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Updated results from the D-ALBA trial of dasatinib plus blinatumomab in newly diagnosed adult Ph+ ALL

Jul 5, 2021
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The outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) are historically poor; however, they have markedly improved since the introduction of tyrosine kinase inhibitors (TKIs). To explore if a chemotherapy-free strategy is feasible to treat patients with newly diagnosed Ph+ ALL, the GIMEMA LAL2116 D-ALBA trial (NCT02744768) was conducted.1

This phase II trial examined the efficacy of dasatinib plus glucocorticoids, followed by 2–5 cycles of blinatumomab and central nervous system (CNS) prophylaxis, with the primary endpoint of sustained molecular response. The primary results demonstrated that 60% of patients achieved a molecular response after the second cycle of blinatumomab, which continued to increase after additional blinatumomab cycles. At a median follow-up of 18 months, overall survival (OS) was 95% and disease-free survival (DFS) was 88%; and the DFS lower among patients who had an IKZF1 deletion plus additional genetic aberrations (IKZF1plus).

During the European Hematology Association (EHA) 2021 Virtual Congress, Sabina Chiaretti presented results of the updated follow-up ancillary observational study, GIMEMA LAL2217,2 and we are pleased to summarize the findings here.

Methods

  • Following the primary endpoint, patients were followed for 12 months, with data collected regarding subsequent treatment and survival.2
  • Trial design and endpoints have been previously reported.1 In brief:
    • Prior to dasatinib, patients received a 7-day steroids pre-phase, and steroids were continued for a further 24 days and stopped at Day 31.
    • Dasatinib (140 mg/day) was administered as induction for 85 days.
    • Patients who obtained a complete hematologic response (CHR) received post-induction consolidation treatment with blinatumomab (28 μg/day; 2–5 cycles).
    • Dasatinib was continued during treatment with blinatumomab.
    • CNS prophylaxis was provided during the whole treatment course.
    • Post-consolidation treatment was decided by the investigator.
  • Primary endpoint: a molecular response (a complete molecular response and a positive nonquantifiable response [i.e., minimal residual disease positive samples outside of the quantitative range) with induction therapy, including dasatinib and glucocorticoids, followed by a minimum of two cycles of blinatumomab.1

Results

The 63 patients were followed-up for a median of 28.81 months (0.9–45.2 months). The molecular responses were recorded and are shown in Table 1.

Table 1. Molecular responses*

Assessment

Overall molecular response, %

Indication period

 

              Day 85

29

Blinatumomab cycle

 

              After Cycle 1

64

              After Cycle 2

60

              After Cycle 3

70

              After Cycle 4

81

              After Cycle 5

72

Follow-up

 

              3-month

77

              6-month

77

              9-month

95

              12-month

89

*Adapted from Chiaretti et al.2
Analyses conducted in a subset of the whole population.

  • The results in Table 1 demonstrate that the molecular responses remained stable over the course of the 12-month follow-up.
  • The estimated OS rate at 36 months was 80% (confidence interval [CI], 68–93) and the DFS rate was 71% (CI, 58–87).
  • Patients who had a complete molecular response or positive nonquantifiable response had an improved DFS at 36 months compared with patients without a molecular response (100% vs 78%; p = 0.018).
  • Patients with IKZF1plus had an inferior DFS at 30 months (41%; CI, 19–89) compared with patients who had only IKZF1 deletion (55%; CI, 24–100) and patients without IKZF1 deletions (79%; CI, 62-100; p = 0.052).

Deaths and relapses

  • A total of nine relapses were recorded; four in the CNS, four hematologic, and one nodal.
  • The median time to relapse was 4.4 months (range, 1.9–25.8 months).
  • There were ten recorded deaths, of which six were in first CHR and three were in second CHR.

Post-blinatumomab treatment

  • TKI treatment was continued by 29 patients.
    • Of these 29 patients, 21 continued with dasatinib, five patients continued with dasatinib and then switched to another TKI (ponatinib, n = 3; imatinib, n = 1; ponatinib and imatinib, n = 1), two patients switched to imatinib, and one patient switched to ponatinib.
  • From the 58 patients that began blinatumomab treatment, 29 (55%) were allografted following 2–3 cycles of blinatumomab.
    • Nine patients received a transplant from a sibling, 13 from a matched unrelated donor, six from a haploidentical donor, and one from a cord blood donor.

The relationship of transplantation and patient outcome was assessed, and it was revealed that allograft transplantation had no impact on OS and DFS. However, the patient population was small, with a short follow-up. Furthermore, it is important to note that the allografted population were primarily minimal residual disease positive.

Conclusion

The updated D-ALBA trial results demonstrate the feasibility of chemotherapy-free induction/consolidation therapy for the treatment of adult patients with Ph+ ALL. These results confirm the previously reported favorable outcomes of high OS and DFS in patients who achieved a molecular response. These results also highlight the adverse prognostic impact of the IKZF1plus genotype, which represents a primary unmet need in this patient population. Furthermore, CNS relapses were high, which is a concern for the chemotherapy-free approach. The authors stated that in an upcoming trial for newly diagnosed adults with Ph+ ALL, CNS prophylaxis will be increased and the relationship between transplantation and patient outcomes will further be examined.

  1. Foà R, Bassan R, Vitale A, et al. Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383:1613-1623. DOI: 1056/NEJMoa2016272
  2. Chiaretti S, Bassan R, Vitale A, et al. Updated results of the GIMEMA LAL2116, D-ALBA trial, for newly diagnosed adults with PH+ ALL. Oral abstract #S112. European Hematology Association (EHA) 2021 Virtual Congress; June 11, 2021; Virtual.

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