Acute Lymphoblastic Leukemia Occurring in a Case of Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is a disease characterized by variable clinical presentation and a prolonged course. However, a small proportion of cases may evolve to more aggressive forms. These include acute leukemic blastic crises of both myeloid and lymphoid types, prolymphocytoid transformation, lymphoma and multiple myeloma. We describe a case of B-CLL treated with chlorambucil, in whom a picture of acute lymphoblastic leukemia of pre-B type developed. The diagnosis of both forms of leukemia is well documented on the basis of morphological, cytochemical and immunological findings. Documentation and investigation of cases of ALL occurring in CLL is of importance to determine whether the transformation represents a clonal evolution of the original CLL or an independent second malignancy in an immunocomprimised patient.     

Acute Myelogenous Leukemia Concurrent With Untreated Chronic Lymphocytic Leukemia

We report a case of acute myelogenous leukemia (AML) concurrent with untreated chronic lymphocytic leukemia (CLL). An 84-year-old Japanese man was admitted to the Chihaya Hospital with persistent high-grade fever. Morphologic observation of peripheral blood and bone marrow smears revealed a proliferation of blasts and lymphocytosis with small and mature phenotypes. Immunophenotyping of the blast cells revealed CD13+, CD33+, CD34+, and HLA-DR+, and that of the lymphocytes revealed CD5+, CD19+, CD20+, and lambda+ on the cell surface. The peripheral lymphocytes revealed an IgH gene rearrangement. Chromosome analysis of 20 metaphase cells from bone marrow showed numerous abnormalities, containing +8,+11,+21. The patient's disease was diagnosed as AML with trilineage dysplasia concurrent with CLL. The simultaneous occurrence of AML and CLL is extremely rare but should not be overlooked as a possible underlying cause of lymphocyte abnormalities in AML patients.     

No Evidence of a Lymphocytopenia State before Manifestation of Chronic Lymphocytic Leukemia

ABSTRACT Total lymphocyte counts were determined on an average 13.4 years before establishment of the diagnosis in 20 of 95 consecutive patients with chronic lymphocytic leukemia (CLL). The reasons for performing the white blood cell and differential counts did not include diabetes, autoimmune diseases or verified viral infections which are conditions well known to be associated with lymphocytopenia or lymphocytosis. The mean total lymphocyte count in the patient group was 2.6times10⁹/1 and did not differ from that of an age-matched control group. There was no significant association between the pretreatment lymphocyte count and the time between test and diagnosis. We conclude that patients with CLL have not a lymphocytopenic state antedating the diagnosis of CLL.     

Central Nervous System Involvement of Previously Undiagnosed Chronic Lymphocytic Leukemia in a Patient with Neuroborreliosis

Leukemic involvement of the central nervous system (CNS) in previously undiagnosed chronic lymphocytic leukemia (CLL) is very rare. We report the case of a 62-year-old man with neuroborreliosis in which cytologic, immunocytochemical, and flow cytometry analyses revealed the presence of clonal B-lymphocytes in the cerebrospinal fluid (CSF). After the patient received antimicrobial therapy, his meningeal symptoms cleared up, and the number of cells in the CSF decreased. Monoclonal lymphocytes were still detectable at the same percentage, however, despite systemic chlorambucil therapy. The application of intrathecal dexamethasone therapy led to the disappearance of B-cell CLL (B-CLL) cells in the CSF. We presumed that the neuroborreliosis enabled the transmigration of leukocytes, including B-CLL cells, across the blood-brain barrier via activation of matrix metalloproteinase 9, an enzyme known to open the blood-brain barrier.     

Chronic Lymphocytic Leukemia: An Unusual Cause of Upper Gastrointestinal Hemorrhage

In contrast to the acute leukemias, chronic lymphocytic leukemia (CLL) is a hematological malignancy with a generally good prognosis. Gastrointestinal (GI) involvement with CLL is unusual, and GI complications generally occur after malignant transformation to diffuse large cell lymphoma (Richter's syndrome). We present a case of CLL directly infiltrating the gastroesophageal junction resulting in upper GI hemorrhage. This is only the second such case in the literature. We emphasize the consideration of direct leukemic infiltration in addition to Richter's syndrome in the differential diagnosis of GI bleeding in patients with CLL. Whereas the prognosis of Richter's syndrome is poor, CLL involvement of the GI tract may respond to treatment with chemo- or radiotherapy.     

'Prolymphocytoid' Transformation of Chronic Lymphocytic Leukaemia

S ummary . 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, Richter's 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.     

