In the Treatment of Patients with Chronic Lymphocytic Leukemia 55

Home , Cladribine

Leukemia (1999) 13, 518–523  1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu 2-Chlorodeoxyadenosine (Cladribine) in the treatment of patients with chronic lymphocytic leukemia 55 years old and younger T Robak1, JZ Błon´ski1, H Urban´ska-Rys´1, M Błasin´ska-Morawiec1 and AB Skotnicki2

1Department of Hematology, Medical University of Ło´dz´,Ło´dz´; and 2Department of Hematology, Jagiellonian University Krako´w, Poland

The aim of the study was to determine the effectiveness of 2- CLL shortens expected survival by an average of 19 years.11 chlorodeoxyadenosine (2-CdA) administered in 2-h i.v. Thus, in particular for younger patients, new treatment infusions in the treatment of B cell chronic lymphocytic leukemia (B-CLL) in patients 55 years old and younger. One hundred modalities that have the potential to provide long-term and thirteen patients received three to 10 courses of 2-CdA remissions or to completely eradicate the disease are required. administered at a dose of 0.12 mg/kg daily for 5 consecutive Newer nucleoside analogues, especially fludarabine days. Sixty-seven patients were previously treated with chlor- (FAMP) and 2-chlorodeoxyadenosine (2-CdA), are highly ambucil and prednisone, COP and some of them also with active against CLL.12–14 Complete response rate (CR) induced CHOP, and 46 were untreated. Complete remission (CR) was with these agents is significantly higher than in patients treated achieved in 21 (18.6%) (19 in untreated and two in previously 15,16 treated) patients and partial response (PR) in 38 (33.6%) (23 and with conventional chemotherapy. High quality of 15, respectively) giving an overall response rate in 52.2%. The response to first-line therapy is especially important in selec- differences in CR and overall response rate between previously ted younger patients with CLL, who might be candidates for treated and untreated patients were statistically significant (P stem cell transplantation. = 0.001). Surface immunophenotyping by flow cytometry using Here, we report the efficacy and toxicity of 2-CdA given in dual-color staining on the peripheral blood and/or bone marrow 2-h infusions as a first-line therapy in 115 patients with CLL, was performed in 38 patients who responded to 2-CdA therapy. Residual disease had been demonstrated in five out of 17 aged 55 years and younger. (29.4%) patients who were in CR and in all 21 investigated PR patients. 2-CdA-induced thrombocytopenia occurred in 24 (35.8%) of previously treated and in 13 (28.3%) previously Patients and methods untreated patients (P = NS). Neutropenia was observed in eight (11.9%) and in five (10.9%) patients, respectively (P = NS). Sev- Patients ere infections, including pneumonia and sepsis, occurred more often in previously treated (44.8%) than untreated patients (26.1%) (P Ͻ 0.05). Twenty-seven (23.9%) patients died, 11 Between September 1994 and August 1998, 113 patients aged because of infections, five because of drug-related thrombocy- 55 years or less with progressive or symptomatic B-CLL were topenia and hemorrhage, one because of second malignancy treated with 2-CdA. The characteristics of the patients are and eight because of disease progression. In conclusion, our shown in Table 1. All the patients fulfilled the National Cancer results indicate that 2-CdA is an effective agent in younger Institute-Sponsored Working Group diagnostic criteria for patients with B-CLL, especially used as a first line therapy. 17 Keywords: 2-chlorodeoxyadenosine; chronic lymphocytic leuke- CLL. They had peripheral lymphocytosis greater than × 9 mia; younger patients; efficiency; side-effects; immunophenotyping 10 10 /l and more than 30% lymphocytes in a normal to hypercellular bone marrow. Immunologically all patients were CD5, CD19, CD20 and CD23 positive and showed Introduction monoclonality for light chain immunoglobulin membrane surface receptors. Pretreatment evaluation included medical B cell chronic lymphocytic leukemia (CLL) is the most com- history, physical examination, complete blood cell count, mon adult leukemia in Western countries. CLL is generally differentiation analysis, chemical survey, bone marrow exam- perceived as an indolent, but incurable disease predominantly ination and serum immunoglobulin level quantitation. affecting elderly people. The median age of patients at diag- The clinical stage of disease was determined at the time of initiation of 2-CdA treatment according to Rai’s classi- nosis is 65 years, with only 10–15% of them being less than 18 55 years of age.1,2 Cases below the age of 40 are extremely fication. The distribution is shown in Table 1. Fifty-two rare.3 The disease is characterized by a variable course with patients with Rai stage III or IV were included in the study. overall survival ranging from less than 1 year to more than 25 Patients with stage 0, I and II were eligible if they had evi- years.4 Older age has been consistently shown to confer a dence of active disease, including progressive lymphocytosis, poorer prognosis in CLL.5–7 However, when non-CLL mortality massive splenomegaly or bulky lymphadenopathy, recurrent disease-related infections, weight loss у10% over a 6-month is eliminated from an older population, there is no difference ° in median survival time between the patients younger than period, fever of above 38 C related to disease or extreme 8 fatigue. At the start of therapy they had normal renal the age of 50 and the older group. Ͻ Ͻ CLL is currently an incurable disease when using conven- (creatinine 1.0 mg/dl) and hepatic (bilirubin 1.0 mg/dl) tional chemotherapy such as alkylating agents, combined functions and were free of active infections. Sixty-seven chemotherapy and even newer purine analogues.9,10 For patients had been previously treated with chlorambucil and patients younger than 50 years, the diagnosis of early stage prednisone followed by polychemotherapy according to COP and/or CHOP schedules (49 patients) when they relapsed or were refractory to an alkylating agent. Forty-six patients were newly diagnosed or previously untreated and given 2-CdA Correspondence: T Robak, Department of Hematology, Medical Uni- versity of Ło´dz´, 93–513 Ło´dz´, ul. Pabianicka 62, Poland; Fax: 4842 because of progressive disease. 6846890 The study was approved by the Local Ethical Committees Received 6 October 1998; accepted 15 December 1998 and the patients had signed the consent form. 2-CdA in younger patients with CLL T Robak et al 519 Table 1 Clinical characteristics of B-CLL patients before 2-CdA treatment

