Clara D. Bloomfield

All-trans-Retinoic Acid in Acute Promyelocytic Leukemia

BACKGROUND All-trans-retinoic acid induces complete remission in acute promyelocytic leukemia. However, it is not clear whether induction therapy with all-trans-retinoic acid is superior to chemotherapy alone or whether maintenance treatment with all-trans-retinoic acid improves outcome. METHODS Three hundred forty-six patients with previously untreated acute promyelocytic leukemia were randomly assigned to receive all-trans-retinoic acid or daunorubicin plus cytarabine as induction treatment. Patients who had a complete remission received consolidation therapy consisting of one cycle of treatment identical to the induction chemotherapy, then high-dose cytarabine plus daunorubicin. Patients still in complete remission after two cycles of consolidation therapy were then randomly assigned to maintenance treatment with all-trans-retinoic acid or to observation. RESULTS Of the 174 patients treated with chemotherapy, 120 (69 percent) had a complete remission, as did 124 of the 172 (72 percent) given all-trans-retinoic acid (P=0.56). When both induction and maintenance treatments were taken into account, the estimated rates of disease-free survival at one, two, and three years were 77, 61, and 55 percent, respectively, for patients assigned to chemotherapy then all-trans-retinoic acid; 86, 75, and 75 percent for all-trans-retinoic acid then all-trans-retinoic acid; 75, 60, and 60 percent for all-trans-retinoic acid then observation; and 29, 18, and 18 percent for chemotherapy then observation. By intention-to-treat analysis, the rates of overall survival at one, two, and three years after entry into the study were 75, 57, and 50 percent, respectively, among patients assigned to chemotherapy, and 82, 72, and 67 percent among those assigned to all-trans-retinoic acid (P= 0.003). CONCLUSIONS All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.

Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia.

The National Cancer Institute (NCI) sponsored a workshop to develop a set of standardized diagnostic and response criteria for acute myeloid leukemia (AML) clinical trials. The French-American-British (FAB) classification was retained for diagnosing AML, with the addition of patients with bone marrow morphologic features of a myelodysplastic syndrome and less than 30% bone marrow blasts, but with greater than or equal to 30% blasts in the peripheral blood. In this report, there are four important subgroups of AML not defined in the FAB classification that are discussed: undifferentiated acute leukemia, MO (AML lacking definitive myeloid differentiation by morphology or conventional cytochemistry but with ultrastructural or immunophenotypic evidence for AML), mixed lineage leukemia, and hypocellular AML. Definitions of response for clinical trials are presented to facilitate comparisons among different studies. Complete remission is considered the only response worth reporting in phase III trials, since lesser responses do not improve survival. Partial remissions may be of interest to identify active new agents in phase I and II studies. Monoclonal antibodies and cytogenetic studies are not part of the routine assessment of remission or reassessment at relapse, and their role in the evaluation of patients with AML is currently being evaluated in clinical trials. Although we recognize that some of the definitions in this report are arbitrary, generalized use of these guidelines will make results of clinical trials more comparable and interpretable.

What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies.

We performed a retrospective comparison of presenting features, planned treatment, complete remission (CR) rate, and outcome of 321 adolescents and young adults (AYAs) ages 16 to 20 years with newly diagnosed acute lymphoblastic leukemia (ALL) who were treated on consecutive trials in either the Childrens Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001. CR rates were identical, 90% for both CALGB and CCG AYAs. CCG AYAs had a 63% event-free survival (EFS) and 67% overall survival (OS) at 7 years in contrast to the CALGB AYAs, in which 7-year EFS was only 34% (P < .001; relative hazard rate [RHR] = 2.2) and OS was 46% (P < .001; RHR = 1.9). While CALGB AYAs aged 16 to 17 years achieved similar outcomes to all CCG AYAs with a 7-year EFS of 55%, the EFS for 18- to 20-year-old CALGB patients was only 29%. Comparison of the regimens showed that CCG AYAs received earlier and more intensive central nervous system prophylaxis and higher cumulative doses of nonmyelosuppressive agents. There were no differences in outcomes of those who reached maintenance therapy on time compared with those who were delayed. Based on these observations, a prospective study for AYAs with ALL using the more successful approach of the CCG has been initiated.

