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J Mirro

Publications and source records attributed to J Mirro.

At least 91 records · Page 5Linked to original sources
PubMed1988

T cell receptor gene rearrangements in B-precursor acute lymphoblastic leukemia correlate with age and the stage of B cell differentiation.

Children with ALL diagnosed at less than 2 years of age have a poor prognosis when compared with older children. In an effort to identify biologic features of ALL in children less than 2 that might explain this difference, we performed extensive immunophenotypic and molecular genetic analyses on a series of patients. For comparison purposes patients were divided into four groups: CALLA- (CD10-) infants less than 2 years of age at diagnosis (n = 10), CALLA- children greater than 2 years of age at diagnosis (n = 10), CALLA+ infants (less than 2 years, n = 21) and CALLA+ children (older than 2 years, n = 21). No immunophenotyping differences in CALLA- or CALLA+ subgroups were identified when cases less than 2 were compared with cases greater than 2 years of age at diagnosis. The most interesting results were in the CALLA- group where 94% of the samples expressed the B cell antigen CD19 but 27% co-expressed CD7. Double labeling experiments confirmed leukemic blast cells co-expressed CD19 and CD7. The double-labeled cells represent either leukemic conversion of a precursor cell which has not yet committed to B or T cell lineage or aberrant expression of these antigens. Molecular genetic studies demonstrated that all samples, regardless of the patients' age or immunophenotype, had rearrangement of the Ig heavy chain gene. The most striking molecular results were in CALLA- patients; in patients less than 2 at diagnosis neither the beta- nor the gamma-chain gene of the T cell receptor (TCR) was rearranged, whereas DNA from 5 of 10 patients over the age of 2 demonstrated beta- or gamma-chain TCR gene rearrangements. The percentage of CALLA+ cases under the age of 2 years with rearrangements in TCR genes is less than that found in CALLA+ cases over the age of 2 years. The finding of no TCR rearrangements in CALLA- ALL and a decreased number of gamma-TCR rearrangements in CALLA+ cases under the age of 2 suggest that age may affect TCR gene rearrangements in lymphoblasts. The molecular differences in TCR gene rearrangements do not appear to correlate with the response to therapy.

Aging↗
PubMed1988

Intensified chemotherapy for childhood lymphoblastic leukemia: modifications and results of induction treatment in St. Jude Study XI.

The value of intensified chemotherapy for improving event-free survival rates in childhood lymphoblastic leukemia (ALL) is now widely accepted among leukemia therapists. Still to be determined are (1) the optimal method of intensification, (2) the subset or subsets of patients for whom such treatment may be excessive, and (3) whether or not cure rates in ALL can be further improved by alternative approaches to intensification. St. Jude Total Therapy Study XI, based on predictions of the Goldie-Coldmand model of drug resistance, addresses some of these questions by use of rotational "non-cross-resistant" drug pairs throughout the course of therapy. A new method of risk classification has been developed to refine distinctions among prognostic subgroups, especially to identify patients with biologically unfavorable ALL. Unacceptable toxicity noted in the first 134 children enrolled in this study led to two protocol modifications. One hundred thirty-two patients have been treated subsequently without undue toxicity. The treatment is now being delivered safely. Our early experience with this regimen demonstrates some of the hazards of intensive multidrug combination treatment, but gains in leukemia control appear to justify this approach.

Antineoplastic Agents↗
PubMed1988

Acute myeloid leukemia with T-lymphoid features: a distinct biologic and clinical entity.

We studied the clinical and biologic features of 10 cases of acute leukemia that met standard French-American-British (FAB) criteria for acute myeloid leukemia (AML) but in which the blast cells also expressed the T-cell-associated CD2 surface antigen. All cases had greater than 3% myeloperoxidase and Sudan black B-positive leukemic blasts, and blasts from seven cases contained Auer rods. Reactivity of the cells with a panel of monoclonal antibodies (MAbs) indicated that leukemic cells in all cases expressed myeloid-associated (CD11b, CD13) surface antigens, further supporting the diagnosis of AML. However, blasts from every patient coexpressed the T-cell-associated surface CD2 and CD7 as well as cytoplasmic CD3 antigens. Blasts from five patients expressed surface CD25, whereas blasts from only one expressed surface CD3. Five patients had rearranged T-cell receptor beta-chain genes, whereas only three had rearranged T-cell receptor gamma-chain genes. This pattern of lineage-related gene expression appears to define a distinct subtype of AML with T-lymphoid features (CD2+ AML) and could reflect either aberrant gene expression in leukemic blasts or transformation of a pluripotent stem cell having a flexible pattern of gene expression. Clinically, these 10 patients presented at an older age with a higher leukocyte count and a higher frequency of lymphadenopathy than did children whose blast cells were characteristic of myeloid leukemia. Patients with CD2+ AML also had poorer responses to remission induction therapy (50% v 80% entered complete remission, P = .05). However, each of the five children who failed induction chemotherapy on AML protocols had a striking response to drug combinations usually reserved for lymphoid leukemia. We conclude that this leukemia with mixed lymphoid and myeloid characteristics is a distinct biologic and clinical entity.

