Biomedical subjects

D C Arthur

Publications and source records attributed to D C Arthur.

At least 37 records · Page 2Linked to original sources

PubMed1997

MLL gene rearrangement, cytogenetic 11q23 abnormalities, and expression of the NG2 molecule in infant acute myeloid leukemia.

To study prognostic factors in infant acute myeloid leukemia (AML), we analyzed 44 children treated on Childrens Cancer Group protocols for MLL gene rearrangement by Southern blot, cytogenetic 11q23 abnormalities, and reactivity with monoclonal antibody 7.1. This antibody detects the human homologue of the rat NG2 chondroitin sulfate proteoglycan molecule, which has previously been reported to be expressed on human melanoma. NG2 has been found to be expressed on human leukemic blasts but not on other hematopoietic cells. In childhood AML, NG2 cell surface expression correlated with poor outcome and with some but not all 11q23 rearrangements. In childhood acute lymphoblastic leukemia, NG2 expression correlated with poor outcome and with balanced 11q23 translocations. In this study, 29 of 44 (66%) of infants with AML showed MLL rearrangement and, as expected, this group had a high incidence of French-American-British M4/M5 morphology (22/29). Of the cases tested, 35.1% (13/37) were NG2 positive. All (13/13) NG2-positive cases were rearranged at MLL, whereas only 46% (11/24) of NG2-negative cases had MLL rearrangement. NG2 expression did not correlate with poor outcome (P = .31); there was a trend towards a worse outcome with MLL rearrangement (P = .13). Thus monoclonal antibody 7.1 does not detect all cases of MLL rearrangement in infant AML.

Acute Disease↗

PubMed1997

Value of molecular monitoring during the treatment of chronic myeloid leukemia: a Cancer and Leukemia Group B study.

PURPOSE: Disappearance of the Philadelphia chromosome during treatment for chronic myeloid leukemia (CML) has become an important therapeutic end point. To determine the additional value of molecular monitoring during treatment for CML, we performed a prospective, sequential analysis using quantitative Southern blot monitoring of BCR gene rearrangements of blood and marrow samples from Cancer and Leukemia Group B (CALGB) study 8761. PATIENTS AND METHODS: Sixty-four previously untreated adults with chronic-phase CML who were enrolled onto CALGB 8761, a molecular-monitoring companion study to a treatment study for adults with chronic-phase CML (CALGB 9013). Treatment consisted of repetitive cycles of interferon alfa and low-dose subcutaneous cytarabine. Blood and marrow Southern blot quantitation of BCR gene rearrangements was compared with marrow cytogenetic analysis before the initiation of treatment and of specified points during therapy. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis was performed to detect residual disease in patients who achieved a complete response by Southern blot or cytogenetic analysis. RESULTS: Quantitative molecular monitoring by Southern blot analysis of blood samples was found to be equivalent to marrow monitoring at all time points. Twelve of 62 (19%) follow-up samples studied by Southern blot analysis had a complete loss of BCR gene rearrangement in matched marrow and blood specimens. Southern blot monitoring of blood samples was also found to be highly correlated to marrow cytogenetic evaluation at all points, although there were four discordant cases in which Southern blot analysis of blood showed no BCR gene rearrangement, yet demonstrated from 12% to 20% Philadelphia chromosome-positive metaphase cells in the marrow. RT-PCR analysis detected residual disease in five of six patients in whom no malignant cells were detected using Southern blot or cytogenetic analyses. CONCLUSION: Quantitative Southern blot analysis of blood samples may be substituted for bone marrow to monitor the response to therapy in CML and results in the need for fewer bone marrow examinations. To avoid overestimating the degree of response, marrow cytogenetic analysis should be performed when patients achieve a complete response by Southern blot monitoring. This approach provides a rational, cost-effective strategy to monitor the effect of treatment of individual patients, as well as to analyze large clinical trials in CML.

Adult↗

PubMed1997

Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461.

