aGvHD,   cGvHD

Impact of CD34+ cell dose on the outcome of patients with acute myeloid leukemia in complete remission after T-cell replete haploidentical HSCT using peripheral blood stem cells

The impact of graft CD34+ cell dose on transplant outcomes may be crucial not only for engraftment but also for non-relapse mortality and survival. In a retrospective analysis, recently published in American Journal of Hematology, Enrico Maffini and colleagues evaluated the impact of CD34+ cell doses, in peripheral blood stem cells (PBSC) grafts, on the outcome of patients with acute myeloid leukemia (AML) in complete remission (CR) after T-cell replete haploidentical hematopoietic stem cell transplantation (HSCT).

This study, which was endorsed by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, analyzed the outcomes of patients who received HSCT from 2006─2018 based on Blood and Marrow Transplantation registry data.1

Study design and patient characteristics1
  • Patients (N = 414) ≥ 18 years, receiving a first allogeneic HSCT with AML in first and second CR were included
  • Endpoints of the study were neutrophil engraftment, platelet recovery, acute graft-versus-host disease (aGvHD), chronic GvHD (cGvHD), relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse-free survival (GRFS)
  • Patient characteristics are reported in Table 1

Table 1. Patient characteristics

 

Characteristics

Patients

(N = 414)

Median age, years (range)

54 (18─74)

Patients in

First CR

Second CR

 

70%

30%

s-AML

18%

Cytogenetics

Unfavorable

Intermediate

Good

Unknown

 

21%

59%

7%

13%

Median donor age, years (range)

37 (20─71)

Time from diagnosis to HSCT, months (range)

6.3 months (1.3─97.9)

Conditioning

MAC

RIC

 

43%

57%

CR, complete response; HSCT, hematopoietic stem cell transplantation; MAC, myeloablative conditioning; RIC, reduced-intensity conditioning; s-AML, secondary-acute myeloid leukemia

  • Median follow-up was 23.3 months (12.1─8)
  • Patients were analyzed base on the GvHD prophylaxis they had received
    • Anti-thymocyte globulin (ATG) (n = 249; 71%)
    • Post-transplant-cyclophosphamide (PT-Cy) (n = 120; 29%)
  • Patients were divided in two cohorts based on the optimal threshold defining high versus low values for CD34+/kg dose regarding its impact on NRM according to the Hothorn and Zeileis method.
    • High CD34+ dose (n = 334) had received a CD34+ dose > 4.96 × 106/kg
    • Low CD34+ dose (n = 80) had received CD34+ dose <96 × 106/kg
Results1

Overall population

  • Median PBSC doses were
    • CD34+: 6.58 × 106/kg (2.2─25; interquartile range 5.1─8.02)
  • A total of 13 patients experienced graft failure, the remaining 399 engrafted without complications
  • Neutrophil engraftment:
    • 2% (95% confidence interval [CI], 88─93.6) at Day 30
    • median time to engraftment 20 days (10─79)
  • Platelets engraftment (> 20.000/μL at 6 months):
    • 7% (95% CI, 79.6─87)
    • median time to engraftment 21 days (1─37)
  • At a median follow-up of 23.3 months (12.1─8), 2-year
    • OS, 64.5 % (59.3─7)
    • LFS, 57.3 % (51.8─7)
    • Disease RI, 19.5 % (15.2─2)
    • NRM, 23.3 % (19.0─7)
  • The incidence of GvHD and GRFS is reported in Table 2

Table 2. Incidence of GvHD and GRFS

 

Incidence

aGvHD at Day +100, % (95% CI)

Grades II─IV

Grades III─IV

 

32.3 (27.8─36.9)

14.6 (11.3─18.2)

2-year cGvHD, % (95% CI)

Overall

Extensive

 

36.3 (30.9─41.6)

14.4 (10.7─18.6)

2-year GRFS, % (95% CI)

43.5 (38─48.9)

aGvHD, acute graft-versus-host disease; cGvHD, chronic GvHD; GRFS, GvHD-free/relapse-free survival

Comparing outcome after myeloablative conditioning versus reduced intensity conditioning

  • Recipients of myeloablative conditioning showed a higher incidence of Grade III/IV aGvHD compared with recipients of reduced intensity conditioning, 18.9% 11.9%, respectively (p = 0.05)

Comparing outcome after GvHD prophylaxis with ATG versus PT-Cy

  • Compared with patients receiving PT-Cy, patients receiving ATG-based prophylaxis had better engraftment:
    • neutrophil: 89.4% 95.8%, respectively (p = 0.02)
    • platelet: 81.3% 89.9%, respectively (p = 0.002)
  • Patients in the ATG cohort experienced fewer Grades II─IV aGvHD than patients in the PT-Cy cohort (hazard ratio [HR] 0.57; 95% CI, 0.37─88) while no differences were observed for the incidence of Grade III─IV aGvHD or cGvHD

Comparing outcome after receiving low versus high CD34+ cell dose

  • Patients in the high-dose group had better engraftment than those in the low-dose group:
    • neutrophils: 92.1% 87.3%, respectively (p = 0.005)
    • platelets: 86% 73.3%, respectively (p = 0.001)
    • median time to neutrophil engraftment: 19 days (10─79) 22 days (14─46), respectively (p = 0.0001)
  • Patients receiving a CD34+ cell dose > 4.96 x 106/kg
    • had lower NRM (HR 0.48; 95% CI, 0.30─76)
    • better LFS (HR 0.63; 95% CI, 0.43─91)
    • improved OS (HR 0.60; 95% CI, 0.40─88)
    • trend for improved GRFS (HR 0.85; 95% CI, 0.60-1.18)
  • No differences in RI were observed between the two groups

Other prognostic factors in multivariate analysis

  • Younger patients showed better OS (69.9% 59%, p = 0.043) because of a trend towards lower NRM (18.9% vs. 27.7%, p = 0.10)
  • Recipients of cytomegalovirus-positive donors experienced better GRFS (HR 0.75; 95% CI, 0.55─01, p = 0.058)
Conclusion

This study, on patients with AML in CR, showed that recipients of a CD34+ dose > 4.96 × 106/kg experienced prolonged survival, mainly due to a reduced NRM rate. No differences were observed in RI rates, indicating that higher doses of CD34+ cells did not protect from disease recurrence. Taken together these results suggested that, in this patients’ population, an infusion of a CD34+ dose > 4.96 × 106/kg, using PBSC from haploidentical donors, in T-cell replete HSCT could be beneficial.1 Further studies are required to confirm these findings.

A similar study, summarized here, evaluated the correlation between outcome and CD34+ cell dose in patients receiving PBSC as donor source in HLA-matched related transplantation. The results showed that patients with low-risk hematological malignancies receiving high-CD34+ cell dose had a reduced risk of relapse and improved disease-free survival, but an increase of aGvHD was observed with an excessive dose of CD34+. The recommended CD34+ cell dose for patients with low-risk diseases was 4.5–8.0 × 106/kg.2

References
  1. Maffini E, Labopin M, Blaise D et al. CD34+ cell dose effects on clinical outcomes after T‐cell replete haploidentical allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia using peripheral blood stem cells. A study from the acute leukemia working Party of the European Society for blood and marrow transplantation (EBMT). Am J Hematol. 2020;1─ DOI: 10.1002/ajh.25826

  2. Yokoyama Y, Maie K, Fukuda T et al. A high CD34+ cell dose is associated with better disease-free survival in patients with low-risk diseases undergoing peripheral blood stem cell transplantation from HLA-matched related donors. Bone Marrow Trans. 2020. DOI: 1038/s41409-020-0817-5

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