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Biomedical subjects

L E Robertson

Publications and source records attributed to L E Robertson.

At least 19 recordsLinked to original sources
PubMed2000

Fluorescence in situ hybridization identifies inversion 16 masked by t(10;16)(q24;q22), t(7;16)(q21;q22), and t(2;16)(q37;q22) in three cases of AML-M4Eo.

Bone marrow or peripheral blood from three patients had a t(10;16)(q24;q22), t(7;16) (q21;p13.1), and t(2;16)q37;q22), respectively. In all cases, fluorescence in situ hybridization confirmed an inv(16) masked by the translocation. The three patients were diagnosed with acute myelomonocytic leukemia and increased eosinophils. Because inv(16) has a favorable prognosis, identification of masked inv(16) will promote improved management of these cases. Therefore, all cases that have atypical rearrangement of chromosome 16 should be investigated for a possible inversion.

Adult↗
PubMed2000

Prediction of prognosis following fludarabine used as secondary therapy for chronic lymphocytic leukemia.

A prognostic factor analysis for survival and response was conducted on 374 previously treated patients who were treated with one of four fludarabine regimens. As several prognostic factors were associated with response and survival, multivariate analyses were conducted to identify the combination of factors which best describe the prognosis as regards response to fludarabine and survival. Statistical models to identify the hazard for survival and probability of response were developed. The characteristics which were included in the model predicting for survival were sex, age, number of prior treatments, performance status, hemoglobin level, serum albumin, and alkaline phosphatase levels. The characteristics most strongly associated with response were the hemoglobin levels, serum albumin, and the number of prior treatments. These models can be used to identify risk groups to guide physicians in decision-making and to assist in the design and analysis of clinical trials.

Adult↗
PubMed1999

Sequential cis-platinum and fludarabine with or without arabinosyl cytosine in patients failing prior fludarabine therapy for chronic lymphocytic leukemia: a phase II study.

Patients with chronic lymphocytic leukemia (CLL) who fail fludarabine (Fluda) therapy have a poor response to subsequent salvage regimens and a poor prognosis. This study was undertaken to determine the efficacy and toxicity of a cis-platinum, (cis-p)fluda and arabinosyl cytosine (ara-C) combination in patients who were refractory to fluda or had relapsed following prior fluda therapy for CLL. Forty-one patients who had progressive CLL were treated on study. Eleven patients (27%) were sensitive to fluda and thirty (73%) refractory prior to study entry. Therapy consisted of cis-p 100 mg/m2 continuous intravenous (i.v.) infusion over 4 days, fluda 30 mg/m2 i.v. over 15 minutes on Days 3 and 4 either given alone (PF) or with ara-C 500 mg/m2 i.v. over 1 hour on Day 4 (PFA). The median number of PF or PFA courses received was two. No patient achieved a complete response. Eight patients (19%) achieved a partial response (PR), 28 were taken off study with progressive or refractory disease and 5 had induction deaths. The overall median survival was 6 months, 15 months in responding patients, and 4 months in non-responding patients. Rai stage I-II patients had a median survival of 7 months and stage III-IV patients had a median survival of 3 months. Major toxicities (myelosuppression, sepsis, renal failure and tumor lysis syndrome) were frequent. In conclusion, it can be said that the PF and PFA regimens have equivalent modest activity in patients with progressive CLL following prior fluda therapy, predominantly among patients whose disease was sensitive to fluda at last prior exposure. Ara-C did not add to the activity of the cis-p/fluda combination in this study group.

Adult↗
PubMed1998

Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy.

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.

Adult↗
PubMed1998

Cellular pharmacodynamics and plasma pharmacokinetics of parenterally infused hydroxyurea during a phase I clinical trial in chronic myelogenous leukemia.