PURPOSE: To examine the prognostic significance of extramedullary leukemia (EML) at presentation in patients with t(8;21)(q22;q22) karyotype. PATIENTS AND METHODS: Consecutive patients with t(8;21) treated on Cancer and Leukemia Group B de novo acute myeloid leukemia (AML) treatment studies were examined for the presence of EML (granulocytic sarcoma, subcutaneous nodules, leukemia cutis, or meningeal leukemia) at initial presentation. Clinical features and outcome of t(8;21) patients with and without EML were compared. RESULTS: Of 84 patients with t(8;21), eight (9.5%) had EML manifesting as granulocytic sarcoma (five paraspinal, one breast, and one subcutaneous) or symptomatic meningeal leukemia (n = 1). The pretreatment prognostic variables of t(8;21) patients with and without EML were similar. The hematologic complete remission (CR) rate for t(8;21) patients with EML was 50% versus 92% for those without EML (P=.006). The median CR duration for EML patients was 14.7 months. Patients with EML had a shorter survival (P = 0.002, median 5.4 months versus 59.5 months). This poor outcome may relate to inadequate local (radiation or intrathecal) therapy for patients with spinal or meningeal EML, resulting in residual/recurrent EML following induction chemotherapy (n = 2) or at relapse (n = 1) and permanent neurologic deficits (n = 4). Only one of the EML patients received high-dose cytarabine (HDAC) intensification; this is the only EML patient remaining alive in CR. CONCLUSION: Patients with t(8;21) and EML have a low CR rate and overall survival. An aggressive local and systemic induction therapy should be considered for this patient subset. The effectiveness of HDAC intensification in t(8;21) patients with EML is uncertain and warrants further study.

Adult↗

PubMed1997

Secondary cytogenetic changes in acute promyelocytic leukemia--prognostic importance in patients treated with chemotherapy alone and association with the intron 3 breakpoint of the PML gene: a Cancer and Leukemia Group B study.

PURPOSE: To examine, in newly diagnosed patients with acute promyelocytic leukemia (APL), the prognostic significance of secondary cytogenetic changes and the relationship between such changes and the two major promyelocytic leukemia-retinoic acid receptor alpha (PML-RAR alpha) mRNA types. PATIENTS AND METHODS: One hundred sixty-one patients with t(15;17)(q22;q11-12) enrolled onto Cancer and Leukemia Group B (CALGB) protocol 8461, a prospective study of cytogenetics in acute myeloid leukemia (AML), were studied. Eighty of these 161 patients were treated solely with chemotherapy and evaluated for response to treatment and survival. PML-RAR alpha mRNA type was determined using reverse transcriptase polymerase chain reaction (RT-PCR) in 56 patients. RESULTS: The incidence of secondary cytogenetic abnormalities was 32%. Among 80 patients treated with chemotherapy, the presence of a secondary chromosome abnormality was associated with longer complete remission (CR) duration (median, 29.9 v 15.7 months; P = .03) and longer event-free survival (EFS) duration (median, 17.0 v 12.2 months; P = .03). There was no difference in overall survival (P = .28). In a separate group of 56 patients with both cytogenetic and molecular data, 32 had the type L PML-RAR alpha transcript (intron 6 PML breakpoint). Of these 32 patients, four (12.5%) had chromosome changes in addition to t(15;17), whereas 12 of 20 patients (60%) with the type 5 PML-RAR alpha transcript (intron 3 PML breakpoint) had secondary cytogenetic changes (P < .001). CONCLUSION: (1) Secondary cytogenetic changes do not confer a poor prognosis in APL patients treated with anthracycline/cytarabine (Ara-C)-based chemotherapy; and (2) A highly significant relationship exists between the PML-RAR alpha 5 isoform (intron 3 PML genomic breakpoint) and secondary cytogenetic changes in APL.

Adolescent↗

PubMed1996

Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group.

