Marino Brunori

Paroxysmal atrial fibrillation after high-dose melphalan in five patients autotransplanted with blood progenitor cells

Among the drugs used in conditioning regimens for stem cell transplantation, high-dose melphalan (HDM) plays an important role for both its strong myeloablative effect and for its favourable dose–response ratio. Here we report five cases of high frequency atrial fibrillation (AF) developing after HDM. Duration of the arrhythmia was always very short, beginning at variable intervals after the administration of HDM, in the absence of other factors potentially able to trigger AF. In all patients sinus rhythm was restored within 72 h and the follow-up did not show any cardiac damage. To the best of our knowledge, this side-effect has never been reported to occur after HDM.

Common and rare side-effects of low-dose thalidomide in multiple myeloma: focus on the dose-minimizing peripheral neuropathy

Objectives:  Thalidomide has demonstrated a remarkable efficacy in the treatment of multiple myeloma but its use may cause several toxicities. We have investigated the common and rare side‐effects, especially analysing peripheral neuropathy, in order to optimise the thalidomide dose for minimizing this harmful side‐effect.

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.

Efficacy and tolerability of bendamustine, bortezomib and dexamethasone in patients with relapsed-refractory multiple myeloma: a phase II study

Bendamustine demonstrated synergistic efficacy with bortezomib against multiple myeloma (MM) cells in vitro and seems an effective treatment for relapsed-refractory MM (rrMM). This phase II study evaluated bendamustine plus bortezomib and dexamethasone (BVD) administered over six 28-day cycles and then every 56 days for six further cycles in patients with rrMM treated with ⩽4 prior therapies and not refractory to bortezomib. The primary study end point was the overall response rate after four cycles. In total, 75 patients were enrolled, of median age 68 years. All patients had received targeted agents, 83% had 1–2 prior therapies and 33% were refractory to the last treatment. The response rate⩾partial response (PR) was 71.5% (16% complete response, 18.5% very good PR, 37% partial remission). At 12 months of follow-up, median time-to-progression (TTP) was 16.5 months and 1-year overall survival was 78%. According to Cox regression analysis, only prior therapy with bortezomib plus lenalidomide significantly reduced TTP (9 vs 17 months; hazard ratio=4.5; P=0.005). The main severe side effects were thrombocytopenia (30.5%), neutropenia (18.5%), infections (12%), neuropathy (8%) and gastrointestinal and cardiovascular events (both 6.5%). The BVD regimen is feasible, effective and well-tolerated in difficult-to-treat patients with rrMM.

A Predictive Model of Varicella-Zoster Virus Infection after Autologous Peripheral Blood Progenitor Cell Transplantation

Varicella-zoster virus (VZV) frequently causes severe infections in patients who have undergone bone marrow transplantation. The frequency of, characteristics of, and risk factors for this infection were studied in 164 patients undergoing autologous peripheral blood progenitor cell transplantation (PBPCT). Twenty-six patients (15.8%) developed VZV infection, and the actuarial risk was 10% at 1 year. No patient had visceral dissemination or died because of VZV, although one-third of the patients developed postherpetic neuralgia. By multivariate analysis, a CD4(+) lymphocyte count of <200 cells/microL (P<.0001; odds ratio [OR], 2.0) and a CD8(+) lymphocyte count of <800 cells/microL (P=.0073; OR, 2.0) at day 30 after transplantation were factors associated with VZV infection. Patients with both these adverse factors had an actuarial risk of VZV of 48% at 1 year. Patients with deficiency in both CD4(+) and CD8(+) lymphocytes are at high risk of VZV infection. These patients should be considered as candidates for preventive therapy, but whether for antiviral therapy or vaccination remains to be investigated.

Long-term hematologic reconstitution after autologous peripheral blood progenitor cell transplantation: a comparison between controlled-rate freezing and uncontrolled-rate freezing at 80°C

BACKGROUND : The most widely used system for peripheral blood progenitor cell (PBPC) cryopreservation is controlled‐rate freezing (CRF). Uncontrolled‐rate freezing (URF) at –80°C has also been used, but its clinical impact has not been studied sufficiently yet.

Very low toxicity and good quality of life in 48 elderly patients autotransplanted for hematological malignancies: a single center experience.

