Comparison of reduced intensity conditioning regimens for allo-HSCT in patients with ALL

Older adults with acute lymphoblastic leukemia (ALL) have poor outcomes, partly due to their inability to tolerate intensive treatments. Transplant-related mortality (TRM) associated with myeloablative conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) increases with age and, therefore, many older patients undergo reduced intensity conditioning (RIC). Studies have shown reductions in transplant-related mortality but no increase in overall survival (OS) with RIC. Comparison studies to date have focussed mainly on acute myeloid leukemia and results have been contradictory, so the optimal RIC regimen for improved outcomes in ALL remains unclear.

The Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT) have carried out a retrospective study comparing the effect of three commonly used RIC regimens following allo-HSCT on the outcomes of older patients with ALL in first complete remission (CR1). These results were published in Bone Marrow Transplantation on May 2, 2020.¹

Study design and patient characteristics

• In total, 417 patients meeting the following criteria were selected from the EBMT database:
  • Diagnosis of ALL (including immunophenotyping and assessment of Ph-positivity)
  • In first complete remission (CR1)
  • Received an initial allo-HSCT between 2005 and June 2006
  • Aged 45 years or older at the time of transplantation
  • HLA-matched related or unrelated donor (full match or one HLA locus mismatch)
  • Received peripheral blood hematopoietic stem cells
  • Underwent one of the following RIC regimens: Fludarabine (FLU) with intermediate doses of busulfan (BU) (6.4 mg/kg, FLUBU), FLU with intermediate doses of melphalan (MEL) (140 mg/m², FLUMEL), or FLU with low-dose total body irradiation (TBI) (2 Gy, FLUTBI).
• Patients receiving a previous allo-HSCT or T-cell depleted grafts were excluded
• The primary endpoint for RIC comparisons was OS at 2 years
• Secondary endpoints: Leukemia-free survival (LFS), cumulative incidence of relapse, TRM, extensive chronic graft-versus-host disease (GvHD), and GvHD-free, relapse-free survival (GRFS) at 2 years
• Significant differences were identified for some patient characteristics
  • Median follow-up of patients in the FLUTBI group was significantly longer than for patients in the FLUBU and FLUMEL groups (51 months vs 35 months and 23 months, p = 0.001)
  • Patients in the FLUBU group were significantly older than patients in the FLUTBI and FLUMEL groups (59 years vs 54 years and 57 years, p = 0.001)
  • There were fewer patients with Ph+ ALL in the FLUMEL group compared with FLUBU or FLUTBI groups (52% vs 69%, p < 0.001)
  • Only 12% of patients in the FLUTBI group had in vivo T-cell depletion compared with 94% in the FLUBU group and 82% in the FLUMEL group

Key findings

• The 2-year outcomes of allo-HSCT for the three RIC groups are shown in Table 1
  • There were no significant differences in OS, LFS, cumulative incidence of relapse or cumulative incidence of TRM between the RIC groups
  • There was a significantly higher cumulative incidence of extensive chronic GvHD in the FLU/TBI group than in the FLUMEL or FLUBU groups (p = 0.001), resulting in significantly lower GRFS for the FLUTBI regimen (p = 0.01)

Table 1. Comparative 2-year outcomes of allo-HSCT for different RIC regimens¹

Outcome, % (95% CI)	FLUBU (n = 127)	FLUMEL (n = 190)	FLUTBI (n = 100)	p value
FLUBU, fludarabine/busulfan; FLUMEL, fludarabine/melphalan; FLUTBI, fludarabine/total body irradiation; GvHD, graft-versus-host disease; GRFS, GvHD-free, relapse-free survival; RIC, reduced intensity conditioning
Overall survival	55 (45–65)	50 (42–59)	60 (49–70)	0.62
Leukemia-free survival	43 (33–52)	42 (34–51)	45 (35–56)	0.99
Cumulative incidence of relapse	40 (30–49)	36 (28–44)	41 (30–51)	0.21
Cumulative incidence of transplant-related mortality	18 (11–26)	22 (16–29)	14 (8–22)	0.09
Cumulative incidence of extensive chronic GvHD	16 (9–23)	12 (7–18)	39 (29–50)	0.001
Cumulative incidence of GRFS	35 (25–44)	28 (20–36)	18 (10–26)	0.01

 

• Relapse was the most frequent cause of death in all RIC groups (FLUBU, 42%; FLUMEL, 41%; FLUTBI, 60%)
• The FLUMEL group had the highest cumulative incidence of death associated with infection (11%, 95% CI, 7–16)
• FLUMEL conditioning was the only regimen identified as a risk factor for higher TRM in multivariate analysis (p = 0.04)
• As shown in Table 2, older age was the only variable to be associated with worse outcome across all endpoints in multivariate analysis
• When adjusting for T-cell depletion, there was no difference between the RIC regimens in the cumulative incidence of chronic GvHD or GRFS

Table 2. Statistically significant risk factors identified in multivariate analysis¹

Outcome	Variable	Hazard ratio	95% CI	p value
CI, confidence interval; CMV, cytomegalovirus; FLUMEL, fludarabine/melphalan; UD, unrelated donor; MSD, matched sibling donor; GRFS, GvHD-free, relapse-free survival Statistical significance if p < 0.05
Overall survival	Age (per 10 years)	1.56	1.21–2.03	0.0007
Patient female	0.67	0.49–0.93	0.01
Leukemia-free survival	Age (per 10 years)	1.57	1.23–2.01	0.0003
Cumulative incidence of relapse	Age (per 10 years)	1.4	1.05–1.87	0.02
Patient CMV positive	0.66	0.45–0.97	0.03
Cumulative incidence of transplant-related mortality	FLUMEL	1.97	1.05–3.72	0.04
Age (per 10 years)	2.08	1.37–1.52	0.0006
UD vs MSD	2.22	1.23–4.01	0.008
Cumulative incidence of GRFS	Age (per 10 years)	1.53	1.23–1.90	0.0001

 

Conclusions

In the largest comparative study so far, Peric et al.¹ have shown similar transplant outcomes for three favoured RIC regimens in older adults with ALL receiving allo-HSCT. FLUMEL conditioning was the only regimen associated with higher transplant-related mortality in multivariate analysis. The authors attributed a higher incidence of chronic GvHD with FLUTBI conditioning compared with FLUBU and FLUMEL, mainly due to low use of in vivo T-cell depletion in this group of patients.

Older age was independently associated with worse outcomes and the authors advised that transplantation should be undertaken with caution in older adults. Poor transplant outcomes regardless of RIC regimen (2-year LFS < 50%) led the authors to highlight the importance of investigating strategies to prevent relapse after allo-HSCT in ALL.