T-cell involvement in benign phase chronic myelogenous leukemia

T cells from the peripheral blood of patients with chronic myeloid leukemia (CML) were cultured with phytohemagglutinin and T-cell growth factor (TCGF) in agar culture. These T-cell colonies were pooled and expanded further in liquid culture with TCGF and then simultaneously analysed for the E-rosette receptor with the monoclonal antibody OKT11 and for the presence of the Philadelphia (Ph¹) chromosome. OKT11 analysis showed these populations to be composed 99.5% or more of T cells. In four of the seven patients the T-cell suspension showed 7/50 (14%), 3/36 (8%), 2/34 (6%), and 4/44 (9%) Ph' metaphases. Furthermore, Ph¹ metaphases were demonstrated in T-cell cultures in two patients when bone marrow metaphases simultaneously showed 90 and 100% Ph¹ negative metaphases secondary to human leukocyte interferon therapy or combination chemotherapy. A minority of T cells in benign phase CML have the Ph¹ abnormality despite reduced number of Ph¹ metaphases in bone marrow from therapy.     

Central nervous system niche involvement in the leukemia

Central nervous system (CNS) impairment is commonly involved in leukemia, as it can be observed upon onset or relapse of the disease. It is associated with poor prognosis and is a challenging clinical problem. The objective of this paper was to provide a characterization of the CNS niche in leukemia, to elucidate the culprits of CNS involvement, including diagnostic micro RNAs (miRs) and early leukemia prognosis. CNS niche is a proper location for homing of leukemic stem cells, thus representing a candidate target in the treatment of leukemia. Recent advances in the study of leukemia hallmarks have enlightened miRs as novel biomarkers for diagnosis and detection of CNS involvement in leukemia, thus providing the opportunity to develop novel therapeutic approaches. Given the importance of prognosis and early diagnosis of CNS involvement in leukemias as well as the severe side effects of current treatments, diagnostic and therapeutic approaches should focus on identification and inhibition of the factors contributing to CNS involvement, including CXCR3, P-selectin glycoprotein ligand-1 and MCP1. MiRs such as miR-221 and miR-222 are emerging as potential tools for an innovative non-invasive therapy of CNS in leukemia affected patients.     

Central nervous system involvement in adult acute leukemia

Central nervous system (CNS) involvement was present in 16 of 59 (27%) adults with leukemia, i.e. in 13 of 40 (33%) with AML, of 3 (33%) with AMoL, and 2 of 8 (25%) with ALL. CNS leukemia was found at the time of diagnosis in 2 patients, during induction therapy in 2 patients, early in remission in 2 patients, during remission in patients, and at relapse in 4 patients. Fifteen of the 16 patients responded to intrathecal methotrexate, cytosine arabinoside or cranial irradiation. Only patients developed CNS relapse. CNS leukemia had no effect on survival. In 3 of 5 patients without CNS prophylaxis, the onset of neurologic manifestations was observed within one year of remission, whereas it was delayed for more than one year in all patients who had received prophylactic intrathecal methotrexate.     

Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy

We report two patients with Philadelphia (Ph) chromosome positive chronic myelogenous leukemia (CML) in myeloid blastic phase that developed central nervous system disease while on imatinib mesylate therapy. Patient 1 presented with CML in myeloid blastic phase and responded to imatinib, cytarabine, and idarubicin-based treatment achieving complete cytogenetic remission in the marrow, but developed myeloid blasts in his cerebrospinal fluid (CSF) during treatment. Patient 2 developed CML myeloid blastic phase after initially being in hematologic and cytogenetic remission with imatinib treatment. He represented with an extramedullary mass at the base of his skull and CSF involvement. Both patients were treated with intrathecal chemotherapy and received craniospinal irradiation to clear the spinal fluid of disease. Both patients have undergone related allogeneic stem cell transplant and are in complete hematologic remission; one is in complete cytogenetic remission, the other is too early to evaluate. Central nervous system involvement with myeloid blasts is previously unreported for patients with CML in blastic phase on imatinib and warrants cautious observation and vigilance in these patients.     

Monoblastic transformation in chronic myelogenous leukemia: presentation with massive hepatic involvement

Monoblastic transformation developed in a 26-year-old white man with chronic myelogenous leukemia and was manifested by acute, fulminant hepatic failure due to massive blastic infiltration of the liver. The hepatic failure responded dramatically to radiation therapy. The monocytic origin of the blasts was confirmed by means of light and electron microscopic examination and cytochemical studies. Cytogenetic studies of the leukemic blasts revealed a Philadelphia-chromosome-positive karyotype and a clonal evolution of chromosome changes resulting in multiple karyotypes.     

