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Biomedical subjects

Jane F Apperley

Publications and source records attributed to Jane F Apperley.

At least 37 records · Page 2Linked to original sources
PubMed2004

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS).

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein-1alpha (MIP-1alpha), markers of bone resorption [N-telopeptide of collagen type-I (NTX), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)] and bone formation [bone-alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender- and age-matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0.0001). Furthermore, TRACP-5b, MIP-1alpha and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0.001), while OPG and bALP were increased (P < 0.001). Serum levels of MIP-1alpha, as well as TRACP-5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP-1alpha, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.

Adult↗
PubMed2004

Post-transplantation tumour load in bone marrow, as assessed by quantitative ASO-PCR, is a prognostic parameter in multiple myeloma.

High-dose therapy (HDT) and autologous transplantation prolongs remission duration and survival in multiple myeloma (MM), but relapse still occurs at a median of 2 years post-HDT. In order to investigate whether the number of residual tumour cells in the bone marrow (BM) after transplantation can predict the duration of response, a quantitative allele-specific oligonucleotide polymerase chain reaction (qASO-PCR) assay was used to measure tumour load in BM at 3-6 months post-HDT in 67 patients. The method of maximally selected log-rank statistics was used to test for the existence of a cut-off value in the BM tumour load data set. A cut-off value with respect to progression-free survival (PFS) was identified (P = 0.001). The estimated threshold for placing patients into a "good" or "bad" prognostic group was 0.015% (n = 22 and 38 respectively) with a median PFS of 64 months vs. 16. Multivariate analysis showed grouping by PCR result to be an independent prognostic factor for PFS (estimated hazard ratio after shrinkage, 3.91). This study identifies for the first time a threshold of the post-HDT tumour load with prognostic significance for PFS in MM. Quantitative molecular assessment thus may help to identify those patients who are in need of further treatment early after autologous transplantation.

Adult↗
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

Influence of extracorporeal photopheresis on clinical and laboratory parameters in chronic graft-versus-host disease and analysis of predictors of response.

We report 28 patients with advanced chronic graft-versus-host disease (cGVHD) treated with extracorporeal photopheresis (ECP). All had failed conventional immunosuppressive therapy. Of the patients, 27 had extensive cGVHD and 20 had more than 50% cutaneous surface area involvement. ECP was initiated approximately 2 years after onset of cGVHD and 3 years following allogeneic stem cell transplantation and administered fortnightly for 4 months and then monthly. Response was assessed using quantifiable disease measures, including skin score, liver function tests (LFTs), blood counts, and lung function tests. Regression analysis allowed assessment of any pretreatment clinical or laboratory parameters that predicted response. There were 25 patients who completed 3 months and 21 who completed 6 months of treatment. Systemic immunosuppression was stable or reduced in 86% of patients. There were 3 patients who died from cGVHD. After 6 months, median skin scores were 53% lower (P =.003) in sclerodermoid and lichenoid disease. Of 6 patients with mucosal ulceration, 3 improved. A nonsignificant improvement of LFTs occurred. We infer that ECP is effective even in patients with extensive cutaneous cGVHD of 2 years duration that is resistant to conventional therapy. Furthermore, both sclerodermoid and lichenoid subtypes responded. However, no baseline parameters predicted a favorable response to ECP, so patient selection must continue to be made on clinical grounds.

Adolescent↗
PubMed2003

Stem cell transplantation for chronic myeloid leukemia in children.

Hematopoietic stem cell transplantation (SCT) is the only proven cure for chronic myeloid leukemia (CML), a rare disease in childhood. We report outcomes of 314 children with Philadelphia-chromosome-positive (Ph+) CML undergoing SCT from HLA-matched siblings (n = 182) or volunteer-unrelated donors (VUD; n = 132). Three-year overall survival (OS) and leukemia-free survival (LFS) rates were 66% and 55% (n = 314). For 156 children in first chronic phase (CP1) who underwent transplantation from HLA-identical siblings, OS and LFS rates were 75% and 63%. For 97 children who underwent SCT in CP1 from VUD, 3-year OS and LFS rates were 65% and 56%, reflecting higher transplantation-related mortality (TRM) after VUD SCT (35% vs 20%; multivariate hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0-3.5; P =.05). In a multivariate model for OS and LFS, outcomes were superior in CP1 than in advanced phase (AP/CP1) (OS HR, 2.0; 95% CI, 1.3-3; P =.001; LFS HR, 1.8; 95% CI, 1.2-2.6; P =.003). For relapse, donor source (VUD/sibling) (HR, 0.38; 95% CI, 0.19-0.76; P =.006) and disease stage (AP/CP1) (HR, 2.4; 95% CI, 1.36-4.3; P =.003) were significant. This is the first large series to show that SCT confers long-term LFS in most children with CML and helps assess alternative therapy, including tyrosine kinase inhibitors.

