Yttrium-90/indium-111-DOTA-peptide-chimeric L6: pharmacokinetics, dosimetry and initial results in patients with incurable breast cancer.

BACKGROUND: Radioimmunotherapy (RIT) using 131I-Chimeric L6 (ChL6) antibody has shown therapeutic promise for patients with breast cancer. To enhance this potential, a novel immunoconjugate was developed that targets adenocarcinomas like breast cancer and tightly binds yttrium-90 (90Y) for therapy and indium-111 (111In) for imaging. The radioimmunoconjugate consists of a macrocyclic chelator (DOTA) linked to ChL6 by a catabolizable peptide. 90Y-DOTA-peptide-ChL6 was designed to minimize the radiation dose to critical normal tissues, thereby improving the therapeutic index. MATERIALS AND METHODS: Three patients with incurable metastatic breast cancer received 90Y/111In-DOTA-peptide-ChL6 for 5 pharmacokinetics/dosimetry studies and one of these patients also received 2 therapy doses. Quantitative imaging of 111In and in vitro assay of 90Y and 111In in blood urine and bone marrow samples were obtained. RESULTS: 90Y/111In-DOTA-peptide-ChL6 was prepared at high purity and was stable in vivo. Assays of bone marrow revealed no evidence for escape of 90Y or 111In from the chelate. 111In imaging of tumors was excellent, providing a therapeutic index for tumor to marrow radiation as high as 229 to 1. 90Y and 111In provided comparable pharmacokinetics, as did tracer and therapeutic doses of radioimmunoconjugates. One patients that received 2 therapeutic doses of 90Y-DOTA-peptide-ChL6 showed regression of tumors and tumor markers. Toxicities were relatively minor and no anti-globulin response developed despite 5 immunoconjugate infusions. CONCLUSIONS: This first study in patients of radioimmunoconjugates with a catabolizable linker between the metal chelator and the antibody confirmed that these novel 90Y/111In-DOTA-peptide-ChL6 radioimmunoconjugates have significant potential. Tracer doses of 111In-DOTA-peptide-ChL6 for imaging predicted the behavior of therapeutic doses of 90Y-DOTA-peptide-ChL6. The latter radioimmunoconjugate induced regression of tumors and tumor markers without significant toxicity. When compared to earlier 131I-ChL6 dosimetry, 90Y-DOTA-peptide-ChL6 provided a therapeutic index several times better.

A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study.

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.

Carboplatin infusion in relapsed and refractory acute myeloid leukemia--a Southwest Oncology Group trial.

Carboplatin (CBDCA) is an active agent in the treatment of acute leukemia and is associated with limited extramedullary toxicity. Simultaneous phase II trials were conducted by the Southwest Oncology Group in adult patients with relapsed or refractory acute myeloid leukemia (AML). CBDCA was given as a continuous infusion at a dose of 300 mg/m2 daily for 5 days. Three (8%) of the 37 eligible patients in the relapsed group achieved complete remissions (CRs) lasting 3, 4, and 26 months. Entry of patients was stopped early in the refractory group due to slow accrual and in the relapsed group due to low CR rate. For both groups combined, the CR rate was 3/45 or 7% (95% confidence interval 3-18%). There were 12 fatal toxicities. Four patients died of intracerebral hemorrhage, three of infection, and five of hepatic and/or renal failure. Nonhematologic grade 4 toxicity included diarrhea in three patients, hyperbilirubinemia in four, and mucositis and renal toxicity in one each. These results suggest that CBDCA should not be considered for treatment of relapsed or refractory AML patients with prior high-dose therapy.

Impact of reinduction regimens for relapsed and refractory acute lymphoblastic leukemia in adults.

The clinical outlook for adults with acute lymphoblastic leukemia (ALL) has improved with the use of intensive chemotherapy. Complete remissions (CR) are achieved in 80% of adults but the majority relapse on maintenance chemotherapy and a few exhibit primary resistance to induction therapy. This report compares the various salvage treatments and provides guidance in selecting a regimen with the optimum clinical outcome. Regimens using high-dose ara-C (HDAC) in combination with mitoxantrone, amsacrine, or idarubicin are superior to HDAC alone or with L-asparaginase. The sequential administration of methotrexate and L-asparaginase is equally effective. The duration of second CR is short for all chemotherapeutic regimens.

Trisomy 21 and cystic hygromas in early gestational age fetuses.

