David A. G. Galton

Proposals for the Classification of the Acute Leukaemias French-American-British (FAB) Co-operative Group

Summary. A uniform system of classification and nomenclature of the acute leukaemias, at present lacking, should permit more accurate recording of the distribution of cases entered into clinical trials, and could provide a reference standard when newly developed cell‐surface markers believed to characterize specific cell types are applied to cases of acute leukaemia. Proposals based on conventional morphological and cytochemical methods are offered following the study of peripheral blood and bone‐marrow films from some 200 cases of acute leukaemia by a group of seven French, American and British haematologists. The slides were examined first independently, and then by the group working together. Two groups of acute leukaemia,‘lymphoblastic’and myeloid are further subdivided into three and six groups. Dysmyelopoietic syndromes that may be confused with acute myeloid leukaemia are also considered. Photomicrographs of each of the named conditions are presented.

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...

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.

Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French-American-British (FAB) Cooperative Group.

Peripheral blood, bone marrow films, and bone marrow biopsy specimens from 110 patients, well characterised by clinical and laboratory studies, including electron microscopy, were reviewed, to determine proposals for the classification of chronic (mature) B and T cell leukaemias. On the basis of cytology and membrane phenotype the following disorders were defined: (i) B cell type: chronic lymphocytic leukaemia (CLL); CLL of mixed cell type, which includes cases with more than 10% and less than 55% prolymphocytes (CLL/PL), and a less well defined form with pleomorphic lymphocytes but less than 10% prolymphocytes; prolymphocytic leukaemia (PLL); hairy cell leukaemia (HCL); HCL variant; splenic lymphoma with circulating villous lymphocytes; leukaemic phase of non-Hodgkins lymphoma (follicular lymphoma, intermediate, or mantle zone lymphoma and others); lymphoplasmacytic lymphoma with peripheral blood disease (mostly Waldenströms macroglobulinaemia); and plasma cell leukaemia. (ii) T cell type: T/CLL, which was differentiated from reactive T/lymphocytosis; T/PLL; adult T cell leukaemia/lymphoma; and Sézarys syndrome. The recognition of distinct entities within the B and T cell leukaemias seems to have clinical and epidemiological connotations. It is hoped that these proposals may serve as the basis for further work, discussion, and improved management of patients.

Septicaemia caused by viridans streptococci in neutropenic patients with leukaemia.

10 neutropenic leukaemic patients had septicaemia caused by viridans streptococci, organisms not commonly recognised as opportunist pathogens. 1 patient died; in the remainder recovery was generally dependent on an adequate circulating granulocyte count (seven patients) rather than specific antimicrobial therapy. Seven of the infections were caused by Streptococcus mitis, and seven of the eight strains tested were resistant to cotrimoxazole, which the patients had received as prophylaxis against infection. It is suggested that oral ulceration caused by cytotoxic chemotherapy provided a portal of entry for cotrimoxazole-resistant viridans streptococci. The increasing incidence of infections with gram-positive organisms as a complication of neutropenia prompts a reconsideration of current empirical antimicrobial therapy.

The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. I. Clinical and laboratory features of 300 patients and characterization of an intermediate group.

Summary. The clinical and laboratory features of 300 patients with chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL) of B‐cell type were studied in order to investigate the relationship between these two diseases. Statistical analysis demonstrated that more than 55% circulating prolymphocytes (PROL) was a defining criterion for PLL, disorder characterized by marked splenomegaly without lymph‐node enlargement, cells with high density of membrane‐immunoglobulin (Smlg), low mouse‐rosettes (M‐rosettes) and strong reactivity with the monoclonal antibody FMC7. Patients with typical CLL, defined as having less than 10% PROL, were on average 10 years younger than those with PLL and showed preferential lymph‐node to spleen involvement. Characteristic markers of CLL were weak Smlg, high M‐rosettes and low reactivity with FMC7. Patients with 11‐55% PROL, group designated as CLL/PL, were found to have intermediate features between CLL and PLL: the degree of splenomegaly was disproportionate to the lymph‐node enlargement, the number of cases with strong Smlg was closer to that found in PLL, but the other markers were not significantly different from CLL. The CLL/PL group appeared to be heterogeneous and includes at least two types of CLL, one with increased proportions of PROL but otherwise typical disease, and another in ‘prolymphocytoid’ transformation. Our study suggests that although PLL cannot be considered as the extreme end of a continuous spectrum from typical CLL, the spleen may be the source of PROL both in PLL and in CLL/PL.

'Prolymphocytoid' transformation of chronic lymphocytic leukaemia.

