Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies.

Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with hematological malignancies receiving chemotherapy. We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase >ten times the normal upper limit and total bilirubin >5 mg/dl) during chemotherapy in 268 patients with hematological malignancies. Eight patients (3.0%) were infected with HBV and 22 patients (8.2%) were infected with HCV. One patient (0.4%) was infected with both HBV and HCV. HBV- or HCV-infected patients showed severe liver dysfunction at a significantly higher incidence than non-infected patients (11/31 (35.5%) vs. 0/237 (0%), p<0.0001). Furthermore, the incidence of severe liver dysfunction in HBV-infected patients was significantly higher than in HCV-infected patients (6/8 (75.0%) vs. 4/22 (18.2%), p<0.01). Three of eight HBV-infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV-DNA by polymerase chain reaction (PCR). Although post-transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Since HBV-infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV-infected patients before chemotherapy for hematological malignancies, it is recommended that HBV-DNA should be tested by PCR to detect HBV marker-negative carriers and liver function tests should be carefully monitored.

Fulminant hepatitis type B after chemotherapy in a serologically negative hepatitis B virus carrier with acute myelogenous leukemia.

We report a case of a 41-year-old man with acute myelogenous leukemia who developed fulminant hepatitis from reactivation of trace hepatitis B virus (HBV) 2 months after complete remission. Although he became positive for HB surface antigen at the onset of fulminant hepatitis, he had been negative for HBV serum markers, and only HBV DNA was detected by polymerase chain reaction (PCR) amplification on admission. The original stocks of serum samples from all blood donors were tested again for HBV DNA by PCR, and all samples were negative. This case demonstrates that testing for HBV DNA by PCR is necessary before chemotherapy, because silent HBV carriers are rare and fulminant hepatitis may be induced by chemotherapy in patients with hematologic malignancies.

Effect of Interferon-α on Patients with Previously Untreated Chronic Myelogenous Leukemia in the Early Chronic Phase: Comparison between Interferon-α Continued Patients and Interferon-α Discontinued Patients.

In order to confirm the effect of interferon-α (IFN-α) in inducing a prolonged duration of the chronic phase (CP) on patients with chronic myelogenous leukemia (CML), we retrospectively compared the duration of CP between patients who continued on IFN-α and the patients in whom IFN-α was discontinued before the blast phase. Of the 32 patients not pretreated for CML in the early CP who received IFN-α therapy, 25 continued on IFN-α while seven discontinued the therapy (side effects, 5; resistance, 1; patient's refusal, 1). Only four of the 25 patients in whom IFN-α was continued (16.0%) progressed to the blast phase or accelerated phase, but six of the seven patients who discontinued IFN-α (85.7%) progressed to the blast phase or accelerated phase. Fourteen of the 25 patients who continued on IFN-α therapy showed cytogenetic response (complete cytogenetic response, 3; minimal cytogenetic response, 11) whereas 11 patients showed no cytogenetic response. However, non-responders showed a longer duration of CP than the patients whom IFN-α was discontinued. Although elderly patients showed a high incidence of side effects, and some patients progressed early after the beginning of IFN-α therapy, our data clearly demonstrated that in accordance with previous large multi-centric randomized studies the continuation of IFN-α, even in low doses, prevents disease progression.

Serum-soluble c-kit levels during mobilization of peripheral blood stem cells correlate with stem cell yield.

c-Kit is expressed in hematopoietic stem cells and plays an important role in hematopoiesis. In 16 patients with malignancies, serum-soluble c-Kit levels and the expressions of c-KIT messenger RNA (mRNA) and protein in peripheral blood mononuclear cells were analyzed serially during 26 courses of peripheral blood stem cell (PBSC) mobilization after granulocyte colony-stimulating factor administration following chemotherapy for PBSC harvest. Serum-soluble c-Kit levels were significantly lower in patients than in controls (179.7+/-17.7 arbitrary units [AU]/mL versus 274.5+/-18.9 AU/mL; P < .001), decreasing after chemotherapy (167.7+/-18.2 AU/mL), increasing from day 14, and peaking at day 19 (193.3+/-16.4 AU/mL). The numbers of both c-Kit+ cells and CD34+ cells and granulocyte-macrophage colony-forming units in peripheral blood peaked at day 17, following the peak of the expression of c-KIT mRNA. Serum-soluble c-Kit levels showed a significant positive correlation with the numbers of CD34+ cells in both peripheral blood and leukapheresis products (r = 0.553, P < .01, and r = 0.640, P < .001, respectively) and changed at higher levels in patients with large numbers of PBSCs versus patients with small numbers of PBSCs (P < .05). Serum-soluble c-Kit may reflect the capacity for hematopoiesis after chemotherapy and may be useful in predicting the number of PBSCs that can be mobilized and harvested after mobilization, as well as for monitoring the timing for PBSC harvest.

Liver dysfunction in patients with acute myelogenous leukemia: studies on patients not infected with hepatitis C virus during intense therapy.

Liver dysfunction often occurs during chemotherapy for AML, but the etiologies are many and varied. To determine liver dysfunction that is not related to HCV, liver function during intense therapy for one week after complete remission was studied in eight patients not infected with HCV (38 courses) and six HCV-infected patients (19 courses) with AML. There were remarkable differences in changes of ALT levels among HCV-infected patients. ALT level changes among patients not infected with HCV were similar. Changes in mean serum ALT levels in HCV-infected patients occurred at higher serum levels as compared with those in patients not infected with HCV. The mean serum ALT levels in patients not infected with HCV significantly increased at one week (45 +/- 5 IU/l) and further increased at two (58 +/- 8 IU/l) and three weeks (57 +/- 5 IU/l) as compared with pretreatment levels (24 +/- 21 IU/l) (p < 0.001, p < 0.001, p < 0.0001, respectively). ALT levels returned to normal at four weeks. During 31 of 38 courses (81.6%) in patients not infected with HCV, febrile episodes occurred at three weeks. The mean serum ALT levels in patients with febrile episodes were significantly higher than those in patients without febrile episodes at three weeks, and serum ALT levels at three weeks showed a significant positive correlation with CRP levels at three weeks. These findings indicate that liver dysfunction during chemotherapy for AML is due to hepatocellular injury, and infection or inflammatory cytokine induced by infection results in the worsening of the liver dysfunction.

Serum soluble c-kit receptor and expression of c-kit protein and mRNA in acute myeloid leukemia.

To investigate the clinical role of the soluble form of c-kit receptor (s-kit) in patients with acute myeloid leukemia (AML), we determined the levels of serum s-kit and expression of c-kit antigens and mRNA in leukemic cells. The serum s-kit level was measured using ELISA assay in 30 AML patients and 20 normal controls. C-kit antigens of leukemic blasts were stained immunohistologically, and c-kit mRNA was detected by RT-PCR. The serum s-kit level in M1 and M2 were significantly increased (p<0.01) and that in M4 or M5 was significantly decreased (p<0.05) compared to that in the controls. In the comparisons among subtypes of FAB classification, M1 and M2 showed significantly higher levels than M4 or M5 (p<0.05 and p<0.01, respectively). Both expression of c-kit antigens and mRNA were observed in M0 (1/4), M1 (2/4) and M2 (6/8), but neither was observed in M4 or M5. The serum s-kit levels were correlated with the absolute number of AML blasts in peripheral blood (r=0.564, p<0.05). These results indicate that the serum s-kit level is related to the stage of differentiation of AML blasts in accordance with the expression of c-kit protein and mRNA in AML blasts, and is useful for assessment of leukemic cell burden.