Timed sequencing of cycles of induction chemotherapy in acute myeloid leukemia (AML) has been proposed as a way to achieve maximal leukemic cell kill through recruitment and synchronization of residual neoplastic cells. Furthermore, whether intensive induction therapy should be continued in the presence of profound myelosuppression is an important question. The Children's Cancer Group (CCG) conducted a prospective randomized trial in which 589 patients with AML were randomized at diagnosis to one of two induction approaches involving a 4-day cycle of five active chemotherapeutic agents, with the second cycle administered either 10 days after the first cycle, despite low or dropping blood counts (intensive timing), or 14 days or later from the beginning of the first cycle, depending on bone marrow status (standard timing). All patients achieving remission received a total of four cycles of induction therapy. They were then allocated to allogeneic bone marrow transplantation (BMT) if a compatible family donor was present or randomized to aggressive nonmyeloablative therapy or to myeloablative therapy with purged autologous BMT rescue. The three postremission arms remain coded. Induction success and median days to complete induction were similar for the 295 patients randomized to the intensive timing arm (75%, 99 days) compared with the 294 patients randomized to the standard timing arm (70%, 105 days; P = .18 for remission). However, a marked improvement in outcome was demonstrated in patients randomized to the intensive timing arm, with an actuarial event-free survival at 3 years of 42% +/- 7% (95% confidence interval [CI]) versus 27% +/- 6% for patients on the standard timing arm (P = .0005). Disease-free survival results at 3 years from the end of induction were superior for patients receiving intensively timed induction therapy (N = 211), 55% +/- 9% versus 37% +/- 9% for standard timing patients (N = 195, P = .0002), with a median follow-up from achieving remission of 28 months. Superior results were documented for patients receiving intensive timing irrespective of the postremission therapy to which they were allocated. Intensively timed induction therapy for patients with AML markedly improves event-free survival, even for patients undergoing myeloablative therapy with BMT rescue. Without controlling for the type of induction therapy received, results of various BMT studies in AML comparing different preparative regimens will be difficult to interpret.

Acute Disease↗

PubMed1996

Partial tandem duplication of ALL1 as a recurrent molecular defect in acute myeloid leukemia with trisomy 11.

Gains of a single chromosome are frequent cytogenic findings in human cancer, but no molecular rearrangement has been consistently associated with any trisomy. In acute myeloid leukemia (AML), trisomy 11 (+11) occurring as a sole abnormality is the third most common trisomy. We have shown that the ALL1 gene, located at 11q23, can be rearranged as a result of a partial tandem duplication in two such cases of AML. To test the hypothesis that the partial tandem duplication of ALL1 is the recurrent molecular defect in cases of AML presenting with +11 as a sole cytogenic abnormality, we performed Southern analysis and PCR for defects of ALL1 in 17 cases of AML and one case of myelodysplastic syndrome with +11 or +11q but without cytogenic evidence of a structural abnormality involving 11q23. Twelve cases (67%) had rearrangement of ALL1, including 10 of 11 patients (91%) with +11 as a sole abnormality and 2 of 7 cases (29%) with +11 and other aberrations; all were classified as FAB M1 or M2. In 10 of the 12 cases, material was available for additional characterization; a partial tandem duplication of ALL1 was detected in each of these 10 cases (100%). Four cases demonstrated previously unreported duplications, two of which were detectable only by reverse transcription-PCR. Four patients with the ALL1 duplication also displayed a loss of material from 7q, suggesting an association between these two findings. We conclude that the partial tandem duplication of ALL1 is present in most, if not all, cases of AML with +11 as a sole abnormality, and can be found in cases of AML with +11 or +11q accompanied by other cytogenic abnormalities. The duplication is more prevalent in AML than was recognized previously in part because its size and location vary considerably, requiring a variety of molecular probes for detection. Our finding of the ALL1 duplication as a consistent defect in patients with +11 represents the first identification of a specific gene rearrangement associated with recurrent trisomy in human cancer.

