aGvHD

Decitabine-containing conditioning regimen for allo-HSCT decreases incidence of acute GvHD

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still considered the only curative treatment option for most patients with intermediate and high-risk acute myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, this therapy is also associated with an increased risk of graft versus host disease (GvHD) and relapse of active disease. Therefore, researchers are exploring ways to alter conditioning regimens in order to minimize those risks by using combined treatment regimens.

One of the promising candidates to use in combination with a standard conditioning regimen for patients undergoing transplantation is decitabine (Dec). This pyrimidine analog, also known as 5-aza deoxycytidine, has been approved for the treatment of AML and MDS and has also been reported to lower incidence of GvHD.1–5  

In order to further evaluate the efficacy, role in GvHD prophylaxis, and safety of Dec-containing conditioning regimen in patients with intermediate/ high-risk MDS/AML, Qing Ya Wang from Peking University, CN, and colleagues carried out a retrospective analysis in 76 patients.6

Study design6
  • The analysis was based on 76 patients diagnosed with intermediate- or high-risk MDS or transformed AML (t-AML)
    • Dec group (n= 40) received Dec-containing conditioning before allo-HSCT
    • The control group received non-Dec conditioning before allo-HSCT (n= 36)
  • Patients were classified according to the 2008 WHO MDS classification and the risk was assessed using the revised international prognostic scoring system (IPSS-R)
  • Patients with MDS in high/higher-risk categories received allo-HSCT immediately after diagnosis followed by conditioning
  • Before conditioning, t-AML patients received induction with:
    • Standard ‘3+7’ induction therapy (cytarabine 100–200 mg continuous infusion for seven days plus idarubicin 12 mg/m2 or daunorubicin 60–90 mg/m2 for three days), or
    • CAG priming chemotherapy (cytarabine 10 mg/m2 infusion every 12 hours for 14 days, plus Granulocyte-colony stimulating factor (G-CSF) and aclarubicin)
  • Conditioning regimens
    • Cytarabine 2 g/m2 daily for three days; busulfan 3.2 mg/kg daily for three days plus cyclophosphamide 1.8 g/m2 daily for two days or fludarabine 50 mg for 3–6 days (total dose: 200 mg/m2)
    • Dec 15 mg/m2 from Day −16 to −12 intravenously
    • Rabbit anti-thymocyte globulin (ATG) was used for three days before transplantation:
      • 7.5–10 mg/kg in patients with haploidentical or unrelated donors
      • 0 to 5 mg/kg in patients with HLA identical sibling donors
  • GvHD prophylaxis and treatment:
    • Mycophenolate mofetil (MMF) 50 mg twice daily from the start of conditioning up to 30 days after transplantation
    • Cyclosporin A (CsA) 5 mg/kg daily (intravenously from Day −6 to the time of bowel function recovery, then orally); the dosage adjusted to achieve serum concentration 150–250 ng/mL
    • Methotrexate (MTX) 10–15 mg/m2 Days 1, 3, 5, and 11 after transplantation
    • Grade I acute GvHD (aGvHD) was controlled by topical treatment and optimization of CsA
    • Grade II–IV aGvHD was treated with methylprednisolone 1–2 mg/kg
  • Bone marrow (BM) aspiration was performed monthly in the first six months after transplantation to assess response to treatment
    • Presence of > 5% blasts in patients with previously normal BM or evidence of extramedullary leukemia was defined as relapse
    • Successful engraftment was defined according to the European Society for Blood and Marrow Transplantation criteria for hematopoietic repopulation:
      • Three consecutive days with leucocytes ≥ 1×109/L, neutrophils ≥ 0.5×109/L, and thrombocytes ≥ 50×109/L without any transfusion in the immediately preceding seven days
  • Disease-free survival (DFS) was defined as the period from diagnosis to relapse or death
  • Overall survival (OS) was defined as the time from diagnosis to death or the most recent follow-up
  • No relapse mortality (NRM) was defined as death caused by any reasons before Day 28, or death caused by reasons other than relapse after Day 28
Results6
  • In total data from 76 patients were used in the analysis; patient characteristics are outlined in Table 1
  • Neutrophil engraftment was successful in all 76 patients, with the median time of 13 days similar between groups
  • Platelets engraftment was successful in 39 patients in the Dec group and 35 patients in the non-Dec group, with the median of 21 (range, 8–86) days and 18 (range, 8–80) days, respectively (p = 0.321)

Table 1. Baseline patient characteristics

Characteristics

Dec (N= 40)

Non-Dec (N= 36)

p value

Age at HSCT, years

41 ± 12

33 ± 14

0.028

Gender

Male (%)

Female (%)

 

50

50

 

47

53

 

0.809

Prior transplant therapy

Chemotherapy (%)

CsA (%)

None (%)

 

60

2.5

27.5

 

44.5

33.3

22.2

0.093

WHO classification

RA (%)

RCMD (%)

RAEB-1 (%)

