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E J Freireich

Publications and source records attributed to E J Freireich.

At least 73 records · Page 4Linked to original sources
PubMed1994

Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside.

The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP), or amsacrine (AMSA-OAP). All patients have been followed at least 5 years. Patients in first CR at 5 years (FCR5) treated on protocols prior to CIHDAC had only 5% chance of relapse (median subsequent follow-up of 9 years). Therefore, we considered patients in FCR5 potentially cured. The two groups were similar with respect to known prognostic factors and CR rates. Although remission duration and survival were shorter with CIHDAC than Ad-OAP/AMSA-OAP, the percent of patients potentially cured was similar (10 vs. 15%). Marked differences between regimens were seen in inv(16) and t(15;17) patients. CIHDAC was better for patients with inv(16) with more patients in FCR5 (80 vs. 38%), longer remission duration and survival, and lower incidence of CNS relapse (0 vs. 43%). The Ad-OAP/AMSA-OAP protocols were superior in patients with t(15;17). We also measured steady-state ara-CTP concentrations (ara-CTPss) in 54 CIHDAC-treated patients presenting with high-blast count. While there was no correlation between ara-CTPss and response duration, all five patients in FCR5 in whom ara-CTPss was measured had high concentrations. These data support the concept that patients with AML should be treated differently according to cytogenetics. Inv(16) patients should be treated with high-dose ara-C while t(15;17) should rely more on anthracycline exposure.

Adolescent↗
PubMed1993

Detection of the AML1/ETO fusion transcript in the t(8;21) masked translocation in acute myelogenous leukemia.

The fusion transcript AML1/ETO was detected in the bone marrow of two t(8;21)-negative acute myelogenous leukemia (AML) patients by means of reverse transcription-polymerase chain reaction. This fusion transcript is identical to the one transcribed from the t(8;21) translocation base, as deduced from (a) the size and restriction pattern of the amplified DNA fragment and (b) the DNA sequence analysis of the fusion junction. We also showed that the ETO gene is highly expressed in these patients, much as it is in the t(8;21)-positive AML. Southern blot analysis showed rearrangement of the AML1 gene in one of the patients. Together, our results demonstrate that there is a masked t(8;21) translocation in AML that is not detectable by cytogenetic analysis but is able to transcribe an AML1/ETO fusion transcript similar to that transcribed in t(8;21)-positive AML-M2 patients.

Base Sequence↗
PubMed1993

Preliminary results of treatment with filgrastim for relapse of leukemia and myelodysplasia after allogeneic bone marrow transplantation.

BACKGROUND: Patients whose leukemia relapses after allogeneic bone marrow transplantation have a poor prognosis; few respond to further chemotherapy, and almost none survive over the long term. We present preliminary observations on the use of filgrastim (granulocyte colony-stimulating factor) for relapse after transplantation. METHODS: Seven female patients with leukemia (one with chronic myelogenous leukemia, five with acute myelogenous leukemia, and one with a myelodysplastic syndrome that transformed into acute myelogenous leukemia) whose disease relapsed within 360 days after allogeneic bone marrow transplantation received filgrastim (5 micrograms per kilogram of body weight per day by subcutaneous injection) to reinduce remission by stimulating residual donor marrow cells. Cytogenetic analysis of bone marrow, fluorescence in situ hybridization, and determination of restriction-fragment--length polymorphisms were used to assess response and chimerism. RESULTS: Three of the seven patients had a complete hematologic and cytogenetic remission, with reestablishment of hematopoiesis of donor origin. Mild chronic graft-versus-host disease developed in one patient, and acute graft-versus-host disease in none. One patient had a relapse 12 months after treatment, and two others remained in remission after 10 and 11 months. In two of the patients with a response, fluorescence in situ hybridization demonstrated stimulation of donor cells without differentiation of the leukemic clone. CONCLUSIONS: Filgrastim may be effective in selected cases of leukemic relapse after allogeneic bone marrow transplantation.

Adolescent↗
PubMed1993

Long-term follow-up of patients with chronic lymphocytic leukemia treated with fludarabine as a single agent.

