Immunophenotype of adult and childhood acute lymphoblastic leukemia: changes at first relapse and clinico-prognostic implications.

The immunologic features of leukemic cells at the time of 1st hematologic relapse were compared to those obtained at initial diagnosis in 128 patients (69 children and 59 adults) with acute lymphoblastic leukemia (ALL) treated at a single institution. An immunophenotypic change was observed in 59 cases (46%), more frequently in T (20/25) than in B (39/103) lineage ALL (80 vs 38%, P=0.0008), but with a similar incidence in adults and children. Of these cases, 34 (24 B- and 10 T-ALL) changed at relapse their intralineage subgroup affiliation, although no complete shift from B to T lineage ALL, or vice versa, was observed. The myeloid antigens CD13 and/or CD33 were frequently lost (2/5 cases) or acquired (12/123 cases) at relapse. In 21 cases, the immunophenotype at relapse was more undifferentiated than at diagnosis, while it was more differentiated in 13 cases. Initial treatment intensity or preceding treatment with teniposide did not affect the phenotypic profile at relapse. Complete response (CR) rate to salvage therapy and event-free survival were not influenced by the immunophenotypic shifts, nor by the presence, at relapse, of leukemic cells expressing the myeloid antigens CD13 and/or CD33. Univariate analysis suggested that prognosis after relapse was dependent on the duration of 1st CR, patients' age and immunophenotype at the time of diagnosis, with a worse outcome for patients with T lineage ALL and for patients with the less differentiated subgroup of B lineage ALL (CD19+ and CD10-). Multivariate analysis showed that only two factors, duration of 1st CR and grade of immunologic differentiation at diagnosis, have independent prognostic value in relapsed ALL.

Mitoxantrone, etoposide and intermediate-dose Ara-C (MEC): an effective regimen for poor risk acute myeloid leukemia.

A total of 74 patients with poor risk AML (median age 36.7 years, range 4.5-60.6) received a single course of a regimen including mitoxantrone (6 mg/m2 intravenous bolus daily, days 1 to 6), etoposide (80 mg/m2 intravenous over 1 h, daily, days 1 to 6) and intermediate-dose Ara-C (1 g/m2 over 6 h, daily days 1 to 6). 28 patients had failed initial remission induction with daunorubicin and conventional doses of Ara-C, 16 patients had secondary AML and 30 patients had relapsed from initial remission (five within six months, 15 over six months and ten after autologous or allogeneic bone marrow transplantation). Overall 41/74 patients (55%) achieved complete remission, 26 (35%) had resistant disease and seven (10%) died of infection during marrow hypoplasia. A 4-day course of the same regimen was given as consolidation to patients in complete remission. Subsequent antileukemic therapy was individualized. Profound myelosuppression and pancytopenia were universal resulting in fever or documented infections in almost 100% of patient; major hemorrhagic complications occurred in 39% of patients. Extrahematologic toxicity was mild to moderate consisting mostly of nausea and vomiting, oral mucositis and transient liver and cardiac dysfunction. We conclude that the MEC combination chemotherapy program seems to be an effective antileukemic regimen for secondary and advanced AML, with acceptable toxicity.

Partial deletions of long arm of chromosome 6: biologic and clinical implications in adult acute lymphoblastic leukemia.

