Rapid response of B-cell prolymphocytic leukemia to 2-chlorodeoxyadenosine.
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Aged↗
Biomedical subjects
R A Larson
Publications and source records attributed to R A Larson.
A pilot study of prophylactic aerosolized amphotericin B in patients at risk for prolonged neutropenia.
Invasive aspergillosis continues to be a significant cause of morbidity and mortality in patients with prolonged neutropenia. We performed a phase I trial of escalating doses of aerosolized amphotericin B given by a face mask nebulizer system with a disposable bacterial exhale filter. Five, 10, 15, and 20 mg of drug were dissolved in sterile water and inhaled over 10 to 15 minutes twice daily. Tolerance was studied in 26 patients (18 transplant recipients, and 8 leukemia patients). No side effects were observed at any dose level. Prophylactic treatment ended for 14 patients (54%) when intravenous (IV) amphotericin B was begun empirically for antifungal coverage following fevers. Eleven patients (43%) continued inhaled amphotericin B until blood counts recovered. One patient was taken off study when she developed cardiogenic pulmonary edema. No patient developed clinically suspicious or pathologically documented infection with invasive aspergillosis. Prophylactic aerosolized amphotericin B is well tolerated at 5, 10, 15, and 20 mg twice daily dosing. In addition, prophylactic aerosolized amphotericin B does not appear to sensitize patients to the subsequent use of IV amphotericin B. Although this study suggests that prophylactic inhaled amphotericin B is well tolerated and effective, a large scale controlled trial is needed.
Adult↗
Phase I study of busulfan, cyclophosphamide, and timed sequential escalating doses of cytarabine followed by bone marrow transplantation.
In both animal models and human studies in leukemia, residual disease on day 8 following myelosuppressive therapy is in a proliferative phase and therefore may be sensitive to the S-phase specific drug cytarabine. Based on this concept, 17 patients with refractory or relapsed leukemia or lymphoma undergoing either autologous or allogeneic bone marrow transplantation (BMT) were treated on a Phase I protocol using high doses of busulfan (16 mg/kg, days -10, -9, -8, -7) and cyclophosphamide (120 mg/kg, days -6, -5) followed by escalating doses of a 48-h continuous infusion of cytarabine (starting dose 1000 mg/m2/48 h, days -3, -2). Ten patients received autologous transplants (two with Hodgkin's disease, seven with non-Hodgkin's lymphoma, one with chronic myelogenous leukemia (CML) in blast phase). Seven received allogeneic BMT (two with refractory acute myelocytic leukemia (AML), one with refractory acute lymphoblastic leukemia (ALL) undergoing a second BMT, one with Burkitt's-type leukemia, one with ALL in fifth relapse and two with CML in accelerated/blast phase). Two of these patients received a T cell-depleted haploidentical transplant. The maximum tolerated dose of cytarabine was 1500 mg/m2/48 h; a pulmonary syndrome including dyspnea, hypoxemia, and interstitial infiltrates which responded to aggressive diuresis was the dose limiting toxicity. Of the 10 patients who received cytarabine doses of 2000 or 2500 mg/m2/48 h, five patients developed adult respiratory distress syndrome (ARDS) with three patients requiring intubation; two recovered. Of the nine patients with lymphoma, seven responded with complete tumor clearance (CTC) with two patients tumor-free 13 and 15 months post-BMT, one remained refractory and one died too early to evaluate (TETE).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Cancer and Leukemia Group B (CALGB) studies in adult acute lymhocytic leukemia.
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Antineoplastic Combined Chemotherapy Protocols↗
Trisomy 6: a recurring cytogenetic abnormality associated with marrow hypoplasia.
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Adult↗
Inhibition of hydroxymethylglutaryl coenzyme A reductase activity induces a paradoxical increase in DNA synthesis in myeloid leukemia cells.
