Ferritinemia and serum inflammatory cytokines in Swedish adults with Gaucher disease type 1.

BACKGROUND: The storage of glucosylceramide in macrophages produces an inflammatory response in Gaucher disease type 1 (GD1) resulting in iron metabolism dysregulation and cytokine release. PATIENTS AND METHODS: The study included 16 adults with GD1 aged 20-86years. All but one patient carried at least one allele with the c.1226A>G (N370S) mutation in the GBA1 gene. Ferritinemia, iron metabolism profiles including hepcidin, and inflammatory cytokine concentrations were assessed in GD1 patients in Sweden. RESULTS: Hyperferritinemia was present in 81% of patients. There was no correlation between hyperferritinemia and patient's gender, spleen status, or clinical status. Hepcidin was discrepantly low in relation to ferritin levels. TNF-α was moderately increased in 5 of 11 patients; 2 patients with the highest TNF-α concentrations showed mildly elevated IL-6 levels. The concentrations of IL-1ß, IL-8, and IL-10 were normal in all patients. Upon treatment, ferritinemia ameliorated but S-ferritin levels did not normalize. The increased TNF-α level however, normalized in all treated patients, reaching the lowest values after 2years of therapy and continued to be stable during the remaining 2years of follow-up. CONCLUSIONS: Hyperferritinemia is a frequent finding in GD1 in Sweden. The relatively low hepcidin levels reveal a distorted relationship between hepcidin and ferritin in GD1. Therapy has the potential to not only ameliorate hyperferritinemia but to also normalize the serum TNF-α concentration in GD1.

Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in severe hemophilia A.

Recombinant VIII (rVIII)-SingleChain is a novel B-domain-truncated recombinant factor VIII (rFVIII), comprised of covalently bonded factor VIII (FVIII) heavy and light chains. It was designed to have a higher binding affinity for von Willebrand factor (VWF). This phase 1/3 study investigated the efficacy and safety of rVIII-SingleChain in the treatment of bleeding episodes, routine prophylaxis, and surgical prophylaxis. Participants were ≥12 years of age, with severe hemophilia A (endogenous FVIII <1%). The participants were allocated by the investigator to receive rVIII-SingleChain in either an on-demand or prophylaxis regimen. Of the 175 patients meeting study eligibility criteria, 173 were treated with rVIII-SingleChain, prophylactically (N = 146) or on-demand (N = 27). The total cumulative exposure was 14 306 exposure days (EDs), with 120 participants reaching ≥50 EDs and 52 participants having ≥100 EDs. Hemostatic efficacy was rated by the investigator as excellent or good in 93.8% of the 835 bleeds treated and assessed. Across all prophylaxis regimens, the median annualized spontaneous bleeding rate was 0.00 (Q1, Q3: 0.0, 2.4) and the median overall annualized bleeding rate (ABR) was 1.14 (Q1, Q3: 0.0, 4.2). Surgical hemostasis was rated as excellent/good in 100% of major surgeries by the investigator. No participant developed FVIII inhibitors. In conclusion, rVIII-SingleChain is a novel rFVIII molecule showing excellent hemostatic efficacy in surgery and in the control of bleeding events, low ABR in patients on prophylaxis, and a favorable safety profile in this large clinical study. This trial was registered at www.clinicaltrials.gov as #NCT01486927.

Rituximab, cladribine, and cyclophosphamide (RCC) induction with rituximab maintenance in chronic lymphocytic leukemia: PALG - CLL4 (ML21283) trial.

OBJECTIVES: PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS: The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS: In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P < .0001) significantly decreased the HR of disease progression. CONCLUSIONS: The study confirmed the high efficacy and acceptable safety profile of induction therapy with RCC and maintenance therapy with rituximab in previously untreated patients with CLL.

Primary Cardioprotection Reduces Mortality in Lymphoma Patients with Increased Risk of Anthracycline Cardiotoxicity, Treated by R-CHOP Regimen.

