the ACA than in the noACA group (70.5% vs. 57.2%, p=0.009). The use of myeloablative conditioning was more frequent in noACA than in ACA pts (87% vs. 75.9%, p=0.003), with TBI-based being the most frequent conditioning in both groups (51.9% vs. 40.2%). Post-transplant cyclophosphamide was administered to 12.9% vs. 14.8%, respectively (p=0.55). Day 30 absolute neutrophil count (>109/L) was 97.9 % vs. 98.2 % and day 60 platelet count (>20x109/L) was 93.9 % vs. 95.5%, for the ACA and noACA groups, respectively. The incidence of day 100 acute (a) GVHD grades II-IV was 26.4% vs. 31% and of grades; III-IV was 8.6% vs. 9.7%, respectively. 4-year incidence of chronic (c) GVHD was 40.5 % vs. 39.9 % and of extensive cGVHD was 19.3% vs. 20.1 %. 4-year NRM was 13.1 % vs. 13. 5%, and 4-year RI was 19.2 % vs. 21.1 %, respectively. The 4-year LFS and overall survival rates were 67.7% vs. 65.4 % and 76.3% vs. 78.5%, respectively. 4-year GRFS was 48.5% vs. 45%, respectively. In multivariate analysis, having ACA and the number of ACAs did not affect transplant outcomes significantly. Compared to noACA, hazard ratios for LFS were 0.93, 0.90, and 1.06 for 1 ACA, 2-3 ACA, and ≥4 ACA, respectively. Year of HSCT and age were poor prognostic factors for NRM, LFS, and OS. Year of HSCT was also a poor prognostic factor for RI, GRFS, and total and extensive cGVHD. Greater than 6 months from diagnosis to HSCT was a negative prognostic factor for NRM, LFS, OS, GRFS, and aGVHD II-IV. MRD-positivity pre-HSCT was a poor prognostic factor for LFS, OS, and NRM. A mismatched related donor was associated with lower RI and higher NRM. An unrelated donor was associated with higher NRM and aGVHD II-IV, while reduced intensity conditioning was associated with a lower incidence of aGVHD II-IV. Female-to-male donor was associated with a higher incidence of total cGVHD. Conclusions: In this registry-based retrospective analysis of Ph+ ALL pts receiving a TKI and subsequent HSCT, no significant differences were observed in transplantation outcomes between pts with or without ACA, including those with additional CK. Notably, achieving MRD-negativity pre HSCT was significantly higher in pts with ACA. These data may indicate that the administration of a TKI upfront, followed by HSCT, may overcome the poor prognosis influence of the ACA, including CK in Ph+ ALL.