Advanced-phase chronic myeloid leukemia

Chronic myeloid leukemia (CML) typically runs a biphasic or triphasic course, with diagnoses usually made in the chronic phase (CP). Without effective treatment, patients eventually progress to a blastic phase (BP), frequently through an intermediate or accelerated phase (AP). Because the definition of AP varies among studies, comparisons of outcome and prognosis are difficult. The management of patients in these advanced phases of the disease has been much less satisfactory than that of patients in CP. Treatment with interferon-alfa (IFNalpha)-based therapy is ineffective for most patients in AP and for all of those in BP. Imatinib mesylate has demonstrated significant activity AP and BP disease, although the results are inferior compared to treatment in CP. In AP, 82% of patients achieve a hematologic response, with 24% achieving a major cytogenetic remission (MCR). Early MCR (within 3 months of diagnosis) provides a survival advantage over patients who do not achieve this response or achieve it later. In BP, 21% of previously treated patients and 36% of previously untreated patients have responded to imatinib, and up to 17% of patients may achieve a major cytogenetic response. However, responses are frequently short-lived. Several agents are being investigated for treatment of advanced-phase CML, including decitabine (DAC), homoharringtonine (HHT), troxacitabine, clofarabine, farnesyl transferase (FTase) inhibitors (FTI), and others. Many have also proven to be synergistic with imatinib in vitro and combination studies are ongoing. Continued investigation of these approaches is needed to improve the long-term prognosis of advanced-phase CML.     

Treatment-related chronic myelogenous leukemia

 Treatment-related (Tr) AML and MDS after chemotherapy, radiotherapy, or the combination of both have been well characterized. However, tr-CML seems to differ from these better-known entities in frequency, clinical course, and prognosis. Tr-CML cannot be distinguished from de novo CML cytogenetically, and, in contrast to tr-AML and tr-MDS, typical chromosomal aberrations related to tr-CML have not been described. Treatment-related CML is a late effect of cytotoxic or immunosuppressive therapy which might be increasingly recognized due to a higher number of patients treated with intensive therapy regimens. We review here the available data on incidence of tr-CML as well as the affected individual's characteristics with regard to different treatment options in malignant and nonmalignant diseases. Received: November 19, 1998 / Accepted: April 20, 1999     

Familial chronic lymphocytic leukemia

Familial aggregation of chronic lymphocytic leukemia (CLL) has been observed more frequently than familial aggregation of any other type of oncohematologic disorder. The presence of cells with a CLL-like immunophenotype (CLL-like cells) was recently documented in 13.5% healthy first-degree relatives of CLL patients. We present a family with CLL in which 2 brothers, a sister and their mother were affected.     

Cytofluorometric detection of chronic myelocytic leukemia supervening in a patient with chronic lymphocytic leukemia

An 82-year-old woman with stage I chronic lymphocytic leukemia presented with systemic symptoms, minimal adenopathy, hepatosplenomegaly, and anemia five years after the initial diagnosis was made and while receiving no therapy. Her white blood cell count was 231,000/mm3 with an absolute neutrophil count of 164,360/mm3 and lymphocyte count of 43,890/mm3. Peripheral blood smear inspection revealed both increased mature lymphocytes and myeloid cells at all stages of maturation. Flow cytometric analysis of forward- and right-angle light scatters demonstrated the presence of two populations of cells, one lymphoid, bearing predominantly lambda light chain surface immunoglobulin and showing phenotypic characteristics of B cell chronic lymphocytic leukemia (HLA-DR-positive, BL-1-positive, BL-2-positive, BL-7-positive, Leu-1-positive, Leu-10-positive, BL-5-negative, BL-6-negative, and OKM1-negative), and another granulocytic population expressing phenotypic features compatible with myeloid lineage (HLA-DR-negative, Leu-1-negative, BL-1-negative, BL-2-negative, BL-7-negative, Leu-10-negative, BL-5-positive, BL-6-negative, OKM1-positive, and surface immunoglobulin-negative). All of the peripheral blood cell metaphases were Philadelphia chromosome-positive after 24 hours of culture, confirming the diagnosis of chronic myelocytic leukemia, whereas all of the Epstein-Barr virus-treated B lymphocyte metaphases showed a normal karyotype after two weeks of culture. In this patient, analysis of surface antigens and immunoglobulin fractions by flow cytometry proved to be useful in recognizing concomitantly expressed leukemic lineages. This approach allows the increasing recognition of the heterogeneity of leukemic populations.     

Chemoimmunotherapy of chronic lymphocytic leukemia

The past two decades have seen a major paradigm shift in the therapy of chronic lymphocytic leukemia (CLL), with the treatment goal shifting from symptom palliation to the attainment of maximal disease control using the most effective frontline regimens available, thus prolonging survival and possibly leading to cure. The most potent therapeutic regimens developed to date include the chemoimmunotherapy combinations incorporating purine analogs and monoclonal antibodies. We review the evolution of modern chemoimmunotherapy for CLL, and discuss current research directions for further refining the potency of these regimens.     

Immunobiology of chronic lymphocytic leukemia

B-cell chronic lymphocytic leukemia increasingly is being recognized as a useful model disease with which to study more general processes involved in the evolution of neoplastic disease. The accessibility of the tumor cells and the capacity to confirm their clonal relatedness allow for evaluation of the processes associated with neoplastic transformation and/or disease progression. Recent studies have provided fascinating insight into the potential pathogenesis and pathophysiology of this disease. In addition, features of leukemia cells have been identified that can distinguish subsets of patients that have different tendencies for disease progression. Gene expression studies have identified a relatively small number of genes that are differentially expressed between these subsets, allowing for focused attention on proteins that might contribute to the noted differences in clinical behavior. Finally, recognition that chronic lymphocytic leukemia cells depend upon specific microenvironmental growth and survival factors identifies novel targets for disease intervention. This article focuses on the reports of the past year that have contributed to these areas of active research on chronic lymphocytic leukemia, the most common adult leukemia in Western societies.     

Biology of chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a clonal proliferation of mature-appearing, but maturationally immature B cells; T cells are rarely involved. Most data suggest that CLL cells are frozen at an early step in maturation; this can be overcome by several techniques such as in vitro incubation with tumor promotors. Although B-CLL involves B cells, and abnormal T cell function is common, its etiology is uncertain. Oncogene abnormalities and retroviral infection have been reported in rare cases of CLL; their role in more typical cases is unknown.     

Priapism complicating chronic granulocytic leukemia

Since 1952 we have seen nine patients with priapism leading to a diagnosis of chronic granulocytic leukemia (CGL) and a tenth patient who gave a history of priapism when CGL was diagnosed as a result of other symptoms. Seven patients had had one or more transient episodes of prolonged erection before the diagnosis of CGL was established. All ten had high blood leukocyte counts (mean 380 × 10⁹/liter, range 186-782) in comparison with other newly diagnosed patients. We estimate the incidence of this complication at 1%–2% of all male patients presenting with CGL. Treatment of patients in this series varied greatly. Five patients were treated mainly by local measures with or without cytotoxic drugs at conventional dosage, three were treated by sapheno-cavernous bypass operations and leukapheresis followed by cytotoxic drugs at high dosage, and two were treated initially by leukapheresis alone. In general, the prompt initiation of measures designed to reduce the leukocyte count seemed more valuable than the surgical procedures employed in these patients.