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PubMed2003

Severe epidermal necrolysis after treatment with imatinib and consecutive allogeneic hematopoietic stem cell transplantation.

Imatinib is a new promising therapeutic option for chronic myeloid leukemia (CML) with efficacy even in the blast phase of the disease. However, most patients treated with imatinib in the blast phase develop progressive disease rapidly. Thus, treatment with imatinib has to be followed by other treatment strategies. The normally mild to moderate side effects of imatinib including skin rashes might therefore be aggravated. Here, we describe a patient with severe epidermal necrolysis after treatment with imatinib and consecutive allogeneic hematopoietic stem cell transplantation. Prolonged inhibition of platelet-derived growth factor by imatinib may be an explanation for this observed skin toxicity.

Benzamides↗
PubMed1982

Natural antibodies to the structural core protein (p24) of the human T-cell leukemia (lymphoma) retrovirus found in sera of leukemia patients in Japan.

In Japan, adult T-cell leukemias and lymphomas are more common than in the United States and Europe, and in the southwest part of Japan these T-cell malignancy cases appear in clusters. Therefore, we investigated the involvement in these leukemias and lymphomas of the human T-cell leukemia virus (HTLV) that was previously isolated in one of our laboratories from cultured T cells of some patients in the United States with leukemias and lymphomas involving relatively mature T cells. High titers of antibodies capable of quantitative precipitation of (125)I-labeled p24, a well characterized core protein of HTLV, were detected in 12 of 12 patients with untreated adult T-cell leukemia (ATL). (One negative was a patient on chemotherapy.) Ten of the 12 positive samples were from an area where the disease is endemic. Strong precipitating antibodies were also detected in five of seven cases of T-cell malignant lymphoma (TML) which differs from ATL by having fewer leukemic cells in the peripheral blood. High antibody titers were also observed in one of five cases of acute monoblastic leukemia and one of eight cases of chronic myelogenous leukemia in the blast phase of the disease. Low to moderate titers of antibodies were detected in several categories of leukemia (two cases of blast-phase chronic myelogenous leukemia, two cases of acute lymphoblastic leukemia of the null-cell type, and one case of acute myelogenous leukemia). Among all categories of leukemias, except ATL and TML, more cases were negative than positive for anti-p24 activity. All of 79 sera from normal Japanese, including 39 collected from the endemic ATL area of southwest Japan, were negative for antibodies to HTLV p24. All the positive reactivities observed were highly specific to HTLV. The only competition observed in the precipitation of HTLV p24 was with HTLV or with cell lines expressing HTLV and not with various animal retroviruses or a large number of human and subhuman primate cell lines, not known to be producing HTLV. The data strongly indicate an association of HTLV with the increased incidence of ATL in parts of Japan, probably with other forms of leukemias in Japan, and, less commonly, with certain T-cell malignancies in the United States.

Antigens, Viral↗
PubMed1988

Prolonged high dose ARA-C infusions in acute leukemia.

High doses of cytosine arabinoside (ara-C) were administered by continuous infusion to 24 patients with acute leukemia in relapse or blast phase of chronic myelogenous leukemia (CML). Ara-C was infused at a dose rate of 250 mg/M2/hr for 36 to 72 hr. The major toxicities were myelosuppression, diarrhea, and abdominal pain. Other toxicities included pulmonary edema, neurotoxicity, and liver function abnormalities. The gastrointestinal toxicity was dose-limiting and a phase II dose was established at 250 mg/M2/hr for 60-72 hr. Four patients treated with this dose schedule had objective responses. Two patients with CML in blast phase returned to chronic phase and have remained stable without maintenance therapy for 12 and 18 months. Two patients with acute myelogenous leukemia in relapse entered complete remissions which continued unmaintained for 4 and 6 months. Steady-state plasma ara-C levels ranged between 7 and 24 x 10(-6) M, while ara-U levels were as high as 4.5 x 10(-4) M. There was no detectable accumulation of ara-C or ara-U during the infusion period. These findings would suggest that the continuous infusion of high dose ara-C may be useful in the treatment of acute leukemia and CML in blast crisis.

Adult↗
PubMed2001

Cooperation of BCR-ABL and AML1/MDS1/EVI1 in blocking myeloid differentiation and rapid induction of an acute myelogenous leukemia.

