1 Oncology Specialists, S.C., Lutheran General Hospital Cancer Care Center, Park Ridge, IL; 2 Division of Hematology and Oncology, 3 Department of Medicineand 4 Division of Pathology, Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, Chicago, IL, USA
* Correspondence to: Dr M. S. Tallman, Division of Hematology and Oncology, Northwestern University Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, 676 N. St Clair Street, Suit No. 850, Chicago, IL 60611, USA. Tel: +1-312-695-6180; Fax: +1-312-695-6189; Email: m-tallman{at}northwestern.edu
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Abstract |
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Patients and methods: We performed a retrospective review of all patients treated at our institution with single-agent GO, either as initial therapy or in the relapsed and refractory setting. All patients were planned to receive GO 9 mg/m2 in two doses, 14 days apart. We reviewed liver function tests before and after administration and analyzed hepatic injuries in the context of patients' other comorbid conditions. Patients were classified as experiencing liver toxicity if their liver function(s) abnormality lasted for >7 days, as documented by repeated serum studies.
Results: Forty-seven patients were analyzed. Response rate (27.2%) and median duration of response (6 months) were comparable to other reports. All patients were assessable for liver toxicity, of which 23 (48%) had elevation of at least one of their liver function tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin or alkaline phosphatase). Elevations in liver function test(s) were noted at a median of 14 days (range 7175 days). Eight patients had other comorbid conditions that could explain their liver abnormality, making the incidence of direct GO-induced liver injury 31%. However, only one patient had radiographic and clinical evidence suggesting SOSVOD.
Conclusions: When administered using the recommended dose and schedule, GO has little association with VODSOS if given as a single agent. In this retrospective review, the incidence of GO-related SOSVOD is as low as 2%.
Key words: gemtuzumab ozogamicin, single-agent therapy, sinusoidal obstructive syndrome, veno-occlusive disease
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Introduction |
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Using the approved dose and schedule, the incidence of grade 3 and/or 4 acute toxicities is relatively low [5]. In addition to infusion-related toxicities that are usually controlled with antipyretics and antihistamines, the most significant additional drug-related adverse event observed is liver injury manifested by elevations in transaminases and bilirubin values. However, these abnormalities are transient and self-limited [5
]. Stadtmauer et al. investigated the predisposing factors for hepatic injury in patients treated with GO, and while grade 1 and 2 elevations of transaminases were observed in 26% of patients (48 of 188), grade 3 and 4 elevations were seen in only 16% [5
]. However, three patients developed veno-occlusive disease (VOD) before exposure to another agent, although this was not documented by liver biopsy, and all three patients had previous stem cell transplantation (SCT). The authors concluded that the incidence of VOD after GO treatment (but before other therapies) was 2% and the death rate was <1%, and suggested that previous transplantation might be a risk factor for developing VOD. Others also have reported increased incidence of hepatic injury, but most of these reports included GO in combination with other therapeutic agents, or were conducted after SCT and occasionally used different dosing schedules, confounding their interpretation [6
, 7
]. It has been suggested that the liver toxicity is related to the delivery of calicheamicin to CD33-positive cells residing in the sinusoids of the liver, such as Kupffer cells [8
] and sinusoidal endothelial cells [9
], which may explain why some have called this phenomenon sinusoidal obstructive syndrome (SOS) [7
].
To investigate the association between GO and VOD, we initiated a retrospective analysis of all patients treated at Northwestern University Hospital who received GO as a single agent. We further analyzed the incidence of such a syndrome in light of patients' previous therapies and their history of SCT, as well as associated comorbidities. Our results indicate that the incidence of hepatic injury is as reported in other studies, but that SOSVOD was an unlikely occurrence.
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Patients and methods |
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Assessment of liver injury
Serum transaminases, bilirubin and chemistries were all assessed before (within 14 days of initial infusion) and after GO administration (within 14 days). Data were followed serially as required for each protocol. For the purpose of this analysis, patients were classified as having liver toxicity if their liver function(s) abnormality lasted for >7 days, as documented by repeated serum studies. Where indicated clinically, imaging studies were performed to exclude SOSVOD or any hepatic injury. These indications included unexplained weight gain, new hepatomegaly, or elevations in liver function tests that did not improve with expectant management. Patients were considered as having SOSVOD if they met the criteria defined by Rajvanshi et al. [7] without evidence of other etiologies for hepatic dysfunction. None of the 47 patients studied underwent a liver biopsy. Comorbidities were also recorded in an attempt to distinguish GO-induced liver injury from other potential etiologies.