All patients Previously untreated Previously treated

Total 113 (100%) 46 (40.7%) 67 (59.3%) Sex male 31 (27.4%) 14 (30.4%) 17 (25.4%) female 82 (72.6%) 32 (69.6%) 50 (74.6%) Age median ± s.d. 47.3 ± 6.5 47.5 ± 5.3 47.1 ± 7.2 (range) (31–55) (31–55) (31–55) Rai stage 0 11 (9.7%) 8 (17.4%) 3 (4.5%) I 10 (8.8%) 5 (10.9%) 5 (7.5%) II 40 (35.4%) 15 (32.6%) 25 (37.3%) III 20 (17.7%) 11 (23.9%) 9 (13.4%) IV 32 (28.3%) 7 (15.2%) 25 (37.3%) Median disease duration in months ± s.d. (range) 45.6 ± 34.4 25.6 ± 23.4 59.6 ± 34.1 (2–161) (2–126) (14–161) Mean number of WBC × 109/l (range) 84.9 89.7 81.5 (5.4–378) (5.4–360) (8.5–378) Mean Hb concentration g/dl (range) 11.6 12.3 11.2 (5.1–17.1) (5.2–16.0) (5.3–17.1) Mean number of platelets × 109/l (range) 149.5 170.1 135.7 (6–431) (35–322) (6–431)

