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R A Larson,
M Boogaerts,
E Estey,
C Karanes,
E A Stadtmauer, E L Sievers,
P Mineur,
J M Bennett,
M S Berger,
C B Eten,
M Munteanu,
M R Loken,
J J M Van Dongen,
I D Bernstein,
F R Appelbaum
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ABSTRACT: We analyzed the safety and efficacy of Mylotarg (gemtuzumab ozogamicin, an antibody-targeted chemotherapy consisting of a humanized anti-CD33 antibody linked to calicheamicin, a potent antitumor antibiotic) in the treatment of 101 patients > or =60 years of age with acute myeloid leukemia (AML) in untreated first relapse in three open-label trials. Mylotarg is administered as a 2-h intravenous infusion at 9 mg/m(2) for two doses with 14 days between doses. The overall remission rate was 28%, with complete remission (CR) in 13% of patients and complete remission with incomplete platelet recovery (CRp) in 15%. Median survival was 5.4 months for all patients and 14.5 months and 11.8 months for patients achieving CR and CRp, respectively. CD33 antigen is present on normal hematopoietic progenitor cells; thus, an expected high incidence of grade 3 or 4 neutropenia (99%) and thrombocytopenia (99%) was observed. The incidences of grade 3 or 4 elevations of bilirubin and hepatic transaminases were 24% and 15%, respectively. There was a low incidence of grade 3 or 4 mucositis (4%) and infections (27%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Mylotarg is an effective treatment for older patients with CD33-positive AML in first relapse and has acceptable toxicity.
Leukemia 09/2002; 16(9):1627-36. · 9.56 Impact Factor
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ABSTRACT: Mylotarg (gemtuzumab ozogamicin, CMA-676; Wyeth-Ayerst Laboratories, Philadelphia, PA) recently was approved by the US Food and Drug Administration for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse, age 60 years or older, who are not considered candidates for other types of cytotoxic chemotherapy. In combined phase II studies of 142 patients with CD33-positive acute myeloid leukemia in first relapse, Mylotarg monotherapy was associated with a 30% overall response rate. Although treated patients had relatively high incidences of myelosuppression, hyperbilirubinemia, and elevated hepatic transaminases, the incidences of severe mucositis and infections were low compared with what might be expected in association with conventional chemotherapeutic treatment. Preliminary data in pediatric patients also suggest that the immunoconjugate is reasonably well tolerated. Studies of Mylotarg in combination with anthracycline, cytarabine, and agents that inhibit P-glycoprotein are underway.
Current Opinion in Oncology 12/2001; 13(6):522-7. · 4.10 Impact Factor
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E L Sievers
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ABSTRACT: Gemtuzumab ozogamicin (CMA-676, Mylotarg, an antibody-targeted chemotherapy agent, was recently approved by the FDA for the treatment of patients with CD33+ acute myeloid leukaemia (AML) in first relapse who are 60 years of age or older and who are not considered candidates for other types of cytotoxic chemotherapy. In combined Phase II studies of 142 patients with CD33+ AML in first relapse, gemtuzumab ozogamicin monotherapy was associated with a 30% overall response rate. While treated patients had relatively high incidences of myelosuppression, grade 3 or grade 4 hyperbilirubinaemia (23%) and elevated hepatic transaminases (17%), the incidences of grade 3 or grade 4 mucositis (4%) and infections (28%) were low compared with what might be expected in association with conventional chemotherapeutic treatment. In contrast with the usual in-patient administration of cytarabine and anthracycline-containing induction regimens, a large number of patients were treated with gemtuzumab ozogamicin as outpatients (38% and 41% for the first and second doses, respectively). Two prognostic factors for patients with AML in first relapse, age and duration of complete remission, had relatively little effect on response rates to gemtuzumab ozogamicin. Preliminary data in pediatric patients also suggest the immunoconjugate to be reasonably well tolerated. Studies of gemtuzumab ozogamicin in combination with anthracycline and cytarabine are underway. Gemtuzumab ozogamicin, administered to patients with CD33+ AML in first relapse, has shown overall response rates comparable to conventional agents and a safety profile that appears to be favourable.
