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Biomedical subjects

M S Tallman

Publications and source records attributed to M S Tallman.

At least 73 records · Page 4Linked to original sources
PubMed1996

High-dose chemotherapy for breast cancer.

The role of high-dose chemotherapy in the management of women with breast cancer remains one of the most controversial issues in oncology. During the past decade, numerous pilot studies have shown the feasibility of administering high-dose chemotherapy followed by autologous bone marrow transplantation or peripheral blood stem-cell transplantation (referred to as high-dose chemotherapy) to women with metastatic disease. However, it appears that survival improves in few treated patients. This treatment strategy is now being evaluated in the adjuvant setting in patients who are at high risk for developing recurrent disease. The National Cancer Institute has selected two randomized, adjuvant breast cancer trials for its High-Priority Clinical Trials Program. These trials are comparing conventional-dose chemotherapy with high-dose chemotherapy in patients in the early stages of breast cancer who are at high risk for disease recurrence. This paper focuses on the rationale for the randomized studies evaluating adjuvant high-dose chemotherapy in the early stages of breast cancer and reviews the efforts to overcome physician and patient biases so that the trials can be completed.

Antineoplastic Agents↗
PubMed1996

Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience.

Although 2-chlorodeoxyadenosine (2-CdA) is effective in inducing complete remissions (CRs) in the majority of patients with hairy cell leukemia (HCL), neither the actual relapse rate, the clinical factors that may predict relapse, the long-term outcome, nor the response rate to re-treatment at relapse has been clearly determined. Fifty-two consecutive patients with previously untreated or treated HCL were treated with 2-CdA at a dose of 0.1 mg/kg/d by continuous intravenous infusion for 7 days. Of 50 assessable patients, 40 (80%) achieved CR, and 9 (18%) achieved partial remission (PR). A total of 7 patients (14%) have relapsed, at a median duration of 24 months (range, 12 to 44). Of the 7 relapsed patients, 5 were re-treated with a second cycle of 2-CdA; 2 achieved a second CR and 3 attained a PR. The progression-free survival (PFS) rate is 72% at 4 years for all 52 patients and 83% for patients achieving CR. The overall survival (OS) rate is 86% at 4 years. Only prior therapy was predictive of relapse. The majority of patients achieve durable CRs with a single cycle of 2-CdA. The relapse rate is low and the long-term prognosis is excellent. The few patients who relapse can attain second remissions after re-treatment with 2-CdA.

Adult↗
PubMed1996

Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine.

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin-embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

Antibodies, Monoclonal↗
PubMed1996

Phase II trial of 2-chlorodeoxyadenosine for the treatment of cutaneous T-cell lymphoma.

We investigated the efficacy of 2-chlorodeoxyadenosine (2-CdA) therapy in patients with mycosis fungoides (MF) and the Sezary syndrome (SS). Between February 1991 and November 1993, 21 patients with relapsed or refractory MF/SS were treated with 2-CdA. 2-CdA was administered by continuous intravenous infusion at a dose of 0.1 mg/kg/d for 7 days initially (13 patients), but was subsequently reduced to 5 days (nine patients) due to hematologic toxicity. All patients had failed to respond to at least one prior treatment for MF/SS (median number of total prior therapies, five; median number of systemic prior therapies, three) and had an Eastern Cooperative Oncology Group performance status of two or better. Cycles were administered at 28-day intervals. Assessable patients received at least 5 days of 2-CdA. Fourteen patients received more than one cycle of 2-CdA. An overall response rate of 28% was achieved. Three patients (14%) had a complete response with a median duration of 4.5 months (range, 2.5 to 16). Three (14%) had a partial response with a median duration of 2 months (range, 2 to 4). Fifteen patients (72%) had no response. The most significant toxicities encountered were bone marrow suppression (62% of patients) and infectious complications (62% of patients). Thirty-eight percent of patients experienced no toxicity from 2-CdA. 2-CdA has activity as a single agent in patients with previously treated relapsed MF/SS. Studies in less heavily pretreated individuals with 2-CdA alone or in combination will be undertaken.

