Meningeal leukemia complicating chronic lymphocytic leukemia

Two patients with classic chronic lymphocytic leukemia had meningeal leukemia as a complication of their disease. Intrathecal chemotherapy was successful in eradicating signs and symptoms of meningeal involvement. One of these patients is alive without evidence of central nervous system leukemia 30 months after diagnosis of meningeal leukemia, and 5 1/2 years after the diagnosis of chronic lymphocytic leukemia. Although uncommon, meningeal involvement in chronic lymphocytic leukemia may occur at various times in the course of the disease, it responds to conventional therapy.     

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.     

Polymorphism of the human Ha-ras oncogene locus in chronic lymphocytic and chronic myelogenous leukemia.

DNA from white blood cells from healthy controls demonstrates a restriction fragment length polymorphism (RFLP) of the Ha-ras oncogene locus after cleavage with the restriction enzymes BamH I or MspI plus HpaII, representing frequent and rare alleles. We have studied the RFLP of 15 patients with B-cell chronic lymphocytic (CLL) and of 16 patients with chronic myelogenous leukemia (CML). As in healthy controls the RFLP in the leukemic cells indicates the occurrence of frequent and rare Ha-ras alleles. But rare alleles are not more frequent in the patients than in the healthy control group. The frequency of rare Ha-ras alleles also does not differ between chronic lymphocytic and chronic myelogenous leukemia. While rare alleles of this oncogene locus occur in CML and CLL as frequently as in healthy controls, they do not reflect an inherent increased risk for chronic leukemia in man.     

Clinical and epidemiologic burden of chronic myelogenous leukemia

Chronic myelogenous leukemia represents 7-20% of all leukemia cases, with a worldwide incidence projected at less than one to two per 100,000 people. Approximately 85% of patients are diagnosed with chronic-phase chronic myelogenous leukemia and up to 40% are asymptomatic. Treatment strategies include chemotherapy, interferon-alpha therapy, transplantation (bone marrow/stem cell transplant) and imatinib mesylate (Gleevec), with the impact of treatment best realized during the chronic phase of the disease. Only transplantation has been clinically demonstrated to eradicate the Philadelphia chromosome, alter the natural course of the disease and cure patients diagnosed with chronic myelogenous leukemia. Interferon-alpha is currently considered for first-line treatment, however, the recent introduction of targeted therapy may change clinical practice. Ongoing research focused on new drug combinations and target therapies may eventually expand the armamentarium available to cure this disease.     

Hyperkalemia complicating splenic irradiation of chronic lymphocytic leukemia.

Hyperkalemia is an infrequent complication of the therapy of malignant disease. In previously reported cases, hyperkalemia following the institution of chemotherapy has been associated with acute renal failure. In this report, we present a patient with chronic lymphocytic leukemia who developed hyperkalemia following splenic irradiation. Necrosis of tumor cells, either as direct or an abscopal effect appears to be implicated as a cause of hyperkalemia. It seems appropriate to monitor potassium levels when therapy of a responsive tumor is instituted.     

Cyclic lymphocytic vasculitis associated with chronic lymphocytic leukemia

Lymphocytic cutaneous vasculitis associated with a haematological malignancy has rarely been reported. Here, we describe a 61 year-old woman with chronic lymphocytic leukemia (CLL) who presented with cutaneous lesions on both hands. These lesions improved after all combination chemotherapy courses and recurred before each course. Repetitive skin biopsies revealed lymphocytic vasculitis. After 7 courses of chemotherapy, she had a complete remission. Skin lesions disappeared and did not recur. The cyclic pattern of lymphocytic vasculitis and its relation with CLL disease activity are interesting clinical features in this case.     

Role of immunochemotherapy in the treatment of chronic lymphocytic leukemia

Major advances have been made in our understanding of the biology and opportunities for treatment of chronic lymphocytic leukemia in recent times. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in chronic lymphocytic leukemia patients. Moreover, recent combination chemoimmunotherapy regimens have produced more frequent complete molecular remissions, and early evidence seems to suggest that this could result in prolonged duration of responses, although this association remains to be clearly demonstrated. This review will summarize recent advances in the biology and the management of chronic lymphocytic leukemia, including prognostic factors, pointing mainly on combination chemotherapy based on nucleoside analogs and monoclonal antibodies. In our opinion, in the future a significant improvement of clinical benefits in chronic lymphocytic leukemia will be obtained through the administration of cocktails of monoclonal antibodies combined with chemotherapy in different modalities.     

