Melanoma is the deadliest form of skin cancer. Over 160 000 new cases of melanoma are diagnosed annually worldwide with 40 800 deaths/year from stage IV disease 1. With a median survival of 8–9 months and a 3-year overall survival rate of less than 15%, the prognosis for patients with metastatic disease is generally poor 2. The approval of ipilimumab represents a groundbreaking new development in the field of melanoma therapeutics because it is the first drug to improve overall survival for patients with metastatic disease in large randomized controlled clinical trials 1,2. Ipilimumab is a human monoclonal antibody that binds and inhibits cytotoxic T-lymphocyte antigen (CTLA-4). A negative regulator of T-cell function, CTLA-4 is essential in T-cell homeostasis. By antagonizing CTLA-4 signaling, ipilimumab promotes the costimulation of CD28, leading to the subsequent upregulation of T-cell activation pathways 3,4.
Multiple doses of ipilimumab have been tested in clinical trials. Moreover, there is published evidence for both higher efficacy and toxicity with increasing dosage 5,6. Ipilimumab received Food and Drug Administration (FDA) approval after Hodi et al.7 reported the pivotal findings of a large phase III trial of ipilimumab. Including 676 patients diagnosed with metastatic melanoma, the trial compared ipilimumab and gp100 peptide vaccine therapy with either treatment modality alone. Ipilimumab with or without gp100 vaccination improved overall survival (10.1 months) compared with gp100 alone (6.4 months) 7. On the basis of this study, ipilimumab is now FDA approved at induction dosing of 3 mg/kg every 3 weeks for four doses. In a recently published phase III trial, Robert and colleagues 8,9 found that patients receiving combination therapy with ipilimumab and dacarbazine had improved overall survival compared with patients receiving dacarbazine and placebo (11.2 vs. 9.1 months).
The most concerning side effects reported in clinical trials of ipilimumab fall into the category of immune-related adverse events (IRAEs), including dermatitis, hepatitis, enterocolitis, hypophysitis, and uveitis 7–11. These side effects are reversible when immunosuppressive therapy is administered promptly 8,9. The most common adverse events reported by Hodi et al.7 were immune-related, occurring in ∼60% of patients treated with ipilimumab. Most of these immune-related events were dermatologic, with 43.5% of patients experiencing one or more immune-related dermatologic events (pruritus, rash, or vitiligo) 7. Hepatic-related immune events were the rarest in this cohort, with only 0.8 and 1.5% of patients experiencing aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation, respectively 7. In the trial, half of the patient deaths associated with the study drug were immune-related (1.2%) and 10–15% of patients experienced grade 3 or 4 immune-related toxicity, with the most severe outcomes reported in patients with colitis 7. Robert and colleagues 8,9 established a higher incidence of hepatotoxicity in patients receiving ipilimumab with dacarbazine (33.2%) in comparison with patients receiving dacarbazine and placebo (5.6%).
Over the course of treating patients at the Mount Sinai Medical Center, we observed a surprisingly high frequency of hepatotoxicity in patients receiving ipilimumab therapy. We sought to better characterize these adverse events and determine whether they differed from expected rates based on the findings of Hodi and colleagues when using a comparable dose and schedule of ipilimumab. A retrospective review of all patients treated at our center with ipilimumab from June to December 2011 with subsequent follow-up information available was conducted 7–9.
The 11 patients described in this report had been diagnosed with biopsy-proven stage IV melanoma according to the modified WHO criteria. These represent all the cases of late-stage or unresectable metastatic melanoma receiving ipilimumab therapy at the Mount Sinai Medical Center in New York City between June and December 2011 with subsequent clinical follow-up available. Patients were scheduled to receive induction therapy consisting of four separate 90-min intravenous doses of ipilimumab every 3 weeks (q3wk×4; until week 12).
To assess disease course and monitor for adverse reactions, patients were scheduled for follow-up examinations and comprehensive laboratory testing at the Ruttenberg Clinic at Mount Sinai every week during the treatment period. Patients received their care from Dr Yvonne M. Saenger and Dr Philip Friedlander, who, along with the authors of this report, was granted approval by the Mount Sinai IRB to conduct this research. The de-identified medical records of participants included in this study were obtained through Epic and reviewed to examine the treatment course, outcomes, and side effect profile characterizing this specific patient cohort.
Assessment of treatment response and toxicity
Treatment response was determined by the physician study investigators through the use of modified WHO criteria to evaluate measurable lesions 10. When clinically indicated, computed tomography (CT) with contrast material, PET, or MRI of anatomical locations affected by tumor burden was performed. The National Cancer Institute’s CTCAE, version 4.0, was used to grade adverse events occurring during treatment and follow-up periods.