Within 285 adult acute lymphoblastic leukemias (ALL) included in the multicenter GIMEMA 0496 trial and prospectively studied by conventional cytogenetics, 18 cases (6%) with long arm deletion of chromosome 6 (6q) were identified. These cases were divided into: (i) del(6q) only (n = 6); (ii) del(6q) plus other numerical and/or structural abnormalities (n = 8); (iii) del(6q) and other 'specific' translocations (n = 4). The biologic and clinical features of the patients carrying this anomaly, as well as their outcome, were compared with those of 267 patients without del(6q). A T cell phenotype was more frequently associated with del(6q) cases in general (P = 0.001) and particularly with cases presenting del(6q) as the isolated abnormality (P = 0.0027). No significant difference with respect to multidrug resistance (MDR)/P glycoprotein expression was observed between the two groups of patients (21% vs 28% of MDR-positive cases, respectively). A BCR-ABL fusion transcript was less frequently detected in cases with del(6q) (11%) compared with those without the anomaly (29%). p15 and p16 deletions were identified by Southern blot analysis in 21% of cases with del(6q) and in 26% of cases without del(6q). In this latter group, a T cell phenotype was less frequently associated with p15 and/or p16 deletion than in the group carrying del(6q) (36% vs 100% of cases, P = 0.011). Overall, patients with ALL and del(6q) had a high complete remission (CR) rate (83%); however, they had a lower 18 month event-free survival (31% vs 41%) and a higher relapse rate (70% vs 37%, P = 0.02) compared with patients without del(6q). To date, this is the largest series of adult ALL cases reported with del(6q) homogeneously treated, which have also been prospectively studied for MDR expression and for the detection of known fusion genes. This anomaly, as an isolated change, identifies a subset of cases with hyperleukocytosis (median WBC count 52 x 10(9)/l) and a strict correlation with a T cell phenotype. Overall, del(6q) seems to be associated with an unfavorable clinical outcome, although this finding will need to be confirmed by extended FISH analysis.

Centre effect on treatment outcome for patients with untreated acute myelogenous leukaemia? An analysis of the AML 8A Study of the Leukemia Cooperative Group of the EORTC and GIMEMA. European Organization for Research and Treatment of Cancer (EORTC) Leukemia Cooperative Group and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA).

In the AML 8A study patients were treated with remission-induction therapy followed by one consolidation course. Patients in complete remission (CR) were randomised between autologous bone marrow transplantation (ABMT) and a second intensive consolidation course, except for those with a histocompatible sibling donor, who received allogeneic bone marrow transplantation (alloBMT). This analysis was performed to determine whether centres which only performed induction and consolidation therapy, achieved similar results as centres who also performed transplantation. 542/676 (80%) from transplantation centres and 150/194 (77%) from referring centres achieved CR, with an early death rate of 5% and 11%, respectively (P = 0.01). 66% of patients with a donor from transplantation centres received alloBMT in first CR compared with 57% from referring centres (P = 0.2). Transplantation centres randomised 64% of patients without a donor, referring centres 47% (P = 0.04). The full protocol treatment was completed by 275/542 (51%) and 61/150 (41%) patients, respectively (P = 0.04). The overall survival rate at 6 years from diagnosis was 34% and 36%, respectively (P = 0.9). In conclusion, the type of centre did not appear to have an influence on overall survival. The feasibility of the study was acceptable for both types of centres. The referring centres applied more selection for transplantation. Despite a more intensive second-line treatment at transplantation centres, the overall outcome remained similar to that of referring centres.

Prognostic factors of patients with acute myeloid leukemia (AML) allografted in first complete remission: an analysis of the EORTC-GIMEMA AML 8A trial. The European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) Leukemia Cooperative Groups.

The Leukemia Cooperative Groups of the EORTC and the GIMEMA conducted a prospective randomized phase III trial, in order to assess the value of autologous BMT (ABMT) vs a second intensive consolidation course (IC2), following a common intensive consolidation course (IC1) for patients with AML. Patients with an HLA-identical sibling donor were not randomized, but were included in an allogeneic BMT (alloBMT) program. This is an analysis of prognostic factors which influence the outcome of treatment after alloBMT in first complete remission (CR). The study included 730 patients < 46 years of age in CR, 270 having a histocompatible sibling donor. In 169 of these patients alloBMT was performed in first CR. Early remitters (122 patients achieving CR with one course of treatment) had a DFS at 3 years of 67%, significantly longer than that of 44% for late remitters (47 patients achieving CR after more than one course of treatment) (P = 0.006). The relapse risk for early vs late remitters was 16 and 40% at 3 years (P = 0.001) and the treatment-related mortality (TRM) at 2 years was 21 vs 27%. Age appeared to be a prognostic factor for TRM, WBC for DFS, whereas the FAB classification was not of prognostic importance. Patients with poor risk cytogenetic abnormalities showed a trend towards a higher relapse risk. Patients transplanted shortly after achieving CR appeared to have a worse prognosis than those transplanted further into remission. Overall, the number of courses of induction therapy needed to achieve CR was the most important prognostic factor for outcome after allogeneic BMT.

