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PubMed1979

[Subacute and chronic monocytic leukemia: diagnostic and clinical problems].

The authors report on 16 cases of either subacute (SMML) or chronic (CMML) myelomonocytic leukemia as well as chronic monocytic leukemia (CMoL). All these cases were oligoblastic and, according to their clinical course, they could be termed as smouldering leukemias. The chronic types affected mainly males. The diagnostic cytomorphological and cytochemical criteria are discussed. Erythro- and thrombocytopoiesis were distinctly less impaired than in acute leukemias (AL). The leucocyte count in the peripheral blood of the SMML cases was within the normal range. Hepato- and splenomegaly were markedly increased as compared to AL. According to our materials leukemic skin infiltrations were less frequent in CMoL, CMML and SMML than in acute monocytic leukemias. In each of the three types of leukemia discussed monocytic leukemic cells could be readily identified by cytochemical tests and usually showed fairly normal maturation. In accordance with these observations lysozyme levels in urine and serum usually were strongly increased. The patients in the CMML and CMoL groups showed a mean survival of more than 13 months (2 out of 7 are still alive), whereas the SMML patients survived an average of 8 months. Deaths were frequently due to advanced age rather than to leukemia. In other cases a terminal accumulation of blasts marked a transition to acute leukemia. During the smouldering phase of the disease no beneficial effect of combined chemotherapy could be noted. Supportive and symptomatic therapy might improve length and quality of survival.

Aged↗
PubMed1978

Treatment of chronic granulocytic leukemia by chemotherapy, total body irradiation and allogeneic bone marrow transplantation.

Fourteen patients with chronic granulocytic leukemia received bone marrow grafts from HLA identical siblings. Ten patients were in blast crisis prior to grafting, three were in an accelerated phase of their disease, and one was aplastic secondary to chemotherapy. Prior to transplant all patients were conditioned with chemotherapy including cyclophosphamide plus 1,000 rad of total body irradiation. Ten patients achieved engraftment while four died 1 to 26 days after marrow infusion without functioning grafts. Two patients received a second infusion of donor marrow because of delayed engraftment. Neither marrow cell dose nor presence of myelofibrosis correlated with successful engraftment. Three out of ten engrafted patients developed graft-versus-host disease. Interstitial pneumonia occurred in seven patients. The immediate cause of death was bacterial septicemia in six patients. All evidence of leukemia disappeared in nine out of ten evaluable patients. The median survival was 43 days. One patient had a complete remission of 16 months duration.

Adolescent↗
PubMed1978

A morphologic study of intracerebral hemorrhage in a case of acute leukemia.

Morphologic studies have thus far failed to demonstrate the nature of the vessel involved in the brain hemorrhages of patients with acute leukemia. A detailed study of such hemorrhages was carried out in a patient with leukemic phase of mycosis fungoides. Plastic-embedded lesions showed that blast cells blocked the lumen of the capillary, leading to severe dilation and rupture of the vessel. The rheologic properties of blast cells in vessels of critical diameters seem to be an important factor in the pathogenesis of intracerebral hemorrhages.

Acute Disease↗
PubMed1993

Methodological aspects of DNA image cytometry in normal bone marrow smears.

The possibility of using DNA image cytometry in hematological material was evaluated in 27 Feulgen stained normal bone marrow smears. The 95% normal limits of DNA index (DI) determined separately for each cell population in bone marrow were 0.89-1.15, 0.93-1.09 and 0.92-1.12 for blasts, granulocytes and lymphocytes, respectively. The mean DI for blasts, granulocytes and lymphocytes was 1.02, 1.01 and 1.02, respectively. In the blasts population the mean percentage of cells in S+G2/M phase was 38.1% (S.D. 12.9%, range 14.3-65.6%), whereas the corresponding values for granulocytes and lymphocytes were below 1%. Calculation of DI and G0/G1 C.V. obtained in bone marrow smears subjected to Feulgen hydrolysis (5 N HCl, 22 degrees C) for different periods of time revealed the presence of a plateau of results between 60 and 120 min for all of the cell types. The intraobserver and interobserver reproducibility was confirmed by duplicate measurements of each subpopulation (P > 0.05). A comparison of DI and G0/G1 C.V. using smears from the same donors stained with the Feulgen method either straight away or after destaining from May-Grunwald-Giemsa confirmed that destained smears can be used, provided applying appropriately prepared reference cells. We conclude that image cytometry can be used reliably to analyze DNA content in hematological material.

