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John Goldman

Publications and source records attributed to John Goldman.

18 recordsLinked to original sources
PubMed2006

Evolving concepts in the management of chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet.

The introduction of imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML). Although experience is too limited to permit evidence-based evaluation of survival, the available data fully justify critical reassessment of CML management. The panel therefore reviewed treatment of CML since 1998. It confirmed the value of IM (400 mg/day) and of conventional allogeneic hematopoietic stem cell transplantation (alloHSCT). It recommended that the preferred initial treatment for most patients newly diagnosed in chronic phase should now be 400 mg IM daily. A dose increase of IM, alloHSCT, or investigational treatments were recommended in case of failure, and could be considered in case of suboptimal response. Failure was defined at 3 months (no hematologic response [HR]), 6 months (incomplete HR or no cytogenetic response [CgR]), 12 months (less than partial CgR [Philadelphia chromosome-positive (Ph(+)) > 35%]), 18 months (less than complete CgR), and in case of HR or CgR loss, or appearance of highly IM-resistant BCR-ABL mutations. Suboptimal response was defined at 3 months (incomplete HR), 6 months (less than partial CgR), 12 months (less than complete CgR), 18 months (less than major molecular response [MMolR]), and, in case of MMolR loss, other mutations or other chromosomal abnormalities. The importance of regular monitoring at experienced centers was highlighted.

Antineoplastic Agents↗
PubMed2006

Why do chronic myelogenous leukemia stem cells survive allogeneic stem cell transplantation or imatinib: does it really matter?

It is generally accepted that allogeneic stem cell transplantation can 'cure' chronic myelogenous leukemia (CML), although occasional patients relapse more than 10 years after the transplant procedure. Such cures presumably result from the combined effects of leukemia stem cells (LSCs) of the conditioning regimen and the graft-vs.-leukemia (GvL) effect mediated by donor-derived T lymphocytes. The advent of imatinib has revolutionized the management of patients with CML, but much evidence suggests that it does not eradicate all LSCs, which theoretically remain a potential source of relapse to chronic phase or advanced phase disease. Moreover, sub-clones of Philadelphia-positive cells bearing mutations that code for amino-acid substitutions in the Bcr-Abl kinase domain can be identified in patients receiving treatment with imatinib and are associated with varying degrees of resistance to this agent. In the present review, we postulate that LSCs, similar to their normal counterparts, may alternate between cycling and quiescent modes. In the cycling mode, they may express Bcr-Abl protein and be susceptible to the acquisition of additional mutations, whereas, in the quiescent mode, they may express little or no Bcr-Abl oncoprotein, cannot acquire additional mutations and are unaffected by imatinib. Thus, a patient who starts treatment early in the natural history of CML, and who responds to imatinib clinically, may not have had the opportunity to acquire additional mutations in LSCs. In this case, the persistence long-term of quiescent 'non-mutated' LSCs despite imatinib treatment might be consistent with freedom from relapse to chronic or advanced phase disease, provided that they remain vulnerable to imatinib when they are recruited into cycle. Conversely, when imatinib resistant Philadelphia-positive sub-clones predominate, this is likely to be due to the recruitment to hematopoiesis of quiescent stem cells that had been in cycle before administration of imatinib and that had acquired additional mutations; in such cases, the best approach to eradication of residual LSCs might be to target expressed proteins thought to be targets for the GvL effect.

Benzamides↗
PubMed2005

Adoptive transfer of cytomegalovirus-specific CTL to stem cell transplant patients after selection by HLA-peptide tetramers.

Stem cell transplantation is used widely in the management of a range of diseases of the hemopoietic system. Patients are immunosuppressed profoundly in the early posttransplant period, and reactivation of cytomegalovirus (CMV) remains a significant cause of morbidity and mortality. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones has been shown to reduce the rate of viral reactivation; however, the complexity of this approach severely limits its clinical application. We have purified CMV-specific CD8+ T cells from the blood of stem cell transplant donors using staining with HLA-peptide tetramers followed by selection with magnetic beads. CMV-specific CD8+ cells were infused directly into nine patients within 4 h of selection. Median cell dosage was 8.6 x 10(3)/kg with a purity of 98% of all T cells. CMV-specific CD8+ T cells became detectable in all patients within 10 d of infusion, and TCR clonotype analysis showed persistence of infused cells in two patients studied. CMV viremia was reduced in every case and eight patients cleared the infection, including one patient who had a prolonged history of CMV infection that was refractory to antiviral therapy. This novel approach to adoptive transfer has considerable potential for antigen-specific T cell therapy.