The clinical response and survival of 113 patients with at least 3-year follow-up after treatment with fludarabine as a single agent for chronic lymphocytic leukemia has been evaluated. Seventy-eight patients were previously treated and 35 were untreated. The response to therapy and survival were strongly correlated with the degree of previous therapy, the stage of disease, and whether or not the patients were refractory to alkylating agents. Other characteristics associated with survival were the age of the patient and the serum albumin level at the start of therapy. The median time to progression of responders who had not received prior therapy was 33 months and was 21 months for previously treated patients. Survival after progression of disease was also strongly correlated with the degree of prior therapy. No successful salvage regimen after initial fludarabine therapy was shown for patients refractory to alkylating agents, although fludarabine achieved further remissions in patients who had received fludarabine as their initial treatment or were not refractory to alkylating agents. The morbidity of patients in unmaintained remission on discontinuation of fludarabine was low, with less than one episode of infection per patient-year at risk. The morbidity during this time was correlated with clinical response and whether the patients had received prior therapy. Although fludarabine is a very effective cytoreductive regimen, most patients, including those who achieved true complete remissions, will have recurrent disease. Longer follow-up and comparative trials are required before the effect of fludarabine on survival is shown.

Adult↗
PubMed1993

Treatment of malignancies, past and present.

Clinical research has provided both insights into the biology of malignancy and therapeutic approaches that will eradicate cancer in at least half of the million patients who will be diagnosed in the United States this year. New tactics are being pursued for those with advanced metastases. Biological therapy and gene therapy hold much promise.

Biological Products↗
PubMed1993

Treatment of Waldenstrom macroglobulinemia with 2-chlorodeoxyadenosine.

OBJECTIVE: To evaluate the activity of 2-chlorodeoxyadenosine (2CdA) in the treatment of patients with Waldenstrom macroglobulinemia. DESIGN: Uncontrolled phase II trial. SETTING: Tertiary, referral cancer center. PATIENTS: Twenty-nine consecutive, symptomatic patients with Waldenstrom macroglobulinemia, of whom 9 were previously untreated. INTERVENTION: 2-Chlorodeoxyadenosine was administered as a continuous intravenous infusion at a dose of 0.1 mg/kg body weight per day for 7 days. Only two courses of 2CdA were given and responding patients were then followed without further treatment. MEASUREMENTS AND MAIN RESULTS: A total of 17 (59%) patients responded, including all of those who were newly diagnosed and 40% of those who had failed previous therapies. Treatment was well tolerated except for one death in a patient who had presented with severe pancytopenia. With a median follow-up of 7 months, only one responding patient has relapsed. CONCLUSION: 2-Chlorodeoxyadenosine is a nucleoside analog that was effective in most patients with Waldenstrom macroglobulinemia and was associated with little toxicity.

Adult↗
PubMed1993

Expression of differentially phosphorylated Rb and mutant p53 proteins in myeloid leukemia cell lines.

We studied the structure and expression of Rb and p53 genes in six myeloid leukemia cell lines (HL-60, KBM3, K562, KBM5, EM2, KBM7) in the light of the published reports that structural abnormalities of these genes are rarely seen in leukemic cells and also a recent finding that Rb gene expression can be regulated by the p53 protein. Except for HL-60 cells which have a truncated p53 gene, none of the other cell lines revealed any gross structural abnormalities in the Rb and p53 genes. KBM3, KBM5 and EM-2 expressed lower levels of Rb mRNA than HL-60, K562 and KBM7. The amount of Rb protein was lowest in KBM3 cells and in this and two other cell lines (KBM5, KBM7) Rb was markedly hypophosphorylated compared to the other three cell lines. HL-60 and K562 did not express p53 m-RNA, while the other four cell lines all expressed high levels of mutant p53 protein. Thus even in the absence of gross structural alterations, subtle abnormalities in the expression pattern of Rb and p53 genes occur in myeloid leukemia cells.

Base Sequence↗
PubMed1993

Depletion of patients' plasma tryptophan using tryptophan side-chain oxidase columns.