Adolescent↗
PubMed1993

Predictors for prognosis of chronic myelocytic leukemia.

Bone marrows from 30 newly diagnosed Ph+chronic myelocytic leukemia (CML) (21 in chronic phase, CML-CP, 9 in accelerate phase, CML-AP) and 8 followed up patients in blast crisis (CML-BC) were tested by DNA strand breaks (%D value), DNA-aneuploidy, flow cytometry-cell surface antigen expression for CD15 and HLA-DR ratio. Our results showed that all these three parameters changed as the disease escalated. A very low value of %D and DNA-aneuploidy occurrences were high risk factors. Cell surface antigen expression CD15 and HLA-DR ratio measurement was simple and reliable. The ratio < 1.0 appeared earlier than morphology clarifying CML-AP and should be followed up regularly.

Aneuploidy↗
PubMed2001

A multicentre, open, non-comparative phase II study of a combination of fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor in relapsed and refractory acute myeloid leukaemia and de novo refractory anaemia with excess of blasts in transformation.

The primary objective of this study was to determine the complete remission (CR) rate achieved with the FLAG (fludarabine phosphate, cytarabine and granulocyte colony-stimulating factor) regimen in patients with relapsed or refractory acute myeloid leukaemia (AML) or de novo refractory anaemia with excess of blasts in transformation (RAEB-t). Secondary objectives were to evaluate survival and toxicity. Induction treatment consisted of between one and two courses of FLAG. Patients achieving CR received between one and two courses of consolidation treatment. Eighty-three of the 89 patients entering the study were eligible for assessment. CR rates were: 17 out of 21 (81%) in late relapse AML (Group 1), 13 out of 44 (30%) in early relapse/refractory AML (Group 2), and 10 out of 18 (56%) in de novo RAEB-t (Group 3). Thirty-four of the 40 responders (85%) achieved CR after one induction course. Median survival times were 1.4 years, 3 months and 1.6 years in Groups 1, 2 and 3 respectively. Other than myelosuppression, the FLAG regimen was not generally associated with clinically significant toxicity and was well tolerated by most patients including the elderly. The FLAG regimen offers a very effective alternative treatment for CR induction in poor prognosis adult patients with either relapsed or refractory AML or de novo RAEB-t. FLAG delivers high-dose treatment without increasing overall toxicity, an approach which is of particular value in older patients, who constitute the majority in these diseases. It is therefore an important advance in developing new treatment options for these patients.

Acute Disease↗
PubMed2006

Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukemia in blast crisis.

The prognosis for patients with chronic myeloid leukemia (CML) in myeloid blast crisis (MBC) or lymphoid blast crisis (LBC) remains poor. Although imatinib can induce responses in a subset of these patients, resistance to the drug develops rapidly. Dasatinib is a novel, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases. After promising phase 1 results, we report the results of phase 2 clinical trials of dasatinib in patients with imatinib-resistant or -intolerant blast crisis CML (MBC, n = 74; LBC, n = 42). At the 8-month follow-up, dasatinib induced major hematologic responses (MaHRs) in 34% and 31% of MBC- and LBC-CML patients and major cytogenetic responses (MCyRs) in 31% and 50% of these patients, respectively. Most (86%) of these MCyRs were complete cytogenetic responses (CCyRs). Responses were rapid and durable: 88% and 46%, respectively, of MBC- and LBC-CML patients achieving MaHR had not experienced disease progression at the 8-month follow-up. Response rates were similar in patients with and without BCR-ABL mutations known to confer resistance to imatinib. Dasatinib was well tolerated. Nonhematologic adverse events were mild to moderate. Cytopenias were common and could be managed by dose modification. Dasatinib is highly active and produces hematologic and cytogenetic responses in a significant number of patients with imatinib-resistant or -intolerant MBC- and LBC-CML. These trials were registered at www.clinicaltrials.gov as #CA180006 and #CA180015.

Administration, Oral↗
PubMed2004

Expression of constitutively active nuclear-kappa B RelA transcription factor in blasts of acute myeloid leukemia.