Adoptive Transfer↗
PubMed2005

Monitoring minimal residual disease in BCR-ABL-positive chronic myeloid leukemia in the imatinib era.

PURPOSE OF REVIEW: The total number of leukemia cells in the body is reduced very substantially in patients with BCR-ABL-positive chronic myeloid leukemia (CML) responding to imatinib. This reduction is seen first as restoration of Ph negativity in blood and marrow and thereafter as decreasing BCR-ABL transcript levels assayed by quantitative polymerase chain reaction (PCR). Most patients with newly diagnosed chronic-phase CML who receive imatinib achieve complete cytogenetic remission (CCYR) and low levels of BCR-ABL transcripts, a status that seems to predict for relatively long survival compared with previous treatments. RECENT FINDINGS: Patients treated with 400 mg daily who achieved a reduction in BCR-ABL transcript numbers equal or greater than 3 logs compared with a baseline value have a significantly better progression-free survival than those who achieved lesser degrees of response. The presence of Ph-positive subclones with point mutations in the ABL kinase domain correlates with "acquired" resistance to imatinib and some mutations are associated with greater resistance than others. Preliminary evidence suggests that P-loop mutations are especially likely to be associated with progression to advanced-phase disease. SUMMARY: Patients with CML should be monitored routinely by serial cytogenetic analysis of bone marrow until Ph negativity is achieved. Thereafter serial quantitative-PCR studies should be undertaken at approximately 3-month intervals and probably also bone marrow cytogenetic studies at longer intervals. Routine studies for ABL kinase domain mutations may also be advisable. The observation of increasing quantities of residual leukemia or expansion of a mutated clone suggests the need to modify therapy.

Antineoplastic Agents↗
PubMed2004

Adjuvant interleukin-2 therapy for patients refractory to donor lymphocyte infusions.

OBJECTIVE: Donor lymphocyte infusions (DLI) can induce durable second remissions in patients relapsed after allogeneic stem cell transplantation (SCT) for hematologic malignancies. However, some patients are refractory or respond only partially to DLI. Recombinant interleukin-2 (IL-2) can increase the anti-leukemic activity of donor lymphocytes and has previously been reported as a potential enhancer of DLI. We assessed the response to adjuvant IL-2 on relapsed SCT who had failed to respond to DLI alone. PATIENTS AND METHODS. A total of 13 patients (8 with CML, 2 with AML, 2 with MM, 1 with NHL) relapsed after SCT and were treated with DLI. All had achieved only partial or no response after DLI. Recombinant IL-2 was thereafter administered. RESULTS: Five patients achieved a CR and four a PR after DL/IL-2 therapy. Those achieving a CR appeared to have a survival advantage compared to partial or nonresponders. The IL-2 was well tolerated; the most frequent side effects were fever (100%), lethargy (69%), and anorexia and vomiting (31%). Five patients experienced graft-vs-host disease (grade II-IV) after the treatment. CONCLUSIONS: IL-2 increases the response rate with improved survival in a proportion of patients who relapse after allo-SCT and do not respond well to DLI alone. There is no major toxicity. It may therefore be valuable as adjuvant therapy in conjunction with DLI.

Graft vs Host Disease↗
PubMed2002

Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia.

