Gruppo Italiano Malattie Ematologiche Dell ' Adulto Research Articles

Imatinib in chronic myeloid leukemia elderly patients

The median age at diagnosis of Chronic Myeloid Leukemia (CML) reported in clinical trials is generally of 50-55 years; it is higher (more than 60 years) in epidemiologic registries and in observational studies [1]. Therefore, a significant proportion of CML patients are “elderly”, according to the most widely accepted definition of “old person” (age > 65 years). Prior to imatinib (IM) introduction, an orally taken tyrosine kinase inhibitor, older age was associated to a worse outcome (lower response rates and lower long-term survival), regardless of the treatment used (busulfan, hydroxyurea, interferon alpha), basically, for unknown reasons. It can be speculated that, with interferon, the reason of an inferior outcome of elderly patients lied in a poorer compliance; however, this worsen prognosis of elderly CML patients have been described even employing well tolerated drugs (like hydroxyurea). Age was included in the 2 most used risk scores for CML: Sokal score (1984), referring to patients treated with conventional chemotherapy, and EURO score (1998), for patients treated with interferon [2, 3]. The introduction of IM has revolutionized the therapy of CML patients, significantly improving survival [4]. However, in the early days of IM, many physicians felt that the prognosis of an old CML patient, particularly those older than 75-80 yrs, could not be positively influenced by IM and a not negligible part of elderly patients are still not allocated to IM (or enrolled in clinical trials) for different reasons (co-morbidities, toxicity, long term outcome, socio-economic factors) [5]. The importance of age in the IM era has been investigated in different studies, leading to a re-evaluation of its prognostic significance. A large study in late chronic phase patients treated with IM after interferon failure, conducted by GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML Working-Party (WP), showed lower hematologic and cytogenetic response rates in older patients (> 65 years old), but similar overall survival with a 36 months median follow-up [6]. In another large but heterogeneous (early chronic phase, late chronic phase, and advanced phases) series of patients treated with IM at the MDACC, older age appeared to be not associated with a worse outcome; however, the cut-off to define older patients was 60 years, elderly early chronic phase patients were few (49) and no long term data were available [7]. The first study to evaluate the effect of age in large series of front-line IM treated patients and with a long follow-up was recently published by the GIMEMA CML WP [8]. Five hundred and fifty nine patients, of whom 115 ≥ 65 years old, were enrolled in 3 prospective, multicenter, trials. After a median follow-up of 60 months, hematologic, cytogenetic and molecular response rates were identical in older and younger patients while survival was significantly inferior in older patients. This lower survival was due to a higher number of deaths occurred in chronic phase, reasonably unrelated to IM therapy or toxicity, and not to a higher progression rate in older patients. Recently a new prognostic score was elaborated based on 2060 patients enrolled in studies of first-line IM-based regimes and collected by the European Leukemia Net / EUTOS Registry [9]. Of the all variables analyzed, only spleen size and basophils percentage, best discriminated between high-risk and low-risk patients; age had no more a prognostic impact, a further confirmation that IM has cancelled the differences in prognosis between younger and older patients. No doubt, the overall toxicity and the need for dose optimization are higher for IM with respect to conservative and palliative treatments, like hydroxyurea, particularly when older patients are treated; however, in the hands of expert physicians IM is generally manageable. Moreover, as the lower survival of elderly patients is mainly determined by age-related factors and co-morbidities, rather than by the progression of CML, a geriatric assessment (frailty status) may be helpful in the decision to allocate selected patients to IM therapy [10]. In conclusion, age had relevance when therapeutic strategies, like IM, were not available. However, today, older age per se must not be a limitation for treating patients with IM and the enrollment of these patients in clinical trials should be encouraged. Second generation tyrosine kinase inhibitors (dasatinib and nilotinib) as front-line therapy showed higher response rates and lower toxicities compared to IM [11, 12]; probably these results will be confirmed also in elderly patients. Importantly, extra-hematologic toxicities are distinct between IM, dasatinib and nilotinib, allowing the selection of the more appropriate drug in relation to the presence of co-morbidities. Although data on dasatinib and nilotinib in elderly patients are still few and the follow-up is still short, these second generation tyrosine kinase inhibitors will probably further improve the outcome of CML elderly patients.