Acute Disease↗

PubMed1996

Improved clinical outcome for children with T-lineage acute lymphoblastic leukemia after contemporary chemotherapy: a Children's Cancer Group Study.

The prognostic importance of T-lineage acute lymphoblastic leukemia (ALL) in contemporary programs of intensive chemotherapy has been controversial. We therefore assessed the impact of this biological feature in risk-adjusted frontline chemotherapy studies of the Children's Cancer Group (CCG), conducted from 1983 to 1994. A substantially greater proportion of T-lineage patients (N = 730) presented with poor-risk features as compared to B-lineage patients (N = 3668) treated in the same studies (71.1% vs. 39.7%, P < 0.0001). Consequently, in the CCG-100 series of clinical trials (1983-1989), which tested regimens that were largely of moderate intensity, T-lineage ALL patients had an excess of adverse early events compared to patients in the B-lineage group: 3-year event-free survival (EFS) estimate, 65.8% vs 78.2% (P < 0.0001). With the introduction of more intensive chemotherapy in studies from 1989 to 1994 (CCG-1800 series). We observed a progressive and significant improvement in the clinical outcome of patients with T-lineage immunophenotype. Three- and 5-year EFS probabilities increased from 65.8% to 78.1% and from 61.0% to 75.2%, respectively, becoming comparable to or slightly better than results for B-lineage ALL patients. When adjusted for the competing effects of leukocyte count, age, organomegaly and other poor-risk features, T-lineage immunophenotype showed no important impact on the overall EFS pattern. These findings demonstrate the loss of adverse prognostic by T-lineage ALL in a large program of intensive chemotherapy developed over the past decade.

Adolescent↗

PubMed1996

Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group.

The purposes of this report are to reaffirm concordance difficulties with the acute myeloid leukemia (AML) French-American-British (FAB) classification, to present the frequency of previously delineated AML syndromes in pediatric patients and to describe additional characteristic AML profiles utilizing composite morphologic, cytogenetic and immunophenotypic data. Profiles of 124 children with acute myeloid leukemia (AML) and 13 children with myelodysplastic syndrome entered on the Childrens Cancer Group (CCG) pilot study CCG-2861 were examined. Concordance between institutions and reviewers for FAB designation was 65%. Discordance was found principally between M1 and M2, M2 and M4, and M4 and M5. In 49% of marrow specimens, leukemic blasts expressed at least one T lineage-related antigen; 24% expressed the B lineage-related antigen CD19. CDw14 correlated with FAB M4 or M5 morphology and was the only surface antigen associated with a specific FAB subtype. Normal karyotypes were found for 15% of the 75 children with satisfactory karyotype preparations. Recurring aberrations, found in 76% of children, included t(15;17)(q22;q11), t(8;21)(q22;q22), inv(16)(p13q22), rearrangements of band 11q23, t(6;9) (p23;q34), trisomy 8 and monosomy 7. Results from this pilot study and from the current CCG randomized trial correlating morphology, immunophenotyping and cytogenetics, will help to classify AML into unique subgroups with differing clinical consequences or therapy requirements.

Adolescent↗

PubMed1996

Unrelated donor bone marrow transplantation for Fanconi anemia.

Patients with Fanconi anemia (FA) commonly develop bone marrow failure, which may evolve to myelodysplasia or acute myeloid leukemia (AML). Treatment of these patients is complicated by their marked hypersensitivity to DNA cross-linking agents. In this report we describe the results of allogeneic unrelated donor bone marrow transplantation in seven FA patients, using a low-dose cyclophosphamide (40 mg/kg) and TBI (400-450 cGy) conditioning regimen. Two patients had bone marrow failure with normal chromosomes and no dysplasia prior to transplant. The remaining five had clonal chromosomal abnormalities. One patient had refractory anemia with excess blasts in transformation and two had early AML with 20 and 25% blasts, respectively. Two patients died early (before day 28) without hematological evidence of engraftment, one of veno-occlusive disease and one of infection (fungal). Four of the remaining five patients achieved sustained engraftment after the first marrow infusion; one patient had secondary graft failure requiring repeat marrow infusion but subsequently achieved engraftment. Of five evaluable patients, three had mild (grades I-II) acute GVHD and two had grade IV GVHD, which was fatal in both cases. Two of three evaluable surviving patients have chronic GVHD controlled with immunosuppression. Three patients survive 9 months to 3 years post-unrelated donor BMT: two who had early leukemia and one with severe aplasia at the time of transplant. These data indicate that unrelated donor BMT can be performed successfully in FA patients using cyclophosphamide 40 mg/kg and TBI 400 to 450 cGy, even after evolution to early leukemia. However, significant problems with both GVHD and engraftment remain. Future studies will evaluate the role of T cell depletion in improving the results of unrelated donor marrow transplantation in FA patients.