The effects of competitive inhibition of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase by compactin on the in vitro proliferation of peripheral blood myeloid leukemia cells were studied using the cells from 45 patients with acute myeloid leukemia or chronic myelogenous leukemia in blast phase. The cells from 58% of these patients showed a dose-related inhibition of DNA synthesis when incubated with compactin. Unexpectedly, cells from 18% of the patients were resistant to the inhibitory effects of compactin on DNA synthesis and responded to the HMG CoA reductase inhibition with an actual increase in the incorporation of 14C-labeled thymidine into DNA. Another 18% of the patients studied displayed both inhibition and stimulation of DNA synthesis in a biphasic response depending on the particular concentration of compactin used. The maximum enhanced rates of cellular DNA synthesis were observed with lower compactin concentrations (5 x 10(-7) mol/L) than were required for maximum inhibition of DNA synthesis (10(-5) mol/L). Leukemia cells displaying a stimulated response to compactin had a significantly lower baseline DNA synthetic rate than did cells that showed an inhibitory response of DNA synthesis to compactin. There was no correlation between these cells' varying DNA synthetic response to compactin and measures of baseline HMG CoA reductase activity or acetate conversion to cholesterol. Whereas the observation of cellular DNA synthesis stimulation by HMG CoA reductase inhibition has not been observed in other mammalian cells and seems paradoxical, explanations may emerge in light of our growing knowledge concerning the importance of isoprenylation for the function of certain cell regulatory proteins.
Cell Cycle↗
Interphase cytogenetic analysis detects minimal residual disease in a case of acute lymphoblastic leukemia and resolves the question of origin of relapse after allogeneic bone marrow transplantation.
We used in situ hybridization with a probe for the X chromosome to study interphase cells of bone marrow and peripheral blood specimens from a male patient with acute lymphoblastic leukemia characterized by hyperdiploidy, including trisomy X. In a posttreatment bone marrow specimen, which was interpreted as a regenerating bone marrow morphologically and which demonstrated a normal karyotype cytogenetically, trisomy X was found in 16 of 1,000 interphase cells. This finding indicated the presence of leukemic cells that were undetected by conventional morphologic and cytogenetic techniques (ie, minimal residual disease). Cytogenetic studies of a relapse specimen obtained after a sex-mismatched bone marrow transplant showed only a normal female karyotype in each of 40 metaphase cells, suggesting that the relapse occurred in donor cells. However, interphase analysis demonstrated trisomy X in more than 80% of interphase cells and indicated that the relapse was of the original clone and was not a transformation of donor cells. This case illustrates that interphase analysis can be useful as an adjunct to conventional cytogenetic analysis in the detection of minimal residual disease and in the analysis of interphase cells that are not accessible to routine cytogenetic methods. It also illustrates that previously reported instances of relapse of leukemia in donor cells could have been incorrect if supported by cytogenetic data alone.
Adult↗
Therapy for acute myeloid leukemia and acute lymphoblastic leukemia in adults.
Using intensive induction chemotherapy, primarily with combinations of an anthracycline and cytarabine, complete remission rates of greater than 70% are now achieved in patients with acute myeloid leukemia under the age of 60 years. The treatment of elderly patients with acute myeloid leukemia is difficult and remains controversial. The prognosis for both adults and children with acute lymphoblastic leukemia has improved as more extensive chemotherapy regimens have been used. Recently, a group of leukemias have been identified that have features of both acute lymphoblastic leukemia and acute myeloid leukemia, and these are referred to as biphenotypic or hybrid leukemias. These hybrid leukemias represent an important subgroup, which appears to have a worse outcome regardless of the therapy administered.
Adult↗
The treatment of patients with newly diagnosed poor prognosis acute myelogenous leukaemia: response to treatment and treatment failure.
The failure of poor prognosis patients with newly diagnosed AML to enter remission is usually due to two phenomena: a high mortality rate and resistance of the leukaemia to chemotherapy. We conducted a pilot study of a regimen designed to overcome these two types of treatment failure. Patients were carefully selected for therapy on the basis of their likelihood of surviving. Chemotherapy consisted of high dose cytosine arabinoside (HDaraC) with the doses modified on the basis of patient age so as to reduce the risk of toxicity. Finally, daunorubicin was administered only to those patients for whom HDaraC was not likely to produce sufficient antileukaemia effects to produce a remission. The median patient age was 67 years and 69/88 (78%) patients had a history of preleukaemia and/or toxic exposure. Only 11/84 (13%) patients died during remission induction therapy and 40/84 (48%) entered CR. Patients with only one risk factor had a higher CR rate than those with more than one risk factor (56% v. 30%, P = 0.02) and also had longer durations (222 d v. 113.5 d, P = 0.035). Two types of resistance to chemotherapy were observed: 'classical resistance' (the failure of chemotherapy to produce substantial killing of leukaemia cells) and the rapid regrowth of leukaemia cells subsequent to a level of cytoreduction which otherwise would have been sufficient to produce a CR.
