Meningeal involvement in early stage chronic lymphocytic leukemia

Two patients with early stage chronic lymphocytic leukemia were found to have meningeal involvement. The diagnosis was confirmed by cerebral spinal fluid cytology in the first patient and by flow cytometric analysis in the second patient. Both patients responded well to intrathecal chemotherapy and cranial irradiation. Central nervous system infiltration by tumor cells has rarely been described in chronic lymphocytic leukemia but must be considered in all patients regardless of stage who present with lethargy, dementia, or focal neurologic signs.     

Fludarabine may induce durable remission in patients with leptomeningeal involvement of chronic lymphocytic leukemia

Leptomeningeal involvement (LI) is a rare complication in the course of B-cell chronic lymphocytic leukemia (CLL). It is difficult to assess, thus several cases may go unrecognized. Here we report on six patients with LI of B-CLL. Neurologic symptoms were present in five of six patients. Cerebral MRI, although performed in all subjects, was diagnostic in two patients only. Examination of cerebrospinal fluid by cytology and immunophenotyping revealed LI in all six cases. One patient received whole brain irradiation, two patients received intrathecal therapy or intravenous fludarabine respectively. Clinical responses occurred in one patient after irradiation and two patients after fludarabine. Response in CSF was observed in all four evaluable patients after intrathecal therapy (n = 2) and fludarabine (n = 2). Survival for the patient who received irradiation was five months and for the two patients treated with intrathecal therapy three and six months respectively. One of the patients on fludarabine treatment survived for 21 months with an 11 month event-free survival for the CNS manifestations while the other patient has been in an ongoing meningeal CR and hematologic PR for 20 months. We conclude that fludarabine may be useful in meningeal involvement of CLL with impact on systemic disease.     

Meningeal involvement in patients with acute nonlymphocytic leukemia. Incidence, management, and predictive factors

Between 1977 and 1983, symptomatic meningeal leukemia was diagnosed in 9 of 93 adult patients with acute nonlymphocytic leukemia (10%). All cases occurred after complete remission had been achieved (46 patients), either as the only site of relapse (3 patients), or together with a first bone marrow relapse (3 patients), or after a bone marrow relapse (3 patients). Extramedullary involvement at initial diagnosis was the only independent predictive factor (P = 0.005), the number of patients with initial hyperleukocytosis being too small (three) for evaluation. Remission of the meningeal leukemia was obtained after treatment in four of eight patients. The presence of meningeal leukemia and the response to therapy had no influence on survival. However, the morbidity and therapy related toxicity of meningeal leukemia were impressive. Some recommendations for prophylactic treatment are suggested.     

Diagnosis of meningeal leukemia using immunoperoxidase methods to demonstrate common acute lymphoblastic leukemia cells in cerebrospinal fluid

The immunological phenotype of cells in the cerebrospinal fluid (CSF) was determined with immunoperoxidase techniques. A medium was used which allowed cells to stand at room temperature for 24 h without appreciable loss of cells. From 62 patients a total number of 208 CSF specimens were analysed. It proved possible to perform 4 determinations and a control reaction on 2.5 ml of CSF: cell count, cytology, E-rosetting and staining with a monoclonal antibody, provided that more than 1 cell per mm3 were present. This study focussed on the presence of the common acute lymphoblastic leukemia marker (cALL, determined with the monoclonal antibody J5). All 21 CSF specimens containing more than 5% cALL positive cells were from patients with an initial diagnosis of common ALL, 8 of these samples were considered to be normal and 3 uncertain by standard cytological criteria. Six of the 8 samples which were cytologically normal, were from patients who had clear meningeal involvement at diagnosis, or developed a relapse later. There were no patients who developed a meningeal relapse on cytological criteria that was not detected by immunocytology. In one patient a cytological diagnosis of meningeal relapse was not confirmed by immunocytology, this patient is disease free 2 yr later without cytostatic treatment. Immunoperoxidase methods to detect cALL positive cells in CSF are an invaluable aid to the diagnosis of meningeal leukemia.     