Biochemical Characteristics of Chronic Lymphocytic Leukaemia

Chronic lymphocytic leukaemia (CLL) has a variable clinical course and there is a great need of new prognostic laboratory parameters in this disease. 24 CLL patients were subjected to routine haematological and clinical investigation. The leukaemic cells were analyzed for surface immunoglobulins, complement and sheep red blood cell receptors, Concanavalin A-induced agglutination, cytoplasmic glucocorticoid receptor and for proliferative activity by measurement of tritiated thymidine incorporation. The surface markers studied indicated that all cases were of B-cell origin. Only 5 of 23 patients studied had normal serum immunoglobulin levels. These cases showed a nonprogressive disease. 8 patients had increased infection tendency, all of whom had subnormal IgG levels; 4 of them also had subnormal IgA and IgM and 2 had subnormal IgA levels. 5 out of 6 patients with progressive disease and 3 of 11 with nonprogressive disease had an increased proliferative index, indicating a correlation between this parameter and disease progression. ConA agglutinability was not correlated to disease activity. Cells from 17 of 22 patients showed measurable amounts of glucocorticoid receptor. The 5 patients lacking this receptor had inactive disease.     

Effect of Treatment on T-Cell Function in Chronic Lymphocytic Leukaemia

T-cell functions were studied in vitro on enriched T-lymphocyte populations obtained from three groups of patients with chronic lymphocytic leukaemia (CLL): (a) untreated, (b) treated with chlorambucil, and (c) treated with chlorambucil and prednisone. The results were compared to age-matched controls and patients without CLL on comparable doses of prednisone. T cells obtained from untreated and chlorambucil-treated patients showed significantly decreased responses to phytohaemagglutinin (PHA) at short-term cultures (4 d) and in the mixed lymphocyte response (MLR). The lymphocyte responses to PHA, after 8 d in culture, were not significantly decreased. T cells obtained from CLL patients treated with chlorambucil and prednisone showed markedly reduced responses to MLR and to PHA at both time intervals. These responses were significantly less than those of cells obtained in the same manner from untreated or chlorambucil-treated patients with CLL or from patients with bronchial asthma treated with equivalent doses of prednisone. These results suggest that T cells from patients with CLL are particularly susceptible to inhibitory effects of corticosteroids. An increased susceptibility to infection has been reported in patients with CLL treated with chlorambucil and prednisone. The marked suppression of lymphocyte responses to PHA and in MLR demonstrated in this group of patients may play a role in increasing susceptibility to infections.     

Leukapheresis Therapy of Chronic Lymphocytic Leukemia

The effects of repeated leukapheresiswith the IBM Blood Cell Separator wereassessed in 13 patients with chroniclymphocytic leukemia (CLL). Five patients had from 14 to 25 leukapheresesat intervals ranging from 7 to 33 days.The median total number of lymphocytes removed was 18.0 x 10¹¹ (range11.9 x 10¹¹-26.6 x 10¹¹). Two of thesepatients had a decrease in lymphocytecount and in lymphadenopathy. One ofthe above and eight additional patientshad intensive leukapheresis therapyconsisting of five procedures per weekfor 1-4 wk. The median total number oflymphocytes removed from these patients was 11.34 x 10¹¹ (range 3.30 x10¹¹-47.4 x 10¹¹). Eight of these patients had a decrease in lymphocytecount, five in spleen size, eight inlymph node size, seven in bone marrow infiltration, and one in liver size.Lymphocyte counts before beginningleukapheresis therapy ranged from20,500 to 684,000 (median 70,900). Themedian lymphocyte count on completion of treatment was 19,200 (range6,590-40,000). After leukapheresis therapy, the median doubling time of thelymphocyte count was 71 days (range29-118 days). In addition to demonstrating a significant proliferative component in CLL, the objective regressionof disease in ten of the 13 patients suggests that leukapheresis is a potentiallyuseful treatment for CLL.

Submitted on June 21, 1971 Revised on August 9, 1971 Accepted on August 10, 1971     

Identification of a Pure Splenic Form of Chronic Lymphocytic Leukaemia

We have recently proposed a new staging system for chronic lymphocytic leukaemia (CLL) in which patients with isolated splenomegaly are classified into a distinct stage (stage II). Twenty-three such patients (from two institutions) have been studied without recorded death in a follow-up of 18 months to 30 years. This favourable prognosis justifies separation of these 'pure splenic forms' (SCLL) which must be distinguished from what Galton has termed prolymphocytic leukaemia (PL). This distinction can be made on the basis of three criteria: (i) Clinically, SCLL has a slow uneventful course and neither anaemia and/or thrombocytopenia: (ii) cytologically PL can be distinguished from other forms of CLL though atypical forms of CLL may be confused with the former; and (iii) the study of surface membrane immunoglobulins (SmIg) showed that while lymphocytes from most patients with both PL and SCLL bore uniform SmIg, suggesting a monoclonal B-cell proliferation, there was a major quantitative difference in that whereas PL lymphocytes had a number of antigenic sites close to that of normal lymphocytes (mean: 82 000 sites per cell), SCLL lymphocytes had a drastically reduced number of sites. It is our opinion that this is an important criterion for the differential diagnosis between PL and SCLL.     

