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Biomedical subjects

J U Gutterman

Publications and source records attributed to J U Gutterman.

At least 55 records · Page 3Linked to original sources
PubMed1992

Comparison of in vivo and in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with acute myeloid leukemia.

We studied the in vitro effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) in 13 patients with acute myeloid leukemia (AML) and one patient with refractory anemia with excess of blasts in transformation using the AML blast (AML colony-forming units, AML-CFU) and mixed (granulocyte erythrocyte macrophage megakaryocyte colony-forming units, CFU-GEMM) colony culture assays. In parallel, these patients received GM-CSF s.c. at 125 micrograms/m2/day, or in escalated doses starting with 10 micrograms/m2/day for a week or until circulating blast counts reached 50 x 10(9)/liter, in an effort to sensitize leukemic blasts to cell-cycle-specific agents. Results of in vivo GM-CSF treatment were correlated with those of in vitro assays. In 9 of 12 patients (75%), GM-CSF treatment increased peripheral blood blast counts (in vivo effect). GM-CSF also stimulated in vitro AML blast colony proliferation in these nine patients and increased the S+G2M phases of the cell cycle in five out of five of these patients' samples. Two of three patients in whom an in vivo response could not be demonstrated also failed to have a detectable in vitro response. These observations suggest that the AML blast colony culture assay may be useful in predicting the response of AML to cytokine therapy. Finally, GM-CSF stimulated granulocyte-macrophage (granulocyte-macrophage colony-forming units, CFU-GM) and erythroid (erythroid burst-forming units, BFU-E) colony proliferation in 14 and 11 patients, respectively, including the 3 individuals who demonstrated no clinical effect on blast counts. It is, therefore, possible that GM-CSF may be used to stimulate proliferation of progenitors that differentiate into mature granulocyte, monocyte-macrophage, and erythroid cells.

Acute Disease↗
PubMed1992

The effect of granulocyte-macrophage colony-stimulating factor on undifferentiated and mature acute myelogenous leukemia blast progenitors.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used recently to recruit undifferentiated acute myelogenous leukemia (AML) blasts into the S-phase of the cell cycle and increase the fraction of cells killed by cell cycle-specific drugs. Using three AML blast colony assays combined with a suspension culture (delta assay), we determined the in vitro effect of GM-CSF on mature and undifferentiated AML blast progenitors obtained from bone marrow aspirates of six AML patients. GM-CSF stimulated AML blast colony proliferation at a concentration of 5 ng/ml in the methylcellulose and the agar clonogenic assays in six of six AML marrow samples. However, in the delta assay, which selects for immature AML progenitors, GM-CSF did not affect AML blast colony-forming cells in five of six AML marrow samples at concentrations ranging from 5 to 300 ng/ml. Our data imply that GM-CSF stimulates mature but not undifferentiated AML blast progenitors. It is therefore possible that GM-CSF may not be beneficial as a recruiting agent in most AML patients.

Adult↗
PubMed1992

Minimal residual disease in interferon-treated chronic myelogenous leukemia: results and pitfalls of analysis based on polymerase chain reaction.

Therapy with interferon-alpha results in complete cytogenetic remission in 15-20% of patients with chronic myelogenous leukemia. Even during prolonged clinical follow-up, most of these patients do not relapse. However, because of the limited sensitivity of cytogenetic techniques (approximately 5%) and Southern blots (approximately 1%), it is uncertain whether the residual malignant clone becomes extinct or persists below the limit of detection in these patients. We used polymerase chain reaction to amplify the chimeric BCR-ABL transcripts in 18 patients with chronic myelogenous leukemia who became Ph1 chromosome negative while receiving treatment with interferon-alpha, either alone or in combination with interferon-gamma. At the time of study, these patients had been Ph1-negative for a median of 22+ months. Fifteen patients were positive for residual BCR-ABL transcripts. No residual BCR-ABL message was detected on analysis of multiple serial samples in three patients. In order to confirm these results, the samples from these three patients, along with positive and negative controls, were analyzed by two independent laboratories in a blinded fashion. In the first laboratory, RNA specimens from all three patients were considered negative using chemiluminescent acidinium-ester-labeled probes. In the second laboratory, samples from all three patients were also negative by conventional polymerase chain reaction (PCR). However, when a second round of amplification was carried out on the amplified samples using a different combination of primers, samples from two of the three patients were positive. The results confirm the presence of a small proportion of BCR-ABL-positive cells in the majority of patients who are in complete remission and highlight some of the potential problems of PCR-based analysis. There is a need to standardize PCR methodology and potential confounding factors need to be addressed before PCR can be generally applied to analysis of minimal residual disease in CML. The implications of BCR-ABL positivity for these patients are discussed.