New developments in the diagnosis, prognosis and treatment of chronic lymphocytic leukemia

PURPOSE OF REVIEW: The remarkable progress witnessed over the past few years in the diagnosis, prognosis, and therapy of chronic lymphocytic leukemia has profoundly changed the clinical approach to this disease. This review focuses on the most recent advances in the diagnostic and prognostic examination of patients with chronic lymphocytic leukemia, with particular emphasis on their implications in clinical management, taking into account the broadening of the therapeutic possibilities available today. RECENT FINDINGS: Through the biologic improvements achieved during the past few years it is now possible to effectively stratify chronic lymphocytic leukemia patients prognostically at presentation on the basis of several laboratory parameters. Furthermore, the availability of purine analogs and monoclonal antibodies and the extension of autografting and allografting procedures have allowed the achievement of higher response rates, including molecular remissions. With the aim of investigating whether early and aggressive treatment intervention may improve the survival of patients with a poor prognosis, new therapeutic trials have been specifically designed. SUMMARY: A complete biologic and clinical examination now allows the establishment of a correct diagnostic characterization of patients with chronic lymphocytic leukemia and to identify patients with early disease with a different prognostic likelihood. Multicenter prospective trials, in which the enrolled patients are stratified and treated according to their prognostic risk, will determine the best treatment for the different categories of patients. It is likely that in the near future each chronic lymphocytic leukemia patient can be offered a targeted treatment algorithm based on the clinical and biologic characteristics at presentation.     

Acute nonlymphocytic leukemia and acute myeloproliferative syndrome following radiation therapy for non-Hodgkin's lymphoma and chronic lymphocytic leukemia: clinical studies.

Seven cases of acute nonlymphocytic leukemia (ANLL) and one case of a malignant myeloproliferative syndrome have been seen after extensive radiation therapy for non-Hodgkin's lymphoma or chronic lymphocytic leukemia. A myeloproliferative syndrome with abnormalities in granulocytic, erythrocytic, and thrombocytic cell lines was present in all patients and in seven patients preceded ANLL by 2--18 months. The median time to the development of ANLL after primary disease therapy was 61 months (33--98 range). The leukemia was extremely refractory to therapy and median survival after diagnosis of ANLL was two months (range 0--9 months). Leukemia was seen only in those patients who received multiple courses and multiple techniques of radiation therapy.     

Hodgkin's disease variant of Richter's transformation: a case report

Hodgkin's disease rarely develops in patients with B-chronic lymphocytic leukemia. Patients developing Hodgkin's disease after the diagnosis of chronic lymphocytic leukemia have been called the "Hodgkin's disease variant of Richter's transformation." We present a 62-yr-old man with a 17-mo history of chronic lymphocytic leukemia, who clinically and hematologically on remission was admitted to our clinic because of rapidly developing right cervical lymphadenopathy. He was diagnosed with lymph node biopsy as a mixed-cellularity Hodgkin's disease.     

Chronic lymphocytic leukemia with hyperleukocytosis. The hyperviscosity syndrome

A 47-year-old man with hyperleukocytic chronic lymphocytic leukemia progressively developed retinal hemorrhages, headache, diplopia, dysequilibrium, slurred speech, nystagmus, ataxic gait, and hearing loss as his leukocyte count rose to a maximum of 968,000/mm3. All of these symptoms and signs resolved promptly after leukapheresis. The authors reviewed records of 210 patients with chronic lymphocytic leukemia seen at our institution over a 12-year period, and found 16 patients with sustained hyperleukocytosis above 500,000/mm3, 3 of whom had features of the hyperviscosity syndrome. No laboratory values consistently predicted the occurrence or lack of occurrence of the hyperviscosity syndrome. The key to the management of hyperviscosity syndrome in the setting of hyperleukocytic chronic lymphocytic leukemia is to consider the diagnosis and to rapidly lower the lymphocyte count.     

Monoclonal antibodies in chronic lymphocytic leukemia

Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.     

