During B cell development, immunoglobulin heavy chain (IgH) variable region (VH) genes are rearranged and expressed in a programmed manner and accumulating evidence suggests recurrent utilization of developmentally restricted VH genes in malignant B lymphoid populations. We have used polymerase chain reaction gene amplification in conjunction with a panel of VH family-specific amplimers to directly compare the repertoire of VH region rearrangement in mature, CD5+ B cell chronic lymphocytic leukemia with that in immature, CD5 B lineage acute lymphoblastic leukemia. The results revealed a diverse pattern of VH family utilization common to both disease groups in which VH regions most proximal to the IgH joining locus were preferentially rearranged relative to their family sizes with recurrent utilization of several known developmentally restricted VH genes in close to germ-line configuration. These results indicate that biased VH family usage is independent of tumor cell phenotype in B lineage leukemias. This bias may reflect similar stages or compartments in normal B lymphopoiesis from which diverse types of B cell malignancy may arise. Moreover, since blast cells in acute lymphoblastic leukaemia do not express functional immunoglobulin, we infer that the tumor cell-associated VH family repertoire is determined through antigen-independent mechanisms.
Summary. The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course.Median survival times were 1´4 years, 3 months and 1´6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.
Rearrangement of the immunoglobulin heavy chain (IgH) gene is widely exploited as a marker of B cell lineage and clonality in the pathology of lymphoproliferative disorders. We have developed a simple, polymerase chain reaction (PCR) based method for detecting IgH gene rearrangement which relies on the observation that by using a panel of PCR amplimers specific for each of the six heavy chain variable region families in conjunction with a common joining region amplimer, clonal rearrangement can be detected in over 90% of cases of B lymphoid malignancy. By using radiolabelled amplimers and exploiting the size heterogeneity resulting from independent IgH rearrangement events, we show that high resolution gel electrophoresis can be used to generate a 'fingerprint' representing the spectrum of B cell clonality in complex populations of B lymphocytes. The method effectively scans the entire IgH gene rearrangement repertoire and is capable of detecting rare clonal or oligoclonal B lymphoid cell populations. In normal bone marrow mononuclear cells, clonal IgH rearrangement could be readily detected at a sensitivity of 10(-3). We illustrate the application of the method in assessing the spectrum of B cell clonality occurring in an autoimmune condition. Hashimoto's thyroiditis, and in a malignant B cell disorder, chronic lymphocytic leukaemia. In addition, we explore the potential application of the technique in tracking minimal residual disease and for monitoring clonal evolution in acute lymphoblastic leukaemia.
Summary:immune mediated. This is evidenced by the observations of a reduced risk of leukaemia relapse after allogeneic BMT Anti-leukaemia activity after allogeneic bone marrow when compared with autologous or syngeneic BMT. Furtransplantation has been studied extensively but its antithermore, an increased incidence of leukaemic relapse has gen specificity and effector cell phenotype remain been reported after aggressive GVHD prophylaxis with unknown. Here we report a study in three recipients of cyclosporin A, 1 or lymphocyte depletion. The association autologous bone marrow transplantation done as part between GVHD and the graft-versus-leukaemia activity of of the treatment for acute leukaemia, in whom we were allogeneic BMT is strong and has led to a number of workable to detect innate specific anti-leukaemia activity ers concluding that GVL might be inseparable from GVHD. post-transplant. One patient maintained selective cellHowever, the lymphocyte subsets responsible for GVHD mediated cytolytic activity against her autologous leuand GVL remain to be elucidated in man despite intensive kaemic cells in the absence of cytolysis of her normal efforts. leukaemia (M5). A second patient was trans-Studies of GVL in the allogeneic setting are beset with planted for acute lymphoblastic leukaemia and had the problem of alloreactivity against major and minor histodetectable anti-leukaemia activity up to 20 weeks postcompatibility antigens. A number of studies have been per-ABMT. At this point anti-leukaemia activity could no formed in the autologous setting but none have reported longer be demonstrated and the patient suffered a evidence of innate cytotoxic activity which is specific for relapse 2 weeks later. A third patient was transplanted autologous leukaemic cells. Lotzova and colleagues 6 demfor AML (M4 Eo) and lacked detectable leukaemiaonstrated that patients prior to chemotherapy had low sponspecific immune reactivity at 1, 3 and 6 months posttaneous NK activity against the erythroblastoid leukaemic ABMT. She relapsed 6 months after her ABMT and cell line K562 and no detectable activity against autologous returned to complete remission after further chemoleukaemic cells. However, both were enhanced following therapy. She commenced treatment with alpha interin vitro culture with IL-2, although the leukaemia-speciferon and regained NK function. Furthermore, she ficity of the activity remains unknown since cytotoxicity of developed high level cytolytic activity against her autoautologous normal myeloid cells by the IL-2 stimulated logous leukaemic cells in the absence of activity against cells was not studied. A recent study of CLL patients after her remission bone marrow samples. She remains in fludarabine treatment demonstrated recovery of NK cell complete remission 17 months after her initial relapse.killing of K562 targets to normal levels and, in three of This is the first report of an apparent association five patients, a specific lytic action against their autologous between in vitro leukaemia-specific cyt...
Immunoglobulin heavy chain gene rearrangement serves as a marker of cell lineage and clonality in B lymphoproliferative disorders. We have used polymerase chain reaction (PCR) gene amplification to detect immunoglobulin gene rearrangements involving VH251, a heavy chain variable region preferentially utilized in B lymphoproliferative disorders. Using synthetic amplimers derived from VH251 and the heavy chain joining region, under conditions of high stringency, a homogeneous VH251-specific fragment of approximately 350 bp could be amplified from leukaemic DNA. Of 53 cases of B lineage acute lymphoblastic leukaemia screened for VH251 rearrangement by PCR, 10 were positive. A background level of VH251 rearrangement could also be amplified from normal peripheral blood and bone marrow DNA, but a VH251 rearranged leukaemic clone representing 0.01% of bone marrow mononuclear cells could be readily detected. The application of PCR to detect immunoglobulin gene rearrangement involving VH251 and potentially other preferentially utilized V regions provides a sensitive method both for tracking malignant B cells and for the study of normal B cell developmental pathways through which B lineage malignancies arise.
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