The use of the enzyme tryptophan side-chain oxidase, isolated from Pseudomonas XA, was explored in 3 patients with refractory acute lymphocytic leukemia. Patients were given either a low-tryptophan diet or tryptophan-free hyperalimentation, prior to and during therapy. Their plasma, separated by pheresis, was continuously passed through a tryptophan depletion column containing the immobilized tryptophan side-chain oxidase. Up to 4 plasma volumes were passed through the column daily, 5 days per week for 2-3 weeks, and plasma tryptophan levels, both free and total, were measured by high-performance liquid chromatography. Pre- and postcolumn plasma samples were collected throughout the pheresis procedure. All postcolumn plasma samples had unmeasurable tryptophan levels throughout the treatment period, whereas precolumn samples were always measurable. Generally, tryptophan levels of plasma isolated from peripheral blood decreased after therapy, but rebounded by the next day. The enzyme depletion column reduces circulating plasma tryptophan levels, and its use is well tolerated by patients. However, further development of this method will require study of the effects of diet and of the duration, interval, and frequency of use of this column on therapeutic efficacy. Problems include difficulties with extended diet compliance and apparently intensive mobilization of tryptophan from body stores, which may preclude the clinical application of this enzyme depletion column.

Chromatography, High Pressure Liquid↗
PubMed1992

Detection of minimal residual disease by polymerase chain reaction in Philadelphia chromosome-positive chronic myelogenous leukemia following interferon therapy.

The significance of the polymerase chain reaction (PCR) in the detection of minimal residual disease in Philadelphia chromosome (Ph')-positive chronic myelogenous leukemia (CML) following interferon therapy was investigated. Forty remission blood samples obtained at various remission time points from 29 patients in complete cytogenetic remission were analyzed. All 40 samples showed minimal residual Ph'-positive cells by PCR: 22 in remission for less than 12 months, 12 in remission for 12 to 24 months, four in remission for 25 to 60 months, and two in remission for more than 60 months. Of these 29 patients, seven relapsed at 4, 6, 9, 14, 17, 19, and 50 months after their first PCR-positivity during remission. One developed extramedullary myelopoiesis at 49 months after PCR-positivity. The remaining 21 patients remained in complete hematologic and cytogenetic remission with median follow-up of 13 months (range, 4 to 36 months) after PCR analysis. These findings indicate that PCR-positivity is not associated with immediate disease recurrence. Long-term follow-up is essential to determine the relevance of PCR-positivity, since late recurrence is observed in our study.

Biomarkers, Tumor↗
PubMed1992

Specific expression of the annexin VIII gene in acute promyelocytic leukemia.

Since the translocation breakpoint t(15;17) (q22;q21) in acute promyelocytic leukemia (APL) occurs within the retinoic acid receptor-alpha (RARA) gene, the expression of many genes normally regulated by RARA may be affected by this translocation. To identify genes that may be aberrantly expressed in APL, a subtraction cDNA library of an APL patient with t(15;17) was constructed. A cDNA, pRD1, specifically expressed in APL was identified. DNA sequence analysis of pRD1 showed that this gene is similar to the DNA sequence of annexin VIII, a gene which encodes a vascular anticoagulant. The annexin VIII gene was assigned to chromosome 10, which indicates that specific expression of this gene in APL is not directly involved in the t(15;17) breakpoint region. We have analyzed the expression of annexin VIII gene in nine t(15;17)-positive APL patients and one APL patient with a chromosome 17q-abnormality. We found that all APL samples expressed high levels of the annexin VIII gene. Expression of the annexin VIII gene in all other leukemias, including acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphoblastic leukemia, was undetectable, except in one patient with acute myelogenous leukemia in which a very low level of expression was detected. Annexin VIII is highly expressed in the APL cell line, NB4. Its expression was significantly reduced after 8 hours of all-trans retinoic acid (ATRA) treatment, whereas the expression of RARA increased several-fold within 4 hours postinduction. Thus, increased expression of RARA preceded the downregulation of annexin VIII after ATRA induction, suggesting an inverse relationship between RARA and annexin VIII expression. Since increased expression of the fusion transcript was seen after ATRA induction and an APL without a t(15;17) translocation expressed high levels of annexin VIII, it appears that increased expression of annexin VIII in APL is not related to the fusion transcript. Therefore, dysregulation of the RARA gene may be related to the overexpression of annexin VIII in APL.

Amino Acid Sequence↗
PubMed1992

The t(15;17) breakpoint in acute promyelocytic leukemia cluster within two different sites of the myl gene: targets for the detection of minimal residual disease by the polymerase chain reaction.