Between May 1994 and May 2000, we autotransplanted 48 consecutive patients, 21 females and 27 males aged over 60 years (range: 60–78, median: 63). Sixteen patients had multiple myeloma (MM), 14 high-grade non-Hodgkins lymphoma (HGNHL), six low-grade non-Hodgkins lymphoma (LGNHL), nine acute myeloid leukemia (AML), one chronic lymphocytic leukemia (CLL), one Hodgkins disease (HD) and one breast cancer; the performance status (WHO) was 0–1. Seventeen patients were in 1st CR (35.4%) and one in 2nd CR (2.1%), 25 in PR (52.1%), while five patients had been transplanted with progressive disease (10.4%); seven patients with MM received a double transplant. Patients received high-dose therapy including melphalan alone (13) or associated with other drugs (26), busulfan-cyclophosphamide (three), BEAM (11) and TBI (two). All patients took a median of 11 (range: 8–25) days to reach neutrophils >500/μl, 13 (range: 9–83) days to reach platelets >20 000/μl and 17 (range: 11–83) days to reach platelets >50 000/μl. Hematological toxicity, hospital stay and supportive care did not differ from those of a cohort of younger patients. At present, 31 patients are alive (14 in CR, five in PR, five in PD and seven in relapse) and 16 died from PD at a median follow-up of 37 months (1–67). Only one patient died from transplant-related toxicity. Quality of life, evaluated using a QLQ-C30 questionnaire in 25 patients at day +90, was good. In our experience PBPC mobilization and transplantation is feasible in patients aged ⩾60 years and the toxicity of this procedure is acceptable, with an early transplant-related mortality of 1.8%; therefore patients with hematological malignancies potentially curable with high-dose therapy (HDT) should also be candidates for HDT. Bone Marrow Transplantation (2001) 27, 1189–1195.

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.

Technetium-99m sestamibi scintigraphy is sensitive and specific for the staging and the follow-up of patients with multiple myeloma : a multicentre study on 397 scans

We evaluated the additional benefit of Technetium99‐sestamibi (99mTc‐MIBI) scanning in comparison with standard X‐ray techniques for multiple myeloma patients either at diagnosis or during follow‐up. Between February 2001 and January 2005, 397 whole body scans were acquired. On 229 scans performed at diagnosis, 146 (64%) were positive and 81 cases have discordant X‐ray results. The sensitivity of 99mTc‐MIBI and X‐ray were 77% and 45% respectively. As a result of 99mTc‐MIBI, 40% of asymptomatic myeloma patients were up‐staged. The positivity of 99mTc‐MIBI correlated significantly with all of the most relevant clinical and biological parameters. Multivariate analysis selected only high reactive C protein (P = 0·0005), bone marrow infiltration (P = 0·02) and bone pain (P = 0·002) as factors affecting 99mTc‐MIBI pattern. In 22 patients with solitary myeloma, 99mTc‐MIBI was positive in 86% of cases and detected more disease sites than X‐ray. Among 168 scans performed during follow‐up, 99mTc‐MIBI presented high specificity in patients showing a complete response (CR; 86%), and correlated with myeloma activity and with response to therapy. At multivariate analysis, a positive pattern correlated with bone marrow infiltration (P = 0·002) and disease status other than CR (P = 0·03). We conclude that 99mTc‐MIBI scanning is an additional diagnostic tool with a high specificity for the staging and the follow‐up of multiple myeloma patients.

Tailored therapy in an unselected population of 91 elderly patients with DLBCL prospectively evaluated using a simplified CGA.

BACKGROUND Elderly patients with diffuse large B-cell lymphoma (DLBCL) are a heterogeneous population; clinical trials have evaluated a minority of these patients. PATIENTS AND METHODS Ninety-one elderly patients with DLBCL received tailored treatment based on a comprehensive geriatric assessment (CGA). Three groups were identified: I, fit patients; II, patients with comorbidities; III, frail patients. Group I received 21-day cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP-21), group II received R-CHOP-21 with liposomal doxorubicin, and group III received 21-day cycles of reduced-dose CHOP. Fifty-four patients (59%) were allocated to group I, 22 (25%) were allocated to group II, and 15 (16%) were allocated to group III. RESULTS The complete response (CR) rates were 81.5% in group I, 64% in group II, and 60% in group III. With a median follow-up of 57 months, 42 patients are alive, with 41 in continuous CR: 31 patients (57%) in group I, seven patients (32%) in group II, and four patients (20%) in group III. The 5-year overall survival, event-free survival, and disease-free survival rates in all patients were 46%, 31%, and 41%, respectively. Multivariate analysis selected group I assignment as the main significant prognostic factor for outcome. CONCLUSIONS This approach in an unselected population of elderly DLBCL patients shows that treatment tailored according to a CGA allows the evaluation of elderly patients who are currently excluded from clinical trials.