High incidence of meningeal leukemia in lymphoid blast crisis of chronic myelogenous leukemia

Fifteen patients with lymphoid blast crisis of chronic myelogenous leukemia (LyBC-CML) and five patients with acute lymphoblastic leukemia converting to Philadelphia-positive (Ph+) chronic myeloid leukemia (ALL Ph + CML) were followed. Seven of 15 (46.7%) LyBC-CML patients developed meningeal leukemia within a median period of 6 months (range 2–11 months), while there was no medullary relapse. Five of these responded well to triple intrathecal therapy. In the ALL Ph + CML patients, in spite of central nervous system (CNS) prophylaxis with IT MTX and 18 Gy cranial radiation, two of five patients (40%) experienced meningeal leukemia, one isolated and the other with medullary relapse. The data confirm that LyBC-CML patients experience a high incidence of meningeal leukemia. The role of CNS prophylaxis is not very clear, but its use may delay development and reduce morbidity due to CNS disease.     

Philadelphia-chromosome-negative chronic myelogenous leukemia with lymphoid stem cell blastic transformation

A patient is described who had blastic transformation of Ph1 negative chronic myelogenous leukemia (Ph1 - CML). Characterization of the leukemic cells revealed a population with a lymphoid stem cell phenotype (cALL-, TdT+, Ia+, cIgM-). This particular phenotype may be responsible for the refractoriness to vincristine and prednisone and the rapid downhill course.     

Effects of sCD23 on proliferation of leukemic cells from a patient with chronic myelogenous leukemia during blast crisis

The present study has attempted to further delineate the growth factor requirements of peripheral blasts of a patient with CML in acute phase. Phenotypic analysis of leukemic blasts from this patient before culture has shown a homogenous population of CD34⁺ cells at the onset of blast crisis. In the second and third samples the percentage of CD34⁺ DR⁺ blast cells decreased slightly and up to 32% of cells in the third sample expressed the CD19 antigen. Optimal proliferation of cells derived from the first sample required the presence of exogenous sCD23 and to a lesser extent IL7. The stimulatory effects of sCD23 and IL7 were clearly reduced 4 months later and no longer detected after 6 months. This variability in growth factor response along with disease progression may be related to phenotypic differentiation. There was no evidence for lymphoid or myeloid maturation after 4 days of liquid culture. Our results in conjunction with previous studies are in agreement with sCD23-involvement in the complex control of proliferative processes at both normal and leukemic stages, demonstrating that cytokines are critical in determining CML cell proliferation. © 1993 Wiley-Liss, Inc.     

Complex chromosomal abnormalities in a patient with lymphoid blast crisis of chronic myelogenous leukemia

A 46-year-old Chinese man underwent lymphoid blast crisis (Ia+, CALLA+, TdT+) after 5 years of chronic phase, Philadelphia-chromosome positive chronic myelogenous leukemia. Chromosome analysis revealed a hyperdiploid karyotype, including two Philadelphia chromosomes--55,XY,t(9;22) (q34;q11), +2, +5, +5, +6, +10, +18, +19, +21, +del(22)(qll----qter)--in the majority of the leukemic blasts. The constellation of a lymphoid blast crisis and complex chromosomal abnormalities usually associated with myeloid blast crisis as well as the clinical data are discussed.     

Erythroid blast crisis in chronic myelogenous leukemia

Blood or bone marrow specimens from 22 patients with chronic myelogenous leukemia in blast crisis were studied for the surface expression of glycophorin-A, a marker for early erythroid differentiation. The leukemic blasts were stained with rabbit anti- glycophorin-A antiserum. The glycophorin-A molecules detected by the rabbit antiserum were identified by polyacrylamide slab gel electrophoresis of the immunoprecipitates from the membrane lysates of surface-labeled blasts. Blasts expressing surface glycophorin-A were found in 9 of the 22 patients. In 4 patients, almost all blasts were glycophorin-A positive, and in 5 patients, less than half of the blast population expressed glycophorin-A. The present study shows that when glycophorin-A is used as a marker for erythroid blasts, involvement of the erythroid lineage during blast crisis of chronic myelogenous leukemia seems to occur more frequently than previously recognized.     