Aged↗
Circulating immune complexes correlate with remission duration in acute myeloid leukemia.
It has been suggested that circulating immune complexes (CIC) favor tumor progression by suppressing the host's immune response to malignant cells via blocking factors to cell-mediated cytotoxicity. We prospectively measured CIC by the C1q binding assay in 100 untreated patients with acute myeloid leukemia (AML) de novo. The median CIC level was 135, the range 0-1000, and the mean +/- standard error (SE) 175 +/- 18 micrograms/ml. Sixty-eight patients, termed abnormal, had C1q binding levels greater than 2SE above the mean of the normal population (61 +/- 15 micrograms/ml). There were no significant differences between the 32 patients with normal CIC and the 68 with abnormally elevated CIC in any pretreatment characteristic: gender, age, white blood cell count (WBC), platelets, leukemia cell mass, LDH, immunoglobulins, or fibrinogen. Abnormal CIC levels did not correlate with FAB morphology, the presence of a clonal chromosomal abnormality (76% of all patients), or with specific cytogenetic subgroups, although nine of 11 patients with acute promyelocytic leukemia and t(15;17) had abnormal CIC. There were no significant differences in complete remission (CR) rates after the first chemotherapy course (45 vs 40% for normal vs abnormal CIC) or after all courses of treatment (55 vs 65%). Survival from diagnosis was not significantly different for the normal and abnormal groups (9.3 vs 5.8 months, p = 0.24), but survival after achieving a CR was markedly longer for those with normal pretreatment CIC (33.8 vs 11.7 months, p = 0.0068). Pretreatment CIC strongly correlated with remission duration for the 59 patients who achieved CR (16.5 months for 17 normal patients vs 6.9 months for 42 abnormal patients, p = 0.0002). This was independent of age, WBC, leukemia cell mass, or FAB morphology. Within the lowest C1q quartile (less than 60 micrograms/ml), 43% of the patients have not relapsed with a minimum follow-up of 18 months compared to only 6-14% for the three higher quartiles. We conclude that host immunity as assessed by CIC levels has little effect on the initial response to therapy but may play a role in maintaining remission in AML.
Adolescent↗
t(3;21)(q26;q22): a recurring chromosomal abnormality in therapy-related myelodysplastic syndrome and acute myeloid leukemia.
We have identified an identical reciprocal translocation between the long arms of chromosomes 3 and 21 with breakpoints at bands 3q26 and 21q22, [t(3;21)(q26;q22)], in the malignant cells from five adult patients with therapy-related myelodysplastic syndrome (t-MDS) or acute myeloid leukemia (t-AML). Primary diagnoses were Hodgkin's disease in two patients and ovarian carcinoma, breast cancer, and polycythemia vera in one patient each. Patients had been treated with chemotherapy including an alkylating agent for their primary disease 1 to 18 years before the development of t-MDS or t-AML. We have not observed the t(3;21) in over 1,500 patients with a myelodysplastic syndrome or acute myeloid leukemia arising de novo or in over 1,000 patients with lymphoid malignancies. We have previously reported that the t(3;21) occurs in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Thus, the t(3;21) appears to be limited to t-MDS/t-AML and CML, both of which represent malignant disorders of an early hematopoietic precursor cell. These results provide a new focus for the study of therapy-related leukemia at the molecular level.
Acute Disease↗
Continuous infusion mitoxantrone in relapsed acute nonlymphocytic leukemia.
