The Use of Checkpoint Inhibitors before and after Allogeneic Stem Cell Transplantion: A Double-Edged Sword
Authors: Khan Ali Younas , Ijaz Awais , Usman Muhammad , Tariq Muhammad Junaid , Fraz Muhammad Asad , Khalil Muhammad Jahanzeb , Durer Ceren , Durer Seren , Sagar Fnu , Ahmad Malik Qistas , Sohail Chaudhry Saad , Shah Zunairah , Aslam Shehroz , Anwer Faiz 
Published: October 2019

Abstract
Introduction:
Allogenic stem cell transplantation (allo-SCT) is a potentially curative option for hematological malignancies. Checkpoint inhibitors (CPI) have been successful in achieving remission for patients that relapse after allo-SCT. CPI can help relapsed/refractory (RR) patients to respond and bridge towards allo-SCT after achieving remission. Check point inhibition after allo-SCT carries an increased benefit of graft vs malignancy effect (GvL) but it may exaggerate the risk of immune system related toxicity such as graft versus host disease (GvHD).
Methods:
To assess the safety and efficacy of CPI use in conjunction with allo-SCT, after a comprehensive literature search, we included data (n=283) from a total of twenty-four studies (11 original manuscripts, 13 case reports or case series) and analysed the results.
Results:
Most common indication for CPI use was Hodgkin lymphoma (n=182). CPIs used in various studies included CTLA-4 inhibitors (ipilimumab, n=93) and PD-1 inhibitors (nivolumab, n=167 and pembrolizumab, n= 27). In patients who were exposed to CPI before allo-SCT (n=107), 56% patients developed acute (a) GvHD and 29% patients developed chronic (c) GvHD. The overall mortality risk (11/107) associated with GvHD was 11%. Interval between last dose of CPI and allo-SCT ranged from 28-62 days. Median cycles of CPI therapy ranged from 4-9 cycles. The overall response rate (ORR) was observed (42/62) to be 68% patients with complete remission (CR) in 47% patients and partial remission (PR) in 21% patients. Most common adverse events reported were non-infectious febrile syndrome (12%), infections (5%), hepatic sinusoidal obstruction syndrome (4%) and encephalitis (3%).
In patients (n=150) who received CPI after allo-SCT for treatment of disease relapse, 13% patients developed aGvHD and 11% patients developed cGvHD. The overall mortality risk with GvHD was around 7% in this population. The interval between allo-SCT and first dose of CPI ranged from 12.5 months to 29 months. Nivolumab was given at doses 1 mg/kg to 3 mg/kg, weekly or two-weekly. Ipilimumab dose ranged from 0.1 mg/kg to 5 mg/kg. A combination with lenalidomide was also tried. Pembrolizumab was administered at 200 mg/kg every three weeks. An ORR of 48% (59/123) was observed with CR in 34 (28%), PR in 25 (20%) and disease stabilization in 7 (6%) patients. Complications, other than GvHD, include hematological side effects (22%), most notably neutropenia followed by respiratory and hepatic complications (16% and 14% respectively). Thirteen case reports evaluated safety and efficacy of CPIs after allo-SCT. Among 26 cases, the reported ORR was 85% with fifteen and seven patients achieving CR and PR, respectively. Of the four patient deaths that occurred during the study period, one died of GvHD. Most common adverse reactions noted were in the GI tract, notably hepatitis (32%), followed by skin (25%) and pulmonary disease (25%).
Conclusion:
CPI use before and after allo-SCT can be highly effective for relapse disease control. For patients who received Allo-SCT, CPI exposure can lead to significantly increased risk of GvHD, GvHD related morbidity and mortality. There is need for caution while making decision for CPI use in this population. Prospective well-designed clinical trials are required to further explore the safety of CPIs in allo-SCT setting.

Disclosures
No relevant conflicts of interest to declare.