Adolescent↗

PubMed1996

Related donor marrow transplant for chronic myeloid leukemia: patient characteristics predictive of outcome.

Pre-transplant characteristics of 137 consecutive patients (including 103 patients with one or more features suggesting advanced disease) undergoing related donor marrow transplant for chronic myeloid leukemia (CML) were analyzed to determine their association with outcome. Multivariate analysis identified increased recipient age (relative risk (RR) for patients over 30 years of relapse or death 2.37; P = 0.004), and longer interval between diagnosis and transplant (RR 1.20; P = 0.0001) as significant adverse influences on disease-free survival (DFS). The 5-year DFS for patients transplanted within 1 year of diagnosis (¿early transplant', n = 71) was significantly higher (51%) than that for patients transplanted beyond 1 year from diagnosis ('delayed transplant', n = 55) (34%; log rank P = 0.02). For early transplant patients, poor prognostic features included myelofibrosis (RR 3.53; P = 0.018), splenomegaly (RR 2.22; P = 0.029) and the use of a female donor (RR 3.16; P = 0.002). The 5-year DFS for patients transplanted within 1 year of diagnosis and without signs of advanced disease was 67%. The presence of increasing numbers of features suggesting acceleration prior to transplant had a cumulative adverse influence of DFS. The risk of relapse (5 year estimate 20%) was also independently and significantly increased in association with a longer interval from diagnosis to transplant (P = 0.012). Early transplant is an important influence on DFS and relapse after related donor transplant therapy for CML, although additional patient characteristics influencing outcome can be identified and may have cumulative adverse effects.

Adolescent↗

PubMed1995

Molecular analysis of infant acute lymphoblastic leukemia: MLL gene rearrangement and reverse transcriptase-polymerase chain reaction for t(4; 11)(q21; q23).

Molecular techniques to detect MLL (11q23) and AF-4 (4q21) gene rearrangements are being evaluated for use in stratification of patients into prognostic groups. We studied 15 cases of infant acute lymphoblastic leukemia (ALL) with Southern blotting for MLL gene rearrangement and reverse transcriptase-polymerase chain reaction (RT-PCR) for t(4;11) fusion transcripts and compared the results to cytogenetic and clinical data. Our results indicate that classic t(4;11)(q21;q23) translocations are detected by RT-PCR; however, unusual 4;11 translocations still require additional investigation. We also extended and updated our original study of MLL gene rearrangement in infant ALL to 40 patients with longer follow-up and show that the group with germline configuration of the MLL gene continues to have an excellent outcome. The results of salvage therapy (bone marrow transplantation or chemotherapy) suggest that transplant may show advantage. Preliminary results of the use of RT-PCR to assess minimal disease are also reported.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Acute leukemia and the transient myeloproliferative disorder associated with Down syndrome: morphologic, immunophenotypic and cytogenetic manifestations.

