Page 66 - 2021_02-Haematologica-web

J, Henes et al.
Table 3. Baseline characteristics and results from the pretransplant evaluation in patients who died during the follow-up.
Ageat SAP/DBP Resting 24h-Holter Echo Echo Cardiac RHC
Proteins
Positive
Negative
Negative
Negative
Positive
Negative
Positive Negative
Haematuria
Positive
Serum creatinine (mmol/L)
36
Mobilization CYC (g/m2)
Conditioning regimen (mg/kg)
Time to death (days)
Cause of death
aHSCT related: cardiac toxicity
aHSCT related: cardiac toxicity and CYC toxicity
aHSCT related: cardiac toxicity and CYC toxicity
aHSCT related: cardiac toxicity and CYC toxicity
aHSCT related: infection + MOF
Progression:
Pulmonary toxicity Progression Progression
aHSCT/ gender
28/F
46/F
55/F
35/F
52/M
58/M
43/M
51/F
(HR)
90/60 (80)
110/75 (90)
125/75 (65)
100/70 (88)
135/85 (72)
120/80 (82)
120/80 (100)
120/70 (70)
ECG ECG
Normal Normal
Normal Not done
Normal Abnormal
Normal Not done
Normal Abnormal
Normal Normal
Normal Normal
Normal Normal
LVEF PASP (%)
60 19
67 23
68 31
62 .
55 20
66 30
64 16
72 30
MRI
Normal
Normal
Normal
Not done
Not done
Not done
Not done
Not done
Negative 48
Negative 56
Negative 35
Negative 62
Negative 115
Positive 35 Negative 37
2 CYC200 1
2 CYC200 1
3 CYC200 9
2 CYC200 61
3 CYC100+ 26 Thiotepa 10
3 CYC200 128
4 CYC200 131
3 CYC200 414
Abnormal Mean PAP=17 No fluid
challenge
Not done
Not done
Not done
Normal
Normal
Normal
aHSCT: autologous hematopoietic stem cell transplantation; SAP/DAP: systolic arterial pressure/diastolic blood pressure; HR: heart rate; ECG: electrocardiography; Echo: echocardiographic; LVEF: left ven- tricular ejection fraction; PASP: pulmonary arterial systolic pressure; MRI: magnetic resonance imaging; RHC: right heart catheterization; CYC: cyclophosphamide; M: male; F: female; MOF: multiorgan fail- ure; NA: not applicable.
relapse were related to a cardiac event, due to cyclophos- phamide toxicity in three patients. A 35-year old female, who died from cardiac toxicity and multiorgan failure on day +61 after autologous HSCT, had normal resting ECG and LVEF (62%) on echocardiography, and abnormal LVEF on heart scintigraphy (47%); MRI and RHC were not per- formed at baseline. Three other patients died from cardiac toxicity at day +1 (n=2) and day +9 (n=1), with normal cardiac MRI and no RHC evaluation at baseline. A fifth patient (conditioning with thiotepa + reduced-dose cyclophosphamide) died from cytomegalovirus reactiva- tion with viral copies detectable also in the lung, with bac- terial (Pseudomonas) pneumonia and multiorgan failure at day +21. This patient had a normal resting ECG, with an abnormal 24 h ECG, abnormal MRI and a mean pul- monary artery pressure of 17 mmHg on RHC performed without fluid challenge at baseline. During the 24 months of follow-up, three additional patients died, all due to dis- ease progression. Baseline characteristics of all patients who died during the follow-up and the respective causes of death are presented in Table 3.
During the 100 days after transplantation, a total of 119 adverse events were reported among the 80 patients as detailed in Table 4. The percentage of infectious complica- tions was not significantly different between the patients who did or did not receive CD34+-selected grafts (P=0.44), or according to the cyclophosphamide dose at the time of mobilization (2 g/m2 vs. 4 g/m2, P=0.16) or depending on whether they were or were not given G-CSF after their transplant (P=0.32) (Online Supplementary Table S3).
Discussion
The NISCC1 study is the largest prospective cohort today analyzing the efficacy and safety of autologous
HSCT in 80 patients with severe SSc in a real-life set- ting. The PFS rate was 82% and significant improve- ments were observed in skin score, lung function and quality of life during the 2 years of follow-up, consistent with results of previous randomized controlled trials14-16 and earlier studies.11-13 Nevertheless, the NRM rate asso- ciated with autologous HSCT was 6.25%, with most (4 out of 5) of the deaths being related to early cardiac events; this is similar to the 6% NRM rate reported ret- rospectively among 89 SSc patients transplanted between 2002 to 2011 in one USA and one Brazilian expert center using a non-myeloablative conditioning regimen.21
We used PFS as the primary endpoint to assess autol- ogous HSCT efficacy rather than event-free survival, as previously used14,15 and which was defined as survival without respiratory, renal, or cardiac failure. PFS, which encompasses disease progression and toxic deaths, bet- ter reflects safety and efficacy of HSCT.
In NISSC1, the incidence of progression was 6.3% and 11.9% at 1 and 2 years, respectively, highlighting the need to identify patients who may benefit from early maintenance therapy after autologous HSCT. Several mechanisms contribute to the resetting of the immuno- logical response and disease control after autologous HSCT, and vary according to individual patients.12 We showed that the immune reconstitution profile and T- cell repertoire diversity together with a decrease in mRSS >25% and in FVC >10% at 1-2 years after trans- plantation could identify long-term responders and non- responders/relapsing patients at 4-5 years.22 The immune reconstitution process and the balance between reinduction of tolerance and sustained autoreactivity after transplantation will depend on the type of condi- tioning regimen used to ablate the original immune sys- tem, the effect of ATG or ex vivo CD34+-cell selection to
380
haematologica | 2021; 106(2)