Case of chronic-phase chronic myelogenous leukemia with an abdominal hematopoietic tumor of leukemic clone origin

We report a 59-year-old man with chronic myelogenous leukemia (CML) in chronic phase who presented with a large abdominal tumor. Biopsy revealed proliferation of granulocytic-, erythroid-, and megakaryocytic-lineage cells in a retroperitoneal lymph node. The BCR/ABL fusion gene was detected on a paraffin-embedded tissue section of the lymph node by double-color fluorescence in situ hybridization, indicating an extramedullary hematopoietic tumor of CML origin. This patient has achieved a complete cytogenetic response for 19 months with imatinib mesylate (STI571; Gleevec), in association with the regression of the tumor. However, the development of an extramedullary tumor in chronic-phase CML generally indicates a poor prognosis, because it commonly consists of blast proliferation and is followed by blast crisis in the marrow within a few months. This case, therefore, points to the importance of histological examination of extramedullary tumors in CML for evaluation of disease status and for therapeutic decisions.     

Isolation of myeloid progenitor cells from peripheral blood of chronic myelogenous leukemia patients

Myeloid progenitor cells (colony- and cluster-forming cells in semisolid medium, CFU-GM) were purified from the peripheral blood of chronic myelogenous leukemia (CML) patients. Lymphocytes, monocytes, and most immature myeloid cells were simultaneously depleted with specific monoclonal antibodies using an erythrocyte rosette technique for cell separation. Cells expressing Ia-like antigen were then selected from the residual cell population. Day 7 CFU-GM were enriched 44--116-fold in the IA+ cell fraction, when compared to the unseparated cells, and up to 47% of the cells could form a myeloid colony or cluster in culture. This cell fraction contained up to 92% undifferentiated blasts, with the remainder mostly promyelocytes. The enriched CFU-GM cells were dependent on an exogenous supply of colony- stimulating factor for growth, and colony formation was linear with cell concentration over a large range (10(4)-10(1) cells/ml). This technique of rosette depletion and enrichment with specific monoclonal antibodies provides a unique method for purifying a homogenous population of myeloid precursor cells with defined surface antigen characteristics.     

Identification of human chronic myelogenous leukemia progenitor cells with hemangioblastic characteristics

Overwhelming evidence from leukemia research has shown that the clonal population of neoplastic cells exhibits marked heterogeneity with respect to proliferation and differentiation. There are rare stem cells within the leukemic population that possess extensive proliferation and self-renewal capacity not found in the majority of the leukemic cells. These leukemic stem cells are necessary and sufficient to maintain the leukemia. Interestingly, the BCR/ABL fusion gene, which is present in chronic myelogenous leukemia (CML), was also detected in the endothelial cells of patients with CML, suggesting that CML might originate from hemangioblastic progenitor cells that can give rise to both blood cells and endothelial cells. Here we isolated fetal liver kinase-1-positive (Flk1+) cells carrying the BCR/ABL fusion gene from the bone marrow of 17 Philadelphia chromosome-positive (Ph+) patients with CML and found that these cells could differentiate into malignant blood cells and phenotypically defined endothelial cells at the single-cell level. These findings provide direct evidence for the first time that rearrangement of the BCR/ABL gene might happen at or even before the level of hemangioblastic progenitor cells, thus resulting in detection of the BCR/ABL fusion gene in both blood and endothelial cells.     