Simultaneous Presence of Two Hematological Malignancies: Chronic Lymphocytic Leukemia and Myelofibrosis in a Patient

Coexistence of chronic lymphocytic leukemia (CLL) with myelofibrosis is a rare association with only isolated case reports in the literature. We report an unusual case of CLL in which the cause of anemia was coexistent myelofibrosis. In a case of CLL presenting with refractory anemia, besides common causes like autoimmune hemolytic anemia and marrow infiltration, other causes like myelofibrosis should be searched for.     

Skin Infiltration with Chronic Lymphocytic Leukemia is Consistent with a Good Prognosis

Skin infiltration with B-lymphocyte chronic lymphocytic leukemia (B-CLL) is rare. In contrast to Richters transformation of CLL or myeloid leukemias, skin involvement in CLL may be consistent with prolonged survival, as illustrated by the currently reported two cases. As in these patients, local therapy for skin disease may delay or obviate the need for systemic therapy in B-CLL.     

Chronic Granulocytic Leukemia (CGL) During the Course of Chronic Lymphocytic Leukemia (CLL): Correlation of Blood, Marrow, and Spleen Morphology and Cytogenetics

Second malignancies occur with a greaterfrequency in patients with chronic lymphatic leukemia than in the general population. Previously, 20 patients having CLLhave been reported as developing acuteleukemia, but no cases of development ofchronic granulocytic leukemia have beenobserved. In the present report, we willdescribe patients with Ph¹ chromosomepositive CGL associated with previouslydescribed CLL. One patient received totalbody radiation treatment for his CLL, whilethe second was not treated. It is apparentthat previous therapy may not necessarilybe a prerequisite for the development of asecond malignancy in CLL. Cytogeneticsoffers a useful tool to confirm morphologiccriteria in establishing the diagnosis of asecond neoplasm.

Submitted on July 24, 1973 Revised on August 27, 1973 Accepted on September 14, 1973     

Antisera with la Specificity Selected by Lymphocytes from Patients with Chronic Lymphocytic Leukemia

Cells from patients with chronic lymphocytic leukaemia (CLL) have been used to screen the sera of pregnant women for antibodies specifc for B lymphocytes. The sera have been divided into groups showing Ig specificity: group I (UK 3) had a positive association with HLA-B8 and DW3, and group II (UK 2) with HLA-B7 and DW2. Groups III, IV and X were independent of each other and of HLA-A, B and C locus antigens. Certain sera with B-cell activity showed specific blocking activity in the mixed lymphocyte reaction (MLR), and this activity was dependent on the Ia sepcificities and DW specificities of cells used in the MLR. Some sera specifically blocked the responding cells, other the stimulating cells.     

Evaluation of Interleukin-9 Expression as a Potential Therapeutic Target in Chronic Lymphocytic Leukemia in a Cohort of Egyptian Patients

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy that has a highly variable clinical course. Genomic features as zeta-chain-associated protein kinase 70 (ZAP70) expression and CD38 expression provide further differentiation of disease prognosis. Extensive studies have confirmed the oncogenic activities of IL-9 in lymphoma. The aim of the current study was to investigate the contribution of IL-9 expression to the pathogenesis of CLL and its correlation to other prognostic parameters. This study was conducted on 80 patients at diagnosis with CLL and 80 healthy controls. Using real time polymerase chain reaction and enzyme linked immunosorbant assay, IL-9 mRNA expression and its serum level were compared between patients and controls. They were both correlated with other prognostic factors. Results: There was an overexpression of IL-9 in CLL patients that correlated with modified Rai staging, ZAP70, CD38 and all hallmarks of an active and aggressive disease. The correlation between IL-9 upregulation and patient characteristics provided direct clinical evidence for its contribution to the pathogenesis of CLL. In conclusion, significantly higher expression of IL-9 measured at both the mRNA and the protein levels in patients with CLL that correlates with more complex course of the disease and worse prognosis may allow one to speculate its importance in the pathogenesis of the disease and its possible impact on prognosis.     

