Giacinto La Verde

Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma

The prognostic value of absolute lymphocytic count (ALC), has been a recent matter of debate in non-Hodgkin-lymphoma (NHL). We assessed prospectively the value of ALC at diagnosis and also after the completion of immuno-chemotherapy in 101 diffuse-large-B-cell-lymphoma (DLBCL). Analysis of prognostic factors with respect to overall survival (OS), event free survival (EFS) and progression free survival (PFS) was done by two-tailed log-rank test. The ALC cut-off value was calculated as <0.84 × 109/L at diagnosis: this was a strong negative prognostic factor for OS (p = 0.0004), EFS (p < 0.00001) and PFS (p < 0.00001) and in multivariate analysis was independent from the revised-international-prognostic-index (R-IPI). ALC after chemo-immunotherapy was not of prognostic value. As R-IPI and ALC < 0.84 × 109/L, were the factors better discriminating poor prognosis, a new trichotomous score (ALC/R-IPI) was built up: (1) low risk: R-IPI = very good or good and ALC < 0.84 × 109/L; (2) intermediate risk: patients with at least one risk factor (R-IPI = poor or ALC < 0.84 × 109/L). (3) high risk: patients with both risk factors. This new prognostic score was highly significant in univariate analysis for OS (p = 0.0002), EFS (p < 0.00001) and PFS (p < 0.00001). In multivariate analysis ALC/R-IPI was the most predictive factor for OS (OR = 2.954; p = 0.002) and EFS (OR = 2.381; p < 0.00001) and the only predictive factor for PFS (OR = 4.018; p < 0.00001).Our data, show that ALC at diagnosis has a strong prognostic relevance and is independent from the R-IPI. The new score including both values proved the most powerful predictor at multivariate analysis.

Pomalidomide, cyclophosphamide, and prednisone for relapsed/refractory multiple myeloma: a multicenter phase 1/2 open-label study

We performed a phase 1/2 trial to determine the maximum tolerated dose (MTD) of pomalidomide and to explore its efficacy when combined with cyclophosphamide-prednisone in relapsed/refractory myeloma patients. Pomalidomide was given at 1 to 2.5 mg/d, cyclophosphamide at 50 mg every other day, prednisone at 50 mg every other day, for 6 28-day cycles, followed by pomalidomide-prednisone maintenance therapy. Thromboprophylaxis was recommended. Sixty-nine patients were enrolled, 55 received the MTD (2.5 mg/d) and were evaluated. Best responses included complete response in 3 patients (5%), very good partial response in 10 (18%), partial response in 15 (27%), minimal response in 11 (20%), stable disease in 15 (27%), and progressive disease in 1 (3%), for an overall response rate of 51%. The median time-to-response was 1.83 months. After a median follow-up of 14.8 months, median progression-free survival was 10.4 months and 1-year overall survival was 69%. At the MTD, grade 3 to 4 toxicities included anemia (9%), thrombocytopenia (11%), neutropenia (42%), neurologic events (7%), dermatologic events (7%), and thromboembolism (2%). Grade 3 to 5 infections occurred in 5 patients (9%). Five patients (9%) discontinued treatment for toxicity. New grade 3 to 4 adverse events were low during maintenance. Pomalidomide-cyclophosphamide-prednisone is safe and effective in relapsed/refractory myeloma patients. This trial was registered at www.clinicaltrials.gov as #NCT01166113.

Disseminated intravascular coagulation and myocardial infarction in a haemophilia B patient during therapy with prothrombin complex concentrates.

A case of disseminated intravascular coagulation (DIC) and fatal myocardial infarction in a haemophilia B patient is described. DIC occurred after 4 days of therapy with unactivated prothrombin complex concentrates during the post-operative period. Therapy with fresh frozen plasma, heparin and antithrombin III concentrates was started without efficacy; after autopsy myocardial infarction was evident.