Possible effect of medroxyprogesterone acetate (MPA) in lymphoid blast crisis of chronic myelogenous leukemia

Summary A patient with a lymphoid blast crisis of a chronic myelogenous leukemia (CML) was treated with vindesine, vincristine and prednisone. Blasts disappeared from the peripheral blood but persisted at a level of 60% in the bone marrow. After 5 weeks of continuous therapy, the patient became thrombopenic, and 2 weeks later blasts rose to 31%. After 7 weeks, 1 g MPA was given daily p.o. and weekly vincristine treatment was resumed. Blasts disappeared again from the peripheral blood, thrombocytes rose to a maximum of 274 g/l, and a remission with less than 5% blasts was demonstrated in the bone marrow. In another relapse after withdrawal of MPA, estrogen and progesterone receptors (PR) were found in the leukemic cells. Thus, a remission was seen during treatment with vincristine, prednisone, and MPA after a deterioration with vincristine and prednisone alone in a PR-positive leukemia, and an effect of MPA in this lymphoid blast crisis of a CML has to be discussed.This work was presented at the Annual Congress of the German and the Austrian Society of Hematology and Oncology, Essen, 10–13 October 1993     

Extramedullary presentation of blast crisis in chronic myelogenous leukemia

We present a case with the clinical and pathological impression of Ph1-positive chronic myelogenous leukemia in extramedullary blast crisis involving lymph nodes as demonstrated by morphological and cytogenetic studies. The hyperploid cell lines that were present in the lymph node were not present in the bone marrow. The present case demonstrates that cytogenetic and morphological studies of extramedullary organs are helpful in the confirmation of the diagnosis of blast crisis, especially when lymph nodes are the site of original presentation.     

Autografting with philadelphia chromosome-negative mobilized hematopoietic progenitor cells in chronic myelogenous leukemia

Intensive chemotherapy given in early chronic phase of chronic myelogenous leukemia (CML) has resulted in high numbers of circulating Philadelphia (Ph) chromosome-negative hematopoietic progenitor cells (HPC). We have autografted 30 consecutive patients with CML in chronic phase with HPC collected in this way to facilitate restoration of Ph-negative hematopoiesis in bone marrow after high-dose therapy. Hematopoietic recovery to greater than 0.5 x10(9)/L neutrophils and to greater than 25 x 10(9)/L platelets occurred in all patients, a median of 13 (range, 9 to 32) days and 16 (range, 6 to 106) days postautograft, respectively. Regenerating marrow cells were Ph-negative in 16 (53%) patients and greater than 66% Ph-negative in 10 (33%) patients. Twenty-eight patients are alive 6 to 76 months (median, 24 months) after autografting. Three patients have developed blast crisis from which 2 have died. Eight patients are in complete cytogenetic remission at a median of 20 (range, 6 to 44) months with a median ratio BCR-ABL/ABL of 0.002 (range, <0.001 to 0.01). Eight patients are in major cytogenetic remission at a median of 22 (range, 6 to 48) months. No patient died as a consequence of the treatment. All patients had some degree of stomatitis that was severe in 15 (50%) patients. Gastrointestinal and hepatic toxicities were observed in about one fourth of patients. Thus, autografting with Ph-negative mobilized HPC can result in prolonged restoration of Ph-negative hematopoiesis for some patients with CML; moreover, most autograft recipients report normal or near normal activity levels, suggesting that this procedure need not to be associated either with prolonged convalescence or with chronic debility.     

Rearrangement and expression of p53 in the chronic phase and blast crisis of chronic myelogenous leukemia

We tested a population of over 60 patients with chronic myelogenous leukemia (CML) for changes in the structure and expression of the p53 gene, which is located on chromosome 17. Six of 27 (22%) blast crisis samples and 3 of 5 (60%) accelerated phase samples had rearrangements of chromosome 17, whereas only 3 of 42 (7%) chronic phase patients had cytogenetic changes in chromosome 17. There was no loss of heterozygosity during the transition to blastic crisis among seven individuals who were informative for polymorphic probes for regions in or around the p53 gene on 17p. One patient in the chronic phase and one patient in the blastic phase of the 61 CML patients studied exhibited rearrangements of the p53 gene that were detectable by Southern analysis. One p53 allele was rearranged in the chronic phase patient and both p53 alleles were rearranged in the blastic phase patient. The p53 messenger RNA (mRNA) was of normal size (2.8 kb) in chronic phase and blast crisis, and the expression of the p53 gene was at least as high or higher in blast crisis as in the chronic phase of CML. The high incidence of abnormalities of chromosome 17 in blast-crisis CML found in our studies and the discovery of rearrangements of the p53 gene in two CML patients studied suggest that further study with probes for the p53 gene and anonymous polymorphic sites in chromosome 17 should be conducted in CML.     

