Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

BL22 is a recombinant immunotoxin containing a truncated form of the bacterial toxin Pseudomonas exotoxin A attached to an Fv fragment of an anti-CD22 monoclonal antibody. Its mechanism of action involves binding to CD22, being internalized into the target cell by endocytosis, being processed to generate a free toxin fragment which is translocated into the cytoplasm, and finally induction of cell death by catalytic inactivation of elongation factor 2. In phase-I testing BL22 was very active in chemoresistant hairy-cell leukemia (HCL), with 19 (61%) of 31 patients achieving complete remission (CR). The low blood counts (cytopenias) which are characteristic of HCL improved in all complete and partial responders. Dose-limiting toxicity in HCL was due to a reversible hemolytic uremic syndrome (HUS), observed only during cycles 2 or 3. Already under way are a phase-II trial in HCL and phase-I trials in chronic lymphocytic leukemia (CLL) and acute lymphocytic leukemia (ALL) administering BL22 in a modified protocol in an effort to prevent HUS.
Best Pract Res Clin Haematol 2006
PMID:BL22 and lymphoid malignancies. 1699 77

In recent decades rapid improvements in the results of treatment of adult acute lymphoblastic leukaemia (ALL) have been achieved. This progress has been based mainly on intensification and optimization of chemotherapy, risk-adapted use of stem-cell transplantation, and improved supportive care. However, results in adult patients are still considerably inferior to those in paediatric ALL, and a barrier to further intensification of chemotherapy appears to have been reached regarding toxicity. More recently, the most significant progress has therefore been achieved by individualized and targeted therapy - for example, treatment with monoclonal antibodies (MoAbs). ALL blast cells express a variety of specific antigens which may serve as targets: e.g. CD19, CD20, CD22, CD33, and CD52. Most experience is available for anti-CD20 (rituximab). In ALL, rituximab is combined with chemotherapy mainly in mature B-ALL and Burkitt's lymphoma, and interim results are very promising. Recently studies with rituximab have also been initiated in B-precursor ALL. Other antibodies would be of interest due to a high rate of antigen (e.g. CD19) expression in ALL, but these are not yet generally available. Clinical application in smaller studies or case reports was reported for anti-CD52 and anti-CD33. Overall it can be stated that MoAb therapy in ALL is a promising treatment approach. Monotherapy with MoAbs in relapsed ALL has also occasionally achieved responses, but greater effects can be expected from combination with chemotherapy and treatment in the state of minimal residual disease. Details of these regimens - required level of antigen expression, timing, schedule, dosage and stage of disease - remain to be defined.
Best Pract Res Clin Haematol 2006
PMID:Novel antibody-based therapy for acute lymphoblastic leukaemia. 1699 78

The use of monoclonal antibodies for patients with acute myeloid leukemia is based on targeting cell-surface antigens preferentially expressed on leukemic blasts while sparing normal cells and tissues. The majority of studies performed to date have used antibodies reactive with the CD33 antigen. Phase II studies have demonstrated antileukemic responses with all agents, although less so with unlabeled antibodies. The most promising results have been obtained in the treatment of minimal residual disease in patients with acute promyelocytc leukemia. Antibody-targeted chemotherapy with gemtuzumab ozogamicin has also shown significant activity in patients with relapsed acute myeloid leukemia. Radioimmunotherapy with beta-particle emitters may be most effective for the treatment of bulky disease or as part of a conditioning regimen for hematopoietic stem-cell transplantation, whereas radioimmunotherapy with alpha-particle emitters may be better suited to the treatment of small-volume or minimal residual leukemia. Whether or not monoclonal antibody therapy will improve disease outcome compared with conventional treatment regimens remains to be demonstrated by well-designed clinical trials.
Best Pract Res Clin Haematol 2006
PMID:Monoclonal antibodies and immunoconjugates in acute myeloid leukemia. 1699 79