Mitoxantrone is a substituted anthraquinone with considerable activity against human acute leukemia. The authors' goal was to treat patients with continuous infusion mitoxantrone in order to maintain cytotoxic steady state levels with acceptable toxicity and to assess the results. Daily mitoxantrone levels showed a mean steady state plasma level of 16.8 +/- 1.4 ng/ml (range, 9.1-25.1) with a systemic clearance of 519 +/- 47 ml/minute/m2. No drug accumulation occurred. Mitoxantrone was undetectable 24 hours postinfusion. All patients, including two patients with chronic myelogenous leukemia in blast phase, had greater than 90% reduction in leukemia cell mass (marrow cellularity X percent leukemia cells) by day 6. However, six patients received 3 days of etoposide at that point because of residual acute nonlymphocytic leukemia (ANLL). Overall four patients (36%) had a complete remission; one additional patient had a bone marrow remission but also had a persistent granulocytic sarcoma. Toxicities included severe but tolerable myelosuppression, mucositis, and hepatic dysfunction. There was no correlation between mitoxantrone levels, toxicity, or clinical response. Continuous infusion produces cytotoxic plasma mitoxantrone levels and rapid clearing of ANLL from bone marrow. Further dose escalation may be possible.
Adult↗
Deletions of interferon genes in acute lymphoblastic leukemia.
Structural rearrangements involving the short arm of chromosome 9, including bands 9p21 and 22, are found in the leukemia cells of 7 to 13 percent of patients with acute lymphoblastic leukemia. The interferon-alpha gene cluster and the interferon-beta 1 gene have been localized to this chromosomal region. We have previously demonstrated deletions of these genes in several cell lines established in vitro from patients with lymphoblastic leukemia. We report here homozygous or hemizygous deletions of the interferon-alpha and interferon-beta 1 genes in samples of leukemia cells from patients with lymphoblastic leukemia. Of 62 patients examined, 18 (29 percent) had such deletions. Four patients (7 percent) had homozygous deletions of the interferon-alpha gene cluster; of these, one also had a homozygous deletion and three had hemizygous deletions of the interferon-beta 1 gene. Fourteen patients (23 percent) had hemizygous deletions of both the interferon-alpha gene cluster and the interferon-beta 1 gene. In 8 of the 18 patients with deletions, the deletions of interferon genes were submicroscopic; in the 11 other patients, chromosomal rearrangements of 9p, including translocations or deletions, were visible on light microscopy. These chromosomal and molecular deletions are likely to be related to the loss of a tumor-suppressor gene (or genes) located on 9p, which may be an interferon gene or an unrelated but closely linked gene.
Adolescent↗
Clinical, morphologic, and cytogenetic characteristics of patients with lymphoid malignancies characterized by both t(14;18)(q32;q21) and t(8;14)(q24;q32) or t(8;22)(q24;q11).
Six patients with an aggressive leukemia/lymphoma disorder had a t(14;18) as well as either a t(8;14) (three patients) or a t(8;22) (three patients). Leukemia cells from all three patients with the t(8;22) had a mature B cell phenotype (Smlg + and TdT-), whereas two of three patients with the t(8;14) had a pre-B phenotype and were Smlg-. None of the patients with the t(8;22) had a prior history of follicular lymphoma, whereas two of the three patients with the t(8;14) had had a follicular lymphoma. The clinical, cytogenetic, and morphologic characteristics of these six patients along with eight previously reported cases with both the t(14;18) and the t(8;14), the t(8;22) or the t(2;8) are discussed.
Adult↗
Morphology in Ki-1(CD30)-positive non-Hodgkin's lymphoma is correlated with clinical features and the presence of a unique chromosomal abnormality, t(2;5)(p23;q35).
Ten patients with strongly Ki-1(CD30)-positive non-Hodgkin's lymphoma (NHL) were identified at our institution during the past 5 years. Based on morphology, the lymphomas of five of these patients were classified as anaplastic large-cell lymphoma (ALCL); the lymphomas of four patients lacked the morphologic features of ALCL (non-ALCL); and the lymphoma of one patient was unclassifiable. Significant clinical and cytogenetic differences were observed between patients with ALCL and those with non-ALCL. The patients with ALCL tended to be young at the time of diagnosis. They presented with peripheral lymphadenopathy, and two of the five patients had skin involvement. An identical reciprocal translocation involving chromosomes 2 and 5 [t(2;5)(p23;q35)] was observed in lymph nodes from each of the two ALCL patients whose chromosomes were studied. Four of the five patients with ALCL are alive and in complete remission 10-27 months after receiving systemic chemotherapy. In contrast, the patients with non-ALCL were heterogeneous with respect to clinical findings. All of the non-ALCLs were histologically aggressive; however, their morphology varied. The t(2;5) was absent in the lymphoma specimens from each of three non-ALCL patients studied. Three of the four patients died within 17 months after receiving systemic chemotherapy. Thus, differences in morphology are correlated with differences in the clinical findings, karyotype, and outcome in Ki-1-positive NHL.