Adult↗
PubMed1996

Karyotype correlates with peripheral blood morphology and immunophenotype in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is recognized as a distinct entity. However, morphologic and immunophenotypic heterogeneity exist. Twenty-six patients with CLL were studied to investigate whether an association exists among peripheral blood karyotype, morphology and immunophenotype. Clonal cytogenetic abnormalities were detected in 14 patients (53%), using conventional karyotyping techniques in addition to fluorescence in situ hybridization (FISH) for chromosome 12. By FAB guidelines, 7 of the 8 patients (88%) with trisomy 12 had mixed cell morphology compared to only 3 of 18 (17%) without trisomy 12 (P = .004). One patient (12%) with trisomy 12 had lymphocyte morphology typical for CLL. Six of the eight (75%) with trisomy 12 had atypical immunophenotype including one or more of the following: strong CD20 expression, strong surface light chain expression, or absence of CD23 expression. Only 2 of the 18 patients (11%) without trisomy 12 had atypical immunophenotype (P = .005). None of the three patients with clonal structural abnormalities of chromosome 13q14 had mixed cell morphology or atypical immunophenotype. One of the 12 patients (8%) without clonal cytogenetic abnormalities had mixed cell morphology and one had atypical immunophenotype. This study suggests that a correlation exists among karyotype, morphology, and immunophenotype in CLL, and that CLL subgroups can be identified based on laboratory parameters. Although normal karyotypes or clonal structural abnormalities of 13q14 are associated with morphology and immunophenotype considered typical for CLL, trisomy 12 is associated with mixed cell morphology and atypical immunophenotype. These findings may have implications for evaluating variation in both disease course and response to emerging therapies.

Aged↗
PubMed1996

Differentiating therapy with all-trans retinoic acid in acute myeloid leukemia.

The standard treatment of patients with acute myeloid leukemia (AML) has depended on the elimination of the leukemic clone with cytotoxic myeloablation. Differentiation therapy is receiving increasing attention due to the remarkable activity of a vitamin A derivative, all-trans retinoic acid (ATRA), in patients with acute promyelocytic leukemia (APL). The majority of patients treated have achieved complete remission and with rapid resolution of the life-threatening bleeding diathesis. Phase II studies with ATRA in APL indicate certain limitations in the therapeutic use of retinoic acid. Patients achieving complete remission with ATRA alone require postremission chemotherapy, once remission is achieved, to extend remission. The results of differentiating therapy in APL patients has encouraged the use of differentiating therapy in patients with non-M3 AML. A number of areas await research, such as the need to develop ways to overcome acquired retinoic resistance and the development of cytochrome P450 inhibitors. Other novel retinoids, such as 9-cis-retinoic acid, may be even more effective than ATRA in APL. Additional important areas of research involve studying combinations of retinoids and other putative differentiating agents, and identifying different selected treatments targeted at specific molecular defects.

Antineoplastic Agents↗
PubMed1996

Differentiating therapy in acute myeloid leukemia.

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.

Acute Disease↗
PubMed1996

Differentiating therapy in acute myeloid leukemia.

Differentiating therapy is a new antineoplastic strategy which has received increasing attention due to the remarkable activity of the vitamin A derivative, all-trans retinoic acid (ATRA) in patients with acute promyelocytic leukemia (APL). Although it has been known for years that a variety of agents, including retinoids, could induce leukemic cells to differentiate in vitro, it was not until the initial report from Shanghai in 1988 that laboratory studies translated into clinical activity and benefit in patients. Since this initial report, a number of studies have confirmed that the majority of patients with both newly diagnosed and previously chemotherapy-treated patients with APL achieve complete remission (CR) with ATRA. In addition, the characteristic life-threatening coagulopathy resolves quickly. Several limitations to this approach have emerged, including the development of retinoid resistance, hyperleukocytosis and the retinoic acid syndrome, a constellation of findings including unexplained fever, fluid retention, pleuropericardial effusions and pulmonary infiltrates. Although ATRA is very effective in inducing CR, its benefits compared to conventional chemotherapy are only now being addressed. The first prospective randomized trial comparing ATRA plus chemotherapy to chemotherapy alone was terminated early because of an improved event-free survival for patients receiving ATRA. The benefit was attributable to a difference in relapse rate. A large, intergroup, prospective, randomized trial comparing conventional chemotherapy to ATRA for induction and ATRA to observation for maintenance has recently completed accrual and will provide insight into the emerging role of ATRA in patients with APL. ATRA represents the first example of a specific form of antileukemic therapy targeting a specific genetic abnormality and may serve as a paradigm for the development of differentiating therapy for patients with other hematologic malignancies.

