TKI maintenance therapy post-allogeneic HCT improves outcomes in patients with Ph+ ALL

Tyrosine kinase inhibitor (TKI) therapy is administered to patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) following allogeneic hematopoietic cell transplantation (allo-HCT) as a means to lower relapse rates. Previous studies aimed at determining the role and duration of maintenance TKI therapy have generated conflicting results, and a definitive randomized trial for TKI therapy had not been established. A recent retrospective study published in Blood by Saini et al.¹ compares the clinical outcomes of patients with Ph+ ALL receiving allo-HCT with and without TKI maintenance, and attempts to identify the optimal duration of maintenance TKI therapy.

Study and patient characteristics

• Patients undergoing first allo-HCT at The University of Texas M.D. Anderson Cancer Center from January 2001–December 2018
• A total of 165 patients were included in the analysis (Table 1), with a median follow-up at 67 months (range, 7–180 months)
• Qualitative polymerase chain reaction (qPCR) was used to detect BCR-ABL1 transcripts
  • Complete molecular response (CMR) was defined as no detectable BCR-ABL1 transcript with a sensitivity of ≤ 0.01%
  • A major molecular response was defined as BCR-ABL1:ABL1 ratio of ≤ 0.1% on the International Scale for p210 BCR-ABL1 or a 3-log reduction in p190 BCR-ABL1 transcripts, but not meeting criteria for CMR

Table 1. Patient characteristics¹

allo-HCT, allogeneic hematopoietic cell transplantation; CMR, complete molecular response; CR1, first complete remission; CR2, second complete remission; CR3+, third or subsequent remission; HCT-CI, hematopoietic cell transplantation-specific comorbidity index; HCVAD, hyper-CVAD [cyclophosphamide + vincristine + doxorubicin + dexamethasone]; MMR, major molecular response; MRD, measurable residual disease; Ph+, Philadelphia chromosome–positive; TKI, tyrosine kinase inhibitor
Characteristic	Patients (N = 165)
Age, years (range) ≤ 40 >40	41 (3–70) 49% 51%
Sex, male	61%
Cytogenetics at diagnosis Ph+ alone Ph+ plus other cytogenetics Unknown	54% 42% 4%
Decade of allo-HCT 2001–2009 2010–2018	44% 56%
HCT-CI score 0 1 ≥ 2 Unknown	55% 8% 34% 3%
Disease status at allo-HCT CR1 CR2 CR3+	68% 26% 3%
Presence of MRD at allo-HCT CMR MMR No CMR/MMR Unknown	49% 13% 28% 10%
TKI Maintenance post allo-HCT	59%
Median time to initiate TKI therapy, months post allo-HCT	2.4
Induction of chemotherapy prior to allo-HCT HCVAD + TKI Others Not available	88% 10% 2%

Results

• Significant predictors of relapse, as assessed by multivariate analysis, were
  • disease status at transplant (complete remission [CR] ≥ 2 vs first complete remission [CR1]; HR, 3.36; 95% CI, 1.54–7.32; p = 0.002)
  • depth of measurable (minimal) residual disease (MRD; others vs CMR; HR, 2.5; 95% CI, 1.09–5.71; p = 0.03)
  • cytogenetic status (Ph+ alone vs Ph+ other cytogenetic abnormality; HR = 0.3; 95% CI, 0.133–0.7; p = 0.006)
• Progression-free survival and overall survival were better in patients transplanted in CR1 compared with the entire patient cohort (Table 2)
• A total of 97 (59%) patients received TKI maintenance therapy, either as prophylaxis (n = 71) or triggered by MRD positivity (n = 26)
  • Most patients received imatinib (n = 38) or dasatinib (n = 31), while others had ponatinib, bosutinib, nilotinib, or a combination of these
  • The median time to starting TKI maintenance was 2.3 months in the prophylactic group and 3.2 months MRD-triggered group

• Of the total number of patients receiving TKI maintenance,
  • 27 patients stopped TKI maintenance because they had completed their planned therapy and were still in remission
  • 21 patients stopped TKI maintenance because of disease recurrence
  • 31 patients stopped TKI maintenance because of adverse events, mostly cytopenia, fluid retention recurrent infections, and gastrointestinal symptoms.
• A landmark analysis was performed at 3 months in 42 patients who had a CMR prior to allo-HCT and 3 months after allo-HCT to investigate the impact of early TKI initiation after transplant
  • In 24 patients who received prophylactic TKI within 3 months posttransplant, the 2-year progression-free survival was 94.5% compared with 75% in those that had either not received TKI (n = 16) or initiated TKI treatment later than 3 months posttransplant

• Imatinib was administered to 28 patients, and 33 patients received newer-generation TKI, excluding patients that required a different TKI due to toxicity or other reasons
• The overall relapse rate was similar in both treatment groups, however, when patients in the MRD-triggered group were analyzed, 6 of 8 patients (75%) that received imatinib relapsed, compared with only 6 of 11 patients (45%) that received other TKIs
• To determine the optimal length of TKI maintenance, 84 patients in CMR at 3 months post-allo-HCT were analyzed
  • These patients received TKI for a median of 13 months (range, 0.23–74 months), with 29 patients receiving TKI for more than 2 years
  • Using a competing risk-regression model, patients continuing TKI for more than 2 years had a lower relapse risk than those that ended TKI therapy before 2 years (HR, 0.12; p = 0.045), with only one patient relapsing in the > 2 year TKI maintenance group

Table 2. Summary of clinical outcomes¹

CR1, first complete remission; OS, overall survival; PFS, progression-free survival; Ph+ ALL, Philadelphia chromosome–positive acute lymphoblastic leukemia
Outcome	Percentage (%)
Patients that had progressed at last follow-up (Median follow-up, 67 months [range, 7–180])	53
Patients that had died at time of last follow-up	51
All Ph+ ALL patients 2-year/5year PFS 2-year/5-year OS	54/46 59/49
Ph+ ALL patients transplanted in CR1 2-year/5-year PFS 2-year/5-year OS	69/57 73/53

Conclusion

The study demonstrates that early initiation of TKI maintenance therapy posttransplant decreases the incidence of relapse and improves outcome in patients with Ph+ ALL. TKI maintenance therapy should be continued for at least 2 years post allo-HCT, however prospective trials are needed to better determine the optimal maintenance duration.