Adult↗
PubMed1991

A phase II study alternating alpha-2a-interferon and gamma-interferon therapy in patients with chronic myelogenous leukemia.

Patients with Philadelphia chromosome-positive chronic myelogenous leukemia (CML) were treated with a combination of alpha-interferon and gamma-interferon. Recombinant alpha-2a-interferon (Roferon-A, Hoffmann-LaRoche, Inc., Nutley, NJ) and recombinant gamma-interferon (Genentech, Inc., South San Francisco, CA) were administered on alternating weeks each at doses ranging from 2 to 10 MU/m2 given intramuscularly. Of the 27 patients, 11 (41%) achieved complete hematologic remission (CHR) and 3 (11%) achieved partial hematologic remission (PHR). Responses were seen among 9 of 22 (41%) patients treated during the chronic phase of the disease and in 2 of 5 (40%) patients treated during the accelerated phase/second chronic phase. Cytogenetic responses were seen in six patients, including one complete response and five minor responses. Toxicities included flu-like symptoms, which appeared to be more severe with gamma-interferon than with alpha-interferon, hypertriglyceridemia, and thrombocytopenia. In this limited study, an improved outcome was not observed for the combination regimen compared with alpha-interferon alone.

Adolescent↗
PubMed1991

Alteration in bone marrow adherent layer growth factor expression: a novel mechanism of chronic myelogenous leukemia progression.

Philadelphia chromosome1 positive (Ph1) chronic myelogenous leukemia (CML) is characterized by metamorphosis of the chronic phase to blastic crisis. However, cellular events associated with this transition are poorly understood. To examine the possible participation of hematopoietic growth factors in this process, we studied growth factor expression in adherent layers of bone marrows derived from CML Ph1 patients in various stages of the disease. Interleukin-1 beta (IL-1 beta) and IL-6 mRNA were expressed in five of six patients, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in one of six patients with myeloid/undifferentiated blast crisis. In addition, leukemia inhibitory factor (LIF) expression was increased in four of six patients with myeloid/undifferentiated blast crisis phase of the disease. IL-1 beta was also detected in bone marrow adherent layer conditioned medium from two of these patients. These results were in sharp contrast to the lack of detectable levels of uninduced IL-1 beta, IL-6, and GM-CSF mRNA, in samples derived from 4 patients in lymphoid blastic crisis, 3 in accelerated, and 11 in chronic phases of the disease, or from normal controls. The possibility of a paracrine loop formation, whereby the adherent layers representing the bone marrow stroma are induced to express hematopoietic growth factors, was supported by our finding IL-1 beta mRNA expression in the leukemic blast cells in three of four studied patients in blast crisis and IL-1 beta protein production in seven of eight patients studied. Finally, coculturing CML blast crisis cells onto pre-established adherent layers induced the expression of both IL-1 beta and IL-6 genes. From this preliminary study, it appears that abnormal expression of growth factors is a common event with CML Ph1 progression. We hypothesize that IL-1 beta generated by the transformed malignant clone stimulates the marrow stroma to produce various growth factors, and that this process may play a role in disease progression.

Blast Crisis↗
PubMed1991

Development of systemic lupus erythematosus after interferon therapy for chronic myelogenous leukemia.

A 19-year-old man with Philadelphia-positive chronic myelogenous leukemia treated with interferon-alpha (IFN-alpha) therapy for 45 months had systemic lupus erythematosus disease features: malar rash, migratory arthralgias, elevated antinuclear antibodies, elevated antinative DNA, hypocomplementemia, lymphopenia, and proteinuria. After discontinuation of the IFN and initiation of corticosteroids, there was gradual recovery of symptoms, a decline in antinative DNA and antinuclear antibodies to normal levels, and a decrease in proteinuria. The potential association between IFN therapy and the development of systemic lupus erythematosus, and the role of IFN in other autoimmune diseases, is discussed.

Adult↗
PubMed1991

Suppression of chronic myelogenous leukemia colony growth by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors: a novel application for inhibitors of IL-1 activity.