Antigens, CD↗
Long-term survival of patients with intermediate and high grade lymphoma treated with COMLA/ABP.
Between September 1983 and April 1985, 15 patients with previously untreated intermediate and high grade lymphoma were treated with COMLA/ABP (cyclophosphamide, vincristine, cytarabine, methotrexate, leucovorin, adriamycin, bleomycin, prednisone). There were nine males and six females; age ranged between 36 and 77 years (median, 58). Histologic diagnoses included five patients with diffuse large cell, six patients with immunoblastic, three patients with composite, and one patient with follicular large cell with diffuse areas. Following therapy, 10 patients (67%; 95% confidence interval (Cl), 43-91%) achieved a complete remission (CR) including five of six patients with immunoblastic; three patients (20%) had a partial remission, and two patients (14%) had no response. Toxicity was acceptable. After a minimum follow up of 4 years, there has been only one relapse which occurred 7 months after CR. The 4-year survival for all 15 patients is 65% (95% Cl, 40-89%). The COMLA/APB program produced a high rate of complete and durable remissions especially among patients with immunoblastic lymphoma.
Adult↗
Complex rearrangement of the T cell receptor in large granular lymphocytosis associated with myeloid suppression.
A patient is described with neutropenia associated with large granular lymphocyte proliferation, whose peripheral blood cells were analyzed with the beta chain gene probe of the T cell receptor (TCR). The pattern of rearrangement of the TCR was unusually complex, and apparently involved rearrangement of both J beta 1 loci with upstream V beta segments and of both J beta 2 loci with a downstream V beta by inversion. This case represents a unique pattern of rearrangement of the beta-chain of TCR. These results suggest caution in estimating the number of clones present in apparent oligoclonal proliferations.
Adolescent↗
Heterogeneity of O6-alkylguanine-DNA alkyltransferase activity in peripheral blood lymphocytes: relationship between this activity in lymphocytes and in lymphoblastoid lines from normal controls and from patients with Hodgkin's disease or non-Hodgkin's lymphoma.
We determined O6-alkylguanine-DNA alkyltransferase (AGT) activity in the peripheral blood lymphocytes (PBLs) of normal controls and patients with Hodgkin's disease or non-Hodgkin's lymphoma and compared these values with those of Epstein-Barr virus (EBV)-transformed cell lines prepared from the same PBL samples. PBLs have an AGT level characteristic of the individual from whom the cells were obtained. The AGT activity of lymphoblastoid cell lines obtained from a control group of PBLs was significantly correlated with the activity of the PBLs from which they were derived (r = 0.742). There was no significant correlation between PBLs and EBV-transformed lines derived from these PBLs in Hodgkin's disease/non-Hodgkin's lymphoma patients (r = 0.407, -0.225, and 0.270 for patients prior to, during, or after therapy, respectively). The lack of significant correlation between lines and PBLs was not due to random fluctuations in AGT activity, because multiple lines prepared from the same PBL sample were found to be highly correlated in AGT activity. In order to account for these results, we suppose that PBLs from a given individual are a heterogeneous population with respect to AGT activity. In normal individuals, the AGT activity of early passages of the multi-clonal EBV-transformed cell lines reflect the AGT activity of the PBLs from which they were derived. Malignancy and/or treatment with chemotherapeutic agents may selectively affect those lymphocytes which are targets for EBV-transformation so that the resultant cell line is no longer representative (with respect to AGT activity) of the total PBL population. Long-term culture of lymphoblastoid cell lines results in changes in AGT activity in some but not all cell lines suggesting that with time in culture, subsets with different AGT activities may be selected. There appears to be no growth advantage of low AGT activity and only rarely have we obtained lines with no measurable AGT activity, even after long periods in culture.
Cell Transformation, Viral↗