Monoclonal antibodies in chronic lymphocytic leukemia

Multiple options are now available for the treatment of chronic lymphocytic leukemia. Over the last 10 years, monoclonal antibodies have become an integral part of the management of this disease. Alemtuzumab has received approval for use in patients with fludarabine-refractory chronic lymphocytic leukemia. Rituximab has been investigated extensively in chronic lymphocytic leukemia both as a single agent and in combination with chemotherapy and other monoclonal antibodies. Epratuzumab and lumiliximab are newer monoclonal antibodies in the early phase of clinical development. This article will review the monoclonal antibodies more commonly used to treat chronic lymphocytic leukemia, the results obtained with monoclonal antibodies as single agents and in combination with chemotherapy, and other biological agents and newer compounds undergoing clinical trials.     

Chromosome analyses of lymphoid cell lines derived from patients with chronic lymphocytic leukemia

To study chromosome complements of chronic lymphocytic leukemia cells, six Epstein-Barr virus-transformed lymphoid lines were established from two patients with this disease who were heterozygous for the X-chromosome-linked enzyme glucose-6-phosphate de-hydrogenase (G6PD). Immunoglobulin and G6PD were used as markers of the leukemic versus normal cell origin of the cell lines. The two lines, derived from putative normal cells, had no chromosomal changes. In contrast, chomosome abnormalities were found in each of the four cell lines of presumed leukemic cell origin. Although the chromosome aberrations are not as specific as the Philadelphia chromosome, there appears to be non-random involvement in chronic lymphocytic leukemia of some chomosomes, such as the No. 12.     

Enzymatic differences between chronic lymphocytic leukemia and prolymphocytic leukemia

Chronic lymphocytic leukemia and prolymphocytic leukemia of the B-cell immunophenotype are closely related disorders, but differ in their cytomorphologic and clinical features. In an attempt to differentiate further between these two forms of leukemia, we measured adenosine deaminase and purine nucleoside phosphorylase activities by using a linked-enzyme spectrophotometric assay on peripheral-blood leukemic cells from seven patients with chronic lymphocytic leukemia, three patients with prolymphocytic leukemia, and one patient with prolymphocytoid transformation of chronic lymphocytic leukemia. By using discriminant analysis, we were able to distinguish the two groups only on the basis of purine nucleoside phosphorylase activity (F1,9; p less than 0.001). The purine nucleoside phosphorylase activity in leukemic cells with prolymphocytic cytomorphology was significantly elevated (mean = 58.6 nM/min/mg protein) compared to the activity in leukemic cells with lymphocytic cytomorphology (mean = 25.6 nM/min/mg protein). There was only one patient with chronic lymphocytic leukemia who was assigned to the prolymphocytic leukemia group on the basis of her purine nucleoside phosphorylase activity. Our study suggests that purine nucleoside phosphorylase activity in leukemic cells may be useful in the distinction of prolymphocytic leukemia from chronic lymphocytic leukemia, and that it may be an enzymatic marker for the early detection of prolymphocytoid transformation of chronic lymphocytic leukemia.     

Coexistence of chronic myelogenous leukemia and chronic lymphocytic leukemia

A 55-year-old man is reported who initially developed chronic lymphocytic leukemia. Seven years later, after chemotherapy with chlorambucil, chronic myelogenous leukemia was diagnosed in addition to the chronic lymphocytic leukemia. Four previously reported cases with the same sequence of events are reviewed as well as cases of chronic myelogenous leukemia following chemotherapy alone.     

Characterization of immunoglobulin heavy and light chain gene expression in chronic lymphocytic leukemia and related disorders