PURPOSE: To determine the maximum-tolerated dose (MTD), toxicities, and antileukemic activity of hydroxyurea (HU) administered intravenously to patients with advanced-phase chronic myelogenous leukemia (CML). Further objectives were to analyze pharmacodynamic effect on deoxynucleotides (dNTPs) and to seek relationships between the decrease in dNTP pools and inhibition of DNA synthesis in CML blasts. PATIENTS AND METHODS: HU (8, 12, 18, 27, and 40 g/m2) was administered intravenously by a 24-hour continuous infusion to 19 adults with CML in blastic or accelerated phase. Plasma levels of HU were analyzed in all patients. To determine the role of HU in inhibiting ribonucleotide reductase, dNTP pools in the leukemia cells were quantitated. Correlations were sought with these parameters and DNA synthesis inhibition measured ex vivo by [3H]thymidine incorporation. RESULTS: The MTD of HU given as a 24-hour infusion was 27 g/m2. The dose-limiting toxicity was mucositis. There was a significant but transient myelosuppression, with nadir counts generally seen 3 to 4 days after the dose. The steady-state concentration of HU in plasma was achieved by 6 hours, and was proportional to the dose. There was a median 57% decrease in the deoxyadenosine triphosphate (dATP) pool in circulating blasts. In contrast, deoxyguanosine triphosphate (dGTP) and pyrimidine dNTPs were not significantly affected. The extent of DNA synthesis inhibition was related to the residual concentrations of intracellular dATP. CONCLUSION: A 24-hour infusion of HU results in significant but transient myelosuppression in advanced-phase CML. The specific decrease of intracellular dATP correlated with the inhibition of DNA synthesis in CML blasts. This pharmacodynamic action of HU provides a rationale for combination with other chemotherapeutic agents, the effects of which could be augmented by the decline in dATP pools.

Adenosine Triphosphate↗
PubMed1997

2-Chlorodeoxyadenosine therapy for idiopathic hypereosinophilic syndrome.

Idiopathic hypereosinophilic syndrome (HES) is a rare disease with no established effective therapy. It has been reported that interleukin-5 (IL-5) produced by helper T cells plays a major role in the proliferation of eosinophils. The nucleotide analogue 2-chlorodeoxyadenosine (2-CdA), which induces excellent clinical responses in hairy cell leukemia, is known to suppress helper T cells; therefore, we used 2-CdA, alone or in combination with cytarabine, to treat patients with idiopathic HES. 2-CdA alone and combined with cytarabine resulted in a rapid and sustained decrease in circulating eosinophils in two patients with idiopathic HES that was refractory to steroids, hydroxyurea and cytarabine. The efficacy of 2-CdA alone and combined with cytarabine exceeded by far that of cytarabine alone. However, reverse transcription-polymerase chain reaction (RT-PCR) did not show production of IL-5 or granulocyte-macrophage colony-stimulating factor mRNA in T cells as previously reported, and multiple cytokine receptors were found on eosinophils in idiopathic HES, suggesting that IL-5 may not be the sole cytokine involved in the regulation of idiopathic HES. The clinical efficacy of 2-CdA in idiopathic HES needs to be established on a large group of patients.

Adult↗
PubMed1996

Natural killer cell activity in chronic lymphocytic leukemia patients treated with fludarabine.

Fludarabine, the 5'-monophosphate of 9-beta-D-arabinofuranosyl-2- fluoroadenine (FaraAMP), is effective in the treatment of chronic lymphocytic leukemia (CLL) and has been demonstrated to increase natural killer (NK) cell lytic activity (NKa) in humans and mice. To determine the effect of FaraAMP on NK cells in CLL, we analyzed NKa toward K562 targets after in vitro incubation with FaraAMP and after in vivo exposure to fludarabine. Pretreatment analysis of peripheral blood from 12 CLL patients (9 untreated) revealed: median number of NK cells 500/microliter (range 290-1160); median NKa lytic unit30/10(6) cells (range 5-80). These results were similar to those from healthy adult donors. After exposure to 3, 30 or 300 microM FaraAMP, the median maximum stimulation index (NKa FaraAMP/NKa) was 1.2 (range 0.9-1.5), within the range observed in normal adults. FaraA also stimulated NKa in vitro toward autologous CLL cells in two of five patients as measured by a dye-exclusion assay. In three patients following three or more treatment courses of fludarabine (30 mg/m2 per day for 5 days) the NK cell number and NKa were maintained near pretreatment values. Phenotypic analysis of the peripheral mononuclear cells in 34 consecutive CLL patients revealed a marked reduction in CD5/CD20 and CD4 cell numbers after three courses of fludarabine with less effect on CD8 and CD56 cells. These results indicate that fludarabine spares NK cells and may stimulate NKa in some CLL patients.

Adult↗
PubMed1996

Result of interferon-alpha therapy in patients with chronic myelogenous leukemia 60 years of age and older.