Expert Opinion on Biological Therapy 10/2001; 1(5):893-901. · 3.51 Impact Factor
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S L Soignet,
S R Frankel,
D Douer,
M S Tallman,
H Kantarjian,
E Calleja,
R M Stone,
M Kalaycio,
D A Scheinberg,
P Steinherz, E L Sievers,
S Coutré,
S Dahlberg,
R Ellison,
R P Warrell
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ABSTRACT: To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL).
Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study.
Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes.
This study establishes ATO as a highly effective therapy for patients with relapsed APL.
Journal of Clinical Oncology 09/2001; 19(18):3852-60. · 18.37 Impact Factor
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ABSTRACT: Approximately half of children with acute myeloid leukemia (AML) can be cured with contemporary chemotherapy regimens; however, various forms of drug resistance pose considerable obstacles for curing the remaining patients. Recent advances in immunology, cytogenetics, and cellular and molecular biology have provided new insights into fundamental biological differences between leukemic myeloid blasts and their normal counterparts. This article focuses on new technologies involving: (1) antibody- or growth factor-mediated targeting of antigens or growth factor receptors found on AML blasts and restricted sub-groups of normal cells, (2) pharmacologic targeting of the pathologic t(15;17) translocation of acute promyelocytic leukemia with all-trans retinoic acid, (3) pharmacologic and immunologic targeting of mutant RAS oncogenes and related aberrant signaling in AML blasts, and (4) targeting of pathological signaling of the Bcr-Abl oncoprotein and c-kit tyrosine kinase in myeloid leukemias. These advances herald an exciting new era of AML-specific therapies.
Hematology/Oncology Clinics of North America 09/2001; 15(4):677-701, viii-ix. · 2.64 Impact Factor
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ABSTRACT: Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33(+) relapsed AML. However, the contribution of Pgp to gemtuzumab ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for gemtuzumab ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% (P =.003) or 24% (P <.001) among samples from responders. In vitro gemtuzumab ozogamicin--induced apoptosis was also evaluated using an annexin V--based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to gemtuzumab ozogamicin and suggest that treatment trials combining gemtuzumab ozogamicin with MDR reversal agents are warranted. (Blood. 2001;98:988-994)
Blood 08/2001; 98(4):988-94. · 9.90 Impact Factor
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E L Sievers,
R A Larson,
E A Stadtmauer,
E Estey,
B Löwenberg,
H Dombret,
C Karanes,
M Theobald,
J M Bennett,
M L Sherman,
M S Berger,
C B Eten,
M R Loken,
J J van Dongen,
I D Bernstein,
F R Appelbaum
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ABSTRACT: Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse.
The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events.
Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less.
Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.
Journal of Clinical Oncology 08/2001; 19(13):3244-54. · 18.37 Impact Factor
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V Rocha,
J Cornish, E L Sievers,
A Filipovich,
F Locatelli,
C Peters,
M Remberger,
G Michel,
W Arcese,
S Dallorso, [......],
A Woolfrey,
A L Pay,
A Green,
F Garnier,
I Ionescu,
P Wernet,
G Sirchia,
P Rubinstein,
S Chevret,
E Gluckman
