Biomedical subjects
Publications and source records attributed to Ray Powles.
We report an analysis of the value of a second high-dose melphalan autograft, performed at relapse, on a series of newly diagnosed myeloma patients entered into the high-dose program at our center. We conclude that relapse-free survival after the first autograft is a major prognostic factor in determining outcome.
PURPOSE: To develop 2D 1H-MRS measurement sequences for the evaluation of bone marrow lipids, and to assess these measurement sequences in healthy and diseased bone marrow. MATERIALS AND METHODS: Single-voxel localized variants of COSY and DQF-COSY 2D 1H-MRS sequences were developed for use at 1.5 T to investigate the biochemical composition of human bone marrow in vivo. The performance of each sequence was initially tested in vitro using lipid phantoms. An unsaturated lipid proton index was developed to interrogate the degree of unsaturation within the triacylglyceride (TAG) acyl chains. Localized 2D 1H-MRS data were obtained from the bone marrow of healthy controls (N = 6), patients presenting with acute leukemia (N = 6) and patients with acute leukemia in remission (N = 4). RESULTS: The COSY and DQF-COSY data recorded from all subject cohorts were similar, and the unsaturated lipid proton index did not reveal significant differences between patient groups. Variations in water content and measured relaxation times showed minor differences between the measurement groups. CONCLUSIONS: No significant differences were observed in the spectra obtained from bone marrow using the 2D 1H-MRS sequences. A novel unsaturated lipid proton index was developed.
If standard infusional therapy (IC) has been used to treat myeloma at presentation, it is a matter of debate whether patients should receive the original induction therapy or a different drug combination in first relapse. Instinctively, most clinicians may switch treatment, particularly since the advent of new drugs for the treatment of myeloma. Hitherto, there has been no data on the efficacy of repeating standard IC in the salvage setting. We studied 62 myeloma patients whose initial treatment consisted of C-VAMP and a single high dose melphalan procedure and who were retreated with C-VAMP at the time of first relapse. Response to salvage C-VAMP was seen in 50% (95% confidence interval = 0.37-0.62) but we were unable to identify any predictors for response to salvage C-VAMP. Only patients resistant to salvage C-VAMP benefited from a second autograft. The survival of patients who responded to salvage C-VAMP was not prolonged by a second transplant. In conclusion, our data supports the use of C-VAMP for patients with myeloma in first relapse and suggest that only patients resistant to salvage C-VAMP should be offered a second autograft.
Induction chemotherapy followed by high-dose melphalan (HDM) is the standard treatment for fitter patients with myeloma. The place of bortezomib and the thalidomide analogues within this treatment paradigm is yet to be established. We sought to identify patients who may benefit from the introduction of novel agents during their initial management. An intention-to-treat analysis was performed on 383 patients with newly diagnosed myeloma eligible for HDM to determine whether the extent of response to induction therapy and HDM correlated with long-term survival. Early response [complete response (CR) and partial response (PR)] to induction therapy was predictive of overall survival (OS) [median OS, 7.47 years for responders (CR and PR) versus 4.89 years for non-responders; P = 0.035]. The attainment of CR at 3 months post-HDM correlated with a prolonged progression-free survival (PFS) (median PFS, 7.4 years in CR group versus 5.3 years in non-CR group; P = 0.023). This data suggests that, at every stage of treatment, the aim should be to achieve CR. Patients with suboptimal responses could be offered alternative therapy. We propose a multiparametric risk-adapted model that includes response to induction chemotherapy and HDM, for identifying patients who may benefit from novel approaches to treatment.
Multiple myeloma is a malignant disease of plasma cells that manifests as one or more of lytic bone lesions, monoclonal protein in the blood or urine, and disease in the bone marrow. Treatment for myeloma has changed beyond recognition in the past decade, and now includes state of the art supportive treatment and infusional chemotherapy courses, followed for younger patients by high-dose melphalan and an autologous transplant. Patients younger than 70 years can now expect a doubling of median survival to 5 years, a 20% chance of surviving longer than 10 years, and a 50% chance of attaining complete morphological and biochemical remission. Bisphosphonate control of bone disease is essential. Exploitation of the understanding of the biology of myeloma has led to the development of biological treatments, such as thalidomide, CC-5013, and bortezomib, which target the myeloma cell and the bone-marrow microenvironment, which plays a crucial part in the disease's pathogenesis. These treatments will hold the key to future success.