Treatment modality centration Ͼ11.0 g/dl, platelet count Ͼ100 × 109/l) and bone marrow with less than 30% of lymphocytes for at least 2 2-Chlorodeoxyadenosine was supplied by the Foundation for months. Partial response (PR) was considered as 50% or the Development of Diagnostics and Therapy, Warsaw, greater decrease in the size of lymph nodes, liver and spleen, Poland, and was synthesized according to the method of Kazi- and peripheral blood findings either identical to those of CR mierczuk et al.19 More recently it was commercially available or improved over pre-therapy values by at least 50%. No bone from the Institute of Biotechnology and Antibiotics (Warsaw). marrow evaluation was required for determination of PR. The Treatment course consisted of 2-CdA at a dose of patients who had not achieved CR or PR were classified as 0.12 mg/kg/24 h in a 2-h infusion for 5 consecutive days. In non-responders (NR). Clinical relapse was defined according patients in whom 2-CdA induced hematological compli- to Robertson et al12 as increase in the absolute lymphocyte cations (thrombocytopenia Ͻ50 × 109/l and/or neutropenia count above 10 × 109/l, more than 50% increase in the sum Ͻ1 × 109/l) or severe infections developed, the drug was re- of the sizes of at least two lymph nodes, appearance of new administered at time intervals longer than 1 month, ranging lymph nodes, more than a 50% increase in the liver or spleen from 2 to 3 months, until the hematological parameters below the costal margin, new appearance of palpable hepato- increased or infections were resolved. If a complete response splenomegaly or development of an aggressive lymphoma. was achieved, no further 2-CdA treatment was administered. Packed red blood cells were transfused for symptomatic anemia or prophylactically if the hemoglobin level was lower Toxicity monitoring than 7.0 g/dl. Platelets were administered prophylactically if the platelet count was less than 15.0 × 109/l. In order to pre- Hematological toxicity was evaluated according to criteria vent hyperuricemia, allopurinol (300 mg daily) was routinely developed by the NCI-Sponsored Working Group.17 2-CdA- given. No patients received antibiotics prophylactically. In the induced anemia, thrombocytopenia and neutropenia were patients in whom 2-CdA induced autoimmune hemolytic ane- assessed if after the treatment course further decrease of hem- mia (AIHA) or progressive thrombocytopenia developed, oglobin level and/or platelets and neutrophils number was prednisone at a initial dose of 0.5–1.0 mg/kg/24 h was observed. Other toxic effects were monitored and assessed introduced. according to the standard criteria.20 The blood counts, creatinine, bilirubin, GOT, GPT, ECG, urinalysis and general physical examination were serially evaluated and recorded. Response criteria