The nuclear transcription factor NF-kappa B regulates cell survival, proliferation, and differentiation. Little is known about NF-kappa B in myeloid malignancies. In this report, we assessed NF-kappa B in a group of myeloid neoplasms by using an electrophoretic mobility shift assay (EMSA) and immunofluorescence methods in freshly isolated leukemia cells. We analyzed 30 cases of acute myeloid leukemia (AML), 5 cases of myelodysplastic syndrome (MDS), 3 cases of chronic myelomonocytic leukemia (CMML), 15 cases of chronic myeloid leukemia in chronic phase (CML-CP), and 2 cases of chronic myeloid leukemia in blast crisis (CML-BC). Unstimulated cells (bone marrow and peripheral blood) from 17 normal donors and apheresis samples from 6 peripheral blood stem cell donors treated with granulocyte colony-stimulating factor (G-CSF) were used as controls. When EMSA was used, NF-kappa B was elevated in 14 of 30 (47%) cases of AML, in both cases of CML-BC, and in all reference donors treated with G-CSF, but it was at basal levels in all cases of MDS and CML-CP and in normal donors (P = <.01). Immunofluorescence analysis confirmed strong nuclear RelA/NF-kappa B immunoreactivity in AML blasts but not in normal bone marrow. Bcl-2, a downstream molecule, was expressed in cases with elevated NF-kappa B, but not in cases with basal levels of NF-kappa B, suggesting that NF-kappa B is active and provides the cells with survival advantages in vivo. These results suggest that suppression of NF-kappa B may be a useful therapeutic strategy for a subset of patients with AML.

Adolescent↗
PubMed2002

Induced volatiles in elicitor-treated and rice blast fungus-inoculated rice leaves.

The volatiles released from elicitor (copper chloride, jasmonic acid, UV, L-methionine and chitosan oligomer)-treated and rice blast fungus-inoculated rice leaves were collected by the solid-phase microextraction technique and analyzed by GC-MS. (Z)-3-Hexen-1-ol, monoterpenes, methyl salicylate, and sesquiterpenes were identified as elicitor-induced volatiles by a comparison of their GC retention times and mass spectra with those of authentic compounds. The different elicitors resulted in some qualitative and quantitative differences in the production of volatiles. Monoterpenes and sesquiterpenes were identified as the rice blast fungus-induced volatiles.

Chitin↗
PubMed1989

c-myc protein kinetics during growth and differentiation of CD34 (MY10)-positive blast cells from normal human marrow.

We have used flow cytometry to quantitate nuclear c-myc protein, at each phase of the cell cycle, during in-vitro differentiation of CD34-positive stem cells isolated from normal human bone marrow by the monoclonal antibody, MY10. Mean c-myc protein levels in CD34-positive cells, consisting of greater than 70% blasts, are lower than a marrow fraction containing myeloid cells of intermediate maturation, but have an invariant proportional relationship, with regard to nuclear mass, over the cell cycle. The majority of these primitive cells are non-cycling, as revealed by DNA content. Under our assay conditions, nuclear c-myc protein distribution over the cell cycle did not change as these progenitors entered a proliferative phase in culture. In cultures containing factors supporting myeloid maturation, mean G0/G1 p62c-myc levels initially decline, then rise above starting values as promyelocytes and myelocytes differentiate from CD34-positive cells, and as proliferation begins. With further myeloid maturation, and while cell numbers are increasing, c-myc protein continues to increase. C-myc protein kinetics differ in cultures in which macrophages, rather than myeloid cells, predominate. These data indicate that a complex relationship exists between c-myc gene expression and proliferation, maturation and lineage in haemopoietic cells, and lend support to the notion that early down regulation may be causally associated with the differentiation process.

Antigens, CD34↗
PubMed1999

High-level expression and purification of the recombinant diphtheria fusion toxin DTGM for PHASE I clinical trials.