The retinoic acid receptor alpha (RAR alpha) and the myl gene are involved in the translocation breakpoint t(15;17)(q22;q21) in acute promyelocytic leukemia (APL). The majority of the breakpoint sites have been mapped within the second intron of the RAR alpha gene; however, the breakpoint sites on the myl gene are variable. Using primer sets derived from exon 2 or exon 3 of the RAR alpha gene and a primer derived from the myl cDNA, we were able to amplify the breakpoint sites of the fusion transcripts of all six APL RNA samples by the reverse transcriptase-polymerase chain reaction (RT-PCR). A DNA fragment of 290 bp (breakpoint A) was amplified using RNA samples from three patients, whereas two DNA fragments of 630 and 774 bp (breakpoint B) were amplified using RNA samples from the other three APL patients. DNA sequence analysis of the amplified fragments suggests that the APL breakpoints clustered within two different introns of the myl gene. Northern blot analysis demonstrated that fusion transcripts RAR alpha/myl and myl/RAR alpha of varying sizes were detected in patients with different breakpoint sites on the myl gene. In addition, we analyzed five APL samples in complete remission and detected t(15;17)-positive cells. We conclude that the t(15;17) breakpoints in APL can be amplified by PCR using a single primer set and that minimal residual disease can be demonstrated in APL using RT-PCR.

Base Sequence↗
PubMed1992

Detection of extrachromosomal circular DNA sequences from tumor cells by an alkaline lysis, Alu-polymerase chain reaction technique.

Extrachromosomal circular DNAs ranging in size from submicroscopic molecules of approximately 100 kb to cytogenetically resolvable structures of 1000+ kb called minute and double-minute chromosomes have been shown to harbor amplified genes in primary tumor cells, tumor cell lines, and drug-resistant cells grown in vitro. The presence of these molecules in transformed and malignant cells trends to reflect genetic instability and also suggests that role in tumor progression. Using a colon carcinoma cell line, we developed a technique to detect extrachromosomal circular DNA-specific sequences by Alu-polymerase chain reaction. Circular DNA was enriched by selective alkaline denaturation of genomic DNA. We have successfully performed this procedure with a minimum of 5 x 10(5) cells. The technique does not require any prior knowledge of the sequences located on the covalent circular DNA molecules for their detection. The procedure should be useful as a routine screen of primary tumor cells for the presence of extrachromosomal circular DNA and should permit the preparation of specific probes ot aid in their detailed characterizations.

Base Sequence↗
PubMed1992

Characterization of a fusion cDNA (RARA/myl) transcribed from the t(15;17) translocation breakpoint in acute promyelocytic leukemia.

A nonrandom chromosomal translocation breakpoint, t(15;17)(q22;q21), is found in almost all patients with acute promyelocytic leukemia (APL). Most of these breakpoints occur within the second intron of the retinoic acid receptor-alpha (RARA) gene. We screened a cDNA library of APL and have identified and sequenced a cDNA transcribed from the t(15;17) translocation breakpoint. The 5' end of cDNA p1715 consists of 503 bp of the RARA exon II sequence. A 1.76-kb cDNA without homology to any known gene available in GenBank was found truncated downstream. This cDNA sequence was assigned to chromosome 15 by dot blot hybridization of the flow cytometry-sorted chromosomes. We designate this fusion cDNA RARA/myl, which is different from myl/RARA reported by de The et al. (H. de The, C. Chomienne, M. Lanotte, L. Degos, and A. Dejean, Nature (London) 347:558-561, 1990). This result demonstrates that the two different types of hybrid mRNA can be transcribed from this breakpoint. We screened a non-APL cDNA library and identified a 2.8-kb myl cDNA. This cDNA is able to encode a polypeptide with a molecular weight of 78,450. Alternative splicing of the myl gene which resulted in myl proteins with different C terminals was found. Southern blot analysis of the genomic DNA isolated from 17 APL patients by using the myl DNA probe demonstrated that the myl gene in 12 samples was rearranged. Northern (RNA) blot analysis of RARA gene expression in two APL RNA samples showed abnormal mRNA species of 4.2 and 3.2 kb in one patient and of 4.8 and 3.8 kb in another patient; these were in addition to the normal mRNA species of 3.7 and 2.7-kb. The myl DNA probe detected a 2.6-kb abnormal mRNA in addition to the normal mRNA species of 3.2, 4.2, and 5.5 kb. Using the polymerase chain reaction, we demonstrated that both RARA/myl and myl/RARA were coexpressed in samples from three different APL patients. From this study, we conclude that the t(15;17) translocation breakpoint results in the transcription of two different fusion transcripts which are expected to be translated into fusion proteins.

Amino Acid Sequence↗