A Randomized Study in Non-Hodgkin's Lymphoma Patients Carrying Hepatitis B Surface Antigen
A Randomized Study in Non-Hodgkin's Lymphoma Patients Carrying Hepatitis B Surface Antigen
* AIMS OF THE STUDY (STUDY OBJECTIVES)

 1. To test the effect of daily lamivudine (100 mg) in reducing the risk of HBV reactivation
 and hepatitis development in HBsAg (+) NHL patients.

 2. To test the efficacy of daily lamivudine in preventing and treating hepatitis B
 reactivation and in circumventing hepatic failure and death.

 3. To test whether lamivudine can improve the overall outcome of NHL patients who are HBV
 carriers.

 (Study end-points: The major end-point: hepatitis B reactivation in NHL patients---defined by
 higher than 10-fold increase of serum HBV DNA level and/or reappearance of HBeAg in the serum
 during and within 6 months after chemotherapy. The minor end-point I : events of hepatic
 failure and death---defined by jaundice with hepatic encephalopathy. The minor end-point II:
 the response rate and survival rate in HBsAg-positive NHL patients receiving lamivudine
 prophylaxis and treatment.)
-  TREATMENT PLANS

 1. Systemic chemotherapy with CHOP regimen Schedule and Dose for CHOP Cyclophosphamide
 750 mg/m2 i.v. Day 1 Doxorubicin 50 mg/m2 i.v. Day 1 Vincristine 1.4 mg/m2/d i.v.
 Day 1 Prednisolone 60 mg/m2/d p.o. Day 1-7 1.1 Courses will be repeated every 21
 days. 1.2 For patients with CR, give at least 2 additional courses for a minimum of
 6 courses.

 1.3 For patients with maximal response as PR or SD, change to second-line
 chemotherapy. The regimens for second-line chemotherapy are at the discretion of
 the investigators. Local radiotherapy is allowed for residual localized 1.4 For
 patients with PD, change to second-line chemotherapy. The regimens of the latter
 are at the discretion of the investigators.

 2.1 Arm I Patients take lamivudine 100 mg P.O. qd, starting from Day 1 of the first
 course of CHOP, and until 2 months after the completion of chemotherapy. Lamivudine
 is to be maintained no matter hepatitis occurred or not during chemotherapy. If
 second-line chemotherapy is used, lamivudine with the same dose and schedule will
 be continued until 2 months after completion of the second-line chemotherapy.

 If third-line chemotherapy is needed, the use of lamivudine will be at the 2.2 Arm
 II Patients are treated with CHOP alone. If the patients develop clinical
 hepatitis, as defined in section 7.2, lamivudine 100 mg, P.O., qd., will be given,
 and continued until hepatitis is resolved. Prophylactic lamivudine is not to be
 given in subsequent chemotherapy. (Our previous study has indicated that nearly all
 clinical hepatitis developed in HBV carriers during systemic chemotherapy is caused
 by HBV reactivation. Therefore, for practical reason, the investigators are not
 advised to wait for the results of HBV DNA serology examination before starting
 lamivudine treatment. )

 3.0 DOSE MODIFICATION 3.1 Hematological Toxicity* Drug administration is postponed
 if there is no full hematological recovery (AGC > 2,000/mm3 and Platelet >
 100,000/mm3 ) from prior course at scheduled treatment day. Full doses will be
 given as soon as the hematological recovery is documented. If two weeks after the
 due day recovery is still incomplete, the treatment may be started and the dosage
 be reduced according to the following

 schedule:

 AGC*/mm3Platelet/mm3 1,500-2,00075,000-100,000 1,000-1,49950,000-74,999
 <1,000<50,000 Cyclophosphamide 80% 60% ** Doxorubicin 80% 60% **

 -  G-CSF is allowed to be used prophylactically for older ( > 60 years old) patients and
 for patients with previous or ongoing prolonged myelosuppression.

 -  Postpone for another week. If the counts remain AGC<1,500 or Platelet <75,000 three
 weeks after the due day, patients should be off study.

 3.2 Hepatotoxicity For patients with normal prechemotherapy serum ALT, hepatitis flare-up is
 defined as ALT elevation greater than 1.5 fold of upper normal limit. For patients with
 abnormal prechemotherapy serum ALT, hepatitis flare-up is defined as 2.0 fold or greater
 increase of serum ALT level. The hepatitis or hepatitis flare-up is attributed to
 reactivation of HBV when there is a sudden elevation (>10-fold) in serum HBV DNA level or
 reappearance of HBV DNA and/or HBeAg in the serum.

