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E J Freireich

Publications and source records attributed to E J Freireich.

At least 91 records · Page 5Linked to original sources
PubMed1992

AML-associated cytogenetic abnormalities (inv (16), del (16), t(8;21)) in patients with myelodysplastic syndromes.

Evidence suggests that prognosis in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML) depends more on karyotype than on formal classification as either MDS or AML according to the French-American-British (FAB) system. We provide further evidence of overlap between these two entities, reporting 4 patients who presented with either inv(16) (p13q22), del(16) (q22), or t(8;21) despite an FAB diagnosis of MDS rather than the diagnosis of AML with which these abnormalities are generally associated. In 3 patients, disease was relatively long-standing (3-10 months) prior to diagnosis, suggesting that the association between MDS and these cytogenetic abnormalities may not merely reflect a transient phenomenon. Two patients with inv(16) and the MDS subtype refractory anemia with excess blasts in transformation (RAEB-t) received AML-type chemotherapy as did a patient with t(8;21) and RAEB-t. All entered CR paralleling the high CR rate seen in patients with AML and these abnormalities. Our data support the concept that MDS and AML may be different manifestations of the same disease.

Adolescent↗
PubMed1992

Cytogenetics for detection of minimal residual disease in acute myeloblastic leukemia.

Bone marrow samples collected from acute myeloblastic leukemia (AML) patients in complete clinical and hematological remission were studied for the persistence of cytogenetic abnormalities. AML patients from the three favorable cytogenetic categories [inv 16, t(8;21) and t(15;17)] and patients from the unfavorable cytogenetic categories (+8, -5, -7 and Philadelphia-positive) were studied. Seventy-one patients had evaluable metaphase spreads in remission marrows and 20 (28%) had one or more abnormal metaphases identical to that present in the pretreatment marrow. All 20 of these patients relapsed within 78 weeks, thus there were no false positive studies. Fifty-one patients had only diploid metaphases in their complete remission marrow, 25 relapsed, and 21 remained in continuous complete remission. Thus there was a 49% false negative rate of this study. These data indicate that the failure to detect residual chromosomally abnormal cells in the bone marrow does not guarantee continuous complete remission. Cytogenetic study was most useful in the favorable cytogenetic groups and least useful in the unfavorable groups. The persistence of normal metaphases in pretreatment marrows did not affect outcome or risk of recurrence. Twenty-five of 34 evaluable patients who relapsed after remission had either the identical cytogenetic abnormality present in the pretreatment marrow or showed the identical abnormality with additional chromosomal changes. Thus study indicates that cytogenetic examinations of complete remission bone marrow samples in patients with AML provides an objective method for detecting residual leukemia, and identifies patients with a potential for prolonged disease-free survival.

Bone Marrow↗
PubMed1991

Intensive chemotherapy induction followed by interferon-alpha maintenance in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

In a pilot study, 32 patients with Philadelphia chromosome-positive chronic myelogenous leukemia were treated with intensive chemotherapy induction followed by interferon-alpha (IFN-A) maintenance. Intensive chemotherapy consisted of three cycles of daunorubicin 120 mg/m2 on day 1, cytarabine 80 mg/m2 daily for 10 days, vincristine 2 mg on day 1, and prednisone 100 mg daily for 5 days (DOAP). Maintenance therapy with IFN-A at a doses of 3 x 10(6) to 5 x 10(6) units/m2 daily was adjusted according to counts and toxicity. The outcome of patients was compared with a matched historic population of 64 patients treated with IFN-A alone. Overall, 60% of patients had a cytogenetic response (partial or complete) with induction chemotherapy, but only eight (25%) had a sustained cytogenetic response with IFN-A maintenance. After a median follow-up of 67 months, the 6-year survival rate of the 32 patients was 58%, compared with 36% for the matched historic group (P = 0.084). The incidence of lymphoid blastic transformation in the two groups was 25% and 48%, respectively (P = 0.10) and durable cytogenetic responses, 25% and 19%, respectively (P = 0.48). In summary, the addition of intensive chemotherapy induction to IFN-A maintenance does not improve the survival rate, incidence of lymphoid blastic transformation, or incidence of durable cytogenetic response compared with the results achieved with IFN-A therapy alone.