RAEB-2 (%)

t-AML (%)

 

0

20

20

17.5

42.5

 

2.8

36.1

8.3

13.9

38.9

0.299

Type of donor

MSD-HSCT (%)

Haplo-HSCT (%)

MUD-HSCT (%)

 

27.5

55

17.5

 

25

58.3

16.7

0.956

Graft source

BM + PB (%)

PB (%)

 

75

25

 

80.6

19.4

0.562

MNC (×108/kg)

9.76 ± 3.37

12.48±5.07

0.007

CD34+ (×106/kg)

5.77 ± 2.73

3.65 ± 3.10

0.004

Conditioning regimen

Bu/Flu (%)

Bu/Cy (%)

 

100

0

 

86.1

13.9

0.015

ATG (g/kg)

Yes (%)

No (%)

 

97.5

2.5

 

86.1

13.9

0.066

ATG, anti-thymocyte globulin; BM, bone marrow; Bu, Busulfan; Cy, cyclophosphamide; Flu, fludarabine; Haplo-HSCT, HLA haploidentical allogeneic hematopoietic stem cell transplantation; HCT-CI, hematopoietic cell transplant-comorbidity index; IPSS-R, Revised international prognostic scoring system; MSD-HSCT, HLA matched sibling donor allogeneic hematopoietic stem cell; MUD-HSCT, HLA-matched unrelated donor allogeneic hematopoietic stem cell transplantation; PB, peripheral blood; RA, refractory anemia; RAEB, refractory anemia with excess blasts; RCMD, refractory cytopenia with multilineage dysplasia; t-AML, transferred acute myeloid leukemia.

GvHD and infections

  • Cumulative incidence of grade II–IV aGVHD was significantly lower in patients in the Dec group compared with non-Dec; 12.4% (95% CI, 4.9–30.9) vs 41.5% (95% CI, 28.1–61.2%), respectively; p= 0.005
  • Multivariate analysis also found a protective benefit of Dec conditioning against aGvHD (HR= 0.279; 95% CI, 0.102–0.765; p= 0.013)
  • The incidence of chronic GvHD showed a trend in favor of the Dec vs the non-Dec group but was not statistically different with 17.5% vs 25%, respectively (p= 0.436)
  • The incidence of cytomegalovirus, Epstein-Barr virus, and hemorrhagic cystitis was similar between groups. The de novo incidence of respiratory infection was higher in the non-Dec group compared to that seen in patients in Dec group (53% vs 22.5%, p= 0.006)

Efficacy

  • The median follow-up for the whole cohort was 40 months (range, 1–155)
    • Dec-group 27.5 months (range, 1–57)
    • Non-Dec groups 70 months (range, 1–155)
  • There were no significant differences in 3-year OS, DFS, or relapse rate between study groups
  • Subgroup analyses performed in the higher-risk subgroup suggest that Dec-containing conditioning showed a trend towards:
    • Decreasing the relapse rate (10.6% vs 21.6%, p= 0.37)
    • Increasing 2-year disease-free survival rate (72.2% vs 57.1%, p= 0.314)
    • Prolonging 2-year overall survival rate (72.2% vs 64.3%, p= 0.628)
Conclusion6

The results of this retrospective analysis in a small cohort suggest that the addition of Dec to the conditioning regimen may lower the risk of aGvHD and active disease relapse. The impact of Dec-containing regimens on OS, DFS and NRM is inconclusive due to the limited numbers of patients studied. A larger prospective study with a longer follow-up is required to confirm those findings.

References
  1. Cruijsen M. et al., Addition of 10-day decitabine to fludarabine/total body irradiation conditioning is feasible and induces tumor-associated antigen-specific T cell responses. Biol Blood Marrow Transplant. 2016;22(6):1000–1008. DOI: 10.1016/j.bbmt.2016.02.003
  2. Potter VT. et al., Comparison of intensive chemotherapy and hypomethylating agents before allogeneic stem cell transplantation for advanced myelodysplastic syndromes: a study of the myelodysplastic syndrome subcommittee of the chronic malignancies working party of the European Society for Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2016;22(9):1615–1620. DOI: 10.1016/j.bbmt.2015.05.026
  3. Pusic I. et al., Maintenance therapy with decitabine after allogeneic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome. Biol Blood Marrow Transplant. 2015;21(10):1761–1769. DOI: 10.1016/j.bbmt.2016.05.026
  4. Zhou J. et al., Therapeutic efficacies of decitabine application prior to hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia. Natl Med J China. 2015;95(12):920–924
  5. EMA. Dacogen, INN-decitabine Summary of Product Characteristics. https://www.ema.europa.eu/en/documents/product-information/dacogen-epar-product-information_en.pdf [Accessed 29 January 2020]
  6. Wang QYet al., Decitabine-Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft versus Host Disease. Cancer Manag Res. 2019 Dec 4;11:10195-10203. DOI: 10.2147/CMAR.S229768
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