Adolescent↗
PubMed1987

Comparison of two clonogenic assays for determining cell growth patterns in childhood acute myeloid leukemia: relationships to clinical findings and prognosis.

Bone marrow cells from 99 patients with acute myeloid leukemia were cloned in either agar stimulated by leukocyte feeder layers (AG/F) or methylcellulose supplemented with medium conditioned by phytohemagglutinin stimulation of leukocytes (MC/P). Although cell growth in the two systems was correlated (r = 0.74, p less than 0.0001), there was increased formation and size of clusters and colonies in AG/F, suggesting that the clonogenic cells from children with AML are more readily assayed in AG/F. The number and size of clones in either system did not show a relationship to the morphologic subtype of leukemia. Depending on the scoring system used, increased growth in MC/P was related to abnormal karyotype. Also dependent on scoring system, the ability of leukemic cells to form small clusters in AG/F was associated with resistance to induction therapy: cells of patients with resistant disease were more likely to produce small clusters (p = 0.02). Our results suggest that clonogenic cells from children with AML grow more readily in AG/F than in MC/P, but that neither culture system supports the growth of cells from all patients. Depending on scoring criteria, in-vitro growth patterns in AG/F correlate with response to induction therapy.

Adolescent↗
PubMed1987

Methotrexate bioavailability after oral and intramuscular administration in children.

Although methotrexate is one of the most commonly used drugs for maintenance therapy in childhood acute lymphocytic leukemia (ALL), its oral absorption is highly variable and its intramuscular bioavailability at dosages used for ALL therapy has not been assessed in children. We therefore determined the absolute bioavailability of orally and intramuscularly administered methotrexate in 12 pediatric patients receiving 13 to 120 mg/m2 methotrexate every week as maintenance therapy for ALL. Mean bioavailability, as determined by comparing the area under the concentration-time curve after oral or intramuscular administration with that produced by the same dosage given intravenously, was 33% (range 13% to 76%) for oral (n = 11) and 76% (54% to 112%) for intramuscular (n = 7) administration (P less than 0.01). Median bioavailability (with orally administered dosages less than or equal to 40 mg/m2 (range 13 to 40 mg/m2) was 42% (19% to 76%); at dosages greater than 40 mg/m2 (43 to 76 mg/m2), bioavailability was significantly lower, 17.5% (12.7% to 22.3%, p less than 0.02). Conversely, there was no significant relationship between dosage and bioavailability with intramuscularly administered drug. The substantially higher bioavailability for intramuscularly injected methotrexate may warrant its consideration as an alternative to oral administration, especially for dosages greater than 40 mg/m2.

Administration, Oral↗
PubMed1987

Provocative pattern of rearrangements of the genes for the gamma and beta chains of the T-cell receptor in human leukemias.

To examine the distribution of rearrangements of the gamma- and beta-chain T-cell receptor (TCR) genes in T- and non-T acute lymphoblastic leukemias (ALLs), and potentially to determine which genes rearrange first in ontogeny, we analyzed high molecular weight DNA from 102 patients with acute leukemia. Rearranged gamma- and beta-chain genes were found in all T-cell ALLs (22/22) examined. Overall, 27% (18/66) of B-lineage ALLs had beta-chain gene rearrangements, and 41% (24/58) had gamma-chain gene rearrangements, but the distribution of rearranged genes varied according to the stage of B-cell differentiation. The gamma-chain genes were rearranged in 11% (1/9) of the B-lineage patients negative for the common acute lymphoblastic leukemia antigen (cALLA) and 50% (23/46) of cALLA+ ALL patients, while the beta-chain genes were not rearranged in any of the 7 cALLA- ALL patients examined but were rearranged in 32% (18/56) of the cALLA+ patients. Neither TCR gene was found to be rearranged in acute nonlymphoid leukemia patients (0/12) or in patients with B-cell (surface immunoglobulin-positive) leukemia (0/3). Of the 44 cALLA+ patients in which a direct comparison of gamma- and beta-chain gene rearrangements could be made, 34% had both genes rearranged, 16% had only gamma-chain gene rearrangements, and the remaining 50% had both genes in the germ-line configuration. beta-Chain rearrangements have not been found in the absence of gamma-chain rearrangements, thus supporting a proposed hierarchy of TCR gene rearrangements. A provocative finding was that only a small percentage (11%) of the patients with cALLA- B precursor cell ALLs had rearranged TCR genes, while 50% of the cALLA+ leukemia patients had at least gamma-chain rearrangement, raising a question as to whether indeed cALLA- cells are precursors to cALLA+ cells. Interestingly, 18% (2/11) of the cytoplasmic immunoglobulin (cIg)-positive cALLA+ (pre-B) ALLs involved TCR gene rearrangements, compared to 60% (21/35) of the cIg-negative cases, suggesting the possibility that the majority of functional B cells are derived from the cALLA+ pool that contains immunoglobulin but not TCR gene rearrangements.

