Combination ATG and PTCy results in low rates of cGvHD and aGvHD

Both thymoglobulin (ATG) and post-transplant cyclophosphamide (PTCy) have been used as monotherapy for GvHD prophylaxis, resulting in reduced rates of aGvHD and cGvHD. However, there is currently no research into whether the drugs can be combined safely to prevent GvHD.

On 29 March 2019, Shruti Prem, from the Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, CA, and colleagues published their findings on the combination of ATG and PTCy for GvHD prophylaxis. This combination was evaluated in patients who had received matched unrelated donor (MUD) transplants and mismatched unrelated donor (MMUD) transplants.

Patient characteristics
  • N = 102
  • Median age 59 years (range 22—74)
  • 76 patients received 10/10 MUD transplants, 26 patients received 9/10 MMUD transplants
  • Mismatches in MMUD group: A antigen (n = 14), A allele (n = 3), B antigen (n = 3), C antigen (n = 2), C allele (n = 1), DQ antigen (n = 1), DQ allele (n = 1) and DRB1 allele (n = 1)
  • MUD male to female ratio, 43:33, (56.6% and 43.4%)
  • MMUD male to female ratio, 16:10, (61.5% and 38.5%)

Diagnosis

MUD, N = 76 (%)

MMUD, N = 26 (%)

AML

40 (52.6)

15 (57.7)

ALL

4 (5.3)

1 (3.8)

MDS

14 (18.4)

6 (23.1)

MPN

8 (10.5)

1 (3.8)

Lymphoma

5 (6.6)

1 (3.8)

CMML

3 (3.9)

0 (0)

CML

2 (2.6)

2 (7.7)

Table 1: Baseline characteristics of patients in each group. AML: Acute myeloid leukemia; ALL: Acute lymphoid leukemia; MDS: Myelodysplastic syndrome; MPN: Myeloproliferative Neoplasm; CMML: Chronic myelo-monocytic leukemia; CML: Chronic myeloid leukemia

Methods
  • Reduced intensity conditioning (RIC):
    • Day -5 to -2: intravenous fludarabine (30mg/m2/day)
    • Day -3 to -2: intravenous busulfan (3.2mg/m2/day)
    • Day -1: low-dose TBI (200cGy)
  • Rabbit ATG (thymoglobulin):
    • Day -3: 0.5mg/kg
    • Day -2: 2mg/kg
    • Day -1: 2mg/kg
  • Day 0: T cell replete PBSC grafts infused
  • Day +3 to +4: intravenous PTCy 50mg/kg/day
  • Day +5 onwards: intravenous cyclosporine initiated at 2.5mg/kg q12h and was adjusted to achieve therapeutic dose of 200—400ng/ml
Key findings

Group

OS (%)

CI

MUD

75

95% CI; 64%—83%

MMUD

50

95% CI; 55%—76% 

Table 2: OS in MUD and MMUD after a median follow-up of 15 months (range 0.6—33 months)

Group

OS (%)

CI

MUD

67

95% CI; 30%—67%

MMUD

35

95% CI; 17.5%—52.5% 

Table 3: PFS in MUD and MMUD after a median follow-up of 15 months (range 0.6—33 months)

The GvHD data for each donor type is presented in table 4. Median time to onset of aGvHD was 66 days, with skin (78%) being the most commonly affected site followed by the gut (33%) and the liver (33%). The median time to onset of cGvHD was 188 days. The liver, skin and mouth were equally the most common sites of cGvHD (33% each).

GvHD

MUD (n=76)

MMUD (n=26)

aGvHD grade II—IV

24 (31.6%)

4 (15.3%)

aGvHD grade III—IV

9 (11.8%)

1 (3.8%)

Steroid refractory aGvHD

1 (1.3%)

0 (0%)

cGvHD

16 (21%)

3 (11.4%)

NIH moderate/severe cGvHD

8 (10.5%)

2 (7.6%)

Table 4: GvHD data for each donor group.

Conclusions

The combination of PTCy and ATG for patients with GvHD prophylaxis undergoing MUD PBSCTs results in low rates of Grade III/IV aGvHD and cGvHD. This combination has an acceptable safety profile, with an adequate NRM and relapse rates, however, patients may need to be monitored for viral infections and may require adjustments of the ATG dose. A prospective randomized study is warranted to compare the combination of PTCy and ATG, with PTCy alone.

Reference

Prem, S. et al. Low rates of acute and chronic GVHD with ATG and PTC y in matched and mismatched unrelated donor peripheral blood stem cell transplants. Eur J Haematol. 2019 Mar 29. DOI: 10.1111/ejh.13230

Download this article:

You can now download this article in Adobe PDF® format.

Download as PDF
Based on the results of this study, do you think this combination will be successful in future trials? Thank you for your feedback!