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ABSTRACT: In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBTs) or bone marrow transplants, 541 children with acute leukemia (AL) transplanted with umbilical cord blood (n = 99), T-cell-depleted unrelated bone marrow transplants (T-UBMT) (n = 180), or nonmanipulated (UBMT) (n = 262), were analyzed in a retrospective multicenter study. Comparisons were performed after adjustment for patient, disease, and transplant variables. The major difference between the 3 groups was the higher number in the UCBT group of HLA mismatches (defined by serology for class I and molecular typing for DRB1). The donor was HLA mismatched in 92% of UCBTs, in 18% of UBMTs, and in 43% of T-UBMTs (P <.001). Other significant differences were observed in pretransplant disease characteristics, preparative regimens, graft-versus-host disease (GVHD) prophylaxis, and number of cells infused. Nonadjusted estimates of 2-year survival and event-free survival rates were 49% and 43%, respectively, in the UBMT group, 41% and 37% in the T-UBMT group, and 35% and 31% in the UCBT group. After adjustment, differences in outcomes appeared in the first 100 days after the transplantation. Compared with UBMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR] = 0.37; 95% confidence interval [95CI]: 0.27-0.52; P <.001), increased 100 day transplant-related mortality (HR = 2.13; 95CI: 1.20-3.76; P <.01) and decreased acute graft-versus-host disease (aGVHD) (HR = 0.50; 95CI: 0.34-0.73; P <.001). T-UBMT recipients had decreased aGVHD (HR = 0.25; 95CI: 0.17-0.36; P <.0001) and increased risk of relapse (HR = 1.96; 95CI: 1.11-3.45; P =.02). After day 100 posttransplant, the 3 groups achieved similar results in terms of relapse. Chronic GVHD was decreased after T-UBMT (HR = 0.21; 95CI: 0.11-0.37; P <.0001) and UCBT (HR = 0.24; 95CI: 0.01-0.66; P =.002), and overall mortality was higher in T-UBMT recipients (HR = 1.39; 95CI: 0.97-1.99; P <.07). In conclusion, the use of UCBT, as a source of hematopoietic stem cells, is a reasonable option for children with AL lacking an acceptably matched unrelated marrow donor.
Blood 05/2001; 97(10):2962-71. · 9.90 Impact Factor
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ABSTRACT: Combination chemotherapy produces remissions in patients with acute myeloid leukemia (AML). However, the majority of patients ultimately relapse and die with cytotoxic drug resistant blasts. Novel agents which circumvent resistance are needed. One such class are AML-cell surface targeted proteins. These genetically engineered polypeptides are hybrid molecules composed of two moieties--a haptophore which triggers AML cell binding and a toxophore which kills the cell. The haptophore or ligand portion consists of a monoclonal antibody or antibody fragment or a cytokine. These peptides react with cell surface receptors or antigens on AML cells. The haptophore is genetically or chemically linked to the toxophore. The toxophore may consist of an antibody Fc domain which triggers antibody-dependent cell cytotoxicity, a DNA-damaging cytotoxic drug, a radionuclide or a protein synthesis-inactivating peptide toxin. The toxophore may provide a cell death signal that overcomes standard resistance phenotypes. Further, the targeting provided by the haptophore may reduce normal tissue toxicities. This review describes some of the properties of the cell surface molecular targets, the reactive haptophores and toxophores and how these functional peptides have been optimally combined to kill leukemic blasts in patients with AML.
Cancer Biotherapy and Radiopharmaceuticals 11/2000; 15(5):459-76. · 1.79 Impact Factor
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ABSTRACT: Children with neurofibromatosis type 1 (NF1) carry germline mutations in one allele of the NF1 gene and are predisposed to myeloid malignancies, particularly juvenile myelomonocytic leukemia (JMML). Disruption of the remaining NF1 allele can be found in malignant cells. Flow cytometric cell sorting techniques to isolate the malignant cell populations and molecular genetic methods to assay for somatic loss of the normal NF1 allele were used to study an unusual child with NF1 and JMML who subsequently had T-cell lymphoma. The data show that malignant JMML and lymphoma cells share a common loss of genetic material involving the normal NF1 gene and approximately 50 Mb of flanking sequence, suggesting that the abnormal T-lymphoid and myeloid populations were derived from a common precursor cell. These data support the hypothesis that JMML can arise in a pluripotent hematopoietic cell.