BACKGROUND AND OBJECTIVES: Disruption of either the p14ARF- mdm2- p53 or p16INK4A- Rb1 pathways produces a breakdown of regulatory mechanisms and creates a gateway for tumorigenesis. Since the incidence and clinical implications of abnormalities of TP53, CDKN2A (encoding for p16 and p14) and MDM2 genes (chromosome 12) in multiple myeloma (MM) is not clear, we investigated allelic loss at the former two loci and gain at the latter locus in a series of 82 MM patients. DESIGN AND METHODS: Dual color fluorescence in situ hybridization (FISH) was applied to bone marrow samples to establish the incidence of changes at the above mentioned loci. The CDKN2A locus was tested using a probe which hybridizes to 9p21 and also targets the p15INK4B gene. RESULTS: FISH analysis revealed the presence of monoallelic TP53 deletions in 12% of patients. Ten percent of patients had hemizygous deletion at 9p21, while a further 8% had loss of 1 of 3 loci in the presence of trisomy 9. MDM2 amplification in the face of chromosome 12 diploidy was seen in 8%, while another 8% had trisomy 12 with an equivalent increase in signals for MDM2. Clinical correlations revealed that allelic loss of TP53 was the only factor associated with resistance to chemotherapy. The presence of 9p21 deletion was associated with an IgA isotype but none of the abnormalities had a significant influence on overall or event-free survival. INTERPRETATIONS AND CONCLUSIONS: P53 and CDKN2A (9p21) allelic loss and amplifications of the MDM2 gene are infrequent events in myeloma. The incidence of the latter two events was, however, higher than previously reported. Deletion of the TP53 gene predicted resistance to chemotherapy, highlighting its importance in this disease process.
UNLABELLED: The Philadelphia chromosome translocation (Ph(+)) confers a poor prognosis in patients with acute lymphocytic leukemia (ALL). CD19 is highly expressed (CD19(+)) on ALL cells and is an attractive target for antibody-based therapies. CLB-CD19 is an IgG1kappa murine monoclonal antibody (mAb) directed against an epitope on the CD19 antigen. METHODS: Radiolabeled CLB-CD19 antibody was evaluated for targeting ALL in a severe combined immunodeficient (SCID) mouse model engrafted with primary human leukemia cells. Lodgment of CD19(+) ALL cells in spleen and liver was confirmed using immunohistochemistry analyses. Circulating CD19(+) ALL cells in blood were also detected by flow cytometry. RESULTS: Antibody was labeled directly with the radiohalogen (125)I and radiometal (111)In via the bifunctional metal ion chelate CHX-A"-diethylenetriaminepentaacetic acid (DTPA) with retention of immunoreactivities. After intravenous injection of radioconjugates, biodistribution studies showed rapid localization of the (111)In-conjugate to leukemia-infiltrated spleen, reaching a maximum (mean +/- SD) of 72.78 +/- 13.67 % injected dose per gram of tissue (%ID/g) by 24 h after injection. In contrast, peak localization of coinjected (125)I-CLB-CD19 occurred by 4 h and was significantly lower (11.41 +/- 12.79 %ID/g) (P < 0.001). Uptake of (111)In-conjugate in the liver containing tumor was also evident but not in other normal tissues. Uptake of radiolabeled CLB-CD19 in tumor-bearing organs was specific, as uptake of radiolabeled isotype-matched antibody control was low. Gamma-camera imaging detected the uptake of (111)In-CHX-A"-DTPA CLB-CD19 in enlarged tumor-bearing spleen of engrafted mice. A single injection of 32 micro g CLB-CD19 mAb had a delayed suppressive effect on the level of circulatory leukemia cells in surviving mice and extended the median survival from 48.5 to 58 d (n = 8; P = 0.03). CONCLUSION: The radiolabeled anti-CD19 antibody showed specific targeting and rapid internalization in ALL cell-engrafted SCID mice and may also be used for selective intracellular delivery of cytotoxic radionuclides with beta-, Auger, or alpha-emissions.