PURPOSE: To determine the response rate to interferon-alpha (IFN-alpha) in patients with chronic myelogenous leukemia (CML) aged 60 years and older. PATIENTS AND METHODS: Patients with CML aged 60 years and older included in all protocols with INF-alpha therapy for chronic phase CML at the M.D. Anderson Cancer Center were analyzed. They were treated with human leukocyte or recombinant human IFN-alpha 5x10(6) U/m2 daily alone or in combination with hydroxyurea or IFN gamma. The clinical characteristics of the patients were analyzed and their hematologic and cytogenetic responses to IFN-alpha and survival from the initiation of therapy were determined. Results were compared with those of younger patients treated in the same protocols. Treatment-related toxicity was also analyzed. RESULTS: Thirty-five of 274 (13%) patients included in trials of IFN-alpha-based regimens for CML were 60 years and older. Older patients had a higher percentage of bone marrow blasts (P = 0.04) and basophils (P = 0.09) than younger patients. Sixty-nine percent achieved a complete hematologic remission with IFN-alpha therapy, and 51% had a cytogenetic response, which was major in 26% and complete (Philadelphia chromosome-positive cells = 0%) in 20%, Their median survival was 64 months, and the estimated 5-year survival rate was 62%. These results were not different from those in younger patients. Twenty-two patients (63%) had at least grade 2 toxicity requiring dose adjustment. The most frequent side effects were neurotoxicity in 31% and chronic fatigue in 29%. CONCLUSIONS: Patients with CML 60 years of age and older respond well to IFN-alpha therapy, but experience more toxicity. This therapy should be considered for these patients if they are otherwise in good condition, with careful attention to IFN-alpha toxicity and its management.

Age Factors↗
PubMed1996

Hodgkin's disease variant of Richter's syndrome: experience at a single institution.

Patients developing Hodgkin's disease (HD) after a diagnosis of chronic lymphocytic leukemia (CLL), are frequently included in a series of patients with Richter's syndrome (RS). We sought to determine the natural history of the association of CLL and HD. Over a 21 year period, 1374 patients with CLL have been registered in our computer data base. Seven cases of CLL and HD have been documented and confirmed. The median age of these patients was 71 years (range 44-77) and clinical features included male gender (86%), B symptomatology (86%), rapidly progressive lymphadenopathy (71%), prior CLL therapy (71%), advanced Ann Arbor stage (86%), marrow involvement with HD (43%), and autoimmune hemolytic anemia (29%). HD was documented by excisional lymph node biopsy in six cases and splenectomy in one. Mixed cellularity HD was shown in six and nodular sclerosis in one. Five of the biopsies revealed intervening areas consistent with small lymphocytic lymphoma. The Sternberg-Reed (SR) cells were CD15+ in 6/7 cases, and Ki-1+ in the 6 patients tested. CD45 and CD20 staining of the SR cells was nonreactive. The median time to development of HD was 45 months (range 0 to 96). The overall responses to different chemotherapy regimens was approximately 25% with only one CR. Six patients have died at 3, 9, 10, 13, 15 and 36 months and one patient is alive with progressive disease at 11 months. Our data suggests that CLL patients have a heightened risk for HD, features of advanced HD on presentation, and a poor response rate with short survival.

Adult↗
PubMed1996

Bcl-2 expression in chronic lymphocytic leukemia and its correlation with the induction of apoptosis and clinical outcome.

Transcriptional deregulation of the Bcl-2 gene has been demonstrated to extend cell viability via an inhibition of apoptotic cell death. Chronic lymphocytic leukemia (CLL) cells are inherently susceptible to apoptosis during short-term culture. Because increased expression of the Bcl-2 gene has been reported in CLL, we sought to correlate Bcl-2 protein expression with the in vitro propensity towards apoptosis and also clinical outcome. Immunoblot analysis of Bcl-2 protein revealed interpatient variability with nine of 42 (21%) cases demonstrating similar or greater expression than a t(14;18) containing lymphoma cell line and 18 of 42 (43%) cases demonstrating a level of expression similar to or less than that seen in normal peripheral blood lymphocytes. Bcl-2 expression did not correlate with clinical features, or with apoptosis, as measured by an in vitro DNA fragmentation assay. However, analysis of survival in the 33 untreated patients revealed significant differences based on the level of Bcl-2 expression, with higher expression being an adverse feature (P<0.02). This data suggests that Bcl-2 is important in the pathogenesis and progression of CLL and that quantitation of Bcl-2 protein may provide useful prognostic information.

Apoptosis↗
PubMed1996

Acute lymphoblastic leukemia following preleukemic syndromes in adults.

