Comparison of cladribine plus cyclophosphamide with fludarabine plus cyclophosphamide as first-line therapy for chronic lymphocytic leukemia: a phase III randomized study by the Polish Adult Leukemia Group (PALG-CLL3 Study).

PURPOSE Little is known about comparison of the activity of different purine nucleoside analogs in chronic lymphocytic leukemia (CLL). We conducted a randomized phase III trial to compare efficacy and safety of cladribine and fludarabine, each combined with cyclophosphamide, in previously untreated progressive CLL. PATIENTS AND METHODS Patients received cladribine at 0.12 mg/kg combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (CC regimen) or fludarabine at 25 mg/m(2) combined with cyclophosphamide at 250 mg/m(2) for 3 days intravenously (FC regimen), every 28 days for up to six cycles. The primary end point was complete response (CR) rate. Secondary end points included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and treatment-related toxicity. RESULTS Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms. CONCLUSION Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion.

Infectious complications in patients with acute myeloid leukemia treated according to the protocol with daunorubicin and cytarabine with or without addition of cladribine. A multicenter study by the Polish Adult Leukemia Group (PALG).

OBJECTIVES: The addition of cladribine to the standard regimen consisting of daunorubicin and cytarabine has been reported to increase the efficacy of induction therapy in acute myeloid leukemia (AML). The goal of this study was to determine the effect of this modification on the incidence and spectrum of infectious complications. METHODS: Case report forms of 309 patients with newly diagnosed AML who had been enrolled in the prospective, randomized 'DAC-7 vs. DA-7' trial were reviewed. The frequency, etiology, localization, severity, and outcome of infections were compared for patients receiving only daunorubicin and cytarabine (DA-7) and those additionally treated with cladribine (DAC-7). RESULTS: A total of 443 febrile episodes were reported with no significant difference between the treatment groups. A trend towards a higher frequency of bacteremias was observed among DA-7 patients compared to those in the DAC-7 group (31% vs. 21%; p=0.08). The treatment arms did not differ in terms of the distribution of the isolated Gram-positive, Gram-negative, fungal, and viral organisms. However, when bacteremias were considered, Gram-positive blood cultures tended to be more frequent in the DA-7 compared to the DAC-7 group (16% vs. 8.5%; p=0.07). This difference reached statistical significance when major blood bacteremias were analyzed separately (13% vs. 5%; p=0.02). Complete recovery from infections was observed in the majority of patients across both treatment arms and no significant difference was noted regarding infection-related mortality. CONCLUSIONS: The addition of cladribine to standard induction chemotherapy has no impact on the incidence and spectrum of infectious complications in newly diagnosed AML patients.

The effect of an antibiotic policy on the control of vancomycin-resistant enterococci outbreak and on the resistance patterns of bacteria isolated from the blood of patients in a hematology unit.

INTRODUCTION: Antibiotic resistance has become one of the main medical problems worldwide. This is mainly due to an overuse and misuse of antibiotics. OBJECTIVES: The aim of the study was to assess the effect of an antibiotic policy and enhanced infection control on the occurrence of epidemic strains of vancomycin-resistant enterococci (VRE) and resistance patterns of bacteria isolated from the blood of patients hospitalized in two departments of a hematology center in Poland. PATIENTS AND METHODS: Antibiotic use was calculated in daily defined doses (DDD) per 100 patient-days during the two 5-month periods, before and after the introduction of the policy. Infection control measures included a 1-week screening for VRE rectal carriage and contact isolation. RESULTS: Antibiotic consumption decreased from 82.1 to 57.3 DDD per 100 patient-days, mainly because of a decrease in the use of co-trimoxazole, other antimicrobials active against anaerobes, and cephalosporins. A significant change in antibiotic resistance patterns was observed and in vitro efficacy of antibiotics against bacteria isolated from the blood increased remarkably. We managed to eradicate the outbreak of VRE. CONCLUSIONS: The introduction of antibiotic policy and enhanced infection control measures may prove efficacious in VRE control.

Karyotype changes during long-term targeted therapy of chronic myeloid leukemia with imatinib.