Blood 10/2000; 96(6):2310-3. · 9.90 Impact Factor
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ABSTRACT: A significant proportion of patients with acute leukemia who achieve remission subsequently experience frank relapse of their disease, and their ultimate prognosis is typically poor. Although such disease recurrences have been impossible to predict using standard laboratory techniques, new methods have been studied that identify patients destined to relapse. Sensitive polymerase chain reaction analyses of unique breakpoint fusion regions, and, in cases of acute lymphoblastic leukemia, patient-specific gene rearrangements have been used to detect minimal residual disease. Multiparameter flow cytometry has also been used to identify rare leukemia cells among populations of predominantly normal cells. Because these types of studies in pediatric acute lymphoblastic leukemia have convincingly demonstrated that patients with evidence of minimal residual disease during remission have a much higher incidence of relapse, therapeutic protocols have been initiated that intensify therapy for patients with minimal residual disease detected during remission.
Current Opinion in Hematology 08/2000; 7(4):212-6. · 4.52 Impact Factor
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ABSTRACT: Up to 80% of children with acute myelogenous leukemia treated with intensive chemotherapy achieve remission; however, a large proportion of patients develops recurrent disease. Because interleukin (IL)-2 can induce remission in patients with overt evidence of acute myelogenous leukemia, we hypothesized that it might prevent relapse when administered to patients in first remission after intensive consolidation chemotherapy. A pilot Children's Cancer Group (CCG) trial (CCG-0941) demonstrated the feasibility of this approach, and we initiated a prospective randomized trial (CCG-2961) to further evaluate the safety and potential efficacy of IL-2 therapy in preventing relapse of acute myelogenous leukemia.
In trial CCG-0941, 21 pediatric patients in complete remission following induction and consolidation chemotherapy on protocol CCG-2941 received IL-2 therapy. In CCG-2961, 79 patients in complete remission were randomized as of February 1999 to receive either IL-2 (n = 39) or no further therapy. In both trials, recombinant IL-2 was given at a dose of 9 million IU/m2/d by continuous intravenous infusion for 4 days. After 4 days of rest, IL-2 was resumed at a dose of 1.6 million IU/m2/d for 10 days by continuous infusion. We monitored patients for toxicity and relapse.
The majority of patients treated with IL-2 in these two trials experienced some degree of fever. Seven of 60 patients (12%) had clinically significant rashes, and grade 3 vascular leak syndrome and hypotension have each been observed in five patients (8%). Hypotension resolved promptly after treatment with intravenous fluids. No patients have experienced renal toxicity or required cardiac vasopressors or transfer to an intensive care unit; there have been no treatment-related deaths. Overall, the incidence and severity of adverse events remain similar in the two trials. Total projected accrual to the IL-2 randomization is anticipated to be 326 patients, and relapse and survival data remain blinded.
The dose and schedule of IL-2 used in these two trials continue to be reasonably well tolerated by children with acute myelogenous leukemia in first remission. Any conclusions with regard to efficacy must await completion of the randomized trial.
The cancer journal from Scientific American 03/2000; 6 Suppl 1:S39-44.
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E L Sievers
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ABSTRACT: Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.
Current Opinion in Oncology 02/2000; 12(1):30-5. · 4.10 Impact Factor
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E L Sievers
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ABSTRACT: Traditional chemotherapy for acute leukemia often causes life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target cell surface antigens on leukemic blasts are being evaluated for their cytotoxic effects and as a means of delivering chemotherapeutic agents or radiation directly to malignant cells. It is hoped that this strategy might selectively ablate malignant cells without many of the toxic effects commonly associated with conventional chemotherapy. In acute myeloid leukemia (AML), the cell surface antigens CD33 and CD45 are especially suitable targets. Although CD33 is expressed on AML blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all nonhematopoietic tissues. For that reason, anti-CD33 antibodies have been created to target malignant myeloid and immature normal cells selectively while sparing normal stem cells. Anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. Since the vast majority of leukemias and normal stem cells express the cell surface antigen CD45, another targeting approach allows the delivery of myeloablative radiation to bone marrow and spleen, common sites of leukemic involvement. Consequently, 131I-labeled anti-CD45 antibody has been combined with traditional preparative regimens for patients receiving bone marrow transplantation for acute leukemia. Finally, fusion proteins such as those combining diphtheria toxin with granulocyte-macrophage colony-stimulating factor (GM-CSF) to target the GM-CSF receptor are now being evaluated in clinical trials. Both unconjugated and conjugated antibodies have shown promise in early clinical trials, and may represent appealing therapeutic alternatives for patients with AML.