Preleukemic syndromes (PLS) evolve to acute myeloid leukemia (AML) in 15-50% of cases, but rarely transform to acute lymphoblastic leukemia (ALL). AML following preleukemic syndromes has a poor prognosis, but little is reported about the outcome of secondary ALL. From the adult leukemia database at MD Anderson Cancer Center, nine patients with ALL following myelodysplastic syndrome (MDS) (n=6), smoldering leukemia (n=1), or cytopenias with dysplastic features (n=2) were identified. Clinical and laboratory features were abstracted from the database, patient charts, review of the bone marrows and special laboratory studies. The median interval from diagnosis of PLS to ALL was 6 months. Blasts with lymphoid morphology and terminal deoxynucleotidyltransferase (TdT) and periodic acid Schiff (PAS) staining were present in eight of nine cases and four of six cases respectively. T cell and myeloid markers were expressed in the majority of cases, but T cell gene rearrangements were not detected. Only one patient had electron microscopic myeloperoxidase-positive staining. Two patients later transformed to AML. Patients were predominantly male (89%) with a median age of 69 years. The complete remission (CR) rate with ALL-directed chemotherapy (78%) was comparable to that of other adult ALL patients (74%) (n=327) without excess myelosuppression. Marrow dysplasia persisted in CR in three of seven cases. The median remission duration of 16 months (range 4.5 to 51+ months) and the median overall survival of 21 months (range 1 to 55+ months) were comparable to that of ALL patients overall. ALL following preleukemic syndromes is a distinct syndrome with T cell and myeloid markers and responds well to ALL-directed therapy. The presence of myeloid and lymphoid markers suggests the transformation of an early stem cell.

Adult↗
PubMed1995

Homoharringtonine therapy induces responses in patients with chronic myelogenous leukemia in late chronic phase.

Homoharringtonine (HHT) is a plant alkaloid with potent myelosuppressive activity and little toxicity when used in a continuous infusion schedule. The antileukemic efficacy of HHT has been shown in acute myeloid leukemia, but has not been investigated in chronic myelogenous leukemia (CML). Seventy-one patients with Philadelphia chromosome-positive (Ph+) CML in late chronic phase (time from diagnosis to therapy longer than 12 months) were treated with a continuous infusion of HHT at a daily dose of 2.5 mg/m2 for 14 days for remission induction and for 7 days every month for maintenance. The median number of courses given was 6 (range, 1 to 35) and 21 patients (30%) continue on treatment. Forty-two of 58 patients (72%) evaluable for hematologic response achieved a complete hematologic remission, and 9 (16%) had a partial hematologic remission. Twenty-two of 71 patients (31%) developed a cytogenetic response; it was major (Ph+ cells less than 35%) in 11 (15%) and complete (Ph+ cells 0%) in 5 (7%). Significant myelosuppression occurred in 39% of induction courses and 9% of maintenance courses. Fever or documented infection was present in 26% of induction courses and in only 8% of maintenance courses. Nonmyelosuppressive toxicity was minimal. Homoharringtonine produced hematologic remissions in the majority of patients with advanced chronic-phase CML. Cytogenetic response occurred in some patients without an association with myelosuppression, and these responses may be prolonged. Future studies investigating homoharringtonine in combination with other active agents in CML, such as interferon, are warranted.

Adult↗
PubMed1995

Interferon maintenance therapy for patients with chronic lymphocytic leukemia in remission after fludarabine therapy.

Many patients with chronic lymphocytic leukemia (CLL) achieve remission after treatment with fludarabine chemotherapy. Most of these patients, however, later experience relapse. In addition, immunologic deficits may persist even in patients in complete remission; lymphopenia, predominantly involving the CD4 population, is universal after fludarabine therapy. We used recombinant alpha interferon (IFN-alpha) maintenance therapy in patients with CLL who achieved remission in response to fludarabine therapy to determine its effect on residual disease, assessed by either bone marrow biopsy or flow cytometry, and on immune restoration. Thirty-one patients were treated with IFN-alpha (3 x 10(6) U by subcutaneous injection three times weekly). Twenty-two patients (71%) were in complete remission (CR) and nine (29%) were in partial remission (PR). Of the 22 patients in CR, 21 (95%) had evidence of residual disease at the start of IFN-alpha therapy. Low CD4 levels were noted in 93% of patients, low IgG levels in 45%, and anergy or hypoergy in 52%. Only one patient in PR achieved a CR on IFN-alpha therapy: the only patient who had had no prior fludarabine but had been treated with chlorambucil and prednisone. All patients in CR with minimal residual disease had persistent disease after IFN-alpha treatment. There were no increases in CD4 counts or IgG levels; three patients with borderline responses to skin testing had an increase in the number of positive tests while on IFN-alpha. The time to progression was no different in patients treated with IFN-alpha than in a historical control group of patients who had received no further therapy after fludarabine. In summary, the use of IFN-alpha maintenance did not eradicate residual disease, restore immune function, or prolong remissions in patients with CLL responsive to fludarabine.