Assessment of response
All bone marrow aspirates and biopsies were reviewed centrally by a single hematopathologist (L.C.P.). Bone marrow aspirates and biopsies were obtained when clinically indicated, such as by the emergence of newly documented cytopenias or when required by the protocol on which patients were enrolled. In all protocols, bone marrows were usually performed 30 days after the initiation of therapy unless analysis was required earlier as determined by the treating physician. Complete response was defined as by Cheson and colleagues [10]. Cytogenetic analysis was performed on initial bone marrows and was included in the final analysis of response.
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Results |
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Response to therapy
Forty-four patients were evaluable for response. Twelve patients (27.2%) achieved a complete response (CR) or a complete remission without platelet recovery (CRp). Thirteen patients (29%) had residual disease after the second dose of GO. Thirteen patients (29%) had no response or had progressive disease after therapy. Six patients died from progressive disease before completing therapy. Median duration of response in those who achieved a CR or CRp was 6 months (range 3.334.3 months).
Hepatic toxicity
All patients were assessable for liver toxicity, of which 23 (48%) had elevation of at least one of their liver function tests [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin or alkaline phosphatase]. Any patient who had an elevation in any of these tests that lasted for >7 days was considered to have had a hepatic toxicity and this was graded according to the National Cancer Institute Common Toxicity Criteria. Elevations in liver enzymes and/or total bilirubin were noted at a median of 14 days after the first infusion (range 7175 days). The median elevation in bilirubin was 2.5 mg/dl (range 2.07.9). Median AST level in the cohort of patients with elevated liver function tests was 168 µ/l (range 54479 µ/l). Median ALT level in the same cohort was 156.5 µ/l (range 67305 µ/l). Four patients had evidence of bacteremia and were being treated with antibiotics, and three were receiving empiric anti-fungal therapy with amphotericin B. Five patients experienced neutropenic fever at the time of liver abnormalities, but were treated successfully. Five patients underwent imaging studies of the abdomen with an emphasis on the liver and gallbladder, with only one patient having signs suggestive of SOSVOD. There was no correlation between response and hepatic toxicity in our cohort. If we exclude the eight patients who had either bacteremia or neutropenic fever at the time of documented liver abnormalities (as these may have contributed to liver toxicity), then the incidence of direct, GO-induced liver disease would be reduced in our cohort to 31%. Table 2 summarizes essential findings in all patients who developed hepatic toxicity. Table 3 describes the radiographic findings of patients who underwent imaging studies during the time of hepatic toxicity.
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Discussion |
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Stadtmauer et al. studied the incidence of VOD in patients who underwent additional therapies such as SCT after GO administration. Six of 36 patients (17%) who underwent a transplant following therapy with GO were diagnosed with VOD [5]. While three of these died of VOD after allo-SCT, the remaining three patients resolved their disease. Although the above data suggest a low incidence of VOD in the non-transplant setting, some investigators have proposed a higher incidence.
Giles et al. reported the incidence of VOD in all patients treated with GO in combination therapies who were enrolled on several clinical studies at the M. D. Anderson Cancer Center [6]. This report suggested a 12% incidence (14 of 119), despite the lack of transplant history for all patients. However, this study has some limitations. First, most patients described have received GO in combination with other cytotoxic agents, making the interpretation of these results somewhat difficult. Secondly, some patients in that report received GO at more frequent intervals than currently recommended (79 days between doses compared with the recommended 14 days). Thirdly, many of those patients had concurrent medical conditions and comorbidities, which may contribute to liver injury and damage such as sepsis and other infectious complications. These issues, as well as the fact that only two patients had a biopsy-proven VOD and that most others had liver abnormalities that could be explained by other etiologies, make the reported high percentage of VOD incidence questionable. Despite these limitations, it is worth noting that the report by Giles et al. [6
] highlighted a potential problem that requires further investigation. In contrast to that report, when analyzing our data in patients who received GO as recommended and as a single agent, only one of 47 patients had signs and symptoms that suggest, with confidence, the development of SOSVOD; this represents an incidence as low as 2%.
Recently, Rajvanshi et al. performed a retrospective analysis of all patients who received GO after SCT [7]. Twenty-three patients were studied, 11 of whom developed liver toxicity (48%). In eight of these (35%), this manifested as weight gain, hepatomegaly, ascites and jaundice; all symptoms and signs suggestive of, but not conclusive for VOD. Since all patients studied in the report had undergone a previous transplantation, it is difficult to assess whether GO as a single agent or the previous exposure to high-dose therapy and preparative regimens were the contributing factor(s) to the hepatic injury. Based on the report, it is reasonable to conclude that administering GO in patients with relapsed disease who failed previous high-dose therapy should be done with caution, and hepatic functions should be monitored frequently. In our report, six patients had undergone previous SCT (three had allo-SCT and three had auto-SCT); all of them had elevations in their liver function tests, but none had clinical evidence of SOSVOD.