A genetically engineered fusion toxin targeted to acute myeloid leukemic (AML) blasts was designed with the first 388 amino acid residues of diphtheria toxin with an H-M linker fused to human granulocyte-macrophage colony-stimulating factor. The cDNA was subcloned in the pRK bacterial expression plasmid and used to transform BL21 (DE3) Escherichia coli harboring pUBS500 plasmid. Transformants were grown in Superbroth and induced with IPTG. Inclusion bodies were isolated, washed, and denatured in guanidine hydrochloride with dithioerythritol. Recombinant protein was refolded by diluting 100-fold in cold buffer with arginine and oxidized glutathione. After dialysis, purified protein was obtained after anion-exchange, size exclusion on FPLC, and polymixin B affinity chromatography. The final material was filter sterilized, aseptically vialed, and stored at -80 degrees C. Fifty-four 3-liter bacterial culture preparations were made and pooled into 27 batches. The final product was characterized by Coomassie Plus protein assay, Coomassie-stained SDS-PAGE, limulus amebocyte lysate endotoxin assay, human AML HL60 cell cytotoxicity assay, HPLC TSK3000, N-terminal sequencing, E. coli DNA contamination, C57BL6 mouse toxicity, and immunohistochemistry. Yields were 23 mg/liter bacterial culture of denatured fusion toxin. After refolding and chromatography, final yields were 24 +/- 4% or 5 mg/liter. Vialed product was sterile and 1.7 +/- 0.4 mg/ml in PBS. Purity by SDS-PAGE was 99 +/- 1%. Aggregates by HPLC were <1%. Potency revealed a 24-h IC50 of 2.7 +/- 0.5 pM on HL60 cells. Endotoxin levels were 1 eu/mg. The N-terminal sequence was confirmed, and E. coli DNA was <113 pg/mg. The LD10 in mice was 110 microg/kg/day x5. There was no evidence of loss of solubility, proteolysis, aggregation, or loss of potency over 3 months at -80 and -20 degrees C. Further, the drug was stable at 4, 25, and 37 degrees C in human serum for 48 h. Drug reacted only with human monocytes, granulocytes, and myeloid precursors in frozen human tissue sections by immunohistochemistry. The synthesis of this protein drug should be useful for production for clinical phase I/II clinical trials and may be suitable for other diphtheria fusion toxins indicated for clinical development. This is the first report of the scaleup of a recombinant fusion toxin for clinical trials.

Acute Disease↗
PubMed1990

Bone marrow transplants in chronic myelogenous leukemia: an overview of determinants of survival.

The success of bone marrow transplantation in chronic myelogenous leukemia (CML) is strongly associated with the phase of the disease at the time of transplantation. For allogeneic transplants from siblings with identical human leukocyte antigens, the 3-year survival rate for recipients in chronic phase ranges from 55% to 70%, whereas survival falls to approximately 30% for recipients in accelerated phase and to 0% to 20% for patients receiving transplants during blast crisis. Detailed analysis of data pooled from 405 patients demonstrated that the 3-year probability of relapse was 48% for recipients of T-cell-depleted bone marrow, but only 9% for recipients of non-T-cell-depleted bone marrow (relative risk, 5.4; P less than .0001). Regardless of transplant T-cell status, however, patients who developed chronic graft-versus-host disease (GVHD) were less likely to relapse at 4 years when compared with recipients without chronic GVHD (6% v 24%; relative risk, 3.1; P less than .01). Survival was correlated with severity of acute GVHD and age. Allogeneic bone marrow transplantation from unrelated donors can be useful in expanding the patient population eligible for transplantation. A study of recipients of transplants from unrelated donors showed a 3-year projected survival of 55% for chronic phase patients, and 22% for patients with advanced disease. However, a high rate of graft failure (10%) and grade II to IV acute GVHD can be expected. Preliminary data suggest that ex vivo treatment of autologous bone marrow with interferon can effect complete or partial Philadelphia (Ph) chromosome negative bone marrow mosaicism, although appearance of Ph chromosome negative metaphases may not be persistent. Thus, interferon treatment of autologous bone marrow may play a more significant role in the treatment of CML.

Bone Marrow Transplantation↗
PubMed1994

Altered levels of interleukin-1 beta and interleukin-1 receptor antagonist in chronic myelogenous leukemia: clinical and prognostic correlates.

We have recently demonstrated that interleukin (IL)-1 beta levels are elevated in advanced chronic myelogenous leukemia (CML) and that IL-1 inhibitors can suppress CML clonogenic growth. To further assess the clinical implications of increased IL-1 beta expression in CML, we analyzed IL-1 beta and IL-1 receptor antagonist (IL-1RA) levels in leukocyte lysates from a series of CML patients and from normal volunteers. Both IL-1 beta and IL-1RA were measured by enzyme-linked immunosorbent assays (ELISAs), with the lower limits of sensitivity of the assays being 20 pg/mL and 6.5 pg/mL, respectively. The median IL-1 beta level in the 81 CML patients tested was higher (115.8 pg/2.4 x 10(7) cells; range, 0 to 2,000 pg/2.4 x 10(7) cells) than the median level in 25 control samples (10.8 pg/2.4 x 10(7) cells; range, 0 to 95.5 pg/2.4 x 10(7) cells) (P < .01). IL-1 beta was bioactive, as demonstrated with a bioassay based on cytotoxicity to a melanoma cell line (A375). For survival analysis, elevated IL-1 beta levels were defined as those exceeding the mean + 2 SD of normal levels (83 pg/2.4 x 10(7) cells). The survival of the 44 patients with elevated IL-1 beta levels was significantly shorter than that of those who had low IL-1 beta levels (median, 44 v 58 months; P = .049 by Wilcoxon-Gehan method). An association between IL-1 beta and CML prognostic criteria shows that IL-1 beta levels were significantly higher in patients in accelerated/blastic crisis phases of the disease (364.0 pg/2.4 x 10(7) cells) compared with patients in chronic phase (102.0 pg/2.4 x 10(7) cells) (P < .01), and that high IL-1 beta levels correlated with increased blasts in the marrow and peripheral blood (P < .01). In contrast, while IL-1RA levels did not differ between chronic-phase CML patients (median, 471.7 pg/2.4 x 10(5)) and healthy volunteers (median, 454.4 pg/2.4 x 10(5)), patients with accelerated/blast crisis disease had significantly lower levels of IL-1RA (median, 218.7 pg/2.4 x 10(5); P = .03). Finally, although IL-1 beta has been previously shown to increase IL-1RA levels, there was no correlation between IL-1 beta and IL-1RA levels in our CML patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Bone Marrow↗
PubMed2004

