Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial.

The efficacy and toxicity of cladribine (2-CdA) + prednisone (P) versus chlorambucil (Chl) + P were compared in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia (CLL) in a randomized, multicenter prospective trial. Eligible patients were assigned to either 2-CdA 0.12 mg/kg per day in 2-hour infusions and P 30 mg/m(2) per day for 5 consecutive days or Chl 12 mg/m(2) per day and P 30 mg/m(2) per day for 7 consecutive days. Three courses were administered at 28-day intervals or longer if myelosuppression developed. The therapy was finished if complete response (CR) was achieved. Of 229 available patients 126 received 2-CdA+P and 103 received Chl+P as a first-line treatment. CR and overall response rates were significantly higher in the patients treated with 2-CdA+P (47% and 87%, respectively) than in the patients treated with Chl+P (12% and 57%, respectively) (P = .001). Progression-free survival was significantly longer in the 2-CdA-treated group (P = .01), but event-free survival was not statistically different. Thirteen percent of patients were refractory to 2-CdA+P and 43% to Chl+P (P = .001). Drug-induced neutropenia was more frequently observed during 2-CdA+P (23%) than Chl+P therapy (11%) (P = .02), but thrombocytopenia occurred with similar frequency in both groups (36% and 27%, respectively). Infections were seen more frequently in the 2-CdA+P-treated group (56%) than in the Chl+P-treated group (40%; P = .02). Death rates have so far been similar in patients treated with 2-CdA (20%) and with Chl (17%). The probability of overall survival calculated from Kaplan-Meier curves at 24 months was also similar for both groups (78% and 82%, respectively). (Blood. 2000;96:2723-2729)

2-chlorodeoxyadenosine (cladribine) in the treatment of hairy cell leukemia and hairy cell leukemia variant: 7-year experience in Poland.

Between January 1991 and December 1997, 103 patients, 97 with typical hairy cell leukemia (HCL) and 6 with HCL-variant (HCL-V) were treated with 2-chlorodeoxyadenosine (2-CdA) given as 2-h infusion for 5 consecutive d at a daily dose 0.12 mg/kg. To our knowledge this is the largest cohort of HCL patients treated with this type of regimen. Median follow-up amounted to 36 months. Fifty-six of 97 patients with typical HCL were newly diagnosed and 41 were relapsed after previous treatment. Splenectomy as a first-line therapy was performed in 23 patients and 18 remaining patients received prednisone, chlorambucil or interferon-alpha (IFN-alpha) alone or in combinations. Seventy-five (77.3%) patients entered CR and 18 (18.6%) achieved PR, giving an overall response rate of 95.9%. The mean time of first CR duration amounting to 32 months (range 3-72) did not correlate to the number of 2-CdA cycles. 2-CdA was equally effective in treatment of newly diagnosed patients and patients who relapsed after previous therapeutic procedures. Relapse of the disease occurred in 20 of 75 patients who achieved CR after 2-CdA and was usually manifested by very discrete changes in peripheral blood counts (neutropenia and/or relative lymphocytosis). The mean progression-free survival (PFS) time in this group was 37.4 (range 10-66) months. Ten of 20 relapsed patients were retreated with 2-CdA given an identical course to the first one. Seven patients entered second CR lasting 19+ (range 8-47) months and 3 experienced PR. This confirms the previous observations that 2-CdA gives no resistance to leukemic clone. Ten remaining patients have not required retreatment so far and remain in a good clinical and hematological state. The results of HCL-V treatment with 2-CdA were poor. Only 2 patients achieved PR and 4 patients did not respond to this drug. Seven patients (5 with typical HCL and 2 with HCL-V) died, 3 of causes unrelated to the disease. Second neoplasms were noted in 5 patients. 2-CdA-related side effects resulted mainly from myelosuppression and infectious complications. In conclusion we confirm the effectiveness of 2-CdA in inducing CR in patients with typical HCL, but this drug is unable to completely eradicate the leukemic clone which results in the relapse of the disease. The real incidence of the relapse rate may be underestimated unless bone marrow biopsy is performed. The results of our study indicate that a 2-h infusion of 2-CdA in HCL patients is at least as effective as a 24-h infusion but more convenient to the patients, and may be given on an outpatient basis.

Comparison of seroprevalences of human herpesvirus-6 and -7 in healthy blood donors from nine countries.

