Successful treatment of leukaemia cutis with cladribine in a patient with B-cell chronic lymphocytic leukaemia.

Cutaneous presentation of B-cell chronic lymphocytic leukaemia (B-CLL) is uncommon, and the influence of skin changes on B-CLL prognosis is unclear. We report a patient with B-CLL Rai II, with multiple nodular skin infiltrations on the trunk, upper arms and thighs as well as constitutional symptoms, who was successfully treated with cladribine. The peripheral blood (PB) lymphocytes were CD19, CD20, CD23 and CD5 positive, which confirmed the diagnosis of B-CLL. Skin biopsy of one of the lesions showed an intense infiltrate composed of small lymphocytes with no epidermotropism. These cells also showed the expression of CD19, CD20, CD23 and CD5 antigens similar to those presented on PB lymphocytes. Polymerase chain reaction performed on bone marrow lymphocytes and a lesional skin biopsy using consensus primers for immunoglobulin heavy-chain genes also showed the same monoclonal population of B lymphocytes both in the bone marrow and in the skin. The patient received four courses of cladribine 0.12 mg kg-1 daily as a 2-h infusion for five consecutive days. The courses were repeated at monthly intervals. The lymphocytosis gradually decreased and the PB count normalized after three courses. At the same time, a significant decrease in the cutaneous symptoms was observed. The patient became free of skin tumours after the fourth course of cladribine; only slight discoloration at the previous sites of cutaneous infiltration remained. There was no relapse of leukaemia cutis during a further 7 months of observation.

Diagnostic and therapeutic quandaries in primary manifestation of Hodgkin's disease in the central nervous system.

We report the case of a 23-year-old female with severe neurologic dysfunction without a clear cause at the time of initial presentation. The search for an underlying malignancy revealed a slightly enlarged cervical lymph node with Hodgkin's disease (HD). There was no evidence of a brain tumor despite nonspecific bright changes in proton density in the basal ganglia of the right hemisphere of the cerebellum, right cerebellar tonsil, posterior limb of the internal capsule, and the right side of the medulla spinae as shown by magnetic resonance imaging (MRI) as well as reactive lymphocytosis with slightly elevated protein levels in the cerebrospinal fluid (CSF). The findings suggested a cerebellar disorder, with main differential diagnosis between neurologic paraneoplastic syndrome (NPS) and HD involving the CNS. Based on limited experience with NPS and HD in the CNS, possible diagnostic and therapeutic options are discussed.

Plasmablastic lymphoma in a patient with chronic lymphocytic leukemia heavily pretreated with cladribine (2-CdA): an unusual variant of Richter's syndrome.

Patients with chronic lymphocytic leukemia (CLL) may develop a large-cell transformation known as Richter's syndrome (RS). RS usually presents as diffuse large-cell lymphoma (DLCL) or its immunoblastic variant, and it can be recognized simultaneously with CLL or even 23 yr after its diagnosis. We describe an unusual case of CLL treated with cladribine (2-CdA) in whom DLCL of the plasmablastic type (PBL) developed 4 yr after CLL (Rai IV) diagnosis and 1.5 yr after the 10th course of 2-CdA treatment. Immmunologic, cytogenetic, and molecular studies performed at the time of CLL and PBL coappearance indicated that both tumors originated from different B-cell progenitors. Both malignancies were refractory to VAD (vincristine, doxorubicin, dexamethasone)-based chemotherapy, and only partial response was achieved with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) salvage treatment. However, the patient died 6 months after the occurrence of RS due to rapid progression of PBL. This is the first description of a CLL patient who developed an unusual plasmablastic variant of RS. Recently, the PBL entity has been identified among DLCL associated with the human immunodeficiency virus (HIV) infection. We suggest that in our CLL patient heavily pretreated with 2-CdA, PBL arose as a second clone due to the prolonged and severe state of the host's immunosuppression. Overall survival with current strategies is poor, and further insight into the natural history, biology, and treatment of PBL are needed.

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)

Prognostic factors in Hodgkin's disease: multivariate analysis of 327 patients from a single institution.

