GvHD prophylaxis with PTCy allows for rapid hematopoietic reconstitution and improved survival in transplanted patients with severe aplastic anemia

Severe aplastic anemia (SAA) is an acquired (mostly) or inherited nonmalignant stem cell disorder characterized by a hypocellular marrow and pancytopenia, affecting both morbidity and mortality. Premature death is often caused by infection in cases of extreme neutropenia. Current approaches are effective at controlling acute clinical features of SAA, but late complications, including the risk of relapse and secondary clonal neoplasms, still need management. For patients < 25 years, most guidelines recommend allogeneic bone marrow transplant (allo-BMT) with a suitable human leukocyte antigen (HLA)-matched sibling donor (MSD) after failure of frontline immunosuppressive therapy (IST). However, for patients ≥ 25, allo-BMT is considered a last resource in the late stages of the disease due to transplant-related morbidity and mortality. Additionally, identification of a MSD may be difficult for allo-BMT and limits this approach.¹

There is an unmet need in patients with SAA for rapid hematopoietic reconstitution and elimination of clonal disease, which is not achieved with IST. Posttransplant cyclophosphamide (PTCy) provides a safe and effective option to decrease the risk of graft-versus-host disease (GvHD) for haploidentical (haplo) donor BMT, which allows expansion of the donor pool while achieving outcomes close to those with MSDs. DeZern and colleagues¹ conducted a study (NCT02224872) to investigate the efficacy of intensive GvHD prophylaxis with PTCy to improve outcomes after haplo BMT in patients with SAA. Here, we summarize their results including updated results from 16 refractory/relapsed patients from another phase II trial (NCT02833805), published in Blood Advances.^{1, 2, 3}  

Study design¹

Methods

The selection criteria included the following:

• Diagnosed with acquired or inherited SAA (according to Camitta criteria), excluding Fanconi anemia
• Had refractory/relapsed (R/R) disease, defined as the lack of response to prior IST or a decrease in previously improved blood count
• Aged < 25 years and undergoing allo-BMT without an available MSD
• Met additional criteria of Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and Karnofsky and Lansky performance status of 70–100%, and the availability of an appropriate donor

Patients with monosomy 7 was excluded as it is considered to be consistent with myelodysplastic syndromes and acute myeloid leukemia.

Further details of the selection criteria and methods are summarized in Table 1.

Table 1. Summary of the selection criteria and methods¹

 Supportive care included oral antibiotic prophylaxis (a quinolone and an azole), Pneumocystis jiroveci, anti-herpes and varicella prophylaxis, and preemptive therapy with ganciclovir if ≥ 500 copies of cytomegalovirus/mL serum.

Patient characteristics

The total number of patients with haploidentical donors was 37, and the median age at the time of BMT was 25 years. Thirty-five patients had acquired SAA and two had inherited SAA. Patients who were TN only received transfusion support prior to transplant as the previous therapy. Clonality was 70% at the time of transplant. The patient characteristics are detailed below in Table 2.

Table 2. Demographics of patients with haploidentical donors (N = 37)¹

Results¹

The median follow-up was 32 months (range, 4–101). The rates of overall survival and GvHD-free survival were 94.6% and 84%, respectively. Key outcomes for both patient groups are summarized in Table 3.

In patients with R/R disease,

• all patients were alive and transfusion-independent at last follow-up
• three patients had GvHD: one patient with Grade 2 acute GvHD (aGvHD), one with severe pulmonary chronic GvHD (cGvHD), and one with Grade 2 aGvHD and mild oral and skin cGvHD
• no cytomegalovirus reactivation was observed; only one patient had Epstein–Barr virus reactivation

In TN patients,

• no cGvHD occurred, but two patients experienced Grade 2 aGvHD
• graft failure was observed in 3/7 patients who received 200 cGY total body irradiation (TBI), two of whom died. The protocol was amended, increasing the dose to 400 cGy TBI
• no graft failure was observed in those who received 400 cGy TBI

Table 3. Summary of key outcomes by patient group¹

Overall, 95% of patients with R/R disease and 71% of TN patients are beyond 12 months follow-up and not in need of immunosuppressive therapy, suggestive of full donor chimerism and complete tolerance to donor cells. Three patients experienced line-related bacteremia, which was treated by intravenous antibiotics and catheter removal. There were no events of sinusoidal obstruction syndrome, idiopathic pulmonary syndrome, or transplant-associated thrombotic microangiopathy.

Conclusion

In patients with SAA, GvHD prophylaxis with PTCy after haplo BMT is associated with high overall survival and GvHD-free survival rates, low morbidity and mortality rates in both R/R and TN patients, and compares favorably with standard therapies. Using haplo donors allows expansion of the donor pool, resulting in a shorter time to transplant and accelerated hematopoietic recovery—a major benefit for patients who suffer from severe and long lasting cytopenia and infections. Shorter time to neutrophil recovery can reduce morbidity and mortality due to infection and Haplo BMT appears to be a feasible option for patients, irrespective of patient age and pretreatment. For R/R patients, conditioning with 200 cGy TBI was adequate for engraftment, but 400 cGy results in better engraftment and no additional toxicity in TN patients. In the light of this data, the authors recommend that haplo BMT with PTCy should become standard of care for the management of patients with R/R SAA who are fit enough to tolerate nonmyeloablative conditioning. More patients, a multi-center setting, and longer follow-up are needed to determine the best TBI dose for TN patients and to address survivorship issues, such as fertility.