Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent data suggest that STI571 (Imatinib) induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML) who relapse after allogeneic stem cell transplantation (SCT). However, little is known about molecular responses to STI571 and the duration of leukemia-free survival in these patients. We report on a 43 year old female patient who presented with a relapse from Ph+ CML in December 2000. Five years earlier she had received an SCT from an unrelated male donor in accelerated phase. At the time of relapse, she presented with marked leukocytosis (89,000 microl) and 10% blasts. In December 2000, therapy with Imatinib was started. After 3 months, the karyotype showed an XY, with trisomy 8 in about 50% of all metaphases, but without evidence of residual Ph+ cells. Moreover, in response to Imatinib, BCR/ABL transcripts decreased and were no longer detectable after 6 months. After a total observation period of 36 months, the patient is still in complete cytogenetic and molecular remission without signs of occurrence of a donor-type hematopoietic neoplasm or CML relapse. These data suggest that Imatinib is a useful agent for long term treatment of relapsed CML after allogeneic SCT.
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PMID:Detection of trisomy 8 in donor-derived Ph- cells in a patient with Ph+ chronic myeloid leukemia successfully treated with Imatinib (STI571) in relapse after allogeneic transplantation. 1535 47

Donor lymphocyte infusions (DLIs) induce potent graft versus tumor (GVT) effects for relapsed chronic myelogenous leukemia (CML) after allogeneic stem cell transplantation (SCT) but are disappointing for other diseases. Disease resistance can occur if donor T cells are not appropriately activated in vivo. Ex vivo T-cell activation might overcome disease-induced anergy and augment GVT activity. We performed a phase 1 trial of ex vivo-activated DLI (aDLI) for 18 patients with relapse after SCT. Activated donor T cells are produced through costimulation with anti-CD3- and anti-CD28-coated beads. Patients with aggressive malignancies received induction chemotherapy, and all patients received conventional DLI (median, 1.5 x 10(8) mononuclear cells/kg) followed 12 days later by aDLI. Activated DLI was dose escalated from 1 x 10(6) to 1 x 10(8) CD3+ cells per kilogram in 5 levels. Seven patients developed acute graft versus host disease (GVHD) (5 grade I-II, 2 grade III), and 4 developed chronic GVHD. Eight patients achieved complete remission, including 4 of 7 with acute lymphocytic leukemia (ALL), 2 of 4 with acute myelogenous leukemia (AML), 1 with chronic lymphocytic leukemia (CLL), and 1 of 2 with non-Hodgkin lymphoma (NHL). Four complete responders relapsed while 4 remain alive in remission a median 23 months after aDLI. Overall, 10 of 18 remain alive 11 to 53 months after aDLI. Adoptive transfer of costimulated activated allogeneic T cells is feasible, does not result in excessive GVHD, and may contribute to durable remissions in diseases where conventional DLI has been disappointing.
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PMID:A phase 1 trial of donor lymphocyte infusions expanded and activated ex vivo via CD3/CD28 costimulation. 1626 10

Although dramatically effective for relapsed chronic myelogenous leukemia (CML), successful donor leukocyte infusion (DLI) remains limited primarily by inadequate responses for patients with diseases other than CML and by toxicity related to graft-versus-host disease (GVHD). Acute GVHD grades 2 to 4 follows 34% to 47% of infusions and chronic GVHD occurs in 33% to 61% of cases. Strategies to reduce the incidence and severity of GVHD while preserving the graft-versus-leukemia (GVL) effect, such as low-dose DLI, depletion of GVHD effector cells, and tumor-specific DLI, are reviewed.
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PMID:Graft-versus-host disease and graft-versus-leukemia after donor leukocyte infusion. 1641 89

