Combination of myeloablative conditioning with regulatory and conventional T-cell immunotherapy for AML

The most effective treatment for high-risk acute myeloid leukemia (AML) is allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, only 40–50% of patients become long-term survivors with no relapse and/or chronic graft-versus-host disease (cGvHD). Recently, HSCT has become more feasible in older patients due to reduced-intensity conditioning regimens. Despite the advances in treatments, relapse remains a key cause of transplantation failure.¹

In a study published in Blood Advances by Pierini et al.,¹ a combination of myeloablative conditioning with regulatory and conventional T-cell immunotherapy was investigated for patients with AML. The findings from this study are summarized here.

Study design

The phase II clinical trial (NCT03977103), conducted in Italy, included 50 patients with AML. The patients were aged <75 years (range, 20–65 years) with an ECOG status ≤2 and the availability of an HLA-matched donor family member.

• The primary endpoint was 2-year moderate/severe GvHD/relapse-free survival.
• Secondary endpoints were the incidence of full donor engraftment, cumulative incidence of Grade ≥2 acute GvHD (aGvHD), cGvHD, non-relapse mortality (NRM), and relapse.

The conditioning regimen was total body irradiation (TBI) in patients ≤50 years of age and total marrow/lymphoid irradiation (TMLI) for patients aged 51–65 years or unfit for TBI. Patients received an age-adapted myeloablative conditioning regimen based on TBI, either fractionated (nine fractions delivered twice a day for 4.5 days; total dose, 13.5 Gy) or a single dose of 8 Gy for those aged <50 years or based on TMLI for those aged 51–65 years. TBI or TMLI were followed by thiotepa (5–10 mg/kg), fludarabine (150–200 mg/m²), and cyclophosphamide (30 mg/kg) (see Figure 1).

*Figure adapted from Pierini et al.¹ 

Results

Baseline characteristics¹

Five patients had favorable risk, 22 intermediate risk, and 20 adverse genetic risk leukemia (see Table 1). Measurable disease at transplantation by cytogenic, immunophenotypic, and/or molecular analyses was observed in 33 patients. Eight patients underwent transplantation with active disease and 42 while in hematologic complete remission.

Table 1. Baseline characteristics*

AML, acute myeloid leukemia; CR, complete remission; DRI, Disease Risk Index; HCT-CI, Hematopoietic Cell Transplantation–Specific Comorbidity Index; HSCT, hematopoietic stem cell transplantation; MRD, measurable residual disease; NA, not applicable; PIF, primary induction failure; TBI, total body irradiation; TMLI, total marrow/lymphoid irradiation. *Data from Pierini et al.1
Characteristic	TBI based (n = 19)	TMLI based (n = 31)	Total (N = 50)	p value
Sex, female	11	13	24	0.87
Median age, years (range)	33 (20–50)	56 (38–65)	53 (20–65)	0.01
Genetic stratification at diagnosis (%)               Favorable               Intermediate               Adverse               Missing information	11 42 47 0	10 45 35 10	10 44 40 6	0.9 0.4 0.2 0.3
Other risk factors (%)               Secondary AML               PIF	26 26	35 39	32 34	0.15 0.1
Disease status at HSCT (%)               First CR, MRD−               First CR, MRD+               ≥ Second CR, MRD−               ≥ Second CR, MRD+              Advanced	42 37 0 5 16	29 32 0 23 16	34 34 0 16 16	0.18 0.4 NA 0.1 1
DRI (%)               Low               Intermediate               High               Very high               Missing information	11 32 53 5 0	6 45 39 13 10	8 40 36 10 6	0.5 0.2 0.3 0.45 0.3
HCT-CI risk score (%)               0 (low)               1–2 (intermediate)               ≥3 (high)	69 26 5	45 39 16	54 34 12	0.1 0.2 0.2

GvHD, NRM, relapse, and survival

• Grade ≥2 aGvHD developed in 15 patients (cumulative incidence, 33%; 95% confidence interval [CI] 30–35) and 12 of 15 patients developed Grade 3–4 aGvHD.

• aGVHD occurred in three patients from the TBI group and 12 from the TMLI group (TBI: cumulative incidence, 16%; 95% CI, 13–18 vs TMLI: cumulative incidence, 41%; 95% CI, 39–43; [p = 0.05]).
• The median onset of aGvHD was 41 days (range, 23–69).
• Twelve of the 15 patients with aGvHD did not progress to moderate/severe cGvHD, were alive, and did not require prolonged immunosuppressive therapy. Of the remaining three patients, two died due to aGvHD and one due to leukemia relapse.
• NRM occurred in ten patients (cumulative incidence, 21%; 95% CI, 20–23). There was no difference in NRM between the two treatment groups.
• Two patients relapsed (cumulative incidence, 4%; 95% CI, 3–6) at a median follow-up of 34 months (range, 5–72 months).
• GvHD/relapse-free survival was 48% (95% CI, 44–51), and moderate/severe cGvHD/relapse-free survival was 75% (95% CI, 71–78).
• Survival was not affected by irradiation protocol, i.e., TBI vs TMLI, or by adverse genetic risk at diagnosis.

Engraftment and immune rebuilding

• Median time to platelet recovery was 17 days (range, 14–72 days).
• All patients except one achieved full donor-type engraftment and an absolute neutrophil count >0.5 × 10⁹/L in a median time of 13 days (range, 8–23 days).
• The median duration of CD⁺ and CD8⁺ attaining 100/µL was 45 days (range, 29–95 days) and 27 days (range, 19–60 days), respectively, and attaining 200/µL was 74 days (range, 39–81 days) and 50 days (range, 25–81 days), respectively.

Adverse events

The majority of conditioning regimen-related adverse events (AEs) were Grade 1–2. One patient developed Grade 5 central nervous system toxicity and died. Two patients died of septic shock. Febrile neutropenia was experienced by all patients during the aplastic phase. There were 19 cases of sepsis observed in a total of 65 febrile neutropenia events. Organ-specific toxicities were reported in all patients (Table 2). Twenty-two of 50 patients had cytomegalovirus reactivations or cytomegalovirus detection in tissue biopsies.

Table 2. Organ-specific toxicities*^,†

CNS, central nervous system; TBI, total body irradiation; TMLI, total marrow/lymphoid irradiation. *Data presented as %. †Data from Pierini et al.1
	Grade 2		Grade 3		Grade 4		Grade 5
	TBI	TMLI	TBI	TMLI	TBI	TMLI	TBI	TMLI
Oral cavity	68	81	32	19	—	—	—	—
CNS	—	6	—	6	—	—	—	3
Hepatic	5	10	—	3	16	6	—	—
Gastric	95	94	5	6	—	—	—	—
Intestinal	58	68	42	32	—	—	—	—
Renal	—	—	—	—	—	—	—	—
Pulmonary	32	35	5	—	—	—	—	—
Bladder	—	6	5	—	—	—	—	—
Cardiac	32	10	5	—	—	—	—	—

Conclusion

The study achieved notably low leukemia relapse and cGvHD rates in patients with AML. This was achieved even though the majority of patients were aged 50–65 years, suggesting that T cell-depleted haploidentical HSCT with TMLI-based conditioning and Treg/Tcon immunotherapy may be applied in patients who are not eligible for standard myeloablative conditioning regimens due to their age. The findings from this study need to be challenged further in a larger, multicenter trial.