In this study, we investigated the role of interleukin-1 beta (IL-1 beta) in the malignant evolution of chronic myelogenous leukemia (CML) and the functional activity of IL-1 inhibitors. Bone marrow (BM) and peripheral blood (PB) low-density cells from 38 CML patients were studied in the colony-forming unit-granulocyte, erythrocyte, monocyte, megakaryocyte colony culture assay. Samples from patients with early stage, interferon-alpha (IFN)-sensitive disease formed hematopoietic colonies in the presence of fetal calf serum (FCS), erythropoietin (Epo), and one of the following: granulocyte-macrophage colony-stimulating factor (10 ng/mL), IL-3 (15 ng/mL), both, or phytohemagglutinin-conditioned medium. The addition of IL-1 beta augmented IFN-sensitive CML colony growth in a dose-dependent manner at concentrations of 10 to 100 U/mL. In sharp contrast, addition of the above growth factors did not augment the colony growth-promoting effect of FCS and Epo in samples from IFN-resistant patients; further, adherent cell fractionation or T-lymphocyte depletion attenuated the "autonomous" colony growth. Lysates of 2.5 x 10(7) low-density cells from each of six IFN-resistant and six IFN-sensitive CML patients and three normal volunteers were tested for intrinsic IL-1 beta content in an enzyme-linked immunosorbent assay and yielded a mean of 610 pg, 54.6 pg, and 49.4 pg of IL-1 beta, respectively (P less than .045). Interestingly, both soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) at concentrations of 5 to 100 ng/mL (sIL-1R) and 10 to 500 ng/mL (IL-1RA) inhibited CML colony growth in a dose-dependent fashion, with maximal inhibition of 64% and 65%, respectively. A similar effect was noted with the use of anti-IL-1 beta neutralizing antibodies. These data implicate IL-1 beta in CML disease progression and suggest that the inhibitory effects of molecules such as sIL-1R and IL-1RA could conceivably be the basis of a novel therapeutic strategy against this disorder.

Adolescent↗
PubMed1991

Interferon-alpha produces sustained cytogenetic responses in chronic myelogenous leukemia. Philadelphia chromosome-positive patients.

OBJECTIVES: To evaluate the frequency and the course of complete cytogenetic responses in interferon-alpha (IFN-alpha)-treated patients with chronic myelogenous leukemia. DESIGN: Two prospective trials in consecutive patients. SETTING: A major tertiary cancer center. PATIENTS: Ninety-six consecutive patients with chronic myelogenous leukemia with disease duration of less than 1 year. INTERVENTION: Patients received partially pure IFN-alpha intramuscularly, from 3 to 9 million U/d (51 patients) or recombinant IFN-alpha 2a (Roferon, Hoffmann-LaRoche, Inc., Nutley, New Jersey), 5 million U/m2 body surface area daily (45 patients). MEASUREMENTS: Hematologic and cytogenetic tests were administered. MAIN RESULTS: Seventy of the patients (73%) achieved hematologic remission (95% CI, 63% to 81%), and 18 (19%) had complete suppression of the Philadelphia chromosome on at least one cytogenetic test. A complete cytogenetic response was induced in 7 of 51 or 14% (CI, 6% to 26%) of the patients treated with the partially pure IFN-alpha and in 11 of 45 or 24% (CI, 13% to 40%) of the patients treated with recombinant IFN-alpha 2a. The difference in complete cytogenetic response between the two groups was 10.7% (CI, - 5% to 26%; P greater than 0.2). Eleven patients had durable, ongoing, complete cytogenetic responses from 6 to more than 45 months (median, more than 30 months). CONCLUSION: This study was the first to show sustained, complete cytogenetic responses in a subset of patients with chronic myelogenous leukemia treated with single-agent therapy. The nature of this remission, that is, whether it depends on continuous therapy, requires further study.

Adult↗
PubMed1991

Expression of the macrophage colony-stimulating factor and its receptor in gynecologic malignancies.

Recently, hematopoietic growth factors have been implicated in protean nonhematopoietic processes. In the current study, expression of macrophage colony-stimulating factor (M-CSF) and its receptor (the c-fms proto-oncogene) was investigated in 42 samples of gynecologic tissues. There were 15 samples of normal ovarian and uterine tissue or benign conditions of these organs; 11 samples of primary ovarian cancer tissue; seven samples of metastatic ovarian cancer tissue; and nine samples of primary endometrial cancer tissue. Steady state transcript levels were assessed by Northern Blot analysis. Macrophage colony-stimulating factor (M-CSF) expression was not observed in any of the specimens of benign abnormalities or of normal organs; c-fms expression was detected in two of 15 (13%) of these specimens, albeit at very low levels. In contrast, 14 (78%) of 18 ovarian tumor specimens, and five (55%) of nine endometrial tumor specimens expressed M-CSF. Similarly, 16 (89%) of 18 ovarian tumor specimens and six (67%) of nine endometrial tumor specimens expressed c-fms. Most positive malignant tissues (19 [86%] of 22) showed coexpression of M-CSF and c-fms. Of interest, M-CSF and c-fms mRNA were detected in tumor, but not in adjacent normal tissue. Furthermore, M-CSF and c-fms transcripts were produced by all metastatic tumors, including two cases in which the corresponding primary tumor from the same patient was negative. Because M-CSF mediates its effects by binding to its receptor, the increased levels of both these gene products in gynecologic malignancies suggest that an interaction between M-CSF and c-fms may participate in the development of ovarian and endometrial carcinomas and especially in progression to the metastatic state.