The main risk factors during imatinib therapy of chronic myeloid leukemia are still subject to discussion. A group of 39 patients was cytogenetically examined and monitored before and during long-term treatment with imatinib. The cytogenetic response was investigated using karyotype analysis and fluorescence in situ hybridisation method. Different therapy effects were shown for three subgroups distinguished before the start of treatment: patients with the sole translocation t(9;22) with a typical pattern of BCR/ABL fusion vs. patients with submicroscopic deletion in the fusion region ABL/BCR of the sole t(9;22) vs. patients with aberrations additional to t(9;22) and without submicroscopic deletion. Of the two group with sole t(9;22) the group with deletion in the ABL/BCL region suffered a poorer treatment outcome than the group without deletion. The risk of progression of cytogenetic changes in group with deletion was more than nine times higher than in patients with sole t(9;22) without deletion (statistically significant).

Activity of cladribine combined with cyclophosphamide in frontline therapy for chronic lymphocytic leukemia with 17p13.1/TP53 deletion: report from the Polish Adult Leukemia Group.

BACKGROUND: The 17p13.1 deletion that causes loss of the p53-encoding TP53 gene is the most powerful predictor of a poor response to conventional therapy and shortened survival in patients with chronic lymphocytic leukemia (CLL). The results of this study have demonstrated that the cladribine and cyclophosphamide regimen may improve treatment results in this poor-risk patient population. METHODS: In this study, the authors retrospectively analyzed the efficacy and toxicity of 2-CdA with cyclophosphamide combination (the CC regimen) in 20 patients with previously untreated B-cell CLL who had 17p13.1 deletion reported to the Polish Adult Leukemia Group (PALG) registry. The CC regimen consisted of 2-CdA at a dose of 0.12 mg/kg and cyclophosphamide at a dose of 250 mg/m2 given intravenously for 3 consecutive days. The CC cycles were repeated at 28-day intervals for up to 6 cycles. RESULTS: Overall, 16 of 20 patients (80%) responded to CC therapy, including 10 patients (50%) who obtained a complete response and 6 patients (30%) who obtained a partial response. The median progression-free survival reached 23 months (95% confidence interval, 5-41 months). The overall survival probability at 2 years was 52.5% (95% confidence interval, 26%-79%). Treatment toxicity generally was acceptable. Infections were the most common grade 3/4 complications and occurred in 6 patients (30%). CONCLUSIONS: In this retrospective analysis, the results demonstrated that the CC regimen produced a relatively high response rate in patients with previously untreated CLL who had 17p13.1/TP53 deletion, although the response duration and survival were not satisfactory. It is possible that a combination of the CC regimen with p53-independent agents may improve treatment results in this poor-risk patient population.

Complete cytogenetic and molecular response after imatinib treatment for chronic myeloid leukemia in a patient with atypical karyotype and BCR-ABL b2a3 transcript.

The molecular hallmark of CML is the BCR-ABL fusion gene, usually with specific breakpoints within ABL intron 1 and BCR introns b2, b3, and e19. The amplification of the BCR-ABL hybrid gene resulting from additional copies of the Ph chromosome has been identified as a mechanism for imatinib (IM) resistance. Cytogenetic clonal evolution correlates with the accelerated phase of leukemia, whereas deletions in the derivative chromosome 9 are associated with a poor prognosis. Relevance in IM therapy is unclear. We report a case of a 39-year-old male with chronic phase CML. Cytogenetic studies showed a complex karyotype with additional copies of the Ph chromosome, sextasomy 8, and ASS gene deletion. An unusual aberrant fusion gene product was derived from the joining of BCR exon 13 (b2) and ABL exon 3 (a3). During IM treatment, the patient was monitored in 3- to 6-month intervals. Major cytogenetic response was achieved after 5 months; complete cytogenetic and molecular remission was reached after 8 months; after 22 months, normal karyotype and absence of the BCR-ABL product continued. Our data seem to confirm the data of others in regards to the b2a3 breakpoint, suggesting a better prognosis, regardless of other unfavorable factors.

Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial.

Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progression-free survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference -8.2%; 95% confidence interval [CI] -23.2% to 6.9%; P = .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI -4.3% to 7.0%; P = .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol.

