Immune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of ...autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi‐AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range IQR, 22‐110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2‐12.9 g/dL) and 6.3 g/dL (IQR, 6.1‐8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi‐AIHA were similar in DAT positive and negative patients. ICPi‐AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi‐AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first‐line treatment in the majority of patients with ICPi‐AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.
Introduction: Despite a well-established risk of chronic kidney disease (CKD) in 20-30% of patients undergoing AlloHCT, the benefits of treating serious infections, such as cytomegalovirus (CMV), ...with nephrotoxic drugs often outweigh this risk. Given a lack of consensus on the optimal management of post-transplant Human-Herpes Virus 6 (HHV6) reactivation, our center has taken an aggressive stance toward screening for and treating HHV-6 viremia with foscarnet, a nephrotoxic drug with an unknown impact on long-term renal function.
Methods: To clarify the impact of foscarnet exposure on long-term renal function after transplant, we conducted a retrospective cohort study of all adult patients who underwent AlloHCT at Duke from June 2002 - Feb 2016 (n=997). HHV6 viral loads were checked weekly for the first 90 days after umbilical cord blood and haploidentical transplants, and as clinically indicated (e.g. cytopenias, encephalopathy) in others. Foscarnet treatment for HHV6 viremia was given at the physician's discretion. Data were abstracted with a web-based clinical research query tool and manual chart review. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPI equation based on repeated measures of serum creatinine (Cr) values at baseline, 90 days (n=839), 6 months (n=720), and 12 months (n=491) after transplant. Acute Kidney Injury (AKI) and Acute Kidney Failure (AKF) were defined as 2 and 3x baseline Cr, or >50% and >75% decrease in eGFR, respectively. Multivariate logistic regression was used to estimate the association of foscarnet exposure on the probability of >30% decline in eGFR at 90 days, 6 months, and 12 months after adjustment for confounders.
Results: Of the 997 patients included in the study, 45% (n=448) were treated with foscarnet. Patients treated with foscarnet were slightly older (median age 52yrs vs. 49yrs), less likely to receive myeloablative conditioning, and more likely to be CMV positive, receive an alternative donor graft (umbilical cord blood or haploidentical), and experience acute GvHD. The most frequent indications for treatment were CMV (n=257, 57.4%) and HHV6 (n=140, 31.3%). In the first 90 days post-transplant, when most patients were treated with foscarnet, patients exposed vs. unexposed had similar rates of AKI/AKF: AKI 59.2% vs. 59.2%; p=0.99; AKF 26.1% vs. 27.3%; p=0.67. There was no difference in eGFR at 90 days, but patients treated with foscarnet had significantly lower eGFRs at 6 months and 12 months (Figure 1). There was a significant difference in the decline in eGFR from baseline to 12 months: median -29.1 (mL/min/1.73m2) (interquartile range (IQR) -50.8 to -10.7) vs. -22.2 (-37.4 to -7.4); p=0.002. After adjustment for age, race, acute and chronic GVHD, conditioning regimen, donor type, treatment with alemtuzumab, and HHV6 status, patients treated with foscarnet were more likely to experience a >30% decrease in eGFR from baseline to 12 months compared to those who were not (Odds Ratio 1.8 (95% CI 1.11-2.93); p=0.02). In this multivariate model, acute and chronic GVHD were not significant predictors of eGFR decline at 12 months. Unadjusted median survival was 11.9 months (95% CI; 10.1-14.0 months) and 20.8 months (95% CI; 15.8-25.4 months) for patients treated vs. not treated with foscarnet, respectively (p<0.001).
Conclusion: Foscarnet use post AlloHCT had a profound impact on long-term renal function independent of other transplant-related factors. As declines of >30% in eGFR are strongly associated with a 10-year risk of end-stage renal disease and mortality in >60% and 50% of patients in the general population, respectively, (Coresh, et al. JAMA 2014), this information should be considered as one weighs the risks vs. benefits of treating HHV6 viremia following AlloHCT.
Horwitz:Gamida Cell: Research Funding.