Intermediate-dose cyclophosphamide and granulocyte colony-stimulating factor is a valid alternative to high-dose cyclophosphamide for mobilizing peripheral blood CD34+ cells in patients with multiple myeloma

Peripheral blood stem cells (PBSC) are widely used in the setting of dose-intensive chemotherapies in patients with multiple myeloma (MM). Although the granulocyte colony-stimulating factor (G-CSF), following chemotherapy or not, is considered the standard growth factor for mobilizing PBSC, the optimal chemotherapeutic regimen still remains to be defined. Cyclophosphamide (CTX) is an effective drug in the treatment of MM which is capable of mobilizing PBSC if followed by growth factors, even though administration of high-dose CTX (7 g/m2) results in severe toxicity requiring hospitalization and increasing costs. We have retrospectively analyzed the results obtained in 38 newly diagnosed MM patients treated with 1.2 g/m2 CTX on days 1 and 3 combined with 40 mg dexamethasone daily for 4 days. The results were compared with those obtained in 25 newly diagnosed MM patients treated with 7 g/m2 CTX. A higher number of CD34+ cells/kg was collected during the first leukapheresis and a statistically significant lower consumption of G-CSF was observed following two doses of 1.2 g/m2 CTX compared to the 7 g/m2 CTX dose. The possibility of treating patients with day-hospital regimens, with a satisfactory yield of hematopoietic cells harvested, may have relevant economic implications for treatment strategies in MM patients.

IgD multiple myeloma a descriptive report of 17 cases: survival and response to therapy

BackgroundImmunoglobulin D multiple myeloma (MM) is rare and has a poorer prognosis than other MM isotypes.Design and methodsSeventeen patients (pts) diagnosed from 1993 to 2009 with IgD MM were selected from six institutions of Multiple Myeloma Latium-Region GIMEMA Working Group.ResultsMedian age was 55 years, 14 patients had bone lesions, eight had renal impairment with estimated glomerular filtration rate (eGFR) < 50 ml/min, one serum calcium ≥ 12 mg/dl, 11 had lambda light chains, five stage III of ISS, six with chromosomal abnormalities. Six pts received conventional chemotherapy (CT): five melphalan + steroids based regimens. Eleven underwent high-doses of chemotherapy with autologous stem cell transplantation (HDT/ASCT), five single and six tandem ASCT: six received bortezomib and/or thalidomide as induction therapy and five VAD. Thalidomide maintenance was used in two pts: one in HDT/ASCT and one in CT group; bortezomib was used in one patient after HDT/ASCT. At a median follow up of 38 (range 19-60) and 50 months (range 17-148) for pts treated with CT and HDT/ASCT, respectively, the overall response rate (ORR) was 83% and 90%. In the group of patients treated with CT, median overall survival (OS) was 34 months (95% CI 15- 54 months), median progression free survival (PFS) was 18 months (95% CI 3-33 months) and median duration of response (DOR) was 7 months (95% CI 5-9 months). Median OS, PFS and DOR were not reached at the time of this analysis in the HDT/ASCT group of patients. Death was observed in 27.3% of pts treated with HDT/ASCT and in 66.7% undergone CT.ConclusionsDespite the retrospective analysis and the small number of pts our study showed that the use of HDT/ASCT seems to improve also the prognosis of IgD MM patients. Treatment options including new drugs, before and after stem cell transplantation, may further improve the outcomes of these patients.

Prognostic Factors Associated With Progression of Smoldering Multiple Myeloma to Symptomatic Form

Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy‐MM). Herein, we analyzed some predictors of development of sy‐MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA).

Coexistent Multiple Myeloma and Myelofibrosis

Although the association of bone marrow fibrosis with plasma cell dyscrasias has already been described in several reports, the close relationship between these entities still remains unclear. In this report we describe a patient with clinical and pathologic findings which initially suggested a diagnosis of myelofibrosis, subsequently shown to be coexistent with multiple myeloma. Possible explanations for this association are discussed.

Continuous Low Dose of Melphalan and Prednisone in Patients with Multiple Myeloma of Very Old Age or Severe Associated Disease

Introduction and ObjectiveThe management of elderly patients with multiple myeloma is a relevant problem because it concerns a great number of patients. Patients with multiple myeloma who are very old or who have severe associated diseases have a dismal outcome. For these patients we retrospectively evaluated the effect of a mild approach with continuous low-dose melphalan and prednisone (cMP).Design and Methods109 patients with multiple myeloma, observed between 1985 and 2000, were treated with cMP; 67 were treated at time of diagnosis (group A; median age 78 years) and 42 as a second or subsequent line of therapy (group B; median age 72 years). The toxicity of the treatment was compared with a control group of 29 patients aged over 70 years, treated in the same institution with the conventional cyclical melphalan/prednisone regimen.ResultsMajor or minor responses were obtained in 32% of patients in group A and 13% of patients in group B. Disease was stabilised in 45% of group A and 47% of group B and progressed in 5 and 18%, respectively. Median survival was, respectively, 19 and 24 months in group A and B.Among the 42 patients who received cMP as a second-line therapy (group B), 36 (86%) had previously been treated according to the standard cyclical melphalan/prednisone schedule; of these 12 (33%) obtained a better M protein reduction after cMP compared with the previous response to first-line cyclical melphalan/prednisone.The cMP schedule was generally well tolerated, and the rate of haematological toxicity was lower than for a historical control group receiving cyclical melphalan/prednisone.ConclusionThe cMP treatment schedule is well tolerated and results in a high proportion of patients with stable disease, with acceptable survival even in patients with advanced disease.