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.

Chromosome 5q deletion and epigenetic suppression of the gene encoding α-catenin ( CTNNA1 ) in myeloid cell transformation

Interstitial loss of all or part of the long arm of chromosome 5, or del(5q), is a frequent clonal chromosomal abnormality in human myelodysplastic syndrome (MDS, a preleukemic disorder) and acute myeloid leukemia (AML), and is thought to contribute to the pathogenesis of these diseases by deleting one or more tumor-suppressor genes. Although a major commonly deleted region (CDR) has been delineated on chromosome band 5q31.1 (refs. 3–7), attempts to identify tumor suppressors within this band have been unsuccessful. We focused our analysis of gene expression on RNA from primitive leukemia-initiating cells, which harbor 5q deletions, and analyzed 12 genes within the CDR that are expressed by normal hematopoietic stem cells. Here we show that the gene encoding α-catenin (CTNNA1) is expressed at a much lower level in leukemia-initiating stem cells from individuals with AML or MDS with a 5q deletion than in individuals with MDS or AML lacking a 5q deletion or in normal hematopoietic stem cells. Analysis of HL-60 cells, a myeloid leukemia line with deletion of the 5q31 region, showed that the CTNNA1 promoter of the retained allele is suppressed by both methylation and histone deacetylation. Restoration of CTNNA1 expression in HL-60 cells resulted in reduced proliferation and apoptotic cell death. Thus, loss of expression of the α-catenin tumor suppressor in hematopoietic stem cells may provide a growth advantage that contributes to human MDS or AML with del(5q).

The clinical significance of karyotype in acute myelogenous leukemia.

To evaluate further the prognostic significance of karyotype at diagnosis of acute myelogenous leukemia (AML), we have made a follow-up study of 711 patients who were diagnosed between January 1, 1980, and March 31, 1982, and who were originally reported by the Fourth International Workshop on Chromosomes in Leukemia (4IWCL). Three different chromosomal classifications were evaluated, including presence of normal and abnormal metaphases (NN-AN-AA classification), a modification of the Chicago classification, and a complexity classification. All three chromosomal classifications were shown to correlate significantly with outcome in patients with de novo AML. Furthermore, the NN-AN-AA classification and the complexity classification had independent prognostic significance when age, sex, and FAB morphology were also considered in multivariate analyses of survival. These data provide further evidence that karyotype is an important factor in predicting the outcome of patients with AML.

Detection of minimal residual disease in patients with AML1/ETO -associated acute myeloid leukemia using a novel quantitative reverse transcription polymerase chain reaction assay

The AML1/ETO fusion transcript can be detected by reverse transcription polymerase chain reaction (RT-PCR) in patients with t(8;21)-associated acute myeloid leukemia (AML) in long-term complete remission (CR). Quantitation of the amount of the fusion transcript during CR may therefore be more predictive of cure or relapse than a simple qualitative assessment. Real Time PCR, a fluorometric-based technique, allows simple and rapid quantitation of a target sequence during the extension phase of PCR amplification, in contrast to end-point quantitative methods. Six patients with t(8;21)(q22;q22) AML, who achieved CR were studied by Real Time RT-PCR at different time intervals following diagnosis and high-dose cytarabine and anthracycline-based induction therapy. Five patients had a diagnostic bone marrow (BM) sample available for molecular analysis. Each patient showed ⩾103 copies of the AML1/ETO fusion transcript at diagnosis, and each showed a 2- to 4-log decrease in copy number following successful induction chemotherapy. This is comparable to the log-fold reduction in leukemic blasts that is thought to occur in patients successfully cytoreduced into CR by induction chemotherapy. The sixth patient showed a relatively high copy number immediately following successful remission induction chemotherapy, which continued to increase during early CR and was later followed by relapse. Real Time RT-PCR appears to offer advantages over previously used quantitative RT-PCR methods by providing absolute quantitation of the target sequence, expanding the dynamic range of quantitation to over six orders of magnitude, eliminating the post-PCR processing, and reducing labor and carryover contamination. These features make this an attractive method to prospectively evaluate the prognostic value of AML1/ETO fusion transcript quantitation in a larger patient population with t(8;21)(q22;q22) AML in CR.

