Outcomes in hepatitis C virus seropositive lymphoma and myeloma patients after autologous stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is the cornerstone therapy for many hematological disorders. Advances in HSCT with better supportive care and earlier referral for HSCT have led to an increase in the number of patients undergoing HSCT. However, the post-HSCT period is often accompanied by infections and complications involving the liver, the lungs and the hematopoietic system.

The prevalence of hepatitis C virus (HCV) in cancer patients varies with different cancers, ranging from 1.4 to 32%.1, 2, 3 Overall in the pre-HSCT patient population with hematological malignancies, the prevalence of HCV is around 6%.3

The common HSCT-related causes of liver dysfunction are conditioning-regimen hepatotoxicity, toxicity due to antibiotics or antifungal drugs and virus reactivation. Advances in treatment of hematological malignancies with monoclonal antibodies, chemotherapeutic drugs and HSCT have led to an increased incidence of acute exacerbation (AE) and reactivation of hepatitis in HCV patients.4, 5 Several HSCT studies involving HCV patients have examined early post-HSCT liver complications,6 survival post-HSCT 7 and pre-HSCT risk factors for post-HSCT liver injury.8 Most of those studies involved allogeneic-HSCT patients only, and similar studies of autologous stem cell transplantation (ASCT) recipients are scarce. In this retrospective study, we sought to determine the incidence of AE in HCV seropositive lymphoma and myeloma patients after ASCT, to identify risk factors for AE in those patient populations, and to assess the impact of HCV seropositivity on patients’ survival rates.

We retrospectively reviewed the medical records of 64 consecutive myeloma and lymphoma patients with HCV seropositivity who underwent ASCT at The University of Texas MD Anderson Cancer Center between August 1997 and March 2013. The study protocol was approved by the institutional review board of The University of Texas MD Anderson Cancer Center. A waiver of informed consent was obtained. HCV viral load was measured in majority of the patients before ASCT. Post-ASCT viral load was measured in patients whose post-ASCT alanine transaminase (ALT) level was more than twice the pre-ASCT ALT level. After ASCT, the patients were followed every 3–6 months to assess the response of their primary malignancy to the ASCT, and during each visit liver function tests were performed.

The primary endpoint of the study was the cumulative incidence of AE, estimated by considering death or progression of the underlying malignancy before the occurrence of AE as competing risks. Secondary endpoints included overall survival (OS), PFS and non-relapse mortality (NRM). Survival time was estimated from the date of transplant until the date of death or the date of last follow-up date (November 2013) for censored observations. Actuarial OS and PFS were estimated using the Kaplan–Meier method. The cumulative incidence of NRM was estimated by considering progression of the underlying malignancy or death due to malignancy as competing risks. The impact of AE on OS was assessed on univariate analysis considering AE as a time-dependent variable using Cox proportional hazards regression analysis. Cox regression univariate analysis was also used to assess predictors of AE. Statistical significance was defined at the 0.05 level. Statistical analysis was performed using Stata11 software (Stata Corp., Stata Statistical Software: Release 11, College Station, TX, USA).

Characteristics of and risk factors for AE of HCV seropositive patients at 1 year and at last follow-up post-ASCT are listed in Table 1. No cases of veno-occlusive disease occurred in the 64 ASCT patients. Median follow-up in surviving patients was 19 months (range, 3–172). During this period, AE defined as a threefold or greater increase in serum alanine aminotransferase level from the pre-ASCT value,4 was diagnosed in 20 patients (31%). Median time to have AE was 87 days from the date of conditioning regimen. The cumulative incidences of AE, 1 year after ASCT, 2 years after ASCT, and at the time of last follow-up were 26%, 28%, and 38%, respectively. Univariate analysis showed that patients who were older than 60 years at the time of ASCT were marginally more likely to experience AE with a hazard ratio (HR) of 2.6 (95% confidence interval (CI): 0.99–6.9; P=0.05) than patients 60 years of age or younger. Assessed as a time-dependent variable, AE was not found to affect 2-year OS (HR: 1.5; 95% CI: 0.5–4.3; P=0.5).

Table 1 Assessment of potential risk factors for AE of HCV seropositive patients at 1 year and at last follow-up post ASCT

Pre- and post-ASCT viral loads were known for 31 (48%) patients. Five of the 31 patients could not be evaluated because either their pre- or post-ASCT viral count exceeded the maximum quantification range of the laboratory method used. Of the 26 patients whose pre- and post-ASCT viral counts could be compared, four patients (15%) had reactivation of HCV, defined as an HCV viral load increase of at least 1 log10 IU/mL over baseline viral load measured before ASCT.4 The median viral load change post ASCT for the four patients was 1.23 log10 IU/mL (range 1.11–1.47). Three of the four patients also had AE at the same time.