Physical examination and peripheral blood analysis were per- Immunophenotype analysis formed before and after every 2-CdA course, and the response to the drug was estimated. Bone marrow biopsy and immuno- Immunophenotyping was performed on peripheral blood and phenotypic studies were performed to confirm complete bone marrow by flow cytometry using a simultaneous dual- remission, after every 2–3 courses of 2-CdA. Guidelines for color staining technique, before treatment, after three and six response were those developed by the NCI-Sponsored Work- courses of 2-CdA, and then after every 6 months. Blood was ing Group.17 Complete response (CR) required the absence of collected in vacuum tubes with EDTA as anticoagulant. Bone symptoms and organomegaly, a normal complete blood cell marrow cells were aspirated from the dorsal iliac crest and count (absolute neutrophil count Ͼ1 × 109/l, hemoglobin con- immediately put into heparinized tubes.21 Flow cytometry 2-CdA in younger patients with CLL T Robak et al 520 analysis was performed by EPICS-XL (Coulter, Hialeah, FL, observed after a median of three cycles (range 2–6) and after USA). A combination of phycoerythrin (PE)-conjugated and a median four (range 3–7), respectively. The influence of Rai fluorescein isothiocyanate (FITC)-conjugated monoclonal stage before 2-CdA therapy on the response to the treatment antibodies was used. Residual disease was determined by is shown in Table 2. CRs were achieved more frequently in coexpression of CD5/CD19 and CD5/CD20 on B lymphocytes the early stages of the disease (Rai 0, I and II), than in more in conjunction with monoclonality of surface light-chain advanced stages (Rai III and IV, P Ͻ 0.05). Treatment with expression on CD5-positive B cells. The presence of more 2-CdA was discontinued when response was observed. The than 10% of the total lymphocytic population coexpressing median duration of response was 10.4 months, with a range CD19/CD5 and CD20/CD5 with monotypic light-chain of 2–34. Disease progression occurred in 54 patients, includ- expression was considered positive for residual disease ing 50 in the previously treated group and four in the according to criteria developed by Robertson et al.12 A ␬:␭ or untreated group. Eighteen patients are still in CR and 22 in PR. ␭:␬ ratio exceeding 3:1 was considered as monotypic light- Surface immunophenotyping by flow cytometry using dual- chain expression.12,21 color staining on the peripheral blood and/or bone marrow was performed in 38 patients who responded to 2-CdA therapy. Residual disease was demonstrated in five out of 17 Statistical analysis (29.4%) patients who were in CR and in all 21 investigated PR patients. The significance of differences was evaluated by Mann–Whit- Toxicity of 2-CdA in the patients previously untreated as ney U test at the level of confidence P Ͻ 0.05. Statistical well as treated with conventional chemotherapy are presented analysis of the difference in percentages of patient responses in Table 3. There was no significant difference between mye- was evaluated by the ␹2 test. losuppressive effects of 2-CdA in both groups of patients. 2- CdA-induced thrombocytopenia occurred in 24 (35.8%) of previously treated and in 13 (28.3%) previously untreated Results patients (P Ͼ 0.05). The treatment with prednisone was introduced in 25 patients with thrombocytopenia and in 11 of The results of the treatment of 113 patients with B-CLL, 55 them improvement was noticed. However, the percentage of years old and younger using 2-CdA in a 2-h infusion, are sum- autoimmune thrombocytopenia in this group is uncertain. marized in Table 2. All patients received at least three cycles Neutropenia was observed in eight (11.9%) of previously of 2-CdA (range 3–10). The mean time from diagnosis to 2- treated and in five (10.9%) untreated patients (P Ͼ 0.05). Sev- CdA administration was 18 months (range 3–39) if it was a ere infections, including pneumonia and sepsis, occurred first-line regimen in comparison with 23 months (range 3–80) more often in previously treated (44.8%) than untreated in previously treated patients (P Ͼ 0.05). The criteria for CR patients (26.1%) (P Ͻ 0.005). were fulfilled in 21 cases (18.6%) and PR in 38 (33.6%), giv- 2-CdA-related eosinophilia was observed in two patients. In ing an overall response rate in 52.2% of patients. Fifty-four one of them, marked eosinophilia (absolute eosinophil count patients (47.8%) did not respond to 2-CdA. In the group of 46 Ͼ1.6 × 109/l) followed allergic dermatitis, which occurred previously untreated patients, CR was obtained in 19 (41.3%) after two cycles of 2-CdA. Five patients experienced auto- and PR in 23 patients (50.0%), giving an overall response rate immune hemolytic anemia (AIHA) after 2-CdA and one of 91.3%. In the group of patients treated prior to adminis- patient pure red cell aplasia (PRCA). AIHA was successfully tration of 2-CdA, CR was achieved in two (3.0%) and PR in treated with prednisone in four patients and one was refrac- 15 (22.4%) patients, giving an overall response rate of 25.4%. tory to such treatment. There were also simple episodes of CR and overall responses were achieved more frequently in non-hematologic toxic effects of 2-CdA in both groups. The the patients in whom 2-CdA was first-line treatment than in observed side-effects comprised polyneuropathy in two previously treated patients and the differences were statisti- patients, dermatitis in three patients, abnormal aminotransfer- cally significant (P Ͻ 0.001, Table 2). The median duration of ases in three and increased LDH level in two patients. CR for previously untreated patients was 10.1 months (range Increased creatinine level or overt renal insufficiency were 4–34) and for patients previously treated with one or more found in two patients. In five patients skin manifestations were regimens 5.9 months (range 3–27) (P = 0.001). The CRs were observed including erythema anulare, vasculitis allergica and

Table 2 Results of the treatment of B-CLL patients with 2-CdA

Rai All patients (%) Previously untreated (%) Previously treated (%) stage n = 113 n = 46 n = 67

n CR PR NR n CR PR NR n CR PR NR

0 112 6 3 8 2 60 30 0 3 (18.2) (54.5) (27.3) (25.0) (75.0) (100.0) I + II 50 11 18 21 20 10 9 1 30 1 9 20 (22.0) (36.0) (42.0) (50.0) (45.0) (5.0) (3.3) (30.0) (66.7) III + IV 52 8 14 30 18 7 8 3 34 1 6 27 (15.4) (26.9) (57.7) (38.9) (44.4) (16.7) (3.0) (17.6) (79.4) Total 113 21 38 54 46 19 23 4 67 2 15 50 (18.6) (33.6) (47.8) (41.3) (50.0) (8.7) (3.0) (22.4) (74.6) 2-CdA in younger patients with CLL T Robak et al 521 Table 3 2-CdA induced side-effects