The development of acute myelogenous leukemia (AML), which is characterized by a block of myeloid differentiation, is a multi-step process that involves several genetic abnormalities, but the molecular mechanisms by which these genetic alterations cooperate in leukemogenesis are poorly understood. The human chronic myelogenous leukemia (CML) is a model for multi-step leukemogenesis. BCR-ABL, a constitutively active tyrosine kinase, is a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of CML patients. BCR-ABL efficiently induces a myeloproliferative disorder (MPD) in mice, but progression to CML blast phase requires additional mutations. The AML1/MDS1/EVI1 (AME) transcription factor fusion protein, is a product of the human t(3;21)(q26;q22) translocation found as a secondary mutation in some cases of CML during the blast phase. We have previously shown that AME can induce an AML in mice but with a greatly extended latency, suggesting a requirement for additional mutations. Here we demonstrate that AME alone does not block myeloid differentiation in vivo during the 4-month pre-leukemia stage, yet co-expression of BCR-ABL and AME in mice can block myeloid differentiation and rapidly induce an AML. Our results suggest that block of myeloid differentiation and induction of AML involves cooperation between mutations that dysregulate protein tyrosine kinase signaling and those that disrupt hematopoietic gene transcription.

Acute Disease↗
PubMed2002

Detection of stem cell factor mRNA expression in leukemic cells by in situ reverse transcriptase-PCR.

OBJECTIVE: To evaluate the feasibility of detecting low copy stem cell factor (SCF) mRNA in leukemic cells by in situ reverse transcriptase-PCR (RT-PCR). METHODS: In situ RT-PCR was carried out on PE480 DNA Thermal Cycler to determine the expression of SCF mRNA in K562, HL-60 and chronic myelogenous leukemia (CML) cells in blast phase. RESULTS: SCF mRNA was detected in the 3 cell lines by direct or indirect in situ RT-PCR, but not by in situ hybridization. CONCLUSION: SCF mRNA is present in K562, HL-60 and CML cells in blast phase but with very low expression level which can be detected by in situ RT-PCR carried out on PE480 DNA Thermal Cycler.

3T3 Cells↗
PubMed1982

Enrichment of cell populations containing terminal deoxynucleotidyl transferase activity by free flow electrophoresis.

Terminal deoxynucleotidyl transferase (TdT) is an enzyme that has been utilized as a biochemical marker for following certain leukemia patients during treatment and remission. The potential usefulness of this enzyme in predicting the onset of relapse before any morphological indications has been demonstrated in chronic myelogenous leukemia patients in blast phase of the disease. In order to be able to detect low levels of TdT activity, especially during remission phase, we have used the technique of free flow electrophoresis to enrich cell populations containing TdT. With this technique we have achieved up to 20-fold enrichment of TdT-positive cell populations from normal human bone marrow, cells from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in blast phase of the disease. TdT positive cells were not detected in patients with acute myelogenous leukemia and B cell lines. This technique should prove to be useful in early detection of relapse in patients in remission and for enrichment of cell populations containing other biochemical markers.

Bone Marrow↗
PubMed1987

Differentiation of blasts from patients in myeloid crisis of chronic myelogenous leukemia by in-vivo and in-vitro plicamycin treatment.

Two cases in myeloid blast phase of chronic myelogenous leukemia (CML) responded to treatment with plicamycin alone. Their total white blood cell (WBC) count and immature myeloid cells fell in one case rapidly and in the other gradually. Approximately two to three weeks after initiation of plicamycin their total WBC count began to rise again, whereas the mature myeloid cells remained constant throughout the treatment. These results suggest that plicamycin may be effective in suppressing proliferation of blasts and promoting their maturation in the myeloid blast phase of CML, but that plicamycin alone may not be effective enough to sustain duration of response.

Adult↗
PubMed1985

Evidence for two isozymes of leukocyte alkaline phosphatase in leukemic leukocytes.

Leukocyte alkaline phosphatase (LAP) is a granulocyte enzyme whose level of expression is markedly altered in various disease states. We have characterized LAP from normal cells and leukemic cells with a high level of LAP activity in order to determine whether increased enzyme levels are caused by increased levels of the same enzyme or induction of a different alkaline phosphatase. Leukocyte alkaline phosphatase was purified from normal granulocytes and from leukemic cells of a patient with chronic granulocytic leukemia (CGL) in blast phase with an elevated LAP level. LAP was partially purified utilizing diethylaminoethyl (DEAE)-cellulose ion exchange chromatography, gel filtration, and preparative electrophoresis. The sample prepared from normal granulocytes contained a single protein with LAP activity having a molecular weight of 61,000 as determined by SDS gel electrophoresis. The sample from the CGL blast-phase cells, however, demonstrated two proteins with alkaline phosphatase activity, one with a molecular weight of 61,000 (LAPs) and one with a molecular weight of 45,000 (LAPf). Differential heat inactivation and distinct isoelectric points of the two isozymes suggest that they are different proteins. We interpret our data to suggest two closely related LAP alleles whose expression is controlled independently. This may represent either genetic heterogeneity or induction of "tumor marker" gene expression.