Adolescent↗
PubMed1991

A study of the status of clinical cancer research in the United States (1990).

This study has confirmed a continuing decrease in the quality and quantity of young physicians entering academic careers in clinical oncology research, defined as cancer research requiring a clinician-patient interaction. Two major contributing factors were identified: the training programs and the research environment. The primary problems for the trainees were the financial insecurity of embarking on an academic career and the poor academic status of their role models in clinical cancer research. The problems regarding the environment of academic oncology and oncology research relate primarily to the strong and widespread perception that grant proposals for clinical oncology research are at a competitive disadvantage with proposals for cancer research in the laboratory. The study results yielded two basic recommendations. The first recommendation is to improve training for clinical cancer research and to implement unique funding mechanisms for trainees. Because physicians devote 3-10 years to clinical training, a minimum of 10 years of clinical research is needed for a clinician to compete effectively as a principal investigator in the R01 and P01 grant areas. The second recommendation is to develop peer review mechanisms that allow clinical research proposals to compete within a pool restricted to proposals in this category. The consensus in the study was that when programs in clinical research and laboratory research are in competition, the clinical proposals have a lower success rate. The problem appears to rest with the fact that the reviewers are frequently from disciplines other than clinical research and, more importantly, that clinical research proposals fare badly in competition against laboratory research proposals even when they are reviewed by appropriate peers. Implementation of this recommendation will require development of a clinical oncology research study section in the Division of Research Grants at the National Institutes of Health to review R01 grant proposals for innovative clinical cancer research, providing an academic environment that would enable the clinical investigator, through increased success in obtaining grants, to be a positive role model for the young physician/scientist.

Clinical Medicine↗
PubMed1991

Prevention of chemotherapy-induced leukemia and of leukemia relapses.

Fifty percent of patients with the myelodysplastic syndrome, frequently following treatment by radiation or chemotherapy, have prognostically unfavorable deletions of the long arms of chromosomes 5 and 7, or trisomy 8, as have the 25% of patients with acute myeloblastic leukemia where remissions last 6-12 months, and where relapse cannot be prevented. In contrast, patients with prognostically favorable cytogenetics (translocation 15; 17 or 8; 21 or inversion 16) maintenance chemotherapy may prevent relapses. Of chronic myelocytic leukemia patients, 85% can achieve hematological remission with interferon alpha, and 40% a partial cytogenetic remission, which probably delays relapse.

Antineoplastic Agents↗
PubMed1991

Highly oncolytic adherent lymphocytes: therapeutic relevance for leukemia.

We have generated and characterized a highly oncolytic adherent lymphocyte subset (A-LAK) from eight leukemic patients with non-lymphocytic leukemia (NLL) in remission and one NLL patient in relapse. Our studies demonstrated that A-LAK was superior in its oncolytic activity (tested in a 3-h 51Cr release assay) to conventionally prepared (LAK) and non-adherent (NA) IL-2 cultures. No activity was observed by this highly oncolytic subset against normal bone marrow (BM). A-LAK also displayed highest proliferative activity in 7-11 day cultures (5- to 58-fold expansion) in comparison to LAK (0.7- to 2.7-fold) or NA (1.0- to 2.6-fold) cultures. Analysis of phenotype of unseparated, NA and adherent (A-LAK) lymphocytes 24 h after IL-2 activation showed that the A-LAK was composed predominantly of high intensity (bright) CD11a+ (LFA-1) lymphocytes (75 +/- 4.8%) when compared to the other two populations (12 +/- 2.1%). Similarly, A-LAK contained higher proportion of CD11b (CR3 receptor)-positive lymphocytes (39 +/- 2.1%) than unseparated and NA lymphocytes (11 +/- 1.4%). Double marker phenotypic studies showed that A-LAK cultures were heterogeneous and distribution of individual lymphocyte subsets differed among NLL patients. While in A-LAK culture of some patients the CD56+, CD3- natural killer (NK) cell subset was predominant, CD3+, CD56- lymphocyte subset was prevalent in others. Highest A-LAK lytic activity was always correlated with highest NK cell content. Characterization studies (using the complement-depletion technique) showed that independently of the distribution of lymphocytes in A-LAK cultures, CD16+, CD56+, CD3- NK cell subset displayed highest oncolytic effect. CD5+ subset also participated in cytotoxic function. These observations indicated that A-LAK may represent a new therapeutic approach to treatment of leukemia.