BACKGROUND: Advances in anti-lymphoma therapy prolong overall survival, making late adverse effects, like doxorubicin-related cardiotoxicity, an even more important clinical issue. The effectiveness of cardioprotective strategies with close monitoring, angiotensin-converting enzyme inhibitors and/or ß-blockers as well as liposomal doxorubicin are still unconfirmed in clinical practice. METHODS: This study evaluated the role of a primary cardioprotection strategy in preventing cardiovascular mortality and heart failure occurrence in non-Hodgkin lymphoma (NHL) patients with a high risk of anthracycline cardiotoxicity. Thirty-five NHL patients were subjected prospectively to ramipril and/or bisoprolol at NHL diagnosis, before implementing doxorubicin-containing regimens. Additionally, patients with a diagnosis of asymptomatic/mild heart failure received the liposomal form of doxorubicin. The clinical outcome and frequency of all serious cardiac events were compared with the results in a historical cohort of 62 high-risk cases treated without primary cardioprotection. RESULTS: NHL patients with a primary cardioprotection strategy did not experience cardiovascular deaths in contrast to the retrospective control group where cardiovascular mortality was 14.5% at 3 years (p < 0.05). Primary cardioprotection also decreased the frequency of new cardiotoxicity-related clinical symptoms (2.8 vs. 24.1%; p < 0.05) and prevented the occurrence of cardiac systolic dysfunction (0 vs. 8.5%, respectively; p < 0.05). Although the study was not planned to detect any survival benefit, it demonstrated a trend towards increased response rates (complete response 82 vs. 67%; p not significant) and prolonged survival (projected 5-year overall survival 74 vs. 60%; p < 0.05) for patients treated with primary cardioprotection. CONCLUSIONS: A primary personalized cardioprotection strategy decreases the number of cardiac deaths and may potentially prolong overall survival in NHL patients with increased risk of anthracycline cardiotoxicity.

Mild chronic graft-versus-host disease may alleviate poor prognosis associated with FLT3 internal tandem duplication for adult acute myeloid leukemia following allogeneic stem cell transplantation with myeloablative conditioning in first complete remission: a retrospective study.

Internal tandem duplication (ITD) of the FLT3 gene (Fms-like tyrosine kinase 3) is the most commonly found mutation in acute myeloid leukemia (AML). The significance of FLT3-ITD at diagnosis was retrospectively estimated for allo-HSCT (allogeneic hematopoietic stem cell transplantation) outcomes in 140 patients, median age of 38, undergoing allo-HSCT after myeloablative conditioning in first complete remission of AML. FLT3-ITD was detected at AML diagnosis in 42/140 (30%) of included into this study patients. At 3 years, relapse incidence (RI) following allo-HSCT in AML patients with intermediate or normal karyotype was significantly higher in those FLT3-ITD positive than FLT3-ITD negative [52.9 vs. 20.4%, P = 0.002]. Additionally, patients with mild chronic graft-versus-host disease (cGvHD) had significantly lower RI compared to patients with moderate or severe grade cGvHD or those not experiencing cGvHD, respectively, 4.8 vs. 36.0 vs. 27.8%, P = 0.032. FLT3-ITD was harboring a poor prognosis in AML with intermediate or normal karyotype and significantly increased risk of relapse following allo-HSCT. It appears that allo-HSCT does not cure patients with FLT3-ITD, unless they develop symptoms of mild cGvHD and graft versus leukemia, which may decrease RI.

[Psychological health's predictors of patients after bone marrow transplantation (BMT) 40 years of psychological researches of patients with blood cancers].

A study on the psychological health`s predictors of patents after BMT is presented. The theoretical base of researches is Helena Wrona- Polanska's Functional Model of Health (FMH Wrona-Polanska 2003), in which health is a function of creative coping with stress. 110 patients after BMT - 64 males and 46 females ­ at the Hematology Clinic of Jagiellonian University of Collegium Medicum, were studied clinically. Examined methods were the questionnaires: Spielberger`s STAI, Endler`s, Parker`s CISS and CHIP, Antonovsky`s SOC-29, Rosenberg`s self-esteem scale, 10-point rating scales: of sense of health, sense of calm and sense of anxiety. Objective health was examined by physician on the 10-point rating scale. Cluster analysis to show psychological health`s predictors of patients after BMT: level of stress, styles and effective coping strategies with stress, personal resources, temporal factor since transplantation and gender. The psychological predictors of health are the base of health promotion of patients after BMT.