χ2-Analysis using Fisher’s exact test was performed with GraphPad Prism 5 (GraphPad Software, La Jolla, California, USA) to determine whether the number of adverse events we observed in our cohort (n=11) differed from those reported by Hodi et al. (n=131) 7 and Robert and colleagues (n=247) 8,9. This software was used to conduct a Kaplan–Meier analysis to determine overall survival of our cohort over the 84-day ipilimumab treatment period.
Study design and patient selection
We conducted a retrospective review of all patients treated with ipilimumab at the Mount Sinai Medical Center from June to December 2011 to better characterize our observation of frequent hepatotoxicity in this patient cohort. Eleven patients received ipilimumab therapy for late-stage melanoma at our center between June and December 2011. The clinical characteristics of this cohort are summarized in Table 1. All patients were diagnosed with stage IV melanoma with nine cases of stage IVc disease and isolated cases of stage IVa and stage IVb melanoma. Biopsy-proven metastatic liver involvement had been established in five cases and indeterminate liver lesions were present on abdominal CT in one patient. Other treatments had been used in most cases with six patients having at least one prior systemic therapy and 10 who had undergone local–regional treatment with surgery, radiation, or cryotherapy in the past. Two patients had documented BRAF V600E-positive melanoma, whereas all others tested negative for this mutation.
Increased hepatotoxicity rates observed relative to clinical trials in patients receiving commercial ipilimumab
In a cohort of 11 patients receiving ipilimumab for stage IV melanoma, we documented frequent hepatotoxicity during treatment. In Table 2, the percentage of patients experiencing adverse events in our cohort is compared with the frequencies reported by Hodi et al.7 and Robert and colleagues 8,9. In our 11-patient cohort, AST and ALT elevation (≥grade 1) occurred in six of 11 cases, a notably higher frequency reported by Hodi and colleagues. This difference was found to be statistically significant by χ2-analysis using a Fisher’s exact test (P<0.0001). As is common after FDA approval, three of our study patients treated with ipilimumab would not have met the stringent inclusion criteria used by Hodi and colleagues. After the exclusion of these three patients, the difference between observed rates of aminotransferase elevation in our cohort compared with those reported by Hodi and colleagues. remained statistically significant (P=0.0024).
Although no patients in the clinical trial conducted by Hodi et al.7 experienced grade 3 or 4 transaminitis, three of 11 and one of 11 patients in our cohort were documented with grade 3 AST and ALT elevation, respectively. χ2-Analysis was also statistically significant for grade 3 AST elevation in our cohort when compared with Hodi and colleagues (P=0.0004). Surprisingly, by comparison, our toxicity levels were more similar to those reported by Robert and colleagues, where all patients received dacarbazine chemotherapy in addition to ipilimumab. No difference was found in AST (P=0.0937) and ALT (P=0.193) elevation (≥grade 1) when compared with the findings of Robert and colleagues 8,9 by Fisher’s exact test. The elevated rates of hepatotoxicity did not reflect a higher level of overall toxicity as χ2-analysis was not statistically significant (P>0.05) between our cohort and that of Hodi and colleagues with regards to dermatologic, gastrointestinal, and endocrine-associated adverse events. This suggests that observed hepatotoxicity was an isolated phenomenon and did not reflect a general elevation in immune-related events or an overall higher rate of adverse events.
To rule out that the rate of hepatotoxicity was not caused by a confounding factor or differences between the treated populations, we compared our cohort of 11 patients to that of Hodi and colleagues (Table 3). No significant differences were noted between the populations treated in terms of sex, age, Eastern Cooperative Oncology Group performance, and metastasis stage. Our group of patients did contain a smaller population having received previous systemic therapy (six of 11), compared with patients in Hodi and colleagues (100%), because of the fact that ipilimumab can now be used first line after FDA approval. All of our patients were taking concomitant medications, with the majority receiving analgesics and antiemetics. Similarly, the most common concomitant medication in Hodi and colleagues were analgesics.