Allogeneic hematopoietic stem cell transplantation is the only curative therapy for myelodysplasia (MDS). To identify factors influencing transplantation outcome, we studied 452 recipients of HLA-identical sibling transplants for MDS from 1989 to 1997, reported to the International Bone Marrow Transplant Registry. Patients with treatment-related MDS or unclassified MDS were excluded. Median age was 38 years (range, 2-64 years). Sixty percent had refractory anemia with excess blasts (n = 136) or with excess blasts in transformation (n = 136). Conditioning regimens included total body irradiation in 199 (44%) cases. Marrow was T-cell depleted for 58 (13%) transplants. Cumulative incidences of neutrophil engraftment, grades II-IV acute graft-versus-host disease (GVHD), and chronic GVHD were 91% (95% confidence interval [CI], 88%-93%), 36% (95% CI, 31%-40%), and 39% (95% CI, 33%-44%), respectively. Three-year transplantation-related mortality (TRM), relapse, disease-free survival, and overall survival rates were 37% (95% CI, 32%-42%), 23% (95% CI, 19%-27%), 40% (95% CI, 36%-45%), and 42% (95% CI, 37%-47%), respectively. Multivariate analyses showed that young age and platelet counts higher than 100 x 10(9)/L at transplantation were associated with lower TRM and higher disease-free and overall survival rates. Relapse incidence was higher in patients with high percentages of blasts in the marrow at transplantation or presentation, with high International Prognostic Scoring System scores at diagnosis, and with T-cell-depleted transplants. These findings indicate that transplantation from an HLA-identical sibling offers the possibility of long-term, disease-free survival to patients with MDS. Best candidates are younger patients with a low percentage of blasts and preserved platelet counts.

Adolescent↗
PubMed2002

Not so NICE for CML.

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Antineoplastic Agents↗
PubMed2002

Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia.

BACKGROUND: Chronic myelogenous leukemia (CML) is caused by the BCR-ABL tyrosine kinase, the product of the Philadelphia chromosome. Imatinib mesylate, formerly STI571, is a selective inhibitor of this kinase. METHODS: A total of 532 patients with late--chronic-phase CML in whom previous therapy with interferon alfa had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for cytogenetic and hematologic responses. Time to progression, survival, and toxic effects were also evaluated. RESULTS: Imatinib induced major cytogenetic responses in 60 percent of the 454 patients with confirmed chronic-phase CML and complete hematologic responses in 95 percent. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 89 percent of patients, and 95 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were infrequent, and hematologic toxic effects were manageable. Only 2 percent of patients discontinued treatment because of drug-related adverse events, and no treatment-related deaths occurred. CONCLUSIONS: Imatinib induced high rates of cytogenetic and hematologic responses in patients with chronic-phase CML in whom previous interferon therapy had failed.

Administration, Oral↗
PubMed2002

Relationship between the clinical manifestations of sickle cell disease and the expression of adhesion molecules on white blood cells.

BACKGROUND: The severity of sickle cell disease (SCD) increases with leukocyte count. The biological basis could be that leukocyte adherence to vascular endothelium mediated by adhesion molecules (AMs) facilitates vaso-occlusion, the basic pathological process in SCD. OBJECTIVE: To find out if there is a relationship between expression of AMs by leukocytes and the clinical manifestations of SCD. METHODS: Flow cytometry was used to study the relationship between leukocyte AM expression and disease manifestations in 100 patients with homozygous (HbSS) sickle cell disease and 34 genotype HbAA controls. The effect of hydroxyurea therapy on AM expression was also examined. We excluded HbSS patients with any other disease, pregnancy in the previous 3 months, or Haemogloben F (HbF) > or = 10%. RESULTS: Patients with complications of SCD showed high expression of alphaMbeta integrin by the neutrophils; and l-selectin by lymphocytes and neutrophils (P < 0.03). CD18 was highly expressed by neutrophils in patients with sickle nephropathy (P = 0.018), and l-selectin by lymphocytes in those with stroke (P = 0.03). Monocyte l-selectin increased in sickle cell crisis relative to steady state (P = 0.04). Expression of alphaLbeta2 integrin by neutrophils, monocytes, and lymphocytes decreased within a month of hydroxyurea therapy (P < 0.05), with symptomatic improvement in the patients and no more than 3.3% rise in HbF level. CONCLUSIONS: The findings suggest that in SCD (1): High steady-state expression of alphaMbeta2 integrin and l-selectin by leukocytes predisposes to severe manifestations. (2) Increased leukocyte AM expression above steady-state levels could be important in the genesis of crisis. (3) The early symptomatic improvement that follows hydroxyurea therapy is mediated via mechanisms independent of increased HbF, and may involve reduced AM expression in leukocytes. (4) Other treatment modalities that reduce leukocyte AM expression might also confer clinical benefit.

Adult↗