Chromosomal aberrations are associated with 60% of cystic hygromas and the majority of these are females with a 45,X karyotype. Trisomy 21 has rarely been reported. Six cases of cystic hygromas with trisomy 21 were detected during a 6-month time period in our laboratory. An earlier gestational age of 14 weeks was present in our cases compared with a gestational age of 18 weeks reported in the literature. Because of the high rate of fetal loss prior to 16 weeks, many cases of trisomy 21 with cystic hygromas may go undetected. This suggests that cystic hygromas detected before 16 weeks of gestation may be clinically different from those detected later in gestation. With the increasing use of chorionic villus sampling and amniocentesis at 10 to 12 weeks of gestation, trisomy 21 may be a common finding in fetuses with cystic hygromas.

Banding resolution of human chromosomes: a method of accuracy and simplicity.

Methods of estimating chromosome band resolution have been published but their accuracy has not been established. Banding resolution was determined by 4 methods which included a computerized linear correlation, the sum of bands on chromosomes 1 and 2, interpolation of the number of bands on chromosome 10, and interpolation of the number of bands on chromosomes 1p, 10, 11p, 12q, and X. The sum of bands on chromosomes 1 and 2 multiplied by 6 is the most accurate and simple. The use of a simple and reliable method is important for cytogenetic laboratories to document quality assurance of routine chromosome analyses, to enhance the exchange of information between laboratories, and to establish criteria for appropriate band resolution for specific types of specimens.

Correlation of marrow iron patterns with disease status of chronic myelogenous leukemia.

Greater than 80% of patients in the stable phase of chronic myelogenous leukemia (CML) have no detectable stainable iron in the marrow yet have normal serum iron, total iron binding capacity, and serum ferritin values. We studied the pattern of marrow iron in 187 marrow aspirates from 67 patients with Philadelphia chromosome positive CML in the chronic, accelerated and blast crisis stages. Sequential marrow aspirates in 30 patients confirm that the switch from negative iron to positive iron is coincident with the development of the accelerated phase of blast crisis of CML. Our data suggest that the pattern of marrow iron staining in CML is a useful prognostic indicator of the disease evolution.

HRX involvement in de novo and secondary leukemias with diverse chromosome 11q23 abnormalities.

Chromosome band 11q23 is a site of recurrent translocations and interstitial deletions in human leukemias. Recent studies have shown that the 11q23 gene HRX is fused to heterologous genes from chromosomes 4 or 19 after t(4;11)(q21;q23) and t(11;19)(q23;p13) translocations to create fusion genes encoding proteins with structural features of chimeric transcription factors. In this report, we show structural alterations of HRX by conventional Southern blot analyses in 26 of 27 de novo leukemias with cytogenetically diverse 11q23 abnormalities. The sole case that lacked HRX rearrangements was a t(11;17)-acute myeloid leukemia with French-American-British M3-like morphology. We also analyzed 10 secondary leukemias that arose after therapy with topoisomerase II inhibitors and found HRX rearrangements in 7 of 7 with 11q23 translocations, and in 2 of 2 with unsuccessful karyotypes. In total, we observed HRX rearrangements in 35 leukemias involving at least nine distinct donor loci (1q32, 4q21, 6q27, 7p15, 9p21-24, 15q15, 16p13, and two 19p13 sites). All breakpoints localized to an 8-kb region that encompassed exons 5-11 of HRX, suggesting that fusion proteins containing similar portions of HRX may be consistently created in leukemias with 11q23 abnormalities. We conclude that alteration of HRX is a recurrent pathogenetic event in leukemias with 11q23 aberrations involving many potential partners in a variety of settings including acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia in blast crisis, and topoisomerase II inhibitor-induced secondary leukemias of both the myeloid and lymphoid lineages.

Unique clinical features and prognostic significance of the translocation (6;11) in acute leukemia.

A translocation (6;11)(q26-27;q23) was detected in four male patients diagnosed with acute T-cell lymphoblastic leukemia and acute myelomonocytic and monocytic leukemias. This acquired reciprocal translocation appears to be associated with acute leukemias in young men who present clinically with localized infection, and a moderate leukocytosis. There was a poor response to antileukemic chemotherapy and a short overall survival. Aggressive treatment strategies should be considered in the treatment of these high-risk leukemias.

Impact of polydonor mixed lymphocyte culture media on quantity and quality of myeloid metaphases.

A novel mitotic stimulator of myeloid hematopoietic cells was prospectively evaluated to detect enhanced quantity and quality of metaphases from bone marrow (BM) cultures for cytogenetic analysis. This polydonor mixed lymphocyte conditioned (PMLC) media decreased the culture failure rate, improved detection of chromosomal aberrations, and reduced technologists' analysis time. The conditioned media is recommended as a highly effective culture system for normal and neoplastic cells of myeloid lineage.