Although donor lymphocyte infusion (DLI) induces complete remissions in 70% of patients with relapsed chronic myeloid leukemia (CML) after allogeneic stem-cell transplantation (SCT), some patients are refractory to DLI by showing disease persistence. In a patient who received DLI for relapsed CML, we observed persisting molecular disease despite a hematological and cytogenetic remission in the absence of graft-versus-host disease (GVHD). To determine the nature of this immune response, we isolated leukemia-reactive donor T-cell clones from the bone marrow (BM) of the patient at the time of clinical response. Four different types of CD8+ HLA class I restricted T-cell clones were obtained that were cytotoxic against Ebstein-Barr virus-transformed B-cell lines (EBV-LCL) of the patient, but not the donor, indicating recognition of minor histocompatibility antigens (mHags). By using survival studies with CFSE labelled BM cells populations, a hematopoietic progenitor cell inhibition assay and direct morphological examination we showed that the T-cell clones recognized mature monocytic and myeloid cells, whereas immature BM progenitor cells were insufficiently lysed. This patient's refractoriness for DLI appears to be caused by inadequate lysis of progenitor cells by these cytotoxic T cells. These findings support the hypothesis that for eradication of CML a cytotoxic T-cell response against leukemic progenitor cells is essential.
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PMID:Molecular persistence of chronic myeloid leukemia caused by donor T cells specific for lineage-restricted maturation antigens not recognizing immature progenitor-cells. 1652 95

We retrospectively analyzed 83 consecutive recipients of donor lymphocyte infusions (DLI) after allogeneic transplantation for factors associated with disease response and graft-versus-host disease (GVHD). DLI was highly effective in relapsed chronic phase chronic myeloid leukemia (CML), with 71% of patients achieving durable complete remissions (CR). In relapsed acute myeloid leukemia, DLI led to durable CRs in 31% of patients; the rate was <20% in all other diseases. Achieving full donor chimerism and GVHD were predictive of CR. Grade II or higher acute or chronic GVHD occurred in 36 (43%) patients and contributed to death in 13 (16%). Even more patients, 33 (40%), died of their underlying malignancy, including 10 who developed active GVHD. In relapsed CML, most durable CRs occurred without clinically apparent GVHD, yet all responders achieved full donor chimerism, including 6 with coincident normal host hematopoiesis at the time of DLI. Thus, in CML, potent lymphohematopoietic graft-versus-host reactions occurred even in the absence of clinically apparent GVHD; this confirms the ability to dissociate these processes and argues against a leukemia-specific immunologic effect. DLI clearly has efficacy in the treatment of relapsed disease after allogeneic transplantation. However, with the exception of CML, most patients die of their underlying disease because of insufficient antitumor activity even with active GVHD.
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PMID:Graft-versus-host reactions and the effectiveness of donor lymphocyte infusions. 1654 25

Imatinib mesylate is highly effective in relapsed chronic myelogenous leukemia (CML) after allogeneic hematopoetic stem cell transplantation (HSCT). However, it is unknown whether imatinib produces durable molecular remissions. The outcome of CML patients transplanted at our center who had received only imatinib for relapse after HSCT was compared with that of patients treated with donor lymphocyte infusions (DLI). Imatinib therapy resulted in a higher incidence of relapse and inferior leukemia-free survival (p=0.006 and p=0.016, respectively). These data suggest that imatinib alone probably does not cure relapse after HSCT.
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PMID:A comparison of donor lymphocyte infusions or imatinib mesylate for patients with chronic myelogenous leukemia who have relapsed after allogeneic stem cell transplantation. 1662 51

Donor leukocyte infusion (DLI) provides direct and potent graft-versus-leukemia (GVL) activity to treat relapse after allogeneic stem-cell transplantation. DLI is dramatically effective for relapsed chronic myelogenous leukemia (CML), but has been less effective for relapse of other myeloid malignancies. Nevertheless, most recipients of DLI for relapsed CML, and many patients with relapsed acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), will experience prolonged remissions and probable cure. Graft-versus-host disease remains the major complication of DLI. New strategies for GVL induction explore novel dosing regimens and both methods of enhancing GVL activity of donor T cells and of minimizing toxicity from graft-versus-host disease. Ultimately, the identification of the effector cells and target antigens for GVL induction will lead to the use of tumor-specific adoptive immunotherapy to both prevent and treat relapse with minimal toxicity. Although many issues remain unsettled, the potential to harness the graft-versus-leukemia activity of allogeneic donor cells provides a powerful new paradigm for the immunotherapy of cancer.
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PMID:Donor leukocyte infusions in myeloid malignancies: new strategies. 1699 80

