Franco Leoni

Treatment of elderly patients (≥60 years) with newly diagnosed acute promyelocytic leukemia. Results of the Italian multicenter group GIMEMA with ATRA and idarubicin (AIDA) protocols

In all, 134 elderly patients (median age 66 years, range 60–75 years) with newly diagnosed acute promyelocytic leukemia (APL) were enrolled in two successive protocols of the Italian multicenter group GIMEMA. All patients received an identical induction with all-trans retinoic acid and idarubicin; 116 (86%) entered complete remission (CR), two (2%) were resistant and 16 (12%) died during induction. After CR, 106 patients received further therapy whereas 10 did not, because of refusal (n=5) or toxicity (n=5). Consolidation consisted of three chemotherapy courses in the AIDA protocol (AIDA, 67 patients) or, since 1997, of an amended protocol including only the first cycle (amended AIDA, aAIDA, 39 patients). In the AIDA group, 43 patients (64%) completed consolidation, while seven (11%) and 17 (25%) patients were withdrawn after first and second courses, respectively; nine patients (13%) died in CR and 12 (18%) relapsed. In the aAIDA group, all patients received the assigned treatment; two patients (5%) died in CR and six (15%) relapsed. In the AIDA and aAIDA series, the 3-year overall and discase-free survival rates were 81 and 83% (P=NS), 73 and 72% (P=NS), respectively. We highlight here the frequency and severity of complications linked to intensive chemotherapy in this clinical setting and suggest that, in APL of the elderly, less intensive postremission therapy allows significant reduction of severe treatment-related toxicity and may be equally effective.

Low dose velcade, thalidomide and dexamethasone (LD-VTD): An effective regimen for relapsed and refractory multiple myeloma patients

From January 2004, R/R MM cases referred to the Institution received LD-VTD regimen. Patients, irrespective of age, PS and life expectancy, were enrolled in the study once they had a measurable disease. Planned therapy: Velcade 1.0 mg m−2 i.v. twice weekly for 2 weeks of a 28-day cycle for up to 6 cycles, oral Dexamethasone 24 mg on the day of and the day following each Velcade dose and Thalidomide 100 mg each evening. DVT prophylaxis with warfarine to maintain international normalized ratio between 2.0–3.0 was planned in all patients. As of 1 June 2005, 18 were the treated patients: median age 63 years, median time from diagnosis 5.8 years, a median of 4 previous therapy lines. Seventeen were the valuable patients and 9 (53%) were the responders: 2 CR, 6 PR, 1 MR. Six were the stable disease and 2 the progressive ones. Median time to best response was 2 months. Toxicity was negligible. No case of DVT was recorded. Except for the first cycle, subsequent cycles were delivered on an outpatient basis. After a median follow-up of 11 months, 12 patients were alive and 5 died (3 disease progression, 1 heart failure, 1 intestinal bleeding). Thus, the LD-VTD regimen applied appears feasible and effective in elderly and heavily pre-treated R/R myeloma patients.

The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leukemia patients

The size of duplication does not add to the prognostic significance of FLT3 internal tandem duplication in acute myeloid leukemia patients

Clearance of leukaemic blasts from peripheral blood during standard induction treatment predicts the bone marrow response in acute myeloid leukaemia : a pilot study

Although several parameters are useful for risk stratification of patients with acute myeloid leukaemia (AML), there are no firm criteria for predicting response to induction treatment of individual patients. Daily flow cytometry (FC) analysis, carried out during induction treatment in 30 AML patients, showed that the clearance of blasts from peripheral blood (PBC) correlated closely with response, as assessed by bone marrow FC on day 14, and by morphologic analysis at haematopoietic recovery. Therefore, a major treatment outcome can be predicted very early in AML patients, thus providing an opportunity for tailoring treatment modalities from the outset.