Side-effect Number of patients

Total Previously untreated Previously treated n = 113 n = 46 n = 67

Thrombocytopenia Ͻ50 × 109/l 37 (32.7) 13 (28.3) 24 (35.8) Neutropenia Ͻ1 × 109/l 13 (11.5) 5 (10.9) 8 (11.9) Anemia Hb Ͻ11 g/dl 10 (8.8) 6 (13.0) 4 (6.0) (AIHA-5, PRCA-1) (AIHA-3, PRCA-1) (AIHA-2) Alopecia 2 (1.8) 1 (2.2) 1 (1.5) Infections and fever of unknown origin 42 (37.2) 12 (26.1) 30 (44.9) Eosinophilia 2 (1.8) 1 (2.2) 1 (1.5) Dermatitis 5 (4.4) 1 (2.2) 4 (6.0) Polyneuropathy 2 (1.8) 1 (2.2) 1 (1.5) Aminotransferases increased 3 (2.6) 1 (2.2) 2 (3.0) LDH increased 2 (1.8) — 2 (3.0)

urticaria. Three patients reported nausea and gastrointestinal be crucial for prolongation of survival time and an increase disorder. Twenty-seven (23.9%) patients died 4–12 months in the efficacy of the bone marrow transplantation procedure. (mean 7 months) from the start of 2-CdA, 22 (32.8%) in the The present study estimates the efficacy of 2-CdA therapy previously treated and five (10.9%) in the previously untreated in 113 B-CLL patients aged up to 55 years. The drug was given group. The causes of death are shown in Table 4. Infectious in a 2-h infusion for 5 consecutive days. The whole group complications were the cause of death in 11 patients from the consisted of 46 untreated and 67 patients, who became pro- previously treated group. Seven patients died because of sev- gressively or were resistant to previous therapy with chloram- ere bilateral pneumonia, two in septic shock and two because bucil, COP or CHOP. The highest overall response (91.3%) of viral meningitis. Five patients died of hemorrhage, seven and CR (41.3%) rates were noted in previously untreated B- because of disease progression and one patient developed CLL patients in comparison to those who received 2-CdA as lung cancer. a second- or third-line therapy (overall response rate 25.4%, CR rate 3.0%). These differences were statistically significant (P Ͻ 0.001). In our previous study similar results were Discussion obtained in older B-CLL patients, who were given 2-CdA in a 2-h infusion achieving a CR in 16% of untreated vs 5.4% in The therapeutic procedure in CLL is different and depends previously treated patients.13 Keating et al24,25 did not observe mainly on the clinical stage of disease and age of patients at any difference in the response to FAMP among untreated or diagnosis. The results of multicenter randomized trials indi- previously treated CLL patients aged Ͼ60 years. It should be cate that therapy for indolent CLL using chlorambucil and noted, however, that retrospective analysis of 374 CLL 22 prednisone does not prolong survival time. However, the patients treated with FAMP revealed that older age was an treatment of CLL should be undertaken in advanced stages of unfavorable prognostic factor in pretreated as well as in disease (stage B and C according to Binet’s classification) or untreated patients.26 in progressive cases. The new purine analogs, fludarabine It should be emphasized that in our study 2-CdA was (FAMP) and 2-CdA, have been recently shown to be the most administered in a 2-h infusion for 5 days and using this proto- effective in CLL treatment, giving the highest response rate, col we obtained the results comparable to those published particularly CR.15,16,23 However, the main aim for purine ana- earlier in CLL patients receiving both 2-h infusion and a con- log administration in CLL, whose clinical course is usually tinuous 24-h infusion for 7 days.27–29 The efficacy of 2-CdA chronic and often indolent, has not yet been precisely defined. given as a 2-h vs a 24-h infusion was essentially the same also The significance of the new purine analogs is particularly in hairy cell leukemia.30 Pharmacokinetics studies confirm the important for younger patients in whom achieving a CR may effectiveness of 2-CdA given as 2-h bolus for shorter periods of time, ie for 5 instead of 7 days.31,32 Taking into account Table 4 Causes of