CEBPA copy number variations in normal karyotype acute myeloid leukemia: Possible role of breakpoint-associated microhomology and chromatin status in CEBPA mutagenesis.

Copy number variations (CNV) in CEBPA locus represent heterogeneous group of mutations accompanying acute myeloid leukemia (AML). The aim of this study was to characterize different CEBPA mutation categories in regard to biological data like age, cytology, CD7, and molecular markers, and identify possible factors affecting their etiology. We report here the incidence of 12.6% of CEBPA mutants in the population of 262 normal karyotype AML (NK-AML) patients. We confirmed that double mutant AMLs presented uniform biological features when compared to single CEBPA mutations and accompanied mostly younger patients. We hypothesized that pathogenesis of distinct CEBPA mutation categories might be influenced by different factors. The detailed sequence analysis revealed frequent breakpoint-associated microhomologies of 2 to 12bp. The analysis of distribution of microhomology motifs along CEBPA gene showed that longer stretches of microhomology at the mutational junctions were relatively rare by chance which suggests their functional role in the CEBPA mutagenesis. Additionally, accurate quantification of CEBPA transcript levels showed that double CEBPA mutations correlated with high-level CEBPA expression, whereas single N-terminal CEBPA mutations were associated with low-level CEBPA expression. This might suggest that high-level CEBPA expression and/or accessibility of CEBPA locus contribute to B-ZIP in-frame duplications.

The roles of consolidation and maintenance therapy with novel agents after autologous stem cell transplantation in patients with multiple myeloma.

Novel agents including immunomodulatory drugs and proteasome inhibitors incorporated into induction regimens and subsequently followed by autologous stem cell transplantation in cases of multiple myeloma have resulted in enhancement of response rate and its depth. Maintaining or even improving the response is an important treatment goal. Most clinical trials have revealed increased progression-free survival after consolidation and maintenance therapy. Some of them have also shown prolongation of overall survival. However, continuous therapy may be associated with significant side effects and costs, and therefore remains controversial. Treatment decisions should be individualized and based upon projected benefits and risks.

Assessing the efficacy of allogeneic hematopoietic stem cells transplantation (allo-HSCT) by analyzing survival end points in defined groups of acute myeloid leukemia patients: a retrospective, multicenter Polish Adult Leukemia Group study.

The importance of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-HSCT. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999-2008. The Mantel-Byar approach was used to assess allo-HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo-HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41-60. The CIR demonstrated that allo-HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41-60. The allo-HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis.

[The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma]. / Rola mikrosrodowiska szpiku kostnego w patogenezie szpiczaka plazmocytowego.

Multiple myeloma (MM) is one of the most common hematologic malignancies. It remains an incurable disease, so far. The mainstay of treatment for decades was pointless therapy with cytostatic agents and immunosuppressant's. Because myeloma is most common in the elderly population, vulnerable to aggressive therapy, non-specific treatment approaches led to poor patient survival. Intensive study of MM, allowed identification of the molecular interactions between myeloma cells and bone marrow tumour microenvironment, responsible for the development of the disease and associated complications, such as osteolytic bone lesions. Understanding the molecular mechanisms of action of adhesion molecules, cytokines and signalling pathways involved in the development of myeloma, has led to develop of novel, targeted therapies to improve the quality of patients life and significantly prolong the median survival time. This paper discusses the current state of knowledge of signalling pathways involved in the progression of cancer and the destruction of bone tissue, with particular emphasis on interactions with the bone marrow microenvironment of the tumour.

[Thalidomide induced peripheral neuropathy in multiple myeloma patients]. / Polekowa neuropatia obwodowa u pacjentów ze szpiczakiem plaZmocytowym leczonych talidomidem.