 Since results of our previous study has indicated that nearly all clinical hepatitis
 developed in HBV carrier during chemotherapy is caused by HBV reactivation, and serum HBV DNA
 data are not readily available in most hospitals, all patients with hepatitis flare-up are
 considered HBV reactivation until proved otherwise. For patients in the second arm,
 biochemical hepatitis will prompt a start of daily lamivudine, even before a definite
 documentation of 10-fold increase of HBV DNA. For patients with only minor hepatic
 dysfunction (total bilirubin <3.0 mg/dl and ALT <200 I.U./L), full-dose chemotherapy is
 recommended on the scheduled treatment day without delay. For patients with more severe
 hepatic dysfunction (total bilirubin ≧ 3.0 mg/dl or ALT ≧ 200 I.U./L), subsequent course is
 postponed for 1 week and the dosage modified as followings if the values remain abnormal
 after 1 week:

 Total Bilirubin (mg/dl) <3.0 3.0 ~ 4.9 5.0 ~ 7.5 >7.5 ALT (I.U./L) <200 200 ~ 399 400 ~ 800
 >800 Doxorubicin 100% 75% 50% *

 -  Wait until recovery with serum levels below these values. Patients will be off study if
 Bil > 7.5 mg/dl or ALT > 800 I.U/L, 3 weeks after the due day.

 3.3 Gastrointestinal Toxicity In case of severe (≧ NCI Gr III) anorexia, nausea, vomiting,
 diarrhea, stomatitis or abdominal pain, all therapy should be delayed until improvement of
 symptoms to ≦ GrII.

 Patients will be off study if ≧ Gr III toxicity persists ≧ 3 weeks after due day. Patients
 are allowed to use H3-blockers in the subsequent courses for severe nausea and vomiting. If
 gastrointestinal toxicity is still ≧ Gr III during the next course, doses of cyclophosphamide
 and doxorubicin should be reduced by 25% in the subsequent courses. If no further episodes of
 severe reaction, the doses can be escalated, 12.5% each time, and back to 100%.

 3.4 Cardiotoxicity In case of NCI grade II cardiotoxicity, doxorubicin should be reduced by
 50%. If cardiotoxicity is resolved, the dose may be carefully deescalated, 12,5% each time,
 in the subsequent courses. If severe (≧ NCI grade III) cardiotoxicity develops, doxorubicin
 should be discontinued and should not be used again in the subsequent courses.

 3.5 Multiple Toxicity In the event of multiple toxicity, dose modification should be based on
 the guideline that requires the greatest reduction of doses.

 4.0 CRITERIA FOR REMOVAL FROM STUDY

 All patients who are still under or have completed protocol treatments (1st-line or 2nd-line)
 should be continuously followed-up for all study end points. Patients are removed from study
 if they have major violation of the protocol due to the following reasons:

 1. Completion of assigned therapy and observation.

 2. Progressive of disease.

 3. Excessive of complication or toxicity.

 4. Patient death.

 5. Patient withdrawal or refusal.

 5.0 MEASUREMENT OF EFFECT ： Authorized physicians or research nurses must call Ms. Yueh-Ling
 Ho at the TCOG Operations Office (Tel: 02-26534401 ext 6655) for patients registration and
 randomization.

 A permuted block randomization will be used to generate the list by the Statistical Center
 housed at the Division of Biostatistics, NHRI. Treatment assignment is given only when the
 patient passes the eligibility check.

 6.0 REPORT OF ADVERSE EFFECT : Adverse effect of treatments should be reported to TCOG
 Operations Office at 02-26534401 ext 6655, 6657, 6658 and FAX: 02-2782-3755, within 48 hours.
 See appendix for the TCOG ADR (Adverse Drug Reaction) Form of reporting adverse effect.
-  Inclusion Criteria:

 1. Histologically proven NHL, and for which intensive chemotherapy is considered
 treatment-of-choice.

 2. HBsAg-positive.

 3. No previous chemotherapy and radiotherapy, no concurrent radiotherapy.

 4. AGC ≧ 2,000/mm3, Platelet ≧ 100,000/mm3 of peripheral blood.

 5. Total bilirubin < 2.5 mg/dl. Alanine aminotransferase (SGPT) < 200 I.U./L

 6. Serum creatinine ≦1.5 mg/dl Blood urea nitrogen (BUN) ≦ 25 mg/dl

 7. Objectively measurable or valuable disease

 8. Signed informed consent

 -  Exclusion Criteria:

 1. Age > 75 years old, or Age < 15 years old

 2. Pregnant or breast-feeding women.

 3. Patients with history of brain metastasis or CNS involvement.

 4. Child's class B or C in patients with liver cirrhosis.

 5. Impaired cardiac function with NYHA (New York Heart Association) classification ≧
 Gr II.