death in B-CLL patients treated with 2-CdA that a 2-h infusion is more convenient and may be given on an out-patient basis, our results seem to be important from a Cause of death Total Previously Previously practical point of view. n = 27 untreated treated The most dangerous and frequent 2-CdA related side-effect = = n 5n22 was thrombocytopenia which was noted in 32.7% of CLL patients, and in five of them the hemorrhagic complications Pneumonia 7 — 7 were a cause of death. It should be noted, however, that we Septic shock 2 — 2 Meningitis 2 — 2 did not observe the difference in frequency of thrombocyto- Hemorrhage 5 2 3 penia in untreated vs pretreated younger B-CLL patients. Disease progression 8 1 7 Nevertheless, in older CLL patients 2-CdA-induced profound Second malignancy 1 1 0 thrombocytopenia was noted more frequently in patients treated previously with chlorambucil or polychemothera- 2-CdA in younger patients with CLL T Robak et al 522 peutic regimens.13 This may be explained by a higher bone response rate in CLL patients aged 55 years or less. The effi- marrow reserve and, therefore, a better tolerance of myelosup- cacy of the drug is higher and the toxicity is lower if 2-CdA is pressive drugs in younger patients. administered as first-line therapy. Immunophenotyping studies In our series an autoimmune hemolytic anemia (AIHA) was show that the complete eradication of leukemic clone may noted in five and pure red cell aplasia (PRCA) in one patient. be achieved in some CLL patients. However, their chance for These immune complications subsided after 2-CdA with- recovery seems to be less probable. drawal and steroid administration. AIHA was observed in CLL patients treated with 2-CdA and FAMP.33,34 However, it can- not be definitely established whether this immune phenom- Acknowledgements enon is drug-induced or appears spontaneously in the natural course of CLL. We would like to thank Dr Aleksandra Musial for correcting Infections were another severe and undesirable 2-CdA side- the English version of the manuscript, and Ms Krystyna Marsz- effect being a cause of death in 11 (9.7%) patients. All of them alek for typing the manuscript. This work was supported in were previously treated with cytostatics. It is well known that part by Grant KBN No. 4P05B02711, Warsaw, Poland. infectious complications are frequent causes of death in CLL, despite which treatment schedule is used, and they result mainly from severe and profound dysfunction of humoral and References cellular immunity observed in this malignancy. However, pro- longed treatment with 2-CdA, which is a potent immunosup- 1 Catovsky D, Foa R. B-cell Chronic Lymphocytic Leukemias. But- pressive agent, may deepen the immune deficiency in CLL terworths: London, 1990, pp 73–112. 35 2 Rozman C, Monsterrat E. Chronic lymphocytic leukemia: an patients as was noted after FAMP administration. Our obser- update on current treatment approaches. Hematology 1997; 2: vations indicate that 2-CdA-related myelo- and immuno- 1–9. suppression occurs also in younger CLL patients, becoming 3 De Lima M, O’Brien S, Lerner S, Keating MJ. Chronic lymphocytic an important therapeutic problem. Betticher et al36 reported a leukemia in the young patient. Semin Oncol 1998; 25: 107–116. lower frequency of infections after a reduction of 2-CdA dose 4 Rozman C, Bosch F, Montserrat E. Chronic lymphocytic leukemia: from 0.7 mg/kg given intravenously to 0.5 mg/kg administered a changing natural history? Leukemia 1997; 11: 775–778. 5 French Cooperative Group on Chronic Lymphocytic Leukemia. subcutaneously in low-grade non-Hodgkin’s lymphoma Natural history of stage A chronic lymphocytic leukaemia patients. Interestingly, the efficacy of both schedules was simi- untreated patients. Br J Haematol 1990; 76: 45–57. lar, which indicates that a lower 2-CdA dose may be thera- 6 Catovsky D, Fooks J, Richards S. Prognostic factors in chronic lym- peutically successful being at the same time less toxic. phocytic leukaemia: the importance of age, sex and response to An alternative route for the reduction of myelosuppressive treatment in survival. A report from the MRC CLL 1 trial. Br J 2-CdA effect may be the administration of cytokine stimulat- Haematol 1989; 72: 141–149. 