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Biomedical subjects

E Estey

Publications and source records attributed to E Estey.

At least 145 records · Page 8Linked to original sources
PubMed1993

Therapy-related acute myeloid leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the literature.

PURPOSE: To analyze therapy-related acute myeloid leukemias (tAMLs) with t(8;21), inv(16), or t(8;16). PATIENTS AND METHODS: Twenty-five patients with tAML and t(8;21)(q22;q22), inv(16)(p13;q22), or t(8;16)(p11;p13) from seven centers, along with 23 previously published cases, were studied. RESULTS: Twenty-six, 16, and six patients, respectively, had t(8;21), inv(16), and t(8;16). Prior cancer was a solid tumor in 27 cases, and a hematologic malignancy in all other patients. Five patients had received prior radiotherapy (RT) alone, and 43 had received prior chemotherapy with or without RT. Prior chemotherapy included a drug that directly reacts with DNA (alkylating agent or cisplatin) and/or an agent that targets topoisomerase II (ATTop, an anthracycline or derivative or, less often, epipodophyllotoxin) in most patients. The interval between prior tumor and diagnosis of tAML was less than 3 years in most cases, and only seven patients had a preleukemic phase of disease. Morphology was M2 AML for t(8;21), M4eo for inv(16), and M4 or M5 for t(8;16). Sixteen of 21 (76%), 12 of 14 (86%), and zero of four patients with t(8;21), inv(16), and t(8;16), respectively, achieved complete remission (CR) with intensive chemotherapy. The actuarial disease-free survival rate at 24 months was 47% and 54% in patients with t(8;21) and inv(16), respectively. CONCLUSION: Like other tAMLs with a karyotype specific of de novo AML [balanced 11q23 rearrangement or t(15;17)], tAMLs with t(8;21), inv(16), or t(8;16) are usually characterized by a short latent period, previous treatment often combining a drug that directly reacts with DNA and an ATTop, and absence of preleukemic phase. Hematologic characteristics and response to treatment are also identical to those of de novo AML with the same karyotypes.

Actuarial Analysis↗
PubMed1993

All-trans retinoic acid: tolerance and biologic effects in myelodysplastic syndrome.

PURPOSE: We conducted a study to evaluate the tolerance to and biologic effects of all-trans retinoic acid in patients with myelodysplastic syndrome. PATIENTS AND METHODS: Thirty-nine patients with myelodysplastic syndrome were treated with oral all-trans retinoic acid for 6 weeks. Dose levels were 10, 25, 50, 100, 150, 200, and 250 mg/m2/d. At least three patients were treated on each dose level. RESULTS: The most common side effects were mucocutaneous dryness and erythema, and hypertriglyceridemia. Dose-limiting side effects were diverse and included dermatitic problems, sensorineural hearing loss, headaches, nausea and vomiting, myalgias, and dyspnea. The maximum-tolerated dose was 150 mg/m2/d. Only one response was seen among 29 patients considered assessable for response. CONCLUSION: All-trans retinoic acid can be safely administered to patients at doses up to 150 mg/m2/d for 6 weeks. However, as administered in this study, this compound does not appear to have significant activity in myelodysplastic syndromes.

Administration, Oral↗
PubMed1993

Phase II clinical trial of fludarabine in chronic lymphocytic leukemia on a weekly low-dose schedule.

The major complication during therapy of chronic lymphocytic leukemia (CLL) with the purine nucleotide analogue fludarabine is infection, which is also the main cause of morbidity and mortality in the disease. As the incidence of infectious episodes during therapy correlated with severity of neutropenia, stage of disease, and response to therapy, an effort was made to reduce therapy-related myelosuppression and improve response by altering the conventional therapy regimen. The protocol which yielded a response rate of 57% in previously treated patients with CLL consisted of five consecutive daily doses of 25-30 mg/m2 fludarabine given every three to four weeks. Based on observations from intracellular pharmacology studies it was hypothesized that repetitive single weekly doses of fludarabine would allow normal bone marrow cells to recover while maintaining cytotoxic levels in the leukemic cells. The cumulative four-week dose of the once-weekly regimen was approximately 80% of the original protocol. Eleven out of 46 evaluable patients (24%) responded to the therapy. Seven patients (15%) achieved a complete remission, and four (9%) a partial remission. While myelosuppression was reduced by about 30% compared with the original protocol, the incidence of febrile episodes was increased by 17%. Pretreatment serum IgG levels below the normal range correlated significantly with a high incidence of infectious episodes and with a short median survival time. These observations suggest that in addition to myelosuppressive therapy, disease related depressed immune function causes morbidity and mortality due to infections. The results further show that changes in the scheduling of the therapy regimen, associated with a slightly lower dose, resulted in reduced efficacy as measured by the response rate.