Blotting, Northern↗
PubMed1991

A phase I trial of recombinant alpha-2a interferon (Roferon-A) with weekly cisplatinum.

Eighteen patients with advanced solid tumors were treated in a phase I study of cisplatinum in combination with recombinant alpha-2a interferon (Roferon-A, Hoffman-LaRoche, Inc, Nutley, NJ). Roferon-A was administered at a dose of 5 MU/m2 S.C. three times a week and the dose levels of cisplatinum were 15, 20, 25, 33, and 42 mg/m2/week given intravenously. All patients experienced grade I/II fatigue, nausea and vomiting. Grade III toxicity occurred in 4/6 patients at dose level 4. The dose limiting toxicities were myelosuppression [leukopenia (two patients), neutropenia (one patient), thrombocytopenia (one patient)], vomiting (one patient) and severe fatigue leading to a decrease in performance status (one patient). One patient with non-small cell lung carcinoma had a mixed response and another a minor response. The recommended dose level of this combination for phase II studies is cisplatinum 25 mg/m2/week and Roferon-A 5 MU/m2 three times a week.

Adult↗
PubMed1991

Granulocyte-macrophage colony-stimulating factor and interleukin-3 in combination: a potent and consistent myelodysplastic syndrome bone marrow stimulant in vitro.

In an effort to overcome bone marrow failure in myelodysplastic syndrome (MDS), we have investigated recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) in phase I-II clinical trials. Although these agents partially increased peripheral blood granulocyte counts, their effect on other hematopoietic lineages was generally sporadic. Since in vitro analysis and in vivo studies in primates indicate that GM-CSF and IL-3 synergistically enhance hematopoietic stem cell proliferation, we evaluated their combined effect on marrow progenitors obtained from ten MDS patients. When used singly, each growth factor stimulated replication of granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) colony-forming cells in a dose-dependent fashion. When colony-stimulating activity was compared at concentrations that maximally amplified individual MDS patients' colony numbers, IL-3 was a more potent stimulant in some patients and GM-CSF in others. When used in combination, IL-3 plus GM-CSF was more effective than each growth factor by itself in five of six patients. Our data indicate that the MDS hematopoietic progenitor stimulatory effect of these growth factors varies from patient to patient. However, the combination of GM-CSF and IL-3 appears to be more potent than the individual molecules in the majority of patients.

Bone Marrow↗
PubMed1991

Phase II evaluation of interferon added to tamoxifen in the treatment of metastatic breast cancer.

This phase II trial evaluated the clinical role of interferon (IFN) in overcoming tamoxifen (TAM) resistance in breast cancer. Twenty women and 1 man received recombinant alpha interferon (5 million units per meter squared intramuscularly, 5 times per week) plus TAM (10 mg orally, twice daily) for the treatment of metastatic breast cancer, either after failing tamoxifen therapy or as frontline hormonal therapy. Of the 9 evaluable patients with disease progression after an objective response to TAM, there were no partial or complete responses with the addition of IFN. Ten evaluable patients received TAM plus IFN as frontline hormonal therapy with 2 complete and 3 partial responses for an overall response rate (RR) of 50% (95% confidence interval = 19-81), a 71% RR for ER-positive patients (95% confidence interval = 29-96) and no responses in ER-unknown patients. Sixteen patients required dose reductions of IFN and 8 patients discontinued therapy due to toxicity. It is unlikely that the RR for TAM plus IFN is greater that than seen with TAM alone, or that the addition of IFN to TAM therapy can overcome clinical TAM resistance.

Breast Neoplasms↗
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

Hairy cell leukaemia: review of treatment.