Multimodality treatment of thymoma: a prospective study.

BACKGROUND: Thymomas are a heterogeneous group of tumors. Treatment of invasive lesions is not well standardized. The aim of this study is to propose a clinicopathologically based protocol for multimodality therapy. METHODS: Between 1965 and 1988, we operated on 83 patients with thymoma who did not receive standardized adjuvant therapy. In 1989, on the basis of the retrospective analysis of the data, we started a multimodality therapy protocol and used it for 65 patients. Twelve patients had medullary thymoma (11 stage I and 1 stage II), 13 had mixed type (6 stage I and 7 stage II), and 40 had cortical thymoma (4 stage I, 11 stage II, 12 stage III, and 13 stage IV). We considered three groups. Group I (n = 18 patients), benign thymoma, included stage I and II medullary and stage I mixed thymomas; radical resection with no adjuvant therapy was performed. Group II (n = 22), invasive thymoma, included stage I and II cortical and stage II mixed thymomas; postoperative chemotherapy plus radiotherapy was always administered. Group III (n = 25), malignant thymoma, comprised stage III and IV cortical thymomas and stage III mixed thymomas; resectable stage III lesions were removed, and highly invasive stage III and stage IV lesions underwent biopsy, neoadjuvant chemotherapy, and surgical resection; postoperative chemotherapy and radiotherapy was administered to all patients. RESULTS: The 8-year survival rate for patients in stages I, II, III, and IV was 95%, 100%, 92%, and 68%, respectively. Patients with medullary thymoma had a 92% 8-year survival rate; those with mixed type, 100%; and those with cortical thymoma, 85%. Group I had an 8-year survival rate of 94%; group II, 100%; and group III, 76%. Survival was compared with that of patients operated on before 1989: differences were not significant for group I; survival improved in group II (100% versus 81%; p = not significant); and group III showed significant improvement (76% versus 43%; p < 0.049). CONCLUSIONS: Multimodality treatment with neoadjuvant chemotherapy and adjuvant chemotherapy plus radiotherapy may improve the results of radical resection and the survival of patients with invasive and malignant thymoma.

Epidemiology of acute promyelocytic leukemia in Italy. APL Collaborating Group.

This retrospective epidemiologic study on 256 cases of Acute Promyelocytic Leukemia (APL) observed in 20 Italian hematology centers between 1980 and 1988 demonstrated that APL is different from the other acute non-lymphocytic leukemias (ANLL). The male/female ratio was 0.9; median age at diagnosis was 40 years (with 80% of patients between 15 and 54 years of age). The minimal annual incidence of APL in Italy per 1,000,000 inhabitants was estimated to be 0.6; an increased incidence was observed in spring and in autumn. The overall median survival duration of APL patients was 12.6 months. From an epidemiological point of view APL is a distinctive subtype of ANLL.

Reproducibility of the morphological diagnostic criteria for acute myeloid leukemia: the GIMEMA group experience.

Diagnostic reproducibility of the FAB morphological subtypes of acute leukemia is a basic step in the assessment of the clinical outcome in multicenter trials. Unusual cytologic variables and slightly different interpretations of the FAB morphological criteria have been the most significant factors affecting the overall diagnostic concordance rate among the various centers. An evaluation of the diagnostic concurrence between 35 institutions of the Italian Cooperative Study Group GIMEMA and two reviewers of the ad hoc morphological committee has been performed on 377 patients entering the AML 8A and AML 8B GIMEMA protocols. Overall concordance rate was 62.6%. The most significant differences were observed for M2 vs M4, M4 vs M5, M1 vs M2, and M2 vs M5 subtypes. In order to minimize the impact of some diagnostic deviations on the mean cytologic concordance rate, a distinction between "major" and "minor" discrepancies in the diagnostic procedures has been proposed. When the results of the single institutions were corrected by considering the "major" discrepancies only, a mean diagnostic agreement of 78.1% was reached.

Acute nonlymphocytic leukemia in the elderly: results of a retrospective study.

