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Prevention of cGvHD by naive T-cell depletion

May 16, 2022
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Learning objective: After reading this article, learners will be able to cite a new clinical development in chronic GvHD.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can potentially cure patients with advanced hematologic cancers; however, it can also lead to morbidity and mortality due to graft-versus-host disease (GvHD). αβT cells in grafts can identify recipient alloantigens and promote engraftment by killing host hematopoietic and immune cells, and reduce relapse rates by destroying neoplastic blood cells, thus mediating the graft-versus-leukemia effect. However, alloreactive T cells can also damage host tissues and thus cause GvHD, therefore warranting pharmacologic immunosuppression or T-cell-depleted grafts.

αβT cells include naive (TN), effector (TE), and memory (TM) subsets, which have a distinct surface phenotype. In murine models, it has been demonstrated that TN cause severe GvHD, whereas TM cause mild-to-no GvHD and maintain graft-versus-tumor capability.

Marie Bleakley et al.1 recently published an article in the Journal of Clinical Oncology that analyzed the effects of TN-depleted allo-HSCT on the occurrence of chronic GvHD (cGvHD) in patients with acute leukemia or myelodysplastic syndromes treated in three prospective phase II clinical trials, which are summarized below.

The GvHD Hub has recently published an editorial theme article on the T-cell depletion strategies to reduce incidence of GvHD in pediatric HSCT recipients here.

Study designs and patient characteristics

In total, data from 138 patients from three phase II trials (NCT00914940 [n = 41], NCT01858740 [n = 20], and NCT02220985 [n = 77]) were analyzed. Study designs can be seen in Table 1.

  • Seven patients from NCT02220985 were not included in this analysis because the donor apheresis products did not meet the protocol-specified criteria for cell selection and therefore they did not receive TN-depleted grafts.
  • Differences across the trials included the age groups eligible, and that there were two treatment arms for NCT02220985, whereas NCT00914940 and NCT01858740 only had one treatment arm.

Table 1. Study design and participants*

 

NCT00914940
(N = 41)

NCT01858740
(N = 20)

NCT02220985
(N = 77)

Eligible age, years

14–55

0–21

0–60

HLA-matched donor type

MRD

MRD (n = 2)
MUD (n = 18)

MRD (n = 41)
MUD (n = 36)

Conditioning
+ prophylaxis

Fludarabine, thiotepa, TBI 13.2 Gy
+ tacrolimus

Fludarabine, thiotepa, TBI 13.2 Gy
+ tacrolimus, MTX

Fludarabine, thiotepa, TBI 13.2 Gy
+ tacrolimus, MTX
(n = 39)

Fludarabine, thiotepa, cyclophosphamide, TBI 4 Gy
+ tacrolimus MMF
(n = 38)

HLA, human leukocyte antigen; MMF, mycophenolate mofetil; MRD, matched-related donors; MTX, methotrexate; MUD, matched-unrelated donors; TBI, total body irradiation.
*Adapted from Bleakley, et al.1

  • Primary outcome: cGvHD (diagnosed by the 2014 National Institutes of Health criteria).
  • Secondary outcomes: graft failure, Grade III–IV acute (a)GvHD within the first year of allo-HSCT, overall survival, relapse, non-relapse mortality (NRM), and survival free of moderate or severe cGvHD or relapse (cGvHD-free, relapse-free survival).
  • Patient characteristics for all patients who received TN-depleted peripheral blood stem cells (PBSCs) can be seen in Table 2. Of note
    • the median age was 37 years;
    • there were more females than males;
    • and most patients received TN-depleted PBSCs for the treatment of leukemia or lymphoma.

Table 2. Patient characteristics*

Characteristic, % (unless otherwise stated)

TN-depleted PBSC recipients
(N = 138)

Median age (range), years

37 (1–60)

Sex

 

              Male

41

              Female

59

Performance status score

 

              ≥90

75

              <90

25

Diagnosis

              Myeloid

52

                            AML

43

                            MDS with excess blasts

4.4

                            Blastic plasmacytoid dendritic cell neoplasm

0.7

                            CML with a history of myeloid blast crisis

1.5

                            Mixed phenotype acute leukemia

2.9

              Lymphoid

48

                            ALL

46

                            CML with a history of lymphoid blast crisis

1.5

Disease risk

              Standard-risk (CR1, no residual disease)

62

              High-risk (beyond CR1 and/or residual disease)

38

Donor

              HLA-MRD

61

              HLA-MUD

39

Conditioning regimen

              High intensity

72

              Intermediate intensity

28

GvHD pharmacologic prophylaxis

              Tacrolimus monotherapy

29.7

              Tacrolimus and methotrexate

43

              Tacrolimus and MMF

27.5

ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; CML, chronic myelogenous leukemia; CR1, first complete remission; CR2, second complete remission; GvHD, graft-versus-host disease; HLA, human leukocyte antigen; MDS, myelodysplastic syndrome; MMF, mycophenolate mofetil; MRD, matched-related donors; MUD, matched-unrelated donors; PBSC, peripheral blood stem cell; TN, naive T cells.
*Adapted from Bleakley, et al.1
Measured by the Karnofsky (age, ≥16 years) or Lansky (age, <16 years) performance status scales. A lower score represents more disability.