Natural killer lymphocyte blast crisis of chronic myelogenous leukemia

We describe for the first time a case report documenting a chronic myelogenous leukemia (CML) patient who developed a blast crisis of natural killer (NK) lymphocytes. Many of the blasts exhibited large granular lymphocytic (LGL) morphology. Single parameter immunophenotyping results determined that the granulated as well as the agranulated blast cells were NK lymphocytes (CD45, NKH1, CD2, LEU 17, and CD16 positive; CD3, CD8, and LEU 7 negative). Dual parameter flow cytometric testing also determined that some of the blasts expressed the CD11b and CD11c markers as reported for some types of NK lymphocytes. Approximately 10% of the cells were in the S phase of the cell cycle as determined by a modified Vindelov DNA content analysis test and may theoretically reflect some of those cells expressing CD11b and CD11c. The cells did not express in vitro NK lymphocyte functional activity against a K562 target and therefore similar to other reported cases of presumably immature NK lymphocytic leukemias. The NK lymphocyte blast crisis was successfully treated with vincristine and prednisone. The patient's disease eventually relapsed and transformed to a progenitor stem cell before she died (CD45, 13, CD38, and CD34 positive). The flow cytometric immunophenotyping results contributed significantly as an important adjunct in determining the appropriate diagnosis, helping to select the type of therapy, and monitoring the patient with this unusual type of blast crisis.     

Ocular complications following blast transformation in chronic myelogenous leukemia.

A number of ocular problems compromising vision occurred in a patient with chronic myeloid leukemia following blastic transformation. Hemorrhagic retinopathy developed with systemic relapse and resolved with control of systemic disease. Optic nerve involvement occurred with meningeal leukemia and was controlled with intrathecal cytosine arabinoside and methotrexate. Leukemic retinal infiltrates developed despite control of systemic and meningeal disease and were successfully treated with radiation therapy. Finally, bilateral vitreous hemorrhages occurred, severely impairing vision. Leukemic infiltration of the eye may occur with increasing frequency in CML as the survival following bastic transformation improves. Infiltration should be recognized and treated promptly if serious loss of vision is to be avoided. Central nervous system prophylaxis should be considered in patients achieving a complete response following therapy for transformation.     

Terminal deoxynucleotidyl transferase activity and B cell markers in chronic myelogenous leukemia blast crisis.

High terminal deoxynucleotidyl transferase activities were found in blast cells having B cell markers in 3 patients suffering from chronic myelogenous leukemia. The blast cells from these patients were lymphoblastic in appearance. Two of these cases were treated with vincristine and prednisolone. They responded well to this therapy.     

Philadelphia-chromosome-positive pre-B-cell leukemia presenting as blast crisis of chronic myelogenous leukemia.

Cytogenetic studies of chronic myelogenous leukemia (CML) have shown that the majority of hemopoietic cells originate from pluripotential stem cells affected in this disease. Evidence that lymphocytes are also progeny of these stem cells, however, has been indirect. Philadelphia-chromosome-positive leukemic blasts from a 4 10/12-yr-old boy with CML in blast crisis had features characteristic of pre-B leukemic cells, including expression of cytoplasmic IgM and absence of surface immunoglobulin. Additional immunologic, enzymatic, and pharmacologic characterization of these cells supported their pre-B-cell phenotype. Together, these features provide direct evidence for CML stem cell ancestry to lymphocytes of the B-cell lineage.