INTRODUCTION: Thalidomide, a sedative popular in the 1950s and withdrawn from the market in the 1960s because of its teratogenic effects, has emerged again on the market in the last decade as an effective agent in the treatment of multiple myeloma. Unfortunately, apart from positive treatment effects, numerous side effects have been shown in multiple myeloma patients, including drug-induced damage to peripheral nerves, leading to clinical neuropathy. OBJECTIVES: A clinical and electrophysiological assessment of the prevalence of peripheral neuropathy in patients with multiple myeloma treated with thalidomide. PATIENTS AND METHODS: The study included 43 patients (19 women and 24 men) with a clinical diagnosis of multiple myeloma and treated with thalidomide (average dose, 100 mg/d). Patients with a history of disorders or the presence of factors leading to nervous system damage were excluded from the study. An electrophysiological assessment of motor and sensory fibers of the median, ulnar, peroneal, and tibial nerves was performed. RESULTS: Polyneuropathy was present in 27 patients. In addition, carpal tunnel syndrome coexisting with polyneuropathy was observed in 6 patients. Carpal tunnel syndrome was reported in 4 patients. Moreover, supracondylar damage to the ulnar nerve was reported in 1 patient and Guyon syndrome--in 1 patient. The results of the electrophysiological study were normal in 10 patients. CONCLUSIONS: Our study showed that over 60% of patients treated with thalidomide have peripheral nerve changes typical for peripheral neuropathy. Owing to the high risk of peripheral neuropathy in patients treated with thalidomide, we recommend a routine electrophysiological study in all patients with multiple myeloma in order to diagnose neuropathy at an early stage. Dose reduction or the use of an equally effective but less neurotoxic drug allows to prevent polyneuropathy, while maintaining the basic parameters of cancer treatment.

[Cutaneous involvement in multiple myeloma--case report and literature review]. / Zajecie skóry w przebiegu szpiczaka plazmocytowego--opis przypadku i przeglad literatury.

Cutaneous involvement in multiple myeloma is a very rare clinical problem. It occurs in less than 1% myeloma patients. Skin manifestation may be primary or secondary to MM. Primary involvement (PCP) according to the current WHO classification is one of the marginal zone lymphomas of the skin. PCP are characterized by significantly better prognosis than infiltrations secondary to MM. Skin manifestations require a thorough diagnosis to differentiate between myeloma-specific changes, MM-associated and non-specific skin disorders. Isolated primary infiltration can usually be successfully treated with radiation therapy or surgery. So far treatment of multiple and secondary to MM involvement are not satisfactory.

[Significant changes in diagnostic and therapeutic procedures in smoldering multiple myeloma]. / Znaczace zmiany w postepowaniu diagnostyczno-terapeutycznym w tlacej postaci szpiczaka plazmocytowego.

Smoldering multiple myeloma (SMM) is a precursor disease of multiple myeloma (MM) with an average annual risk of progression to MM of 10%. Several prognostic factors have been identified and combined in models to discriminate patient groups with different outcomes. These factors include size of the M-protein, plasma cell (PC) infiltration in the bone marrow (BM), serum free light-chain ratio, immunoparesis and percentage of aberrant BMPCs on flow cytometry or the presence of focal lesions on magnetic resonance imaging. The current standard of care has been to initiate treatment with progression to symptomatic MM. Current approaches aim at identifying patients with an ultra-high risk of progression (≥ 80% within the first 2 years) who are considered as 'early myeloma' patients requiring therapy. A recent trial on high-risk SMM patients, comparing early treatment with lenalidomide plus dexamethasone (Rd) versus observation, reported a benefit with respect to time to progression and survival for Rd-treated patients. Therefore, in 2014, the International Myeloma Working Group (IMWG) revised the diagnostic criteria and proposed to treat patients with ultra-high risk SMM as symptomatic MM. Promising markers for further studies may be high levels of circulating and high proliferative rate of PCs, abnormal PC phenotype with > 95% plus immunoparesis, evolving SMM, specific cytogenetic subtypes, genomic and additional biomarkers; all being acknowledged by the IMWG be added to the diagnostic criteria in the future, if any proves to be associated with a risk of progression of SMM to MM of at least 80% within 2 years.

Efficacy and safety of stem cell mobilization with cyclophosphamide plus etoposide versus cyclophosphamide alone.