Central nervous system involvement in adult acute lymphocytic leukemia

With effective CNS prophylaxis, most adults with ALL may remain free of CNS leukemia. Several combinations of IT chemotherapy, high-dose systemic chemotherapy, and cranial irradiation have been used with varying results. Excellent prophylaxis can be achieved without cranial irradiation, and in view of the potential acute and long-term toxicity of radiation, these methods may be preferable. A prophylactic approach tailored to the risk of CNS leukemia was shown to be valuable in childhood ALL and in at least one adult study. Further studies should focus on defining risk groups for CNS leukemia and designing effective prophylaxis for each group. More research is needed to define the intensity and duration of treatment and the role of cranial irradiation in the treatment of isolated CNS relapses.     

Central nervous system involvement in adult T-cell leukemia/lymphoma

Central nervous system (CNS) involvement was reviewed in 99 patients with adult T-cell leukemia/lymphoma (ATLL). Fifteen episodes of CNS involvement developed in ten of 99 patients (10.1%); nine had leptomeningeal involvement, whereas two developed intracerebral invasion, one developed cord involvement, and one developed both. CNS involvement was more frequent in the lymphoma type than in the other types of ATLL. Nuchal rigidity was not common (33%) and a syndrome of inappropriate secretion of antidiuretic hormone (ADH) occurred in association with CNS involvement (40%). Three episodes of marked hypoglycorrhachia also were noticed. The systemic progression of ATLL was the most common setting of CNS involvement (80%) and the major cause of death (80%). As for the acute and lymphoma types of ATLL, no significant difference was observed in survival between patients with and those without CNS involvement. These results indicate that CNS involvement is not an essential prognostic factor of ATLL and that it should be treated with systemic chemotherapy coupled with intrathecal chemotherapy. The control of systemic ATLL is important for the prophylaxis of CNS involvement.     

Chronic myelogenous leukemia in chronic phase

Opinion statement Chronic myelogenous leukemia (CML) is a clonal myeloproliferative disorder characterized by genomic instability leading to its inevitable clinical evolution from an easily controlled chronic phase to a terminal blastic phase. The molecular abnormality responsible for this disease—BCR-ABL—and the critical biochemical aberrations resulting from it have been studied in depth. These discoveries have led to the development of a molecule, STI571, that specifically inhibits the abnormal kinase enzymatic activity exhibited by BCR-ABL. Early results of clinical trials using STI571 have shown responses even in blast crisis. There has also been striking hematologic and cytogenetic remission rates in patients with advanced chronic phase disease, with very little toxicity. It is our opinion that this molecule will revolutionize the treatment of CML. Furthermore, the path leading to its discovery will become a paradigm for cancer therapeutics. At the time of this writing, STI571 remains investigational (although it is widely believed that it will be approved for clinical use in the United States this year [2001]). Although suggested therapy for a disease does not generally incorporate medications that are still investigational, in this case, the impact of a still investigational agent cannot be ignored. The current data suggest that STI571 will be the treatment of choice for patients with advanced or resistant chronic phase. To date, STI571 has not been studied adequately in untreated CML patients. Even so, it is our feeling that, based on its compelling success in patients with interferon-refractory and advanced disease and on its benign side effect profile, it will quickly become the front-line therapy for CML once it becomes available. Despite the ease of administration of STI571, patients should continue to be encouraged to participate in clinical studies so that several vital issues can be resolved: 1) the percentage of untreated CML patients who will eventually develop molecular remissions; 2) the proportion of patients in whom resistance to STI571 will emerge; 3) the optimum length of treatment; and 4) the impact on survival. Because interferon-alfa can also result in cytogenetic remissions, albeit in a small percent (less than 20%) of early chronic phase patients, it seems reasonable to suggest that patients who do not attain cytogenetic/molecular remissions with STI571 alone be treated with a combination of STI571 and interferon-alfa. Patients who are resistant to STI571 with or without interferon-alfa should undergo allogeneic hematopoietic cell transplant. Salvage therapy after transplant may include donor lymphocyte infusions, interferonalfa, additional transplant, and perhaps STI571. Medications such as hydroxyurea appear destined to play a very limited role in CML. They may be used in the palliative treatment of older STI571-resistant patients or those without a transplant donor, although these patients may be best served by being considered for clinical trials of molecules, such as polyethylene glycol-interferon-alfa, on other novel agents.     

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.     

Central nervous system involvement in indolent lymphomas.