Blood transfusion reactions. Which are life-threatening and which are not?

Adverse reactions occur acutely or some time after the fact in 20% of all blood transfusions. Since reactions are so common, it is important to recognize quickly whether the reaction is easily correctable or serious enough to force discontinuation or modification of treatment. The authors present a practical discussion of the topic, classifying reactions in terms of clinical presentation rather than pathophysiologic description.

A three-point approach to anemia.

Anemia is a sign of underlying disease that is causing blood loss, sequestration of red blood cells (RBCs), impaired RBC production, or primary marrow dysfunction. The most efficient clinical approach to a patient with anemia is to ask the following three questions: Is the anemia microcytic, macrocytic, or normocytic? Is pancytopenia present? Is the marrow response appropriate for the anemia as determined by the reticulocyte count? Answers to these questions focus laboratory evaluation on a logical progression and avoid a costly shotgun approach.

Rapid improvement of thrombotic thrombocytopenic purpura with vincristine and plasmapheresis.

Many patients with thrombotic thrombocytopenic purpura (TTP) fail to respond to daily plasmapheresis and the results of alternative treatments have been inconsistent. Vincristine was given weekly with continued plasmapheresis to eight patients who were refractory to plasmapheresis, antiplatelet agents, and/or corticosteroids. A rapid response to the vincristine occurred in all eight patients in 5 days with a marked rise in the platelet count and resolution of symptoms. The results in these patients suggest that early initiation of vincristine therapy in conjunction with plasmapheresis is useful in TTP.

Analysis of mosaic states in amniotic fluid using the in-situ colony technique.

Appropriate counselling and clinical management of the pregnant woman with a mosaic amniotic fluid cell karyotype are difficult. The majority of the data on mosaicism and pseudomosaicism are derived from studies employing the flask technique for the analysis of amniotic fluid cell cultures. Since the majority of laboratories now utilize the in-situ technique, such data may not be relevant when analyzing results from the in-situ colony technique. We reviewed the incidence of mosaicism in 6339 amniotic fluid samples using the in-situ technique. Data are presented on the types of aberrations and clinical outcomes. A classification of mosaicism is presented that distinguishes mosaicism of clinical importance from that which is obviously of extrafetal origin or artifactual. This approach clarifies the significance of mosaic states detected by the in-situ colony technique and provides a rational foundation for genetic counselling and for planning clinical interventions.

Impact of reinduction regimens on the clinical course of adult acute nonlymphocytic leukemia.

All clinical studies in the English literature from 1976 to mid-1987 that address drug management of refractory or relapsed ANLL are reviewed and summarized. We conclude that, although many regimens may induce a CR, none is clearly superior. New drugs and or drug combinations must be sought if treatment outcomes are to be substantially improved. At present it appears that combination chemotherapy with VP-16 has not been extensively studied and may be active in non-cross-resistant regimens.

Improved approach to patients with normocytic anemia.

A precise cause for normocytic anemia can be determined through applied pathophysiology. Examination of the peripheral blood smear may yield evidence of renal disease, liver disease, hemolysis or megaloblastic anemia. A reticulocyte count is performed next; then the creatinine clearance is determined. Bone marrow aspiration with iron stain should further narrow the cause. Physical examination and family history remain important in determining the etiology of normocytic anemia.

Diagnostic and prognostic significance of t(1;3)(p36;q21) in the disorders of hematopoiesis.

We describe a cytogenetic abnormality with important diagnostic and prognostic implications. The translocation t(1;3)(p36;q21) is an acquired chromosomal rearrangement associated with myelodysplastic syndromes, which have a high propensity for conversion to refractory acute nonlymphocytic leukemia.

Mast cell disease followed by leukemia with clonal evolution.

A 29-yr old woman developed urticaria pigmentosa which subsequently progressed through systemic mastocytosis to Philadelphia chromosome negative (Ph neg) chronic myelogenous leukemia (CML) with t(8;17). Further cytogenetic evolution occurred at the time of transformation to the aggressive phase of the disease. Unlike Ph-positive CML, chromosome number 9 was not involved, nor was the breakpoint cluster region located at band 22q11. This clearly separates this case from other Ph-negative CML patients who do have involvement of 9q34 or the breakpoint cluster region. Since this is the first case of its type to be reported with cytogenetic abnormalities, the clinical relevance of the unique chromosomal rearrangement t(8;17)(p11;q25) in the setting of systemic mastocytosis is unclear. Additional cases need to be reported to determine if this genetic rearrangement is a nonrandom marker of leukemia evolving in a setting of malignant mast cell disease.