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.
Best Pract Res Clin Haematol 2006
PMID:Donor leukocyte infusions in myeloid malignancies: new strategies. 1699 80

The humanized monoclonal antibody alemtuzumab binds to the CD52 antigen, a glycoprotein which is widely expressed on normal and malignant B and T lymphocytes. Recently it has been demonstrated in a number of clinical trials that alemtuzumab has clinical activity in mature T-cell diseases such as T-prolymphocytic leukaemia and cutaneous T-cell lymphoma, inducing responses in up to two thirds of heavily pre-treated relapsed/refractory patients. Response was associated with improved survival. The toxicity profile for the antibody is manageable. The major complications are infusional reactions associated with initial injections, and prolonged lymphopenia associated with reactivation of viruses. Future studies will be directed towards alternative (subcutaneous) routes and schedules of administration, use as first-line therapy, combination strategies, and role of alemtuzumab to purge minimal residual bone-marrow disease prior to stem-cell transplantation.
Best Pract Res Clin Haematol 2006
PMID:Alemtuzumab in T-cell lymphoproliferative disorders. 1699 84

Adoptive immunotherapy using natural killer (NK) cells is currently under investigation, especially in situations where anti-neoplastic effect is needed but infusion of T cells is considered hazardous, such as in recipients of haematopoietic stem-cell transplantation (HSCT) from haploidentical donors. NK-cell therapy is mainly but not exclusively investigated in the setting of allogeneic stem-cell transplantation. NK cells may induce potent anti-leukaemic and possibly anti-rejection activity, and may even mitigate graft-versus-host disease (GvHD). It remains to be determined whether such effects are clinically important and whether or not they are mediated mainly or exclusively by KIR-HLA class I interactions. Recent advances in graft engineering has provided methods for isolating large numbers of purified NK cells. Several groups have shown that clinical-grade NK cells at doses up to 10(7)/kg may be collected and purified for the purpose of infusion to patients. Early results in a limited number of patients show that these cell doses may be administered without adverse events and possibly without inducing GvHD. Further study is required to determine whether such infusions will be useful in preventing graft rejection, exerting graft-versus-leukaemia effects, and/or hastening immune recovery.
Best Pract Res Clin Haematol 2006
PMID:Natural-killer-cell-based treatment in haematopoietic stem-cell transplantation. 1699 85

Reduced intensity conditioning (RIC) transplants were first developed almost a decade ago to reduce the transplant-related mortality (TRM) of allogeneic haematopoietic cell transplantation (HCT) and to make the graft-versus-leukaemia effect accessible to patients otherwise ineligible for HCT. Acute myelogenous leukaemia (AML) in elderly patients is now a frequent indication for RIC-HCT. The major reasons for these rapid developments have been on the one hand the high median age of patients with AML coupled with the unsatisfactory results with conventional chemotherapy, and on the other hand with the promising results already reported for RIC-HCT. Using RIC-HCT, overall survival rates at 2 years of 45-50% have been observed in patients with AML. This compares favourably with overall survival rates of 10-15% under chemotherapy in AML CR1, or no long-term survivors in patients >CR2. From the available data we conclude that RIC-HCT is a promising treatment for elderly patients with AML. However, phase-III studies with unrelated donors will have to be done in order to formally prove its superiority in comparison to conventional chemotherapy.
Best Pract Res Clin Haematol 2006
PMID:Reduced intensity conditioning (RIC) haematopoietic cell transplants in elderly patients with AML. 1699 86