The incidence of chronic lymphocytic leukemia is low in the Japanese population compared with populations in western countries, suggesting a role for genetic factors in the occurrence of this disease. We have previously shown that chronic lymphocytic leukemia in Japan rarely expresses the immunoglobulin heavy chain variable region (IGHV) 1-69 gene (1 out of 43 patients, 2.3%), which is a gene most commonly expressed in chronic lymphocytic leukemia cases from western countries. In the current study, we extended the previous study by examining immunoglobulin heavy chain and light chain gene expression in 80 Japanese patients with chronic lymphocytic leukemia and in 52 Japanese patients with other leukemic chronic lymphoproliferative disorders. IGHV1-69 gene expression was again quite low in our cohort, found in only two patients: one with chronic lymphocytic leukemia and the other with splenic marginal zone lymphoma. The IGHV4-34 gene was most frequently expressed in chronic lymphocytic leukemia (27.5%), whereas it was rarely found in leukemic chronic lymphoproliferative disorders (7.7%, P  = 0.005). There was also a significant difference in the expression of IGLV3-21 between chronic lymphocytic leukemia and leukemic chronic lymphoproliferative disorders (29.4 vs 4.8%, P  = 0.018). The IGLV3-21 gene in the majority of chronic lymphocytic leukemia cases was associated with homologous complementarity determining region 3 sequences. Recent studies identified subsets of cases expressing almost identical B-cell receptors. We found that two patients with chronic lymphocytic leukemia and the patient with splenic marginal zone lymphoma expressed IGHV4-39/IGKV1-39 and IGHV1-69/IGKV3-20 , respectively, which belong to these subsets. ( Cancer Sci 2009)     

Risk and prognosis of central nervous system leukemia in patients with Philadelphia chromosome-positive acute leukemias treated with imatinib mesylate.

PURPOSE: In patients with acute leukemias, a lymphoid phenotype, the presence of a Philadelphia chromosome (Ph), and inadequate central nervous system (CNS)-directed prophylactic therapy are risk factors for CNS involvement. Imatinib mesylate has promising single-agent antileukemic activity in patients with advanced Ph(+) acute leukemias. It was the aim of this analysis to determine the incidence of, and risk factors associated with, meningeal leukemia during imatinib monotherapy. STUDY DESIGN: We analyzed 107 consecutive patients with relapsed or refractory Ph(+) acute lymphoid leukemia (ALL; n = 65) or chronic myeloid leukemia blast crisis (n = 42) who were enrolled in successive Phase II trials of single-agent imatinib and who did not receive routine prophylactic intrathecal chemotherapy. RESULTS: CNS leukemia developed in 13 of 107 patients (12%) and was associated primarily with a lymphoid or bilineage phenotype (12 of 78; 15%) and with imatinib refractory Ph(+) ALL (5 of 19; 26%). Meningeal leukemia did not occur among patients who received prior prophylactic cranial irradiation. The median survival with combined CNS and systemic disease was 108 days (range, 58-141), with no patient surviving long term. In contrast, two of three patients with exclusively meningeal leukemia achieved prolonged molecular remissions with intrathecal chemotherapy, cranial irradiation, and continued imatinib. CONCLUSIONS: Patients with Ph(+) ALL are at considerable risk of meningeal leukemia during imatinib monotherapy and should routinely receive CNS prophylaxis. Although the prognosis with combined meningeal and systemic relapse is dismal, patients with an isolated meningeal relapse may still achieve sustained remissions. The optimal type of CNS-directed treatment and the extent of protection afforded by prophylactic cranial irradiation remain to be defined.     

Primary hyperparathyroidism and chronic lymphocytic leukemia.

Although hypercalcemia is a frequent event during the course of many malignancies it has only rarely been described with patients with chronic lymphocytic leukemia. Review of the literature revealed only eleven such case reports. The mechanism of the hypercalcemia in these patients was generally unclear although one patient was found to have a parathyroid adenoma and in another patient tested the level of osteoclast activating factor was high. Two additional chronic lymphocytic leukemia patients with hypercalcemia are described in this report and in each a parathyroid adenoma was found. The patient in whom the diagnosis was made ante mortem had an excellent response to parathyroidectomy. Osteoclast activating factor level was measured in one patient and found to be within normal limits. Since three of the thirteen reported cases of chronic lymphocytic leukemia with hypercalcemia have demonstrated parathyroid adenomas, it is suggested that consideration be given to that possibility in such patients so that appropriate surgery may be done.     