BACKGROUND: Central nervous system (CNS) involvement, a well-recognized complication of aggressive non-Hodgkin's lymphomas (NHL), has rarely been reported in indolent lymphomas. Large series have reported this complication in 3% of indolent NHLs, generally following histological transformation. PATIENTS AND METHODS: We retrospectively reviewed the disease characteristics and clinical course in seven patients (six females, one male) with indolent B-cell lymphomas who developed CNS involvement during various stages of their illness. RESULTS: The median ages at diagnosis of systemic and CNS lymphoma were 60 and 63 years, respectively. Histologies were: small lymphocytic lymphoma (two), follicular lymphoma grade I (two), follicular lymphoma grade II (two) and unclear low-grade histology (one). There were diverse neurological symptoms. Two patients had parenchymal involvement, three had leptomeningial involvement and two had both. Systemic lymphoma was found in all patients, all but one having bone marrow involvement. Four patients had a transformation to high-grade histology. Six patients were treated with systemic and intra-cerebrospinal fluid chemotherapy, and two received radiotherapy as well. Five patients achieved CNS response. Survival was 1-9 years for treated patients (median 2 years). Three patients died of CNS disease. CONCLUSIONS: CNS involvement is a rare and unexpected complication of indolent NHL, which should be considered in the differential diagnosis of patients presenting with new neurological signs. This condition is treatable and some patients have a long clinical course.     

Hypercalcemia in the accelerated phase of chronic myelogenous leukemia

Within a recent one-year period, 3 patients in the accelerated phase of chronic myelogenous leukemia were admitted to our medical center with severe hypercalcemia. Simultaneous determinations of ionized calcium and parathyroid hormone levels in 2 of the patients confirmed the hypercalcemia and revealed suppression of parathyroid hormone. We conclude that hypercalcemia in the accelerated phase of chronic myelogeneous leukemia may be more common than previously described and is not mediated by parathyroid hormone. An elevated parathyroid hormone level accompanying hypercalcemia in these patients should suggest the additional diagnosis of primary hyperparathyroidism. Mithramycin was necessary for control in 2 of our cases as well as in others reported in the medical literature and should be an early therapeutic consideration whenever saline diuresis is inadequate.     

Central nervous system involvement in mantle cell lymphoma.

BACKGROUND: Extranodal involvement, including central nervous system (CNS), is a frequent event in patients with mantle cell lymphoma (MCL). However, the incidence, risk factors, and impact on outcome remain controversial. PATIENTS AND METHODS: Main clinical, biological, and evolutive features of 82 patients (60 males/22 females; median age: 61 years) diagnosed with MCL (blastoid, 26%) in a single institution were analyzed for risk of CNS involvement and prognosis. RESULTS: Most patients had advanced stage and intermediate or high-risk International Prognostic Index (IPI). Eleven patients eventually developed CNS involvement with an actuarial 5-year risk of 26% (95% confidence interval 10% to 42%). In one asymptomatic patient, cerebrospinal fluid infiltration was detected at staging maneuvers (1/62; 1.6%). The remaining 10 patients developed neurological symptoms during the course of the disease (median time from diagnosis, 25 months). Initial variables predicting CNS involvement were blastoid histology, high proliferative index measured by Ki-67 staining, high lactate dehydrogenase (LDH) and intermediate- or high-risk IPI. Histological subtype and serum LDH maintained significance in multivariate analysis. Treatment of CNS infiltration consisted of intrathecal chemotherapy (two cases), and intrathecal chemotherapy plus systemic treatment (seven cases). Median survival after CNS involvement was 4.8 months, patients with this complication having shorter survival than those with no CNS disease. CONCLUSION: This study confirms the high incidence of CNS involvement in MCL patients. Treatments aimed at preventing this complication are warranted.     

Central nervous system involvement in malignant melanoma

One hundred consecutive patients with cerebral metastases from malignant melanoma were studied in relation to survival from the time of diagnosis of central nervous system (CNS) involvement, response to treatment, characteristics of their primary lesion, and the course of the disease from initial diagnosis to the development of intracranial tumor. After treatment, clinical and investigational evidence of objective regression of cerebral lesions was demonstrable in ten patients who survived with a median of 11.5 months from diagnosis of CNS involvement. In 11 additional patients, CNS disease remained clinically stable for a median period of 7 months. Median survival for the entire group of 100 patients was 2.5 months. However, eight patients (8%) survived longer than 1 year from the time of diagnosis of cerebral metastases, four of whom (4%) survived longer than 2 years; the longest survivor being disease-free and incomplete neurologic remission at more than 82 months. Patients with malignant melanoma metastatic to the brain should be informed of the therapeutic options available for their disease.     

Central nervous system involvement in Hodgkin's lymphoma

Central nervous system involvement in Hodgkin's lymphoma is extremely rare. We report three cases who had a relapse from the disease involving CNS. The most frequent causes are skull contiguity, meningeal invasion and via the hematogenous route. It is frequent that the association between Epstein-Barr Virus and Hodgkin's lymphoma, and a biopsy for confirmation, is always required. Diagnostic imaging tests like CT and MRI are useful. The standard treatment remains holocraneal radiotherapy combined with chemotherapy.     