Adult↗
PubMed1993

High-dose cytosine arabinoside in chronic lymphocytic leukemia: a clinical and pharmacologic analysis.

Twenty-seven patients with B-cell chronic lymphocytic leukemia (CLL) or a related lymphoid malignancy were treated with high-dose cytosine arabinoside (ara-C) at a dosage of 3 gm/m2 administered over 2 hours every 12 hours at one to four doses per course, which were repeated at 4-week intervals. Median patient age was 60 years. Fifty-four percent of CLL patients had Rai stage III or IV disease and the median number of prior therapies was three. Two patients achieved a complete response, five had a partial response, and two had clinical improvement for an overall response rate of 33%. The median duration of response was 9 months. Myelosuppression and infection were the main toxicities. Intracellular levels of the active metabolite ara-C triphosphate varied among patients, but comparisons of pharmacokinetic parameters revealed no significant differences between responders and non-responders. We conclude that high-dose ara-C has modest activity in CLL and that its use in combination with other agents in the treatment of CLL is warranted.

Aged↗
PubMed1993

Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia.

There is a strong association between ability of leukemia blasts to accumulate ara-CTP, the active metabolite of ara-C, and response to ara-C in patients with relapsed or refractory AML. Ara-C dose rates in excess of 0.5 g/m2/h do not produce further ara-CTP formation. In contrast, when given 4 h prior to ara-C at this dose rate, fludarabine, at doses that are free of neurotoxicity in CLL, enhances ara-CTP accumulation. This led us to administer fludarabine and ara-C to 59 patients with AML in relapse or unresponsive to initial therapy. Fludarabine was given at 30 mg/m2 once daily for 5 doses and ara-C at 0.5 g/m2/h for 2-6 h daily for 6 doses. Doses of fludarabine preceded those of ara-C by 4 h. Results with fludarabine and ara-C (FA) were compared with those of patients treated at M.D. Anderson with high-dose ara-C (HDAC) or intermediate-dose ara-C (IDAC). The complete remission rate with FA was 21/59 (36%) and the actuarial median CR duration 39 weeks. FA produced significantly higher remission rates than HDAC or IDAC in patients with initial remissions > 1 yr (14/20 vs 9/23 vs 6/18, p < 0.05). Response rates were similar for all three treatments in patients with initial remissions < 1 yr or with primary refractory disease. The regimen was well tolerated; one patient developed peripheral neuropathy. This low level of toxicity encourages combination with other antileukemia agents.

Adolescent↗
PubMed1993

Biochemical modulation of arabinosylcytosine for therapy of leukemias.

Analysis of different ribonucleotide reductase inhibitors to modulate arabinosylcytosine (ara-C) metabolism suggested that pretreatment with arabinosyl-2-fluoroadenine (F-ara-A) significantly potentiated the rate of ara-CTP (5'-triphosphate of ara-C) accumulation in both quiescent lymphocytes (p = 0.046) and in cycling blasts (p = 0.017). In vitro incubations of freshly isolated leukemia cells from patients with chronic (n = 7) or acute (n = 5) leukemias with F-ara-A, increased the rate of ara-CTP accumulation by a median of 1.5 or 1.7-fold, respectively, when subsequently incubated with ara-C. The objective of the present investigation was to test the hypothesis that ara-C can be biochemically modulated during therapy of leukemias. To test the biochemical modulation of ara-C in the clinical setting, we designed two protocols to administer fludarabine (clinical formulation of F-ara-A) and ara-C in a pharmacologically directed sequence for patients with chronic lymphocytic leukemia (CLL) refractory to conventional fludarabine therapy or for patients with acute myelogenous leukemia (AML) in relapse. Comparison of ara-CTP pharmacokinetics demonstrated a significant increase in the area under concentration curve (AUC) of ara-CTP both in CLL (median 1.5-fold) and AML cells (median 1.8-fold) after fludarabine infusion. Analyses of different processes involved in the metabolism of ara-CTP indicated that the increase in AUC was due to potentiation of the rate of ara-CTP accumulation. These studies demonstrate that protocols designed on biochemical and pharmacological rationales modulate ara-C metabolism during therapies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Nucleoside analogs in treatment of chronic lymphocytic leukemia.