The cardinal features of hairy cell leukaemia are: (i) cytopenias, (ii) splenomegaly, and (iii) mononuclear cells of B-cell origin with cytoplasmic projections and tartrate-resistant acid phosphatase-positivity. The most common complication is infection. In the past, the mainstay of therapy has been splenectomy, and this procedure is still often suggested as a first-line approach. However, research during the last decade has resulted in three new, highly effective therapies for hairy cell leukaemia: interferon-alpha (IFN-alpha), 2'-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (2CDA). IFN-alpha is currently approved for this indication. About 90% of patients have a durable haematologic recovery, and complete remission rates range from less than 5% to greater than 40% in different series. It should be noted that patients with partial remissions generally have normal or near-normal blood counts, and can live indefinitely without disease-related problems, despite a few remaining hairy cells in the bone marrow. In this paper we will discuss the various therapeutic modalities available for patients with hairy cell leukaemia.

2-Chloroadenosine↗
PubMed1991

Interferon alpha in the therapy of CML.

This paper summarizes the experience with interferon alpha (IFN alpha) as single-agent therapy and in combination gathered at M.D. Anderson Cancer Center. It also covers some of the laboratory research associated with these clinical studies.

Combined Modality Therapy↗
PubMed1991

Effects of low doses of recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) in patients with myelodysplastic syndromes.

There has been no previously published experience with granulocyte-macrophage colony stimulating factor (GM-CSF) doses less than 12 micrograms/m2 daily in patients with myelodysplastic syndromes, and most observations have been made at doses greater than or equal to 120 micrograms/m2 daily. We administered 5 micrograms/m2 daily by subcutaneous injection to 29 such patients increasing the dose in patients who did not show a haematologic response. Doses of 5 or 10 micrograms/m2 ('low-dose GM-CSF') produced an increase in neutrophils in 14/29 patients. Response was significantly (P = 0.03) more frequent in patients who had a higher pre-treatment neutrophil count (e.g. 11/16 in patients with greater than or equal to 0.5 x 10(9)/l). A rise in blasts followed administration of low-dose GM-CSF in five patients, all with either refractory anaemia with excess blasts (RAEB) or refractory anaemia with excess blasts in transformation (RAEBT). Platelets decreased in five patients, four of whom had no change in blasts, reverting to baseline when GM-CSF was discontinued. We and others have previously observed similar rises in blasts or decreases in platelets at doses of 120 micrograms/m2 daily. Low-dose GM-CSF produced no constitutional side effects. Our results suggest that low doses of GM-CSF might be initially employed in neutropenic patients with myelodysplastic syndromes who present with pretreatment neutrophil counts greater than 0.5 x 10(9)/l. Increasing the dose, and hence the risk of extramedullary toxicity, only in patients who do not respond to the low dose. Patients who present with lower pre-treatment neutrophil counts might begin treatment at doses above 10 micrograms/m2, but below the 120 micrograms/m2 commonly employed, which may be necessary in relatively few patients.

Aged↗
PubMed1991

Phase I study of recombinant human interleukin-3 in patients with bone marrow failure.

Interleukin-3 (IL-3) is a T-cell-derived colony-stimulating factor (CSF) whose primary targets include relatively early, multipotential, hematopoietic progenitor cells. In this trial, we treated 24 patients with recombinant human IL-3 given by a daily 4-hour intravenous infusion for 28 days. The dose levels were 30, 60, 125, 250, 500, 750, and 1,000 micrograms/m2/d. At least three patients were entered at every dose level. Each participant suffered from bone marrow failure, with the underlying diagnosis being myelodysplastic syndrome (13 patients), aplastic anemia (eight patients), or aplasia after prolonged high-dose chemotherapy (three patients) for multiple myeloma, breast cancer, or acute myelogenous leukemia. Most patients tolerated therapy well, with the most frequent side effects being low-grade fever and headaches. Hematopoietic changes included modest increases in neutrophil counts (eight patients), eosinophil counts (six patients), platelet counts (three patients), and reticulocyte counts (two patients). An increase in blasts occurred in one patient who had refractory anemia with excess blasts in transformation and was reversible once IL-3 was discontinued. In addition, one patient with chronic myelomonocytic leukemia showed an increase in monocytes (and granulocytes). Progression to acute leukemia did not occur. Pharmacokinetic analyses showed a rapid clearance with a mean half-life of 18.8 minutes at the 60 micrograms/m2/d dose, and 52.9 minutes at the 250 micrograms/m2/d dose. Serum concentrations of 10 to 20 ng/mL of IL-3 were achievable at the 250 micrograms/m2/d dose. Our observations indicate that recombinant human IL-3 can be given safely at doses of 1,000 micrograms/m2/d or less. In addition, on the basis of preclinical data and the biologic activity observed in this study, further trials of this molecule, alone and in combination with other growth factors, are warranted in patients with pancytopenia.

Adult↗