Malignant stem cells have recently been described as the source of several types of human cancer. These unique cell types are typically rare and possess properties that are distinct from most other tumor cells. The properties of leukemic stem cells indicate that current chemotherapy drugs will not be effective. The use of current cytotoxic agents is not effective in leukemia because the agents target both the leukemic and normal stem cell populations. Consequently, new strategies are required that specifically and preferentially target the malignant stem cell population, while sparing normal stem cells. Several well known agents are lethal for the leukemic stem cell in preclinical testing. They include parthenolide, commonly known as feverfew, and TDZD-8. They have undergone various levels of preclinical development, but have not been used in patients as yet in the cancer setting. These drugs and combinations of existing therapies that target the leukemic stem cell population may provide a cure in this disease. This article summarizes recent findings in the leukemic stem cell field and discusses new directions for therapy.
Best Pract Res Clin Haematol 2007 Mar
PMID:The leukemic stem cell. 1733 50

Secondary leukemia is a poorly defined term that often refers to the development of acute myeloid leukemia (AML) following the history of a previous disease, such as a myelodysplastic syndrome or a chronic myeloproliferative disorder. Secondary leukemia can also be a consequence of treatment with chemotherapy, including alkylating agents and topoisomerase II inhibitors, and/or radiotherapy, or due to exposure to environmental carcinogens. Outcomes for this large and variable group of patients with secondary AML have been poor compared to people who develop AML de novo. The question arises whether a diagnosis of secondary leukemia per se indicates a poor prognosis or whether their bad outcomes result from an association with certain morphologic and biologic characteristics. Morphologic dysplasia in de novo AML is related to unfavorable cytogenetics, but has no independent prognostic relevance under the conditions of intensive chemotherapy. While there is no significant correlation between cytogenetic risk groups and dysplasia, cytogenetic features do have an impact on outcome among both de novo and secondary AML patients. In various subgroups of secondary AML, the spectrum of cytogenetic abnormalities is similar to de novo AML, but the frequency of abnormalities associated with unfavorable and intermediate risk cytogenetics, such as a complex karyotype, trisomy 8, monosomy 7, and others, is higher in secondary AML. The survival of patients with therapy-related myeloid leukemia (t-AML) is generally shorter than for those with de novo AML within the same cytogenetic risk group. Across the population of t-AML, however, survival varies according to cytogenetic risk group, with longer survival in patients with favorable-risk karyotypes. The term secondary AML is too broad and imprecise to be of importance and should not be used. These AML patients should be enrolled on front-line chemotherapy trials and should be stratified by pretreatment disease status and exposure history, if necessary. Most importantly, the molecular and genetic differences that appear to determine the phenotype and the outcome of these patients need to be investigated further.
Best Pract Res Clin Haematol 2007 Mar
PMID:Is secondary leukemia an independent poor prognostic factor in acute myeloid leukemia? 1733 52

Development of nonablative and reduced-intensity conditioning regimens has enabled older or medically infirm patients with myeloid malignancies to be treated with allogeneic hematopoietic cell transplantation (HCT). These regimens rely largely on graft-versus-leukemia effects rather than high-dose therapy to eliminate malignant cells. Studies indicate that there is sustained engraftment with relatively low transplant-related mortality in the small number of patients who have been treated. This review summarizes the outcome in recent studies of patients with myeloid malignancies who received HCT following nonmyeloablative or reduced-intensity conditioning. Comparison of nonmyeloablative with myeloablative transplant shows that the myeloablative patients are about 10-15 years younger. Toxicity is a major problem in the elderly who have comorbid conditions, but otherwise the patient has a similar outcome, again emphasizing the graft-versus-leukemia effect. Comparison of patients receiving related or unrelated grafts following nonmyeloablative conditioning shows that the outcome in these patients is similar. These studies have demonstrated encouraging overall survival and nonrelapse mortalities with evidence for graft-versus-leukemia responses in elderly patients with hematologic malignancies. Relapse and progressive disease continued to be problems, particularly in patients with large tumor burdens at time of HCT. Elimination of tumor burden prior to transplant with immunotherapy such as with radiolabeled anti-CD45 antibody or vaccines may improve outcome further.
Best Pract Res Clin Haematol 2007 Mar
PMID:Can reduced-intensity allogeneic transplantation cure older adults with AML? 1733 58


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