Alessio Perrotti

Long-Term observation of 208 adults with chronic idiopathic thrombocytopenic purpura**

PURPOSE To define response to therapy and ultimate outcome of adults with idiopathic thrombocytopenic purpura (ITP). PATIENTS AND METHODS We retrospectively analyzed patients with ITP diagnosed between 1978 and 1988, and reexamined them between June 1992 and March 1993. Data from 208 cases were collected. Median patient age was 44 years (range 14 to 78) at the time of diagnosis, and 51 years (range 19 to 86) at reexamination. Length of follow-up ranged from 48 to 151 months (median 92) and was longer than 10 years in 26 patients (12.5%). Reexamination included a careful interview, physical examination, complete blood count, screening for HIV infection, determination of platelet-bound IgG, and, in persistently thrombocytopenic patients, autoimmunity markers and routine laboratory investigations. RESULTS A total of 121 patients with fewer than 50 x 10(9) platelets per liter received an initial treatment with prednisone (PDN) at a dosage of 1 mg/kg of body weight for 1 month. Refractory or relapsed cases underwent splenectomy and/or other therapeutic modalities. In 87 patients with greater than 50 x 10(9) platelets per liter, no therapy was scheduled. An initial complete response to PDN was observed in 38.8% cases. A sustained complete remission (CR) lasting more than 6 months with no maintenance therapy was attained in 18.7%. At the time of last follow-up only 11 of these patients remained in CR. Sixty-three patients underwent splenectomy. Forty-seven (74.6%) had a CR, with 41 achieving a prolonged recovery (> 6 months). Twelve other cases attained a sustained partial remission. Long-lasting recoveries were observed in 7 other cases following alternative treatments. Spontaneous remissions occurred in 8 of 87 untreated cases after observation periods of 6 months or more. Eleven deaths were recorded (6 women and 5 men, median age 73), but only 5 were attributable to thrombocytopenia. At last control, 43 patients were in complete remission and free from therapy, and 52 were still on therapy. Four thrombocytopenic patients had laboratory features and a clinical history consistent with an autoimmune disease. CONCLUSIONS This analysis of ITP in adults suggests that splenectomy remains the most effective treatment. The majority of patients who undergo splenectomy can have a CR for many years, while only a minority of those who do not have this therapeutic modality or fail it are likely to attain similar results. The long-term prognosis of ITP is benign even in refractory cases. Spontaneous remissions can be observed in a significant percentage of untreated patients (about 9%). The development of overt autoimmune diseases is relatively uncommon. Particular attention should be given to the management of ITP in the elderly, where bleeding episodes of the central nervous system tend to occur more frequently.

Fludarabine Plus Mitoxantrone With and Without Rituximab Versus CHOP With and Without Rituximab As Front-Line Treatment for Patients With Follicular Lymphoma

PURPOSE Promising new therapeutic options for follicular lymphoma (FL) include fludarabine plus mitoxantrone (FM) and the mouse/human anti-CD20 antibody, rituximab. We performed a randomized comparative trial of FM with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) front-line chemotherapy with and without sequential rituximab. PATIENTS AND METHODS All previously untreated CD20(+) FL patients presenting in 15 Italian cooperative institutions from October 1999 were randomly allocated to FM or CHOP. Following clinical or molecular restaging, patients in complete remission (CR) with bcl-2/IgH negativity (CR(-)) received no further treatment; those in CR with bcl-2/IgH positivity (CR(+)) received rituximab, as did those in partial remission (PR) with bcl-2/IgH negativity (PR(-)) or positivity (PR(+)); nonresponders (NR subgroup) were off study. RESULTS After chemotherapy, the FM arm achieved higher rates of CR (68% [49 of 72 patients] v 42% [29 of 68 patients]; P =.003) and CR(-) (39% [28 of 72 patients] v 13 of 68 patients [19%]; P =.001). Rituximab elicited CR(-) in 55 of 95 treated patients (58%). The final CR(-) rate was higher in the FM arm (71% [51 of 72 patients] v 51% [35 of 68 patients]; P =.01). However, with a median follow-up of 19 months (range, 9 to 37 months), no statistically significant difference was found among the various study arms in terms of both progression-free (PFS) and overall survival (OS). CONCLUSION These results indicate that FM is superior to CHOP for front-line treatment of FL and that rituximab is an effective sequential treatment option. However, they also confirm that this superiority is unlikely to translate into either better PFS or OS.

Consolidation and maintenance immunotherapy with rituximab improve clinical outcome in patients with B-cell chronic lymphocytic leukemia†

Rituximab in sequential combination with fludarabine (Flu) allowed patients with B‐cell chronic lymphocytic leukemia (B‐CLL) to achieve higher remission rates and longer response duration. Based on their recent experience in indolent non‐Hodgkin lymphomas, in this study, the authors attempted to demonstrate whether consolidation/maintenance therapy with rituximab could prolong the response duration in this patient population.