Characteristics of liver toxicity in melanoma patients receiving ipilimumab
We documented frequent hepatotoxicity in an 11-patient cohort treated with ipilimumab for stage IV melanoma. As hepatotoxicity has been reported as a possible IRAE associated with ipilimumab therapy, the baseline liver integrity and function as well as treatment-associated hepatotoxicity for this patient cohort are provided in Table 47–9. Five patients completed all four cycles of ipilimumab therapy. Of the six patients with at least grade 1 elevations in AST or ALT, three had biopsy-proven metastatic liver involvement and four had elevated lactate dehydrogenase (LDH) at baseline. In two patients, cycles were delayed because of possible ipilimumab-associated hepatotoxicity. Liver function tests including AST, ALT, alkaline phosphatase, and total bilirubin for the patients with hepatotoxicity are graphed over 84 days starting from the first ipilimumab infusion (Fig. 1a–d). One patient underwent ultrasound-guided needle biopsy of the liver to rule out ipilimumab-associated autoimmune hepatitis. Mild macrovesicular and medium drop steatosis accompanied by ballooning and feathery degeneration of hepatocytes as well as hepatocytic, canalicular cholestasis, and bile duct damage with ductular reaction is identified on hematoxylin and eosin in Fig. 1e. Although other etiologies may be considered, these pathological findings are characteristic of drug-induced hepatitis 12. None of the patients with elevations in AST or ALT developed antihepatic antibodies.
Clinical outcomes in patients with hepatotoxicity
Patients treated with ipilimumab are at a risk of experiencing potentially lethal IRAE, including hepatotoxicity. Overall survival of an 11-patient cohort treated with ipilimumab is reported in Fig. 2. There were no observed differences with regard to survival in patients who did or did not experience hepatotoxicity in our patient cohort, and no deaths were thought to be related to ipilimumab-induced hepatotoxicity. All three patients who died during the treatment period had biopsy-proven metastatic liver disease and elevated levels of LDH at baseline. The patient who died after the treatment period had been found to have indeterminate liver lesions on CT with a normal baseline LDH. Disease progression was documented in all cases, although one patient who also developed autoimmune hypophysitis, had a period of stable disease for 6 months. Three deaths occurred during the 84-day treatment period (Fig. 2) and one was documented 159 days after initiation of ipilimumab therapy. Of the seven surviving patients, six had received follow-up in the month before the writing of this report (June 2012) and one received care at a separate institution after October 2011.
Ipilimumab, an immunotherapy, is the first agent shown to improve survival of patients with metastatic melanoma in large-scale randomized controlled trials 7–9. Ipilimumab has demonstrated efficacy and shown benefit as a single agent compared with a peptide vaccine 7. When ipilimumab was combined with dacarbazine, the standard chemotherapeutic agent used in the treatment of metastatic melanoma, overall survival was longer compared with dacarbazine monotherapy 8,9. Furthermore, a subset of patients treated with ipilimumab experienced durable, long-term responses 11,12. Consequently, ipilimumab represents not only a new standard of care in the treatment of advanced melanoma but a new class of ‘immune check point inhibitors’ with the potential to redefine the prognosis of patients with late-stage malignancies 13,14.
Over the course of treating patients with ipilimumab at Mount Sinai School of Medicine, we noted surprisingly high rates of liver function abnormalities. Although our sample size is small for the period studied (n=11), it is nonetheless remarkable that elevations in transaminases were documented in more than half of cases, an unexpected finding given the rate of 0.8% in a similar patient population of 131 patients published by Hodi et al.7. Toxicity rates may be influenced by characteristics of the treated population, as well as unknown variables in the preparation and administration of ipilimumab. Similar to the cohort of Hodi and colleagues, all our patients were at least 18 years of age, had a histologic diagnosis of unresectable malignant melanoma, and had disease progression on recent imaging. None of the patients in our study or in the licensing trial were known to have hepatitis and all patients had a life expectancy of at least 4 months at the start of treatment. There were three differences noted between our cohort and the patients treated by Hodi and colleagues. Patients in the licensing study had to be HLA-A*0201 positive, had to have progressed on prior therapies, and had either stage IV or unresectable stage III disease 7. In contrast, in our cohort, HLA status was unknown, some patients had no prior therapy for melanoma, and all patients had stage IV disease with none having stage III disease. These differences, however, should not account for a large discrepancy in the incidence of hepatotoxicity. Therefore, it is important for clinicians to be aware of potential variability in the side effect profile of ipilimumab.
