Evaluating the Safety of Tyrosine Kinase Inhibitor Discontinuation in Adult Patients with Ph+ ALL Not Undergoing Allogeneic Transplant
Authors: Kugler Eitan , Khaire Niranjan Shiwaji , Jabbour Elias , Short Nicholas J. , Kadia Tapan M. , Haddad Fadi G. , Sasaki Koji , Kanagal-Shamanna Rashmi , Garris Rebecca , Ravandi Farhad , Kantarjian Hagop M. , Jain Nitin 
Published: December 2024

Background

BCR
:ABL1 tyrosine kinase inhibitors (TKIs) have significantly improved outcomes of patients (pts) with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). In the era of measurable residual disease (MRD) kinetics guiding decision-making, the optimal duration of TKI therapy for pts in molecular response who do not undergo allogeneic stem cell transplantation (allo-SCT) remains unclear. Advancements in next-generation sequencing (NGS) and polymerase chain reaction (PCR) methods highlight the potential for safely discontinuing TKI therapy in selected pts. We report outcomes of pts with Ph+ ALL in CR1 who discontinued TKI after being in deep molecular response (DMR) for a variable period of time.
Methods
In this retrospective analysis, we included pts with newly diagnosed Ph+ ALL who received first-line therapy at our institution (MD Anderson Cancer Center) between 2001 and 2023. We selected pts who did not undergo allo-SCT and discontinued TKI therapy after achieving a DMR (BCR::ABL1 transcripts by PCR &lt;0.01% in either blood or bone marrow). Pts who discontinued TKI due to noncompliance, pregnancy-related issues or as a temporary measure to manage side effects were excluded. Molecular relapse was defined as the loss of DMR. Treatment-free remission (TFR) was assessed from the time of TKI discontinuation to molecular/clinical relapse, last follow-up, or death from any cause.
Results
We identified 14 pts with Ph+ ALL in CR1 who achieved DMR and subsequently discontinued the TKI therapy. Fifty percent of the pts were female. The median age at diagnosis was 60 years (range, 19-82). Ten pts (71%) harbored the p190 transcript and 4 (29%) had a p210 transcript. Induction therapy included hyper-CVAD + imatinib, n=2; hyper-CVAD + dasatinib, n=6, hyper-CVAD + ponatinib, n=4; blinatumomab + ponatinib, n=2. One pt on hyper-CVAD + ponatinib regimen was switched to blinatumomab + ponatinib after 2 cycles due to poor chemotherapy tolerance while still in CR1. Three pts transitioned to a different TKI for adverse events while still in CR1 prior to therapy discontinuation. Reasons for TKI discontinuation included pleural effusion (29%), pulmonary arterial hypertension (21%), vascular complications (29%), cytopenia (14%), pancreatitis (7%) and other reasons (21%). Overall, the median duration of TKI therapy was 60 months (range, 31-125) with a median DMR duration of 46 months (range, 2-122) prior to the TKI discontinuation.
With a median follow-up of 51.3 months after TKI discontinuation, a total of 3 pts (21%) (p190, n=2; p210, n=1) experienced a molecular relapse (including 1 pt with clinical relapse) and 11 pts (79%) remained in TFR. Prior to the TKI discontinuation, the 3 pts with molecular relapse were on TKI therapy for 42, 43 and 59 months and in continuous DMR for 41, 40 and 18 months, respectively. The median time to molecular relapse was 6.4 months (range, 4-16) from TKI discontinuation. All 3 pts regained molecular response upon resuming TKI (including 1 pt with clinical relapse who received blinatumomab + TKI). Notably, none of the 8 pts with a DMR duration of more than 4 years prior to TKI discontinuation experienced molecular/clinical relapse. Four pts discontinued TKI with a DMR duration of less than 3 years (2, 18, 31 and 33 months); pt with DMR duration of 18 months had a molecular relapse. Notably, the pt with only 2 months of DMR before stopping TKI was on TKI therapy for 125 months and in DMR for &gt;10 years; however, he had a single PCR result showing loss of DMR (PCR 0.03) followed by immediate regaining of DMR. Two months later, he needed TKI discontinuation due to effusions and remained in DMR and off TKI for 66 months. Additionally, 4 pts were noted to be NGS MRD undetectable (10-6 sensitivity) at the time of TKI discontinuation; these pts were in DMR for 33, 45, 66 and 76 months, respectively. None of these 4 pts had a molecular/clinical relapse with a median follow up of 7 months (range, 4-22) post TKI discontinuation.
Conclusions
Our findings suggest that TKI discontinuation may be safe for a highly selected group of pts with Ph+ ALL in CR1 who are in long-term continuous DMR. DMR duration of more than 4 years was associated with durable remissions in the off-therapy phase without molecular/clinical relapse. Larger studies are needed to confirm these findings.