Clinical implications of cytokine and soluble receptor measurements in patients with newly-diagnosed aggressive non-Hodgkin's lymphoma

Abstract:  Serum levels of 13 different cytokines and receptors were measured serially in 78 patients with aggressive non‐Hodgkins lymphoma (NHL) treated by 4 cycles of an intensive multi‐agent chemotherapy regimen. Recombinant human granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) was administered subcutaneously in 36 of these patients from day + 5 to day + 18 after each chemotherapy. Statistically significantly higher pretreatment levels of interleukin‐2 (IL‐2), interleukin‐6 (IL‐6), interleukin‐8 (IL‐8), interleukin‐10 (IL‐10), the soluble IL‐2 receptor (sIL‐2r), the soluble transferrin receptor (sTf‐r), and neopterin, were observed in NHL patients as compared to controls (p< 0.001 for all molecules). sIL‐2r and sTf‐r levels correlated with tumor burden (p< 0.001 and p = 0.003, respectively) whereas IL‐6 was higher in patients presenting B symptoms (p< 0.001). Cytokine levels progressively declined to normal ranges in responding patients, while they remained elevated in non‐responders. Relapsed patients also presented increased concentrations of several molecules. During the administration of GM‐CSF, we observed the drastic increase of sIL‐2r, while lower elevations were recorded for a number of cytokines, including IL‐8, tumor necrosis factor‐α, interleukin‐1β, IL‐6, and IL‐2. However, upon completion of the induction treatment, cytokine/receptor levels were comparable among individuals with the same type of response, whether or not they had received GM‐CSF. No single parameter was found to be of prognostic significance, but the combination of elevated IL‐10 and of sIL‐2r greater than 3000 U/ml selected a subgroup of 7 patients who failed induction treatment (p = 0.002). These results demonstrate that cytokine and soluble receptor measurements can provide valuable informations for a better management of NHL, in terms both of markers to monitor disease activity and of prognostic indicators.

A phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium‐90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non‐Hodgkin lymphoma

A prospective, single‐arm, open‐label, nonrandomized Phase 2 study of combined fludarabine and mitoxantrone (FM) plus radioimmunotherapy was conducted to evaluate efficacy and safety in patients with untreated, indolent, nonfollicular non‐Hodgkin lymphoma (NHL).

Pain syndromes in the setting of haematopoietic stem cell transplantation for haematological malignancies.

Severe pain syndromes may be recorded during all phases of haematopoietic stem cell transplantation (HSCT) for haematological malignancies: from stem cell mobilization to the long-term post transplant period. Although the major cause of pain in the setting of HSCT is injury to mucosal tissues induced by the conditioning regimen, pain from several other causes has been reported. In this paper, we review pain and its management in the setting of HSCT.

Prolonged survival and low incidence of late toxic sequelae in advanced follicular lymphoma treated with a TBI-free autografting program: updated results of the multicenter consecutive GITMO trial

This study provides an updated report of the consecutive multicenter Gruppo Italiano Trapianto Midollo Osseo trial employing an intensified, purging-free, total body irradiation-free, high-dose sequential chemotherapy schedule with peripheral blood stem cell autograft (i-HDS) in advanced-stage follicular lymphoma (FL). Special interest has been devoted to late toxicities and outcome in terms of molecular status. Ninety-two untreated FL patients aged ⩽60 were enrolled by 20 Italian centers and evaluated on an intention-to-treat basis. Main findings are as follows: (1) 5.5-years overall survival projection of 80% (median follow-up: 68 months), with no differences related to age-adjusted IPI score; (2) 46 (50%) of 92 patients presently in continuous complete remission; (3) projected long-term progression-free survival exceeding 80% for patients collecting PCR-negative stem cell harvests or achieving molecular remission within the first 2 years from the end of therapy; (4) actuarial 5-years risk of developing secondary myelodysplasia and acute myeloid leukemia of 3.7%, with most of these events occurring in patients re-treated for recurrent lymphoma. These results demonstrate that i-HDS is feasible, effective and safe even in terms of long-term outcome. As the HDS schedule can be easily supplemented with Rituximab, it is one of the best options for random comparison with Rituximab-supplemented conventional chemotherapy.

Transfusions at home in patients with myelodysplastic syndromes

We report descriptive data of a home care (HC) program, throughout a 5-years period (2006-2010), focusing on the reliability and the safety of transfusions at home in 211 patients affected by myelodysplastic syndromes (MDS). Our results outline the potentially relevant role of a specifically dedicated HC service in the global management of frail MDS patients for which transfusions at home may represent a valuable option to maintain a good quality of life and avoid the possible discomfort due to hospital admissions and outpatient visits.

