Lamivudine allows completion of chemotherapy in lymphoma patients with hepatitis B reactivation
Federico Silvestri Division of Haematology, Department of Bone Marrow Transplantation, University Hospital, P. le S. Maria della Misericordia, 33100 Udine, Italy.
Reactivation of hepatitis B virus in patients receiving chemotherapy for non-Hodgkin's lymphoma (NHL) may give rise to hepatitis, hepatic failure and death, and prevent further chemotherapy. We report four patients with NHL in whom hepatitis flare-up was observed after two (three patients) and six (one patient) cycles of chemotherapy. After spontaneous recovery, they were treated with Lamivudine (100 mg/day), which enabled completion of chemotherapy without further hepatitis B reactivation. In one patient, high-dose chemotherapy and autologous stem cell transplantation was also performed. These data suggest a possible role for Lamivudine in preventing hepatitis B reactivation during chemotherapy administration to chronic carriers of the hepatitis B virus. Moreover, it enabled the completion of both standard and high-dose chemotherapy in patients with previous hepatitis B reactivation.
Reactivation of hepatitis B virus (HBV) is a well-known complication in patients receiving cytotoxic treatment for non-Hodgkin's lymphoma (NHL) ( Lau et al., 1989 ; Liang et al., 1990 ; Lok et al., 1991 ; Soh et al., 1992 ).
An immunomediated mechanism has been hypothesized for liver damage: chemotherapy depresses the immune system, leading to enhanced viral replication and an increased number of infected hepatocytes. The restoration of immune function, which follows withdrawal of the drugs, results in partial restoration of immunocompetence with subsequent rapid destruction of infected hepatocytes as a result of a T-cell-mediated mechanism.
This may give rise to a clinical picture of acute hepatitis, and even to hepatic failure and death ( Lau et al., 1989 ; Liang et al., 1990 ; Lok et al., 1991 ; Soh et al., 1992 ).
Hepatitis reactivation may prevent subsequent chemotherapy. Moreover the oncohaematological disease may require not only standard treatment, but an intensified programme with high-dose chemotherapy and autologous stem cell transplantation (ASCT): this programme can be stopped by hepatitis flare-up, reducing the chance of cure for these patients.
Taking all these considerations together, it is evident that the availability of a drug that is effective in suppressing HBV replication, protecting HBV carriers against chemotherapy-induced hepatic failure and allowing completion of chemotherapy programmes is greatly needed.
The recent availability of Lamivudine, a reverse transcriptase inhibitor approved for antiviral therapy in HIV infection, seems to accomplish this need.
Here, we report our experience with the use of this drug in four NHL patients with hepatitis reactivation during chemotherapy.
PATIENTS, METHODS AND RESULTS
From January 1997, four patients affected by NHL (mantle cell, follicle centre grade III, peripheral T-cell unspecified and diffuse large B-cell respectively) and carriers of HBV infection were submitted to chemotherapy at our institution (all data are reported in 1 Table I).
Table 1. Table I.
Clinical characteristics and course of the patients. *MCL, mantle-cell lymphoma; FCL, follicle centre lymphoma, grade III; PTCL-U, peripheral T-cell lymphoma, unspecified; DLCL, diffuse large B-cell lymphoma.†Days after the end of last therapy.‡UI/l.§This patient was then submitted to autologous stem cell transplantation.
All were male, aged 39, 47, 52 and 62 years respectively, HCV and HIV negative. In all patients, pretreatment HBV serology was as follows: HBsAg positive, HBeAg negative, total anti-c Ab positive, IgM anti-c Ab negative, anti-e Ab positive, anti-s Ab negative.
Three of them (patients 1, 2 and 3) were treated with the third-generation F-MACHOP regimen ( Infanti et al., 1996), whereas the oldest (patient 4 ) was treated with the classic CHOP regimen.
Hepatitis B reactivation was observed after two cycles of chemotherapy in three out of four patients, and after the sixth cycle in patient 1.
Transaminase increase was observed after a median of 20 (16–30) days from the end of the previous cycle of chemotherapy and reached a peak after a median of 41 (27–60) days, respectively 1523 (430–2820) UI/l for AST and 1317 UI/l (960–2950) for ALT.
HBV-DNA, detected using nested polymerase chain reaction (PCR) as described by Kaneko et al. (1990 ), was negative before starting chemotherapy and became positive in all four patients (measured after the increase but before the peak in transaminase levels) at a median of 26 (19–34) days after the previous cycle of chemotherapy.
All patients recovered without specific therapy with transaminase normalization at a median of 67 (43–100) days; also HBV-DNA spontaneously reverted to a negative result.
In the three patients who were to complete chemotherapy, Lamivudine (Epivir; Glaxo-Wellcome, 100 mg/day) was then started (in two of them before complete transaminase normalization), and chemotherapy resumed: the third cycle (the first after hepatitis flare-up) was given at 50% of the dose to test for toxicity. All three patients subsequently completed the three remaining cycles at full dose intensity without showing any signs of hepatic toxicity.
