The impact of carfilzomib as GvHD prophylaxis in patients transplanted from unrelated donors

Acute graft-versus-host disease (aGvHD) is a severe complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and current standard GvHD prophylaxis includes a combination of a calcineurin inhibitor and methotrexate. Nevertheless, GvHD rates remain high and there is an unmet need to improve outcomes after allo-HSCT.

The proteasome inhibitor bortezomib has shown efficacy when combined with tacrolimus and methotrexate in prevention of GvHD after allo-HSCT. Carfilzomib is a selective second-generation proteasome inhibitor with more sustained inhibitory activity which is approved for the treatment of patients with multiple myeloma. In a phase II study Avichai Shimoni et al. investigated the efficacy of adding carfilzomib to a standard cyclosporine and methotrexate regimen as GvHD prophylaxis after unrelated donor allo-HSCT.¹

Study design

Patients with acute myeloid leukemia (AML) in first or second remission, and patients with myelodysplastic syndrome (MDS) with < 10% blasts at the time of transplant were eligible. A 10/10 or 9/10 HLA match was allowed, and granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood stem cell grafts were used as stem cell source in all patients. Outcomes were compared to a matched historical control group treated with cyclosporine and methotrexate alone.

Treatment schedule:

• Cyclosporine, 3 mg/kg intravenous (IV), daily
• Methotrexate, 15 mg/m² on day 1, 10 mg/m² on days 3 and 6
• Carfilzomib in two doses of 20 mg/m² on day 1 and 2 after allo-HSCT

Prophylaxis was administered for 6 months, then tapered in patients without active GvHD, and no other GvHD prophylaxis was allowed. Anti-T-lymphocyte immune globulin was given for 3 days before allo-HSCT at a daily dose of 5 mg/kg. Antibiotics were used to prevent infections.

Primary endpoint was the rate of aGvHD and chronic GvHD (cGvHD) at 6 months and 2 years following allo-HSCT, respectively. Secondary endpoints were non-relapse mortality (NRM), defined as death of any cause without disease recurrence, relapse incidence, and overall survival at 3 years posttransplant.

Patient characteristics

A total of 126 patients were included in the analysis (n = 26 in the carfilzomib group, and n = 100 in the control group). Patient characteristics among both groups are presented in Table 1.

Table 1. Patients characteristics¹

Characteristic	Carfilzomib (n = 26)	Historical control (n = 100)	p value
Allo-HSCT, allogeneic hematopoietic stem cell transplantation; AML, acute myeloid leukemia; MDS, myelodysplastic syndrome. *n = 13 in first remission, n = 6 in second remission at the time of allo-HSCT. Significant differences between groups are shown in bold.
Median age, years (range)	63 (30–73)	59 (29–76)	0.32
Diagnosis, n (%) AML MDS	19 (73)* 7 (27)	78 (78) 25 (22)	0.16
HLA-matched unrelated donor, n (%) 10/10 9/10	21 (81) 5 (19)	74 (74) 26 (26)	0.27
Year of transplant	2015–2018	2003–2014
Median follow-up, months (range)	34 (18–56)	49 (12–141)	0.02

 Results

In the carfilzomib group, 23 out of 26 patients received carfilzomib as planned. Median time to neutrophil engraftment in carfilzomib and control group was 15 days (range 9–31) and 14 days (range 9–23), respectively. The median time to grade II–IV aGvHD and cGvHD was 36 days (range, 8–157) and 213 days (range, 60–578), respectively. Three patients died, two from aGvHD and one from multi-organ failure.

Comparative data on efficacy outcomes among the two groups are presented in Table 2.

Table 2. Efficacy outcomes¹

Outcomes, % (95% CI)	Carfilzomib group	Control group	p value
aGvHD, acute graft-versus-host disease; cGvHD, chronic graft-versus-host disease; NRM, non-relapse mortality; OS, overall survival. Significant differences between groups are shown in bold.
Grade II–IV aGvHD rate	11 (4–32)	39 (30–50)	0.01
cGvHD rate	49 (32–75)	41 (33–52)	0.98
NRM	11 (4–33)	18 (12–27)	0.45
Relapse rate	8 (2–29)	26 (18–36)	0.06
OS	81 (66–96)	56 (46–66)	0.05

Safety

Grade ≥ 3 adverse events occurred in 69% (n = 18) of patients receiving carfilzomib and are summarized in Table 3.

Table 3. Grade ≥ 3 adverse events that occurred in the carfilzomib group¹

AE	n (%)
AE, adverse event
Mucositis	17 (65)
Infection	8 (31)
Hepatic events	3 (12)
Renal events	2 (8)
Cardiac events   Decrease in cardiac ejection fraction, reversible   Atrial fibrillation	2 (8) 1 (4) 1 (4)
Pulmonary congestions	1 (4)

 Conclusion

This study has suggested that a combination of carfilzomib with cyclosporine and methotrexate can be safely administered as GvHD prophylaxis. It is associated with lower rates of aGvHD, relapse, and NRM leading to improved survival, when compared with a historical control group of patients which received cyclosporine and methotrexate alone. However, cGvHD rates were not improved with this approach. Limitations of this study include the retrospective nature of the control groups. Therefore, the authors emphasize the need for larger randomized studies to further evaluate the potential of this combination.