Cancer Chemotherapy and Pharmacology 02/2000; 46 Suppl:S18-22. · 2.83 Impact Factor
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ABSTRACT: Leukemic blast cells express the CD33 antigen in most patients with acute myeloid leukemia (AML), but this antigen is not expressed by hematopoietic stem cells. We conducted a study to determine whether normal hematopoiesis could be restored in patients with AML by selective ablation of cells expressing the CD33 antigen. In a dose escalation study, 40 patients with relapsed or refractory CD33(+) AML were treated with an immunoconjugate (CMA-676) consisting of humanized anti-CD33 antibody linked to the potent antitumor antibiotic calicheamicin. The capacity of leukemic cells to efflux 3, 3'-diethyloxacarbocyanine iodide (DiOC2) was used to estimate pretreatment functional drug resistance. Leukemia was eliminated from the blood and marrow of 8 (20%) of the 40 patients; blood counts returned to normal in three (8%) patients. A high rate of clinical response was observed in leukemias characterized by low dye efflux in vitro. Infusions of CMA-676 were generally well tolerated, and a postinfusion syndrome of fever and chills was the most common toxic effect. Two patients who were treated at the highest dose level (9 mg/m2) were neutropenic >5 weeks after the last dose of CMA-676. These results show that an immunoconjugate targeted to CD33 can selectively ablate malignant hematopoiesis in some patients with AML.
Blood 07/1999; 93(11):3678-84. · 9.90 Impact Factor
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A E Woolfrey,
T A Gooley, E L Sievers,
L A Milner,
R G Andrews,
M Walters,
P Hoffmeister,
J A Hansen,
C Anasetti,
E Bryant,
F R Appelbaum,
J E Sanders
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ABSTRACT: We analyzed results of 40 infants less than 2 years of age who received bone marrow transplants (BMT) between May 1974 and January 1995 for treatment of acute myelogenous leukemia (AML; N = 34) or myelodysplastic syndrome (MDS; N = 6) to determine outcome and survival performance. Among the AML patients, 13 were in first remission, 9 were in untreated first relapse or second remission, and 12 were in refractory relapse. Patients were conditioned with cyclophosphamide in combination with either total body irradiation (TBI; N = 29) or busulfan (N = 11). Source of stem cells included 6 autologous donors, 15 HLA genotypically identical siblings, 14 haploidentical family members, and 5 unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was methotrexate (MTX) for 17, MTX plus cyclosporine (CSP) for 14, or CSP plus prednisone for 3. Incidence of severe (grade 3-4) regimen-related toxicity was 10% and transplant-related mortality was 10%. Acute GVHD (grades II-III) occurred in 39% of allogeneic patients, and chronic GVHD developed in 40%. Relapse, the most significant problem for patients in this study, occurred in 1 MDS patient and 23 AML patients and was the cause of death for 19 patients. The 2-year probabilities of relapse are 46%, 67%, and 92%, respectively, for patients transplanted in first remission, untreated first relapse or second remission, and relapse. One MDS and 8 AML patients received second marrow transplants for treatment of relapse, and 5 of these survive disease-free for more than 1.5 years. All 6 MDS patients and 11 of 34 AML patients survive more than 1.5 years later. The 5-year probabilities of survival and disease-free survival are 54% and 38% for patients transplanted in first remission and 33% and 22% for untreated first relapse or second remission. None of the patients transplanted with refractory relapse survive disease-free. Outcome was significantly associated with phase of disease at transplantation and pretransplant diagnosis of extramedullary disease. Long-term sequelae included growth failure and hormonal deficiencies. Survival performance was a median of 100% (80% to 100%) and neurologic development for all survivors was appropriate for age. This study indicates that infants with AML have similar outcome after BMT compared with older children and that BMT should be performed in first remission whenever possible. In addition, allogeneic BMT provides effective therapy for the majority of infants with MDS.