Introduction: The development of immune checkpoint inhibitors (ICPis) has ushered in a new paradigm for the treatment of both solid and liquid malignancies. However, these therapies, which promote an ...activated T cell phenotype, can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (IRAEs), which can affect a variety of organ systems. Autoimmune hemolytic anemia (AIHA) has been described as a rare complication of ICPis, but existing data are mostly limited to isolated case reports. Further, guidelines for the diagnosis and treatment of these patients are lacking. We describe the clinical and laboratory features of 14 patients who developed ICPi-associated AIHA.
Methods: We contacted hematology departments at 18 academic medical centers across the U.S. to inquire about potential cases of ICPi-associated AIHA. Nine centers contributed a total of 14 cases to the current series. We defined AIHA as an abrupt decrease in hemoglobin ≥2g/dL, the presence of at least two laboratory features of hemolysis (elevated serum lactate dehydrogenase LDH, elevated reticulocyte percentage, low or absent serum haptoglobin, and spherocytes), and the exclusion of other causes of anemia. We collected data on demographics and comorbidities, features of AIHA, and response to treatment. We defined complete recovery (CR) and partial recovery (PR) of hemoglobin as an increase from the nadir hemoglobin to within 1 and 2 g/dL of the baseline value, respectively, in the absence of recent transfusion.
Results: The clinical features of the 14 patients in our cohort with ICPi-associated AIHA are summarized in the Figure (panel A). Underlying malignancies included melanoma (n = 9), non-small cell lung cancer (n = 3), colorectal cancer (n = 1), and acute myelogenous leukemia (n = 1). Four patients had a pre-existing diagnosis of a lymphoproliferative disorder, and two of these patients were known to have a positive direct antiglobulin test (DAT) prior to initiation of ICPi. ICPis used included ipilimumab, nivolumab, a combination of ipilimumab and nivolumab, and pembrolizumab.
Representative hemoglobin and LDH trends are shown in the Figure (panels B and C). The median (interquartile range IQR) interval from initiation of ICPis to AIHA was 55 (22-110) days. Eight patients (57%) were DAT positive: 3 were positive for both IgG and C3; 3 were positive for IgG alone; 2 were positive for C3 alone; and 1 was weakly positive on polyspecific testing. Five patients (36%) were DAT negative, and in one patient a DAT was not performed. The median (IQR) hemoglobin nadir was 6.3 (6.1-8.0) g/dL,and 11 patients (79%) required red blood cell transfusion. All patients were treated with glucocorticoids, with 3 requiring additional immunosuppressive therapy.
All patients achieved a CR or PR of hemoglobin in response to treatment (CR, n = 11; PR, n =3). The median (IQR) time from the hemoglobin nadir to CR or PR was 47 (30-62) days. Seven patients (50%) experienced at least one other IRAE. Seven patients (50%) were re-challenged with ICPis, and one patient developed recurrent AIHA with re-challenge.
Conclusion: ICPi-associated AIHA is a recently-described phenomenon, which will be encountered more frequently with the widespread use of ICPis. ICPi-associated AIHA shares many clinical features with other forms of AIHA; however, a unique aspect of ICPi-associated AIHA appears to be a relatively high incidence of DAT negativity (36% in our series, compared with 3-11% in other forms of AIHA). It is possible that more advanced DAT testing - i.e., “super-Coombs” - which was not performed in any of the patients in this series, would have yielded different results.
Glucocorticoids appear to be an effective first-line regimen in most patients with ICPi-associated AIHA. Furthermore, we found that AIHA does not necessarily recur with ICPi re-challenge. Additional studies are needed to better understand the mechanisms underlying ICPi-associated AIHA and optimal treatment strategies.
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Anagnostou:ASH Research Training Award for Fellows 2018: Research Funding; Mayo Clinic SPORE: Research Funding; Mayo Clinic Immune Monitoring Core: Research Funding; Mayo Clinic Hematology Research Division: Research Funding. Salama:BMS: Research Funding; Celldex: Research Funding; Dynavax: Research Funding; Genentech: Research Funding; Merck: Research Funding; Reata: Research Funding; Incyte: Research Funding; Immunocore: Research Funding; Array: Consultancy; Merck: Consultancy; Biocryst: Consultancy; BMS: Speakers Bureau.
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