Adolescent↗
PubMed1987

Teniposide plus cytarabine improves outcome in childhood acute lymphoblastic leukemia presenting with a leukocyte count greater than or equal to 100 x 10(9)/L.

Childhood acute lymphoblastic leukemia with an initial leukocyte count greater than or equal to 100 X 10(9)/L responds poorly to conventional chemotherapy. To extend event-free survival (EFS) in this disease, we devised a protocol that specifies intensive 2-week courses of teniposide (VM-26, 165 mg/m2) plus cytarabine (ara-C, 300 mg/m2), before and immediately after standard 4-week remission induction therapy with prednisone, vincristine, and L-asparaginase. The VM-26 and ara-C combination was also administered intermittently for the first year of continuation treatment with oral 6-mercaptopurine and methotrexate. CNS prophylaxis consisted of periodic intrathecal (IT) injections of methotrexate and delayed cranial irradiation. At a median follow-up of 4 years, the estimated EFS rate for 57 consecutive patients with leukocyte counts of 100 to 1,000 X 10(9)/L was 44%, compared with 10% for matched controls (P less than .001). Remission induction rates in the two groups were similar (82% v 72%, P = .16). Twenty-five patients in the VM-26/ara-C group have survived without adverse events for 2.7 to 6.8 years, whereas only nine of the controls achieved more than a year of EFS. The most common complications during early treatment were acute hyperkalemia from rapid tumor cell lysis and infections due to prolonged marrow aplasia. Continuation chemotherapy was well tolerated. We conclude that VM-26 plus ara-C, added to each phase of an otherwise basic regimen of chemotherapy, will substantially improve prognosis in this high-risk form of childhood leukemia.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Clinical significance of low levels of myeloperoxidase positivity in childhood acute nonlymphoblastic leukemia.

The clinical significance of a low percentage of myeloperoxidase-positive blast cells in childhood acute nonlymphoblastic leukemia was determined. Of 155 consecutive cases studied by cytochemical staining methods, 14 were characterized by 4% to 15% (median 6%) myeloperoxidase-positive blasts. All 14 cases showed reactivity to Sudan black B stain, and 7 had Auer rods. The morphological subtypes of leukemia were M1 (8 cases), M2 (3), M4 (1), and M5 (2). Immunological marker studies disclosed the lymphoid-associated T11 antigen on cells from 8 of the 11 cases tested. Other lymphoid-related findings in these 8 cases included the T3 antigen and E rosette formation in 1 case each. Among cases that were prospectively studied for the expression of lymphoid-associated markers, 6 of 8 with low levels of myeloperoxidase positivity compared with only 1 of 44 with higher levels (greater than 15%) possessed such features (P less than 0.001). We conclude that low levels of myeloperoxidase reactivity distinguish cases of acute leukemia in which the blast cells coexpress lymphoid (T11 antigen) and myeloid markers.

Acute Disease↗
PubMed1987

T cell differentiation stages identified by molecular and immunologic analysis of the T cell receptor complex in childhood lymphoblastic leukemia.

