A retrospective study on 73 elderly patients (≥75years) with aggressive B-cell non Hodgkin lymphoma: clinical significance of treatment intensity and comprehensive geriatric assessment.

OBJECTIVE: The clinical outcome of elderly (≥75years) patients with aggressive B-cell non-Hodgkin lymphoma (B-NHL) is not firmly established because few studies have specifically addressed this issue. In addition, the usefulness of a comprehensive geriatric assessment (CGA) in B-NHL still needs to be deeply explored. MATERIALS AND METHODS: We evaluated the prognostic factors of 73 patients aged ≥75years (median age: 78) with B-NHL treated by clinical judgment with curative anthracycline-based approaches (n=36) or with conservative treatments without anthracyclines (n=37). Analysis of clinical outcomes also included baseline CGA stratification. RESULTS: The curative approaches resulted in a better clinical outcome than conservative approaches [overall response rate: 91.2% vs. 69.7%, P=0.003; 2-year progression-free survival: 47.2% vs. 21.6%, P=0.006; and 2-year overall survival (OS): 58.3% vs 24.3%, P=0.003] with similar safety profiles. Independent of treatment type, patients classified as "fit" and "intermediate" by CGA presented with better OS compared to patients classified as "frail" (P<0.001). Patients classified as "fit" and "intermediate" who were receiving curative treatments presented with a significantly better OS when compared with those treated conservatively on the basis of clinical judgment. A curative anthracycline-based therapy (P=0.048), the response to treatment (P=0.017) and a "frail" condition (P=0.031) were the only factors affecting OS in multivariate analysis. CONCLUSIONS: Present data indicates that even in elderly patients with B-NHL curative anthracycline-based therapies are more effective than conservative approaches. However, choice of treatment should rely more on objective than on subjective parameters. Therefore, further prospective trials are warranted to better define the CGA role in hematopoietic malignancies.

Intensive consolidation therapy compared with standard consolidation and maintenance therapy for adults with acute myeloid leukaemia aged between 46 and 60 years: final results of the randomized phase III study (AML 8B) of the European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups.

The most effective post-remission treatment to maintain complete remission (CR) in adults aged between 46 and 60 years with acute myeloid leukaemia (AML) is uncertain. Previously untreated patients with AML in CR after induction chemotherapy with daunorubicin and cytarabine were randomized between two intensive courses of consolidation therapy containing high-dose cytarabine, combined with amsacrine or daunorubicin and a standard consolidation and maintenance therapy containing standard dose cytarabine and daunorubicin. One hundred fifty-eight CR patients were assigned to the intensive group and 157 patients to the standard group. After a median follow-up of 7.5 years, the 4-year survival rate was 32 % in the intensive group versus 34 % in the standard group (P = 0.29). In the intensive group, the 4-year relapse incidence was lower than in the standard group: 55 and 75 %, respectively (P = 0.0003), whereas treatment-related mortality incidence was higher: 22 versus 3 % (P < 0.0001). Two intensive consolidation courses containing high-dose cytarabine as post-remission treatment in patients with AML aged between 46 and 60 years old did not translate in better long-term outcome despite a 20 % lower relapse incidence. Better supportive care and prevention of treatment-related complications may improve the overall survival after intensified post-remission therapy in this age group.

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.

After 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.

Apoptosis susceptibility and cell-cycle distribution in cells from myelodysplastic syndrome patients: modulatory in-vitro effects of G-CSF and interferon-alpha.