Extramedullary intracranial localization of multiple myeloma and treatment with novel agents: A retrospective survey of 50 patients

Intracranial involvement in multiple myeloma is extremely rare. The effect of new drugs (eg, thalidomide, bortezomib, lenalidomide) with respect to old drugs (eg, alkylators, steroids) has not been reported. We collected clinical and biological data of patients presenting with an osteo-dural or primary dural multiple myeloma (OD-DMM) or a central nervous system myelomatosis (CNS-MM) by sending a questionnaire to the centers of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA). A total of 50 patients were registered. New therapies were used in 35 patients, whereas 15 patients received old treatments. Twenty-five out of 50 patients obtained a complete remission or a very good partial remission (CR+VGPR). Overall survival (OS) for CNS-MM was 6 months, for OD-DMM 25 months. OS was 25 months for patients treated with new agents versus 8 months with old agents. Improved OS and progression-free survival were predicted by response (CR+VGPR) and by patients who underwent stem cell transplantation versus chemotherapy. β2-Microglobulin >5 mmol/L was a poor prognostic factor. Multivariate analysis showed poor survival for patients with β2-microglobulin >5 mmol/L and better survival for patients achieving CR+VGPR. The overall data highlight the relevance of therapy with new drugs in intracranial myeloma, providing a framework for future clinical trials.

GIMEMA AIDA 0493 amended protocol for elderly patients with acute promyelocytic leukaemia. Long‐term results and prognostic factors

To reduce toxicity in elderly patients with acute promyelocytic leukaemia, in 1997 the Gruppo Italiano Malattie Ematologiche Dell'Adulto (GIMEMA) started an amended protocol for patients aged >60years, with the same induction [all-trans retinoic acid (ATRA)+idarubicin] as in younger patients, followed by a single consolidation course (idarubicin+ cytarabine) and maintenance with intermittent ATRA. Among 60 enrolled patients, 54 (90%) achieved haematological remission and six died during induction. Four additional patients died in complete remission (CR) from haemorrhage (2) and infection (2) prior or during consolidation therapy. Eleven patients relapsed at a median time of 17·5months from CR. The 5-year overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) rates were 76·1%, 64·6% and 27·4%, respectively. Univariate analysis identified a performance score (PS)=2 as the only significant adverse prognostic factor for both OS (P=0·017) and DFS (P=0·0003). Male sex had an unfavourable impact on DFS (P=0·021) and on CIR (P=0·019), but not on OS (P=0·234). In multivariate analysis for DFS, only PS=2 retained prognostic significance (HR=4·5, P=0·0083). In conclusion, the amended GIMEMA protocol is effective, with similar relapse rate and inferior toxicity compared to the original AIDA 0493. However, considering the recent availability of effective new agents, a less aggressive approach should be tested in this setting.

Variant Philadelphia translocations: molecular-cytogenetic characterization and prognostic influence on frontline imatinib therapy, a GIMEMA Working Party on CML analysis

AbstractVariant Philadelphia (Ph) chromosome translocations have been reported in 5%-10% of patients with newly diagnosed chronic myeloid leukemia (CML). Variant translocations may involve one or more chromosomes in addition to 9 and 22, and can be generated by 2 different mechanisms, 1-step and 2-step rearrangements, as revealed by fluorescence in situ hybridization. The prognostic significance of the occurrence of variant translocations has been discussed in previous studies. The European LeukemiaNet recommendations do not provide a “warning” for patients with variant translocations, but there is limited information about their outcome after therapy with tyrosine kinase inhibitors. To identify the role of variant translocations in early chronic phase (CP) CML patients treated with imatinib mesylate, we performed an analysis in a large series of 559 patients enrolled in 3 prospective imatinib trials of the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) Working Party on CML. Variant translocations occurred in 30 patients (5%). Our data show that the presence of variant translocations has no impact on the cytogenetic and molecular response or on outcome, regardless of the involvement of different mechanisms, the number of involved chromosomes, or the presence of deletions. Therefore, we suggest that patients with variant translocations do not constitute a “warning” category in the imatinib era. This study is registered at www.clinicaltrials.gov as NCT00514488 and NCT00510926.

Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group

AbstractAfter the identification of discrete relapse-risk categories in patients with acute promyelocytic leukemia (APL) receiving all-trans retinoic and idarubicin (AIDA)–like therapies, the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) designed a protocol for newly diagnosed APL (AIDA-2000) in which postremission treatment was risk-adapted. Patients with low/intermediate risk received remission at 3 anthracycline-based consolidation courses, whereas high-risk patients received the same schedule as in the previous, non–risk-adapted AIDA-0493 trial including cytarabine. In addition, all patients in the AIDA-2000 received all-trans retinoic acid (ATRA) for 15 days during each consolidation. After induction, 600 of 636 (94.3%) and 420 of 445 (94.4%) patients achieved complete remission in the AIDA-0493 and AIDA-2000, respectively. The 6-year overall survival and cumulative incidence of relapse (CIR) rates were 78.1% versus 87.4% (P = .001) and 27.7% versus 10.7% (P < .0001). Significantly lower CIR rates for patients in the AIDA-2000 were most evident in the high-risk group (49.7% vs 9.3%, respectively, P < .0001). Our data confirm that anthracycline-based consolidation is at least equally effective as cytarabine-containing regimens for low-/intermediate-risk patients and suggest that a risk-adapted strategy including ATRA for consolidation improves outcome in newly diagnosed APL. Furthermore, our results highlight the role of cytarabine coupled to anthracyclines and ATRA during consolidation in the high-risk group. This trial was registered at www.clinicaltrials.gov as #NCT 001064570.