Antineoplastic Agents↗
PubMed1995

Characterization of acute promyelocytic leukemia cases with PML-RAR alpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid.

Of 113 acute promyelocytic leukemia cases documented to have diagnostic PML-RAR alpha hybrid mRNA, 10 cases (8.8%) had fusion sites in PML gene exon 6 (V-forms) rather than in the two common hybrid mRNA configurations resulting from breaksites in either PML gene intron 6 (L-forms) or intron 3 (S-forms). In 4 V-form cases, a common break/fusion site was discovered at PML gene nucleotide (nt) 1685, abutting a 3' cryptic splice donor sequence. The fusion site was proximal to the common site in 1 case and more distal in 5 cases. The open reading frame encoding a PML-RAR alpha gene was consistently preserved, either by an in-frame fusion site or by the insertion of 3 to 127 unidentified nts. In 2 V-form cases, hybridization analysis of the reverse transcriptase-polymerase chain reaction products with a PML-RAR alpha juction probe was required for discrimination from L-form cases. Two V-form subgroups were defined by in vitro sensitivity to all-trans retinoic acid (tRA)-induced differentiation: 4 of 4 cases tested with fusion sites at or 5' to nt 1685 (subgroup E6S) had reduced sensitivity (EC50 > or = 10(-7) mol/L), whereas 4 of 4 cases with fusion sites at or 3' to nt 1709 (subgroup E6L) had high sensitivity (EC50 < 10(-8) mol/L) indistinguishable from that of L-form and S-form cases. These results provide the first link between PML-RAR alpha configuration and tRA sensitivity in vitro and support the importance of subclassifying APL cases according to PML-RAR alpha transcript type.

Adult↗
PubMed1995

Sequential changes in serum iron and ferritin in patients undergoing high-dose chemotherapy and radiation with autologous bone marrow transplantation: possible implications for treatment related toxicity.

In an effort to define the pattern of iron flux during high-dose chemotherapy or chemo/radiotherapy, we prospectively measured serum iron, iron binding capacity, and ferritin in patients undergoing autologous bone marrow transplantation for various malignancies. Sequential measurement of serum iron from days -7 to +12 was carried out in 88 evaluable patients, and simultaneous measurement of iron, ferritin, and total iron binding capacity was carried out in 32 patients. We found that there was a predictable rise in serum iron on day -2 or -3, and that this was accompanied by an increase in the saturation of transferrin. In addition, there was a similar increase in serum ferritin levels, which peaked by day +2. We suggest that the timing of this change in serum iron and saturation of transferrin may be important in mediating endothelial cell damage and, hence, organ toxicity in the setting of AuBMT. Based on these findings, we suggest that large clinical studies could be a source of patient samples to measure surrogate endpoints such as lipid peroxidation products (malondialdehyde or isoprostanes), or protein oxidation products following high-dose chemo/radiotherapy to determine the role of iron in cellular injury. It is possible that pharmacological manipulations to reduce free radical production or to chelate iron during the days prior to bone marrow reinfusion might help to reduce tissue injury in the setting of bone marrow transplantation.

Adolescent↗
PubMed1995

Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia.

