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Biomedical subjects

David Marin

Publications and source records attributed to David Marin.

At least 19 recordsLinked to original sources
PubMed2006

Imatinib preceding allogeneic stem cell transplantation in chronic myeloid leukemia.

In 37 adults with chronic myeloid leukemia undergoing allogeneic stem cell transplantation imatinib prior to transplant had no discernible negative impact on 100-day mortality (13%) and severe acute (22%) or extensive chronic graft-versus- host disease (31%). After a median of 203 days (range: 18-1419) overall and progression-free survival rates are 62% and 54%, respectively.

Acute Disease↗
PubMed2006

Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy.

We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further.

Adult↗
PubMed2005

Phase I/II trial of adding semisynthetic homoharringtonine in chronic myeloid leukemia patients who have achieved partial or complete cytogenetic response on imatinib.

BACKGROUND: A Phase I/II study was designed to show whether the addition of semisynthetic homoharringtonine (sHHT) would reduce the level of residual disease in patients with Ph-positive chronic myeloid leukemia who appeared to have achieved a suboptimal response to imatinib alone. METHODS: Patients with CML who had achieved >/= 35% Ph-negativity on imatinib were included. All patients had been treated with imatinib at >/= 400 mg/day for at least 2 years and had achieved a plateau in BCR-ABL transcripts defined by measuring BCR-ABL transcripts on at least 4 occasions over a minimum period of 1 year with the latest value not lower than the previous minimum value. Initially sHHT was given subcutaneously at a dose of 1.25 mg/m(2) twice daily for 1 day. Courses were repeated every 28 days. The dosage of sHHT was escalated by adding one day of treatment every two days. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts. RESULTS: Of 10 evaluable patients, 7 had an appreciable decline in BCR-ABL transcript levels; in 5 cases the reduction was greater than 1 log. Asthenia (n = 10) and cytopenias (n = 3) were prominent side-effects, but the drug was generally well tolerated. Mutations in the P-loop of the BCR-ABL kinase domain were found in 2 of the patients who responded to the addition of sHHT. CONCLUSIONS: The addition of sHHT should be considered for patients on imatinib who fail to obtain low levels of minimal residual disease.

Adult↗
PubMed2005

Cyclic AMP affects the haemocyte responses of larval Galleria mellonella to selected antigens.

Signal transduction of the innate immediate responses of insect haemocytes to foreign matter is rarely considered. Herein using a combination of adenylate cyclase inhibitors and activators and phosphodiesterase inhibitors we determined that cyclic adenosine monophosphate (cAMP) at high levels normally impairs non-self response. Haemocyte contact with glass and bacteria lowered cAMP in vitro. Inactive phosphodiesterases, including type 4, impaired haemocyte reactions in vitro. Using the drugs in vivo to modulate adenylate cyclase and phosphodiesterases altered the total and types of haemocytes. Adenylate cyclase inhibitors and etazolate (a type 4 phosphodiesterase inhibitor) alone produced changes in the haemograms similar to those caused by Bacillus subtilis. Sequential injections of an enzyme modulator followed by B. subtilis impaired bacterial removal due (1) in the case of enzyme inhibitors, to the removal of haemocytes prior to bacterial challenge and (2) in the case of forskolin and IBMX to the shut-down of the haemocytes. Activating adenylate cyclase or inhibiting phosphodiesterase impaired bacterial removal when co-injecting the compounds and bacteria.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2005

Personalized medical treatment strategies for patients with chronic myeloid leukemia.

Management of patients with chronic myeloid leukemia has become increasingly difficult over the last few years since there are a variety of treatment options available. The ultimate challenge is to decide the most appropriate treatment strategy for an individual patient. To facilitate this, assessment of an individual patient's disease in terms of status, tempo and response to initial treatment needs to be determined. This review article discusses the current treatment options in the management of chronic myeloid leukemia, the factors that influence management decisions and suggests how treatment for the individual patient may be tailored whilst involving the patient in the decision-making process.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Survival of patients with chronic-phase chronic myeloid leukaemia on imatinib after failure on interferon alfa.

Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09-2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis.

Antineoplastic Agents↗
PubMed2003

Clinical heterogeneity in chronic myeloid leukaemia reflecting biological diversity in normal persons.

