Riccardo Centurioni

Vincristine sulfate for the treatment of thrombotic thrombocytopenic purpura refractory to plasma-exchange

Abstract: Among all the patients treated by the Italian Cooperative Group for TTP, we retrospectively reviewed the results obtained using vincristine (VCR) in 8 TTP patients (4 men and 4 women, average age: 39.25 years, range: 23–48) who did not respond to combined apheretic and pharmacologic treatment. All patients, after failing to respond to treatment, were started on VCR at the dose of 2 mg, i.v., once a week. Despite this treatment, 4 patients (50%) died 1, 7, 12 and 25 days after the first VCR dose, respectively. The other 4 patients who received VCR achieved complete remission 24, 30, 40 and 50 days from the beginning of the treatment. Total doses of VCR ranged from 2 to 6 mg in the deceased group, and from 6 to 14 mg in the cured patients. In our experience, VCR is a promising agent to treat TTP patients resistant to conventional plasma‐exchange and pharmacologic therapy.

Salvage therapy with an outpatient DHAP schedule followed by PBSC transplantation in 79 lymphoma patients: an intention to mobilize and transplant analysis

Chemotherapy followed by autologous transplantation may be an efficient salvage treatment in malignant lymphomas. We investigated the feasibility, tolerability and efficacy of an outpatient schedule of dexamethasone, cytarabine and cisplatin (DHAP), followed by peripheral blood progenitor cell autografting as salvage treatment in patients with high grade (HG), low grade (LG) non‐Hodgkins lymphoma (NHL) and Hodgkins Disease (HD). A total of 159 DHAP courses (median: 2, range: 1–5), was administered on outpatient basis to 79 patients (31 LG‐NHL, 28 HG‐NHL and 20 HD), with the intention to mobilize and to transplant. A successful collection was not achieved in 40% LG‐NHL, 10% HD and 20% HG‐NHL patients. The risk to fail the collection was significantly related to the number of previous chemotherapy courses (>6) (P = 0.005, RR = 1.4), to the pretransplant status (P = 0.04, RR = 13.5) and to the previous fludarabine administration (P = 0.01, RR = 20). High dose therapy (HDT) was feasible in 60 patients (76%). The overall treatment related mortality was 3.8%. The overall response rate (ORR) was 81% with a 57.6% overall survival (OS) at 62 months (95% CI: 45–69.3%) and a progression free survival (PFS) of 42% at 74 months (95% CI: 26.7–58%). The diagnosis of HG‐NHL and the non‐response to DHAP resulted to reduce respectively the OS (P = 0.007, RR = 2.8) and PFS probability (P = 0.01, RR = 4.1). In conclusion this outpatient schedule of DHAP is a well tolerated, efficient salvage and mobilizing regimen not only in HG‐NHL, but also in LG‐NHL and in HD. Randomized studies are needed to better define the role of DHAP in LG‐NHL and HD patients.

Treatment of relapsed adult acute lymphoblastic leukemia with fludarabine and cytosine arabinoside followed by granulocyte colony-stimulating factor (FLAG-GCSF).

The aim of the present study was to evaluate the efficacy of the combination of fludarabine 30/mg/m2 + cytarabine 2g/m2 followed by the administration of G-CSF to achieve a complete remission (CR) in patients with relapsed acute lymphoblastic leukemia (ALL). We treated twelve patients in first relapse, overall 10 patients achieved a second CR, one patient showed resistant disease and one patient died during remission induction. The regimen was well tolerated and we observed a short period of neutropenia with a low incidence of myelosuppression-associated problems. Eight patients in second CR received the same chemotherapeutic regimen as consolidation used for the reinduction. In six patients the chemotherapeutic regimen was well tolerated, two patients died, (cerebral hemorrhage in one patient and sepsis in the other). In conclusion the combination of fludarabine, cytarabine and G-CSF has significant antileukemic activity and non hematological toxicities were acceptable. The addition of G-CSF reduced the period of neutropenia obtaining a low incidence of myelosuppression-associated problems.