Alkaline Phosphatase↗
PubMedDate not supplied

Rubidazone in adults with previously treated acute leukemia and blast cell phase of chronic myelocytic leukemia: a Southwest Oncology Group Study.

Rubidazone, a new anthracycline antibiotic, is the benzoyl hydrazone derivative of daunorubicin. The Southwest Oncology Group carried out a phase II study of the drug in 126 patients with previously treated acute leukemia; 116 patients were evaluable. Good-risk patients were given doses of 450 mg/m2, and poor-risk patients were given doses of 300 mg/m2 approximately every 3 weeks. No complete response was observed in 25 patients with chronic myelocytic leukemia blast cell transformation. In the remaining patients the overall complete response rate was 22% and the rate of complete plus partial response was 29%. In good-risk patients these rates were 27% and 35%, respectively. Toxicity was similar to that observed with other anthracyclines except that acute febrile reactions were more pronounced. On the basis of the results, there are plans for a large-scale comparison study of rubidazone versus doxorubicin, each in combination with cytarabine, vincristine, and prednisone.

Acute Disease↗
PubMed1993

Structural organization of BCR-ABL gene in chronic phase and blast transformation in chronic myeloid leukemia patients.

We studied 36 DNA samples of 18 patients affected with chronic myeloid leukemia (CML) for the presence of mutations in the first exon of the BCR gene was divided into four regions amplified by polymerase chain reaction (PCR). By single strand conformation polymorphism analysis (SSCP) and direct sequencing of amplified fragments, we found different banding profiles in 9 out of 18 patients in the PCR fragment spanning nucleotide 506-826. In one patient, sequence analysis revealed the presence of a point mutation at nucleotide 669 (A-T; Gln-Leu). No difference was found between DNA samples collected during the chronic phase and the blastic transformation. No different mobility shifts of single stranded PCR products were found in the other amplified fragments. The activation of BCR-ABL involves direct interaction between BCR first exon sequences and the tyrosine kinase regulatory domains of ABL. In the first BCR exon, and around the mutated sequences two SH-2-binding sites, are retained. These domains are essential for BCR-ABL-mediated transformation. Our results demonstrate the presence of point mutation in this regulatory region, which may suggest a role for the altered BCR sequence in activation of the BCR-ABL oncogene.

Base Sequence↗
PubMed2002

Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia.

Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, we identified BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib. Fifteen different amino acid substitutions affecting 13 residues in the kinase domain were found. Mutations fell into two groups-those that alter amino acids that directly contact imatinib and those postulated to prevent BCR-ABL from achieving the inactive conformational state required for imatinib binding. Distinct mutations conferred varying degrees of imatinib resistance. Mutations detected in a subset of patients with stable chronic phase disease correlated with subsequent disease progression. Multiple independent mutant clones were detected in a subset of relapsed cases. Our data support a clonal selection model of preexisting BCR-ABL mutations that confer imatinib resistance.

Alleles↗
PubMed1991

Production of colony-stimulating activity by circulating leukocytes from patients with chronic myeloid leukemia at various phases of the disease.

The production of colony-stimulating activity (CSA) by peripheral blood leukocytes (PBL) from 107 patients with chronic myeloid leukemia (CML), 58 at diagnosis, 34 during hematological remission, 33 in relapse from hematological control, 39 in accelerated phase, and 28 in blast phase, was measured in the double-layer agar culture system using normal nonadherent bone marrow cells as the source of CFU-GM. The median CSA levels in various stages decreased to 28-60% of control, whereas in hematological remission, there was a normalization of CSA. Five fractionation experiments using monocytes as feeder layers did not show CSA production in untreated CML. The leukemic PBL of 6 patients in blast crisis had no apparently inhibitory effect on colony formation stimulated by normal PBL. There was no correlation between the CSA of PBL and the number of CFU-GM in their bone marrow or peripheral blood at different disease states. Likewise, we failed to find a relationship between the PBL CSA levels and the total WBC counts or the differential counts in the peripheral blood as well as in the feeder layers. Our study indicated that circulating leukocytes from patients with CML at various phases except in hematological remission produce less CSA, which is not attributed to a low number of monocytes or the inhibitory effects of leukemic cells.

Adult↗
PubMed1982

Enrichment of terminal deoxynucleotidyl transferase activity by cell separation.