De novo acute myeloid leukemia with multilineage dysplasia: treatment results and prognostic evaluation from a series of 44 patients treated with fludarabine, cytarabine and G-CSF (FLAG)

Abstract: Objectives : To evaluate therapeutic results and prognostic factors from a series of 44 patients affected by de novo acute myeloid leukemia with multilineage dysplasia (MD‐AML), treated with the combination of fludarabine, cytarabine and G‐CSF (FLAG). Methods : Forty‐four patients with de novo MD‐AML were treated with the FLAG regimen. The median age was 61 yr (range 31–75 yr). Induction therapy consisted of the FLAG regimen; consolidation included idarubicin plus cytarabine. Patients with a compatible donor and aged less than 55 yr were programmed to receive allogeneic bone marrow transplantation (BMT), while in those without a donor and aged less than 65 yr autologous transplantation with peripheral blood stem cells mobilized by a consolidation regimen plus G‐CSF was planned. Bone marrow harvest was performed in poor mobilizers. Results : Complete remission (CR) was achieved in 28 out of 44 patients (64%). Death in induction occurred in four patients (9%), while 12 patients (27%) were resistant to FLAG. Toxicity of consolidation was negligible. Most patients aged less than 60 yr and achieving CR were eligible for transplantation procedures, the main reason of exclusion being early relapse. Median overall survival and disease free survival were 16 and 22 months, respectively. Unfavorable cytogenetics was the only parameter significantly related to inferior clinical outcome following multivariate analysis. Conclusion : Multilineage dysplasia per se is not an adverse prognostic factor in AML patients treated with the FLAG regimen. Favorable results are obtained in patients with intermediate karyotype, while in those with adverse cytogenetics new approaches are clearly needed. The toxicity of the regimen is also acceptable in the elderly, and following induction/consolidation, most patients may be submitted to transplantation procedures.

The addition of liposomal doxorubicin to bortezomib, thalidomide and dexamethasone significantly improves clinical outcome of advanced multiple myeloma

Relapsed/refractory myeloma has a poor outcome because of multi‐drug resistance, patient low‐performance status and toxicity of conventional chemotherapy. To improve results, standard chemotherapeutics and drugs targeting the microenvironment are applied at the same time. Bortezomib, by inhibiting proteasome function, may enhance chemosensitivity to other drugs and overcome drug‐resistance. Notably, doxorubicin and bortezomib may reciprocally increase their efficacy. Thus, to improve outcome whilst minimizing therapy‐related toxicity, liposomal doxorubicin was added to a bortezomib‐based combination. From January 2004, relapsed/refractory myeloma patients referred to our Institution received bortezomib 1·0 mg/m2 i.v. twice weekly for 2 weeks in a 28‐d cycle for up to six cycles, oral dexamethasone 24 mg with the standard scheduling and thalidomide 100 mg continuously (VTD). From January 2005, liposomal doxorubicin, 50 mg/m2 (30 mg/m2 for patients older than 75 years), was added on day 4 of each cycle [VTD plus Myocet (MyVTD)]. In total, 70 patients were treated: 28 received VTD and 42 MyVTD. Baseline demographic and clinical characteristics were similar between the two groups. Toxicity was manageable although more pronounced with MyVTD. The overall response rate (81% vs. 50%, P = 0·009), time to progression (19 vs. 11 months, P = 0·01) and progression‐free survival (15 vs. 8 months, P = 0·001) were significantly higher with MyVTD regimen, suggesting an improved quality of response.

Attenuated-dose idarubicin in acute myeloid leukaemia of the elderly: pharmacokinetic study and clinical results.

AML in the elderly is characterized by intrinsic biological features implying an enhanced chemoresistance. Intensive chemotherapy should be the treatment of choice, but the standard doses could induce unacceptable rates of aplastic deaths. We evaluated the efficacy of an induction protocol with attenuated‐dose idarubicin (IDA) 8 mg/m2 for 3 d plus cytarabine and etoposide in 26 AML patients aged >60. 18 patients (69%) achieved CR, five (19%) were non‐responders and three (12%) died during induction. To compare the pharmacokinetics of IDA between elderly and young patients, we assayed daily the serum level of the drug and of its metabolite (idarubicinol, IDAol) in a group of eight elderly patients who received a dose of 8 mg/m2 (group A) and in a group of nine younger AML patients treated with 12 mg/m2 (group B). The apparent terminal half‐life of IDAol was significantly longer in the elderly than in the younger patients (mean half‐life 59–7h versus 41–4h, P< 0–05). The values of the area under the serum concentration curve of IDAol indicated that the two patient groups received a very similar exposure to the drug despite the different doses.

Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of acute myeloid leukemia relapsing after autologous stem cell transplantation

Abstract Twenty-six patients affected by acute myeloid leukemia (AML) who relapsed after autologous stem cell transplantation (ASCT) were treated with the FLAG regimen (fludarabine, cytarabine, and G-CSF). Their median age was 39 years (range 14–59). The median interval from achievement of CR to ASCT was 4 months (2–8). The conditioning regimen was BAVC (BCNU, amsacrine, VP-16, cytarabine) in eight patients, BuCy (busulfan, cyclophosphamide) in 13, and TBI-Cy (total body irradiation, cyclophosphamide) in five. Relapse occurred after a median of 7 months (2–18). ASCT had been performed in CR1 for 23 patients and in CR2 for three. Nineteen patients had been given bone marrow, seven peripheral blood stem cells collected following consolidation plus G-CSF. Overall, CR was obtained by 13 patients (50%), all remitters requiring a single course. The median time for hematological recovery of neutrophils >500/μl and platelets >20,000/μl was 24 and 30 days, respectively. The median duration of G-CSF administration was 25 days, while the median hospitalization was 31 days. There were four deaths in induction (15%), while nine patients (35%) were resistant. After achieving CR, two patients received allogeneic BMT, five a second ASCT, and four were consolidated with HD-ARA-C. Only two patients were judged unable to receive any further therapy. There were 14 documented infections, while nine patients experienced fever of unknown origin. WHO >2 nonhematological toxicity consisted of stomatitis (50%), hepatic dysfunction (11%), diarrhea (11%), and lethargy (4%). Median overall survival and disease-free survival were 6 and 13 months, respectively. Six patients are in CCR at present. We conclude that FLAG is effective in patients with AML who are relapsing after ASCT. The toxicity is acceptable, enabling most patients to receive further treatment, including second transplantation procedures.

Epstein–Barr virus-associated post-transplant lymphoproliferative disease with central nervous system involvement after unrelated allogeneic hematopoietic stem cell transplantation

Post-transplant lymphoproliferative disorders (PTLD) represent an heterogeneous group of abnormal lymphoid proliferation related to Epstein–Barr virus (EBV) reactivation that arise early after allogeneic hematopoietic stem cell transplant (HSCT). PLTD with central nervous system (CNS) involvement has been reported in few cases. We describe the case of a 31-year-old-man who developed an EBV-related PTLD with CNS involvement 2 months after an allogeneic unrelated HSCT for acute myeloid leukemia in first complete remission who was successfully treated with rituximab, cidofovir and intrathecal infusion of methotrexate and methylprednisolone.

Internal Tandem Duplications of Flt3 Gene (Flt3/ITD) Predicts a Poor Post-Remission Outcome in Adult Patients with Acute Non-Promyelocytic Leukemia

Despite progress in AML therapy, most patients eventually relapse, even the ones with normal or favorable karyotype. Since survival is poor once relapse occurs, new genetic tools above karyotype at diagnosis are needed to predict leukemia free survival. Recently, Flt3/ITD has been reported as an independent marker for clinical outcome in most studies concerning adult AML patients. To assess the prognostic relevance of activating mutations of Flt3, pretreatment samples of 100 not-M3 AML patients, all of them subjected to an intensive chemotherapy regimen, were analyzed for Flt3/ITD; 25/100 patients had one or more Flt3-ITD. Flt3/ITD patients had higher WBC count (P = 0.005), a lower incidence of a preceding MDS (P = 0.004) and most of them had a normal karyotype. Flt3/ITD had no impact on CR achievement while karyotype remained the most powerful prognostic factor (HR 2.8 95% CI 1.2 – 6.3). However, post-remission outcome was significantly worsened by the presence of Flt3/ITD. Median RFS of the Flt3/ITD patients was 5 vs. 27 months compared to the patients with wild-type Flt3 (P = 0.0002); moreover, Flt3/ITD patients had a significantly poorer post-remission survival (11 vs. 38 months, P = 0.01). On multivariate analysis, the presence of Flt3-ITD significantly affected relapse free survival and post-remission survival (HR 3.1 and 2.1, respectively). Thus, post-remission outcome highly depends on Flt3 status. Flt3 mutations identify patients at high risk of relapse, who should prospectively receive, according to age, either more aggressive or alternative therapeutic approaches.