Differentiating chronic lymphocytic leukemia from monoclonal B-lymphocytosis according to clinical outcome: on behalf of the GIMEMA chronic lymphoproliferative diseases working group

Optimal lymphocyte parameters and thresholds for the diagnosis of chronic lymphocytic leukemia have been proposed by The National Cancer Institute sponsored Working Group and recently updated by the International Workshop on chronic lymphocytic leukemia. However, it is not clear how these criteria apply to patient management in daily clinical practice and whether the lymphocyte thresholds recommended truly predict clinical outcome in early chronic lymphocytic leukemia. For the purpose of this study, an observational database of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) which included 1,158 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991-2000, was used. Among 818 consecutive chronic lymphocytic leukemia patients with Rai stage 0 (i.e. no palpable lymphadenopathy or hepatosplenomegaly) who had flow cytometry evaluations at the time of diagnosis and were included in a GIMEMA database, both absolute lymphocyte count and B-cell count were of a similar value in predicting time to first treatment as continuous variables (P<0.0001). Receiver operating characteristic analysis identified an absolute lymphocyte count of 11.5×10(9)/L and an absolute B-cell count of 10.0×10(9)/L as the best thresholds capable of identifying patients who will require treatment from those with stable disease. However, in a Cox's multivariate analysis only the B-cell count retained its discriminating power (P<0.0001) and the estimated rate of progression to chronic lymphocytic leukemia requiring treatment among subjects with a B-cell count less than 10.0×10(9)/L was approximately 2.3% per year (95% CI 2.1-2.5%) while it was 2-fold higher for patients with a B-cell count of 10.0×10(9)/L or over (i.e. 5.2% per year; 95% CI 4.9-5.5%). Finally, in this community-based patient cohort, the B-cell threshold defined by investigators at the Mayo Clinic (i.e. 11.0×10(9)/L) allowed patients to be divided into two subsets with a higher and lower likelihood of treatment (P<0.0001). Our results, based on a retrospective patients' cohort, provide a clear justification to retain the B-cell count as the reference gold standard of chronic lymphocytic leukemia diagnosis and imply that a count of 10×10(9)/L B cells is the best lymphocyte threshold to predict time to first treatment. The use of clinical outcome to distinguish chronic lymphocytic leukemia from other premalignant conditions, such as monoclonal B-cell lymphocytosis, is a pragmatic approach meeting the patients' need to minimize the psychological discomfort of receiving a diagnosis of leukemia when the risk of adverse clinical consequences is low.

The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party

Recently, in genome-wide analyses of DNA copy number abnormalities using single nucleotide polymorphism microarrays, genetic alterations targeting PAX5 were identified in over 30% of pediatric patients with acute lymphoblastic leukemia. So far the occurrence of PAX5 alterations and their clinical correlation have not been investigated in adults with BCR-ABL1-positive acute lymphoblastic leukemia. The aim of this study was to characterize the rearrangements on 9p involving PAX5 and their clinical significance in adults with BCR-ABL1-positive acute lymphoblastic leukemia. Eighty-nine adults with de novo BCR-ABL1-positive acute lymphoblastic leukemia were enrolled into institutional (n=15) or GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) (n=74) clinical trials and, after obtaining informed consent, their genome was analyzed by single nucleotide polymorphism arrays (Affymetrix 250K NspI and SNP 6.0), genomic polymerase chain reaction analysis and re-sequencing. PAX5 genomic deletions were identified in 29 patients (33%) with the extent of deletions ranging from a complete loss of chromosome 9 to the loss of a subset of exons. In contrast to BCR-ABL1-negative acute lymphoblastic leukemia, no point mutations were found, suggesting that deletions are the main mechanism of inactivation of PAX5 in BCR-ABL1-positive acute lymphoblastic leukemia. The deletions were predicted to result in PAX5 haploinsufficiency or expression of PAX5 isoforms with impaired DNA-binding. Deletions of PAX5 were not significantly correlated with overall survival, disease-free survival or cumulative incidence of relapse, suggesting that PAX5 deletions are not associated with outcome. PAX5 deletions are frequent in adult BCR-ABL1-positive acute lymphoblastic leukemia and are not associated with a poor outcome.

