Cladribine prolongs progression-free survival and time to second treatment compared to fludarabine and high-dose chlorambucil in chronic lymphocytic leukemia.

We conducted a randomized phase III trial to compare the efficacy and safety of two purine analogs, cladribine and fludarabine, with high-dose chlorambucil, in patients with previously untreated chronic lymphocytic leukemia (CLL). Between 1997 and 2004, 223 patients with CLL were randomly assigned to cladribine, fludarabine or chlorambucil, for six cycles of therapy with frequent health-related quality of life assessments. There was no statistical difference for the primary endpoint of overall response with cladribine (70%), fludarabine (67%) and chlorambucil (59%), or complete remission (12%, 7% and 8%), respectively. However, the median progression-free survival (25, 10, 9 months) and median time to second treatment (40, 22, 21 months) were superior with cladribine. There was no significant difference in overall survival (96, 82 and 91 months), nor in toxicity or HRQoL assessments. Monotherapy with cladribine gives superior PFS and longer response duration than fludarabine and chlorambucil as first-line treatment of CLL.

Progression of bone marrow fibrosis in patients with essential thrombocythemia and polycythemia vera during anagrelide treatment.

Anagrelide is a second-line option for reduction of thrombocythemia in patients with chronic myeloproliferative disorders (CMPDs). A multicenter, open, phase II study of anagrelide treatment in 60 patients during 2 yr was performed by the Swedish Myeloproliferative Disorder Study Group. Adequate bone marrow biopsies were obtained from 53 of the CMPD patients [36 essential thrombocythemia (ET), 16 polycythemia vera (PV), 1 chronic idiopathic myelofibrosis (CIMF)] before treatment and compared with biopsies from 30 healthy volunteers and 34 patients with acute myeloid leukemia (AML). Higher reticulin and hyaluronan (HYA) scores were found before anagrelide therapy in the CMPD patients than in the normal controls (p < 0.001 and p < 0.001, respectively) and AML patients (p < 0.001 and p = 0.011, respectively). At the end of the study 30 CMPD patients were still on anagrelide treatment and in 19 of these patients, all diagnosed as ET (n = 16) or PV (n = 3), pretreatment bone marrow biopsies were compared with follow-up samples. After 2 yr of anagrelide therapy the reticulin and HYA scores were significantly higher than before treatment (p = 0.02 and p = 0.002, respectively). The cellularity was significantly higher (p = 0.014), although the number of megakaryocytes did not change significantly. The increase of reticulin and HYA in the bone marrow after 2 yr of treatment with anagrelide indicated progression of fibrosis. Although anagrelide is a valuable drug for reduction of platelet levels, it seems unable to stop progression of bone marrow fibrosis and hypercellularity in ET and PV.

Lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia derives from an extensively hypermutated B cell that lacks ongoing somatic hypermutation.

Lymphoplasmacytic lymphoma (LPL) is a rare lymphoma thought to originate from a B cell stimulated to differentiate to a plasma cell, and which is usually accompanied by clonal IgM secretion, defining the diagnosis of Waldenstrom's macroglobulinemia (WM). However, the immunoglobulin variable heavy chain (VH) gene usage and the somatic hypermutation status have not been widely investigated in LPL. LPL biopsies (CD19+/CD20+/CD22+/CD5-/CD10-/CD23-/kappa+) from 14 patients were included most of whom had a serum IgM component of variable magnitude (two cases with IgG). Highly mutated VH genes (mean mutation rate 8%) were revealed in 13 of 14 LPLs, whereas one case displayed a germline VH gene configuration. Cloning of the VH gene rearrangements in nine cases showed homogeneous sequences without intraclonal heterogeneity. Furthermore, no bias in the VH gene usage was shown, with VH3, VH4, and VH1 gene family members represented. These data confirm that the LPL precursor cell has been exposed to the germinal centre environment, as indicated by extensive hypermutation, but also that the transformation event occurred after affinity maturation, since there was a lack of intraclonal variation. Additionally, the VH gene repertoire was not skewed in LPL/WM as has been demonstrated in other B cell malignancies.

Bone marrow hyaluronan distribution in patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clonal disorder characterized by abnormal proliferation of myeloid cell precursors. Research has mainly focused on the cellular events, but the bone marrow matrix has attracted minor interest. In this study bone marrow biopsies were obtained from 35 newly diagnosed AML patients. The bone marrows were analyzed regarding the occurrence and distribution of hyaluronan (HYA) and reticulin fibers (type III collagen). The bone marrow sections were analyzed histochemically and compared with bone marrows from 30 healthy controls. The HYA staining was significantly stronger in the AML patients compared with the controls. Only one patient demonstrated abnormal reticulin staining score, but in the group of patients with antecedent myelodysplastic syndrome (MDS), the reticulin staining score was significantly higher compared with the patients with de novo AML. There was a significant correlation between the HYA staining and reticulin staining scores in the AML patients as was seen in the control group.

Localisation and distribution of hyaluronan in normal bone marrow matrix: a novel method to evaluate impending fibrosis?

Bone marrow trephine biopsies from 30 healthy volunteers, 10 men and 20 women aged 18-60 yr were obtained for identification and localisation of hyaluronan (HYA). Fixation, decalcification and embedding were performed by two different methods, with identical results in both. For comparison bone marrow trephine biopsies from three patients with different haematological diseases and known fibrosis were studied. All bone marrow specimens were also stained for reticulin grading. HYA was found in the bone marrow specimens from healthy individuals in a pattern that was concordant with the reticulin staining, the common way of visualising bone marrow fibrosis. In bone marrow from the patients with known fibrosis the HYA and reticulin staining were both more intense and abundant. Interestingly, HYA was also found intracellularly in eosinophilic cells in normal bone marrow. HYA is a polysaccharide unique both in structural and biological properties, and in excess it may predict bone marrow fibrosis.

Oral cladribine for B-cell chronic lymphocytic leukaemia: report of a phase II trial with a 3-d, 3-weekly schedule in untreated and pretreated patients, and a long-term follow-up of 126 previously untreated patients.

A phase II study was undertaken to evaluate the efficacy and toxicity of a new schedule of cladribine administration (10 mg/m2 orally daily for 3 d every 3 weeks) in 107 patients with B-cell chronic lymphocytic leukaemia (CLL). To minimize toxicity, treatment withdrawal criteria were defined. The results of the 63 previously untreated patients were retrospectively compared with 63 from an earlier study using a 5-d monthly schedule. The compiled data were analysed for prognostic factors for survival. No significant difference regarding response were seen in the two cohorts of the 126 previously untreated patients. The complete response (CR), nodular partial response (nPR) and partial response (PR) rates were 15%, 21% and 41%. Quality of response had no impact on survival. The 3- and 5-year overall survival for previously untreated patients was 73% and 58%, respectively, with a median follow-up of 54 months. Pretreatment haemoglobin <11.0 g/dl and elevated beta-2-microglobulin had a negative influence on survival. Major infections occurred in 21% of patients in the 3-d study compared with 35% in the 5-d study. The overall response (OR) and CR rates in the 40 previously treated patients were 34% and 5% respectively. Median overall survival was 24 months and median progression-free survival for responding patients was 14 months. Cladribine used as a single agent is an effective treatment with an acceptable safety profile for pretreated and untreated B-CLL. The achievement of complete remission was not a prerequisite for long-term survival.