Adult↗
PubMed1991

Differential dose-related haematological effects of GM-CSF in pancytopenia: evidence supporting the advantage of low- over high-dose administration in selected patients.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multifunctional haematopoietin which can promote production of several blood cell lineages, though the predominant target cells are neutrophils, monocytes, and their precursors. Occasional undesirable clinical effects include eosinophilia, an increase in blasts, or thrombocytopenia. Here, we describe four patients who were treated with GM-CSF, at subcutaneous doses significantly lower than are conventional, and experienced an unusual response pattern. Three patients had severe pancytopenia associated with chronic lymphocytic leukaemia (CLL) or myelodysplastic syndrome (MDS) and exhibited an unexpected switch in the responsive lineage on high- versus very low-dose therapy. The two CLL patients developed marked eosinophilia (up to 10.0 x 10(9) cells/l) without an increase in neutrophils on 125-300 micrograms/m2/d of GM-CSF. In contrast, when the dose was lowered to 10 micrograms/m2/d, the neutrophils rose to physiological levels, without significant eosinophilia. The MDS patient showed a rapid rise in peripheral blasts (baseline level = 0; post-therapy level = 5.0 x 10(9)/l), without a change in other cell types, when receiving 60 micrograms/m2/d of GM-CSF. After GM-CSF was held, blasts returned to baseline levels; reinstituting therapy at the very low dose of 6 micrograms/m2/d was followed by an increase in platelet counts from 50 to 185 x 10(9)/l with only a minor increase in blasts. The fourth patient, who suffered from severe aplastic anaemia complicated by recurrent gastrointestinal haemorrhage, was only treated with the low-dose regimen. He showed a predominant platelet effect with counts rising from 9 to 169 x 10(9)/l. Very low-dose GM-CSF therapy was devoid of constitutional side effects. The biological implications of these GM-CSF responses are discussed. Our results indicate that, in some patients, GM-CSF may stimulate different target cells depending on the dose. Therefore, in contrast to the results of administration of many classical drugs, there may not always be a direct relationship between the amount of GM-CSF given and the optimal effect.

Adult↗
PubMed1991

Fludarabine: a new agent with marked cytoreductive activity in untreated chronic lymphocytic leukemia.

Thirty-three patients with chronic lymphocytic leukemia (CLL) with advanced Rai stage (III-IV) or progressive Rai stage (0-II) disease were treated with fludarabine as a single agent. Eleven patients (33%) obtained a complete remission (CR), 13 (39%) a clinical CR with residual nodules as the only evidence of disease (nodular partial remission [PR]), and two patients (6%) achieved a PR for a total response rate of 79%. Response was rapid, usually occurring after three to six courses of treatment. The major morbidity was infection. Febrile episodes occurred in 13% of the courses (pneumonia 6%, minor infection 4%, and transient fever of undocumented cause 3%). Fludarabine appears to be the most cytoreductive single agent so far studied in CLL.

Adult↗
PubMed1991

Rearrangement of the retinoic acid receptor gene in acute promyelocytic leukemia.

The retinoic acid receptor-alpha (RAR-alpha) gene was previously localized to chromosome 17q21, a region close to the t(15;17) (q22;q21) abnormality in acute promyelocytic leukemia (APL). We used the RAR-alpha gene as a probe and found that eight of nine APL patient samples with t(15;17) (q22;q21) showed rearranged bands. A tenth APL patient was diploid and demonstrated no rearrangement. One patient who had rearrangement as an acute leukemia did not have rearrangement in remission. The results obtained from intron/exon mapping of the RAR-alpha gene demonstrated that breakpoints of seven of the eight patients occurred within intron 1. Northern blot analysis of leukemic samples indicated the expression of two RAR-alpha mRNA of 2.7 and 3.7 kb. However, two additional mRNA of 4.1 and 3.2 kb were found in an APL patient. We conclude that the RAR-alpha gene is directly involved in the t(15;17) translocation in APL and may transcribe aberrant messages.