Terminal deoxynucleotidyl transferase is a unique DNA polymerase that can carry out DNA synthesis on an initiator molecule in the absence of a template. The usefulness of this enzyme as a biological marker for following patients during treatment and remission has been suggested. The potential usefulness of this enzyme in predicting the onset of relapse before any morphological indications has been demonstrated in chronic myelogenous leukemia patients in blast phase of the disease. In order to be able to detect low levels of TdT activity especially during remission phase, we have used cell separation techniques which can enrich cell populations containing TdT activity. A number of cell separation techniques have been developed to separate different cell types. We have used the techniques of unit gravity sedimentation and free flow electrophoresis to achieve enrichment of TdT positive cell populations. Our results show that up to 20 fold enrichment of TdT activity in normal human bone marrow can be accomplished by using cell separation techniques. With the use of free flow electrophoresis, we have achieved enrichment of TdT positive cell populations from normal human bone marrow, cells from patients with acute lymphoblastic leukemia and chronic myelogenous leukemia in blast phase of the disease. No TdT positive cells were detected in patients with acute myelogenous leukemia. These cell separation techniques should prove to be useful in early detection of relapse in patients in remission.

B-Lymphocytes↗
PubMed2004

Determination of secondary chromosomal aberrations of chronic myelocytic leukemia.

Chronic myeloctyic leukemia (CML) is a stem cell disorder characterized by the cytogenetic abnormality of t(9;22)(q34;q11.2), which progresses from a chronic phase to an accelerated phase (AP), and/or a blast phase (BP) of myelocytic or lymphoid phenotype. This progression is frequently preceded or accompanied by recurring secondary chromosomal abnormalities (SCA) that are believed to play a role in the transformation and may also serve as valuable prognostic indicators. Failure to note such abnormalities may lead to an inappropriate clinical evaluation. We observed CML patients with AP or BP who did not show SCA by routine cytogenetic analysis. To determine the presence or absence of specific SCA in those cases, we applied fluorescence in situ hybridization (FISH) to four CML cases with pseudodiploid cytogenetics [t(9;22)(q34;11.2) as the sole abnormality] by conventional karyotyping. Bone marrow biopsies from two AP and two BP of CML patients with pseudodiploid karyotypes by conventional cytogenetics were examined by FISH for trisomy 8 and i(17q). These SCA are major secondary chromosomal changes seen in BP of CML patients. Results were considered positive if more than 2.4% of cells had +8 and >6.25% for i(17q) by FISH. Four out of four patients were positive for +8. These results indicate that FISH techniques are valuable in the determination of SCA in CML, which were t(9;22)(q34;q11.2) positive as the sole cytogenetic abnormality with standard G-banding karyotyping and can be helpful for the early diagnosis of CML progression.

Blast Crisis↗
PubMed2006

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure.

Resistance to imatinib mesylate is an emerging problem in the treatment of chronic myeloid leukemia (CML), often associated with point mutations in the Bcr-Abl kinase domain. Outcome of patients with such mutations after allogeneic stem cell transplantation (Allo-SCT) is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in chronic phase, 4 in accelerated phase, and 2 in blast phase) and 1 had Philadelphia-positive acute lymphocytic leukemia (ALL). Patients harbored 9 different protein kinase mutations (T315I mutation, n = 2). Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after Allo-SCT. Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations.

Adult↗
PubMed2003

Chronic myeloid leukemia: pathophysiology, diagnostic parameters, and current treatment concepts.

Chronic myeloid leukemia (CML) is a stem cell disease characterized by excessive accumulation of clonal myeloid (precursor) cells in hematopoietic tissues. CML cells display the translocation t(9; 22) that creates the bcr/abl oncogene. The respective oncoprotein (= BCR/ABL) exhibits constitutive tyrosine kinase activity and promotes growth and survival in CML cells. Clinically, CML can be divided into three phases: the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP) that resembles acute leukemia. Progression to AP and BP is associated with occurrence of additional genetic defects that cooperate with bcr/abl in leukemogenesis and lead to resistance against antileukemic drugs. The prognosis in CML is variable depending on the phase of disease, age, and response to therapy. The only curative approach available to date is stem cell transplantation. For those who cannot be transplanted, the BCR/ABL tyrosine kinase inhibitor STI571 (Glivec, Imatinib), interferon-alpha (with or without ARAC), or other cytoreductive drugs are prescribed. Currently available data show that STI571 is a superior compound compared to other drugs in producing complete cytogenetic and molecular responses. However, despite superior initial data and high expectations for an effect on survival, long term results are not available so far, and resistance against STI571 has been reported. Forthcoming strategies are therefore attempting to prevent or counteract STI571 resistance by co-administration of other antileukemic drugs. Whether these strategies will lead to curative drug therapy in CML in the future remains at present unknown.

Adult↗