BACKGROUND AND OBJECTIVES: The purpose of the study was to register antibody prevalences of HHV-7 in various locations of the world in comparison to the closely related HHV-6. MATERIALS AND METHODS: Sera of healthy blood donors from nine countries in five continents were titered by indirect immunofluorescent assays using HHV-6 infected HSB2 and HHV-7 infected SupT1 cells. RESULTS: Antibody prevalence for HHV-7 is high (75-98%) in practically all countries except for Northern Japan (44%), with no simple correlation to elevated HHV-6 antibody titers. There were regions of low, intermediate and high mean antibody titers against HHV-7 such as 78.5-91.3 for Belgium, Israel, Japan, USA and Australia, 175.4-182.6 for Mexico and Cologne/Germany, and 389.2 for South Africa for which geographic characteristics may be responsible. CONCLUSION: HHV-7, similar to HHV-6, is a widespread human herpesvirus with elevated antibody titers in the healthy human population essentially everywhere. The data warrant further studies to evaluate its possible pathologic potential, preferentially in persons with defective immune responses.

[Results of treating patients with highly malignant non-Hodgkin's lymphomas; comparison of treatment efficacy with CHOP and CBVPM-AVBP]. / Wyniki leczenia chorych na chloniaki nieziarnicze o wysokiej zlosliwosci; porównanie skutecznosci leczenia schematami CHOP i CBVPM-AVBP.

The treatment of highly of 43 patients with highly malignant non-Hodgkin lymphomas were analysed and assessed. These patients were treated at the Department of Hematology, Pomeranian Medical Academy within 1981-1990. The process was advanced in 76% of and localization of the tumour outside lymph nodes was also seen in 79%. The results of treatment with CHOP regimen used during the first 5 years were compared with CBVPM-AVBP used in 1986-1990. CBVPM-AVBP regimen proved more 4 effective (55% of the complete remissions) than CHOP regimen (37.5% of the complete remission). Mean duration of the complete remission (survival free from the relapse) was 27.5 (1-88) months. Complete remissions were easier to achieve in patients with centroblastic lymphoma in higher percentage. These patients survived longer than those with other highly malignant lymphomas. The authors conclude that further intensification of chemotherapy in case of highly malignant non-Hodgkin lymphomas is justified.

2-Chlorodeoxyadenosine (cladribine)-related eosinophilia in patients with lymphoproliferative diseases.

Eosinophilia and allergic skin reactions are uncommon events after 2-chlorodoxyadenosine (2-CdA, cladribine) administration. A multicentre retrospective analysis of eosinophilia in 360 patients treated with 2-CdA for lymphoid malignancies has been made. B-cell chronic lymphocytic leukaemia (B-CLL) was diagnosed in 153, hairy cell leukaemia (HCL) in 68, low-grade non-Hodgkin's lymphoma (LGNHL) in 119, high-grade NHL in 2 and Waldenstrom's macroglobulinaemia (WM) in 18 patients. 2-CdA was administered at a dose 0.12 mg/kg/d in 2-h intravenous infusion for 5 consecutive d. The courses were repeated monthly. Patients with HCL received 1 cycle of 2-CdA, with NHL 2-6 (mean 3.5) cycles and with B-CLL 3-6 (mean 5) cycles. Twenty patients (5.5%), including 5 with HCL, 6 with LGNHL, 7 with B-CLL and 2 with WM, developed peripheral blood eosinophilia. The mean values of absolute eosinophil count were 0.78x10(9)/l (0.58-1.06x10(9)/l), 0.71x10(9)/l (0.52-1.3x10(9)/l), 85 (0.56-1.82x10(9)/l) and 0.75 (0.74-0.76x10(9)/l), respectively. Eosinophilia occurred in 13 patients after 1 course, in 4 after 2 courses, and in 5 after > or =3 courses of the therapy. In 17 cases it resolved spontaneously. Allergic skin lesions with pruritus were noticed in 3 patients simultaneously with an increase in eosinophil count. All of them required antihistaminic drugs and/or corticosteroids. One patient with B-CLL experienced repeated episodes of eosinophilia. The highest incidence of 2-CdA-induced eosinophilia was noticed in patients with MW (11.1%) and HCL (7.4%) who received only 1 cycle of this drug and entered a complete remission. This side effect was less frequently observed in LGNHL and B-CLL, i.e. in 5.0% and 4.6% of cases, respectively. The mechanism of 2-CdA-induced eosinophilia is not clear. It has been postulated that massive tumour cell lysis may trigger a release of IL-5 and probably other cytokines. The allergic mechanism of 2-CdA-induced eosinophilia is also possible, especially in patients with simultaneous skin reactions.

The effect of 2-h infusion of 2-chlorodeoxyadenosine (cladribine) with prednisone in previously untreated B-cell chronic lymphocytic leukaemia.