Blotting, Northern↗
PubMed1991

Down regulation of myeloperoxidase gene associated with specific nuclease hypersensitive sites during TPA induced differentiation of HL-60.

The level of myeloperoxidase (MPO) mRNA is reduced significantly after HL-60 induced differentiation with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). We examined the chromatin structural changes of the MPO gene during TPA induction. Before TPA induction about nine DNase I hypersensitive sites (HS) were found on the 5' upstream and at various intron regions of the MPO gene. A new HS was found on intron 8 within 4 h of induction; its appearance preceded down regulation of the MPO gene. At the same time DNase I HS found in 0.3 and 1-1.5 kb upstream of the MPO CAP site, were significantly reduced or disappeared after TPA induction. These chromatin structural changes could be closely linked to the mechanism which regulates the MPO gene expression.

Blotting, Southern↗
PubMed1990

RAS mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia.

Previous reports have indicated that mutations of the RAS oncogenes are not associated with the chronic phase of Philadelphia chromosome-positive chronic myelogenous leukemia (Ph1+ CML). However, further studies were needed to determine their association with Ph1- CML and chronic myelomonocytic leukemia (CMML). Therefore, 6 patients with Ph1- CML who were also negative for BCR rearrangements (Ph1-/BCR- CML) and 30 patients with CMML were analyzed for the presence of RAS oncogene point mutations to determine the similarities of these diseases at the molecular level. The assay used the polymerase chain reaction for amplification of the target RAS sequences and panels of specific synthetic oligonucleotide probes for hybridization to wild type and/or mutated sequences. None of the six Ph1-/BCR- CML patients had mutations in the RAS oncogenes, while 17 of 30 (57%) of the CMML patients had RAS oncogene mutations. Eighty percent of the mutations involved substitution of aspartic acid for glycine (G----A) in the 12th or 13th codons of N-ras or K-ras. Furthermore, although not statistically significant, survival studies raise the possibility of shortened survival in patients with RAS oncogene point mutations, with the average survival being 33 months for Ph1-/BCR- CML, 35 months for CMML without point mutations, and 11 months for CMML with RAS mutations. Thus, RAS mutations appear to be associated with CMML and not Ph1-/BCR- chronic phase CML, there is a high propensity for the K-ras or N-ras mutations to involve an G----A substitution in the 12th or 13th codons, and RAS mutations in CMML may relate to prognosis and require further studies.

Gene Rearrangement↗
PubMed1990

Mixed-lineage leukemia revisited: acute lymphocytic leukemia with myeloperoxidase-positive blasts by electron microscopy.

Seven adult patients with untreated acute lymphocytic leukemia (ALL) who manifested 5% to 40% myeloperoxidase (MPO)-positive blasts by electron microscopy (EM) are reported. Six patients had an L2 morphology, and one had an L1 morphology by the French-American-British (FAB) classification. The immunophenotype was T cell in four patients. Molecular analysis showed rearrangement of the immunoglobulin JH in four patients, three of them also having rearrangement of the T-cell receptor beta or gamma. Induction chemotherapy with vincristine-doxorubicin-dexamethasone (VAD) produced a complete remission in five of six patients (83%). Our findings suggest the existence of a previously undescribed subtype of mixed-lineage leukemia, which by morphology and immunophenotype often appears as T-cell ALL but exhibits MPO-positive blasts by EM.

Adolescent↗
PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Adult↗
PubMed1990

Mitoxantrone and high-dose cytosine arabinoside for the treatment of refractory acute lymphocytic leukemia.

