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

Aug 12, 2020
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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.

  1. Saini NY, Marin D, Ledesma C, et al. Impact of TKI maintenance post-allogeneic transplant in Philadelphia positive acute lymphoblastic leukemia. Blood. 2020. DOI: 10.1182/blood.2019004685

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