Susceptibility to apoptosis varies in different forms of myelodysplastic syndromes (MDS). Our in vitro study aimed at better defining the cell kinetic profile by investigating whether G-CSF and interferon-alpha (IFNalpha) were capable of controling apoptotic/proliferative mechanisms in RAEB as well as in RAEB-t forms. Apoptosis and cell-cycle distribution were measured in mononuclear and in CD34+ cells from bone marrow samples of 27 MDS patients with RAEB (n = 15) and RAEB-t (n = 12). In selected samples, the in vitro influence of G-CSF and lymphoblastoid (Ly)-IFNalpha on the apoptotic susceptibility and on the cell kinetics of the above MDS populations was evaluated. RAEB samples showed a significantly greater apoptosis than RAEB-t ones, both in mononuclear cells (14.76%+/-8.73 vs. 5.95%+/-3.88, P= 0.0058) and in CD34+ cells (24.66%+/-16.08 vs. 3.96%+/-2.57, P = 0.0007). Short-term cell culture in the presence of G-CSF reduced apoptosis in CD34+ cells in all 4 RAEB samples tested (39.1%+/-40.7 vs. 21.0%+/-23.5, P = n.s.); the percentage of cells in S-phase significantly increased in 3/4 samples (19.90%+/-4.40 vs. 32.40%+/-7.85, P = 0.03). Ly-IFNalpha protected CD34+ cells from apoptosis in 3/4 RAEB samples (25.7%+/-8.06 vs. 10.9%+/-8.8, P = n.s.), but did not modulate cell-cycle distribution. G-CSF and Ly-IFNalpha failed to affect apoptosis and proliferation in RAEB-t. These observations indicate that in RAEB forms increased apoptosis can be efficiently counteracted in most of the samples by both G-CSF and Ly-IFNalpha, suggesting that only in these forms a retained regulatory mechanism on the apoptotic/ proliferative balance may allow therapeutic intervention with apoptotic regulators.

Clinico-pathological characteristics of myeloid sarcoma at diagnosis and during follow-up: report of 12 cases from a single institution.

The aim of this study was to describe the presenting features, the frequency and outcome of myeloid sarcoma (MS) diagnosed in our Institution from January 1995 to December 2000. Twelve MS were seen and the frequency account for only 2% of all acute myeloid leukemia (AML) patients observed in our department in the same period. Median age was 45 years (range: 4-84). All had been initially misdiagnosed as malignant lymphoma (ML) and a median of 2.9 months (range: 1-6) elapsed between the misdiagnosis and the correct of MS, effectuated in our department. At that time, a bone marrow examination revealed a myelodysplastic condition in seven patients, an infiltration by blast cells >30% in two patients, and normal features in the other three. In the non-leukemic patients a median of 5 months (range: 2-44 months) elapsed between the diagnosis of MS and acute leukemia. In all, 10 patients received intensive treatment. A total of seven patients (70%) achieved MS complete remission (CR). Patients who presented isolated skin localization and received only radiotherapy, obtained a MS-CR, but subsequently developed AML. Only in patients who were treated within 4 months from the initial ML diagnosis we achieved complete remission of both MS and leukemia, whereas in patients who were treated after this time, we obtained a complete disappearance of MS without response at the bone-marrow level, irrespectively of the specific therapy regimen. Median survival time from MS diagnosis was 7 months (range: 1-49 months), and only one patient is still alive, 49 months after bone marrow transplantation. Our data stress the importance of an accurate and prompt identification of this rare form of AML, and suggest that, even in patients with isolated MS, the early administration of AML-like intensive chemotherapy followed by bone marrow transplantation might reduce the risk of subsequently developing systemic disease.

Clinico-biological features and outcome of acute promyelocytic leukemia patients with persistent polymerase chain reaction-detectable disease after the AIDA front-line induction and consolidation therapy.