Seventy-four patients over 60 years of age with new cases of ANLL diagnosed between January, 1980 and December, 1986 were retrospectively evaluated. Twenty-nine (median age 63, range 60-70) received aggressive induction polychemotherapy: 15 achieved CR (52%), 10 were resistant (34.5%) and 4 died during induction (13.5%). Overall median survival was 6 1/2 months, median CR duration and median survival of responders were 9 and 13 months, respectively. Eight patients (median age 70.4, range 64-74) received low doses of Ara-C: 2 achieved CR, 5 were resistant and 1 died during induction, with an overall median survival of 6 1/2 months; 37 patients (median age 72, range 60-86) received only supportive care and cytostatic therapy for disease control with Hydroxyurea and 6-Mercaptopurine if WBC greater than 20 x 10(9)/l: overall median survival was 6 months and 2 patients are still alive after 18 and 26 months. Aggressive chemotherapy seems to be the treatment of choice in patients less than or equal to 70 years, while for those over 70 current supportive care may offer good survival and a good quality of life.

High doses of ara-C and m-AMSA in the treatment of refractory acute non lymphocytic leukemia.

From November, '85 to March, '87, 17 patients (12 males and 5 females, median 28 years) with resistant or relapsed ANLL received HiDAC (3 g/m2 c.i. 3 hs every 12 hs, day 1-4) + m-AMSA (100 mg/m2 i.v. day 5-7) as salvage therapy: 8/17 patients (47.1%) achieved CR, 7/17 (41.1%) were resistant and 2/17 (11.8%) died during induction; 8/10 relapsed patients achieved a 2nd CR, while all 7 primary resistant patients failed to. Median period of PMN less than 0.5 x 10(9)/l was 28 days, median period of PLTS less than 30 x 10(9)/l was 25 days. All patients had infections during aplasia. Median CR duration was 6.6 months, while median survival of responders was 10.6 months. Two patients with severe induction-related complications relapsed after 2 and 5 months, respectively: 1 patient underwent BMT and relapsed after 21 months; 5 patients, 4 of whom had received a prior ABMT during 1st CR, underwent ABMT: 3 died from ABMT related toxicity and 2 relapsed after 8 and 18 months, respectively. We conclude that HiDAC + m-AMSA is highly effective in relapsed, but not in resistant patients with acceptable hematologic and extra-hematologic toxicity. The role and modalities of ABMT in prolonging a 2nd CR are at present controversial.

Idarubicin (4-demethoxydaunorubicin) as single agent for remission induction of previously untreated acute promyelocytic leukemia: a pilot study of the Italian cooperative group GIMEMA.

Because of the reported high sensitivity of acute promyelocytic leukemia to daunorubicin, we treated 27 consecutive, newly diagnosed, acute promyelocytic leukemia (APL) patients with the new anthracycline idarubicin (IDA) as induction therapy. IDA dosage ranged from 0.25 to 0.30 mg/kg/day and the drug was administered as single agent during a single induction course of 6 days. A total of 22/27 patients (81%) achieved complete remission, 4 (15%) died during induction and 1 patient was resistant to IDA. Extrahematological toxicity was acceptable. A total of 13/22 patients having achieved CR are still alive and in first CR after a median follow-up of 12 months. As for the treatment of the coagulopathy present in APL: 17/27 (63%) received tranexamic acid (6 g/daily) in continuous infusion for total of 7 d. None of the patients treated with tranexamic acid experienced thromboembolic complications. In conclusion, this multicentric pilot study confirms the antileukemic potency of IDA and the high sensitivity of APL to anthracycline derivatives.

Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy.

The use of interferon for the induction treatment of multiple myeloma has been shown to be effective in about 20 percent of patients. We studied its effects on long-term survival when it was used for maintenance treatment. Between April 1985 and May 1988, 101 patients with symptomatic multiple myeloma who had had a substantial objective response or a lesser objective response with disappearance of symptoms ("disease stabilization") after 12 courses of induction chemotherapy were randomly assigned to receive recombinant interferon alfa-2b as maintenance therapy (n = 50) or to receive no treatment (n = 51). As of December 1989, 66 of the 101 patients have relapsed (25 given interferon and 41 not treated). The median duration of response (from the time of randomization) was 26 months in the patients given interferon and 14 months in the untreated patients (P = 0.0002). A total of 37 patients have died (14 given interferon and 23 not treated). The median duration of survival (from randomization) was 52 months in the interferon group and 39 months in the control group (P = 0.0526). Among the patients who had had a substantial objective response to induction chemotherapy, the difference in survival time was statistically significant (P = 0.03526). Interferon had to be stopped because of toxic effects in 3 of 12 patients initially treated with 10 MU (megaunits) per square meter of body-surface area. After the dose was reduced to 3 MU per square meter, the only toxic effect was a mild influenza-like syndrome lasting two to three weeks. We conclude that maintenance treatment with interferon prolongs response and survival in patients with multiple myeloma who have responded to conventional induction chemotherapy.

