Daniel Catovsky

Proposed Revised Criteria for the Classification of Acute Myeloid Leukemia: A Report of the French-American-British Cooperative Group

Excerpt The first proposals for the morphologic classification of the acute leukemias by the French-American-British (FAB) group (1) were put forward in the hope that they might serve as a basis fo...

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines

Standardized criteria for diagnosis and response assessment are needed to interpret and compare clinical trials and for approval of new therapeutic agents by regulatory agencies. Therefore, a National Cancer Institute-sponsored Working Group (NCI-WG) on chronic lymphocytic leukemia (CLL) published guidelines for the design and conduct of clinical trials for patients with CLL in 1988, which were updated in 1996. During the past decade, considerable progress has been achieved in defining new prognostic markers, diagnostic parameters, and treatment options. This prompted the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) to provide updated recommendations for the management of CLL in clinical trials and general practice.

Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial

BACKGROUND Previous studies of patients with chronic lymphocytic leukaemia reported high response rates to fludarabine combined with cyclophosphamide. We aimed to establish whether this treatment combination provided greater survival benefit than did chlorambucil or fludarabine. METHODS 777 patients with chronic lymphocytic leukaemia requiring treatment were randomly assigned to fludarabine (n=194) or fludarabine plus cyclophosphamide (196) for six courses, or chlorambucil (387) for 12 courses. The primary endpoint was overall survival, with secondary endpoints of response rates, progression-free survival, toxic effects, and quality of life. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number NCT 58585610. FINDINGS There was no significant difference in overall survival between patients given fludarabine plus cyclophosphamide, fludarabine, or chlorambucil. Complete and overall response rates were better with fludarabine plus cyclophosphamide than with fludarabine (complete response rate 38%vs 15%, respectively; overall response rate 94%vs 80%, respectively; p<0.0001 for both comparisons), which were in turn better than with chlorambucil (complete response rate 7%, overall response rate 72%; p=0.006 and 0.04, respectively). Progression-free survival at 5 years was significantly better with fludarabine plus cyclophosphamide (36%) than with fludarabine (10%) or chlorambucil (10%; p<0.00005). Fludarabine plus cyclophosphamide was the best combination for all ages, including patients older than 70 years, and in prognostic groups defined by immunoglobulin heavy chain gene (V(H)) mutation status and cytogenetics, which were tested in 533 and 579 cases, respectively. Patients had more neutropenia and days in hospital with fludarabine plus cyclophosphamide, or fludarabine, than with chlorambucil. There was less haemolytic anaemia with fludarabine plus cyclophosphamide (5%) than with fludarabine (11%) or chlorambucil (12%). Quality of life was better for responders, but preliminary analyses showed no significant difference between treatments. A meta-analysis of these data and those of two published phase III trials showed a consistent benefit for the fludarabine plus cyclophosphamide regimen in terms of progression-free survival. INTERPRETATION Fludarabine plus cyclophosphamide should now become the standard treatment for chronic lymphocytic leukaemia and the basis for new protocols that incorporate monoclonal antibodies.

Criteria for the Diagnosis of Acute Leukemia of Megakaryocyte Lineage (M7): A Report of the French-American-British Cooperative Group

For the diagnosis of M7, the bone marrow aspirate shows a leukemic cell infiltrate that comprises 30% or more of all cells. These cells are identified as being of megakaryocyte lineage by the platelet peroxidase reaction on electron microscopy or by tests with monoclonal or polyclonal platelet-specific antibodies. Myelofibrosis or increased bone marrow reticulin are a prominent aspect in most patients with M7. In patients with increased reticulin, the bone marrow sample may be difficult to obtain and the counts done on the marrow films may be misleading. In these patients, the diagnosis of M7 should be based on excellent bone marrow biopsy sections that show an excess of blasts and, at times, increased numbers of maturing megakaryocytes; and on the presence of unequivocal megakaryoblasts in the peripheral blood or bone marrow (or both) as shown by immunologic techniques.

Phase II multicenter study of human CD52 antibody in previously treated chronic lymphocytic leukemia. European Study Group of CAMPATH-1H Treatment in Chronic Lymphocytic Leukemia.

PURPOSE CAMPATH-1H is a human immunoglobulin G1 (IgG1) anti-CD52 monoclonal antibody (MAb) that binds to nearly all B- and T-cell lymphomas and leukemias. We report the results of a multicenter phase II trial that used CAMPATH-1H in previously chemotherapy-treated patients with chronic lymphocytic leukemia (CLL). MATERIALS AND METHODS Twenty-nine patients who had relapsed after an initial response (n = 8) or were refractory (n = 21) to chemotherapy were treated with CAMPATH-1H administered as a 30-mg 2-hour intravenous (IV) infusion thrice weekly for a maximum period of 12 weeks. RESULTS Eleven patients (38%) achieved a partial remission (PR) and one (4%) a complete remission (CR) (response rate, 42%; 95% confidence interval [CI], 23% to 61%). Three of eight patients (38%) with a relapse and nine of 21 refractory patients (43%) responded to CAMPATH-1H therapy. CLL cells were rapidly eliminated from blood in 28 of 29 patients (97%). CR in the bone marrow was obtained in 36% and splenomegaly resolved completely in 32%. Lymphadenopathy was normalized in only two patients (7%). The median response duration was 12 months (range, 6 to 25+). World Health Organization (WHO) grade IV neutropenia and thrombocytopenia developed in three (10%) and two patients (7%), respectively. Neutropenia and thrombocytopenia recovered in most responding patients during continued CAMPATH-1H treatment. Lymphopenia (< 0.5 x 10(9)/L) occurred in all patients. Two patients had opportunistic infections and four had bacterial septicemia. CONCLUSION CAMPATH-1H had significant activity in patients with advanced and chemotherapy-resistant CLL. The most pronounced effects were noted in blood, bone marrow, and spleen. Preferential clearance of blood may allow harvesting of uncontaminated blood stem cells for use in high-dose chemotherapy protocols.