Blood 12/1998; 92(10):3546-56. · 9.90 Impact Factor
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ABSTRACT: Although remission can be achieved in 80% of children with acute myelogenous leukemia (AML), many patients experience relapse. Because interleukin-2 (IL-2) can induce remission in patients with overt evidence of AML, we hypothesized that IL-2 given to patients in first remission after intensive consolidation chemotherapy might prevent relapse. This study sought to determine whether such an approach was feasible.
Twenty-one patients in complete remission received IL-2 after completion of treatment on Children's Cancer Group (CCG) protocol 2941. Recombinant IL-2 9 x 10(6) IU/m2 daily by continuous intravenous infusion (c.i.v.) was given for 4 days. After 4 days rest, IL-2 1.6 x 10(6) IU/m2 daily c.i.v. was resumed for 10 days. We monitored patients for toxicity and measured absolute lymphocyte count, the absolute count of cells that express CD56 and CD3 antigen, and soluble IL-2 receptor alpha-chain (sIL-2R alpha) levels before the start of IL-2 and after completion of each of the two courses of IL-2.
Observed toxicities included fever (57%), vascular leak (48%), hypotension (38%), tachycardia (14%), rash (29%), septicemia (5%), thrombocytopenia (29%), elevated transaminase (14%), electrolyte disturbance (29%), and hyperglycemia (10%). No patient required cardiac pressors or transfer to an intensive care unit. All patients studied developed an increase in lymphocyte count, CD56 count, CD3 count, and sIL-2R alpha levels after treatment with IL-2.
This schedule of IL-2 was reasonably well tolerated by children with AML in first remission. After treatment, increased levels of sIL-2R alpha were observed. CCG is conducting a randomized prospective trial to assess the efficacy of IL-2 to prevent the relapse of AML (CCG-2961).
Journal of Clinical Oncology 03/1998; 16(3):914-9. · 18.37 Impact Factor
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ABSTRACT: Expression of T, sialosyl-T and disialosyl-T antigens on normal blood and bone marrow cells as well as transformed cells was examined using specific monoclonal antibodies and multidimensional flow cytometry. Both anti-sialosyl-T (QSH1) and anti-disialosyl-T (QSH2) monoclonal antibodies aggregated erythrocytes. The anti-disialosyl-T antibody was specific for the erythroid lineage and did not react with neutrophils, monocytes or T-lymphocytes, while the anti-sialosyl-T antibody reacted with erythroid cells and a subset of T-lymphocytes. The developing erythroid cells in bone marrow showed coordinate expression of glycophorin A and the two carbohydrate chains, sialosyl-T and disialosyl-T. Analysis of neoplastic cells showed that the anti-disialosyl-T antibody only reacted with glycophorin A-positive blasts from erythroleukemia (FAB M6) patients (4/4) and one patient with chronic myeloid leukemia in erythroblastic transformation (CMLET). Leukemic blasts from these patients demonstrated coordinate quantitative expression of glycophorin A and disialosyl-T. The anti-sialosyl-T antibody reacted with glycophorin A-positive blasts from FAB M6 patients (4/4) and one CMLET patient; however, the antibody also reacted with glycophorin A-negative blasts from one FAB M6 and the one CMLET patients and transformed cells from other types of leukemia. The anti-T monoclonal antibody (HH8) did not react with any of the other cells tested. These results indicate that glycophorin A and disialosyl-T expression are tightly linked during normal erythroid development and erythroid leukemogenesis.