2-Chlorodeoxyadenosine (2-CdA) is a new antimetabolite chemotherapeutic agent active in indolent lymphoid malignancies. In this retrospective study, 69 previously untreated patients with B-cell chronic lymphocytic leukaemia (B-CLL) were treated with 2-CdA administered at a dose of 0.12 mg/kg daily in 2-h intravenous infusion for 5 consecutive days. 45 patients also received prednisone 30 mg/m2 orally each day for 5 days starting with 2-CdA courses. Patients were given 2-6 courses (mean 4.6) of 2-CdA repeated usually at monthly intervals. If a complete response was achieved, no further 2-CdA courses were administered. Guidelines for response were those developed by the NCI Sponsored Working Group. Complete response (CR) was achieved in 26 (38%) and partial response (PR) in 27 (39%) cases, giving an overall response rate of 77%. 16 patients (23%) did not respond to 2-CdA. In the subgroup of 45 patients receiving 2-CdA with prednisone, CR was obtained in 15 (33%) and PR in 20 (44%) patients giving an overall response rate of 78%. CR was achieved in 11 (46%) out of 24 patients treated only with 2-CdA and in 7 cases (29%) PR was observed, giving an objective response rate of 75%. The differences between both subgroups were not statistically significant. However, we observed a relationship between the response and the number of courses of 2-CdA given in patients receiving and those not receiving prednisone. In the subgroup receiving 2-CdA with prednisone, an earlier response to 2-CdA was observed. In this group a response was achieved in 9 (20%) patients after two courses of 2-CdA and in 18 (40%) after four courses. In the subgroup receiving only 2-CdA, 17 (71%) responses were obtained after six cycles.

Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or previously untreated B-cell chronic lymphocytic leukemia.

The purpose of our study was to determine the effectiveness of 2-CdA in 2-hour intravenous infusions in the treatment of B-CLL. One hundred and ten patients with B-CLL received 1 to 10 courses of 2-CdA (median 2.5) at a dosage of 0.12 mg/kg daily for 5 consecutive days. Eighteen of them were untreated and 92 relapsed or became refractory to previous therapeutic modalities. Complete remission (CR) was achieved in 8 (7.3%) and partial remission (PR) in 35 patients (31.8%) giving an overall response rate of 39.1%. In 3 patients, cross-resistance to fludarabine was noticed. Toxic effects of 2-CdA were more frequently observed in previously treated patients. Hemorrhagic complications due to drug-induced thrombocytopenia were noticed in 25 (22.7%) and severe infections including sepsis in 14 (12.7%) patients.

[Bone marrow changes in patients with hairy cell leukemia after 2-chlorodeoxyadenosine treatment]. / Zmiany w szpiku chorych na bialaczke wlochatokomórkowa po leczeniu 2-chlorodeoksyadenozyna.

Bone marrow abnormalities were assessed in 6 patients with hairy cell leukemia after 2-chlorodeoxyadenosine treatment. In spite of clinical and haematological remission in all patients, hairy cells and fibrosis were found within the marrow. However, the hairy cells number, the thickness of argentophilic fibres and the extent of fibrosis. It was stressed that in addition to histological analysis with hematoxylin-eosin also other stainings for fibrosis should be applied in the bone marrow evaluation, followed by immunohistochemical and molecular methods which allow to exclude minimal residual disease after leukemia treatment.

[Gastrointestinal non-Hodgkin's lymphomas. Personal observations]. / Chloniaki zlosliwe nieziarnicze przewodu pokarmowego. Obserwacje wlasne.

The localization, symptoms, endoscopic findings, histologic type, infiltration of bone marrow, lymphoma cell presence in the blood, and results of therapy were evaluated in 18 patients with gastrointestinal lymphoma. Only 9 patients met the criteria of primary gastrointestinal lymphoma, the remaining 9 presenting an extra-nodular localization of systemic disease, i.e. secondary lymphoma. The most common site of process was stomach, and most of the patients had histologically documented a high grade malignant lymphoma. Necessity of supplementing surgery with chemo- and/or radiotherapy was discussed. Such combined treatment should give a 10-year survival time in 60% of the treated patients (confirmed with the Kaplan-Meier's method). The authors concluded that stomach is the most common localization of gastrointestinal lymphoma, and that gastrointestinal non-Hodgkin's lymphoma diagnosis should include peripheral blood and bone marrow haematological examinations which clearly rise the reliability of differentiation between primary or secondary lymphomas.

[Survival of patients and DNA-ploidy of cells in non-Hodgkin's lymphoma of low-grade malignancy]. / Przezycie chorych a DNA-ploidia w komórkach chloniaków nieziarniczych o niskiej zlosliwosci.

DNA-ploidy in lymphoma cells obtained from lymph nodes of 107 patients with non-Hodgkin's lymphomas of low grade malignancy was studied prior to the treatment introduction. The survival of patients was within the range of 24-126 months (median 63 months). There were 70 hyperdiploidic and 37 diploidic patients. The statistical tendency to prolonged survival was seen among patients with lymphocytic lymphoma (CLL) as compared to other histological types of the disease. There were no statistical differences in the probability of survival (p-P) between diploidic and hyperdiploidic patients either in the whole studied group or in particular histologic types of lymphoma.