Central nervous system prophylactic treatment for childhood leukemia: neuropsychological outcome studies

The cognitive sequelae of central nervous system treatments for leukemia have become a major concern as more leukemic children survive the initial consequences of the disease. A review of 28 neuropsychological outcome studies published in the past nine years shows that the preponderance of evidence from the better designed studies suggests that leukemic children who do not suffer overt Central Nervous System (CNS) complications, such as CNS relapse, do not experience significant cognitive deficits as a consequence of their treatment. Also, these studies do not unequivocally suggest that cranial irradiation as a treatment technique results in greater cognitive impairment than treatment without irradiation. Many studies are consistent in finding that leukemic children younger than 8 years of age have a worse outcome than older ones although both groups perform in the average to bright normal range. It is currently difficult to conclude that such differences in intellectual outcome were caused by the CNS treatment alone or other psychosocial aspects of acquiring leukemia. The confusion present in the literature could be greatly reduced by combining the research efforts on the psychosocial aspects of acquiring leukemia with the studies examining neuropsychological outcome.     

Leukocyte interferon in the treatment of chronic myelogenous leukemia in second chronic phase

Four patients with Philadelphia chromosome positive CML were treated with 18-42 x 10(6) IU of purified natural leukocyte IFN-alpha per week, after high-dose chemotherapy for blast phase and attainment of 2nd chronic phase. The second blast phase occurred within 3 months in 3 patients, but one patient is still in second chronic phase after 22 months of treatment. Treatment consisted of interferon only during the first year, and interferon in combination with hydroxyurea during the second year. During the second year suppression of the Philadelphia chromosome was seen in one patient, with 20% Philadelphia negative bone marrow metaphases. The toxicity of purified natural leukocyte IFN-alpha was similar to the toxicity of recombinant IFN-alpha. Antibodies to IFN-alpha were not detected in any patient.     

Central nervous system imaging in childhood leukaemia

The aim of this study was to document the imaging abnormalities seen in the central nervous system (CNS) in cases of childhood leukaemia or as complications of its treatment. Magnetic Resonance (MR) images and Computed Tomographic (CT) scans were reviewed retrospectively in 22 children and adolescents with neurological manifestations/complications of leukaemia or its treatment. Among the 22 patients, nine had two or more different CNS abnormalities. The imaging abnormalities seen in 15 patients before or during treatment included sinus thrombosis, cortical vein thrombosis, cerebral haemorrhage, meningeal leukaemia, infections, skull leukaemic infiltration and treatment-related neurotoxicity. After therapy, seven patients had CNS abnormalities, including secondary brain tumours, skull tumour, mineralising microangiopathy, leucoencephalopathy, transient white matter abnormalities, spinal intradural haematoma, chronic subdural haematoma, radiation necrosis, meningeal leukaemia and leukaemic infiltration at the vertebral body. CNS complications are related to the inherent risk of leukaemia itself, to the treatment method and to the duration of survival.     

Oral idarubicin in patients with late chronic phase chronic myelogenous leukemia or chronic myelomonocytic leukemia

Patients with chronic myelogenous leukemia (CML) who have failed or cannot receive interferon alpha (IFN-alpha) based regimens or patients with advanced chronic myelomonocytic leukemia (CMML) have very limited current therapeutic options. Hence, there is a need to develop new strategies for these patients. This study was undertaken to determine the efficacy and toxicity of a chronic low-dose oral idarubicin regimen in these patients as positive data has been generated on this agent in shorter schedules given to patients with other hematological malignancies. Eighteen patients were treated on study. The starting dose of oral idarubicin was 2 to 5 mg/m2 daily depending in initial WBC count. This dose was escalated in the absence of Grade 4 myelosuppression or Grade 3 or 4 extramedullary toxicity. Oral idarubicin was given daily for 28 days followed by a 21 day break off treatment in repeated cycles until there was evidence of disease progression or intolerable toxicity. The dose of idarubicin was adjusted, at 2-week intervals, by 25% to maintain a white blood cell (WBC) count between 2 and 4x10(9)/L and a platelet count of >75x10(9)/L. The dose was reduced by 25% for grade 2 extramedullary toxicity and held until toxicity resolved to grade 2 or better for grade 3 toxicity. Oral idarubicin was then restarted at 75% of the initial dose. Five out of 14 CML patients achieved a complete hematologic remission. No CMML patient responded (median survival 3 months). The overall median survival was 24 months. CML patients had a median survival of 28 months. Major toxicities (myelosuppression, gastrointestinal, cardiac) were infrequent with a median cumulative dose of 1110 mg/m2 (range 54-9750). Five patients have received oral idarubicin for > 1 year with no overt cardiotoxicity, reaching median cumulative dose of 2756 mg/m2 (range 2550-9750) which is higher than those documented in prior studies. We conclude that oral idarubicin is sufficiently safe and active to warrant phase II studies investigating it as part of interferon-based regimens in patients with advanced CML.