Transformation in lymphomas--morphological, immunophenotypic and molecular features.

During the course of lymphoma, a clinically more aggressive process with different morphology may develop, referred to as lymphoma transformation. Clonal relationship and pathogenic mechanism of this process are widely debated. The aim of the study was to evaluate morphology, immunophenotype (including EBV status) and clonal relationship in nine cases of lymphoma transformation. Among the six patients with low grade B-cell lymphomas three transformed into high grade B-cell lymphomas (two into diffuse large B-cell lymphoma, one into Burkitt lymphoma) and three into Hodgkin lymphoma. Three other patients with Hodgkin lymphoma presented with transformation into diffuse large B-cell lymphoma in two patients and peripheral T-cell lymphoma in one patient. In all cases there was a sudden clinical change as well as change in morphology and phenotype. In five of the nine patients studied EBV-LMP1 was demonstrated by immunohistochemistry in large transformed lymphoma cells. In two cases molecular studies revealed a different pattern of immunoglobulin gene rearrangement in the large transformed cells as compared to the small cells of primary indolent lymphoma. Thus, they represented secondary, arising de novo neoplasm.

Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2).

In this prospective randomized trial, we compared the efficacy and toxicity of cladribine (2-CdA) alone to 2-CdA combined with cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC) in untreated progressive chronic lymphocytic leukemia (CLL). Study end points were complete response (CR), overall response, minimal residual disease (MRD), progression-free survival, overall survival, and toxicity. From January 1, 1998 to December 31, 2003, 508 patients from 15 hematology departments were randomized. Compared with 2-CdA, CMC induced higher CR rate (36% vs 21%, P = .004), and a trend for higher CR rate with CC was observed (29% vs 21%, P = .08). Furthermore, the percentage of patients who were in CR and were MRD negative was higher in CMC compared with 2-CdA (23% vs 14%, P = .042). There were no differences in overall response, progression-free survival, and overall survival among treatment groups. Grade 3/4 neutropenia occurred more frequently in CC (32%) and CMC (38%) than in 2-CdA (20%) (P = .01 and P = .004, respectively). Infections were more frequent in CMC compared with 2-CdA (40% vs 27%, P = .02). In conclusion, CMC used in first-line treatment of CLL results in a higher CR rate and suppresses MRD more efficiently than 2-CdA monotherapy, although associates with increased toxicity. No important differences in efficacy and toxicity were found between CC and 2-CdA regimens.

[A study to determine the safety and efficacy of imatinib mesylate in patients with chronic phase of chronic myeloid leukemia after interferon therapy failure. Four year follow-up]. / Ocena skutecznosci i bezpieczenistwa stosowania imatinibu mesylate u pacjentów z faza przewlekla przewleklej bialaczki szpikowej po niepowodzeniu leczenia interferonem 4 lata obserwacji.

UNLABELLED: Targeted therapy with the use of imatinib mesylate is a recognized option for patients with chronic myeloid leukemia (CML) not eligible for allogeneic hematopoietic cell transplantation. We present results of a multicenter phase II study on the use of imatinib in chronic phase after failure to interferon-alpha (IFN-alpha). Sixty patients (27 female, 33 male), median age 46 (range, 21-64), were included with hematologic relapse (n= 11), hematologic refractoriness (n=4), cytogenetic relapse/ /+65resistance (n=40) or intolerance to IFN-alpha (n=5). The median time from CML diagnosis was 39 months (range, 4-132), the median time of IFN-alpha therapy equaled 23 months (range, 1-78). Imatinib mesylate was administered at a dose of 400 mg/day for 1 year. In patients who achieved major cytogenetic response (MCR) the therapy was continued until progression. Thirty-three (55%) patients achieved MCR after one year of treatment. At 4 years the cumulative incidence of complete cytogenetic response equaled 40% (95% CI, 29-56). Among 27 patients who did not achieve MCR at 12 moths, in 12 cases the study course was discontinued prematurely because of blast crisis (n=9), prolonged neutropenia (n=l), severe transaminases elevation (n=l) or incidental death not related to the study drug or disease (n=l). The probability of OS at 4 years equaled 82% (95% CI, 72-91) and was lower for patients with the disease duration >36 months and those with Sokal index > or =0.8. Among patients who achieved MCR, the probability of progression-free survival was 78% (95% CI, 69-85). Time to progression (cytogenetic, n=6; blast crisis, n=l) varied from 3-36 months. CONCLUSIONS: Imatinib mesylate is characterized by good tolerance and allows achieving cytogenetic response in more than half of late chronic phase CML patients with failure of interferon therapy. However, the progression rate is substantial, which raises concern regarding the curative potential of monotherapy with imatinib in this group of patients.