Thalidomide-dexamethasone versus Interferon-alpha-dexamethasone as maintenance treatment after ThaDD induction for multiple myeloma: a prospective, multicentre, randomised study

Maintenance therapy was explored in multiple myeloma (MM) patients after conventional thalidomide, dexamethasone and pegylated liposomal doxorubicin (ThaDD). Patients with newly or relapsed MM obtaining at least minor response after 6 ThaDD courses, were randomised to receive α‐interferon (IFN) 3 MU 3 times a week or thalidomide 100 mg daily until relapse. Both groups also received pulsed dexamethasone 20 mg 4 d a month. Fifty‐one patients were randomized in the IFN‐dexamethasone (ID) arm and 52 in the thalidomide‐dexamethasone (TD) arm. The characteristics of two groups were similar. A significantly better 2‐years progression‐free survival (PFS; 63% vs. 32%; P = 0·024) and overall survival (84% vs. 68%; P = 0·030) was observed in the thalidomide arm. In high‐risk patients and in those achieving less than very good partial response after induction, TD fared better in term of PFS. Main side effects were peripheral neuropathy and constipation in TD group, fatigue, anorexia and haematological toxicity in ID arm. There was a 21% probability of discontinuation at 3 years in the thalidomide arm and 44% in the IFN arm (P = 0·014). Low‐dose thalidomide plus pulsed low‐dose dexamethasone after conventional thalidomide combination‐based therapy was also feasible in the long term, enabling significantly better residual disease control if compared with a standard maintenance therapy.

Infectious complications in patients with multiple myeloma treated with new drug combinations containing thalidomide.

The literature provides scant data concerning infectious complications and their effect on the outcome of patients with multiple myeloma (MM) treated with new drug combinations. Despite no substantial myelotoxic effect, thalidomide increases the risk of severe infections in patients with MM. We studied 202 patients who received regimens containing thalidomide in order to assess the time, type, outcome, and factors affecting development of severe infections, role of antibiotic prophylaxis, and effect of severe infections on final outcome. Thirty-eight patients (19%) developed a severe infection early during induction therapy and most infections were pneumonia. Only one patient died due to septic shock during neutropenia. No significant differences were reported in terms of progression-free survival (PFS) and overall survival (OS) between patients developing a severe infection and those who did not. Multivariate analysis determined a monoclonal component >3 g/dL and platelets <130 000/μL as factors associated with increased risk of severe infection. Primary antibiotic prophylaxis significantly decreased the probability of severe infection only in patients having both the above risk factors. Patients with MM receiving thalidomide combinations with high tumor burden are at high risk of developing severe infections and require primary antibiotic prophylaxis, whereas in other patients it is questionable. However, patient final outcome was not affected by infection development.

ThaDD plus high dose therapy and autologous stem cell transplantation does not appear superior to ThaDD plus maintenance in elderly patients with de novo multiple myeloma

Objectives: With the aim to address the issue whether high‐dose therapy (HDT) is required after new drugs combinations to improve outcome of elderly newly diagnosed multiple myeloma (MM) patients, we compared the toxicity and the outcome of ThaDD plus maintenance to those of ThaDD plus HDT‐autologous stem cell transplantation (ASCT). Methods: Sixty‐two patients not eligible for HDT receiving six courses of ThaDD regimen plus maintenance with thalidomide were compared to 26 patients eligible for HDT treated with four courses of ThaDD followed by melphalan 100–200 mg/m2 and ASCT. The two groups were matched for the main characteristics except for age favouring the HDT group. Results and conclusions: Complete remission (CR) obtained with ThaDD plus maintenance was 24% whereas it was 57% after ThaDD plus HDT‐ASCT (P = 0.0232). However, after a median follow‐up of 36 months, median time to progression (TTP) and progression free survival (PFS) of the group of patients undergone HDT were not significantly different to those of patients receiving ThaDD plus maintenance (32 vs. 31 months: P = 0.962; 32 vs. 29 months: P = 0.726, respectively). Five‐year overall survival (OS) was 49% in the first group and 46% in the latter one (P = 0.404). As expected, a significantly higher incidence of grade 3–4 neutropenia, thrombocytopenia, infections, mucositis and alopecia were observed in the ThaDD plus HDT group. Our results suggest that in elderly MM patients ThaDD plus HDT, albeit significantly increases CR rate, seems to be equivalent to ThaDD plus maintenance in terms of TTP, PFS and OS. These results challenge the requirement for HDT consolidation in this subset of patients.