PURPOSE: Cladribine (2-CdA), a purine analog resistant to adenosine deaminase, has significant activity in a variety of lymphoproliferative diseases. This study was designed to determine the efficacy of 2-CdA in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Twenty-six patients aged 40 to 88 years (median, 64) who either had relapsed after an initial response or were refractory to conventional chemotherapy with at least an alkylating agent were treated with 2-CdA 0.1 mg/kg/d by continuous intravenous infusion for either 5 or 7 days every 28 days for a maximum of six cycles. RESULTS: No complete remissions (CRs) occurred. Eight of 26 patients (31%) achieved a partial remission (PR). The actuarial median time to progression (TTF) in responding patients is 16 months (range, 6 to 22). The actuarial median survival duration of the responding patients is 12 months (range, 8 to 28). Eight of 26 patients (31%) sustained early toxicity. Seven of these eight patients died before the first reevaluation of infection (n = 3), pericardial tamponade (n = 1), Stevens-Johnson syndrome (n = 1), and stroke (n = 2). No nausea, emesis, alopecia, or renal, hepatic, or cardiac toxicity was observed. CONCLUSION: 2-CdA has activity in patients with relapsed or refractory CLL. However, patients who have received multiple prior regimens that included fludarabine are less likely to respond, and there can be significant morbidity. Treatment of patients with less prior therapy earlier in the natural history of the disease may lead to improved and more durable responses.

Actuarial Analysis↗
PubMed1995

Leukemogenic potential of adjuvant chemotherapy for early-stage breast cancer: the Eastern Cooperative Oncology Group experience.

PURPOSE: Since large numbers of patients with early-stage breast cancer now receive adjuvant chemotherapy containing cyclophosphamide, a known leukemogenic agent, it is important to determine the risk of secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Therefore, we identified all cases of AML or MDS developing in patients treated on six clinical adjuvant chemotherapy trials conducted by the Eastern Cooperative Oncology Group (ECOG). PATIENTS AND METHODS: The patients population included 2,638 patients with previously untreated primary operable breast cancer entered onto six clinical trials conducted by the ECOG between 1978 and 1987. There are 19,200 persons-years of follow-up study and a mean follow-up duration of 7.3 years. Clinical data were obtained from flow sheets submitted to the ECOG Data Management Office. RESULTS: Of 2,638 patients at risk with 19,200 person-years of follow-up study, three patients developed MDS (two with a characteristic cytogenetic abnormality). Two patients developed acute leukemia; however, one had adult T-cell leukemia associated with human T-lymphotrophic virus type 1 (HTLV-1) and a second patient developed AML after receiving additional cyclophosphamide for metastatic breast cancer. The estimated incidence rate for MDS is three per 19,200 or 16 per 100,000 person-years of follow-up study with a 95 percent confidence interval of three to 46 per 100,000 person-years. If all five patients (three MDS and two acute leukemia) are included, the estimated incidence rate is five per 19,200 or 26 per 100,000 person-years of follow-up study with a 95 percent confidence interval of eight to 61 per 100,000 person-years. CONCLUSION: These data suggest that the risk of secondary AML or MDS among patients with early breast cancer who receive standard-dose cyclophosphamide-containing adjuvant chemotherapy is not much higher than in the general population. However, physicians must remain alert to the possible long-term consequences of alkylating agent and anthracycline-based chemotherapy.

Acute Disease↗
PubMed1995

Developments in the treatment of acute leukemia in adults.

Since 1977, when it was first demonstrated that a small number of patients with refractory leukemia could be cured by bone marrow transplantation, there has been an international effort to increase the proportion of patients cured. This article reviews recent developments in the treatment of adult leukemia with particular emphasis on reports published during the past year. Several new preparative regimens for transplantation are discussed. New chemotherapeutic strategies reported during the past year have included modulating the activity of cytarabine, the most active agent in autologous myelogenous leukemia, using other agents such as etoposide, mitoxantrone, and carboplatin, and attempting to overcome the multidrug resistance phenomenon. There has been further experience in the use of autologous marrow for transplantation, with several centers reporting excellent results for patients so treated. Biologic-based strategies are an exciting area of exploration. The implications of the landmark discovery of all-trans retinoic acid as a treatment for acute promyelocytic leukemia continue to be investigated. Reports of the use of targeted monoclonal antibodies, cytokines, and other immunotherapies have generated the hope that these strategies might prove to be non-cross-resistant therapies and thus effective against residual disease following conventional chemotherapy.

Acute Disease↗