Adolescent↗
PubMed2003

Soluble receptor activator of nuclear factor kappaB ligand-osteoprotegerin ratio predicts survival in multiple myeloma: proposal for a novel prognostic index.

Interaction between receptor activator of nuclear factor kappaB ligand (RANKL) and RANK/osteoprotegerin (OPG) plays a dominant role in osteoclast activation and possibly in plasma cell survival in multiple myeloma (MM). We measured soluble RANKL (sRANKL), OPG, and bone remodeling markers in 121 patients with newly diagnosed MM to evaluate their role in bone disease and survival. Serum levels of sRANKL were elevated in patients with MM and correlated with bone disease. The sRANKL/OPG ratio was also increased and correlated with markers of bone resorption, osteolytic lesions, and markers of disease activity. The sRANKL/OPG ratio, C-reactive protein (CRP), and beta2-microglobulin were the only independent prognostic factors predicting survival in multivariate analysis. We generated a prognostic index based on these factors that divided our patients into 3 risk groups. The low-risk group had a 96% probability of survival at 5 years, whereas the intermediate-risk and the high-risk groups had probabilities of survival of 52% and 0%, respectively. Not only do these results confirm for the first time in humans the importance of sRANKL/OPG in the development of bone disease, they also highlight the role of this pathway in the biology of plasma cell growth as reflected by its influence on survival.

Adult↗
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

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1alpha) correlate with the extent of bone disease and survival in patients with multiple myeloma.

The role of serum macrophage inflammatory protein-1 alpha (MIP-1alpha) in bone disease and survival was evaluated in 85 newly diagnosed multiple myeloma (MM) patients. MIP-1alpha was elevated in MM patients and correlated with the extent of bone disease, bone resorption markers and levels of soluble receptor activator of nuclear factor-kappaB (RANK) ligand. MIP-1alpha was also associated with survival; the 3-year probability of survival was 85% and 44% for MIP-1alpha levels below and above 48 pg/ml respectively (P = 0.021). This suggests that MIP-1alpha contributes to the pathogenesis of bone disease in MM and possibly in tumour growth, as reflected by its impact on survival.

Adult↗
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

Chronic myeloid leukemia.

Chronic myeloid leukemia (CML) was the first human malignancy to be associated with a specific genetic lesion, the Philadelphia chromosome, harboring the BCR-ABL oncogene. Since then, it has become a paradigm for the discovery of molecular mechanisms and targeted therapeutic approaches in the field of hematologic neoplasias. The past 5 years or so have been particularly fruitful in the dissection of the signal transduction pathways abnormally activated in CML and in the translation of this knowledge to clinical practice. In this report, we discuss the biological basis for such translation and highlight the current and potential tools for the effective treatment of CML patients. The first part presents a review of the basic concepts on the biology of CML and their application to the design of targeted therapy. The mechanisms of action of the molecular-specific drugs currently used in clinical trials are discussed, with emphasis on the description of the most promising new compounds that are enhancing the potential for effective alternative or combination chemotherapy in CML. In the following section, we explain how molecular monitoring of response to imatinib mesylate in patients with CML can be used as a guide to clinical management. In particular, we discuss the relative value of regular quantitative RT/PCR and cytogenetic analyses, how responding patients should be monitored and managed, and how to investigate patients who are refractory or become resistant to imatinib treatment. In the last part of this report, a discussion on the possibility of managing CML with patient-specific strategies is presented. We review the current treatment options, highlight the factors impacting on decision making, discuss the range of possibilities for future therapeutic strategies and propose a systematic approach for individualizing treatment for patients in different disease categories.