Clinical trials often specify strict inclusion criteria used in patient selection and thus may not reflect the diverse population of patients with advanced melanoma encountered by practicing physicians. In our cohort, three of the 11 patients would have been excluded from the Hodi and colleagues study on the basis of Eastern Cooperative Oncology Group performance status and baseline aminotransferase elevations. Surprisingly, although the number of patients in our case series is small, even after the exclusion of these three patients, the difference between observed elevations in aminotransferase levels in our cohort and Hodi’s remains statistically significant. It is possible that specific characteristics of patient populations explains these differences, however, we found no readily apparent causes for the elevated rates of hepatotoxicity when taking into account age, sex, ethnicity, prior treatments, concurrent medications, or history of infectious hepatitis or other liver disease. Significantly, our study is applicable to the diverse population of melanoma patients with advanced disease who may be treated with ipilimumab in the post-FDA approval era. These findings underscore the importance of postapproval monitoring for adverse events as ipilimumab use is broadened to include patients in whom it was not specifically studied.
Immune-related toxicities have been a major concern with ipilimumab therapy. Principal among these is colitis, which caused several deaths in very early investigations 15. A dose–response study conducted by Wolchok et al. 16 suggested that both efficacy and toxicity correlate with increasing dose. After ipilimumab was tested at doses of 3 and 10 mg/kg, the 3 mg/kg dose was approved by the FDA in March 2011. All patients in the current review received the approved dosage of 3 mg/kg every 3 weeks and were scheduled for four doses as per FDA recommendations. Outcomes were similar between our cohort and patients included in the licensing study by Hodi et al.7. Aside from hepatotoxicity, a higher frequency of other adverse events was not observed 7. Thus, frequent hepatotoxicity appears to be an isolated phenomenon in our patient cohort that is not correlated with other toxicities or poorer outcomes. In this small patient population, the occurrence of liver toxicity did not appear to correlate closely with the presence of liver metastasis.
In most of the major studies using ipilimumab, hepatitis was a rare side effect with rates under 5% reported at all tested doses 17. The major exception to this was the study reported by Robert and colleagues 8,9 in which ipilimumab was dosed at 10 mg/kg and combined with dacarbazine. In this trial, elevations in transaminases were noted in 33.2% of 247 patients treated with the combination regimen, whereas only 5.6% of 252 patients treated with dacarbazine and placebo experienced abnormalities in liver function. Although these findings may be attributed to synergistic hepatotoxicity from these two agents, there was no ipilimumab monotherapy arm in this study 8,9. Results of a study comparing ipilimumab at 3 mg/kg with and without dacarbazine for a maximum of six cycles reported no significant difference in overall hepatotoxicity between groups (<10%). However, one of 35 patients in the combination group had to discontinue therapy because of persistent grade III liver function abnormalities 18. Similarly, hepatotoxicity was generally rare in a population of 27 heavily pretreated melanoma patients receiving ipilimumab at 10 mg/kg with only one patient having to discontinue treatment because of grade 3 elevations in liver enzymes 19.
As reported above, six of 11 patients were documented with elevations in liver function tests treated with ipilimumab. These abnormalities resolved spontaneously unless progressive metastatic melanoma was present in the liver with only minor delays in treatment. These findings suggest that ipilimumab may have hepatotoxic effects in some patient populations due to unknown variables and that the toxicity observed with combination therapy in the Robert study of 33.2% may not be entirely attributable to the presence of dacarbazine 8,9. Similar to the findings of Robert and colleagues, we reported a low (0%) frequency of colitis. However, this may have been because of the small size of our patient population. In our cohort, there was no evidence that the hepatotoxicity was immune mediated. In the one case where a needle-guided liver biopsy was obtained, no histopathological evidence of inflammation was found. Liver toxicity occurred in patients with and without a history of liver metastasis and treatment was delayed in some patients until liver function tests improved.
Although the adverse events documented in this report differed from those in the licensing study, we are not suggesting that clinicians should refrain from administering ipilimumab because of the potential for these adverse events. More data in a larger cohort of patients in conjunction with an explanation behind these findings is needed before definitive conclusions may be drawn from our preliminary findings. Furthermore, no serious outcomes were observed in any patients as liver function tests returned to baseline in those patients without hepatic metastasis. Nonetheless, as the use of ipilimumab expands following FDA approval, clinicians should be aware that the toxicity profile of ipilimumab may potentially be variable. This necessitates careful monitoring of liver function tests, and possibly delaying treatment if results are abnormal, particularly in patients with pre-existing liver conditions as well as those receiving potentially hepatotoxic medications in combination with ipilimumab therapy.
Conflicts of interest
Dr Phillip Friedlander is a consultant for Genentech and previously for Bristol-Myers Squibb. Dr Yvonne M. Saenger has received grant funding from Bristol-Myers Squibb. For the remaining authors there are no conflicts of interest.
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