Leukemia and Lymphoma 06/1997; 25(5-6):403-14. · 2.58 Impact Factor
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ABSTRACT: Children with neurofibromatosis type 1 (NF1) are at increased risk of developing malignant myeloid disorders, particularly juvenile chronic myelogenous leukemia/juvenile myelomonocytic leukemia (JCML/JMML). We investigated bone marrows from 11 such patients (8 boys and 3 girls) and detected allelic losses at the NF1 locus in 4 of them and probable losses in 2 others. To determine which hematopoietic cell lineages were derived from the abnormal clones, Epstein-Barr virus (EBV)-transformed cell lines and CD34+ cells were analyzed from 3 children with JCML with allelic losses in unfractionated marrow. CD34 cells from these 3 patients lacked the normal NF1 allele, whereas EBV cell lines retained it. Erythroblasts plucked from the burst-forming unit-erythroid colonies of one of these children lacked the normal NF1 allele. We also studied a 10-month-old boy with NF1 who developed an unusual myeloproliferative syndrome. His bone marrow and EBV cell line both showed loss of the normal NF1 allele. In our series and in the literature, male sex and maternal transmission of NF1 were associated with the highest risk of myeloid leukemia. These data (1) provide strong genetic evidence that NF1 functions as a tumor-suppressor in early myelopoiesis, (2) confirm the clonal nature of JCML/JMML, (3) suggest that the elevation in fetal hemoglobin seen in JCML/JMML is a result of primary involvement of erythroid progenitors in the malignant clone, (4) show consistent loss of NF1 in the CD34 cells of affected children and show that the malignant clone may also give rise to pre-B cells in some cases, and (5) implicate epigenetic factors in the development of leukemia in children with NF1.
Blood 01/1997; 88(11):4314-20. · 9.90 Impact Factor
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ABSTRACT: Most patients receiving therapy for acute myeloid leukemia (AML) enter an interval in which leukemic blast cells cannot be detected by light microscopy (i.e., morphologic remission). However, many of these patients experience a subsequent relapse. Multidimensional flow cytometry, which allows the discrimination of antigens expressed on normal and malignant cells, can detect small numbers of cancer cells in bone marrow or peripheral blood specimens. This technique enables the detection of one leukemic blast cell among 10(3) to 10(2) normal regenerating hematopoietic cells.
We determined whether the presence of residual leukemic blast cells, identified in the bone marrow of pediatric patients with AML by use of multidimensional flow cytometry, would be predictive of subsequent leukemic relapse.
Multidimensional flow cytometry was performed on 205 marrow specimens collected throughout the course of treatment from 39 patients who had achieved morphologic remission. The analyses employed monoclonal antibodies directed against CD45 in combination with mixed pairs of monoclonal antibodies directed against 10 other antigens. A time-varying Cox regression analysis that controlled for sample time intervals, age, sex, morphologic classification of disease, and white blood cell count at diagnosis was used to relate the multidimensional flow cytometric results to the risk of relapse after achieving remission. Reported P values are two-sided.
Thirty-five of the 39 patients had bone marrow specimens available from the time that first morphologic remission was achieved. Leukemic blast cells were detected in the specimens from 19 (54%) of these 35 patients. Twenty-five of the 35 patients did not receive an allogeneic (i.e., from a different genetic background) bone marrow transplant during first morphologic remission, and 13 of 14 with residual leukemic cells experienced a relapse at a median time of 153 days after diagnosis (range, 48-863 days). Nine of the 11 patients who did not receive an allogeneic bone marrow transplant and lacked evidence of leukemic blast cells at first morphologic remission relapsed at a median time of 413 days after diagnosis (range, 321-794 days). Among the 10 individuals who received an allogeneic bone marrow transplant during first morphologic remission, five were positive for leukemic blast cells and five were negative; one of these patients (positive for leukemic blast cells) experienced a relapse 265 days after diagnosis, and three others died of transplant-related complications. The estimated risk of relapse during intervals of multidimensional flow cytometric positivity (i.e., intervals of remission for which the immediately preceding cytometry measurement was positive) was 2.8 times greater than that during negative intervals (95% confidence interval = 1.1-7.0; P = .02).
Multidimensional flow cytometry identifies residual leukemia in more than half of the patients with AML who are in morphologic remission. The detection of leukemic blast cells in these patients by multidimensional flow cytometry is predictive of a more rapid relapse.
JNCI Journal of the National Cancer Institute 11/1996; 88(20):1483-8. · 13.76 Impact Factor
