Disease-specific complications of chronic lymphocytic leukemia in binet stage a patients

Disease-specific Complications of Chronic Lymphocytic Leukemia in
Binet Stage A Patients: Analysis of Immunodeficiency, Autoimmune
Constellations and Infections in the CLL1-Protocol. Summary
Background Most patients in early stages of chronic lymphocytic
leukemia (CLL) present no disease-related defects such as
hypogammaglobulinemia, impaired cellular immunity or neutrophil
function. Therefore, the standard therapy for patients in early
stages is to date only observation without treatment with
chemotherapeutic agents. Fludarabine is the best studied purine
analogues as well as a very effective drug for the treatment of
CLL. Therefore, the CLL-1 study was designed to examine whether an
early therapy with fludarabine for patients in early stages could
bring clinical benefits, mainly in terms of response and survival.
In this study, the incidence of various complications was evaluated
and analyzed, whether the therapy with fludarabine in patients in
early stages caused more complications. Methods The patients were
assessed in terms of their progression risk through bone marrow
histology (infiltration type), lymphocyte doubling time (LDT),
serum thymidine kinase level and the serum-ß2-microglobulin level.
The combination of a non-nodular bone marrow infiltration type or a
LDT 7 U/l or a
serum-ß2-microglobulin >3.5 mg/l indicates a high progression
risk. Patients with high progression risk would be randomized into
the treatment arm or the “watch and wait” arm. Patients in the
treatment arm (cohort I) received fludarabine i.v. (25 mg/m2/day 5
days long, cycle repeat on day 28, maximum 6 cycles), whereas
patients in the “watch and wait” group (cohort II) were only being
observed. The third group, consisting of patients with low
progression risk according to the definition above (cohort III) was
also only being observed. 98 patients were randomized into cohort I
(also called HR-F) and 95 patients into cohort II (also called
HR-WW). . 535 patients were observed in the cohort III Results The
incidence of infections and serious infections was higher in cohort
I than cohort II & III (41.5% vs. 30.4% and 30.9%, 6.1% vs.
2.5% and 2.4%), although serious infections were rarely observed.
The incidence of infection showed no difference between patients in
the observation arms, regardless of the risk of progression (cohort
II: 30.4%, Cohort III: 30.9%). The most common spectra were viral
(39.8%) and bacterial (36.1%) infections, fungal infections were
rare (1.5%). Respiratory tract and soft tissue were the most common
sites of infection. In the analysis of risk factors for infection,
the serum creatinine can be regarded as the best risk factor in our
study. In addition, alkaline phosphatase, IgA, IgG, IgM,
splenomegaly, low LDH, and low platelet count can be regarded as a
risk factor for infection. Our data show a trend for the hypothesis
that the risk of infection is higher in patients treated with
fludarabine. The overall incidence of AIHA and AITP in all study
arms was evaluated as follows; AIHA Cohort I: 6 patients (6.8%),
cohort II: 4 patients (4.8%), cohort III: 9 patients (2.0%), AITP
Cohort I: 19 patients (21.8%), cohort II: 3 patients (3.6%), cohort
III: 15 patients (3.1%). Through this study, we observed that
patients who received fludarabine therapy (cohort I), had a higher
incidence of AIHA and AITP than in the other study arms. Conclusion
This study shows a trend for the hypothesis that the risk of
infections in patients treated with fludarabine is higher. In
addition, the serum creatinine in our study is considered to be the
best risk factor for infection. The analysis of the incidence of
AIHA and AITP also shows that the risk of autoimmune complications
is increased with fludarabine therapy.