In an attempt to identify major risk factors contributing to hepatic toxicity in GO recipients, Erba et al. reported a multivariate stepwise logistic regression analysis of 139 patients [13]. In the analysis, previous SCT was the factor most strongly correlated with the development of VOD, although other factors suggested possible associations, such as baseline total bilirubin and alkaline phosphatase values, baseline leukemic blasts in the bone marrow aspirate, and acetaminophen use on the day of infusion. These findings bring into question whether GO predisposes patients who undergo SCT to develop VOD or whether high-dose therapy sensitizes hepatic cells to the toxic effects of GO. Cohen and colleagues retrospectively evaluated the safety outcomes of eight patients with relapsed AML, post-SCT, who were subsequently treated with GO to the approved dosing schedule [14
]. At the time of GO treatment, five patients had de novo AML, one patient had MDS in transformation to AML, and two patients had secondary AML. Every patient had received a previous SCT and all patients except one received busulfan and cyclophosphamide as a conditioning regimen. With the exception of one patient who had an underlying graft-versus-host-disease before therapy manifesting as abnormal liver function tests, all other patients had normal hepatic function before undergoing therapy. This patient was the only one from this cohort who developed VOD and who subsequently died.
The mechanism of VOD in the setting of SCT remains unclear, although several theories exist [1517
]. It has been suggested that gluthathione depletion predisposes to hepatic injury and that free radical damage is a common denominator in the pathophysiology of this process [18
]. Pathologic findings of patients developing VOD after GO administration have been also described. Tack et al. described a case of VOD in an AML patient in second relapse receiving GO therapy [19
]; a transjugular biopsy in this patient showed hemorrhage and marked sinusoidal congestion in the centrilobular area surrounding the hepatic venules. Other pathologic findings included intimal edema in the terminal hepatic venules, periventricular fibrosis, and early fibrosis in the lumen. Others have confirmed these pathologic findings and suggested the presence of hepatocyte necrosis and phlebosclerosis [20
].
The management of VOD is generally supportive [21]. Giles et al. reported that the addition of ursodiol and steroids did not prevent VOD [22
]. Supportive care was the reported management for all cases, which to date remains the standard approach to VOD. Some have suggested anti-thrombotic therapy to manage VOD in association with GO treatment, but no clear value to such an approach has been demonstrated [23
]. It is acceptable to say that the approach to this syndrome should be to maximize supportive care, to exercise extreme caution in fluid management, to avoid hepatotoxic drugs, and to prevent and treat any infectious process that could worsen the hepatic injury. Despite best supportive measures, this disease can result in encephalopathy, renal failure, pulmonary compromise, and multiorgan failure. Unfortunately, severe VOD is often fatal within several weeks of onset [24
, 25
].
This report has significant value as it reassures physicians and patients that the hepatic toxicity with GO is reversible and manageable if the drug is used as indicated. The SOSVOD phenomenon reported with this agent is a real and well documented one, but is not as common as might be thought, and careful follow up and monitoring could aid in early detection. However, our report has some limitations. The sample size is relatively small and the majority of our patients were enrolled on clinical trials, potentially contributing to selection bias. Subtle or subclinical SOSVOD may have been missed, as imaging studies were not performed on every patient, but rather on those who did not improve after conservative therapy or who had a compelling reason to undergo radiographic evaluation. We suggest that the administration of GO at the recommended dose and schedule can be accomplished safely with minimal reversible hepatic toxicity when used as a single agent, especially in patients who have not had previous transplantation. When combined with other agents, the dose may need to be altered, but this should only be done in the context of a well designed clinical trial. Such combination therapies are currently under investigation. Also, the median time required to note an elevation in liver function was 14 days, suggesting that this might be a crucial period where more frequent monitoring is needed to eliminate potential worsening toxicity. Choosing patients who are good candidates for GO therapy remains crucial, and stopping therapy at the first sign of hepatic injury could reduce further liver damage. Additional studies are still needed to understand better the pathophysiology of this injury and to identify patients who are at high risk.
Received for publication February 4, 2004. Revision received March 29, 2004. Accepted for publication March 30, 2004.
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