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Checkpoint inhibition before haploidentical transplantation with posttransplant cyclophosphamide as GvHD prophylaxis in patients with classic Hodgkin lymphoma

Jun 1, 2020

Many studies have demonstrated that checkpoint inhibition with monoclonal antibodies targeting the programmed death 1 (PD1) receptor are safe and efficacious in patients with relapsed and refractory classic Hodgkin lymphoma (cHL). However, use of checkpoint inhibitors prior to transplantation has been shown to increase the risk of developing GvHD. Posttransplant cyclophosphamide (PTCy) as a prophylaxis for graft- versus-host disease (GvHD) is used in patients who have undergone haploidentical stem cell transplantation (haplo-SCT), and it has been recently shown to be effective for patients receiving PD1 blockade therapy. 1,2

In a retrospective study, Chiara De Philippis , Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, IT, and colleagues aimed to analyze the effect of checkpoint inhibitors (CPIs) before haplo-SCT with PTCy prophylaxis in patients with cHL. The study was recently published in the journal Blood Advances. 1Watch a video of Chiara De Phillipis discussing the same topic here .

Study design and patient characteristics 1

  • Retrospective study in 59 patients with relapsed or refractory cHL who had received halpo-SCT between February 2014 and December 2018 at the Humanitas Cancer Center, Rozzano, IT; Institut Paoli Calmettes, Marseille, FR; and Hospital Sant-Antoine, Paris, FR
  • Twenty-nine patients had received prior CPI, while 30 patients had not been treated with prior CPI
  • Nonmyeloablative-conditioning regimen used fludarabine 30 mg/m 2from Days −6 to −2, cyclophosphamide 14.5 mg/kg on Days −6 and −5, and total-body irradiation 200 cGy on Day −1
  • Reduced toxicity conditioning regimen comprised of thiotepa 5–10 mg/kg on Day −6, cyclophosphamide 30–60 mg/kg on Day −5, fludarabine 120 mg/m 2on Days −5 to −2, and low-dose total-body irradiation (2 Gy) on Day −1
  • GvHD prophylaxis consisted of cyclophosphamide 50 mg/kg on Days 3 and 4, cyclosporine A (CsA), and mycophenolate mofetil
    • CsA 3 mg/kg was started on Day 5 as a continuous infusion until discharge, and was converted to an oral formulation thereafter and tapered by Day 100–180
    • Mycophenolate mofetil 15 mg/kg was administered 3× daily from Day 5–35
  • Granulocyte-colony stimulating factor was started on Day 5 and antimicrobial prophylaxis was administered as per center guidelines
  • Patient characteristics, shown in Table 1, were similar across both cohorts, except for the number of prior lines of therapy, which was higher in the CPI group compared with the no-CPI group (6 vs4, respectively; p < 0.001)

Table 1. Patient characteristics 1

auto-SCT, autologous stem cell transplant; BM, bone marrow; CMV, cytomegalovirus; CPI, checkpoint inhibitor; CR, complete remission; HCT-CI, hematopoietic cell transplantation-comorbidity index; PBSC, peripheral blood stem cell; PD, progressive disease; PR, partial remission; SD, stable disease

Characteristic

All patients

(N = 59)

No-CPI

(n = 30)

CPI

(n = 29)

p value

Median age, years (range)

30 (19–64)

31 (19–64)

30 (21–61)

0.896

Previous auto-SCT, %

83

90

76

0.181

Previous lines of therapy (range)

5 (2–11)

4 (2–11)

6 (3–9)

< 0.001

Disease status at transplant, %

 

 

 

 

CR

68

73

62

0.355

PR

24

17

31

 

SD/PD

8

10

7

 

CMV serostatus, %

 

 

 

 

Recipient positive

66

67

64

 

Recipient negative

34

33

36

0.849

Stem cell source, %

 

 

 

 

BM

29

23

36

0.345

PBSC

71

77

64

 

Conditioning regimen, %

 

 

 

 

Nonmyeloablative

76

80

72

0.495

Reduced toxicity

24

20

28

 

HCT-CI, %

 

 

 

 

0–2

52

47

59

0.358

3–5

48

53

41

 

Results 1

  • The median follow-up time was 26 months (range, 7.5–55 months) for the entire population
  • 100-day cumulative incidence of Grade 2–4 acute GvHD was not significantly different between the two cohorts (41% in the CPI group vs33% in the no-CPI group; p = 0.456) and neither was the one-year cumulative incidence of moderate to severe chronic GvHD (7% vs8%, respectively; p = 0.673)
  • The two-year cumulative incidence of relapse was lower for the CPI group compared with the no-CPI group (0 vs20%; p = 0.054)
  • At 2 years, there was no significant difference in overall survival, progression-free survival (PFS), and non-relapse mortality between the cohorts ( Table 2)

Table 2 .Outcomes 1

CPI, checkpoint inhibitor; NRM, non-relapse mortality; OS, overall survival; PFS, progression-free survival

 

All patients

(N = 59)

No-CPI

(n = 30)

CPI

(n = 29)

p

2-year OS, %

74

71

77

0.599

2-year PFS, %

65

53

78

0.066

2-year relapse/progression rate, %

13

22

4

0.098

2-year NRM, %

18

15

21

0.578

  • Multivariate analysis revealed CPI before haplo-SCT was an independent factor for improved PFS (HR, 0.32; p = 0.037).
  • Pretransplant disease status (stable/progressive disease) was an independent negative prognostic factor for both overall survival (HR, 14.3; p < 0.001) and PFS (HR, 14.1; p < 0.001)

Conclusion 1

  • Checkpoint inhibition as bridge before haplo-SCT enhanced PFS in patients receiving haplo-SCT with PTCy as GvHD prophylaxis, without increasing the rate of GvHD or non-relapse mortality
  • Limitations to the study include its retrospective nature and small cohort size. Additionally, a high proportion (71%) of patients received PBSCs as a graft source, which may have affected the low relapse rate observed
  1. De Philippis C, Legrand-Izadifar F, Bramanti S, et al. Checkpoint inhibition before haploidentical transplantation with posttransplant cyclophosphamide in Hodgkin lymphoma. Blood Adv. 2020;4(7):1242-1249. DOI: 10.1182/bloodadvances.2019001336

  2. Ikegawa S, Meguri Y, Kondo T, et al. PTCy ameliorates GVHD by restoring regulatory and effector T-cell homeostasis in recipients with PD-1 blockade. Blood Adv. 2019;3(23):4081-4094. DOI: 1182/bloodadvances.2019000134