Individuals with Down syndrome have an increased incidence of leukemia compared to the general population. In addition, Down syndrome children may acquire a myeloproliferation that resembles acute leukemia that undergoes a spontaneous, durable remission. To clarify the relationship between these two disorders, the morphologic, immunophenotypic and cytogenetic characteristics of 28 patients with Down syndrome and the morphologic manifestations of acute leukemia were examined. Three cytomorphological groups were discerned. The first two groups consisted of five patients with acute lymphoblastic leukemia (group I) and three patients with acute myeloid leukemia (group II). These leukemias resembled those of non-Down individuals. The third and largest group (group III) consisted of 20 cases of acute myeloid leukemia that showed prominent megakaryocytic and/or erythroid differentiation and occurred in children under 6 years of age. The blasts in this group were non-reactive for myeloperoxidase or non-specific esterase and expressed CD7, CD34 and CD36 with variable expression of CD61, CD13 and CD33. Four patients in this group had an acquired trisomy 8. Four group III leukemias underwent a durable, spontaneous remission within 2 months of diagnosis. There were no morphologic differences between those leukemias in this group that progressed and those that remitted; however, all remissions occurred in newborns. It is concluded that Down syndrome children acquire a characteristic acute myeloid leukemia that has prominent megakaryocytic and/or erythroid differentiation and an unusual immunophenotype. This group of leukemias may undergo a durable, spontaneous remission in the newborn period.

Acute Disease↗

PubMed1994

Myelodysplastic syndrome after autologous bone marrow transplantation: an additional late complication of curative cancer therapy.

Myelodysplastic syndrome (MDS) is a complication of conventional antineoplastic therapy but has rarely been reported after autologous bone marrow transplantation (ABMT). We reviewed records of 206 patients who underwent ABMT for lymphoma at the University of Minnesota (Minneapolis, MN) between 1974 and 1993. Of 206 patients who underwent ABMT for non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD), 9 patients developed an MDS or secondary acute leukemia between 5 and 60 months (median 34 months) post-BMT. Two patients had relapsed after transplant and received additional therapy before the diagnosis of MDS. They were censored from the statistical analysis, resulting in a cumulative incidence of 14.5% +/- 11.6% (95% confidence interval) at 5 years. Three patients (15.2% +/- 18.0%) had HD, and four (14.0% +/- 14.7%) had NHL. In vitro BM purging had no affect on the incidence of MDS, although patients receiving peripheral blood stem cells had a projected MDS incidence of 31% +/- 33% versus 10.5% +/- 12% if BM cells were used (p = .0035). The patients had received a median of 14 cycles (range, 6 to 40) of chemotherapy before autologous transplantation; Five of nine patients received radiation therapy before BMT conditioning, and all patients received radiation before the diagnosis of MDS. No BM cytogenetic abnormalities were evident pretransplant in three of three patients studied, and all nine had normal pretransplant BM morphology. All patients had morphologic BM findings typical of MDS, and six of six studied had clonal cytogenetic abnormalities. At the diagnosis of MDS, all nine patients were without clinical, radiographic, or autopsy evidence of recurrent lymphoma; Three of the nine patients have died from complications of cytopenias at 23, 36, and 45 months after transplant (3 to 10 months after the diagnosis of MDS), whereas 6 survive 8 to 63 months after transplantation (1 to 34 months post-MDS). These data emphasize the cumulative leukemogenic potential of standard and salvage radiation and chemotherapy regimens and highlight treatment-induced MDS as an important and frequent late complication of potentially curative BM transplant therapy.

Adult↗

PubMed1994

Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group.

