Role of Allogeneic Stem Cell Transplantation in Preventing Relapse in Adult BCR::ABL1-like Acute Lymphoblastic Leukemia
Authors: Ribera Jordi , Morgades Mireia , Granada Isabel , González Teresa , Sánchez Ricardo , Ayala Rosa , Such Esperanza , Avetisyan Gayane , Barrera Susana , Soriano Beatriz , Torrent Anna , Gil Cristina , Botella Carmen , Maluquer Artigal Clara , Barba Pere , Montesinos Pau , González-Campos José , Martínez-Sánchez Pilar , Coll Rosa , Esteve Jordi , Benito Sanchez Maria Rocio , Lopes Thaysa , González Gil Celia , Genescà Eulàlia , Martínez-López Joaquin , Hernández-Rivas Jesús María , Orfao Alberto , Ribera Josep-Maria 
Published: December 2023

Background
Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by the activation of several kinase pathways that promote treatment resistance leading to poor survival of patients at all ages. Despite the use of tyrosine kinase inhibitors in the Ph-like ABL-class subtype (15% Ph-like ALL), there is not a consensus approach for treatment of most patients (JAK-class especially), and the role of allogeneic stem cell transplantation (alloSCT) has scarcely been explored so far (i.e., mandatory vs. MRD-oriented).
Objective
To assess the outcome of Ph-like patients enrolled in the ongoing ALL19 trial from the Programa Español de Tratamientos en Hematología (PETHEMA) for adults (18-60y) with Ph-negative ALL, and to evaluate the effectiveness of alloSCT in first complete remission (CR).
Methods
In the ALL19 trial, patients are allocated to alloSCT according both to the end of induction (EOI) measurable residual disease (MRD) level and to high-risk genetic markers such as low-hypodiploidy, KMT2A rearrangement, TP53 biallelic alteration and concomitant deletion of IKZF1 and CDKN2A/B. Therefore, BCR::ABL1-like subtype was not a criteria for early transplantation unless meeting either poor MRD clearance at EOI or concomitant deletion of IKZF1+CDKN2A/B. Patients with MRD≥0.01% on day+35 (EOI) and/or high-risk genetics were assigned to early alloSCT (preceded by 1 cycle of consolidation chemotherapy) while those with good MRD clearance and standard risk genetics received early and delayed consolidation (3 cycles each) and maintenance therapy. Bone marrow or peripheral blood samples were analyzed by G-banding+FISH, SNP array (750K Affymetrix, Thermo Fisher) and next generation sequencing (NGS, with a custom DNA gene panel, Illumina) at diagnosis in 4 reference laboratories. MRD was centrally assessed by next generation flow cytometry with a sensitivity up to 2x10 -6.
Results
Twenty-four Ph-like out of 248 adult BCP ALL (10%) were detected. Baseline characteristics were similar between Ph-like and the remaining BCP-ALL. Most Ph-like ALL patients showed the JAK-class profile (20/24 [83%]: 17/24 CRLF2 rearrangement[r], 1/24 JAK2r, 1 BLNK::DNTT and 1 JAK2 R683 mutation), 3/24 belonged to the ABL-class subtype (2 ABL2r, 1 NUP214::ABL1) and 1 patient was identified by RNAseq (gene expression profiling similar to BCR::ABL1 ALL) without identifying any rearrangement. Regarding secondary genetic alterations, 17/24 (71%) patients showed the IKZF1 plus profile, 10/23 (43%) harbored JAK2 R683 mutation, 4/23 N/KRAS mutations, 2/23 CRLF2 mutation and 1/23 showed mutations in several genes such as IKZF1, NR3C1 or FLT3, among others.
There were no significant differences in the probability of achieving CR between Ph-like and the remaining BCP ALL (15/20 [75%] vs. 137/162 [85%], p=0.334). However, EOI MRD level of Ph-like individuals was significantly poorer (MRD&lt;0.01% Ph-like 4/15 [27%] vs. other BCP-ALL 85/136 [63%], p=0.007). By intention to treat, most Ph-like patients (17/19, 89%) were allocated to alloSCT (vs. 91/153 [59%] in the other BCP-ALL, p=0.011) due to either EOI MRD≥0.01% (9/18), IKZF1+CDKN2A/B concomitant deletions (3/18) or both (6/18). The 2-y overall survival (OS) in both groups was not significantly different (57% [95% CI, 27%-78%] vs. 67% [55%-77%, p=0.304]) (Figure 1). Interestingly, most Ph-like patients died due to treatment-related toxicity (2 transplant-related mortality, 1 CART-related, 1 during induction, 1 in CR and 1 by COVID-19 infection). The 2-y cumulative incidence of relapse (CIR) was also similar (Ph-like 27% [8%-50%] vs. other BCP-ALL 35% [25%-45%], p=0.946) (Figure 1).
Conclusions
Despite the short follow up of this series, our results show that Ph-like ALL patients have poorer EOI MRD clearance and higher rate of alloSCT realization than the remaining BCP ALL patients, without significant differences in outcome. This suggests that early alloSCT in first CR might overcome the poor prognosis of Ph-like ALL patients.
Funding
Funded in part by: PI10/01417 y FIS PI19/01183 Ministerio de Salud Carlos III, JCyL_SA118P20, FMM21/002_AP176752021, “La Caixa” Foundation, Pfizer Spain, Fundación PETHEMA. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No IMI001-07. The JU receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.