T cell differentiation was investigated by determining the relationship of T cell receptor (Ti) gene rearrangement and transcription to the expression of surface and cytoplasmic T3 antigen using blast cells from five children with acute lymphoblastic leukemia of thymic origin. Patterns of monoclonal antibody (MoAb) reactivity indicated that these cases were representative of the three recognized stages (I, II, III) of human thymocyte development. The T3 antigen, which becomes linked to the Ti to form a functional T cell receptor complex on mature thymocytes, was expressed on the cell surface in two cases (stage III). However, in the remaining three cases that were surface T3 negative (stages I and II), large amounts of T3 were identified in the cytoplasm by immunoperoxidase staining and flow cytometry. Leukemic blasts from all five patients showed rearranged genes encoding the beta-chain portion of the Ti heterodimer. RNA transcripts of Ti beta-chain genes were also evident in lymphoblasts from all five cases, but transcripts coding for the alpha-chain portion of Ti were found only in cases that expressed T3 on the cell surface. Thus the absence of surface T3 (and presumably Ti) coincides with the absence of Ti alpha-chain RNA, suggesting that transcription of alpha-chain genes is a critical regulatory event in the surface expression of the Ti-T3 complex. Leukemic T cells that rearrange and express Ti beta-chain genes but lack Ti alpha-chain messenger RNA (mRNA) may represent a stage of differentiation analogous to pre-B cells, where heavy-chain immunoglobulin (Ig) genes are rearranged and expressed but light-chain Ig genes are not expressed.

Antibodies, Monoclonal↗
PubMed1986

Phagocytic activity and expression of myeloid-associated cell surface antigens by blast cells in acute lymphoblastic leukemia.

The malignant cells of patients with acute lymphoblastic leukemia (ALL) rarely show phagocytic activity. In this retrospective survey, blasts from 7 of 196 patients with newly diagnosed ALL demonstrated phagocytic activity toward platelets and erythrocytes. The morphology and cytochemical staining properties of the cells were typical of ALL. Immunophenotyes were those of common ALL (CALLA+, HLA-DR+) for six patients and of pre-B-cell ALL (positive cytoplasmic immunoglobulin) for one. However, blast cells from six of the seven patients also reacted with myeloid-associated monoclonal antibodies (MCS.2 and/or SJ-D1). The wide overlap in the percentages of blasts expressing CALLA and those expressing myeloid-associated antigens suggests that some cells possessed both lymphoid- and myeloid-associated surface antigens. By a dual staining technique, two patients tested had blasts expressing antigens of both lineages. Each child achieved a complete remission after treatment with agents effective for ALL and remains in remission for 13+ to 20+ months. These morphologic and immunologic findings may define a distinct subtype of acute leukemia.

Acute Disease↗
PubMed1986

Induction failures in childhood acute nonlymphocytic leukemia: etoposide/5-azacytidine for cases refractory to daunorubicin/cytarabine.

Treatment with a combination of daunorubicin (45 mg/m2 IV, days 1-3) and cytarabine (100 mg/m2 continuous IV infusion, days 4-10) failed to induce complete remission in 31 of 87 children (36%) with acute nonlymphocytic leukemia (ANLL). Six patients with monocytic or promyelocytic leukemia died before day 14 of therapy from complications of hyperleukocytosis and coagulopathy; an additional 10 failed because of fatal infections associated with drug-induced marrow hypoplasia, and the remaining 15 had residual leukemia despite receiving two courses of daunorubicin and cytarabine. Alternative therapy with etoposide (250 mg/m2, IV, days 1-3, 7-9) and 5-azacytidine (300 mg/m2 IV, days 4, 5, 9, 10) induced complete remission in nine (60%) of the 15 patients with resistant leukemia. Among the six children who failed to respond to either regimen, three had cytochemical and immunophenotypic features indicative of acute mixed-lineage leukemia, and one had monosomy 7 syndrome. Our findings suggest that the addition of etoposide and 5-azacytidine to a basic daunorubicin-cytarabine regimen would increase remission induction rates in childhood ANLL. Careful determination of pretreatment characteristics, including blast cell immunophenotype and cytogenetic properties, are needed to identify unusual cases of ANLL that may require selective therapy.

Acute Disease↗
PubMed1986

Unfavorable presenting clinical and laboratory features are associated with CALLA-negative non-T, non-B lymphoblastic leukemia in children.

Twenty-four (5.7%) of 424 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have blast cells that expressed HLA-DR antigens but not the common ALL antigen (CALLA), E-rosette receptors, T-cell antigens, or cytoplasmic or surface immunoglobulins. Each of the eight cases tested expressed the B-cell associated antigen B4, but not B1 or B2 antigen. Myeloid-associated antigens were not present in any of the 10 cases tested. By comparison with common (CALLA+ B-cell precursor) ALL, patients having this immunophenotype were more likely to be children less than 2 yr of age (p less than 0.001), to have higher initial leukocyte counts (p less than 0.001), and to have blast cells with a DNA index less than 1.16 (p = 0.05), a pseudodiploid karyotype (p = 0.01) and a chromosomal translocation (p = 0.003). The presence of any chromosomal translocation in these CALLA- ALL was related to measures of increased leukemic cell burden including higher leukocyte counts, larger liver and spleen sizes and higher serum lactic dehydrogenase levels. While the patients were entered into several treatment arms of two protocols, the CALLA- cases appeared to have lower remission rate (p = 0.06) and shorter event-free survival time (p = 0.05) than did those with common ALL. The association with clinical and laboratory features of known adverse prognostic significance provides some explanation for the poor treatment outcome of CALLA- ALL.