Risk-Adapted Maintenance Therapy for Acute Promyelocytic Leukemia

TO THE EDITOR: We read with great interest the article by Kelaidi et al concerning clinical trials for acute promyelocytic leukemia (APL) performed by the European APL group. This article is meaningful because the efficacy of maintenance therapy was separately analyzed in patients with high-risk APL who were defined as APL with presenting WBC count higher than 10 10/L and patients with low/intermediate-risk APL presenting WBC count lower than 10 10/L. We would like to make comments regarding risk-adapted maintenance therapy for APL. Maintenance therapy consisting of all-trans retinoic acid, 6mercaptopurine, and methotrexate has been adopted in some trials since the European APL group proved its efficacy. Kelaidi et al updated this data, and the benefit of this combination maintenance therapy in patients with high-risk APL was confirmed. In contrast, this therapy had a marginal benefit to preventing relapse to patients with low/intermediate-risk APL. This knowledge has been described for the first time. Risk-adapted strategies have been performed mainly concerning consolidation therapy and induction therapy in clinical trials for APL all over the world. There are no other reports in which it was mentioned that the benefit of this maintenance therapy was correlated with presenting WBC count. The European LeukemiaNet APL guidelines commented that the relative benefit of maintenance therapy depends on the prior induction and consolidation therapy and promyelocytic leukemia/ retinoic acid receptor-alpha (PML/RAR) mRNA status after consolidation therapy. In fact, combination maintenance therapy did not confer disease-free survival advantage for patients with negative PML/ RARA mRNA after three courses of consolidation therapy in the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) group, although the European APL group has performed maintenance therapy for patients with unknown PML/RARA mRNA status after two courses of consolidation therapy. Taking these into consideration, we should pay attention to the fact that the combination maintenance therapy has never been proven to be effective for patients with low/intermediate-risk APL. Moreover, the introduction of arsenic trioxide and gemtuzumab ozogamicin into first-line treatment for APL may reduce significance of maintenance therapy. In addition, this combination therapy often causes serious adverse events such as pancytopenia and liver dysfunction. Therefore, it is probable that the combination maintenance therapy should be omitted or amended in patients with low/intermediate-risk APL although many clinical study groups including the European APL group have continued to adopt this therapy for all patients with APL. The Southwest Oncology Group now examines whether this omission is beneficial for patients with low/intermediate-risk APL (ClinicalTrials.gov number, NCT00492856). Because the efficacy of maintenance therapy is dependent on the prior therapy as described above, the other study groups should prospectively and separately examine whether maintenance therapy has a clinical benefit for patients with low/ intermediate-risk and high-risk APL who have received the induction and consolidation therapy of their own. We believe that the answer to this topic would be of great significance in guiding therapy for patients with APL.

Central Nervous System and Intracranial Myeloma: a Retrospective Italian Multicenter Study.

