A comprehensive genetic classification of adult acute lymphoblastic leukemia (ALL): analysis of the GIMEMA 0496 protocol

The Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) 0496 protocol, through the central handling of bone marrow samples at presentation, allowed us to combine cytogenetic and molecular information on a large series of adults with acute lymphoblastic leukemia (ALL) treated homogeneously, enabling us to define as broadly as possible their genetic profile and to determine the impact on outcome of the cytogenetic-molecular signature. Of 414 patients centrally processed, 325 were considered for the categorization into the following cytogenetic-molecular subgroups: normal, t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1;19)/E2A-PBX1, 9p/p15-p16 deletions, 6q deletions, miscellaneous structural abnormalities, and hyperdiploid. The inclusion into each subgroup was based on a hierarchical approach: molecular abnormalities with adverse prognosis had precedence over karyotypic changes with less-defined prognosis and the latter over ploidy. Patients without abnormalities and those with isolated 9p/p15-p16 deletions showed a relatively favorable outcome (median disease-free survival [DFS], > 3 years). The t(9;22)/BCR-ABL, t(4;11)/MLL-AF4, t(1; 19)/E2A-PBX1 defined a group with dismal prognosis (median DFS, 7 months), whereas 6q deletions, miscellaneous aberrations, and hyperdiploidy predicted an intermediate prognosis (median DFS, 19 months). This study highlights the importance of a combined cytogenetic-molecular profiling of adult ALL at presentation as a critical independent determinant of their outcome, providing further evidence of the necessity of a risk-adapted therapeutic algorithm for an optimal management of these patients.     

Hypergranular acute lymphoblastic leukemia (ALL)

Summary We report a case of adult acute lymphoblastic leukemia (ALL) with myeloid-like hypergranulation of blast cells. Like most of the granular ALLs described in the literature, the blast cells had L2 morphology and exhibited a common-ALL immunologic phenotype. The clinical findings at diagnosis were unremarkable. Cytogenetic analysis showed a 46XY karyotype. Molecular genetic analysis revealed T-cell receptor (TCR) and immunoglobulin heavy chain rearrangements; no rearrangement was found at the TCR gene locus. The polymerase chain reaction (PCR) for the BCR-ABL translocation was negative. The clinical course of the patient was uncomplicated. On standard ALL treatment protocol he achieved complete remission (CR) within 4 weeks, and he is currently disease free 8 months after diagnosis. The case contributes well-documented data to the characterization of adult granular ALL, with special regard to changes at the molecular genetic level.     

Rescue of genomic information in adult acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics: a GIMEMA centralized biological study

Metaphase (M‐) and array (A‐) Comparative Genomic Hybridization (CGH) were used to investigate 40 cases of T‐ and 32 of B‐cell acute lymphoblastic leukaemia (ALL) with normal/failed cytogenetics. M‐CGH was performed in all cases and A–CGH in 10/12 T‐ALL cases with uncertain/normal M‐CGH results. M‐CGH was abnormal in 38/72 cases, with a total of 110 imbalances (60 gains, 50 losses). 25/40 patients with T‐ALL (62·5%) showed 77 imbalances, with at least 1 genomic imbalance and a mean of 3 aberrations/patient (range 1–12). 13/32 patients with B‐ALL (40·6%) presented 34 imbalances, with a mean of 2·6 imbalances (range 1–8). A‐CGH detected 4 more T‐ALL cases with genomic imbalances. A‐CGH identified NF1/17q11·2 deletion and interphase fluorescence in situ hybridization provided a 10·8% estimated overall incidence of NF1/17q11·2 deletion in T‐ALL. In all but one case (6/7) with NF1 deletion, denaturing high‐performance liquid chromatography and direct sequencing detected NOTCH1 gene mutations. Three or more imbalances in CGH‐positive cases were significantly associated with resistance to treatment and death during or after induction therapy. We suggest that the work‐up for ALL at diagnosis should include CGH investigations, particularly when cytogenetics is uninformative, because they may provide potentially valuable information with prognostic and therapeutic implications.     

High efficacy of the German multicenter ALL (GMALL) protocol for treatment of adult acute lymphoblastic leukemia (ALL) — a single-institution study

Summary Sixty-one consecutive patients with acute lymphoblastic leukemia (ALL) (B-ALL excluded) were treated with the protocol described by Hoelzer et al. [15]. The complete remission (CR) rate was 85% (52/61 patients). Three patients died during induction therapy; six patients were refractory to treatment. The median duration of continuous complete remission (CCR), disease-free survival (DFS), and overall survival was 41.5, 41.4, and 40.8 months, respectively. At 5 years the probability of CCR was 49%, of DFS 43.5%, and of overall survival 41.6%. In the univariate analysis older age (>35 years,p=0.01), bcr-abl positivity (p=0.007), and time to CR (>4 weeks,p=0.05) were significantly unfavorable prognostic factors. In the multivariate analysis only age (p=0.006) and time to CR (p = 0.02) remained significant. Thus, our data confirm the high efficacy of this treatment regimen with regard to CR rate and remission duration.     

Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report

We treated 109 patients with adult acute lymphoblastic leukemia (ALL) diagnosed by histochemical and immunologic techniques. Patients were excluded only for age greater than 50 years and Burkitt's leukemia. Treatment included a four-drug remission induction phase followed by alternating cycles of noncrossresistant chemotherapy and prolonged oral maintenance therapy. Eighty-eight percent of patients entered complete remission. With a median follow-up of 77 months (range, 48 to 111 months), 42% +/- 6% (SEM) of patients achieving remission are projected to remain disease-free at 5 years, and disease-free survival for all patients entered on study is 35% +/- 5%. Failure to achieve remission within the first 4 weeks of therapy and the presence of the Philadelphia chromosome are associated with a 100% risk of relapse. Remission patients with neither of these adverse features have a 48% +/- 6% probability of remaining in continuous remission for 5 years. Patients with T-cell phenotype have a favorable prognosis with 59% +/- 13% of patients achieving remission remaining disease-free compared with 31% +/- 7% of CALLA-positive patients. Intensive chemotherapy may produce prolonged disease-free survival in a sizable fraction of adults with ALL. Improved therapy is needed, especially for patients with adverse prognostic features.     

GIMEMA ALL 0183: a multicentric study on adult acute Iymphoblastic lecukaemia in Italy

Summary In 1983 a multicentre trial for adult patients with ALL (excluding the B-phenotype) was initi,ated to evaluate: (a) complete remission (CR) rate and length in a protocol with a mild induction and an intensive consolidation therapy; (b) the efficacy of a mild versus an intensive post consolidation treatment in prolonging disease-free survival; (c) CNS relapse rate on a protocol substituting intrathecal chemotherapy and intermediate dose i.v. methotrexate (MTX) and cytosine arabinoside (ARA-C) for cranial radiotherapy. 358 patients entered the protocol between January 1983 and April 1987: 284 (79.3%) attained complete remission, 26 (7.3%) died during induction and 48 (13.4%) had resistant disease. Median overall survival was 21.7 months, with a projection that 29.4% of the patients will survive more than 55 months. The median duration of complete remission was 19.2 months: 21.9% of responders are projected to remain in continuing complete response for more than 50.6 months. Among the 284 responding patients, 154 (54.2%) relapsed (95 while on therapy, 59 off-therapy): major sites of relapse were bone marrow (103). CNS alone (23), or both (11). 14 patients died while in CR. Only 12 patients (2.2%) were lost to follow-up, while therapy was interrupted in 7 (2%) because of side effects and in 12 (3.3%) because of the patient's refusal. By multivariate analysis increasing age and presence of infection at diagnosis were associated with a lower remission rate: risk of relapse was greater in LL subtypes and in patients with higher WBC at diagnosis; survival was inversely correlated to age. The high response rate was not achieved at expense of an increased risk of induction death. The low incidence of isolated CNS relapse (8.0% of responding patients) suggests that CNS prophylaxis as used in this study is effective. No statistically significant difference in survival and relapse rate emerged between the two arms of post consolidation therapy. Moreover, the protocol therapy was well tolerated, required minimal supportive care, which could be provided even in small centres, and compliance proved acceptance for patients and staff.     

Secondary haematological neoplasm after treatment of adult acute lymphoblastic leukaemia: analysis of 1170 adult ALL patients enrolled in the GIMEMA trials

Between 1983 and 1994 the incidence of secondary haematological neoplasms (SHM) was evaluated in 1170 new cases of ALL enrolled in the GIMEMA trials. Of the 942 patients who achieved complete remission (CR); seven developed a SHM: four AMLs and three NHLs.
The median latency from onset of ALL and of secondary haematological neoplasm was 69 months for AML and 61 months for NHL. Three out of four patients with secondary AML were unresponsive to the new chemotherapy and died, whereas the fourth patient achieved a new CR. Among the three NHL cases, two patients are presently alive in CR, whereas the third patient was refractory to chemotherapy and died.
The relative risk of haematological malignancy among the GIMEMA trials population, as compared to that of the Italian Cancer Registries, was 15.25-fold higher, and the actuarial estimated cumulative proportion of ALL patients with a secondary haematological neoplasm at 5 and 10 years were 0.59% and 3.63% respectively.
The incidence of adult ALL who developed a SHM, although apparently lower than in the paediatric ALL series, was higher when compared to the normal population. The difference between paediatric and adult ALL is probably due to the lack of craniospinal radiotherapy and to the lower doses of epipodoxiphyllotoxins used in adult trials. The higher percentage of childhood ALL with a prolonged event-free survival could result in an increase of secondary neoplasms in these cases, which suggests that secondary haematological neoplasms in adult ALL patients are real, although rare, events.     