Intravenous Melphalan and Dexamethasone Followed by Lymphoblastoid Alpha Interferon in Higher Risk Multiple Myeloma Patients

Intermittent courses of melphalan and prednisone is still the standard chemotherapy for the initial treatment of multiple myeloma (MM) in patients who cannot undergo high-dose chemotherapy/radiotherapy with either allogeneic or autologous stem cell transplantation. However, the absorption of the drug from the gastrointestinal tract is highly variable from patient to patient and therefore, different plasma levels of the drug are reached in the blood of individual MM patients. In order to overcome this limitation we decided to use intermediate dose (15-30 mg/m2, day 1) intravenous melphalan in resistant or relapsing MM patients as well as in untreated patients not eligible for a more aggressive protocol. Moreover, considering the good results obtained by other investigators using dexamethasone alone or associated with interferon in the treatment of resistant or relapsing MM patients, dexamethasone (40 mg total dose, day 1) and the lymphoblastoid alpha interferon (3 MU, 3 times a week x 3 weeks, from day 8 to day 26 of each course) were added to intravenous melphalan. Courses were repeated every 5 weeks for a total of 6 cycles. We treated 62 MM patients obtaining a response (defined as reduction > 25% of the initial monoclonal component value associated with disappearance of the clinical symptoms) in 38 out 62 evaluable patients (61%) and stable disease (defined as a decrease of < 25% in the base-line serum monoclonal component level with disappearance of all symptoms present at diagnosis) in 9 (14.5%) more patients. The overall median response duration was 14 months and the overall median survival duration (from the time of inclusion in this protocol) for the 62 patients entered into the study was 34 months. No severe (Grade 3-4 of the WHO) hematological as well as non hematological toxicities were observed. This lack of severe toxicity allowed us to administer the drugs on an outpatient basis. In conclusion, the overall response and the low grade of toxicity in this category of patients are encouraging and suggest that this protocol is both effective and safe treatment for high risk MM patients.

Serum Free Light Chains Removal by HFR Hemodiafiltration in Patients with Multiple Myeloma and Acute Kidney Injury: a Case Series

Background/Aims: Multiple myeloma (MM) represents 10% of all haematologic malignancies. Renal involvement occurs in 50% of MM patients; of them, 12-20% have acute kidney injury (AKI), with 10% needing dialysis at presentation. While hemodialysis (HD) has no effect upon circulating and tissue levels of monoclonal proteins, novel apheretic techniques aim at removing the paraproteins responsible for glomerular/tubular deposition disease. High cut-off HD (HCO-HD) combined with chemotherapy affords a sustained reduction of serum free light chains (FLC) levels. One alternative technology is haemodiafiltration with ultrafiltrate regeneration by adsorption on resin (HFR–SUPRA), employing a “super high-flux” membrane (polyphenylene S-HF, with a nominal cut-off of 42 kD). Aim of our pilot study was to analyze the effectiveness of HFR-SUPRA in reducing the burden of FLC, while minimizing albumin loss and hastening recovery of renal function in 6 subjects with MM complicated by AKI. Methods: Six HD-dependent patients with MM were treated with 5 consecutive sessions of HFR-SUPRA on a Bellco® monitor, while simultaneously initiating chemotherapy. Levels of albumin and FLC were assessed, calculating the rates of reduction. Renal outcome, HD withdrawal and clinical follow-up or death were recorded. Results: All patients showed a significant reduction of FLC, whereas serum albumin concentration remained unchanged. In three, HD was withdrawn, switching to a chemotherapy alone regimen. The other patients remained HD-dependent and died shortly thereafter for cardiovascular complications. Conclusion: Our study suggests that HFR-SUPRA provides a rapid and effective reduction in serum FLC in patients with MM and AKI, while minimizing the loss of albumin. When started early in combination with chemotherapy, blood purification by HFR-SUPRA was followed by the recovery of renal function in half of the patients treated.