The use of the combination of two cytostatics cyclophosphamide (CTX) and etoposide (VEP) and G-CSF is a reasonable alternative, especially for stem mobilization in multiple myeloma (MM) patients from countries in which newer treatments are limited due to financial constraints. The aim of this study was to compare the efficacy and safety of CTX-VEP versus CTX alone for mobilization of hematopoietic stem cells in MM patients. The analysis included 48 consecutive MM patients mobilized with CTX-VEP compared to 43 consecutive historical controls mobilized with CTX alone. The two groups of MM patients did not differ in terms of the median number of apheresis procedures, median yield the first day, median numbers of harvested CD34+ cells, proportion of patients with at least 5 x 106/kg yield and incidence of non-hematological complications. The median cumulative dose of G-CSF given to individuals in the CTX-VEP group was significantly lower than in the CTX group (p < 0.001). The incidence of post-mobilization thrombocytopenia was higher in the CTX group (p<0.001). The median time to platelet count > 20 x 109/l (10 vs. 11 days, p = 0.004) and the median time to neutrophil count > 50 x 109/l (11 vs. 13 days, p < 0.001) were significantly shorter among the patients mobilized with CTX-VEP than in those treated with CTX alone. These findings suggest that CTX-VEP is as efficacious and possibly safer than CTX alone.

[Daratumumab--breakthrough drug in multiple myeloma therapy]. / Daratumumab--przelomowy lek w terapii szpiczaka plazmocytowego.

Multiple myeloma (MM) remains incurable despite important recent advances in treatment. Over the last 2 years, an anti-CD38 monoclonal antibody daratumumab (DARA) has emerged as a breakthrough targeted therapy for patients with MM. Early-stage clinical trials have found DARA to be safe and to have encouraging clinical activity as a single agent and in combination with lenalidomide in heavily pretreated, relapsed patients in whom other novel agents (such as bortezomib, thalidomide and lenalidomide) as well as stem cell transplant has already failed. This review discusses the preclinical and clinical development of DARA, its pathophysiological basis, and its prospects for future use in MM.

[The importance of imaging techniques in the modern treatment of multiple myeloma]. / Znaczenie technik obrazowych w nowoczesnym leczeniu szpiczaka plazmocytowego.

The main symptom of multiple myeloma (MM) are pathological changes in bone. Imaging techniques are useful in determining the proper stage of the disease, follow-up after treatment and, as highlighted in recent times, in predicting prognosis and prediction. In the near future, radiographic examination of the whole body can be replaced by more sensitive techniques, such as low-dose computed tomography (CT) of the whole body. Magnetic resonance imaging (MRI) is a standard in the evaluation of bone marrow infiltration of the spine, allowing the prediction of the risk of vertebral fractures. Positron emission tomography (PET) coupled with CT (PET/CT) provides relevant information on the extent of lesions throughout the body, including soft tissues and is the best tool to distinguish active from inactive disease after treatment. Diagnostic imaging technique of PETIMR has the potential for precisely diagnosing in this condition. Prospective use of new imaging techniques in clinical practice in the near future will help to optimize the therapeutic management in individual cases of MM.

[Atypical BCR-ABL transcripts in patients with chronic myeloid leukemia--the scheme for the diagnosis and monitoring of minimal residual disease]. / Nietypowe odmiany transkryptu BCR-ABL u chorych na przewlekla bialaczke szpikowa--schemat postepowania diagnostycznego w monitorowaniu minimalnej choroby resztkowej.