Abstract 1882Poster Board I-905 Introduction.Intracranial involvement (IC) in multiple myeloma (MM) is extremely rare, most frequently resulting from osseous lesions in the cranial vault and skull base. Central nervous system (CNS) MM is even rarer (arising in less than 1% of the patients) consisting in intraparenchymal localizations, cerebral plasmacytomas or CNS myelomatosis. Patients described in the literature are few and treatments are variegate: systemic chemotherapy, (CHT), intrathecal therapy, (IT), radiotherapy, (RT) with results being discouraging with median survivals of 1 month or less. The impact of new drugs (thalidomide, bortezomib, lenalidomide) on CNS and IC MM has not been reported. Patients and Methods.We retrospectively collected clinical and biological data of patients presenting with a CNS or IC MM irrespective of disease status (diagnosis, response, relapse) by sending a questionnaire to the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) centers. Twelve centers answered. Results.Clinical characteristics. A total of 32 patients (M:F=18:14) were registered. All patients had an IC or CNS MM observed in the period between 2004–2009. Ten patients presented a CNS involvement, while 22 had an IC involvement. 9/32 patients had a CNS /IC involvement at diagnosis (4/5); 23/32 patients has a CNS/IC involvement after a median of 16 months (range 1–104) from MM diagnosis. Median age was 63 years (range 44–83) with no difference in both groups; monoclonal protein was IgG 18 (k16, λ2), IgA 6 (k4, λ2), BJ 6 (k3, λ3), non secretory 2. One patient had a solitary primitive IC plasmacytoma, 1 patient had an extramedullary localization in the lung. β2-microglobulin was available in 23 patients with a median value of 4 (range 1.1–17,5): ≤3.5 in 9 patients; >3.5<5.5 in 8 patients; >5.5 in 6 patients. FISH on bone marrow plasma cells was available in 11/32 patients: 60% of the patients showed genomic abnormalities, the more frequent being in order del 13q, t(11;14), del 17p. The most frequent presenting symptoms were in order headache (30%), confusion (27%), visual disturbances (25%), extremities weakness (21%), cranial nerve palsies (21%), paraesthesias (12%), vertigo (5%), convulsions (4%). Magnetic resonance imaging (MRI) of the brain was the preferred radiological imaging in 23/32 patients; computed tomography (CT) was used in 9/32 patients. Cerebrospinal fluid (CSF) involvement was demonstrated in 5/10 CNS MM. Cytogenetic analysis of cerebrospinal fluid was available in two patients who showed a complex karyotype. Treatment.CHT only was administered to 21 patients, CHT+RT to 5 patients, CHT+RT+IT to 3 patients, RT only to 1 , CHT +IT to 1, RT+IT to 1. Bortezomib was used in 15 patients, Thalidomide in 9, Lenalidomide in 3, MP in 7 , VAD in 3, PAD (with liposomal doxorubicin) in 2, cyclophosphamide in 3, other treatments in 3, and 8 patients received an high dose treatment + stem cells transplant (SCT) (5 Autologous/ 3 Allogeneic). 18/32 patients had a response after treatment defined as at least a reduction of 50% of the mass and /or M component (13 CR+VGPR) ; 17 patients had symptoms disappearance. PFS was at a median of 5 months (range 1–36). Median OS for CNS MM was 5 months (range 1–23), OS for IC MM was 9 months (range 1–42). 5/10 patients with CNS MM died at a median of 2 months (1–6); while 13/22 IC MM died at median of 8 months (1–46). 14/32 patients are alive at the present time (5 CNS, 9 IC). Interestingly, of 5 CNS MM patients alive 1 had AutoSCT , 4 received Bortezomib (1 combined with MP, 2 with liposomal doxorubicin, 1 with thalidomide); while of the 9 IC MM alive 3 received Bortezomib, 3 Auto SCT, 1 thalidomide, 1 lenalidomide, 1 cyclophosphamide. β2-microglobulin > 5.5 was a poor prognostic factor, as well as age >65 years. Conclusions.High dose therapies followed by autologous SCT seem to be the preferable therapy for eligible young patients. Novel drugs such as bortezomib, thalidomide, lenalidomide seem to increase the quality of responses and to prolong survival respect to what reported in the literature. Largest prospective studies are needed to confirm these findings. Disclosures:Petrucci:celgene: Honoraria; Jansenn-cilag: Honoraria. Palumbo:CELGENE: Honoraria.

The utility of a prognostic index for predicting time to first treatment in early chronic lymphocytic leukemia: the GIMEMA experience.

A prognostic index based on widely available clinical and laboratory features was recently proposed to predict survival in patients with previously untreated chronic lymphocytic leukemia. We assessed the utility of this index for predicting time to first treatment in early chronic lymphocytic leukemia. An observational database of the GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto), which included 310 patients with newly diagnosed Binet stage A chronic lymphocytic leukemia who were observed at different primary hematology centers during the period 1991 - 2000, was used for the purpose of this study. The new prognostic index enabled Binet stage A patients to be divided into two subgroups that differed with respect to time to first treatment (P=0.003). The original prognostic index was derived from a database that included cases observed at a reference academic center; these patients were younger (P<0.0001) and had more advanced disease (P<0.0001) than those in the current investigation, which studied community-based patients whose data were recorded at presentation. With this in mind, we used an optimal cut-off search to determine how best to split patients with Binet stage A disease into different prognostic groups. According to the recursive partitioning (RPART) model, a classification tree was built that identified three subsets of patients who scores were 0-2 (low risk), 3-4 (intermediate risk) and 5-7 (high risk). The probability of remaining free from therapy at 5 years was 100% in the low risk group, 81.2% in the intermediate risk group and 61.3% in the high risk group (P<0.0001). The results of this study confirm the utility of a new prognostic index for predicting time to first treatment in a large sample series of community-based patients with early stage chronic lymphocytic leukemia at presentation. Our effort to develop a revised scoring method meets the need to separate Binet stage A patients into different prognostic groups in order to devise individualized and tailored follow-up during the treatment-free period.