Treatment of the mangled lower extremity after a terrorist blast injury.

Terrorist bombings, with resultant blast injuries, have been increasing in frequency during the past 30 years. Injury to the musculoskeletal system is common in victims who survive such attacks. Substantial injury to the limbs may occur through several different mechanisms, each of which may affect prognosis and alter the treatment algorithm. An analysis of the available literature on terrorism and blast events revealed that resource use of the treating medical facility is high during the initial hours after a blast attack, but usually is manageable. A resource management protocol was developed to organize the treatment of limb salvage into four phases. This management protocol may improve the medical facility's ability to manage system resources while treating patients with severe blast injuries. The decision of whether to salvage or proceed with limb amputation is one of the most difficult in orthopaedic trauma. A basic education in the mechanisms of blast damage, a methodical approach to resuscitation, and mangled extremity treatment, likely can improve surgical success.

Amputation, Surgical↗
PubMed2004

Expression and purification of the recombinant diphtheria fusion toxin DT388IL3 for phase I clinical trials.

A genetically engineered fusion toxin targeted to acute myeloid leukemia (AML) blasts was designed with the first 388 amino acid residues of diphtheria toxin with an H-M linker fused to human interleukin-3. The cDNA was subcloned in the pRK bacterial expression plasmid and used to transform BLR (DE3) Escherichia coli. A single transformed colony was grown in Superbroth with ampicillin; bacteria were centrifuged at an OD(650) of 1.3; master cell bank aliquots of bacteria in 30% glycerol/Superbroth were frozen and stored at -80 degrees C. Master cell bank bacteria were diluted 1500-fold into Superbroth and recombinant protein was induced with 1 mM IPTG at an OD(650) of 0.6. After two additional hours of fermentation, inclusion bodies were isolated, washed, and denatured in guanidine hydrochloride and dithioerythritol. Recombinant protein was refolded by diluted 100-fold in cold buffer with arginine and oxidized glutathione. After dialysis, purified protein was obtained after anion-exchange, size exclusion on FPLC, and polymyxin B affinity chromatography. The final material was filter sterilized, aseptically vialed, and stored at -80 degrees C. Seventy-five 3-L bacterial culture preparations were made and pooled for the AT-1 batch (568 mL) and twenty-four 3-L bacterial culture preparations were made and pooled for the AT-2 batch (169 mL). The final product was characterized by Coomassie Plus protein assay, Coomassie-stained SDS-PAGE, limulus amebocyte lysate endotoxin assay, human AML TF/H-ras cell cytotoxicity assay, sterility, tandem mass spectroscopy, IL3 receptor binding affinity, ADP ribosylation activity, inhibition of normal human CFU-GM, disulfide bond analysis, immunoblots, peptide mapping, stability, HPLC TSK3000, N-terminal sequencing, E. coli DNA contamination, C57BL/6 mouse toxicity, cynomolgus monkey toxicity, and immunohistochemistry. Yields were 25.7+/-5.6 mg/L bacterial culture of denatured fusion toxin. After refolding and chromatography, final yields were 20+/-11% or 5 mg/L. Vialed product was sterile. Batches were in 0.25 M sodium chloride/5 mM Tris, pH 8, and had protein concentrations of 1.8-1.9 mg/mL. Purity by SDS-PAGE was 99+/-1%. Aggregates by HPLC were <1 %. Potency revealed a 48 h IC(50) of 6-8 pM on TF/H-ras cells. Endotoxin levels were 1 eu/mg. The remaining chemical and biologic assays confirmed the purity, composition, and functional activities of the molecule. The LD(10) in mice was 250 microg/kg/day every other day for six doses. The MTD in monkeys was 60 microg/kg/day every other day for six doses. Drug did not react with tested frozen human tissue sections by immunohistochemistry. There was no evidence of loss of solubility, proteolysis aggregation, or loss of potency over 6 months at -80 and -20 degrees C. Further, the drug was stable at 4 and 25 degrees C in the plastic syringe and administration tubing for 24 h and at 37 degrees C in human serum for 24 h. The synthesis of this protein drug should be useful for production for clinical phase I/II clinical trials and may be suitable for other diphtheria fusion toxins indicated for clinical development.

