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Biomedical subjects

Jacob M Rowe

Publications and source records attributed to Jacob M Rowe.

At least 37 records · Page 2Linked to original sources
PubMed2005

Intensified induction chemotherapy in adult acute myeloid leukemia followed by high-dose chemotherapy and autologous peripheral blood stem cell transplantation: an Eastern Cooperative Oncology Group trial (E4995).

The feasibility of intensified therapy in adults < 61-years-old with de novo acute myeloid leukemia (AML) was evaluated by adding high-dose cytarabine (HDAC) to conventional induction therapy and in post-remission therapy prior to peripheral blood stem cell transplantation (PBSCT). Patients were treated with conventional induction therapy (daunorubicin days 1-3 and cytarabine days 1-7), followed by HDAC (2 gm/M2) every 12 h ( x 6) on days 8-10. Patients in complete remission (CR) with HLA-matched siblings were assigned to allogeneic PBSCT; the others received two courses of HDAC (3 gm/M2 every 12 h on days 1, 3, and 5) given 1 month apart. Peripheral blood stem cells were then harvested and infused after high-dose chemotherapy. Of 62 eligible, evaluable patients, 47 (76%) achieved CR. The mortality rate was 10% (6 patients); no deaths occurred during the two post-remission courses of HDAC. Fifteen patients were assigned to allogeneic PBSCT and 32 to autologous PBSCT. All surviving patients have been followed for more than 4 years. Including all patients scheduled to receive autoPBSCT in an intent-to-treat analysis, after a median 5-year follow-up the current, non-actuarial, four-year event-free and overall survival was 47% and 47%, respectively. Intensified induction therapy was associated with more toxicity than conventional induction therapy, and the CR rate did not improve. Nevertheless, intensive post-remission therapy was well tolerated, no treatment-related mortality occurred with autologous PBSCT, and disease-free survival and overall survival were lengthy.

Adolescent↗
PubMed2005

Prognostic factors in acute myeloid leukemia.

PURPOSE OF REVIEW: Cytogenetics offers the most important prognostic information at both presentation and relapse. However, this classification appears to be insufficient, especially for patients presenting with standard-risk cytogenetics, whose relapse risk is variable. Other prognostic factors, stratifying this heterogeneous group of patients into more clearly defined risk groups, are warranted. RECENT FINDINGS: Several molecular markers have been described that predict for long-term outcome in this heterogeneous group of patients; however, there is as yet no consensus as to the prognostic significance of each. Time to morphologic and molecular remission may also be important; however, further studies are warranted to establish their prognostic role in acute myeloid leukemia. SUMMARY: Much has been learnt over the past decade and a better understanding of disease biology, determined by gene expression profiling and proteomic analyses, may help to target therapy and improve the outcome.

Biomarkers, Tumor↗
PubMed2005

Hemostatic balance on the surface of leukemic cells: the role of tissue factor and urokinase plasminogen activator receptor.

BACKGROUND AND OBJECTIVES: The frequency of thrombotic complications is increased in patients with acute leukemia. Since coagulation processes take place on cell membranes, we hypothesized that expression of coagulation proteins on blast membrane could determine the hemostatic balance on the surface of leukemic cells and may correlate with thrombotic manifestations. DESIGN AND METHODS: Fifty-one consecutive patients with newly diagnosed acute leukemia were enrolled over an 11-month period. Twenty-five of the patients had acute myeloid leukemia (AML)-M(0-2), 11 had AML-M3, 6 had AML-M(4-5), and 9 acute lymphocytic leukemia (ALL). Peripheral blood and bone marrow were analyzed by flow-cytometry for tissue factor, protease-activated receptor 1, tissue factor pathway inhibitor, urokinase plasminogen activator receptor, and thrombomodulin. RESULTS: Regardless of the leukemia subtype, tissue factor was predominantly present on leukemic blast surfaces as compared to protease-activated receptor 1, tissue factor pathway inhibitor, urokinase plasminogen activator receptor and thrombomodulin and it was significantly elevated (mean 63+/-6%) in AML-M3 and AML-M(4-5) as compared to AML-M0(-2) and ALL (mean 37+/-4%, p<0.001). Likewise, urokinase plasminogen activator receptor expression was greater in AML-M(4-5) (49+/-11%) than in in AML- M(0-2), M3 and, ALL (mean 17+/-3%, p<0.001). Thrombotic manifestations were present in 13 out of 51 (26%) patients. The tissue factor to urokinase plasminogen activator receptor ratio was higher in patients with a thrombotic event than in patients without thrombotic events (16+/-4 vs. 6+/-2, p=0.042). INTERPRETATION AND CONCLUSIONS: This study demonstrates that tissue factor predominates on leukemic blast surface, particularly in M3 and M4-5 subtypes, while urokinase plasminogen activator receptor is increased on M4-5 blasts. The hemostatic balance on the blast surface may contribute to thrombotic manifestations in leukemic patients.