Role of immunochemotherapy in the treatment of chronic lymphocytic leukemia

Major advances have been made in our understanding of the biology and opportunities for treatment of chronic lymphocytic leukemia in recent times. Newer treatment regimens incorporating purine nucleoside analogs have increased the rate of successful remission induction in chronic lymphocytic leukemia patients. Moreover, recent combination chemoimmunotherapy regimens have produced more frequent complete molecular remissions, and early evidence seems to suggest that this could result in prolonged duration of responses, although this association remains to be clearly demonstrated. This review will summarize recent advances in the biology and the management of chronic lymphocytic leukemia, including prognostic factors, pointing mainly on combination chemotherapy based on nucleoside analogs and monoclonal antibodies. In our opinion, in the future a significant improvement of clinical benefits in chronic lymphocytic leukemia will be obtained through the administration of cocktails of monoclonal antibodies combined with chemotherapy in different modalities.     

Megakaryoblastic transformation of chronic myelogenous leukemia

A 52-year-old man with Ph1-positive chronic myelogenous leukemia (CML) developed a blastic transformation in which the predominant cell type micromegakaryocytes. He did not respond to treatment. A review of the 15 previously reported cases of patients with circulating megakaryocyte abnormalities in association with either CML or a Ph1 chromosome positive myeloproliferative disorder suggests a female predominance rather than the usual male predominance of CML. Survival of the six patients reported as megakaryoblastic transformation of CML as well as this patient was poor.     

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.     

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.     

Oncogenes in chronic lymphocytic leukemia

Oncogenes, in the context of retroviruses, are a common cause of leukemia in animals. Recently, activation of cellular oncogenes has been shown to be associated with leukemia in humans. Relatively few studies of oncogene activation in chronic lymphocytic leukemia (CLL) have been reported. In most instances, rearrangement of oncogenes has not been detected. Exceptions include the bcl-1 oncogene in B-cell prolymphocytic leukemia, the tcl-1 oncogene in T-cell CLL, the Hu-ets-1 and Hu-ets-2 oncogenes in small cell lymphocytic lymphoma and c-myc in a Sezary cell leukemia cell/line. Overall, it appears that oncogene abnormalities are less common in CLL than in other leukemias. The reason for it is uncertain and may relate to the relatively few cases evaluated. Alternatively, novel mechanisms of oncogene involvement or gene other than oncogenes may be important in the etiology or pathogenesis of CLL.     

Therapy of chronic myeloid leukemia with interferon

Several modalities are used for treatment of the chronic phase of chronic myelogenous leukemia. Most patients are treated with single agent chemotherapy. However, patients are cured only by isogenic or allogeneic bone marrow transplantation; otherwise the disease regularly proceeds to fatal blastic crisis. Alpha-interferon has an antiproliferative activity against hematopoietic cells in vitro and in vivo. We have treated 10 patients with the chronic phase of Philadelphia--chromosome-positive chronic myelogenous leukemia with alpha-interferon. The median duration of the disease was 10 months. Five patients were previously untreated and five achieved hematologic remission. Patients with a disease duration of less than 1 year, who had had no or only minimal pretreatment, showed the best response rates. These experiences confirm published data on interferon therapy. It remains to be determined whether interferon treatment and the hereby induced suppression of the Philadelphia-chromosome-positive cell clone in some patients will improve survival.     

Four gastrectomized cases associated with chronic leukemia

We reviewed 4 gastrectomized cases associated with chronic leukemia. Three patients had chronic myelogenous leukemia, one had hairy cell leukemia. Subtotal gastrectomy was performed in all cases; two operations were for gastric cancer and two for bleeding gastric ulcers. The spleen was removed in three patients without any trouble. There were no difficulties in managing the patients during and after surgery and their leukemia was not aggravated during these periods.     