The molecular basis of chronic myeloid leukaemia (CML) is well defined and highly consistent, yet prognosis varies considerably. This could reflect the biological diversity occurring in normal populations. We used a colony replating assay to measure the proliferative capacity of progenitor cells from 211 CML patients and 86 normal persons. Results were expressed as the frequency distributions of the proliferation index (PI) for individual cases. Normal PI values varied among individuals but were reproducible in individuals. The PIs for CML patients were moderately but significantly greater (P = 0.004) than normal values, consistent with increased progenitor cell proliferation in CML. Exposure of CML progenitor cells to the Abl-kinase inhibitor imatinib shifted their PI towards the normal range, implicating p210BCR-ABL. as a cause of the increased PI. The PIs of CML patients were higher than those of their human leucocyte antigen (HLA)-matched siblings PI (P = 0.003) and patient PI increased exponentially with sibling PI (r = 0.77; P = 0.001), but not with the PI values of HLA-matched unrelated individuals (P = 0.66). Finally, patients with high-risk prognostic scores (according to the Sokal or Hasford systems) had a significantly higher PI than those with low risk scores (P = 0.01 and 0.03 respectively). We conclude that heterogeneity in the CML patient population is analogous to the constitutional diversity in normal subjects.

Adult↗
PubMed2003

Mobilization of Ph chromosome-negative peripheral blood stem cells in chronic myeloid leukaemia patients with imatinib mesylate-induced complete cytogenetic remission.

Imatinib mesylate (IM, STI 571, Glivec) can induce a high rate of complete cytogenetic response (CCR) in chronic myeloid leukaemia (CML) patients, although to date the majority of patients continue to have detectable disease by sensitive reverse transcription polymerase chain reaction (RT-PCR). It is therefore possible that these patients may ultimately relapse and require treatment such as autologous peripheral blood stem cell transplant (APBSCT). We attempted mobilization of haemopoietic progenitor cells from 58 patients in CCR using recombinant human granulocyte colony-stimulating factor [rHu-G-CSF; 10 micro g/kg/d subcutaneously (s.c.) for at least 4 d] alone, while continuing IM treatment. The median d 5 (peak) CD34+ count was 11.5/ microl (range 0-108/ microl), and 43/58 (74%) patients underwent a median of two (range 1-3) apheresis procedures. A median dose of 2.1 x 10(6)/kg CD34+ cells (range 0.1-6.5 x 10(6)/kg) was collected. Some 84% of 31 collections analysed were negative for the Philadelphia (Ph) chromosome or breakpoint cluster region and Abelson murine leukaemia viral oncogene homologue (BCR-ABL) translocation by cytogenetics or fluorescent in situ hybridization respectively. No toxicity was reported with the regimen. Overall, the target CD34+ dose (2 x 10(6)/kg CD34+) was attained in 23/58 (40%) patients who entered the study. In summary, we have demonstrated that successful mobilization of Ph- CD34+ cells from IM-treated patients in CCR is possible using rHu-G-CSF alone.

Adult↗
PubMed2003

Management decisions in chronic myeloid leukemia.

Until recently, interferon-alfa or interferon plus cytarabine was considered the best initial treatment for newly diagnosed chronic myeloid leukemia (CML) patients not eligible for allogeneic stem cell transplantation. The remarkably rapid and apparently durable control of hematologic features and the high rate of cytogenetic response achieved with imatinib used as a single agent suggest that this drug could prolong life substantially. However, response to the drug is variable between patients and here criteria are tentatively suggested for defining response and nonresponse or response failure. It is likely that patients who fail to respond to imatinib may benefit from alternative therapy initiated as early as possible. The issue of whether to offer allogeneic stem cell transplant to any newly diagnosed patient is addressed and a possible strategy is suggested. Undoubtedly, the suggestions made here will require revision as we acquire further information on the utility of imatinib.

Antineoplastic Agents↗
PubMed2003

Clinical decisions for chronic myeloid leukemia in the imatinib era.

Imatinib is clearly an important contribution to the management of patients with chronic myeloid leukemia (CML). Based on the available data, it seems reasonable to conclude that this exciting new agent is the best primary treatment for the newly diagnosed chronic-phase patient who is not immediately eligible for allogeneic stem cell transplant (allo-SCT). However, the definition of response or failure to respond is not straightforward and the extent to which imatinib prolongs life when used as a single agent cannot yet be estimated with any accuracy. This means that decisions on how best to continue treatment can be extremely difficult. Moreover, the decision whether and when to offer the patient treatment by allo-SCT has become especially complicated in the last 2 years. Imatinib seems to be generally less effective when used to treat patients in advanced phases of CML, although some patients treated in accelerated phase may achieve prolonged disease control. It is likely that the role of imatinib, used alone or in combination with other agents, will be more clearly defined in the near future.