Adult↗
PubMed2004

A randomized trial of washed red blood cell and platelet transfusions in adult acute leukemia [ISRCTN76536440].

BACKGROUND: Platelet transfusion is universally employed in acute leukemia. Platelet concentrate supernatants contain high concentrations of biologic mediators that might impair immunity. We investigated whether washed platelet and red cell transfusions could improve clinical outcomes in adult patients with acute leukemia. METHODS: A pilot randomized trial of washed, leukoreduced ABO identical transfusions versus leukoreduced ABO identical transfusions was conducted in 43 adult patients with acute myeloid or lymphoid leukemia during 1991-94. Primary endpoints to be evaluated were platelet transfusion refractoriness, infectious and bleeding complications and overall survival. RESULTS: There were no significant differences in infectious or major bleeding complications and only one patient required HLA matched platelet transfusions. Minor bleeding was more frequent in the washed, leukoreduced arm of the study. Confirmed transfusion reactions were more frequent in the leukoreduced arm of the study. Overall survival was superior in the washed arm of the study (40% versus 22% at 5 years), but this difference was not statistically significant (p = 0.36). A planned subset analysis of those </=50 years of age found that those in the washed, leukoreduced arm (n = 12) had a 75% survival at five years compared with 30% in the leukoreduced arm (n = 10) (p = 0.037) CONCLUSION: This study provides the first evidence concerning the safety and efficacy of washed platelets, and also raises the possibility of improved survival. We speculate that transfusion of stored red cell and platelet supernatant may compromise treatment, particularly in younger patients with curable disease. Larger trials will be needed to assess this hypothesis.

Journal Article↗
PubMed2004

Activating FLT3 mutations in CD117/KIT(+) T-cell acute lymphoblastic leukemias.

Activating FLT3 mutations are the most common genetic aberrations in acute myeloid leukemia (AML), resulting in the constitutive activation of this receptor tyrosine kinase (RTK), but such mutations are rarely found in acute lymphoblastic leukemia (ALL). Here we describe a unique subset of de novo adult T-cell ALL (T-ALL) cases that coexpress CD117/KIT and cytoplasmic CD3 (CD117/KIT(+) ALL). Activating mutations in the FLT3 RTK gene were found in each of 3 CD117/KIT(+) cases that were analyzed, but not in 52 other adult T-ALL samples from the same series that lacked CD117/KIT expression. Our results indicate the need for clinical trials to test the efficacy of drugs that inhibit the FLT3 RTK in this subset of patients with T-ALL.

Amino Acid Sequence↗
PubMed2004

Mitoxantrone, etoposide, and cytarabine with or without valspodar in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome: a phase III trial (E2995).