Second Malignancies and Richter's Syndrome in Patients with Chronic Lymphocytic Leukemia

Second malignancies are frequent complications in patients with chronic lymphocytic leukemia (CLL). Patients with this leukemia may develop large cell lymphoma (LCL) known as Richter's syndrome (RS). RS occurs in CLL patients of about 3% and may develop in a single lymph node or more often in a group of nodes. However, in some patients extranodal localization of aggressive lymphoma in RS has been observed. Besides LCL, Hodgkin's disease, prolymphocytoid leukemia, multiple myeloma and acute lymphoblastic leukemia may also occur as RS variants. The origin of lymphoid cells in RS remains tentative. However, CLL and RS originate from the same clone for some patients, whereas, in other patients cells of aggressive lymphoma do not have the features of the same clone as the CLL cells. The prognosis of RS is poor. Survival in different studies will be usually 2-5 months. The secondary development or coexistence of myeloproliferative disorders or myelodysplastic syndrome and solid tumors have also been rarely documented in CLL patients. It is of great concern that therapy may further increase the risk of a second neoplasm. However, until now, there are no clear evidence that alkylating agents or purine nucleoside analogs may be associated with an increased incidence of second malignancies in patients with CLL. In this review, epidemiology, biology, clinical characteristic and treatment approaches in RS and other secondary neoplasms in patients with CLL are discussed.     

Early Transformation to Classic Hodgkin Lymphoma in a Chemotherapy-naïve Chronic Lymphocytic Leukemia Patient upon Initial Treatment with Ibrutinib

A 71-year-old woman with a four-year history of chronic lymphocytic leukemia (CLL) received ibrutinib as initial treatment due to progressive anemia and thrombocytopenia. Eleven months after the start of the treatments, although her cytopenia had ameliorated, she developed classic Hodgkin lymphoma, a rare form of Richter''s transformation. She was successfully treated with two courses of adriamycin, vinblastin, bleomycin and dacarbazine followed by radiotherapy. In general, several clinical, genetic and molecular factors are associated with Richter''s transformation. In addition, our present case suggested that ibrutinib could be a potential risk factor for Richter''s transformation in CLL patients.     

GPI-Anchored Fibromodulin as a Novel Target in Chronic Lymphocytic Leukemia: Diagnostic and Therapeutic Implications

Background: We have previously reported the aberrant expression of Fibromodulin (FMOD) in patients with chronic lymphocytic leukemia (CLL). Although FMOD has been considered as a cytoplasmic or secretory protein, we discovered the cell surface expression of FMOD in leukemic B cells via anchoring with glycosylphosphatidylinositol (GPI). Objective: To evaluate FMOD as a new biomarker in CLL patients in comparison with healthy individuals. Methods: A monoclonal antibody was generated against human FMOD. The cell surface expression of FMOD in 52 CLL patients and 45 healthy individuals were compared by flow cytometry. A bacterial phosphatidylinositol-specific phospholipase C (PI-PLC) was used to determine the cell surface localization of FMOD using ELISA and flow cytometry techniques. Annexin V-FITC and propidium iodide (PI) was used to detect apoptosis induction in CLL PBMCs following in vitro incubation with anti-FMOD mAb. Results: The results demonstrated the widespread cell surface expression of GPI-anchored FMOD in CLL patients (median: 79.9 %), although healthy individuals had low FMOD expression (median: 6.2 %) (p≤0.0001). The cut-off value of FMOD expression was estimated with high sensitivity and specificity at 17.9%. Furthermore, in vitro apoptosis induction of leukemic cells following incubation with anti-FMOD mAb showed a direct apoptosis of CLL cells (27.9%) with very low effect on healthy PBMCs (6%). Conclusion: The membrane-anchoring of FMOD by means of a GPI moiety in leukemic cells supports FMOD as a highly potential diagnostic and therapeutic target in CLL patients.     

Studies on the Pseudouridinuria of Chronic Lymphocytic Leukemia

This paper reports a group of investigations attempting to explain theelevated pseudouridine excretion in the presence of normal uric acid excretionwhich occurs in chronic lymphocytic leukemia (CLL). Studies with isotopically labeled uric acid and adenine indicated that diversion of body purinesfrom uric acid does not occur. Similarly the chemical analysis of the whitecells in CLL did not reveal any excess content of pyrimidines, nor did theturnover of the ribonucleotides show any selective retention of purines ascompared with pyrimidines. Studies with isotopically labeled orotic acid,however, indicated on overproduction of other pyrimidines as well as pseudouridine. Though no explanation has yet been found for the selective pyrimidine overproduction seen in CLL, a major portion of these pyrimidines appear to be derived from rapidly renewing sources.

Submitted on October 14, 1963 Accepted on April 5, 1964