Remission from central nervous system involvement in adults with acute leukemia. Effect of intensive therapy and prognostic factors

Eighty-seven adult patients who had achieved bone marrow remission of leukemia developed one or more episodes of meningeal leukemia. Multiple patient characteristics were examined for their effect on probability of achieving complete remission from meningeal disease and for their effect on duration of meningeal remission. Presence of obtundation (P less than 0.01) or other symptoms of meningeal disease (P = 0.02) were associated with a low remission induction rate. Other factors which tended (P = 0.06-0.20) to be associated with low remission induction rates included high cerebrospinal fluid (CSF) opening pressure, absence of splenomegaly at initial diagnosis, high peripheral blood leukocyte count (WBC) at the episode of marrow disease most recently preceding the meningeal disease, and use of only one as opposed to two or more intrathecal drugs as treatment. Factors associated with long duration of meningeal remissions included diagnosis (AML greater than acute undifferentiated leukemia greater than ALL, P = 0.05), absence of symptoms (P = 0.04), low CSF WBC (P = 0.01), rapid attainment of meningeal remission (P = 0.01), rapid attainment of initial bone marrow remission (P = 0.02), and long duration of initial bone marrow remission (P less than 0.01). Absence of cranial or peripheral neuropathies, low CSF protein and opening pressure, and short time interval between diagnosis of marrow and meningeal disease also tended (P = 0.06-0.20) to be associated with long meningeal remissions. Patients treated according to an intensive protocol utilizing cranial irradiation and triple drug treatment via an Ommaya reservoir had substantially longer meningeal remissions than did patients treated with less intensive therapy (P = 0.01). Relapse-free survival curves suggest that some patients are cured of their meningeal disease.     

Splenectomy during chronic lymphocytic leukemia

The combination of discontinuous high-dose chlorambucil therapy with splenectomy greatly increased the prognosis of aggressive forms of chronic lymphocytic leukemia (CLL). The median survival for 43 patients was 84 months from diagnosis and 48 months from splenectomy. For 15 stages O, according to Rai classification, obtained after splenectomy, duration ranged from 3 to 105 months. The median survival of a group of patients showing "nodular splenic infiltration" was 104 months and superior to that of a group of patients showing "diffuse splenic infiltration" (72 months). In four of 15 cases studied, the peripheral blood lymphocytic clone disappeared after splenectomy.     

An autopsy study of 1206 acute and chronic leukemias (1958 to 1982)

Autopsy data on 1,206 children and adult patients with acute myelocytic leukemia (AML) (585), chronic granulocytic leukemia (CGL) (204), acute lymphocytic leukemia (ALL) (308), and chronic lymphocytic leukemia (CLL) (109) obtained from 1958 to 1982 were reviewed. This analysis has shown that, whereas the proportion of patients with residual AML at any anatomic site decreased significantly and uniformly over the entire study period, significant corresponding decreases in patients with CGL and ALL occurred only since 1976 and 1978, respectively. No significant corresponding decreases were noted in patients with CLL at any time. Significant decreases were also noted over time in the rates of extramedullary site involvement by AML, CGL, and ALL. Whereas the lymphoreticular organs, kidneys, adrenals, and pituitary were most often involved at autopsy by CLL, the testes, leptomeninges, dura mater, uterus, large bowel, and pancreas were most often involved by ALL. In general, patients with AML and CGL showed the lowest relative rates of involvement of the various organs by leukemia during the 24-year period. Whereas patients with AML and ALL showed significant decreases in the rates of involvement of nearly all anatomic sites during the most recent study periods, those with CGL and CLL showed corresponding decreases in only a few organ sites. The lower rates of organ involvement in patients with AML and ALL attest to the more aggressive eradication of leukemic cells by therapeutic regimens in these diseases over time. In particular, the significant decrease in the rate of meningeal involvement by ALL during the most recent period is probably attributable to central nervous system prophylaxis.     

Spinal epidural compression in chronic lymphocytic leukemia

Spinal epidural compression is a rare neurologic complication in patients with lymphoma. It occurs mostly in those with intermediate-grade to high-grade malignancy disease. This type of neurologic involvement has not been described in chronic lymphocytic leukemia (CLL). A patient with a long, stable CLL course developed spinal epidural compression and consequently died. The frequency of spinal epidural compression in lymphoma, according to the histologic subtypes and the considerations in making the right choice of therapy are discussed in light of the presented case.