The nucleoside analogs fludarabine monophosphate, 2-chlorodeoxyadenosine, and 2-deoxycoformycin (pentostatin) all have activity in chronic lymphocytic leukemia. The most widely studied drug is fludarabine which is able to obtain complete or partial responses in more than 50% of previously treated patients. The response rate is 44% for 2-CDA and approximately 25% for pentostatin. Fludarabine has also been used to treat patients as initial therapy, and has resulted in overall response rate of 79% with 75% of the patients achieving complete remission. The NCI and International Working Group for CLL criteria for complete remission allow for persistent nodules or lymphoid infiltrates in the bone marrow biopsy. Studies have now demonstrated persistent lymphoid aggregates are associated with a shorter time to progression for responders but no survival disadvantage. There is a strong association of documented refractoriness to alkylating agents with probability of response to fludarabine and also survival. The major morbidity associated with the use of these drugs are infections, which, in some circumstances, are associated with neutropenia but in other circumstances are probably related to the hypogammaglobulinemia and T-cell immunodeficiency which are part of the disease. The T-cell immunodeficiency is aggravated by the nucleoside analogs. Even after discontinuation of therapy the immunodeficiency as measured by CD4 cell number is sustained for 12 to 24 months. Opportunistic organisms such as herpes simplex, herpes zoster, Listeria monocytogenes, and pneumocystis carinii are being noted in patients treated with these agents. The potency of these drugs and low incidence of toxicities to other organs suggests that they will be effectively combined with other agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Antineoplastic Agents↗
PubMed1993

Fludarabine: pharmacokinetics, mechanisms of action, and rationales for combination therapies.

Knowledge of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, an understanding of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as fludarabine are pro-drugs that must enter cells and be phosphorylated to the nucleoside triphosphate before they can elicit biologic activity. Thus, knowledge of the pharmacokinetics of the triphosphate in target cells and an understanding of the mechanisms by which this active form of the drug act are indispensable to the rational design of treatment protocols. This article reviews the essential elements of the pharmacokinetics and mechanisms of action of fludarabine to provide a rationale for combinations of fludarabine with other chemotherapeutic agents and anti-cancer modalities.

Antineoplastic Agents↗
PubMed1993

Ubiquitous expression of cytokines in diverse leukemias of lymphoid and myeloid lineage.

It has recently been suggested that autocrine production of hematopoietic regulatory molecules can modulate the cardinal features of many leukemic states: excessive proliferation of the neoplastic cells and suppression of the normal elements. We therefore analyzed samples obtained from 57 patients with a variety of hematologic malignancies (21, acute myelogenous leukemia; 14, acute lymphoblastic leukemia; 12, Philadelphia chromosome-positive chronic myelogenous leukemia [blast phase] or acute leukemia; 5, chronic lymphocytic leukemia; and 5, chronic myelomonocytic leukemia) for expression of interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) transcripts on Northern blots. TNF-alpha mRNA was discerned in almost half of the samples (47%), and was expressed in some patients with every type of leukemia, except T-cell acute lymphoblastic leukemia (ALL). Expression occurred with great frequency in samples (12 of 15 [80%]) from monocytic (acute or chronic) leukemias, and from advanced chronic lymphocytic leukemia (4 of 5 samples [80%]). IL-1 beta transcripts were detected in 20 of 57 samples (35%). Its presence, like that of TNF-alpha, was ubiquitous, and only chronic lymphocytic leukemia and T-cell acute lymphoblastic leukemia cells consistently failed to produce IL-1 beta message. Therefore it appears that TNF-alpha and/or IL-1 beta mRNA can be found in the leukemic cells from a substantial subset of patients with B cell-derived acute lymphoblastic leukemia as well as with chronic and acute myeloid, monocytic or lymphocytic leukemias. Because these cytokines have potent direct and indirect effects on normal and malignant hematopoiesis, their widespread constitutive expression by neoplastic blood cells may play a fundamental role in driving the leukemic process.