Twenty-five adult patients with refractory acute lymphocytic leukemia received salvage therapy with mitoxantrone 5 mg/m2 intravenously over 1 hour daily for 5 days and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. Overall, nine patients (36%) achieved complete remission, eight (32%) died during induction, and eight (32%) had resistant disease. No significant associations were found between pretreatment patient characteristics and remission. Remission durations toxic effects were related to myelosuppression. Febrile episodes requiring hospitalization occurred in 23 patients (92%), including five episodes of fever of unknown origin (20%) and 18 episodes of documented infections (72%). The authors conclude that the combination of mitoxantrone and high-dose cytosine arabinoside has significant activity in adults with refractory acute lymphocytic leukemia. The addition of colony-stimulating growth factors to the intensive chemotherapy, and the use of the combination regimen as part of front-line maintenance intensification therapy may further improve the prognosis in these patients.

Adolescent↗
PubMed1990

The importance of cytogenetic studies in adult acute lymphocytic leukemia.

PURPOSE: The prognostic importance of pretreatment bone marrow cytogenetic studies in adults with acute lymphocytic leukemia treated at a single institution, with an identical treatment program, is described. PATIENTS AND METHODS: A total of 105 patients with a documented morphologic diagnosis of acute lymphocytic leukemia were reviewed for the purpose of this analysis. All patients had an extensive workup at presentation, and cytogenetic analysis was performed in 103 patients, using the Giemsa banding technique with trypsin pretreatment on 24-hour cultured cells. RESULTS: The specific cytogenetic classification in the 103 patients who had the karyotypic analysis was as follows: diploid 27%; Philadelphia chromosome-positive 13%; hyperdiploid 12%; B-cell karyotype 6%; 6q- and 14q+ abnormalities 4%; pseudodiploid 8%; hypodiploid 2%; and insufficient metaphases 28%. B-cell, 6q- or 14q+, and Philadelphia chromosome-positive karyotypes tended to correlate with other known negative prognostic factors. Patients with diploid, hyperdiploid, pseudodiploid, and hypodiploid karyotypes or with insufficient metaphases could be combined into one group with a favorable prognosis. In this group, the remission rate with induction chemotherapy was 89%, the median complete remission duration was 26 months, and the median survival was 25 months, with a 3-year survival rate of 45%. Patients with Philadelphia chromosome-positive, B-cell, and 6q- or 14q+ abnormalities collectively had an unfavorable prognosis. Their response rate to induction chemotherapy was 65%, the median response duration was 7 months, and the median survival was 8 months, with a 3-year survival rate of less than 10%. CONCLUSION: We conclude that the pretreatment bone marrow karyotype is an important part of the evaluation of adults with acute lymphocytic leukemia and provides significant prognostic information.

Adolescent↗
PubMed1990

Resistance to 4-(9-acridinylamino) methanesulphon-m-anisidide (m-AMSA) in human myeloid leukaemia.

Sublines of a human myeloid leukaemia cell line, KBM-3, with increasing degrees of resistance to the antileukaemic agent 4'-(9-acridinlylamino) methanesulphon-m-anisidide (m-AMSA) were evaluated for their response to this drug using a clonogenic assay to measure cell survival and alkaline elution to assess m-AMSA induced DNA strand breakage. Polyacrylamide gel electrophoresis was used to map the protein profiles of the various cell lines. The resistant lines were obtained by intermittent exposure of the KBM-3 cells to the highest tolerated concentration of m-AMSA so that the culture would be repopulated only by the most resistant subpopulation after each exposure. Two distinct phases were apparent during the development of resistance. During the first 14 months of intermittent exposure to maximally tolerated concentrations of m-AMSA, the cells developed low-degree m-AMSA resistance (5-7-fold as compared with the parent line, as measured by cell survival). This low-degree resistance was characterised by a somewhat suppressed level of DNA strand breakage and no measurable change in cellular protein levels. Subsequently, a single escalation of the m-AMSA retreatment concentration resulted in a cell population that was approximately 100-fold resistant, as assessed by cloning. This rapid phenotypic change temporally coincided with the acquisition of an almost complete refractoriness to m-AMSA-induced DNA strand breakage and the loss of a cellular 76 kDa protein. We suggest that the loss of this protein is important for the development of a highly m-AMSA resistant phenotype.

Amsacrine↗