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

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.¹ Watch a video of Chiara De Phillipis discussing the same topic here.

Study design and patient characteristics¹

• 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/m² from 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/m² on 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 vs 4, respectively; p < 0.001)

Table 1. Patient characteristics¹

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

Results¹

• 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 vs 33% in the no-CPI group; p = 0.456) and neither was the one-year cumulative incidence of moderate to severe chronic GvHD (7% vs 8%, respectively; p = 0.673)
• The two-year cumulative incidence of relapse was lower for the CPI group compared with the no-CPI group (0 vs 20%; 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. Outcomes¹

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)

Conclusion¹

• 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