Long-term survival following acute lymphoblastic leukemia (ALL) in childhood

48 patients with ALL (3%) treated according to two different protocols survived 5 years or longer. The mean survival time was 13.0 +/- 5.0 years, but 29 patients lived 16.5 +/- 3.0 years. Only 18 patients (38%) were 16.9 +/- 3.0 years in them 1. CCR, the longest remission time amounted to more than 25 years. Of the patients relapsed 9 are 8.4 +/- 2.8 years in 2. CR. Late relapses after 5 years were observed in seven cases the last in the 9th year of disease. After 5 years the survival rate in both protocols was not different. As a late sequelae, there was one patient with intrahepatic block and portal hypertension and one with encephalopathy and imbecility. All patients were able to leave their professional examination, 5 patients married and 6 healthy children were born.     

Treatment of acute lymphoblastic leukaemia (ALL).

Forty-six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, l-asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6-mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and l-asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi-squared = 3.91: p < 0.05). Eight of the 10 non-responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow-up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French-American-British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease-free at 65+ months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.     

Treatment of refractory adult lymphoblastic leukemia (ALL) with 4'(9- acridinylamino) methanesulfon-M-anisidide (AMSA)

Twenty-four adults with ALL were treated with AMSA alone or in combination. Twenty-two were treated at time of relapse and two patients after failing primary induction therapy. All had been treated with anthracyclines prior to receiving AMSA. Of the 22 patients with ALL in relapse, 4 achieved a complete remission. Two of these patients have relapsed while receiving maintenance chemotherapy; one died 1 mo after achieving remission due to the occurrence of cholycystitis in the setting of pancytopenia and one patient underwent bone marrow transplantation and is in remission at 8 mo after the second remission. Both patients who failed primary induction therapy remain in remission at 11 and 36 mo, respectively. The use of AMSA should be considered for patients with ALL who fail primary induction as well as those whose leukemia becomes resistant to conventional agents.     

Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL)

Summary Our purpose was to evaluate the ability of re-combinant human granulocyte colony-stimulating factor (r-metHuG-CSF) as an adjunct to induction chemo-therapy of acute lymphoblastic leukemia (ALL) to ameliorate chemotherapy-induced neutropenia and thus allow patients to receive full doses of chemotherapy on time. Sixteen consecutive patients with adult ALL (13 de novo, three relapsed) were treated with induction chemo-therapy according to the BMFT protocol and received in addition r-metHuG-CSF (200g/m²/day). Patients who were treated with the same induction chemotherapy but without G-CSF between 1982 and 1990 served as controls. Fifteen of the 16 patients achieved complete hematological remission. One patient died because of fungal septicemia. Compared with historical controls, G-CSF-treated patients had a significantly faster neutrophil recovery in phase I, resulting in neutrophil counts > 1000/l at day 17 vs day 26 (in median) in controls. In phase II, the onset of severe leukocytopenia (< 1500/l) was significantly (p = 0.01) delayed and the degree of leukocytopenia less pronounced (mean nadir 3300/l) in G-CSF-treated patients compared with controls (1880/l). The number of days of febrile neutropenia was not different in phase I. In phase II it was lower in study patients (0 vs 1.1 days), but the difference did not reach statistical significance (p = 0.09). Full doses of chemo-therapy could be given on time to 11/13 (85%) G-CSF pa-tients but to only 7/30 (23%) controls. These data indicate that (a) G-CSF can be given along with chemotherapy in induction treatment of ALL without compromising efficacy; (b) the duration of neutropenia in phase I is markedly shortened and the degree of leukocytopenia in phase II ameliorated; (c) these beneficial effects allow patients to receive full doses of chemotherapy on time.     

Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up

Twenty-two patients with acute lymphoblastic leukemia in second or subsequent remission and 26 with acute lymphoblastic leukemia in relapse were given cyclophosphamide (60 mg/kg on each of 2 days), total body irradiation (920 rad), and marrow transplants from HLA-identical siblings. With a minimum follow-up of more than 5 yr, an actuarial analysis shows a survival and apparent cure of 27% of the patients transplanted in remission and 15% of the patients transplanted in relapse.