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.