On the basis of a retrospective study of 327 patients with Hodgkin's disease (HD), the prognostic significance of several factors, accepted previously and recently proposed, has been analyzed with regard to response to treatment and the survival time. Multivariate regression analysis strongly decreased the number of potentially prognostic parameters. The only independent, pretreatment factors negatively influenced by either time of survival or response to treatment were the following: age at diagnosis of more than 45 years, advanced (IIIB/IV) clinical stage, poor clinical status according to Karnofsky's scale (score less than 70), presence of systemic symptoms, mixed cellularity/lymphocyte depletion histological type, multisite peripheral nodal localization of the disease, abdominal lymphadenopathy, and large primary tumor mass (bulky disease). Short time to achieve complete remission (during the first four courses of chemotherapy) has proven to be significantly positive predictive factor. Cumulative dose of cytostatics lower than programmed was a significantly negative prognostic factor that correlated with a shorter time of survival. Lack of or a too-low dose of radiotherapy had the same predictive value. High activity of serum lactate dehydrogenase correlated moderately with poor response to the first-line treatment but did not influence the survival time. Other clinical, morphological, and biochemical parameters influenced neither the prognosis nor the response to treatment. Additionally, immunohistochemical examinations for proliferating cell nuclear antigen and the protein products of the p53 and bcl-2 genes were performed on the lymph nodes obtained from the patients with HD. High expression of proliferating cell nuclear antigen, p53, and BCL-2 correlated with poor response to the treatment and/or short time of survival. Statistical analysis has led us to the conclusion that the pretreatment expression of these oncoproteins can be taken into consideration as a new prognostic factor in HD.

Expression of p21 and MDM-2 proteins on tumor cells in responding and non-responding patients with Hodgkin's disease.

Since the prevention of apoptosis can produce resistance to chemotherapy, abnormal expression of oncoproteins engaged in the regulation of this phenomenon in tumor cells may give some prognostic information in patients with neoplasma. To assess this problem in Hodgkin's disease (HD), the cellular expression of two p53 downstreams proteins p21 and MDM-2 was evaluated in the lymph nodes specimens obtained from 68 patients at the time of diagnosis, and compared with some clinical and pathological data. Positive immunoreaction for p21 and MDM-2 on Reed-Sternberg/Hodgkin's (R-S/H) cells was found in a majority of cases (58.8 and 63.2%, respectively). High expression of p21 protein correlated with poor response to the first-line treatment and disease free survival in both univariate and multivariate regression analysis, whereas expression of MDM-2 did not give prognostic information in patients with HD. Expression of p21 and MDM-2 was also compared with p53 protein immunoreactivity of R-S/H cells. The p21+/p53+ immunophenotype occurred to give particularly negative prognostic information in patients with HD. Diversity of p21/MDM-2/p53 patterns of R-S/H cells observed in particular patients may reflect heterogeneity of apoptosis regulatory mechanisms, as well as differences in p53 gene status.

Combination regimen of 2-chlorodeoxyadenosine (cladribine), mitoxantrone and dexamethasone (CMD) in the treatment of refractory and recurrent low grade non-Hodgkin's lymphoma.

The aim of our phase II study was to determine the effectiveness of combined chemotherapy consisting of 2-hour intravenous infusion of 2-CdA, mitoxantrone and dexamethasone (CMD) regimen in the treatment of heavily previously treated patients with refractory or relapsed low grade non-Hodgkin's lymphoma (LGNHL). All of the 14 patients had clinical stage IV disease, most of them had B symptoms and elevated LDH levels. All cases were refractory to standard chemotherapy or had recurrent relapses having received at least 5 courses of prior chemotherapy. All patients received at least one cycle of CMD (range, 14). A total of 35 courses of CMD were given to the entire group. Complete response (CR) was obtained only in one patient (7.1%) and partial response (PR) in 3 (21.4%) with an overall response rate of 28.5%. The major toxicity was myelosuppression and 35% of the patients had infection. One patient died of sepsis. These results suggest that the addition of other drugs to 2-CdA in heavily treated patients with refractory or relapsing disease may not be more advantageous when composed to giving 2-CdA alone.

Expression of proliferating cell nuclear antigen (PCNA) and p53, bcl-2 or C-erb B-2 proteins on Reed-Sternberg cells: prognostic significance in Hodgkin's disease.