Benzamides↗
PubMed2003

Allelopathy as a new strategy for sustainable ecosystems development.

Natural products involved in plant-plant and plant-microorganism ecological interaction (Allelochemicals) are an important potential source for alternative agrochemicals and pharmaceuticals, in order to solve the many problems derived from inadequate culture practices and abuse of synthetic herbicides. Isolation, structural determination, bioassay techniques and applicability for these compounds in crop protection and pharmaceutical research are discussed, and future trends on Allelochemicals applications are examined. The new strategies for sustainable ecosystems controlled by allelochemicals offer a particular interest for the development of human bases in space, since these products can stimulate or inhibit plant germination and growth, and permit to develop crops with low residue amounts in water, facilitating wastewater treatment and recycling.

Agriculture↗
PubMed2003

Chronic myeloid leukemia in chronic phase responding to imatinib: the occurrence of additional cytogenetic abnormalities predicts disease progression.

BACKGROUND AND OBJECTIVES: The acquisition of additional cytogenetic changes (clonal evolution, CE) during treatment of chronic myeloid leukemia (CML) with imatinib mesylate is currently regarded as an index of increasing resistance to imatinib. Therefore, to investigate whether CE as an isolated event increases the risk of disease progression during imatinib treatment, we compared the outcome of patients with CML in chronic phase (CML-CP) who developed CE whilst in complete hematologic remission with the outcome of comparable patients in complete hematologic remission who showed no evidence of CE. DESIGN AND METHODS: We serially studied cytogenetic findings in 102 patients receiving the Abl-tyrosine kinase inhibitor, imatinib mesylate, as sole agent to treat CML-CP who had no evidence of CE before initiation of imatinib treatment. RESULTS: CE was identified during treatment with imatinib in 15 patients, 10 of whom were in complete hematologic remission. In most cases these changes occurred exclusively in the Ph+ population but in three patients additional changes occurred in a co-existing Ph-negative population. Patients with de novo CE in the absence of any other sign of disease progression had a significantly higher incidence of progression by 18 months than did non-CE patients (progression-free survival 34.3% (CI 10.5-69.8%) vs. 94.1% (CI 80.6-98.4%), p<0.0001). INTERPRETATION AND CONCLUSIONS: Based on this relatively small series of patients, we conclude that acquisition of clonal evolution increases the risk of subsequent disease progression also in CML patients in complete hematologic remission on imatinib.

Adolescent↗
PubMed2002

Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta.

BACKGROUND: A small proportion of patients with chronic myeloproliferative diseases have constitutive activation of the gene for platelet-derived growth factor receptor beta (PDGFRB), which encodes a receptor tyrosine kinase. The gene is located on chromosome 5q33, and the activation is usually caused by a t(5;12)(q33;p13) translocation associated with an ETV6-PDGFRB fusion gene. The tyrosine kinase inhibitor imatinib mesylate specifically inhibits ABL, PDGFR, and KIT kinases and has impressive clinical efficacy in BCR-ABL-positive chronic myeloid leukemia. METHODS: We treated four patients who had chronic myeloproliferative diseases and chromosomal translocations involving 5q33 with imatinib mesylate (400 mg daily). Three of the four patients presented with leukocytosis and eosinophilia; their leukemia cells carried the ETV6-PDGFRB fusion gene. The fourth patient had leukocytosis, eosinophilia, and a t(5;12) translocation involving PDGFRB and an unknown partner gene; he also had extensive raised, ulcerated skin lesions that had been present for a long time. RESULTS: In all four patients, a normal blood count was achieved within four weeks after treatment began. In the patient with skin disease, the lesions began to resolve shortly after treatment began. The t(5;12) translocation was undetectable by 12 weeks in three patients and by 36 weeks in the fourth patient. In the three patients with the ETV6-PDGFRB fusion gene, the transcript level decreased, and in one patient, it became undetectable by 36 weeks. All responses were durable at 9 to 12 months of follow-up. CONCLUSIONS: Imatinib mesylate induces durable responses in patients with chronic myeloproliferative diseases associated with activation of PDGFRB.

Adult↗