General AML

EBMT 2019 | Graft-versus-host disease prophylaxis with reduced intensity conditioning regimen combined with anti-thymocyte globulin and post-transplantation cyclophosphamide for AML

Reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation is known to induce graft-versus-host disease (GvHD) and thereby increase non-relapse mortality (NRM). Immunosuppressive therapies to reduce the risk of GvHD may often come at the price of higher relapse rates. Therefore, new strategies to reduce GvHD while maintaining low relapse rates are needed.

On Tuesday 26 March 2019, Oral Session 03 (OS03) took place at the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During that session, Abstract OS03-2 was presented by Maria Queralt Salas from Princess Margaret Cancer Centre, Hans Messner Allogeneic BMT Program, Toronto, Canada.

The primary objective of the study was to assess the safety and efficacy of reducing the intensity conditioning regimen (RIC) combined with anti-thymocyte globulin (ATG), as well as post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis in patients diagnosed with acute myeloid leukemia (AML).

Patient and methods

  • N = 104
  • Median follow up: 19 months: (5-35 months)
  • Patients received the following RIC regimen:
  • Fludarabine (30mg/m2/day day -5 to -2)
  • Busulfan (3.2kg/m2/day, day -3 and -2)
  • Total body irradiation (200 cGy) (day -1)
  • ATG (4.5 mg/kg administered over 3 days, day -3 to -1)
  • PTCy (50mg/kg/day: day +3 and, +4)
  • cyclosporine (2.5 mg/kg iv from day +5 onward)
  • Un-manipulated peripheral blood stem cells (PBSC) were infused

Age (years)

 

Median age range

56 (19-73)

 

Disease risk index

N (%)

Low

6 (6)

Intermediate

81 (78)

High

16 (15)

Very high

0

Not available

1 (1)

 

Cytogenetic at diagnosis

 

Low risk

6 (6)

Intermediate risk

70 (67)

Poor risk

27 (26)

Not available

1 (1)

 

 

Stage at transplant

 

Complete remission 1

86 (83)

Complete remission 2-3

15 (14)

Residual disease

3 (3)

HCT-CI ≥ 4

13 (13)

Karnovsky Performance index (KPS) ≤ 80 %

18 (17)

 

 

Donor type

 

10/10 MRD

22 (21)

10/10 MUD

38 (37)

9/10 MMUD

15 (14)

Haploidentical donors

29 (28)

Table 1: Summary of patients and methods

Key findings

  • One year overall survival (OS): 67.7% (95% CI 58.6-76.8)
  • Progression-free survival (PFS): 60.8% (95% CI 51.1-70.5)
  • Non-relapse mortality (NRM): 16.4% (95% CI 6.9-25.8)

The study identified that the main causes of death were:

  • Relapse (18%)
  • Infection (13%)

The key findings can be found summarized in Table 2 and Table 3.

 

N (%)

Engraftment information (days)

 

Median time neutrophil engraftment

16 (10-43)

Median time platelet engraftment

19 (7-217)

 

 

Infectious complications

 

CMV reactivation / CMV disease

61 (56) / 6 (6)

EBV reactivation

64 (61)

Presumed / Proven -PTLD

3 (3) / 7 (7)

BK Cystitis

7 (7)

Other viral infection

34 (33)

Fungal infection – Presumed / Proved

7 (7) / 0

 

Cumulative incidence of GvHD

 

Grade II-IV Acute (day +100)

16.1 (0-32.9)

Grade III-IV Acute (day +100)

1.9 (0-10)

Chronic (moderate/severe) 1 year

8 (0-16.7)

 

Relapse

27 (26)

Death

41 (29)

Causes of death

 

Infection

14 (13)

GvHD

0

Relapse

19 (18)

Multi-organ failure

2 (2)

Graft failure

3 (3)

Bleeding

2 (2)

Deconditioned (positive)

1 (1)

Table 2: Key findings

 

OS

RFS

Univariate analysis

P value

P value

Disease risk index

0.102

0.196

Cytogenetic at diagnosis

0.886

0.823

Not in complete remission

0.0001

0.002

KPS ≤  80%

0.004

0.014

HCT-CI ≥4

0.657

0.670

Donor type

0.476

0.262

Chimerism ≥95% at day 60+

0.072

0.004

Table 3: Univariate analysis *RFS (Relapse-free survival)

Conclusion

Dr. Queralt Salas concluded that the combination therapy, RIC with ATG and PTCy provided a very low rate of both aGvHD and cGvHD, as well as an adequate relapse rate. The univariant analysis identified that OS and RFS were not significantly affected by donor type or cytogenetic risk type. However, KPS <80% and not achieving CR before the transplant was associated with a significantly lower OS and RFS. Dr. Queralt Salas ended the session by emphasizing that this protocol gives enough graft-versus-leukemia effect in those patients who have high-risk leukemia, however, patients with active disease at the time of transplant may not benefit from this protocol.

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