In patient 1, after transaminase normalization, a peripheral blood stem cell (SC) collection was performed after priming with granulocyte colony-stimulating factor (G-CSF); the patient was then started on Lamivudine and, after 20 days, conditioned with BAVC (cytosine arabinoside 150 mg/m2 twice daily, etoposide 150 mg/m2 twice daily and cyclophosphamide 45 mg/m2 once daily from day −5 to day −2, and carmustine 200 mg/m2 on day −4) before reinfusion. His haematological recovery overlapped that of our other patients with NHL submitted to autologous SC transplantation (data not shown).
In all four patients, Lamivudine was continued for 4–6 months after the end of the last chemotherapy course. During the follow-up period, they were monitored with twice-monthly blood counts, transaminase levels and HBV-DNA: all these parameters remained normal/negative throughout the period.
Currently, patient 1 is in complete remission (CR) 28 months from diagnosis and 20 months after transplantation; patient 2 is in CR 14 months from diagnosis and 8 months after the end of chemotherapy; patient 3 is in partial remission 17 months from diagnosis and 8 months after the end of chemotherapy. He underwent a G-CSF-primed bone marrow harvest and will soon resume Lamivudine treatment before conditioning for autologous SC transplantation. Patient 4 is in CR 18 months from diagnosis and 8 months after the end of chemotherapy.
It is not an unusual problem in clinical practice to face a patient who is a carrier of HBV infection and needs standard chemotherapy. Moreover, in the last few years, even more intensive treatment with high-dose chemotherapy and autologous or allogeneic SC transplantation has been widely used in patients with oncohaematological diseases, either for consolidation of remission or as a salvage treatment. A clinical picture resembling that of acute hepatitis and even fatal fulminant hepatitis caused by HBV reactivation have been reported in cases of HBsAg chronic carriers undergoing either standard or high-dose chemotherapy ( Lau et al., 1989 ; Liang et al., 1990 ; Lok et al., 1991 ; Soh et al., 1992 ).
Among the several proposed methods for completion of chemotherapy programmes in such a patients, the use of Lamivudine seems the best available option at the present time.
This drug suppresses HBV replication by incorporation of its monophosphate form into DNA, which results in chain termination ( Dienstag et al., 1995 ); it was shown to be superior to Famciclovir in terms of HBV-DNA reduction and response in the treatment of chronic HB infection ( Lai et al., 1998a ); and, last but not least, it is devoid of side-effects, particularly those that affect haematopoiesis.
It has also been reported to be effective in the management of HBV reactivation after intensive chemotherapy for NHL ( Clark et al., 1998 ) and of HBV infection after allogeneic bone marrow transplantation ( Picardi et al., 1998 ) but, to our knowledge, its use for the completion of chemotherapy and ASCT has been described in only one case ( Al-Taie et al., 1999 ).
In the report by Al-Taie et al. (1999 ), as in three of our four patients and in two of the four described by Lau et al. (1989 ), HBV reactivation was observed after the first two cycles of chemotherapy, with transaminase increase recorded approximately 3 weeks after its administration. This observation suggests that Lamivudine should be introduced at the beginning of chemotherapy administration to prevent early HBV reactivation. Nevertheless, our experience clearly indicates that, once hepatitis flare-up has occurred, the drug prevents a second reactivation, allowing completion of chemotherapy and even the administration of high doses of chemotherapy.
The optimal duration of therapy has not been established yet, but it can be speculated that, on the one hand, it should be long enough to prevent hepatitis relapses but, on the other hand, it should be suspended quite rapidly to avoid the development of resistance as a result of virus mutations. In our experience, the administration of Lamivudine for 4–6 months after the last chemotherapy cycle accomplished these needs with both transaminase and HBV-DNA levels being normal/negative respectively, throughout the follow-up period.
To this end, it should also be stressed that detection of HBV-DNA (using qualitative PCR if previously negative, or by quantitative assay if previously positive) is required, together with increased transaminase levels, to define hepatitis related to HBV reactivation, as opposed to drug toxicity or other causes.
Also, the optimal dose of Lamivudine for patients receiving chemotherapy has not yet been established. Nevertheless, in our hands, a daily dose of 100 mg, as shown to be the optimal dose in the treatment of chronic hepatitis B ( Dienstag et al., 1995 ; Lai et al., 1998b ), was very effective in preventing second HBV reactivation.
In conclusion, our data suggest a possible prophylactic role for Lamivudine in preventing hepatitis B reactivation during standard and high-dose chemotherapy in patients with NHL.
We suggest that Lamivudine should be administered from the beginning of chemotherapy to patients who are HBsAg positive with or without detectable HBV-DNA. At the moment, the optimal dose and duration of therapy suggested are 100 mg/day for up to 4–6 months after the end of the last chemotherapy cycle. Moreover, in HBV chronic carriers submitted to chemotherapy and with HBV reactivation, the use of Lamivudine enables completion of chemotherapy and even administration of high-dose chemotherapy followed by autologous stem cell transplantation.