Long-term survival in acute myelogenous leukemia: A Second Follow-up of the Fourth International Workshop on Chromosomes in Leukemia

Patients with acute myeloid leukemia (AML, equivalent to acute non-lymphoblastic leukemia [ANLL]) who were studied at the Fourth and Sixth International Workshops on Chromosomes in Leukemia and who have long survival have been re-assessed to identify factors which may be associated with good prognosis in AML. In a long-term survivor (LTS) group, there were more cases than expected in each age decade below 50, more cases than expected with FAB type M3, and fewer cases than expected of secondary leukemia. Of the distribution of chromosome abnormalities, t(15;17), t(8;21), and inv/del(16) were over-represented, and -5, -7, and rearrangements of 11q were under-represented. Multivariate analysis of all patients showed that age group, cytogenetic classification, FAB type, and sex all had independent, significant effects on survival. A new observation from a very small subgroup of patients was that deletion of 7q without concurrent abnormality of chromosome 5 appeared to be associated with a good prognosis.

Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia

To evaluate the importance of pretreatment karyotype in predicting long-term outcome in acute lymphoblastic leukemia (ALL), we performed a follow-up study of the 329 patients from the Third International Workshop on Chromosomes in Leukemia. Living patients have now been followed a minimum of 6 years. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, rearrangements involving 8q24, t(4;11), 14q+, 6q-] or, in the remaining cases, modal number (less than 46, 46, 47-50, greater than 50). As previously reported for achievement and duration of complete remission, and overall survival, disease-free survival differed significantly (p less than 0.001) among chromosome groups for both adults and children. Among children, karyotype was an independent prognostic factor for predicting disease-free survival. Because of the long follow-up, we now have been able to utilize statistical models to estimate the percentage of patients cured, according to karyotype alone and combined with other risk factors. Adults with the highest likelihood of cure (21-33%) were those patients with FAB-L1, a leukocyte count of 50,000/microliters or less, and one of the following chromosome groups: greater than 50, 47-50, 6q-, or normal. In children these same characteristics were associated with the highest percentage of cure (58-71% cured). In addition, we identified several groups of children with less than 15% chance of cure who clearly need to be treated as high-risk patients at diagnosis. Future studies of patients who have received risk-adapted therapy based on these chromosome data are needed to determine if more intensive treatment will improve the outlook of patients with cytogenetically unfavorable types of ALL.

Prognostic significance of mediastinal involvement in Hodgkin's disease treated with curative radiotherapy

We evaluated the prognostic significance of mediastinal involvement in Hodgkins disease in 79 consecutive newly diagnosed patients treated with curative‐intent, nodal radiotherapy. Mediastinal masses were classified large or small depending on whether the ratio of the largest transverse diameter of the mass to the transverse diameter of the thorax at T5–6 was >.35. Forty‐eight patients had mediastinal disease; 20 had large masses, and 28 small masses. Complete remissions were achieved in 19 patients with large masses, 26 with small masses and all patients with no mediastinal masses. Relapses have occurred in 74% of patients with large masses but in only 27% with small masses and 19% without masses (P < .001). This high recurrence rate among patients with large masses could not be explained by other known adverse prognostic factors. Survival was adversely influenced by mediastinal mass size (P = .03). We conclude that curative‐intent, nodal irradiation is inadequate therapy for patients with large mediastinal masses. Controlled studies are needed to determine if survival can be improved by the addition of chemotherapy or whole lung irradiation.