The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group.

Summary. We have reviewed our experience with four of the entities that are included under the generic term chronic myeloid leukaemia (CML), namely the classic Ph+ CGL, both BCR+ and BCR−, aCML and CMML. We have developed a statstical model that confirms that CGL, aCML and CMML can be distinguished from each other with reasonable success employing five quantitative parameters (WBC, percentage immature granulocytes, percentage monocytes, percentage basophils, percentage erythroid precursors in bone marrow) and one qualitative parameter (granulocytic dysplasia). It is hoped that these detailed recommendations will enable investigators to improve their diagnostic accuracy. This should permit more uniform comparisons of molecular biologic and clinical studies.

A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia

We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 × 10−10), 2q37.1 (rs13397985, SP140; P = 5.40 × 10−10), 6p25.3 (rs872071, IRF4; P = 1.91 × 10−20), 11q24.1 (rs735665; P = 3.78 × 10−12), 15q23 (rs7176508; P = 4.54 × 10−12) and 19q13.32 (rs11083846, PRKD2; P = 3.96 × 10−9). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.

1,25-dihydroxyvitamin D3 inhibits proliferation of human promyelocytic leukaemia (HL60) cells and induces monocyte-macrophage differentiation in HL60 and normal human bone marrow cells

1,25-dihydroxyvitamin D3 induces monocyte-macrophage differentiation and inhibits proliferation of cells from the human promyelocytic leukaemia cell line HL60. Similarly human bone marrow progenitor cells differentiate preferentially along the monocyte-macrophage pathway when incubated in the presence of 1,25-dihydroxyvitamin D3. We suggest that the inhibition of growth which occurs after addition of the vitamin to HL60 might be paralleled in vivo by inhibition of proliferation of leukaemic cells; also we speculate that the vitamin may be involved in the control of both monocyte-macrophage and osteoclast production in vivo.

Levels of expression of CD19 and CD20 in chronic B cell leukaemias

AIMS: To investigate whether the antigen levels of the B cell lineage markers CD19 and CD20 can distinguish between normal and neoplastic B cells or characterise distinct expression patterns among the chronic B cell leukaemias. METHODS: Peripheral blood cells from 70 patients with B cell disorders and 17 healthy donors were analysed by quantitative flow cytometry. Direct immunofluorescence staining was performed with phycoerythrin conjugated CD19 and CD20 monoclonal antibodies. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity (MFI) values into number of antigen molecules/cell, expressed as antibody binding capacity (ABC). RESULTS: CD19 and CD20 ABC values in leukaemic B cells differed from those of normal blood B lymphocytes. The results identified distinct profiles of CD19 and CD20 expression in the various types of B cell leukaemias. In all leukaemias studied except hairy cell leukaemia (HCL), CD19 expression was significantly lower than the mean (SD) value in normal B cells (22 (7) x 10(3) molecules/cell), as follows: chronic lymphocytic leukaemia (CLL), 13 (7) x 10(3); B prolymphocytic leukaemia (B-PLL), 16 (9) x 10(3); splenic lymphoma with villous lymphocytes (SLVL), 15 (11) x 10(3); mantle cell lymphoma (MCL), 10 (7) x 10(3). In HCL there was strong CD19 expression (38 (16) x 10(3)). In contrast, the level of expression of membrane CD20 was higher than the mean (SD) value in normal B cells (94 (16) x 10(3) molecules/cell) in MCL (123 (51) x 10(3)); B-PLL (129 (47) x 10(3)); SLVL (167 (72) x 10(3)); and HCL (312 (110) x 10(3)); while it was significantly lower (65 (11) x 10(3)) in CLL compared with normal B cells and the other B cell leukaemias. CONCLUSIONS: Quantitative determination of CD19 and CD20 may provide useful diagnostic information for the study of B lymphoproliferative disorders.

Levels of expression of CD52 in normal and leukemic B and T cells: Correlation with in vivo therapeutic responses to Campath-1H

The CD52 antigen is expressed on most normal and neoplastic lymphoid cells. The reshaped humanized IgG1 anti-CD52 monoclonal antibody (Campath-1H) has been used in the treatment of hemopoietic and non-hemopoietic diseases for its ability to induce lymphocyte depletion both in vitro and in vivo. Good activity has been shown in patients with chronic T and B cell leukemias, in particular T-prolymphocytic leukemia (T-PLL). However, the response to treatment is not uniform and this variability may depend on differences in the level of antigen expression on the leukemic cells. To test this hypothesis, we used quantitative flow cytometry to investigate the intensity of the expression of CD52 in 45 cases of lymphoid leukemia, 24 with B-cell chronic lymphocytic leukemia (CLL), 21 with T-PLL and 12 normal controls. Normal T lymphocytes expressed higher CD52 antigen than B lymphocytes (p < 0.005) and the antigen was also significantly higher in T-PLL compared to CLL (p < 0.001). Moreover, the differences in CD52 expression were somewhat higher in Campath-1H treated patients who responded than in non responders. Although other factors may play a role in the response to Campath-1H in vivo, the quantitative estimation of CD52 expression may provide a rationale for the greater response in T-PLL and help select those patients with a higher probability of responding to this therapy.