Oncogenes and leukemia

Cellular or proto-oncogenes are normal cellular genes important in normal cell growth and development. In some instances abnormal expression of these genes is associated with altered cell growth or with malignant transformation. Abnormalities of cellular oncogenes are common in human leukemias. These arise by multiple mechanisms such as mutation, translocation, amplification, and others. Sometimes more than one abnormality is present within a single oncogene. In other instances, a leukemia cell may contain abnormalities of several different oncogenes. Some oncogene abnormalities are relatively specific for certain leukemias and occur in almost all cases; examples include ABL in chronic myelogenous leukemia or MYC in Burkitt leukemia/lymphoma. Other abnormalities are also relatively specific but occur in only some cases such as NRAS in acute myelogenous leukemia or BCL2 in B-cell acute lymphoblastic leukemia. In other leukemias, such as most cases of acute lymphoblastic leukemia and chronic lymphocytic leukemia, oncogene abnormalities are uncommon. The precise role of oncogenes in the pathogenesis of human leukemia is unknown. Retrovirus transduced versions of some of the oncogenes modified in human leukemias cause leukemia in animals. Other oncogenes, modified or unmodified, transform animal and human hematopoietic cells in vitro. Some oncogene products are hematopoietic growth factors or growth factor receptors while others regulate cell proliferation or differentiation by diverse mechanisms. Disruption of the balance between these processes seems the most likely mechanism of oncogene related leukemogenesis. If the role of oncogenes in human leukemias can be defined, innovative diagnostic and therapeutic strategies may be forthcoming.     

Blastic phase of chronic myelogenous leukemia

Opinion statement Chronic myelogenous leukemia (CML), also known as chronic myelocytic or chronic myeloid leukemia, is a clonal disorder of hematopoiesis that arises in a hematopoietic stem cell or early progenitor cell. This is characterized by the dysregulated production of mature non-lymphoid cells with normal differentiation. Eventually, in spite of the term chronic, there is progression to acute leukemia, usually of the myeloid variety, which is highly resistant to current therapies. Despite recent improvements in the treatment of early-stage disease, CML blast crisis (CMLBC) remains a therapeutic challenge. CMLBC is highly refractory to standard induction chemotherapy, with a response rate in myeloid blast crisis of less than 30%. Conventional chemotherapy has been much less successful in this disease compared with de novo acute leukemia, with a mean survival after diagnosis of blast crisis of only 2 to 4 months for nonresponders. Many regimens of chemotherapies have been tried in CMLBC, with minor success. Although imatinib was evaluated in patients with CMLBC, most CMLBC cases today arise in patients already on imatinib-based therapy and developing blastic phase on that therapy; thus there is no standard therapy for patients with CMLBC. Further studies of the mechanisms of transformation of chronic-phase CMLBC at a molecu-lar level, and methods to target these molecular abnormalities, will determine the future direction of new treatment modalities. The prognosis of CML in blast crisis remains dis-appointing, despite great efforts. Currently, the most successful strategy for improving survival in CML is by prolonging the chronic phase and delaying the onset of blast crisis.     

Coexistent chronic lymphocytic leukemia and polycythemia vera requiring no treatment

Simultaneous presentation of chronic lymphocytic leukemia and polycythemia vera is reported in a previously untreated patient. The course was remarkably mild with almost no treatment, suggesting control of each disease by the other. The association of polycythemia vera (PV) and lymphoid neoplasms in the same patient is very unusual in the absence of previous cytotoxic therapy. Six cases of PV and chronic lymphocytic leukemia (CLL) have been reported, in which the occurrence of the two disorders was simultaneous, or sequential but spontaneous. We describe an additional patient in whom the presence of the two malignancies was clearly established, and who needed almost no therapy for more than 3 yr.     

Leukemic leptomeningeal involvement in stage 0 and stage 1 chronic lymphocytic leukemia

Central nervous system (CNS) involvement in early (Rai Stage 0 and Stage 1) chronic lymphocytic leukemia (CLL) is rare, with only five cases reported. We present the sixth reported case, a 77-year-old male with a 4 year history of Stage 0 CLL who presented with sudden onset of diplopia and headache. Workup revealed a leukemic involvement of his CNS and he responded well to treatment with intrathecal (IT) methotrexate. After his third IT treatment, he developed a change in his mental status, consistent with a chemotherapy induced encephalopathy, which was effectively treated with IT hydrocortisone. In addition to the case presentation, we review the previously reported cases in an effort to determine any characteristics common among the Stage 0/1 CLL patients with reported CNS involvement.