Results

Incidence of GvHD

  • The cumulative incidence of Grade II aGvHD cases was 71% (95% confidence interval [CI], 64–79), which were predominantly Stage I (upper) gastrointestinal GvHD.
  • The cumulative incidence of Grade III aGvHD was low (4%; 95% CI, 18) and did not differ according to graft source (matched-related donor, 5%; matched-unrelated donor, 4%) or conditioning intensity (high intensity, 5%; intermediate intensity, 3%).
  • Only two patients with aGvHD required systemic treatment with agents other than corticosteroids.
  • In total, 7% of patients developed cGvHD, which was commonly mild and responsive to steroids.

Relapse and survival

The median duration of follow-up for surviving patients was 1,485 days (range, 262–1,826 days). The 3-year cumulative incidence of relapse was 23% (95% CI, 16–30). The median time to relapse was 206 days (interquartile range, 111–343 days).

Relapse rates according to patient subgroups can be seen in Table 3.  

Table 3. Relapse rates according to patient subgroups*

Patient group

Relapse rate, % (95% CI)

Graft type

 

              Received MRD grafts

27 (17–37)

              Received MUR grafts

17 (7–27)

Condition treatment

 

              High intensity

19 (11–27)

              Intermediate intensity

35 (18–52)

Diagnosis

 

              Myeloid malignancy

27 (17–38)

              Lymphoid leukemia

19 (9–28)

Age, years

 

              <30

18 (7–29)

              ≥30

26 (17–36)

CI, confidence interval; MRD, matched-related donor; MUD, matched-unrelated donor.
*Data from Bleakley, et al.1

Of the 31 patients who relapsed, 90% were not receiving prednisone at the time and 32.3% had discontinued or were quickly weaned off immunosuppression without developing GvHD. Of these relapsing patients, the median survival from relapse was 273 days (interquartile range, 85–590 days). A total of 21 relapsed patients were given donor lymphocyte infusions or other immunotherapies: 11 reached complete remission for at least 6 months. The survival outcomes of all TN-depleted PBSC recipients are displayed in Table 4.

Table 4. Survival data of TN-depleted PBSC recipients*

 

3-year estimate, % (95% CI)

OS

RFS

CRFS

GRFS

Total group (N = 138)

77 (71–85)

69 (61–77)

68 (61–76)

64 (56–72)

Graft type

 

 

 

 

              MRD (n = 84)

77 (68–86)

67 (58–78)

67 (58–78)

62 (52–74)

              MUD (n = 54)

79 (69–91)

72 (61–85)

70 (59–83)

66 (55–80)

Condition treatment

 

 

 

 

              High intensity
              (n = 100)

77 (69–86)

72 (63–81)

72 (63–81)

67 (58–77)

              Intermediate intensity            (n = 38)

78 (66–93)

60 (45–80)

57 (41–78)

54 (38–75)

Diagnosis

 

 

 

 

              Myeloid (n = 72)

74 (64–85)

66 (55–78)

64 (54–77)

60 (49–73)

              Lymphoid (n = 66)

81 (72–91)

72 (62–84)

72 (62–84)

68 (57–80)

Age, years

 

 

 

 

              <30 (n = 49)

84 (74–95)

76 (64–89)

76 (64–89)

67 (55–82)

              ≥30 (n = 89)

74 (65–84)

65 (55–76)

64 (54–75)

61 (52–73)

CI, confidence interval; CRFS, chronic graft-versus-host disease-free relapse-free survival; GRFS, graft-versus-host disease-free relapse-free survival; MRD, matched-related donor; MUD, matched-unrelated donor; OS, overall survival; RFS, relapse-free survival.
*Adapted from Bleakley, et al.1

NRM, causes of death, adverse events, and infectious complications

  • Of the patients who received TN-depleted grafts, the cumulative incidences of NRM at 100 days and 3 years were 4% (95% CI, 1–8) and 8% (95% CI, 3–13), respectively.
  • The 3-year NRM rates were estimated to be
    • 6% (95% CI, 1–11) and 11% (95% CI, 3–20) for patients who received MRD and MUD grafts;
    • 9% (95% CI, 3–15) and 5% (95% CI, 0–13) for patients who had high-intensity and intermediate-intensity conditioning;
    • and 6% (95% CI, 0–13) and 9% (95% CI, 3–15) in patients aged <30 years and ≥30 years, respectively.
  • The frequency and type of Grade III–V non-hematologic adverse events were typical of patients who receive myeloablative HSCT.
  • Epstein-Barr virus reactivation was uncommon with only one patient requiring treatment. Cytomegalovirus disease occurred in 4.3% of patients.

Conclusion

The authors demonstrated that the depletion of TN from PBSC allografts results in low incidences of severe aGvHD and cGvHD, without increasing the risks of relapse or NRM.

Limitations to the trial included the possibility that the lower total T-cell dose administered with TN-depleted grafts may be correlated with the cGvHD reduction, and the risk of type 1 errors due to the nature of the single arm study. Therefore, randomized trials will be important to confirm these findings. Indeed, two phase II trials have already been initiated (NCT03970096 and NCT03779854).

  1. Bleakley M, Sehgal A, Seropian S, et al. Naive T-cell depletion to prevent chronic graft-versus-host disease. J Clin Oncol. 2022. Online ahead of print. DOI: 1200/JCO.21.01755

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