Cytogenetic analyses of pretreatment bone marrows were performed at local institutions as part of Childrens Cancer Group (CCG) protocol CCG-107 for infants less than 1 year of age with previously untreated acute lymphoblastic leukemia (ALL). Cytogenetic analyses from 39 patients (17 males and 22 females) were accepted after review. Several unique cytogenetic features were observed. Twelve patients (31%) had a t(4;11)(q21;q23) and had a significantly shorter event-free survival (EFS) than did the other patients with adequate cytogenetic analyses (P = .009). Five additional patients had an 11q23 breakpoint, not associated with 4q21. When EFS for these 5 patients was compared with that of the t(4;11) patients, even with these small numbers there was a strong, although not significant, suggestion that the t(4;11) patients have a reduced EFS (P = .09), indicating that the specific translocation, t(4;11)(q21;q23), and not an 11q23 breakpoint per se, may be associated with the poor prognosis of these infants. Structural abnormalities were present in 27 of 28 patients with abnormal karyotypes. A new recurring abnormality, t(5;15)(p15:1;q11) or t(5;15)(p15.3;q13), was identified in 3 patients (Arthur et al, Blood 70:274a, 1987 [abstr, suppl 1]). Two females had structural abnormalities involving Xp11, a breakpoint rarely seen in ALL. Fourteen (36%) patients had a single structural abnormality, and 13 (33%) had complex karyotypes. No patients had hyperdiploidy with more than 50 chromosomes. Only normal chromosomes were observed in 11 patients (28%), and their outcome did not differ from patients with abnormal karyotypes. These cytogenetic abnormalities found in the leukemic cells of infants are clearly different from those in older children and adults, and may explain, in part, the unique biologic characteristics of infant ALL.

Chromosome Aberrations↗

PubMed1994

Prognostic factors for therapeutic outcome of diffuse small non-cleaved cell lymphoma in adults.

Most reports of prognosis and therapy in diffuse small non-cleaved cell lymphoma (DSNCL), an aggressive high-grade non-Hodgkin's lymphoma (NHL) which appears to be of two histopathologic subtypes, have included predominantly a pediatric population and very few adults. We studied 20 newly diagnosed, previously untreated adults with DSNCL. Three patients had Ann Arbor Stage I disease, five Stage II, and 12 Stage IV. Bone marrow involvement was present in seven of 20 (35%) patients; no patient had central nervous system involvement at diagnosis. Clonal chromosomal abnormalities were found on cytogenetic analysis of all 12 cases studied. Ten patients had specific recurring translocations, including t(8;14) (q23;q32) (five patients), t(14;18) (q32;q21) (four patients), and t(2;8) (p12;q24) (one patient). Induction chemotherapy with the COMP regimen (cyclophosphamide, vincristine, methotrexate, and prednisone) or a variant schedule of the same drugs resulted in complete remission for 13 patients (65%), and partial remission for 5 patients (25%). Clinical characteristics predictive of a favorable response to induction therapy included Stage I or II disease, a normal lactic dehydrogenase (LDH), and performance status (PS) of 0 or 1. Remission duration ranged from two to 125+ (median 37+) months. Survival ranged from one to 126+ (median 23) months; ten patients (50%) remain alive, nine with no active disease. Factors predictive of longer survival included achievement of a complete remission with induction therapy, a normal LDH, and PS 0 or 1. As in children with DSNCL, long-term disease-free survival may be achieved in adults with combination chemotherapy.

Adolescent↗

PubMed1994

L3 acute lymphoblastic leukemia. Comparison with small noncleaved cell lymphoma involving the bone marrow.

The relationship between acute lymphoblastic leukemia (ALL-L3) and stage IV small noncleaved cell lymphoma with bone marrow involvement (SNCL) was analyzed by retrospective study of 45 patients. Twelve patients with ALL-L3 had tumour restricted to the marrow and blood with no evidence of an extramedullary tumor at their initial presentation. Nineteen patients with stage IV SNCL had evidence of extramedullary disease in addition to marrow and blood involvement. Fourteen patients with marrow and blood involvement by SNCL at the time of a first or second relapse were also studied. The median age of the ALL-L3 patients was 33.5 years, compared with 13 years for the patients with stage IV SNCL and 10.5 years for the marrow relapse patients. All of the ALL-L3 patients wre male; the male:female ratio for the SNCL patients was 17:2; for the relapse group, 9:5. The majority of the ALL-L3 patients had symptoms related to bone marrow failure; the majority of the SNCL patients had symptoms related to a tumor mass. Laboratory values at the time of initial diagnosis were similar for the ALL-L3 and SNCL patients, except that the median platelet count was lower in the ALL-L3 group. Despite extensive marrow involvement by tumor in most patients, frankly leukemic blood pictures were uncommon. Light-chain-restricted surface immunoglobulin on tumor cells was a consistent finding in all cases tested; the findings were similar in the three groups. Cytogenetic data, available for 19 cases, showed no difference between cases with and without extramedullary disease. The median survival was 5.1 months for ALL-L3 patients and 3.2 months for SNCL patients. The median survival from the time of bone marrow relapse was 2.3 months. These observations suggest that ALL-L3 and SNCL represent different manifestations of the same disease process.