Blotting, Northern↗
PubMed1993

Chronic myelogenous leukemia in the lymphoid blastic phase: characteristics, treatment response, and prognosis.

PURPOSE: To determine the clinical and laboratory characteristics and outcomes of patients with chronic myelogenous leukemia (CML) in the lymphoid blastic phase. PATIENTS AND METHODS: Data from 296 patients with CML blastic-phase disease who were referred to our institution between 1967 and 1991 were analyzed. Sixty-eight patients had CML lymphoid blastic-phase disease. Pretreatment characteristics, responses to different therapies, and survival rates were evaluated. RESULTS: Compared with patients having myeloid or undifferentiated blastic-phase disease, those with lymphoid morphology were significantly younger, presented with significantly lesser degrees of anemia, lower white blood cell and peripheral blast counts, higher percentages of marrow blasts, lower lactic dehydrogenase levels, and higher albumin levels. Accelerated-phase CML preceded the blastic phase in 40% of patients with lymphoid disease, compared with 54% of those with other morphologic findings (p = 0.03). The common acute lymphocytic leukemia antigen (CALLA) was expressed on lymphoid blasts in 97% of patients. The incidence of chromosomal abnormalities was similar in the three morphologic categories, although patients with lymphoid disease tended to have a lower incidence of trisomy 8 (17% versus 27%; p = 0.10) and of isochromosome 17 abnormalities (10% versus 17%; p not significant). The incidence of lymphoid blastic phase disease has not increased over the past decade, and it is not higher in patients with the chronic phase of the disease treated with alpha interferon. Patients with lymphoid disease had a significantly higher response rate to chemotherapy during the first salvage (49% versus below 20% for other morphologies; p < 0.001), particularly with vincristine, Adriamycin, and dexamethasone therapy (complete response rate of 61%). Survival during the blastic phase of the disease was also significantly longer in patients with lymphoid morphology than in those with other morphologies (median survival of 9 months versus 3 months; p = 0.01). The benefit associated with lymphoid blastic-phase morphology is brief, and plans for allogeneic bone marrow transplantation or experimental maintenance or consolidation programs should be implemented rapidly. CONCLUSIONS: Patients with CML lymphoid blastic-phase disease have different clinical and laboratory features than patients with other blastic-phase morphologies. In patients developing CML blastic-phase disease, distinguishing those with lymphoid transformation is extremely important because of the different therapeutic requirements (acute lymphocytic leukemia-type therapy) and prognostic implications.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Neurotoxicity associated with fludarabine and cytosine arabinoside chemotherapy for acute leukemia and myelodysplasia.

Neurological toxicity occurred in 8/219 patients treated with fludarabine (FAMP), 30 mg/m2 per day and cytosine arabinoside (Ara-C), 0.5 g/m2 per hour for 2-6 hours for 5 days, for new or relapsed acute leukemia or myelodysplasia. Two patients developed severe, progressive cerebral dysfunction that was ultimately fatal. This toxicity was similar to that seen with high-dose fludarabine therapy and was limited to patients with serum creatine > or = 2.0 mg/dl and age over 60 years, occurring in 2/9 such patients compared to 0/210 among the other patients (p < 0.005). Since FAMP is partially excreted by the kidney, toxicity in these two patients was likely due to receiving an effectively high dose of FAMP. Five patients developed peripheral neuropathy but there was no association with age, creatinine, dose of Ara-C, or number of courses. A patient, who also received intrathecal Ara-C, developed myelopathy. At this dose rate and duration of Ara-C peripheral neuropathy rarely arises, and cerebral toxicity is not seen. Neither toxicity was observed in 481 chronic lymphocytic leukemia patients treated with FAMP alone, by the same dose and schedule, suggesting that combination with Ara-C is important for the development of at least the peripheral neuropathy. The incidence of neurotoxicity with FAMP/Ara-C is low especially in comparison with high-dose Ara-C therapy (3 g/m2 over 2 hours). Cerebral toxicity can likely be decreased by dose reduction of FAMP in patients with increased creatinine and peripheral neuropathy decreased by detailed neurological examination before courses of FAMP/Ara-C.

Adult↗
PubMed1992

Clinical implications of decreased retinoblastoma protein expression in acute myelogenous leukemia.