PURPOSE: To determine whether adding the multidrug resistance gene-1 (MDR-1) modulator valspodar (PSC 833; Novartis Pharmaceuticals, Hanover, NJ) to chemotherapy provided clinical benefit to patients with poor-risk acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: A phase III randomized study was performed using valspodar plus mitoxantrone, etoposide, and cytarabine (PSC-MEC; n=66) versus MEC (n=63) to treat patients with relapsed or refractory AML and high-risk MDS. RESULTS: For the PSC-MEC versus MEC arms, complete response (CR) was achieved in 17% versus 25% of patients, respectively (P=not significant). For patients who had not received prior intensive chemotherapy (ie, with secondary AML or high-risk MDS), the CR rate was increased--35% versus 15% for the remaining patients (P=.018); CR rates did not differ between treatment arms. The median disease-free survival in those achieving CR was similar in the two arms (10 versus 9.3 months) as was the patients' overall survival (4.6 versus 5.4 months). The CR rates in MDR+ (69% of patients) versus MDR- patients were similar for those receiving either chemotherapy regimen (16% versus 24%). The CR rate for unfavorable cytogenetic patients (45% of patients) was 13% compared to the remainder, 28% (P=.09). Population pharmacokinetic analysis demonstrated that the clearances of mitoxantrone and etoposide were decreased by 59% and 50%, respectively, supporting the empiric dose reductions in the PSC-MEC arm designed in anticipation of drug interactions between valspodar and the chemotherapeutic agents. CONCLUSION: CR rates and overall survival were not improved by using PSC-MEC compared to MEC chemotherapy alone in patients with poor-risk AML or high-risk MDS.

Adolescent↗
PubMed2004

Acute monocytic leukemia (French-American-British classification M5) does not have a worse prognosis than other subtypes of acute myeloid leukemia: a report from the Eastern Cooperative Oncology Group.

PURPOSE: Acute monocytic leukemia is a distinct subtype of acute myeloid leukemia (AML) with characteristic biologic and clinical features. This study was designed to compare the outcome of patients with M5 to that of other subtypes of AML, and to identify differences in M5a and M5b. PATIENTS AND METHODS: We reviewed all patients with AML M5 entered in three clinical trials for newly diagnosed AML conducted by the Eastern Cooperative Oncology Group between 1989 and 1998. Eighty-one patients, 21 with M5a and 60 with M5b, were identified. RESULTS: The complete remission rate was 62% for all patients with M5; 52% for patients with M5a and 65% for patients with M5b (P =.3), and 60% for the 1122 patients with non-M5 AML entered on the same clinical trials (P =.8 for M5 v non-M5). The 3-year disease-free survival was 26% for all M5 patients; 18% for M5a and 28% for M5b (P =.31), and 33% for non-M5 patients (P =.13 for M5 v non-M5). The 3-year overall survival was 31% for all M5 patients; 33% for M5a and 30% for M5b (P =.65), and 30% for non-M5 (P =.74 for M5 v non-M5). The karyotypes of patients with AML M5 were heterogeneous. CD11b was the only leukemic cell antigen expressed differently in M5a (53%) compared to M5b (77%) to a significant degree (P =.02). CONCLUSION: AML M5 represents an immunologically heterogeneous population similar to non-M5 AML with a prognosis that is not dependent on morphology. The disease-free survival and overall survival of patients with M5a, M5b, and non-M5 appear not to differ with currently available therapy.

Adolescent↗
PubMed2004

Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia.

The activation of oncogenic transcription factors defines distinct molecular subsets of T-cell acute lymphoblastic leukaemia and has prognostic relevance in children. We investigated the prognostic effect of the expression levels of eight oncogenic transcription factors--TLX1 (HOX11), TLX3 (HOX11L2), TAL1, TAL2, LYL1, OLIG2 (BHLHB1), LMO1, and LMO2--in 52 adults with T-cell acute lymphoblastic leukaemia. The leukaemia-specific survival rate for the 16 TLX1-positive patients was 88% (90% CI 73-100%), compared with 56% (42-70%) for all other cases (p=0.019). Only the TLX1 oncogene expression subgroup showed difference in leukaemia-specific survival. Our results suggest that overexpression of TLX1 confers a good outlook for adults with T-cell acute lymphoblastic leukaemia. Furthermore, our findings lead to questions about whether stem-cell transplantation in first remission is necessary for effective treatment of patients in the low-risk subgroup of patients with TLX1 oncogene expression.