Heterogeneity in the therapeutic approach to relapsed elderly patients with acute myeloid leukaemia: a survey from the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Acute Leukaemia Working Party

The percentage of long-term survivors in acute myeloid leukaemia (AML) in the elderly does not exceed 10-15% of patients enrolled into clinical trials because of lower complete remission (CR) rates and higher incidence of relapse. However, few data are available as the treatment of elderly patients with relapsed disease is concerned. The aim of this study was of collecting data on criteria adopted for the treatment of these patients. A questionnaire was e-mailed to 32 haematologic institutions involved in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group. Questions to be addressed regarded: (1) per cent of relapsed elderly patients treated with aggressive salvage chemotherapy; (2) the selection criteria adopted for inclusion into intensive reinduction; (3) the specific treatment adopted; (4) the treatment given to patients not eligible for intensive salvage. Per cent of patients enrolled into aggressive salvage regimens varied from 10 to 80% (median 50%). The most frequent factor influencing the therapeutic choice was performance status (97%). Additional factors were age >70 years (44%) and duration of first CR (53%). Fludarabine including regimens were most frequently used as aggressive salvage therapy (59%), while gemtuzumab ozogamicin was adopted in various combinations at 11 out of 32 institutions (34%). For patients not eligible to aggressive therapy, the most frequent approach included hydroxyurea (59%). Low dose ARA-C (LDARA-C) was adopted at five centres: as single agent (n = 1), with 6-thioguanine (n = 1), with vitamin D3 and all-trans retinoic acid (ATRA) (n = 2), or with ATRA alone (n = 1). The FLT3 inhibitor CEP-701 was used at one centre. We conclude that the treatment of AML in elderly relapsed patients is extremely heterogeneous. A marked selection is operated as to inclusion into aggressive salvage regimens and only a small minority of patients are offered experimental approaches.

Therapy with high-dose dexamethasone (HD-DXM) in previously untreated patients affected by idiopathic thrombocytopenic purpura: a GIMEMA experience

AbstractIn idiopathic thrombocytopenic purpura (ITP), corticosteroids have been widely recognized as the most appropriate first-line treatment, even if the best therapeutic approach is still a matter of debate. Recently, a single high-dose dexamethasone (HD-DXM) course was administered as first-line therapy in adult patients with ITP. In this paper we show the results of 2 prospective pilot studies (monocentric and multicentric, respectively) concerning the use of repeated pulses of HD-DXM in untreated ITP patients. In the monocenter study, 37 patients with severe ITP, age at least 20 years and no more than 65 years, were enrolled. HD-DXM was given in 4-day pulses every 28 days, for 6 cycles. Response rate was 89.2%; relapse-free survival (RFS) was 90% at 15 months; long-term responses, lasting for a median time of 26 months (range 6-77 months) were 25 of 37 (67.6%). In the multicenter study, 95 patients with severe ITP, age at least 2 years and no more than 70 years, were enrolled. HD-DXM was given in 4-day pulses every 14 days, for 4 cycles; 90 patients completed 4 cycles. Response rate (85.6%) was similar in patients classified by age (< 18 years, 36 of 42 = 85.7%; ≥ 18 years, 41 of 48 = 85.4%, P = not significant), with a statistically significant difference between the second and third cycle (75.8% vs 89%, P = .018). RFS at 15 months 81%; long-term responses, lasting for a median time of 8 months (range 4-24 months) were 67 of 90 (74.4%). In both studies, therapy was well tolerated. A schedule of 3 cycles of HD-DXM pulses will be compared with standard prednisone therapy (eg, 1 mg/kg per day) in the next randomized Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) trial.

Imatinib High Dose (800 mg): Results of a Phase II Trial of the GIMEMA (Gruppo Italiano Malattie Ematologiche Dell'Adulto) CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio < 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib > 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

Imatinib 400 mg in Early Chronic Phase CML: Results of a Multicentric, Prospective Non Academical Observational Study (by the GIMEMA CML Working Party).