Interferon alpha-2a in cutaneous T-cell lymphoma.

23 newly diagnosed patients affected by cutaneous T-cell lymphoma were treated with sub-cutaneous interferon alpha-2a to evaluate the therapeutic efficacy and the toxicity of this agent. IFN was administered daily with dose escalation from 3 to 18 million units for 12 weeks; thereafter, patients induced into complete (CR) or partial (PR) remission were given IFN at maximal tolerated dose 3 times weekly for 6 or 9 months. The objective tumor response was observed in 17 patients (74%): 8 (35%) were CR and 9 (39%) were PR. A 74-yr-old patient died because of neutropenia and sepsis at the end of induction phase, while receiving IFN at dose of 18 million units. Disease stage is the initial feature predictive of response to IFN therapy. The dose schedule of this study was well tolerated: only 3 patients developed liver toxicity, while leukopenia was evident in 6 patients. Only 2 CR patients have relapsed, 18 and 24 months from response; the remaining 6 CR patients are in continuous complete remission with a median follow-up of 41.8 months. 6 PR patients have progressed from 8 to 17 months after response, and in the 3 PR patients not yet progressed the response duration ranges from 20 to 24 months. In conclusion, interferon alpha-2a is a very effective agent in therapy of untreated cutaneous T-cell lymphoma with an overall response rate of 74%.

Intensification in post-remission treatment of adult acute non lymphocytic leukemia.

In an attempt to reduce the risk of leukemic relapse, different post-remission intensifications based on high-dose Ara-C (HiDAC) and autologous bone marrow transplantation (ABMT) were evaluated in patients with acute non lymphocytic leukemia in first remission and compared as to response and toxicity. Between September, 1985 and May, 1987, 34 patients in complete remission were eligible for our study. Induction therapy consisted of one or two courses of daunorubicin (DNR) and Ara-C (schedule 3 + 7). Fourteen patients receiving intensive post-remission chemotherapy with DNR + Ara-C (schedule 2 + 5), HiDAC + DNR, and ABMT following pretransplant BAVC conditioning entered the first pilot study. A high toxicity was observed and only 5 of them completed the full treatment plan. Thus the second pilot study used a single post-remission intensive course with HiDAC + m-AMSA and ABMT following cyclophosphamide plus TBI or BAVC. This approach was more feasible. The preliminary results show the usefulness of intensive post-remission therapy: in fact, all patients but one who completed the treatment program are still in continuous complete remission. A large number of patients and a longer follow-up are required to draw final conclusions.

A randomized study of the efficacy of postconsolidation therapy in adult acute nonlymphocytic leukemia: a report of the Italian Cooperative Group GIMEMA.

The Italian Co-operative Group GIMEMA conducted a randomized trial in adult acute nonlymphocytic leukemia (ANLL) to assess the role of postconsolidation treatment. Of 448 evaluable patients entered into the study, 305 (68%) achieved a complete remission after a standard induction with daunorubicin and cytosine arabinoside (3 + 7; 2 + 5). Those in remission after a consolidation therapy including 4 courses of daunorubicin, cytosine arabinoside, and 6-thioguanine (DAT) were allocated to one of three arms: no treatment, conventional maintenance, or intensive postconsolidation therapy. The median disease-free survival (DFS) was 13 months, and the median survival was 14 months, with 26% surviving at 6.5 years. There was no difference in survival and in disease-free survival among the three postconsolidation arms. In conclusion our study, as others, suggests that the critical period of ANLL treatment is within the first 5-6 months.