Over the past 30 years, allogeneic hematopoietic stem cell transplantation outcomes in patients with acute lymphoblastic leukemia have generally improved, but transplant outcomes in this type of patient need to be improved

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy that originates primarily from B- or T-line lymphoprogenitor cells and is one of
the most common adult acute leukemias.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for patients with advanced or high-risk ALL, often performed
during the first complete remission (CR1).
Over the past 30 years, advances in allo-HSCT technology and ALL treatment have significantly improved outcomes
for patients with ALL.
Although studies have shown that treatment outcomes for ALL change
over time.
However, there have been no large-scale studies to explore
changes in treatment outcomes for allo-HSCT in ALL.
Therefore, the researchers analyzed changes in allo-HSCT outcomes based on known risk factors with the aim of identifying patient populations
that require further improvement in treatment strategies.

Overview of key information

• Over the past 30 years, allo-HSCT outcomes have improved in patients with ALL, with an overall decrease in non-recurring deaths (NRM) rates, and a decrease
  in recurrence rates (RRR) in patients receiving allo-HSCT during CR1.
  

  
  

• The survival of Ph+ patients receiving allo-HSCT improved steadily, but for non-Ph-at-high-risk patients, the improvement in their survival by allo-HSCT was not significant
  .
  

Research Methods

The researchers analyzed data from ≥ 16-year-old patients with ALL who received their first allo-HSCT between 1990 and 2019
.
Patients are classified by chromosomal abnormalities based on previous case data: (1)t(9; 22)/BCR-ABL1 fusion (Ph+); （2）t(4; 11)； (3) KMT2A translocation; （4）t(1; 19)； （5）t(8; 14)； （6）t(14; 18)； （7）t(12; 21)； (8) Monomer 7 (-7), excluding the above-mentioned patients with confirmed translocation; (9) Complex karyotype (≥ 3 chromosomal abnormalities), excluding the above-mentioned patients with confirmed chromosomal abnormalities; (10) subdiploid (< 45 chromosomes); (11) superdiploid (> 50 chromosomes); (12) Other abnormalities (other abnormal karyotypes other than the above chromosomal abnormalities); (13) Normal karyotype
.

Relapse is defined as a recurrence of hematological leukemia, and NRM is defined as death
during sustained remission.
In total survival (OS) analysis, failure is defined as death from any cause, with survivors masked
at last follow-up.

Results of the study

• Patient baseline features

The study analyzed data from 8467 ALL patients, 1230 patients received allo-HSCT in the period 1990-1999 (D1), 3012 patients received allo-HSCT in 2000-2009 (D2), and 4225 patients received allo-HSCT in 2010-2019 (D3), and the baseline characteristics of patients are shown in Table 1
.

Table 1 Patient baseline features

• 30 years of overall change

In patients transplanted during CR1, the patient's OS improved significantly over time (Figure 1
).

Figure 1 OS curves of patients with allo-HSCT in different disease states and different periods

Recurrence rates (RR) and NRM rates in patients transplanted during CR1 also improved over time, with a 5-year corrected RR of 26.
4% (95% CI: 22.
7%-30.
6%) during D1, 19.
9% (95% CI: 18.
0%-22.
0%) during D2, and 15.
9% (95% CI: 14.
6%-17.
4%) during D3; The 5-year corrected NRM rate was 26.
3% (95% C: 22.
3%-30.
9%) during D1, 23.
5% (95% CI: 21.
5%-25.
7%) during D2, and 16.
8% (95% CI: 15.
3%-18.
3%) during D3 (Figure 2).

Figure 2 RR and NRM in patients undergoing allo-HSCT in different disease states and at different times

In addition, in patients transplanted during CR1, the improvement in RR in Ph+ patients over time was more pronounced than in non-Ph patients, with a 5-year corrected RR of 39.
9% (95% CI: 30.
7%-50.
9%) during D1 in Ph+ patients, 21.
4% during D2 (95% CI: 18.
5% to 24.
8%), and 14.
6% during D3 (95% CI: 12.
7%-16.
7%) (Figure 3).

Figure 3 RR in non-Ph and Ph+ patients

• Differences between non-Ph and Ph+ patients

Survival improvements were observed in both non-Ph and Ph+ patients, but more significant improvements in corrected OS and leukemia-free survival (LFS) in Ph+ patients (Table 2).

Table 2 OS and LFS corrected for disease status, age, donor origin, and Ph status

Compared with non-Ph patients, the degree of improvement in RR in Ph+ patients over time is more pronounced
.
The 5-year corrected RR was 35.
3% (95% CI: 31.
0%-39.
9%) during D1 in non-Ph patients, 31.
5% during D2 (95% CI: 29.
1%-34.
0%), and 30.
2% during D3 (95% CI: 28.
2%-32.
4%); The 5-year corrected RR was 35.
4% (95% CI: 29.
0% to 42.
8%) during D1 in Ph+ patients, 27.
3% during D2 (95% CI: 24.
4% to 30.
4%), and 22.
0% (95% CI: 19.
8% to 24.
4%)
during D3.

In addition, the 5-year corrected NRM was 30.
9% (95% CI: 26.
6%-35.
8%) during D1 in non-Ph patients, 26.
4% during D2 (95% CI: 24.
1%-28.
9%), and 20.
8% during D3 (95% CI: 18.
8%-22.
8%); The 5-year corrected NRM was 35.
0% (95% CI: 27.
8% to 43.
4%) in patients with Ph+ during D1, 31.
3% during D2 (95% CI: 28.
3% to 34.
7%), and 20.
8% (95% CI: 18.
5% to 23.
4%)
during D3.

• Differences in OS and LFS due to chromosomal abnormalities in non-Ph patients

In t(4; 11)、t(8; 14)、t(14; 18) Neither nor subdiploid patients observed sustained improvement
in survival.
When these 4 chromosomal abnormalities are defined as high-risk, OS and LFS have little improvement over time (Figures 4, 5).

Other non-high-risk patients with OS and LFS improved
significantly over time.

Figure 4 Different chromosomal abnormalities at risk and different periods of allo-HSCT in non-Ph patients OS

Figure 5 Different chromosomal abnormalities at risk and LFS in non-Ph patients undergoing allo-HSCT at different times

The findings suggest that outcomes have improved
in patients with ALL who undergo allo-HSCT over the past 30 years.
NRM has a tendency to improve at every 10-year stage, which may contribute to continued improvement in transplant outcomes regardless of disease stage
.
In addition, there was a significant improvement
in RR in Ph+ patients with allo-HSCT during CR1.
Non-Ph patients with high risk of chromosomal abnormalities have little improvement in outcomes after allo-HSCT, and targeted treatment strategies should be developed to improve treatment outcomes
in this type of patients 。 References: Nishiwaki S, Akahoshi Y, Morita-Fujita M, et al.
Improvements in allogeneic hematopoietic cell transplantation outcomes for adults with ALL over the past 3 decades.
Blood Adv.
2022 Aug 9; 6(15):4558-4569.
doi: 10.
1182/bloodadvances.
2022008032.
Editor: Wenting Reviewer: Mia Typography Execution: moly

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