Comparison of cladribine plus prednisone with chlorambucil plus prednisone in patients with chronic lymphocytic leukemia. Final report of the Polish Adult Leukemia Group (PALG CLL1).

BACKGROUND: We previously published an early report of a randomized, multicenter trial on the efficacy and toxicity of cladribine (2-CdA) + prednisone (P) compared with chlorambucil (Chl) + P in previously untreated patients with progressive or symptomatic chronic lymphocytic leukemia. Here we present the final report of this study. MATERIAL/METHODS: Of 229 patients, 126 received 2-CdA+P and 103 Chl+P. Patients with no response or progression after three courses or who relapsed earlier than 12 months after completing one treatment were switched to the other. Patients who relapsed later were retreated with the same schedule as before. RESULTS: Thirty-three patients were retreated with 2-CdA+P and 19 with Chl+P. Overall response (and complete response) rates were 35% (6%) and 47% (16%), respectively. In 50 patients initially treated with Chl+P and then with 2-CdA+P, complete response (CR) was achieved in 12 (24%) and overall response (OR) in 32 (64%). In 28 patients originally treated with 2-CdA+P and then with Chl+P, CR in 1 (3%, p=0.01) and OR in 6 (21%, p=0.003) were obtained. We found no statistically significant difference in overall survival time in patients treated initially with 2-CdA+P and Chl+P aged 60 years (4.63 and 5.27 years, respectively, p=0.45), 60-70 years (3.29 and 3.14 years, p=0.79), and >70 years (1.53 and 1.93 years, p=0.11). CONCLUSIONS: 2-CdA+P is significantly more effective as a second-line treatment and re-treatment than Chl+P. However, we found a trend to longer survival in elderly patients treated with Chl+P.

Re-treatment with cladribine-based regimens in relapsed patients with B-cell chronic lymphocytic leukemia. Efficacy and toxicity in comparison with previous treatment.

The aim of the study was to determine the effectiveness and toxicity of cladribine (2-CdA) used alone or in combination with prednisone (P) or cyclophosphamide and mitoxantrone in re-treatment of patients with progressive B-cell chronic lymphocytic leukemia (B-CLL). We analyzed treatment outcome in 40 patients who had responded to previous treatment with 2-CdA-based regimens. Criteria for re-treatment were the same as for the first treatment. The patients were retreated with the same agents if they responded to the first treatment and then relapsed with progressive disease not earlier than 3 months after achieving the first response. Eight patients received 2-CdA alone (0.12 mg kg(-1) d(-1)) i.v. for 5 d, and 21 patients additionally were given P (30 mg m(-2) d(-1)) orally, also for 5 d. Eleven patients received 2-CdA for 3 d combined with cyclophosphamide (650 mg m(-2)) i.v. and mitoxantrone (10 mg m(-2)) i.v. on day 1 (CMC regimen). The cycles were repeated usually at 4 wk intervals or longer if severe myelosuppression or infections occurred. The therapy was finished if complete remission (CR) was achieved or until maximum of six courses. Overall response (OR) in re-treatment was obtained in 16 out of 40 (40%) patients (95% CI 16-64), including 62% after 2-CdA, 33% after 2-CdA +P and 36% after CMC. CR was obtained in four (10%) patients. Residual disease evaluated in the patients with CR by surface immunophenotyping had been demonstrated in 5 out of 16 (31%) patients after the first treatment and in one out of four (25%) patients after re-treatment. The median progression-free survival (PFS) was 16 months (range 3-39) for the first treatment and 9.5 months (range 3-18) for re-treatment (P=0.34). Grade III or IV neutropenia was observed in 20% patients during the first treatment and in 35% patients during re-treatment (P=0.1). 2-CdA-induced thrombocytopenia occurred in 20% and 42% of the patients, respectively (P=0.05). Anemia was also more frequent during re-treatment (35%) than during the first treatment (7%) (P=0.007). Autoimmune hemolytic anemia developed in four (10%) of the patients during or after re-treatment. Severe infections, including pneumonia and herpes reactivation, occurred in 11 patients during the first treatment and in 10 patients during re-treatment. Twelve (30%) patients died during the study. Infections were the cause of death in six and AIHA in two patients. In conclusion, 2-CdA applied in monotherapy or in combination with prednisone or cyclophosphamide and mitoxantrone has therapeutic activity in some B-CLL patients in whom these drugs induced earlier complete or partial remission. However, since the second response is usually shorter and myelotoxicity more pronounced than during the first therapy, more clinical trials to find other therapeutical approaches are necessary.