More than 95% of patients with detected translocation t(9;22), is characterized by the fusion between exons e13 or e14 of BCR gene, which are located in major breakpoint cluster region (M-bcr) and exon a2 of ABL gene. These fusions are described as b2a2 (e13a2) and b3a2 (e14a2). Other fusions of exons e1, e6, e8, e12, e19, e20 of BCR gene with exons a2 or a3 of ABL gene occur very rarely and lead to formation of so called unusual fusion BCR-ABL genes. The aim of this study is to describe long-term observations of the occurrence and routine procedure in the diagnosis of atypical variants of the fusion gene BCR-ABL in a population of patients with chronic myeloid leukemia (CML). It was found that the vast majority of patients with detected BCR-ABL transcripts were b3a2 and b2a2. Other detected variants, which are described as rare were: e1a2, b2a3, b3a3, c3a2, e6a2, e6a3. At the stage of diagnosis as well as during monitoring of the effects of treatment, molecular methods which are based on polymerase chain reaction were used (multiplex RT-PCR, nested RT-PCR, RQ-PCR). Multiplex RT-PCR reaction gave possibility to detect variants of the fusion BCR-ABL gene in one reaction and was crucial in the selection of appropriate test used for further monitoring of the disease and the effectiveness of treatment. This paper proposes a scheme for dealing with the diagnosis and monitoring of minimal residual disease (MRD) in patients with CML treated with tyrosine kinase inhibitors (TKIs) in the presence of rare fusion of the BCR and ABL genes.

New drugs in multiple myeloma - role of carfilzomib and pomalidomide.

Carfilzomib (CFZ), an epoxyketone with specific chymotrypsin-like activity, is a second-generation proteasome inhibitor with significant activity in patients with relapsed and refractory multiple myeloma. On July 20, 2012, the US Food and Drug Administration approved CFZ to treat patients with multiple myeloma who have received at least two prior therapies including bortezomib (BORT) and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Cytogenetic abnormalities did not appear to have a significant impact on the CFZ activity. Carfilzomib was well tolerated and demonstrated promising efficacy in patients with renal insufficiency. Pomalidomide (POM) (CC-4047) is a novel immunomodulatory derivative (IMID) with a stronger in vitro anti-myeloma effect compared with "older" IMIDs - thalidomide and lenalidomide (LEN). On February 8, 2013, the US Food and Drug Administration approved POM (Pomalyst, Celgene) for the treatment of MM patients who have received at least two prior therapies including LEN and BORT and have demonstrated progression on or within 60 days of completion of the last therapy. Pomalidomide is a novel IMID with significant anti-myeloma activity and manageable toxicity. This compound has shown high efficacy in MM patients who were resistant to prior use of LEN/BORT as well as in patients with a high-risk cytogenetic profile. Carfilzomib and POM have very high efficacy and will be used also in first line therapy in future.

Immune thrombocytopenia in patients with chronic lymphocytic leukemia treated with cladribine-based regiments or chlorambucil--follow-up of PALG-CLL randomized trials.

OBJECTIVES: The relationship between treatments of chronic lymphocytic leukemia (CLL) with cladribine (2-CdA) or chlorambucil and immune thrombocytopenia (IT) has not been yet determined. METHODS: The records of 777 patients in two randomized Polish Adult Leukemia Group (PALG)-CLL programs treated with these agents were retrospectively analyzed. RESULTS: Immune thrombocytopenia occurred in 55 of 777 (7.1%) patients. No significant differences in IT prevalence were seen between patients on chlorambucil or 2-CdA-based regiments (P = 0.33). IT developed at a median time of 0.499 yr (0.06-4.8) from the start of CLL therapy. This time was significantly longer in patients treated with chlorambucil (2.03 yr, 95% CI: 0.06-4.22) in relation to patients treated with 2-CdA-based regiments (0.52 yr, 95%CI: 0.34-0.69, P = 0.049). Overall survival (OS) of patients with IT and those without IT were similar (2.65 yr vs. 3.2 yr P = 0.23) but the severity of bleeding was more pronounced in the 2-CdA group. The responses to IT therapy were 35%, 54% and 75% for steroids, chemotherapy and splenectomy, respectively. CONCLUSIONS: In this study, an unexpectedly high percentage of IT incidence was demonstrated in patients with CLL requiring chemotherapy. Although no marked differences were seen in IT frequency in patients treated with 2-CdA-based regiments compared to chlorambucil regimen, the clinical course of hemorrhagic diathesis was more severe in 2-CdA group. Also, the time elapsed from study screening to IT diagnosis was significantly shorter in the 2-CdA group than in the chlorambucil group suggesting a causative relationship. The appearance of IT did not influence the median time of OS.