How to judge whether adult high-risk Ph-ALL requires allogeneic hematopoietic stem cell transplantation?

Professor Josep-Maria Ribera and others conducted a clinical study to evaluate the choice of chemotherapy alone and induction chemotherapy combined with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in adult high-risk (HR) Philadelphia chromosome (Ph) negative acute lymphoblastic leukemia (Ph-ALL) Efficacy in patients.

Research background and objectives In the past ten years, the efficacy of adult ALL patients has been significantly improved, with complete remission (CR) rates and long-term overall survival (OS) rates of 90% and 40%-50%, respectively.

Among them, specific disease subtypes such as mature B-cell ALL, Ph+ALL, and adolescents and young adults (AYA) ALL have relatively better prognosis.

The current treatment for adult Ph-ALL patients is still based on conventional multi-drug chemotherapy, with or without allo-HSCT.

The prognostic factors at diagnosis and the level of minimal residual disease (MRD) at critical time points are usually considered as the basis for stratified treatment.

Previous studies have shown that for patients with standard risk at baseline and MRD <0.
01% after induction and/or consolidation therapy, conventional chemotherapy alone can be used, while allo-HSCT is required for patients with poor MRD clearance .

However, for patients with HR at baseline, whether follow-up treatment strategies can be selected based on the level of MRD after induction therapy and/or consolidation therapy, there is still a lack of evidence-based medical evidence.

Based on the above, some researchers have designed a clinical study (ALL-HR-11 trial) for adult Ph-ALL patients with HR, and choose whether to perform allo-HSCT in the follow-up based on the MRD level of patients after induction therapy and consolidation therapy.

Research Methods The ALL-HR-11 trial included newly diagnosed Ph-ALL patients aged 15-60 with HR characteristics.

HR is defined as meeting at least one of the following criteria: between 30-60 years old, the white blood cell (WBC) count of precursor B cell (BCP) ALL> 30×109/L or the WBC of thymic T-ALL> 100× 109/L, Pro-B-ALL, early T-ALL or mature T-ALL, diploid ALL, accompanied by t(v;11q23) or KMT2A rearrangement or complex karyotype (≥5 unrelated clone abnormalities) ALL.

All patients on the 14th day and after the end of the first cycle of induction therapy, and after the end of the second cycle of induction therapy, and after the end of the consolidation therapy, the EuroFlow standard operating procedure 2-tube 8-color panel was used for MRD detection.

Patients with CR and MRD levels less than 0.
1% after induction therapy and MRD levels less than 0.
01% after early consolidation treatment will continue to end up to two years of late consolidation chemotherapy and maintenance treatment after CR; the remaining patients will receive allo- HSCT.

The primary study endpoint is the OS of the two treatment strategies in the intention-to-treat (ITT) population.

Results of the study From August 2011 to October 2019, the trial recruited 399 adolescent and adult patients with Ph-ALL with HR characteristics from 51 medical centers in Spain.
Among them, 348 patients eventually met the criteria and entered the study.
And be included in the analysis.

The median age of patients was 40 years (range 15-60 years), 75% of them were 30-60 years old; B-cell ALL accounted for 69%, and 26% of patients had extramedullary lesions.

After the first cycle of induction therapy, 239 patients (83%) achieved CR, of which 220 patients had MRD<0.
1%, and 179 patients (63%) had MRD<0.
01%.

Of the 220 patients assigned by ITT who received chemotherapy alone (because the morphological CR or CR and MRD were less than 0.
1% after the first cycle of induction therapy), 218 patients were finally evaluable; 109 patients received allo-HSCT Medium (because the first induction cycle did not achieve CR or achieved CR but MRD ≥ 0.
1%), 106 patients were finally evaluable; the baseline characteristics of the two groups were balanced. The median follow-up time of the entire cohort was 2.
4 years (range: 0.
2-7.
7 years).
A total of 132 patients died and 216 patients survived.
The median OS was 4.
2 years.
The estimated 5-year OS rate was 49% (42%-56).
%).

Among them, the 5-year OS rate of 48 patients with MRD<0.
01% on the 14th day of the first induction therapy was 82% (69%-95%), which was significantly higher than the MRD level of 0.
01%-0.
1% or ≥0.
1% Of patients.

The expected 5-year cumulative recurrence rate (CIR) in evaluable patients receiving chemotherapy alone and allo-HSCT was 45% and 40%, respectively; while the 5-year OS rate between the two groups was 59% (50%-68 %) and 38% (27%-49%).

Further analysis showed that the 5-year OS rate was 72% (61%-81%) of the patients who actually received treatment in the chemotherapy-only group, and disease progression was the main cause of death; the 5-year CIR and non-relapse mortality (NRM) were respectively 40% (30%-50%) and 3% (1%-7%).

In the transplantation group, the 5-year OS rate was 54% (39%-67%), and the 5-year CIR and NRM were 33% (21%-47%) and 24% (14%-37%), respectively.
.

Research conclusions This study shows that for adult HR Ph-ALL patients ≤60 years old, if they have sufficient MRD clearance after induction therapy and early consolidation therapy, they can choose chemotherapy alone instead of allo-HSCT; but for insufficient MRD Patients with clearance levels require allo-HSCT.

References: Josep-Maria Ribera, Mireia Morgades, Juana Ciudad, et al.
Chemotherapy or allogeneic transplantation in high-risk Philadelphia chromosome-negative adult lymphoblastic leukemia.
Blood.
2021 Apr 8;137(14):1879-1894.
Stamp" Read the original ", we make progress together