The retinoblastoma (RB) protein levels in blast-enriched mononuclear fractions from the peripheral blood of 33 newly diagnosed patients with acute myelogenous leukemia were studied. Ten patients who had previously been treated were also analyzed, nine of whom had achieved prior complete remission. Low RB protein expression was found in 13 of 43 (30%) of the acute myelogenous leukemia patients as determined by Western blotting and immunochemical analysis. Of particular interest among the 20 newly diagnosed patients treated with the same therapeutic regimen, the median survival was 39 days for those with low RB protein expression compared to 333 days for those with high levels of RB protein expression in their leukemic cells (P less than or equal to 0.02). This preliminary study suggests that decreases of RB protein expression in peripheral blood of myeloid leukemic cells occur frequently and may be associated with shortened survival of acute myelogenous leukemia patients.

Blotting, Western↗
PubMed1992

Correlation of CD2 expression with PML gene breakpoints in patients with acute promyelocytic leukemia.

The chromosomal translocation t(15;17)(q22:21) of acute promyelocytic leukemia (APL) fuses PML, a novel gene, with RAR alpha, a retinoic acid receptor gene. PML-RAR hybrid transcripts were studied in 18 cases of APL using RNA-PCR. Two forms were noted: one designated 5', producing a 439-bp chimeric fragment, and a 3' form, producing a pair of fragments of 765 bp and 909 bp. 5' forms were found in 7 of the 18 cases while the other 11 patients expressed the 3' forms. The chromosome 15 specific probes K3 and K2 were used to study genomic breakpoints in 12 APL patients. Comparison of these results with RNA PCR in 11 patients for whom both were available yielded a rearrangement pattern predictive of whether the hybrid transcript was 5' or 3'. In this way, an additional three patients in whom DNA but not RNA was available were identified as having 3' (downstream) breakpoints and, therefore, 3' hybrid forms. Thus, 21 cases categorized as having 5' or 3' PML-RAR transcripts were analyzed for various phenotypic differences. Surface phenotyping of leukemic promyelocytes demonstrated expression of the CD2 antigen in all cases with the 5' splice variant. Only 1 of 11 cases with the 3' form showed CD2 expression. This difference is significant at P = .001.

Adult↗
PubMed1992

Treatment of newly diagnosed acute myelogenous leukemia with granulocyte-macrophage colony-stimulating factor (GM-CSF) before and during continuous-infusion high-dose ara-C + daunorubicin: comparison to patients treated without GM-CSF.

We gave 56 patients with newly diagnosed acute myelogenous leukemia (AML) granulocyte-macrophage colony-stimulating factor (GM-CSF) 20 or 125 micrograms/m2 once daily subcutaneously before (for up to 8 days or until GM-CSF-related complications developed) and during, or only during (patients presenting with blast counts greater than 50,000 or other leukemia-related complications) ara-C (1.5 g/m2 daily x 4 by continuous infusion) and daunorubicin (45 mg/m2 daily x 3) chemotherapy. Because results seemed independent of GM-CSF schedule, we compared results in these 56 patients with results in 176 patients with newly diagnosed AML given the same dose and schedule of ara-C without GM-CSF (110 patients ara-C alone, 66 patients ara-C + amsacrine or mitoxantrone). Comparison involved fitting a logistic regression model predicting probability of complete remission (CR) and a Cox regression model to predict survival (most patients in all three studies were dead) with treatment included as a covariate in both analyses. After adjusting for other prognostically significant covariates [presence of an antecedent hematologic disorder, an Inv (16), t(8;21), or abnormalities of chromosomes 5 and/or 7, performance status, age, bilirubin], treatment with ara-C + daunorubicin + GM-CSF was predictive of both a lower CR rate and a lower survival probability. There were no treatment-covariate interactions, suggesting that the negative effect of this GM-CSF treatment regime was not an artifact of some imbalance in patient characteristics. The unadjusted Kaplan-Meier hazard rate of the ara-C + daunorubicin + GM-CSF group was not uniquely high during the initial 4 weeks after start of therapy, but was highest among the three treatment groups throughout weeks 5 to 16, suggesting that the negative effect of this treatment was not caused by acute toxicity. Patients who did not enter CR with this treatment tended to have persistent leukemia rather than prolonged marrow aplasia, suggesting that this treatment and, in particular, GM-CSF may increase resistance of myeloid leukemia cells to chemotherapy. To date, relapse rates are similar in all three groups (P = .43) (as are survival rates once patients are in CR) but much of the remission duration data is heavily censored, unlike the survival data. Our results suggest caution in the use of GM-CSF to sensitize myeloid leukemia cells to daunorubicin + ara-C chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Inhibition of acute myelogenous leukemia blast proliferation by interleukin-1 (IL-1) receptor antagonist and soluble IL-1 receptors.