Adaptor Proteins, Signal Transducing↗
PubMed2004

Stem cell transplantation post invasive fungal infection is a feasible task.

Between March 1997 and January 2002, 18 consecutive patients (18-47 years) with hematological malignancies and previous proven invasive fungal infection underwent stem cell transplantation (SCT) (10 matched sibling allograft, 6 autograft, and 2 haploidentical). All patients had full myeloablative conditioning. The fungal pathogens diagnosed were Aspergillus (14), Fusarium (2), Mucor (1), Exserohilum (1), and Candida (1), involving the lungs (15), sinuses (5), and liver (1). All patients were treated pre- and during transplant with systemic antifungal therapy. Eleven out of 18 (61%) patients survived the transplant. Only 1 of 5 patients who transplanted with an active fungal infection accompanied with active leukemia survived the transplant, compared with 10/13 (84%) survivals in patients who had no clinical and radiological signs of infection or active leukemia (P < 0.025). None of the autografted patients has died, compared with 7/12 allografted patients, of whom 5 underwent transplant with active hematological/active fungal disease. In only 3 patients was the cause of death reactivation of previous fungal infection. Both active fungal infection and active leukemia place patients at a very high risk for procedure-related mortality. Pre-transplant therapy of fungal infection, aiming to achieve a clinically undetectable state of infection, followed by an antifungal treatment during transplant may allow the SCT with no fungal reactivation in selected patients.

Adult↗
PubMed2004

Current indications for reduced-intensity allogeneic stem cell transplantation.

Stem cell transplantation preceded by reduced-intensity conditioning (RIC) is based on the use of immunosuppressive agents as the sine qua non to ensure donor cell engraftment. It is a curative option for select patients suffering from haematological and non-haematological malignancies. The most beneficial results are observed when a full donor engraftment is achieved with 'tolerable' graft-vs-host disease (GVHD). To date, a vast amount of clinical data has been published, but in an uncontrolled manner. This review summarizes the currently known outcome of allogeneic transplants with RIC, with every disease category analysed separately. Unresolved problems include the optimal combination of immunosuppressive agents, the degree of infectious complications, and GVHD that may appear in some patients. Directions to overcome these complications are discussed. Despite the paucity of controlled clinical data, the current indications for RIC allogeneic transplantation are summarized based on the best-available phase II data.

Hematologic Neoplasms↗
PubMed2004

Modified VAD and PSC-833 in the treatment of resistant or relapsing chronic lymphocytic leukemia (E4996): a trial of the Eastern Cooperative Oncology Group.

BACKGROUND & METHOD: The role of multidrug resistance (MDR) was investigated in patients with relapsed chronic lymphocytic leukemia (CLL). PSC-833 was added to modified VAD (a 4-day infusion of vincristine, doxorubicin, with oral dexamethasone, every 3 weeks), in an attempt to improve the response rate (21%) in a prior study. Laboratory tests to determine MDR and apoptosis proteins were correlated with response. RESULTS: Two of the seven MDR-positive cases and one of the four MDR-negative patients achieved a partial response (no significant difference). No significant correlation with response was found in any of the laboratory tests for apoptosis. CONCLUSION: VAD plus PSC-833 had the same (21%) partial response rate as a prior ECOG study without PSC-833. No correlation of response with MDR or apoptosis testing was found. Other drug resistance factors must play a significant role in determining the response of relapsed patients with CLL.

Aged↗
PubMed2004

The relationship of patient age to the pathobiology of the clonal myeloid diseases.