PURPOSE: Many attempts have been made to improve the results of allogeneic bone marrow transplantation (alloBMT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1). Bone marrow cell dose has been reported to be an important factor in alloBMT; however, its true impact on relapse incidence (RI), leukemia-free survival (LFS), and nonrelapse mortality (NRM) in a large cohort of patients is unknown. PATIENTS AND METHODS: From January 1992 to December 1999, 572 bone marrow transplantation recipients reported to the European Blood and Marrow Transplantation (EBMT) registry underwent allografting from an HLA-identical sibling donor with an unmanipulated bone marrow for AML in CR1. RESULTS: The median number of nucleated cells (NCs) infused was 2.6 x 10(8)/kg. Estimated 5-year NRM, LFS, and RI for patients receiving more or less than 2.6 x 10(8) NCs/kg were, respectively, 18% +/- 5% v 30% +/- 5% (P =.001), 68% +/- 3% v 46% +/- 3% (P <.00001), and 14% +/- 4% v 24% +/- 5% (P =.004). The association of cell dose with the above outcomes was confirmed in multivariate analyses for NRM (relative risk [RR], 0.53; P =.0007), for LFS (RR, 0.53; P =.00008), and for RI (RR, 0.57; P =.02). The cell dose was also an important factor for neutrophil (RR, 0.76; P =.009) and platelet (RR, 0.77; P =.03) recoveries; however, it did not statistically influence the incidence of acute graft-versus-host disease. CONCLUSION: This study shows that marrow cell dose is one of the most important factors influencing relapse, NRM, and LFS after alloBMT for patients with AML in CR1. Therefore, increasing the marrow cell dose should substantially improve the survival of these patients.
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Extending the principle of conventional acute lymphoblastic leukemia (ALL) therapy to transplantation, 77 adult patients receiving autografts in first remission after melphalan with or without total body irradiation were scheduled to receive 6-mercaptopurine (6MP), methotrexate (MTX), and vincristine-prednisone (VP) for 2 years after transplantation to reduce relapse. Seventy-one percent of patients received 6MP, 57% received MTX, and 38% received VP. Thirty patients had a relapse at 1.5 to 80 months (median, 12.5 months), 15 in the first year and 7 beyond 3 years. The cumulative incidence of relapse at 10 years was 42% (95% CI, 31%-55%). The 10-year probabilities of disease-free survival (DFS) and overall (OS) survival were 50% (95% CI, 38%-62%) and 53% (95% CI, 41%-65%), respectively. Age older than 30 years, more than 4 weeks to attain remission, and high-risk karyotypes, for example, t(9;22) or t(4;11), were adverse features contributing to the identification of 3 prognostic risk groups with 0, 1, and 2 adverse features, respectively: standard (47%), intermediate (36%), and high (17%). The 10-year cumulative incidences of relapse (20%, 48%, 85%; P <.0001) and probabilities of DFS (72%, 41%, 10%; P =.0003) were significantly different among these groups. In Cox analysis of the 71 patients alive and well 120 days after transplantation, those receiving 2 or 3 maintenance chemotherapy agents had significantly lower relapse rates and superior DFS compared with those receiving 0 or 1 agent. Our data suggest that maintenance chemotherapy improves the outcome of patients with ALL undergoing autografting. However, it is unlikely that autograft-based strategies are optimal for the high-risk group of patients who should be considered for alternative-donor allograft procedures.
We undertook a randomised prospective observational study to identify the true prevalence of dermatological problems on an acute in-patient haemato-oncology unit treating patients with myeloma and leukaemia (median age 52 years), that could be used to plan for optimum dermatological servicing of such a unit. As a snap-shot, beds were randomly selected each week and the patients in them examined to identify the prevalence and identity of mucocutaneous problems for in-patients. Primary endpoints were the prevalence of integument reactions, prevalence and type of rash. Eighty-four leukaemia and myeloma patients were seen on 200 episodes. Integument changes were seen in 88% of episodes. Predictable changes such as hair loss (74%) and mucositis (38%) were seen commonly. Rashes were seen in 38% of episodes. The most common rash was palm and sole erythema (10% of all episodes) which was associated with allogeneic BMT (20%; p=0.0009). Flexural erythema with subsequent desquamation occurred in 4% of episodes, more commonly in males (p=0.09). Drug allergies were seen in 14 of 200 episodes and were significantly associated with antibiotics (p=0.003). Patients' perceived their skin problems as moderate or severe in 19% of the episodes. The impact on resources in the haematology practice was large; 45% of inpatients were receiving topical or systemic skin treatment, in 5% of patients the oncology treatment was compromised, 11% of patients required extra nursing and 3% of patients stayed longer in hospital. This volume of mucocutaneous problems makes dermatological input to haemato-oncology units vital.