Adolescent↗

PubMed1994

Molecular rearrangements of the MLL gene are present in most cases of infant acute myeloid leukemia and are strongly correlated with monocytic or myelomonocytic phenotypes.

Cytogenetic studies have previously identified abnormalities of chromosome band 11q23 in many cases of infant acute leukemia. Recent studies by ourselves and others have demonstrated breakpoint clustering in acute leukemias bearing translocations involving 11q23, and a Drosophila trithorax gene homologue (called MLL, HRX, or ALL-1) has been shown to span the 11q23 breakpoints of these translocations. To determine if this gene is affected in infant acute myeloid leukemia (AML), we have analyzed 26 infant AML cases for molecular alterations of this 11q23 gene. 15 out of 26 cases studied (58%) showed rearrangement of the MLL gene at the molecular level, and these rearrangements were clustered within an approximately 11-kb region containing nine exons of this gene. Moreover, 14 of the 15 cases with 11q23 rearrangements (93%) had myelomonocytic or monocytic phenotypes (M4 or M5 FAB subtypes, respectively), both of which are associated with a poor prognosis in childhood AML. In contrast, only 1 of 11 nonrearranged cases had an M4 or M5 phenotype (P = 0.00002). Rearrangement also correlated significantly with hyperleukocytosis (P = 0.02), another clinical parameter associated with poor outcome in this disease. Our results demonstrate that molecular rearrangements of MLL are common in M4 or M5 infant AML, and suggest that alteration of this gene may result in abnormal control of proliferation and differentiation in monocytic progenitor cells.

Acute Disease↗

PubMed1994

Fluorescence in situ hybridization (FISH) detection of trisomy 8 in myeloid cells in chronic myeloid leukemia (CML): a study of archival blood and bone marrow smears.

Patients in accelerated phase or blast crisis of chronic myeloid leukemia (CML) frequently develop clonal cytogenetic abnormalities in addition to the Philadelphia chromosome. Using a DNA probe directed to the centromere of chromosome 8, we performed fluorescence in situ hybridization (FISH) on archival Wright-stained blood and bone marrow smears of seven patients with CML and with a known +8 clone by metaphase cytogenetics to determine the distribution of +8 in interphase cells. All slides had been stored at ambient temperature for 12-26 months. The bone marrow aspirate smears of 21 non-leukemic patients served as controls. Trisomy 8 was demonstrated in all myeloid cell lines including the neutrophils, basophils, eosinophils, monocytes, and erythroid precursors, but not in the lymphocytes. The extra chromosome 8 was present in mature segmented granulocytes as well as more immature precursors. The percentage of +8 cells was highest in specimens from patients with CML in myeloid blast crisis (mean 64%), followed by those in accelerated phase (mean 39%). Three specimens from patients in morphologic chronic phase showed the lowest percentage of +8 cells (mean 13%). One patient was studied twice and showed a substantial expansion of +8 cells with progression from accelerated phase to myeloid blast crisis. Compared to metaphase cytogenetics, the proportion of +8 cells detected by FISH was often lower. We conclude that the acquisition of trisomy 8 in CML occurs in a pluripotent myeloid stem cell apparently incapable of expressing mature lymphoid phenotype, and that morphologic progression of disease is generally associated with an expansion of the +8 component.

Adult↗