Adult↗
PubMed1995

Implications of apoptotic cell death regulation in cancer therapy.

The process of programmed cell death, or apoptosis, is now recognized as an important component of multistep carcinogenesis. Traditionally, interventions used in the treatment of cancer patients were predicated on enhanced rates of proliferation in the tumor cells. It is now appreciated that tumor growth may, in many circumstances, be more a function of reduced rates of cell death rather than enhanced proliferation per se. Our understanding of the molecular regulation of apoptotic cell death is leading to the design and implementation of treatment strategies based on cell death induction.

Animals↗
PubMed1995

Survival of young patients with chronic lymphocytic leukemia failing fludarabine therapy: a basis for the use of myeloablative therapies.

We examined the survival of 91 young patients (< or = 55 years) with chronic lymphocytic leukemia from the time of failure of fludarabine therapy, in an attempt to identify those with a poor outcome who may benefit from investigative dose-intensive therapies. The median survival of patients unresponsive to fludarabine (n = 42) was 48 weeks, and only 11% responded to subsequent therapies. The median survival of patients relapsing following a fludarabine-induced remission (n = 49) was 87 weeks, and 83% of those who had received fludarabine as their first therapy (n = 14) responded to further fludarabine-containing therapies, with 60% alive at four years. Only 7% of those relapsing patients who had received fludarabine as salvage therapy (n = 35) responded to subsequent therapies (median survival 72 weeks). The poor outlook for these patients justifies the consideration of innovative dose-intensive therapies, such as bone marrow transplantation, with their attendant risk of toxicity.

Adult↗
PubMed1995

Fludarabine plus doxorubicin in previously treated chronic lymphocytic leukemia.

Based on the activity of fludarabine and doxorubicin in chronic lymphocytic leukemia (CLL), 30 patients received this combination. The median age of these patients was 61 years; median Zubrod performance status was one; median number of prior therapies was three; and median time to treatment was 53 months. Rai stage was 0 for two patients, I/II for 19 patients, and III/IV for nine patients. Prior treatment included fludarabine in 25 patients. In this regimen, fludarabine was administered as 30 mg/m2/d IV x 3 to 10 patients, 25 mg/m2/d IV x 4 to three patients, and to 17 patients as 30 mg/m2/d IV x 4. A 50 mg/m2 IV dose of doxorubicin was given to all patients. The first 17 patients received prednisone 30 mg/m2 x 5 days; however, this was discontinued due to other data demonstrating no therapeutic advantage and increased opportunistic infections when corticosteroids were added to fludarabine. Toxicity consisted primarily of infectious episodes: pneumonia nine, bacteremia one, FUO seven, and minor infection five. Two deaths from pneumonia occurred. Standard guidelines for response were used with the addition of a nodular CR group. Despite prior treatment with fludarabine in the majority of patients, the response rate in the 29 evaluable patients was CR 3%, nodular CR 17%, PR 35%, fail 38% and early death 7%. This combination of fludarabine and doxorubicin is active against CLL and warrants further study.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1995

A 3-day schedule of fludarabine in previously treated chronic lymphocytic leukemia.

This study was undertaken to determine the efficacy and toxicity of a shorter schedule of fludarabine administration (30 mg/m2 i.v. daily for 3 days every 4 weeks) in patients with previously treated chronic lymphocytic leukemia (CLL). Eighty patients with previously treated advanced (Rai III-IV) (54%) or progressive Rai stage 0-II (46%) were treated. The results of this trial were retrospectively compared with those of previous fludarabine trials using different schedules of administration. The complete response (CR), nodular CR and partial response rates were 10, 15 and 21%. The overall response rate (46%) was slightly lower than prior regimens using a 5-day schedule of fludarabine; however, this difference was not significant. Further evaluation by dual-parameter flow cytometry and immunoglobulin gene rearrangement analysis revealed that minimal residual disease was more common in a 3-day schedule. The overall incidence of infections per treatment course (14%) was significantly lower than that observed on the 5-day or weekly regimens (P < 0.001). The incidence of minor, atypical and viral infections were similar. There was no difference in survival in the various trials. In conclusion, a 3-day schedule of fludarabine in previously treated CLL patients was associated with a lower infection rate and similar survival to a 5-day schedule. These data support the use of a 3-day schedule of fludarabine as a single agent and in combination with other active agents.

Adult↗