Imatinib mesylate (IM) is the standard first-line treatment for patients with chronic myeloid leukemia (CML). Surprisingly, 2-15% of patients achieving a complete cytogenetic response develop cytogenetic abnormalities in Philadelphia (Ph)-negative cells. Following hematopoietic stem cell transplantation (HSCT), IM induces complete molecular responses (CMR) in approximately 70% patients with relapsed CML, and no IM-related cytogenetic abnormalities in Ph-negative donor-derived cells have been described after HSCT. We report a 56-year-old female who presented with a relapse from CML in September 2002. She had received a matched related HSCT for CML in chronic phase. Donor lymphocyte infusion was given 3 years post-HSCT for a relapse. Sustained CMR was achieved within 3 months of initiation of IM. In October 2005, routine evaluation demonstrated continuous CMR, full male donor engraftment and an inv (11) on donor cells. Evaluation of the donor demonstrated no dysplasia or cytogenetic abnormalities. This observation reinforces the possibility that IM therapy may be casually linked to the phenomenon of secondary cytogenetic changes in diploid cells.
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PMID:Inv (11)(p15q21) in donor-derived Ph-negative cells in a patient with chronic myeloid leukemia in relapse successfully treated with imatinib mesylate post allogeneic stem cell transplantation. 1730 75

Chronic myeloid leukemia (CML) is a myeloproliferative disease that originates in an abnormal pluripotent bone marrow stem cell and is characteristically associated with the Philadelphia chromosome and/or the bcr/abl fusion gene. Despite the exciting success of the bcr/abl tyrosine kinase-specific inhibitor imatinib for CML treatment, hematopoietic stem cell (bone marrow or peripheral blood stem cell) transplantation (HCT) remains the only "curative" approach for the majority of patients. Although HCT outcomes for patients with CML have improved considerably during the past 2 decades, relapse after HCT may occur. We analyzed the clinical and pathologic features of 16 cases of hematologically relapsed CML after HCT during a 5-year period at City of Hope National Medical Center, Duarte, CA. The results of our analysis showed that relapsed CML after HCT frequently manifested with advanced disease with a more aggressive clinical course and was often refractory to therapy. The frequency of acute leukemic transformation at time of relapse was largely associated with pre-HCT disease status and acquired secondary cytogenetic abnormalities. Disease mortality in patients with relapsed CML after HCT was closely associated with advanced disease and HCT-related complications.
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PMID:Clinical and pathologic analysis of 16 cases of relapsed chronic myeloid leukemia after stem cell transplantation. 1787 6

Tyrosine kinase inhibitors (TKI) have been used to treat relapse of chronic myelogenous leukemia (CML) after allogeneic stem cell transplant (HSCT), with responses seen predominantly in chronic phase (CP) patients. This study aimed to analyze the response to TKI therapy and overall survival for patients relapsing predominantly in advanced phase. We retrospectively reviewed 22 patients treated with imatinib (n=20) and/or dasatinib (n=6) for relapsed CML after HSCT; 8 patients were in CP, and 14 patients had advanced disease. Seven patients also received donor lymphocyte infusions. Hematologic, cytogenetic, and molecular responses were analyzed. Nineteen patients (86%) achieved complete hematologic response (CHR), 17 patients (77%) achieved complete cytogenetic response (CCR), and 14 patients (64%) achieved complete molecular response (CMR). In advanced phase patients, 11 (79%) achieved CHR, 10 (71%) CCR, and 8 (57%) achieved CMR. Grade 3 or 4 cytopenias occurred in 10 cases. With median follow-up of 31.5 months from relapse, 14 (64%) patients remain alive, 13 in CMR. In multivariate analysis, the achievement of CMR was significantly correlated with OS with an odds ratio of 20.5 (95% confidence interval 2.3-182) P=.007. TKI therapy is capable of inducing durable molecular responses for CML relapsing after HSCT, both in chronic and advanced phases. The achievement of CMR appears to be crucial in providing long-term disease control for these patients.
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PMID:Response to tyrosine kinase inhibitor therapy in patients with chronic myelogenous leukemia relapsing in chronic and advanced phase following allogeneic hematopoietic stem cell transplantation. 2000 67


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