Acute Disease↗
PubMed1985

Cytogenetics and flow cytometry may predict phenotype of CML blast crisis.

Twenty-eight patients with chronic myelocytic leukemia (CML) and the Philadelphia chromosome (Ph1) were monitored using cytofluorometry and cytogenetics. During chronic phase, abnormal populations could be detected using commercially available monoclonal antibodies. These abnormal populations fell into two categories based on the presence or absence of HLA.DR. Patients with HLA.DR+ abnormal cells showed no clonal evolution and progressed to lymphoid blast crisis. Patients with HLA.DR- abnormal cells exhibited chromosomal abnormalities in addition to the Ph1 and progressed to a myeloblastic acute phase.

Adult↗
PubMed1999

[Blast crisis of chronic myelocytic leukemia that was difficult to differentiate from Ph+ acute lymphoblastic leukemia].

We encountered a 44-year-old woman with suspected chronic myelocytic leukemia (CML) in the acute phase that was difficult to be differentiate from Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). At disease onset, her bone marrow showed an increase in blasts that were negative for myeloperoxydase (MPO) and Positive for CD10, 19, 34, and HLA.DR. Standard type Ph was detected by chromosome analysis, and both major and minor BCR/ABL m-RNA were detected by reverse-transcriptase polymerase chain reaction (RT-PCR) methods. Neutrophil alkaliphosphatase (NAP) score was normal, and neither eosinophilia nor basophilia was observed in peripheral blood. Under a presumptive diagnosis of Ph-positive ALL (L2), the patient was given AdVP (doxorubicin, vincristine, and prednisolone) therapy followed by a regimen of LMVP (L-asparaginase, mitoxantrone, and VP), and obtained a complete remission 2 months later. At that time, FISH analyses of her bone marrow and blood cells no longer detected bone marrow Ph or BCR/ABL fusion gene. A month later, however, the leukemia relapsed with an increase in MPO-positive blasts in bone marrow, and the patient died soon thereafter. We finally concluded that her leukemia was not Ph-positive ALL, but CML in the acute phase at disease onset.

Adult↗
PubMedDate not supplied

Tiazofurin effects on IMP-dehydrogenase activity and expression in the leukemia cells of patients with CML blast crisis.

Tricot et al have reported that the nucleoside analog tiazofurin can induce hematologic remissions in patients with chronic myelogenous leukemia in blast crisis (CML-BC). These reports prompted us to begin a derivative, phase II trial of tiazofurin in CML-BC to determine if the promising findings reported by these investigators could be reproduced. In our ongoing trial patients receive tiazofurin by IV infusion (2200-4400 mg/m2 over 1 hr) once every 24-48 hrs for up to 10 days. Each of 3 patients, treated to date on this trial, experienced substantial hematologic responses with normalization of WBC counts and complete or partial clearance of blasts from the blood within 4-11 days of treatment. These responses were relatively brief, in that leukemic blasts reaccumulated in the marrow and blood of patients within 4 weeks following treatment, but were re-induced with subsequent courses of treatment. Of interest, the rates of blast cell reaccumulation appeared to increase progressively following sequential courses of treatment. Tiazofurin, which inhibits IMP-dehydrogenase (IMPDH) and blocks guanine ribonucleotide synthesis, has been shown to increase IMPDH mRNA expression in various cell lines in vitro, as an apparently compensatory response to guanylate deprivation. Studies of IMPDH mRNA expression in the leukemic blasts of CML-BC patients receiving tiazofurin treatment showed that this same phenomenon occurs in vivo. Since IMPDH activity is linked to the proliferative activity of neoplastic cells an amplification of IMPDH message expression induced by tiazofurin may lead to an increased sensitivity of the leukemic clone to cycle active agents.

Aged↗