Interleukin-1 (IL-1) has recently been reported to play an important role in acute myelogenous leukemia (AML) blast proliferation. We therefore investigated the effect of soluble IL-1 receptors (sIL-1R) and IL-1 receptor antagonist (IL-1RA) on the growth of AML bone marrow blast progenitors from 25 patients. In the AML blast colony culture assay, sIL-1R and IL-1RA inhibited blast colony-forming cell replication in a dose-dependent fashion, at concentrations ranging from 10 to 500 ng/mL (sIL-1R) and 10 to 1,000 ng/mL (IL-1RA), and their inhibitory effect was partially reversed by IL-1 beta. A similar inhibitory effect was also noted with the use of anti-IL-1 beta neutralizing antibodies. When AML blast progenitors were grown either in the presence of fetal calf serum (FCS) alone or with one of the following: phytohemagglutinin leukocyte-conditioned medium (PHA-LCM), granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, interleukin-3 (IL-3), or stem cell factor (SCF), addition of 100 ng/mL sIL-1R or IL-1RA inhibited blast colony formation by 3% to 96% and 2% to 97%, respectively. In sharp contrast, neither of these IL-1-inhibitory molecules significantly inhibited proliferation of normal marrow hematopoietic progenitors. Lysates of 2 x 10(7) low-density AML marrow cells were tested for intrinsic IL-1 beta content using an enzyme-linked immunoadsorbant assay (ELISA). Samples from five of six patients showed high concentrations (ranging from 501 to 2,041 pg), whereas 2 x 10(7) cells from two normal marrow aspirates yielded 54.6 pg of IL-1 beta. AML blast colony-forming cells from all six patients were inhibited by sIL-1R, IL-1RA, or both. Incubation of nine samples of AML low-density cells with either sIL-1R or IL-1RA reduced GM-CSF concentrations in cell lysates, and supernatants from nine (P less than .01) and six samples (P less than .037), respectively, and G-CSF concentration in lysates from six of nine samples (P less than .03), and in supernatants from five of six samples (P less than .06) when studied by ELISAs. Our data implicate IL-1 in AML blast proliferation and suggest the potential benefits of using IL-1-inhibitory molecules in future therapies for AML.

Adult↗
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

Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia.

PURPOSE: Elevated serum beta-2 microglobulin (beta 2M) levels are associated with poor prognosis in several lymphoproliferative disorders including multiple myeloma and lymphoma. Their prognostic relevance in acute lymphocytic leukemia (ALL) is unknown. We analyzed the associations of serum beta 2M levels at diagnosis with pretreatment characteristics and with prognosis in adult ALL. PATIENTS AND METHODS: One hundred fifty-nine adults with newly diagnosed ALL were investigated. Serum beta 2M levels were determined at diagnosis, on fresh peripheral blood samples, using a radioimmunoassay, the Pharmacia beta 2 Micro RIA (Pharmacia Diagnostics, Uppsala, Sweden). Statistical correlations were assessed by standard methods, and further independent prognostic value of serum beta 2M was determined by multivariate analysis. RESULTS: Patients with beta 2M levels of 4.0 mg/L or above had a lower complete response rate (61% versus 80%; p = 0.02), a significantly worse survival (p < 0.01), and a significantly higher association with development of central nervous system (CNS) leukemia (p < 0.01). High beta 2M levels were more common among patients with older age, with elevated creatinine, bilirubin, and alkaline phosphatase levels, with low albumin levels, and with B-cell disease. Multivariate analysis for survival indicated the beta 2M level to be an independent prognostic variable (after adjusting for pretreatment creatinine level and age). The evaluation of beta 2M levels within low- and high-risk groups for CNS disease suggested an association of elevated beta 2M levels with a worse incidence of CNS disease in the high-risk patients. CONCLUSION: Monitoring serum beta 2M levels may provide significant prognostic information in adults with ALL and should be included in their pretreatment evaluation. Its importance in childhood ALL requires investigation.

Adult↗