Enrichment of normal progenitors in counter-flow centrifugal elutriation (CCE) fractions of fresh chronic myeloid leukemia leukapheresis products.

OBJECTIVES: The aim of this study was to assess the suitability of a technique based on counter-flow centrifugal elutriation (CCE), which should allow one to enrich chronic myeloid leukemia (CML) patients' unstimulated native leukapheresis product (nLP) in CD34+ HLADR- cells and BCR-ABL negative cells. METHODS: Six newly diagnosed CML patients were subjected to leukapheresis, and the products were subfractionated with the use of CCE. nLP and all fractions were studied for the presence of CD34+ cells and a proportion of BCR-ABL fluorescence in situ hybridization (FISH)+ cells. RESULTS: CCE fractions with a high flow rate contained the highest proportion of CD34+ cells [mean (SEM) 6.89% (3.88)]. However, CD34+ cells present in low-rate CCE fractions showed a higher proportion of HLADR-[49.6% (13.5 in 70 mL min-1) and 21.5% (11.6 in 110 mL min-1)] than those in 170 mL min-1[3.2% (2.5)] and "rotor off" [3.4% (1.9)]. This was associated with lower proportions of BCR-ABL FISH+[8.1% (4.8) and 1.9 (1.7)] and smaller BCR-ABL to ABL transcript ratios [0.58 (17) and 0.26 (0.08) in 70 and 110 mL min-1] fractions as compared to 140 and 170 mL min-1 fractions [21.6% (5.2) and 31.6% (15.3) for BCR-ABL FISH+ cells and 0.75 (0.16) and 0.90 (0.24) for BCR-ABL/ABL]. Fractions with the lowest proportions of BCR-ABL-positive cells and the lowest BCR-ABL/ABL transcript ratios (110 mL min-1) contained from 1.3 x 106 to 82.7 x 106 (median: 3.97 x 106) CD34+ cells. CONCLUSIONS: In the present study we have shown that CCE may be used effectively to obtain nLP fractions enriched in normal hematopoietic progenitors.

G-CSF administered in time-sequenced setting during remission induction and consolidation therapy of adult acute lymphoblastic leukemia has beneficial influence on early recovery and possibly improves long-term outcome: a randomized multicenter study.

Sixty-four untreated adult acute lymphoblastic leukemia (ALL) patients were randomized to receive chemotherapy alone, n = 31 or chemotherapy and granulocyte colony stimulating factor (G-CSF), n = 33. During induction patients received G-CSF for 5 days between four weekly Epirubicin+Vcr administrations, starting 36 h after each application and finishing 48 h before the next one with the intention to possibly generate a cell cycle dependent protection of normal hematopoietic progenitors and to stimulate granulopoiesis. The complete remission (CR) rate equaled 94% in the G-CSF group and 87% in controls. Patients who received G-CSF, if compared to the controls, had shorter granulocytopenia during induction and consolidation, displayed a lower infection rate, completed the induction-consolidation quicker and stayed shorter in hospital during induction, p < 0.001-0.04. Follow-up at 2 years revealed a rather higher probability of survival (59 vs. 27%, p = 0.04) and a lower relapse rate (32 vs. 60%) in G-CSF arm than in controls. The beneficial influence of G-CSF administered in time-sequenced fashion on survival needs further confirmation.