Expression of proliferating cell nuclear antigen (PCNA) as well as p53, bcl-2 and C-erb B-2 genes protein products on Reed-Sternberg/Hodgkin's (R-S/H) cells was analyzed by immunohistochemistry in 65 patients with Hodgkin's disease (HD). Their significance as markers of clinical malignancy and prognostic factors was evaluated. Positive reaction for PCNA was present in 57 cases (87.7%), for p53 in 42 (64.6%), for bcl-2 in 41 (63.1%), and for C-erb B-2 in 38 cases (58.5%) of HD. The high proliferate PCNA index and high expression of p53 and bcl-2 correlated with poor response to the treatment. Expression of both p53 and bcl-2 oncoproteins negatively influenced overall survival and disease free survival. Indexes of PCNA, p53 and bcl-2 were significantly higher in patients with advanced disease then in early clinical stages. In LP type of HD the lowest indexes of PCNA or bcl-2, and even lack of bcl-2 expression on R-S/H cells were observed. There was no correlation between expression of C-erb B-2 and response to the treatment, time of survival, clinical stage or histopathological types of HD. Statistical analysis let us to the conclusion, that indexes of PCNA, p53 and bcl-2 expression can be taken into consideration as a new prognostic factors in Hodgkin's disease. C-erb B-2 protein expression seems to be of no value for prognosis in HD.

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.

Activity of 2-chlorodeoxyadenosine (Cladribine) in 2-hour intravenous infusion in 94 previously treated patients with low grade non-Hodgkin's lymphoma.

The purpose of our study was to determine the efficacy of 2-chlorodeoxyadenosine (2-CdA) administered in 2-hour intravenous infusions in previously treated patients with low grade non-Hodgkin's lymphoma (LGNHL). We treated 94 LGNHL patients with 2-CdA at a dosage of 0.12 mg/kg/24h in 2-hour intravenous infusion for 5 consecutive days. The treatment consisted of from 1 to 7 courses (median 3), repeated usually at monthly intervals. All patients were refractory to or relapsed after standard chemotherapy. Of these 94 patients 78 (83%) had clinical stage IV of the disease. Complete response (CR) was obtained in 12 (12.8%) and partial response (PR) in 36 (38.3%) giving an overall response rate of 51.1%. In 12 (12.8%) grade 4 thrombocytopenia with haemorrhagic diathesis was noted, grade 4 neutropenia was observed in 12 (12.8%) and infections complicated the course of treatment in 38 (40.4%) patients. 2-CdA treatment was the cause of death of 3 patients. The results of our study show that 2-CdA given in 2-hour infusions is an effective agent in advanced, heavily pretreated patients with LGNHL.

Hairy cell leukemia-variant treated with 2-chlorodeoxyadenosine--a report of three cases.

Three patients with B-prolymphocytic variant of HCL (HCL-V) were treated with a chlorinated purine analogue, 2-chlorodeoxyadenosine, at a daily dosage of 0.12 mg/kg in 2-hour intravenous infusion for 5 consecutive days. Partial remission was achieved in only 1 patient, who relapsed after 6 months. Two other patients did not respond to the treatment. HCL-V is a distinct clinicopathological entity which seems to be resistant to various therapeutic modalities. However, further observations are necessary in order to establish the efficacy of 2-CdA in the treatment of HCL-V.

Autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia treated with 2-chlorodeoxyadenosine (cladribine).

Autoimmune haemolytic anaemia (AIHA) is one of the major complications in chronic lymphocytic leukaemia (CLL). Treatment with alkylating agents and the adenosine analogue, fludarabine, might trigger the development of AIHA in CLL patients despite the reduction of leukaemic clone. The influence of 2-chlorodeoxyadenosine (2-CdA) on AIHA in patients with CLL is undefined so far. In a group of 114 patients treated at our clinics with this agent, AIHA with direct antiglobulin test (DAT) positively was observed in 25 (21.9%) patients. In 23 patients AIHA was noticed before the starting of 2-CdA and in 2 patients DAT became positive after 2-CdA treatment. In 6 patients the drug caused complete resolution of haemolysis and DAT became negative. Eight patients exhibited partial resolution of haemolysis with significant improvement in haemoglobin level but DAT test remained positive. In 11 patients there was no response to 2-CdA in relation to autoimmune haemolysis. Two patients with no previous history of haemolysis developed AIHA after 5 and 6 courses of 2-CdA therapy and their DAT became positive 1-2 months after the last course of the drug. One of them entered severe haemolytic crisis and severe thrombocytopenia and died because of haemorrhagy to the central nervous system. In the other patient AIHA was controlled by steroids and chlorambucil treatment. Our study indicates that 2-CdA may suppress autoimmunohaemolytic process in some patients with CLL and trigger the development of AIHA in others.