Antigens, Neoplasm↗
PubMed1986

Results of treatment of advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia with high-dose fractionated cyclophosphamide and coordinated high-dose methotrexate and cytarabine.

To address the problem of historically poor results in the treatment of children with advanced-stage Burkitt's lymphoma and B cell (SIg+) acute lymphoblastic leukemia (ALL), an intensive chemotherapy regimen was devised using the most effective single agents in high-dose short courses. Treatment commenced with a fractionated schedule of intravenous (IV) cyclophosphamide (300 mg/m2 every 12 hours for six doses) followed immediately by Adriamycin (50 mg/m2) and vincristine (1.5 mg/m2) with combined intrathecal (IT) methotrexate and cytarabine. Predictably, this treatment produced virtually complete disappearance of all tumor and profound myelosuppression. Immediately on hematologic recovery, IV high-dose methotrexate (1,000 mg/m2 over 24 hours) followed by IV cytarabine (400 mg/m2 over the next 48 hours) was administered with leucovorin rescue and repeated IT treatments. The treatment sequence described above is repeated four times, with the dose of cytarabine doubled in succeeding courses, up to 3,200 mg/m2. The entire planned therapy required approximately 24 weeks. Since 1981, we treated a total of 29 children with this approach, 19 of whom had massive unresectable intraabdominal tumor. According to initial extent of disease, 17 were classified as stage III, four as stage IV non-Hodgkin's lymphoma (NHL), and eight as B cell ALL. Eight of the 12 patients with stage IV NHL or B cell ALL had initial involvement of the CNS. Twenty-seven of 29 patients (93%) attained a complete remission. Fourteen of 17 stage III NHL patients remain disease free, for periods ranging from 3+ months to 4 1/2+ years. The actuarial estimate of the proportion of stage III patients remaining disease free at 2 years is 81%. Results in patients with initial involvement of the CNS and/or marrow are much less favorable, with only two of ten patients who attained remission apparently being cured. In addition to stage, the initial serum lactic dehydrogenase (LDH) level emerged as a prognostic indicator, higher levels (over 1,000 IU/L) being associated with the worst prognosis (P less than .05). Major toxicity consisted of severe hematopoietic suppression and febrile episodes associated with neutropenia. We conclude that this treatment is highly effective for advanced-stage Burkitt's tumors in children free of initial CNS involvement.

Actuarial Analysis↗
PubMed1986

Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin.

We examined the arrangement of the mu heavy-chain immunoglobulin (Ig) genes in the leukemic blast cell DNA of 93 children with acute lymphoblastic leukemia (ALL). All cases met morphologic and cytochemical criteria for ALL, lacked detectable T cell surface antigens, and expressed HLA-DR (Ia) antigens. Eighty-three of the 93 patients (89%) were positive for the common acute lymphoblastic leukemia antigen (CALLA), and 20 of 91 (22%) tested had detectable cytoplasmic immunoglobulin. As expected, the heavy-chain lg gene was rearranged in all cases, and the pattern of rearrangements was variable; 23 had one allele rearranged and one in the germ line configuration; 15 had one rearranged and one deleted; and 37 had two rearranged. Unexpectedly, in 18 patients the presence of more than two mu gene-hybridizing bands was detected. Combinations of enzymes and heavy-chain gene probes were used to confirm that the extra bands were not the result of underdigestion of the DNA or DNA restriction site polymorphism. In eight of the 18 patients, we identified an extra chromosome 14 as a possible cause of the extra bands' hybridizing to the mu heavy-chain constant-region probe. In the remaining ten patients, the presence of three or four bands hybridizing with the mu probe suggests the presence of two populations of leukemic cells that may have arisen either by separate leukemic transformation events or by clonal evolution of one clone into two related lines. Although preliminary (2-year follow-up), our data suggest that childhood ALL of B lineage with more than two mu heavy-chain genes, but without extra copies of chromosome 14, may be more resistant to therapy.

Adolescent↗