Imatinib 400 mg (SD) is the established first line treatment of chronic myeloid leukemia (CML) in chronic phase. The efficacy of imatinib in early chronic phase has been demonstrated by phase 2 and 3 controlled trials like the IRIS study (O' Brien et al NEJM 348:11, 2004). Large multicentric studies aimed to evaluate the impact of imatinib 400 mg outside strictly monitored frameworks are not yet available. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML Working Party opened in January, 2004, an observational study (serial n. CML/023) to investigate the efficacy of imatinib SD in newly diagnosed CML pts. Clinical and anagraphical data were collected through a web-based system. Peripheral blood samples for quantitative molecular analysis (RT-Q-PCR, Bcr-Abl/Abl × 100 - Taqman) were centralized in Bologna. Overall, 55 italian centers enrolled 367 (359 evaluable) newly diagnosed CML pts in chronic phase between Jan 2004 and Jan 2006. Median age was 50 yrs (range 18–84), 220 male and 139 females. Sokal risk at diagnosis was low, intermediate and high in 221 (62%), 123 (34%), 15 (4%) pts, respectively. 359 pts are evaluable for response at 3 months, 310 at 6 months and 187 at 12 months. The median observation time is 12 months. At 3 months, 94% of the pts reached a stable CHR. At 6 months, 80% of evaluable cases obtained a complete cytogenetic response (100% Ph-neg, CCgR). A major molecular response (MMolR) defined as a Bcr-Abl/Abl × 100 ratio < 0.1%, was shown in 52% of CCgR pts. At 12 months, the CCgR rate was 87% and the MMolR rate in CCgR pts was 63%. At 12 months, 3% of CCgR cases showed an undetectable level of transcript (ratio Bcr-Abl/Abl × 100 < 0,0001). With this short observation period, only 4 pts (1,1%) progressed to accelerated/blastic phase. Limiting the observation to low Sokal risk, at 12 months 221 such pts got a CCgR and MMol rates of 88% and 62%, respectively; 201 low Sokal risk pts were enrolled in the IRIS trial: at 12 months CCgR and MMolR (reduction of Bcr-Abl/Bcr ratio level > 3 logs) rates were 76% and 66%, respectively ( (T Hughes et al, NEJM 349:15, 2003). This study confirns that imatinib is efficacious and manageable, confirming and improving the results of the IRIS trial.

Deletions of the Derivative Chromosome 9 Do Not Influence Response to Imatinib of Early Chronic Phase Chronic Myeloid Leukemia Patients (A GIMEMA Working Party Analysis).

Extensive submicroscopic deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and α-interferon (α-IFN). Huntly et al (Blood. 2003; 102.2205–12) reported 275 CML pts who were treated with imatinib in CP, suggesting that der(9) deletions were associated with lower response rates and a shorter time to progression. Different data were reported by Quintas-Cardama et al (Blood. 2005; 105:2281–6), who did not find any difference related with der(9) deletions in other 320 patients treated with imatinib. In these 2 studies, some patients began imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. To establish the relationship of der(9) deletions with the response to imatinib in early CP patients, we planned a prospective study involving 3 consecutive multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML Working Party. 421 CML patients in early chronic phase were enrolled between January, 2004 and January, 2006; Fluorescence in situ hybridization (FISH) analysis of bone marrow cells was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. At diagnosis, 52 (12%) of them had der(9) deletion and 369 (88%) had not. The 2 groups, with/without deletions, were comparable (no difference in age, Sokal risk, imatinib dose). Median observation time is 12 months. At 3 months, the CHR rates in with/without deletions patients were 87%/92%. At 6 months, the complete cytogenetic response (0% Ph-pos; CCgR) rates were 80%/80%, with major molecular response (MMolR, defined as a Bcr-Abl/Abl x 100 ratio < 0.1%) rates of 52%/51%, respectively. At 12 months, CCgR rates were 89%/86% and MMolR 52%/61%. No difference is significant. We conclude that the presence of der(9) deletions at diagnosis do not constitute a negative factor for response to imatinib: the haematological, cytogenetic and molecular response rates resulted equal between the 2 groups of patients with and without der(9) deletions. This finding is relevant to the long term effect of imatinib treatment, since both the CCgR and the MMolR are important and established indicator of long term survival.

Adult T-cell acute lymphoblastic leukemia: biologic profile at presentation and correlation with response to induction treatment in patients enrolled in the GIMEMA LAL 0496 protocol

AbstractBetween 1996 and 2000, 90 newly diagnosed adult patients with T-acute lymphoblastic leukemia (T-ALL) were registered in the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) Leucemia Acuta Limfoide (LAL) 0496 protocol. Cases were centrally processed for morphology, immunophenotype, cytogenetics, molecular biology, and multidrug resistance (MDR). Twenty-two patients were females and 68 were males. Four percent of cases were pro-T, 47% pre-T, 39% cortical T, and 10% mature T-ALL. Fifty-six percent of patients with pro-T + pre–T-ALL achieved complete remission (CR) compared with 91% for cortical + mature cases (P = .002). CD34 expression was associated with a significantly lower CR rate: 54% versus 84% (P = .009). Thirty-one (36.5%) of 85 patients had an abnormal karyotype, the most common abnormality (15%) being a partial del(6q). The cytogenetic profile did not impact on CR achievement. MDR1 function, present in 26% of cases, correlated significantly with CR achievement (P = .004). A highly significant (P = .001) difference in CR rate was observed between patients who did not express the CD13/CD33/CD34 antigens and were MDR functionally negative (96%) compared with patients positive for at least one of these markers (57%). Multivariate analysis showed an impact on CR achievement for CD33 expression and MDR1 function. An extensive biologic workup of adult T-ALL cases at presentation is recommended in order to design tailored therapeutic strategies aimed at improving CR rates.

Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).

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

AbstractThe 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.

Atypical haemolytic–uraemic syndrome at the onset of acute promyelocytic leukaemia

A 68-year-old woman was admitted with fever and pancytopenia (white blood cell count 0AE9 · 10/l, haemoglobin 8 g/dl, platelet count 9 · 10/l). Bone marrow examination showed acute promyelocytic leukaemia; cytogenetic and molecular analysis showed t(15;17) and a PML-RARa fusion protein (BCR3 transcript). Laboratory findings at diagnosis were: blood urea nitrogen 12 mmol/l, creatinine 160 lmol/l, uric acid 0AE4 mmol/l, lactate dehydrogenase 2259 U/l, total bilirubin 42 lmol/l, unconjugated bilirubin 28 lmol/l and haptoglobin <0AE1 lmol/l. Direct and indirect Coombs’ tests were negative; fibrinogen, prothrombin time and activated partial thromboplastin time were normal with a D-dimer of 8AE5 lg/l. The peripheral blood film showed some schistocytes. Urinalysis showed microscopic haematuria and proteinuria. The patient was started on induction chemotherapy with all-trans retinoic acid 60 mg/d followed by idarubicin 10 mg/ m (four doses) according to the Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) protocol. Despite chemotherapy and appropriate supportive therapy, including hydration and red cell transfusions, the acute renal failure worsened, with an increase in creatinine (150 lmol/l) and progressive oliguria for which haemodialysis was started (three times a week). Kidney ultrasound examination was normal. A renal biopsy showed thrombotic microangiopathy with predominant glomerular involvement (arteriolar congestion with thrombi and endothelial damage) without cortical atrophy or necrosis (figures). Direct immunofluorescent microscopy showed diffuse IgM deposition in the mesangium, glomerular capillary subendothelium and focal deposition along capillary walls of IgA and C4 with a marked subendothelial widening with double contours. The clinical and histological findings were in accordance with an atypical (without diarrhoeal prodrome) haemolytic-uraemic syndrome. Despite treatment with dialysis, dexamethasone, plasma infusion and plasma exchange, the acute renal failure did not improve and the patient died 5 weeks after the diagnosis of leukaemia in a condition of haematologic remission. Atypical haemolyticuraemic syndrome, although rare, can be a fatal complication at onset or during induction chemotherapy of acute myeloid leukaemia.

Clinico-biologic features and treatment outcome of adult pro-B-ALL patients enrolled in the GIMEMA 0496 study: absence of the ALL1/AF4 and of the BCR/ABL fusion genes correlates with a significantly better clinical outcome

AbstractTo elucidate the biologic and clinical heterogeneity of adult pro-B acute lymphoblastic leukemia (ALL) (ie, terminal deoxynucletidyl-transferase–positive[TdT+], CD19+, CD10–, surface immunoglobulin–negative [SIg–]), we evaluated 66 patients enrolled in the Italian multicentric Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) 0496 study between October 1996 and December 1999. The ALL1/AF4 fusion transcript, originating from the t(4;11) translocation, was detected in 24 patients (36.4%), and the BCR/ABL chimeric product was found in 6 patients (9%), while the remaining 36 cases (54.6%) were ALL1/AF4-BCR/ABL–negative. A white blood cell (WBC) count higher than 50 × 109/L was found in 13 of 24, 2 of 6, and 6 of 36 of the ALL1/AF4-positive, BCR/ABL-positive, and ALL1/AF4-BCR/AB–negative patients, respectively (P = .007). None of the 24 ALL1/AF4-positive patients coexpressed the CD13 and/or CD33 myeloid antigens. By contrast, CD13 and CD33 molecules were detected, respectively, in 3 of 6 and in 14 of 33 cases of the BCR/ABL-positive patient group, and in 2 of 6 and 9 of 35 cases of the ALL1/AF4-BCR/ABL–negative patient group. These differences still remained statistically significant even if the BCR/ABL-positive patients were excluded from the analysis. A complete remission (CR) was achieved in 52 (83.4%) of the 62 patients with ALL evaluable for response to treatment. CR rates were similar in the 3 genotypic groups. By contrast, comparing patients with or without the ALL1/AF4 gene the probability of remaining in continuous complete remission (CCR) at 3.5 years was 16% and 49.8%, respectively (P = .005). Our data demonstrate that in adult pro-B-ALL a distinction should be made between pro-B-ALL cases with and without the ALL1/AF4 or the BCR/ABL chimeric genes, since the absence of both of these fusion genes correlates with a significantly better clinical outcome after intensive polychemotherapy treatment without hematopoietic stem cell transplantation.