[Treatment of acute lymphoblastic leukemias in adults]. / Leczenie ostrych bialaczek limfoblastycznych u doroslych.

Acute lymphoblastic leukemia (ALL) is one of the few malignant disease for which substantial improvement was achieved during the last two decades. The complete remission (CR) rate is about 80% but the long-term remission rate is only 25-35%. Independent poor-prognostic factors include older age, presenting leukocyte count greater than 25-35 x 10(9)/l, cytogenetic abnormalities, egPh+/bcr-abl+, t(4;11), specific immunophenotype (pre-T, "mature" B) and longer time to achieve remission. Randomized studies show that the addition of anthracyclines to vincristine and prednisone improve the CR rates. Attempts to further intensify induction treatment have been limited to severe toxicity. There is evidence from trials with a variety of schedules that consolidation and maintenance therapy does improve the outcome. Hematologic toxicity is an important limitation in the treatment of adult with ALL. Whether the use of growth factors might improve outcome with chemotherapy requires long-term follow-up of large randomized studies. To reduce the risk of central nervous system (CNS) leukemia early intrathecal chemotherapy is necessary. Concomitant use of high-dose systemic chemotherapy or radiotherapy is useful in prophylaxis CNS leukemia in some studies but a risk oriented approach is needed. Allogenic bone marrow transplantation (BMT) in first CR is recommended for high-risk patients and is appropriate after relapse in all patients less than 55 years old. Autologus BMT in first and next CR as well as methods for purging malignant cells from procured marrow are potential use but require further clinical trials.

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.

2-chlorodeoxyadenosine (2-CdA) in 2-hour versus 24-hour intravenous infusion in the treatment of patients with hairy cell leukemia.

Forty one patients with hairy cell leukemia (HCL) were treated with 2-chloro-deoxyadenosine (2-CdA) administered in various schedules. Complete remission (CR) was achieved in 31 (76%) patients and partial remission (PR) in 9 (22%). The mean duration of remission (CR + PR) was 25.2 months (range 9-45 months). One patient did not respond to therapy. Twelve out of 16 patients (75%) achieved CR after 5-day intravenous infusions of 2-CdA and 19 out of 25 patients (76%) after 7-day courses. In 19 out of 23 patients (82.6%) CR was achieved after intermittent 2-hour infusions and in 12 out of 18 (66.7%) after continuous 24-hour infusion. The differences were not statistically significant. Side effects of 2-CdA were similar in both groups except for infections, which were less frequently observed in the group treated for 5 days. The results of our study suggest that 2-CdA can be effectively administered to patients with HCL using 5-day courses and a 2-hour daily infusion.

[Thrombotic thrombocytopenic purpura successfully treated with plasma exchange]. / Zakrzepowa plamica maloplytkowa skutecznie leczona wymiana osocza.

This study is a presentation of a case of a 43 year old woman suffering from thrombotic thrombocytopenic purpura, the clinical course of which was complicated and in which no improvement was observed after fresh frozen plasma transfusions and treatment with steroids. The complete clinical and haematological remission was obtained only after intensive plasma exchange by therapeutical plasmapheresis.

Characterization of proteins from chronic lymphocytic leukaemic cells: electrophoretic and immunological approach.

The protein composition of cellular fractions (nuclear, mitochondrial, microsomal and cytosolic) from normal and B-chronic lymphocytic leukaemia (CLL) cells isolated by differential centrifugation was analysed by SDS-polyacrylamide gel electrophoresis. Some diversities in electrophoretic characteristics of proteins from various compartments of normal and leukaemic cells were observed, mainly among nuclear proteins. Comparison of nuclear proteins from CLL cells of patients with different stages of the disease revealed that an expression of some specific for leukaemic cells components, especially a polypeptide (MW 46 kD) might be correlated with a stage of CLL. Immunoblotting analysis in the presence of antiserum raised against cancer-associated antigen, described as p65 indicated the association of this particular antigen with a nuclear fraction of leukaemic cells.