The incidence of the major clonal myeloid diseases, clonal cytopenias, acute, subacute (oligoblastic), and chronic myelogenous leukemia, polycythemia vera, thrombocythemia, and idiopathic myelofibrosis increases in a log-linear manner from young adulthood through advanced age. In older patients, diseases requiring cytotoxic treatment are more difficult and less successful to manage because comorbid conditions and poor performance status are more prevalent, decreasing the tolerance to therapy and increasing the frequency of side effects. This age effect is highlighted by the dramatically less favorable outcome in older than younger patients with acute myeloid leukemia with similar "favorable" cytogenetic changes. In addition, in acute and subacute myeloid leukemia in older patients, the disease is intrinsically more resistant to therapy. Overexpression of drug resistance genes and unfavorable genetic mutations are more prevalent in older patients and provide evidence that acute myeloid leukemia is often qualitatively different in these patients. The gradient of age effects is continuous; the frequency of poor outcome increasing by decade (or less). The decline in survival becomes especially steep as quinquagenarians (50-year-olds) age to nonagenarians (90-year-olds). Although improved drug schedules have led to significant improvements in event-free survival in younger patients, these improvements have been far less evident in older patients. New approaches, especially the development of drugs aimed at new targets, will be required to obtain a high frequency of long-term remissions in older patients. Agents that reverse inherent cellular drug resistance, farnesyltransferase inhibitors, BCL-2 inhibitors, and FLT3 inhibitors are early examples of such approaches.

Aged↗
PubMed2004

A simple approximation for busulfan dose adjustment in adult patients undergoing bone marrow transplantation.

Busulfan is an alkylating agent used in preparative regimens before bone marrow transplantation (BMT). Busulfan concentrations in plasma, expressed as the area under the concentration-time curve (AUC), were reported to correlate with treatment outcome. Because busulfan is administered in 16 doses of 1 mg/kg every 6 hours for 4 days, the opportunities to "correct" the dose as a consequence of the measured AUC are limited to the 16-dosage protocol. In the present research busulfan pharmacokinetics were prospectively evaluated in 27 adult patients treated according to the above protocol by measuring the first, second, and fifth dose AUC. The pharmacokinetic analysis was based on a noncompartment model for extravascular absorption, but calculations according to a 1-compartment model gave similar results. A simple mathematical approximation allowed prediction of the AUC of the second dose from that of the first and the busulfan concentration at trough. Fifteen patients had the dose adjusted at the fourth dose to obtain an AUC within the "therapeutic window" of 950-1500 microM-min. This procedure was then validated by the measurement of the fifth dose AUC. It appears that this simple pocket calculator method allows a rapid evaluation of the need and the extent of dose adjustment and proved to be a valuable tool to improve busulfan administration in pre BMT treatment.

Adolescent↗
PubMed2003

A phase 3 study of three induction regimens and of priming with GM-CSF in older adults with acute myeloid leukemia: a trial by the Eastern Cooperative Oncology Group.

The optimal induction for older adults with acute myeloid leukemia (AML) is unknown. Several anthracyclines have been proposed, but the data remain equivocal. Additionally, few prospective trials of priming with hematopoietic growth factors to cycle leukemia cells prior to induction chemotherapy have been conducted. Three hundred and sixty-two older adults with previously untreated AML were randomized to either daunorubicin, idarubicin or mitoxantrone with a standard dose of cytarabine as induction therapy. In addition, 245 patients were also randomized to receive granulocyte-macrophage colony-stimulating factor (GM-CSF) or placebo beginning 2 days prior to induction chemotherapy and continuing until marrow aplasia. No difference was observed in the disease-free overall survival or in toxicity among patients receiving any of the 3 induction regimens or among those receiving growth factor or placebo for priming. However, the complete remission rate for the first 113 analyzable patients, who did not participate in the priming study and started induction therapy 3 to 5 days earlier than those who did, was significantly higher (50% versus 38%; P =.03). None of the anthracyclines is associated with improved outcome in older adults. Priming with hematopoietic growth factor did not improve response when compared with placebo. Furthermore, delaying induction therapy in older adults may lead to a lower complete remission rate.