[Treatment of inflammatory changes and stomatitis in patients with acute leukemias and malignant lymphomas using low pressure hydrotherapy--preliminary report]. / Leczenie zmian zapalnych i owrzodzeniowych jamy ustnej u chorych na ostre bialaczki i chloniaki zlosliwe przy pomocy hydroterapii niskocisnieniowej--doniesienie wstepne.

The management of stomatitis, commonly complicating intensive chemotherapy in patients with acute leukemias and malignant lymphomas has been presented. The hydrotherapy equipment of our own construction was designed to wash the oral cavity with large amounts of fluid given at low pressure and constant temperature. This washing solution contained the addition of drugs; its pH was adjusted to the pH of the patients saliva. Preliminary results of this treatment modality have been reported.

[DNA--ploidy in non hodgkin's lymphomas of low malignancy]. / DNA-ploidia w chloniakach nieziarniczych o niskiej zlosliwosci.

Lymphoma cell DNA cytometry in imprints of dissected lymph nodes was performed in 98 patients with low grade non-Hodgkin lymphomas and in 15 patients with reactive lymphadenopathy. The percentage of resting and proliferating cells was also calculated on the basis of computer analysis of DNA amount and cell image. It has been shown that, in contrast to the control group characterized by diploidic DNA amount, DNA aneuploidy was observed in 63.3% of lymphoma patients (DNA hyperdiploidy in 58.2% and DNA aneuploidio-polyploidy in 5.1% of the studied group). The proliferative activity of lymphoma cells was higher in patients with DNA aneuploidy than in DNA diploidic patients and in the control group.

[Indicators of nonspecific immunity in patients with non-Hodgkin's lymphoma of high grade malignancy in the remission phase of the disease]. / Wskazniki odpornosci nieswoistej u chorych na chloniaki nieziarnicze o wysokiej zlosliwosci w remisji choroby.

Parameters of unspecific immunity (absolute numbers of peripheral blood lymphocytes and their subpopulations, monocytes, blood concentrations of G, A, M immunoglobulins and skin tests with recall-antigens) were evaluated in 25 patients with high grade malignancy non-Hodgkin lymphomas at diagnosis. The frequency, site and gravidity of infections were recorded during the cytostatic treatment with the use of CHOP or CBVPP/ABVD regimens. The same immunological parameters were reevaluated in 9 patients in remission, within 6-52 months following treatment's cessation. Disturbances in at least 2 out of 10 studied parameters were found in all 25 patients at diagnosis. While on treatment, 19 out of 25 patients suffered from various bacterial, viral or fungal infections. The diminished frequency of infections was observed after treatment cessation, in contrast to persisting immunological disturbances. The usefulness of the immunological status monitoring and of immunomodulatory treatment during the remission phase of NHL is postulated.

[The role of leukemic conversion in the development of lymphoma infiltration of the nervous system]. / Rola konwersji bialaczkowej w powstawaniu nacieków chloniakowych w ukladzie nerwowym.

On the basis of neuropathologic studies in 22 patients died from ML it was found that lymphoma cells in the brain and spinal cord were in the form of leukostasis, infiltrations usually limited to perivascular spaces, infiltrations in hemorrhagic foci and their vicinity. In cerebrospinal meninges, spinal roots and peripheral nerves we observed leukostasis and intraparenchymatous infiltrations. It was found that the most important role in the development of lymphoma infiltrations in the nervous system was played by hematogenic metastases whose development in the brain and spinal cord was promoted by leukemic conversion with high leukocytosis. In contrast, marked dissemination of lymphoma cells to peripheral blood is not indispensible for the development of infiltrations in the cerebrospinal meninges and peripheral nervous system.

[Verification of hematological studies and immunologic phenotype of lymphoma cells in the blood by histological examination of the lymph nodes in non-Hodgkin's lymphoma of low and medium degree of malignancy]. / Weryfikacja badan hematologicznych i fenotypu immunologicznego komórek chloniakowych z krwi badaniem histologicznym wezla chlonnego w chloniakach nieziarniczych o malej i posredniej zlosliwosci.

In 125 patients with non-Hodgkin lymphomas of low or medium malignancy the type of lymphoma determined on the basis of morphological features and immunological phenotype of lymphoma cells in then circulation was verified by histological examination of lymph node. Dissemination of lymphoma cells into blood was found to have occurred in 80% of patients. The highest agreement of histological and haematoimmunological diagnoses was found in lymphocytic lymphoma and lymphoplasmoid (immunocyte) lymphoma, and the lowest one was in centrocytic and centroblastic-centrocytic lymphoma. It is stressed that in a part of the patients histological examination of the lymph node could be abandoned.