7 Lee JS, Dixon DO, Kantarjian HM, Keating MJ, Talpaz M. Prog- ing granulopoiesis (ie G-CSF) which decreased the frequency nosis of chronic lymphocytic leukemia: a multivariate regression of infections and neutropenia in CLL patients treated analysis of 325 untreated patients. Blood 1987; 69: 929–936. with FAMP from 37% in a historical control group to 8%.37 8 Molica S, Briugatelli M, Callea V, Morabito F, Levato D, Nobile Until now, there were no studies on the efficacy of thrombo- F, Alberti A. Comparison of younger versus older B-cell chronic poietin or IL-11 in preventing purine analog-related thrombo- lymphocytic leukemia patients for clinical presentation and prog- cytopenia. nosis. A retrospective study of 53 cases. Eur J Haematol 1994; 52: 216–227. The essential problem in younger patients treated with new 9 Byrd JC, Rai R, Sansville EA, Grever MR. Old and new therapies purine analogs for lymphoid malignancies is the monitoring in chronic lymphocytic leukemia: now is the time for a reassess- of minimal residual disease (MRD) in order to qualify them ment of therapeutic goals. Semin Oncol 1998; 25: 65–74. for bone marrow transplantation, thus offering a possibility for 10 Seymour JF, Robertson LE, O’Brien S, Lerner S, Keating MJ. Sur- recovery.38 Using monoclonal antibodies and FACS tech- vival of young patients with chronic lymphocytic leukemia failing nique, we searched for MRD in 17 CLL patients who achieved fludarabine therapy: a basis for use of myeloablative therapies. Leuk Lymphoma 1995; 18: 493–496. a CR according to hematological criteria. Immunophenotype 11 Montserrat E, Gomis F, Vallespi T. Presenting features and prog- 21 remission according to criteria proposed by Briugatelli et al nosis of chronic lymphocytic leukemia in younger adults. Blood was noted in 12 out of 17 (70.6% CLL) patients treated with 1991; 78: 1545–1551. 2-CdA and nine of them still remain in CR. These results are 12 Robertson LE, Hugh YO, Beutler JJ, Pugh WC, Hirsch-Ginsberg C, consistent with observations made by Robertson et al12 in CLL Stass S, Kantarjian H, Keating MJ. Response assessment in chronic patients treated with FAMP, who reported a complete eradi- lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, imunophenotypic and molecular analysis. Blood cation of leukemic clone in 89% of patients in CR and only 1991; 80: 29–36. in 19% of patients in PR according to hematological criteria. 13 Robak T, Błasin´ska-Morawiec M, Krykowski E, Kasznicki M, Moreover, MRD was undetectable exclusively in cases show- Hansz J, Komarnicki M, Konopka L, Durz˙yn´ski T, Ceglarek B, ing only lymphadenopathy at diagnosis. Progression-free sur- Sikorska A, Kotlarek-Haus S, Mazur M, Urasin´ski I, Zdziarska B, vival time in MRD-negative patients was longer than in Maj S, Kopec´ I, Skotnicki AB, Dwilewicz-Trojaczek J, Kuratowska patients with detectable MRD in bone marrow.12 Similar Z, Grieb P. Intermittent 2-hour intravenous infusions of 2-chlorodeoxyadenosine in the treatment of 110 patients with refractory or observations were made in CLL patients, who entered a CR previously untreated B-cell chronic lymphocytic leukemia. Leuk 21,39 after chlorambucil, COP or CHOP treatment. All these Lymphoma 1996; 22: 509–514. data indicate that the chance for achieving a durable CR or 14 Juliusson G, Liliemark J. High complete remission rate from 2- even recovery using new purine analogs in younger CLL chloro-2Ј-deoxyadenosine in previously treated patients with B- patients is low, so other therapeutic procedures should be cell chronic lymphocytic leukemia: response predicted by rapid searched for. 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