BACKGROUND AND OBJECTIVES: Front line treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid (ATRA) and chemotherapy (CHT) results in molecular remission in approximately 95% of patients tested after consolidation. The small fraction of patients with persistence of molecular disease (i.e. those in whom polymerase chain reaction (PCR) is positive for PML/RARalpha) after such therapy are thought to have a dismal prognosis but has not yet been investigated in detail. DESIGN AND METHODS: We analyzed the clinico-biological features at presentation of APL patients who showed PCR-detectable residual disease and compared them to those of patients achieving molecular remission after AIDA induction and consolidation. Furthermore, we report the outcome of patients with molecularly persistent disease treated with salvage therapy. RESULTS: Patients attaining molecular remission (n=650) and patients who tested PCR+ve at the end of consolidation (n=23) were not statistically significantly different as regards median age, white cell and platelet counts, morphologic subtype (M3 or M3v), fibrinogen levels or PML/RARalpha transcript type. As to treatment outcome after salvage therapy, 7 patients were treated before morphologic relapse [3 with chemotherapy and autologous stem cell transplantation (SCT) and 4 with allogeneic SCT], and are alive after 64-118 months. Of 16 patients treated at the time of morphologic relapse, only 2 patients are alive, both of whom received an allogeneic SCT. INTERPRETATION AND CONCLUSIONS: Our findings indicate that APL patients who are molecularly resistant to the AIDA protocol have no distinguishing features at presentation. Their outcome suggests the need for early therapeutic intervention with aggressive treatment prior to the occurrence of hematologic relapse.

Early detection of meningeal localization in acute promyelocytic leukaemia patients with high presenting leucocyte count.

Extramedullary relapse occurs infrequently in acute promyelocytic leukaemia (APL) but has been increasingly reported after the advent of all-trans retinoic acid (ATRA) treatment, probably as a consequence of improved patient survival. We describe our single centre experience of six APL patients who had disease localization in the central nervous system (CNS). In three patients, clinical symptoms (headache and/or nausea) that presented during follow-up led to the performance of a lumbar puncture and detection of overt CNS infiltration. Two of these patients had simultaneous haematological relapse and one was in molecular remission when CNS leukaemia was documented. One patient with no local symptoms showed CNS infiltration at the time of molecular relapse. Following the introduction of routine lumbar puncture, carried out after front-line induction in all newly diagnosed patients with white blood cell count (WBC) greater than 10 x 109/l, two additional patients in molecular remission with no local symptoms were found to have initial APL localization in the CNS. Presenting features included in 6/6 patients an elevated WBC count (> 10 x 109/l) and a predominance of the PML/RAR bcr3 type (5/6 patients) and of microgranular morphology (5/6 patients). Our findings highlight the importance of carrying out lumbar puncture in APL patients presenting with high-risk features.

Complete remission through blast cell differentiation in PLZF/RARalpha-positive acute promyelocytic leukemia: in vitro and in vivo studies.

Acute leukemia with the t(11;17) expressing the PLZF-RARalpha gene fusion is a rare variant of acute promyelocytic leukemia (APL) that has been associated with poor clinical response to all-trans retinoic acid (ATRA) treatment. However, some recent reports have put into question the absolute refractoriness of this leukemia to ATRA. We describe here a patient with PLZF/RARalpha APL who was treated at relapse with ATRA and low-dose hydroxyurea. Complete hematologic remission was obtained through differentiation of leukemic blasts, as proven by morphologic, immunophenophenotypic, and genetic studies carried out in sequential bone marrow samples. Moreover, in vitro studies indicated that blast differentiation was potentiated by the addition of the histone deacetylase inhibitor tricostatin A, but not of hydroxyurea, to ATRA. Our findings indicate that the maturation block may be overcome and terminal differentiation obtained in this leukemia subset and support the view that sensitivity/refractoriness of this form to ATRA should be revisited.

Diabetes insipidus as first manifestation of acute myeloid leukaemia with EVI-1-positive, 3q21q26 syndrome and T cell-line antigen expression: what is the EVI-1 gene role?

Two cases of acute myeloid leukaemia (AML) with CD2 and CD7 expression associated with diabetes insipidus (DI) as the initial symptom are presented. Both patients had t(3;3)(q21;q26) associated with monosomy 7 and EVI-1 overexpression. No neurohypophysis infiltration was evident. One patient died during induction chemotherapy, the other did not respond to therapy and died with persistent DI. Our findings further support the existence of a distinct AML entity characterized by the presence of DI, abnormalities of chromosome 3q, dysmegakaryopoiesis and poor outcome, and provide evidence of EVI-1 gene involvement. The possible role of chromosome 3q26 abnormalities in determining this peculiar clinical-biological association is emphasized.