Summary. We report clinical, morphological and surface marker studies on seven patients with the common type of chronic lymphocytic leukaemia (CLL) whose disease underwent an insidious though progressive change in character with increasing refractoriness to treatment. This transformation was accompanied by the appearance of a population of immature‐appearing cells in the peripheral blood which resembled prolymphocytes, both at light and electron microscopy. The characteristic morphological feature was the presence of two distinct populations of cells, the typical CLL lymphocytes and the ‘prolymphocytoid’ cells. These cells retained the surface marker characteristics of CLL, i.e. the formation of mouse RBC rosettes and sparse surface‐bound immunoglobulin. This transformation can be distinguished by morphological and surface marker criteria from acute leukaemia occurring in CLL, Richters syndrome and prolymphocytic leukaemia. The recognition of this group of CLL patients may add a new prognostic index to CLL and may help plan subsequent trials for the treatment of the disease.

Mouse Red-Cell Rosettes in B-Lymphoproliferative Disorders

Summary. A high proportion of peripheral‐blood lymphocytes formed spontaneous rosettes with mouse red cells in 22 out of 23 cases of chronic lymphocytic leukaemia (CLL); the proportion was significantly higher than in 19 cases of other B‐lymphoproliferative disorders (non‐CLL group) and in 19 normal controls. Intermediate findings were obtained in 10 cases of ‘hairy’ cell leukaemia. Blast cells from various types of acute leukaemia did not bind mouse red cells. Pre‐treatment of the lymphocytes with neuraminidase led to a significant increase in the proportion of rosettes in CLL only. This test may prove useful in distinguishing CLL from other B‐lymphoproliferative disorders, particularly prolymphocytic leukaemia.

The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. IV: Analysis of survival and prognostic features

The prognostic value of biological, clinical and laboratory features was analysed in a series of 265 patients with chronic lymphocytic leukaemia (CLL) and prolymphocytic leukaemia (PLL). On univariate analysis seven features were shown to influence significantly the survival of the whole group of patients: absolute prolymphocyte count (ABS PROL), percentage of prolymphocytes (%PROL), WBC, spleen size, age, intensity of surface‐membrane immunoglobulin (SmIg) and mouse (M) rosettes. Multivariate regression analysis of these features showed that only ABS PROL and spleen size had independent prognostic significance. The survival in PLL (38 cases) was significantly shorter than in CLL (227 cases) (median survival=3 and 8 years, respectively). Patients with CLL with an increased %PROL (11–55%), defined as CLL/PL, could be divided into two groups: those with ABS PROL ≤ 15 × 109/1 (26 cases) fell within the ‘standard‐prognostic risk’ for typical CLL (i.e. ≤ 10% PROL), whereas the survival outlook for the cases with ABS PROL > 15 × 109/1 (40 cases) was as bad as for PLL. A scoring system was generated with the four features that showed high prognostic significance: ABS PROL, spleen size, SmIg and M‐rosettes. The score proved to be superior to any single feature as a predictor of survival, being especially useful in the analysis of the CLL/PL group: cases with high scores (>2) had a median survival of 2·5 years, while the median has not been reached for those with low scores (≤2). We suggest that this scoring system may help to identify the cases of CLL/PL that behave as PLL, and as such may benefit from different treatment.

Clinical staging and immunological findings in chronic lymphocytic leukemia

Several immunological markers were tested in 52 untreated cases of chronic lymphocyte leukemia (CLL) to see whether their frequency differed according to the clinical stage in Rais system. The leukemic cells in all cases had B‐cell features as shown by monoclonal immunoglobulins on the cell surface (SmIg) and/or a high percentage of mouse RBC (M)‐rosettes. Of the two B‐cell markers, the M‐rosette test was the more consistently positive. The frequency of these markers did not correlate with clinical staging. The percentage of T‐lymphocytes, low in all cases, was found to correlate inversely with the lymphocyte counts, which were higher in advanced stages. The absolute number of T‐lymphocytes was above normal in most cases, but did not relate to staging. At least one of the serum Ig, most commonly IgA, was decreased in 87% of cases. Low Ig were slightly less common in Stages 0‐I than in advanced stages (II‐IV). The above features were also examined in two groups of CLL patients: with stable (9) or progressive (16) disease.The only difference observed between the two groups was that surface IgM only was present in 1 of the 9 stable cases as compared to 9 of the 16 progressive ones. Our findings do not support the suggestions that surface IgM is a feature of a benign form of CLL or that the absolute number of T‐lymphocytes correlates with prognosis. Cancer 44:483‐487, 1979.