The Management of Membranous Glomerulopathy in Allogeneic Stem Cells Transplantation: Updated Literature

BACKGROUND membranous glomerulopathy (MG) is an immunomediated disorder which accounts for the most common cause of nephrotic syndrome (NS) following allogeneic hematopoietic stem cell transplantation (HSCT). OBJECTIVE AND METHODS to provide an update on the issue by reviewing pertinent literature on the MEDLINE database. RESULTS sixty-nine post allogenic HSCT patients (42 male) with MG were identified. The median age was 43 (5 to 68) years. Time interval from allogenic HSCT to MG diagnosis ranged from 3 to 134 months (median 17). Most MG patients had a history of acute (70%) or chronic (84%) graft versus host disease (GVHD). Corticosteroids and cyclosporine were the most common therapeutic agents used in this setting; alternative therapies, including rituximab, were given to a lower number of patients. Outcome data were available in 64 out of 69 MG patients; 38 (59%) and 18 (28%) patients achieved a complete and a partial response respectively, whereas treatment failure was recorded in the remaining 8 (13%). CONCLUSION MG after allogenic HSCT appears to be associated with a sub clinical or overt cGVHD, which follows the discontinuation of immunosuppressive prophylaxis. Although a standard therapeutic approach has not been established, the application of available measures can induce favorable response in more than 80% of affected patients, but treatment-failure and progressive deterioration of the renal function may occur in about one fifth of cases.

Rapid response and sustained remission by rituximab in four cases of plasma-exchange-failed acute thrombotic thrombocytopenic purpura

Plasma exchange (PE) with the replacement of fresh frozen plasma is the current treatment of choice for acute thrombotic thrombocytopenic purpura (TTP) [1]. For patients with resistant disease, treatment options are limited and often unsuccessful. The finding of circulating anti-von Willebrand factor-cleaving metalloprotease, ADAMTS13 autoantibodies in the majority of patients [2] constitutes the rationale for the concomitant administration of immunosuppressive drugs in treating acquired TTP. In the light of favorable results achieved by rituximab and its benefit-risk ratio reported in this setting [3–7], this agent was given with salvage intent by us to 4 typical acquired TTP patients refractory to PE and steroids (3) and with suboptimal response to these measures (1). There were four women with median age of 32 (26–50) years. At admission all patients presented Coombs-negative hemolytic anemia and thrombocytopenia; a laboratory hemolytic pattern and the evidence of schistocytes on the examination of the peripheral blood smears were present in all cases. Three patients presented from mild to moderate renal impairment, in two of them associated with severe neurological compromising; one patient was referred to the intensive care unit of our hospital because of a progressive neurological impairment following an intrauterine fetal demise occurred at 12 weeks of gestation. In spite of the therapeutic PE and steroids, given concurrently with all other required supportive measures, no sustained remission could be achieved. In particular, 3 patients were refractory while the remaining patient with coma achieved full neurological recovery but only a little improvement of hematological parameters with persistence of altered hemolytic findings denoting an active disease. Therefore, after 10, 14, 15 and 23 days following the initiation of plasmapheresis, the patients received 4 weekly infusions of 375 mg/m, each administered after the daily PE session and withholding PE until 48 h later. No remarkable rituximab-related adverse effects were observed. All patients responded to treatment. Median time to response after the first dose of rituximab was 10 days (5–24). In particular, the achievement of a platelet count higher than 100.00/lL and a near to full normalization of hemolytic parameters, were observed in 2, 1 and 1 patients after the first, second and third weekly doses of rituximab, respectively. To date, all the patients are well and active, being free of TTP relapse after a median follow-up of 10 months (4–12). Recent advances in our understanding of idiopathic TTP have provided a rationale for the use of rituximab to achieve an effective B-cell depletion and clinical improvement in acute autoimmune TTP [2, 8, 9], which is attributed to the production of anti-ADAMTS13 autoantibodies. Therefore, rituximab has been reported as a useful addition to PE treatment in TTP, although its exact role, dosing need and the best appropriate time to administration remain to establish by prospective studies. In conclusion, we have reported 4 additional patients with PE-resistant TTP successfully resolved by rituximab. Although our experience is limited to a small number of PE-resistant TTP cases with a relatively short follow-up, our data confirm those provided by other reports suggesting the optimal efficacy of rituximab as salvage therapy for this difficult-to-treat subset of patients. L. Scaramucci P. Niscola (&) M. Giovannini M. Ales A. Tendas L. Cupelli G. Natale T. Dentamaro A. P. Perrotti P. de Fabritiis Division of Haematology, Sant’Eugenio Hospital, Tor Vergata University, Rome, Italy e-mail: pasquale.niscola@uniroma2.it