Aged↗
PubMed2003

Long-term follow-up and potential for cure in acute promyelocytic leukaemia.

Acute promyelocytic leukaemia (APL) may be characterized simultaneously as the most potentially rapidly fatal human acute leukaemia if untreated, yet the most frequently cured acute leukaemia if promptly diagnosed and treated without delay. Co-operative group and single-institution studies which include large numbers of patients with relatively long follow-up demonstrate that, with all-trans retinoic acid (ATRA) plus anthracycline-based chemotherapy, the majority of newly-diagnosed patients appear cured of their disease. The 5-year disease-free survival rates range from 75 to 85%. Early death is still observed in approximately 10% of patients and remains a difficult obstacle to increasing the cure rate. Prognostic factors which identify patients at high risk for recurrence are becoming increasingly recognized. Older age (over age 55-60 years), elevated white blood cell count at presentation (higher than 5,000-10,000/microl), and expression of CD56 unfavourably influence outcome. The treatment of such patients remains a challenge, although it is important to note that APL is the only type of AML in which a significant proportion of older patients may be cured. Because more patients are cured of their disease, potential long-term consequences may become increasingly recognized. These include the emergence of extramedullary disease, the development of secondary myelodysplasia or acute myeloid leukaemia and the potential for late-onset cardiac toxicity.

Antineoplastic Agents↗
PubMed2003

Granulocyte colony-stimulating factor administration upregulates telomerase activity in CD34+ haematopoietic cells and may prevent telomere attrition after chemotherapy.

Hematopoietic reconstitution could be associated with premature ageing of the transplanted cells and a high frequency of myelodysplastic syndrome and secondary leukaemia. Telomere length decreases with cell divisions and age, and at a crucial length it is associated with chromosomal instability and cell senescence. Telomerase is a reverse transcriptase enzyme that adds nucleotides to chromosomal ends. Most somatic cells lack telomerase activity yet haematopoietic stem cells retain low levels of telomerase. Some studies have found that chemotherapy and stem cell transplantation lead to the accelerated shortening of telomere length. As granulocyte colony-stimulating factor (G-CSF) is routinely used in the mobilization of stem cells for transplantation, we evaluated its effects on telomerase activity and regulation, and on telomere dynamics, in normal donors and selected lymphoma patients. Administration of G-CSF increased telomerase activity in CD34+ haematopoietic cells compared with controls. In marrow-derived CD34+ cells, telomerase activity increased sevenfold, compared with a 14-fold increase in peripheral-blood-mobilized CD34+ cells. A parallel increase in the expression of human telomerase enzyme reverse transcriptase RNA and protein kinase C alpha occurred. In addition, G-CSF administration to five lymphoma patients after consecutive courses of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, resulted in telomere length preservation or elongation, as opposed to marked attrition in patients who did not receive growth factors. We conclude that the in vivo administration of G-CSF prevents or attenuates telomere attrition associated with chemotherapy administration. This attenuation may contribute to the preservation of telomere integrity inG-CSF-primed transplanted stem cells.

Aged↗
PubMed2003

Acute lymphocytic leukemia: role of hematopoietic stem cell transplantation in current management.

PURPOSE OF REVIEW: It is still unclear what the best postremission therapy is for young adults with acute lymphocytic leukemia (ALL). Encouraging results, supporting the superiority of allogeneic stem cell transplantation in CR1 compared with chemotherapy/ allogeneic stem cell transplantation (ASCT), are coming from the ongoing international prospective MRC UKALL XII /ECOG 2993 study. However, the transplant-related morbidity and mortality remain high. RECENT FINDINGS: The detection of persistent minimal residual disease (MRD) after induction and consolidation therapy is being increasingly used to identify high-risk patients for whom allogeneic transplant may offer the only curative option. SUMMARY: The ultimate aim is to determine whether the absence of MRD pretransplant can be used as a surrogate for low-risk adult ALL that can be cured without allogeneic transplantation.

Disease Management↗