Pre-emptive versus prophylactic use of TKIs after allo-SCT in patients with Philadelphia chromosome-positive ALL

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion gene product have revolutionized therapy for patients with BCR-ABL/Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL); however, it is unclear if outcomes are improved with the use of TKIs as maintenance therapy after allogeneic stem cell transplantation (allo-SCT). During the 26th Congress of the European Hematology Association (EHA2021), Anna Candoni discussed the results of a retrospective subanalysis of the Italian Group for Blood and Marrow Transplantation Nurses Group (GITMO) trial (NCT03821727), to examine the effect of different strategies of posttransplant TKI treatment for Ph+ ALL.¹

Study design

The GITMO trial included 441 patients with Ph+ ALL who were undergoing SCT and had been treated with TKIs in the induction phase.

Eligibility criteria:

• Only patients in morphological complete remission before SCT.
• Patients had to be receiving TKI treatment post-allo-SCT.
• Patients were excluded if they were in cytological relapse (n = 41).

Patients were included regardless of their pre-transplant measurable residual disease (MRD) status. One group of patients were given TKIs prophylactically after allo-SCT, starting when they were MRD-negative. The second group of patients were given TKIs post-allo-SCT, starting at the first time they were found to be MRD-positive (pre-emptive group).

The aim of the study was to assess overall survival (OS) and disease-free survival (DFS) of the patients in the two TKI-treated groups.

The characteristics of patients selected for this subanalysis are shown in Table 1. Of the 122 patients included, 30% were MRD-negative prior to allo-SCT. The pre-emptive TKI group comprised 62 MRD-positive patients and 25 MRD-negative patients. The prophylactic group had 23 MRD-positive patients and 12 MRD-negative patients.

The median age for the whole cohort was 43 years (18.6−67.3) and 50% were female. Other characteristics were comparable between the two groups. Most patients in both groups either underwent matched unrelated donor transplant or received a human leukocyte antigen-identical transplant.

Table 1. Patient characteristics*

Allo-SCT, allogeneic stem cell transplant; ATG, antithymocyte globulin; EBMT, European Group for Blood and Marrow Transplantation; Haplo, haploidentical; HLA-id, human leukocyte antigen-identical; MUD, matched unrelated donor; TBI, total body irradiation; TKI, tyrosine kinase inhibitor. *Adapted from Candoni et al.1
Characteristic	N = 122	Pre-emptive TKI (n = 87)	Prophylactic TKI (n = 35)
EBMT risk score, %
1−2	49	46	54
≥3	51	54	46
Allo-SCT, %
MUD	44	43	46
HLA-id	47	48	40
Haplo	7	6	11
Cord blood	2	3	3
TBI, %	48	47	49
ATG, %	57	58	54

Results

TKI treatment was initiated at significantly different times for the two groups; patients treated pre-emptively started TKI treatment with a median of 4.37 months after transplantation, whereas prophylactic treatment started with a median of 2.97 months after transplantation (p = 0.01).

There was no significant difference in the firstline TKI agent used amongst the two groups. Of the TKIs administered (imatinib, dasatinib, ponatinib, or nilotinib), most patients received imatinib (45.5%) or dasatinib (41%). Overall, the percentage of patients who received secondline TKI treatment was not significantly different between groups (31% in the prophylaxis group, and 46% in the pre-emptive group). However, there was a difference in the number of patients who received secondline TKI therapy for cytological relapse or MRD-positive status; in the prophylactic group, 27% received a TKI following a relapse compared with 69% in the pre-emptive group (p = 0.01). The median TKI duration was 12.5 months (range, 5.9−20.5) in the prophylactic group and 12.2 months (range, 3.2−78.8) in the pre-emptive group.

The results for OS were:

• Prophylactic TKIs, 5-year OS was 72% (median OS was not reached).
• Pre-emptive TKIs, 5-year OS was 58% (median OS of 62 months, p = 0.07).

The results for DFS were:

• Prophylactic 5-year DFS was 72% (median DFS not reached).
• Pre-emptive 5-year DFS was 47% (median DFS of 36 months, p = 0.002).

In the prophylactic group only 17% of patients experienced a cytological relapse compared to 49.4% in the pre-emptive group (p = 0.0001).

Patients who were treated with prophylactic TKIs demonstrated significantly longer DFS regardless of their MRD status prior to SCT compared with patients treated pre-emptively (p < 0.001).

Conclusion

The results of this subanalysis suggest that a prophylactic TKI treatment strategy after allo-SCT may be a viable option for patients with Ph+ ALL, with good OS and DFS achieved in this setting. In addition, regardless of MRD status before SCT, a prophylactic TKI treatment strategy led to a better DFS than a pre-emptive treatment strategy.