In the cohort of 64 patients, the actuarial 2-year OS rate was 65% (95% CI: 49–76%), and the actuarial 2-year PFS rate was 46% (95% CI 32–59%). The median OS duration in the myeloma group was 54 months, and the median PFS duration was 22 months. The 2-year OS and PFS rates for chemosensitive (complete or partial response) lymphoma patients (non-Hodgkin lymphoma (NHL) and Hodgkin disease) were 64% (range 41–80%) and 47% (range 27–64%), respectively. The 2-year OS and PFS rates for chemoresistant patients (stable or progressive disease) were 80% (range 20–97%) and 30% (range 1–72%), respectively. Overall, the cumulative incidence of NRM in the 64 patients was 5% (95% CI: 2–16%) at 2 years after ASCT and 12% (95% CI: 5–29) at the time of last follow-up. There were no cases of fulminant hepatic failure.

Fourteen patients were known to be treated for HCV before they came to our institution for ASCT. Out of them six had a sustained viral response, defined as aviremia 24 weeks after completion of antiviral therapy for HCV at the time of ASCT.9 After ASCT, five patients (three with NHL, and one each with Hodgkin disease and myeloma) received treatment for HCV with interferon alone or in combination with ribavirin. Two of the five patients completed post-ASCT treatment for HCV, and one of the two patients had a sustained viral response.

The survival rates post ASCT for both HCV seropositive myeloma and lymphoma patients in our study were similar to the previously reported survival rates of HCV seronegative myeloma,10, 11 lymphoma patients12, 13, 14 and to our own published historical data.13, 14 The median OS and PFS durations of 54 months and 22 months, respectively, for HCV seropositive myeloma patients were similar to those reported for HCV seronegative myeloma patients post ASCT.10, 11 Likewise, the 2-year OS and PFS survival rates of 64% (range, 41–80) and 47% (range, 27–64), respectively, in HCV seropositive chemosensitive lymphoma patients in our study are similar to those reported for HCV seronegative lymphoma patients post ASCT.12, 13, 14

To our knowledge, ours is the largest study until now reporting survival rates of HCV seropositive lymphoma and myeloma patients post ASCT, and the first study evaluating risk factors for HCV AE in ASCT patients. The AE rate in our study was 31%, comparable to the 16–36% rate5 reported in another study. Differences in AE rates may be due to the lack of standardized definitions of AE, variations in molecular testing for virus detection, and/or changes in immunosuppressive therapy or conditioning regimens over time. However, the previous study did not evaluate risk factors for AE or report OS or PFS data for HCV seropositive ASCT recipients. Also, ours is the only study to focus exclusively on ASCT patients. Ozdogan et al.8 identified risk factors for post-ASCT liver injury, but that study included both autologous- and allogeneic-ASCT patients, and the risk factors for post-ASCT liver injury were not evaluated separately for the two groups.

No cases of fulminant hepatic failure occurred in our patients. It is a rare complication of ASCT, and some but not all studies have reported cases of fulminant hepatic failure after ASCT in HCV-infected patients. In one multicenter study from Italy,5 only one of 36 HCV seropositive transplant patients had fulminant hepatic failure, and in the study by Sperotto et al.15 none of the HCV patients who underwent ASCT had fulminant hepatic failure.

In conclusion, the survival rates of HCV seropositive lymphoma and myeloma patients post ASCT was similar to the survival rate of HCV seronegative patients. Elevated pre-ASCT ALT was not a risk factor for AE of HCV. However, an enhanced awareness of AE among clinicians can help in early diagnosis and optimization of invasive diagnostic procedures. Our finding that HCV seropositive patients do as well as HCV seronegative patients post ASCT suggests that HCV seropositivity is not a contraindication for ASCT. This finding needs to be confirmed in prospective studies with larger numbers of patients.

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Correspondence to U Popat.

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Varma, A., Saliba, R., Torres, H. et al. Outcomes in hepatitis C virus seropositive lymphoma and myeloma patients after autologous stem cell transplantation. Bone Marrow Transplant 51, 999–1001 (2016) doi:10.1038/bmt.2016.28

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