The impact of KMT2A rearrangements and allo-HSCT on survival outcomes in ALL

Acute lymphoblastic leukemia (ALL) with KMT2A rearrangements is classified as a high-risk genomic subtype of ALL. Multiple rearrangements of the KMT2A gene can occur; the most common, t(4;11)(q21;q23)/KMT2A-AFF1, has a poor prognosis, and patients carrying these AFF1 gene partners are often offered an allogeneic hematopoietic stem cell transplant (allo-HSCT) in first complete remission (CR1), with the aim of improving long-term overall survival (OS) and relapse-free survival (RFS).

The benefit of allo-HSCT for patients with KMT2A rearrangements, particularly carrying abnormalities excluding the common t(4;11), is not fully certain. As such, Richard-Carpentier et al.¹ published collected data in Blood Advances, from adult patients with ALL treated at the MD Anderson Cancer Center, Houston, US, between 1984–2019. They investigated the characteristics and outcomes of patients with KMT2A-rearranged ALL and the impact of allo-HSCT in CR1. We summarise the key results below.¹

Study design

• A total of 1,102 adult patients with newly diagnosed ALL between 1984–2019 were reviewed for KMT2A rearrangements
• Presence of t(11;v)(q23;v) was assessed by conventional cytogenetics (G-banding) and/or by fluorescence in situ hybridization (FISH)
• Measurable residual disease (MRD) negativity (sensitivity 10⁻⁴) was evaluated with flow cytometry at complete remission (CR) and at various time points during follow-up
• Patient characteristics at diagnosis were analysed and CR rates, OS, and RFS were evaluated
• A 4-month landmark analysis to evaluate the impact of HSCT during CR1 was performed

Results

Patient characteristics

A total of 50 (5%) patients carried KMT2A rearrangements, with 42 of these patients carrying the common t(4;11) abnormality, and eight (16%) carrying other rearrangements. A total of 44/45 patients (98%) were diagnosed with B-cell ALL, while one (2%) patient was diagnosed with T-cell ALL. Patient median age at diagnosis was 45 years (18–78 years).

CR and MRD rate

• Most patients (n = 35) were treated with a regimen of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD), or one of its variations (n = 7)
• In total, 44 (88%) patients carrying a KMT2A rearrangement achieved CR; 90% (38/42) of patients carried t(4;11) and 75% (6/8) of patients carried other KMT2A rearrangements
• Four (8%) patients died during induction and one (2%) patient with the t(11;19) rearrangement had refractory disease
• MRD negativity at CR was 41% (12/29 evaluable patients); 41% (11/27) of patients carried t(4;11), and 50% (1/2) of patients carried other rearrangements
  • MRD negativity was 76% (26/34 evaluable patients) during the follow-up; 81% (25/31) of patients carried t(4;11) and 33% (1/3) of patients carried other rearrangements

Long-term OS and RFS

• Median follow-up was 63 months with 14 patients (28%) alive at the last follow-up, and 11 (22%) in CR1
• The estimated 5-year OS and RFS rates were 18% (95% confidence interval [CI], 9–35%), and 15% (95% CI, 7–33%), respectively
  • No difference was observed in OS (hazard ratio [HR], 1.08; p = 0.87) and RFS (HR, 1.50; p = 0.41) between patients with t(4;11) and other rearrangements
• Patients positive for MRD at CR had poorer survival; OS (HR, 2.29; 95% CI, 0.87–6.07; p = 0.09) and RFS (HR, 2.25; 95% CI, 0.94–5.38; p = 0.07)

Impact of HSCT on survival

• Of the 44 patients in CR, 18 (41%) received HSCT. A total of 16 of these patients carried t(4;11), and five of these patients were still alive in CR1
  • Of the two patients carrying other KMT2A rearrangements, both were alive, and one patient was still in CR1
• Of the 22 patients who did not receive a HSCT in CR1, a total of 22 carried t(4;11), of whom five patients remained alive in CR1
  • For the six patients with other rearrangements, no patients remained alive in CR1.
• A 4-month landmark analysis revealed a 5-year OS and RFS rate of 32% (95% CI, 14–70%), and 22% (95% CI, 8–58%) in patients receiving HSCT, compared with 11% (95% CI, 3–39%) and 11% (95% CI, 3–41%) in those who did not
  • Although OS and RFS were higher for patients receiving HSCT, these results were not statistically significant (OS: HR, 0.53, p = 0.10; and RFS: HR, 0.54; p = 0.10)
• The difference in OS and RFS was greater when accounting for patients diagnosed after 2010 (to account for more recent improvements in transplant-related morbidity and mortality). The 5-year OS and RFS rates were 47% (95% CI, 21–100%) and 39% (95% CI, 17–94%), respectively, in patients receiving HSCT, compared with no patients surviving at the 5-year point who did not receive HSCT (OS: HR, 0.32; p = 0.08; and RFS: HR, 0.24; p = 0.03)

R/R KMT2A-rearranged ALL

• Eight patients with relapsed or refractory (R/R) KMT2A-rearranged ALL received salvage blinatumomab or inotuzumab ozogamicin
• Of the five patients given blinatumomab, four (80%) achieved CR, while 3/4 (75%) patients receiving inotuzumab ozogamicin achieved CR

Conclusion

Overall, data collected from patients diagnosed with ALL between 1984–2019 confirms the negative prognostic impact of KMT2A rearrangements on OS and RFS, despite a high rate of these patients achieving CR. However, a benefit of allo-HSCT was observed in patients in CR1 regardless of their specific KMT2A abnormality, with survival outcomes improved in patients receiving HSCT, which was further improved when accounting for improved transplant-related mortality and morbidity after 2010. Finally, the incorporation of monoclonal antibody therapy appears to be beneficial for patients with R/R KTM2A-rearranged ALL.