Benzamides↗
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↗
PubMed2002

Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukemia.

Allogeneic mobilized peripheral blood progenitor cells instead of bone marrow are increasingly used to restore hematopoiesis after myeloablative therapy. Data supporting this important change of clinical practice are scarce. We therefore assigned patients with early leukemias to peripheral blood or bone marrow transplantation; the occurrence of acute and chronic graft versus host disease, survival, transplantation-related mortality, and relapse rates were compared. A total of 350 patients between 18 and 55 years of age with acute leukemias in remission or chronic myelogenous leukemia in first chronic phase were randomized to receive either filgrastim-mobilized peripheral blood progenitor cells or bone marrow cells from HLA-identical sibling donors after standard high-dose chemoradiotherapy. Neutrophil and platelet recovery occurred significantly faster after transplantation of peripheral blood progenitor cells than after bone marrow transplantation. Acute graft versus host disease of grades II-IV was significantly more frequent in recipients of peripheral blood progenitor cells than in recipients of marrow cells (52% vs 39%, odds ratio 1.74, 95% confidence interval 1.12-2.69, P =.013). The cumulative incidence of chronic graft versus host disease was 67% with peripheral blood progenitor cells and 54% with bone marrow cells (hazard ratio 1.67, 95% confidence interval 1.15-2.42, P =.0066). The estimated overall probability of survival at 2 years was 65% with either source of stem cells (hazard ratio 1.15, 95% confidence interval 0.79-1.67, P =.46). Disease-free survival, transplantation-related mortality at day 100, and relapse rates did not significantly differ between treatment arms. Peripheral blood is an equivalent source of hematopoietic stem cells compared with bone marrow if administered to patients with standard-risk leukemias. Long-term observation of patients with different diseases and stages of disease is necessary to ultimately define the role of both sources of stem cells.

Adolescent↗
PubMed2002

Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation.

Donor lymphocyte infusion (DLI) can restore durable molecular remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell transplantation, but for patients who do not respond survival is poor. Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse to chronic phase after stem cell transplantation for CML, did not benefit from treatment with DLI, and then was administered STI571 at a dose of 400 mg daily. There was a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis (100% 46, XX marrow metaphases) was achieved after 6 months of therapy, though RT-PCR studies still detected BCR-ABL transcripts in the blood at low level. This case demonstrates that imatinib mesylate can be highly effective in the management of patients who have relapses after allograft for CML.

Adult↗
PubMed2002

Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia.

We analyzed factors having an impact on response to treatment and survival in 78 consecutive patients with chronic myeloid leukemia (CML) in blastic transformation (BT) referred to the Hammersmith Hospital from January 1995 to December 2000. BT was defined as the presence of at least 30% blasts in blood or marrow or extramedullary blastic deposits. Immunophenotyping of blasts showed 57 myeloid, 19 lymphoid, and 2 biphenotypic. The median age of the patients was 39.1 years (range, 11.3-73.4 years), with 55 males and 23 females. The median survival for all patients after onset of BT was 8.2 months (95% CI, 6.4-10). Patients in lymphoid BT survived longer than those in myeloid BT (median, 11.2 months versus 6.9 months, P =.052). Initial treatment varied; 41 patients received cytotoxic drugs, 8 underwent allogeneic or autologous transplantation procedures, 21 received STI571 (imatinib mesylate, Gleevec), 1 received radiotherapy, and 7 received no therapy. Of the 25 (32%) patients who achieved a "second chronic phase" with first therapy, 6 of 21 (29%) were treated with STI571 and 19 of 50 (38%) were treated with chemotherapy, transplantation, or radiotherapy. Patients who achieved a second chronic phase survived longer than those who did not (median time from onset of BT 12.0 months versus 6.3 months, P =.0004). In multivariate analysis the finding of more than 50% blast cells in the blood and the presence of cytogenetic progression were independent adverse prognostic variables for survival. We conclude that survival after onset of BT has improved in recent years but is still unsatisfactory. We speculate that the combined use of STI571 with cytotoxic drugs may offer additional benefit.

Adolescent↗