When should Tyrosine Kinase Inhibitor (TKI) therapy be stopped and restarted in a patient with Acute Lymphoblastic Leukemia (ALL) B-lineage and BCR-Abl p190 mutation undergoing allogeneic Hematopoietic Stem Cell Transplant (HSCT)?

TKI Management in Ph+ ALL B-lineage (BCR-Abl p190) During Allogeneic HSCT

When to Stop TKI Before HSCT

Stop TKI immediately prior to the conditioning regimen to allow for adequate hematologic recovery and minimize toxicity during the transplant procedure. While the available guidelines primarily address CML-BP rather than ALL specifically, the principles of TKI discontinuation apply similarly given the shared BCR-ABL biology 1.

• The exact timing of discontinuation should account for the drug's half-life and allow clearance before conditioning begins 1.
• No evidence suggests increased transplant-related toxicity from recent TKI exposure, with patients safely undergoing HSCT as soon as 34 days after stopping TKI therapy 2.

When to Restart TKI After HSCT

A preemptive approach with close BCR::ABL1 monitoring is preferred over routine prophylactic administration, with TKI restart triggered by specific molecular criteria rather than a fixed post-transplant timepoint. 1

Prerequisites for TKI Restart (Preemptive Approach)

Before initiating TKI therapy post-HSCT, ensure ALL of the following criteria are met 1:

• Sufficient hematologic recovery with adequate counts
• Adequate liver function (bilirubin, transaminases within acceptable range)
• Adequate kidney function
• Controlled graft-versus-host disease (GvHD)

Molecular Triggers for TKI Restart

Restart TKI when either of these molecular criteria are met 1:

1. Loss of major molecular remission (MMR) on a single measurement (BCR::ABL1 ≥0.1% on International Scale), OR
2. Detectable BCR::ABL1 transcripts at lower levels (<0.1%) on two consecutive samples taken at least 2 weeks but no more than 4 weeks apart

Monitoring Schedule

• Monthly BCR::ABL1 monitoring is essential for the preemptive approach 1.
• Use highly sensitive quantitative PCR techniques performed in experienced laboratories with regular quality assessments 1.
• Consider digital droplet PCR for superior sensitivity in detecting minimal residual disease 1.

Rationale for Preemptive Over Prophylactic Approach

While adult data show prophylactic TKI reduces molecular recurrence compared to preemptive therapy, long-term outcomes were equivalent between approaches 1. The preemptive strategy is favored because:

• TKI toxicity is substantial: approximately 70% of patients discontinue or require dose reduction post-HSCT 1.
• Drug interactions occur between TKIs and immunosuppressive therapy 1.
• Pediatric-specific data for prophylactic TKI in Ph+ ALL post-HSCT are lacking (EsPhALL2017/COG AALL1631 trial results pending at time of guideline publication) 1.
• A preemptive approach allows early intervention while harnessing the graft-versus-leukemia effect through reduced immunosuppression 1.

Choice of TKI

Use the same TKI agent that was administered before HSCT, provided no new resistance mutations are detected 1.

• Perform tyrosine kinase domain mutation analysis if BCR::ABL1 transcript level >1% or if there is persistent/increasing molecular disease 1.
• If T315I mutation is present, switch to ponatinib 1.
• Imatinib is considered first choice unless resistance is demonstrated, based on established safety data post-transplant 1.
• Dasatinib may be more effective for converting MRD-positive to negative status, though based on smaller retrospective studies 1.

Duration of Post-HSCT TKI Therapy

Continue TKI therapy for 2 years after achieving stable deep molecular remission (DMR) 1.

• Deep molecular remission is defined as BCR::ABL1 ≤0.01% or undetectable transcripts 1.
• This 2-year duration criterion is based on treatment-free remission studies in CML 1.
• For pediatric Ph+ ALL specifically, dasatinib was administered for a maximum of 2 years in clinical studies 3.

Management of Molecular Relapse

If BCR::ABL1 transcripts are repeatedly detectable at the same or increasing level 1:

1. Restart TKI therapy immediately

2. Discontinue immunosuppressive therapy as soon as clinically feasible

3. Perform diagnostic workup including:

   • Bone marrow morphology and blast percentage
   • Cytogenetics (minimum 15 metaphases analyzed)
   • FISH if cytogenetics fails
   • Tyrosine kinase domain mutation analysis if BCR::ABL1 >1%
   • Cerebrospinal fluid cytology

4. Consider donor lymphocyte infusion (DLI) if poor response to TKI, particularly when combined with TKI therapy 1, 4.

Important Caveats

• Drug interactions: TKIs significantly affect pharmacokinetics of immunosuppressive agents and vice versa; close monitoring and dose adjustments are essential 1.
• Toxicity management: Be prepared for dose interruptions or reductions in approximately 70% of patients 1.
• Adherence: Check adherence before changing therapy, as inadequate response often reflects poor compliance, especially in adolescents 1.
• The evidence base primarily derives from CML-BP and adult Ph+ ALL populations; direct evidence for p190 BCR-ABL ALL is limited but management principles are extrapolated 1.