Serum C-Reactive Protein at Diagnosis and Response to Therapy Is the Most Powerful Factor Predicting Outcome of Multiple Myeloma Treated with Thalidomide/Anthracycline—Based Therapy

BACKGROUND Few studies have focused on factors affecting outcome in patients with multiple myeloma (MM) treated with thalidomide-based therapy. We investigated factors affecting response, progression-free survival (PFS), and overall survival (OS) in patients with MM treated with the thalidomide, dexamethasone, and pegylated liposomal doxorubicin (ThaDD) regimen with the aim to select patients benefiting more from this therapy. PATIENTS AND METHODS Sixty-six patients with MM were treated first line with the ThaDD regimen. We analyzed demographics and disease-related characteristics to search for factors affecting response (> or = very good partial remission [VGPR] vs. < VGPR], PFS, and OS. RESULTS Overall, 45 patients (68%) showed response > or = VGPR; median TTP and OS were 23.5 months and 35.5 months, respectively. Multivariate analysis selected only serum C-reactive protein (sCRP) as a predictive factor for response (P < .0001). By multivariate analysis, normal sCRP level (P = .001) and response to treatment > or = VGPR (P = .007) were found to be associated with longer PFS. The factors that remained significantly associated with a longer OS when assessed by multivariate analysis were normal sCRP level (P = .005) and response to therapy > or = VGPR (P = .019). CONCLUSION Serum C-reactive protein before therapy and response after therapy are the only factors useful in identifying patients benefiting from anthracycline/thalidomide-based therapy.

Comparison of two regimens for the treatment of elderly patients with acute lymphoblastic leukaemia (ALL).

Acute lymphoblastic leukemia (ALL) represents a rare malignancy in the elderly and few authors have specifically focused on the treatment of ALL in this setting. We recently published the results of a prospective phase II study comprising an induction therapy with vincristine, Daunoxome and dexamethasone (VDXD) given to 15 patients aged ⩾̸ 60 years. Here, we update the results after enrolling 17 patients, and we compare these with the results obtained in 17 elderly patients treated according to the GIMEMA ALL 0288 protocol. With the VDXD combination, elderly ALL had a higher CR rate (76.5%) than with the 0288 protocol (41%), and it was likely due to both lower induction mortality (17.5% vs. 35%) and a less resistant disease (6% vs. 24%). Infectious complications were more frequent with the VDXD combination whereas non-hematological side effects were comparable. Despite the similar DFS obtained with the two induction treatments, median EFS (3.9 months with 0288 vs. 12.8 with VDXD; p = 0.0486) and OS (4.5 vs. 21 months; p = 0.0239) were significantly higher with the VDXD regimen. In elderly ALL patients the administration of high-dose daunorubicin as a liposomal compound is feasible and seems able to improve CR rate, EFS and OS without increase in toxicity.

Prognostic role of immunohistochemical analysis of 5 mc in myelodysplastic syndromes.

Aberrant DNA methylation at CpG islands within promoters is increasingly recognised as a common event in human cancers and has been associated with the silencing of important tumour suppressor genes. Epigenetic therapy using hypomethylating agents has demonstrated clinical effectiveness; the drugs azacitidine and decitabine have been approved for the treatment of MDS.

Nitrite and Nitrate Plasma Levels, as Markers for Nitric Oxide Synthesis, in Thrombotic Thrombocytopenic Purpura (TTP)

The enhanced platelet aggregation and thrombosis occurring in TTP is probably due to an unbalance between agents insulting endothelial integrity and natural antithrombotic factors, such as NO. Using a sensitive and specific HPLC assay, we tested the hypothesis of NO involvement in TTP, comparing NO production, as the stable end-products nitrites and nitrates, in the plasma of 29 TTP patients and of 29 healthy subjects matched for sex and age. Average nitrate titer was 25.868 μM/L in the TTP group vs 24.234 μM/L in the control group (p = n.s.), while nitrite were undetectable in both groups. Moreover, nitrate titers did not correlate with hemoglobin value, platelet count, LDH values, or with Rose and Eldors severity score. In conclusion, even though the enhanced platelet aggregation observed in TTP could be due to reduced natural antithrombotic substances, NO involvement in the pathogenesis of TTP appears unlikely.