ALBERT

Description: Eradication of Helicobacter pylori may lead to improvement of chronic immune thrombocytopenic purpura (ITP), although its efficacy over time is uncertain. We report the results of H pylori screening and eradication in 75 consecutive adult patients with ITP. We also used molecular methods to investigate lymphocyte clonality and H pylori genotypes in the gastric biopsies from 10 H pylori–positive patients with ITP and 19 H pylori–positive patients without ITP with chronic gastritis. Active H pylori infection was documented in 38 (51%) patients and successfully eradicated in 34 (89%) patients. After a median follow-up of 60 months, a persistent platelet response in 23 (68%) of patients with eradicated infection was observed; 1 relapse occurred. No differences in mucosal B- or T-cell clonalities were observed between patients with ITP and control participants. Of note, the frequency of the H pylori cagA gene (P = .02) and the frequency of concomitant H pylori cagA, vacAs1, and iceA genes (triple-positive strains; P = .015) resulted statistically higher in patients with ITP than in control participants. All asymptomatic H pylori–positive patients with ITP were suffering from chronic gastritis. Our data suggest a sustained platelet recovery in a proportion of patients with ITP by H pylori eradication alone. Overrepresentation of specific H pylori genotypes in ITP suggests a possible role for bacterium-related factors in the disease pathogenesis.

Description: Abstract 1221 Poster Board I-243 Introduction A subset of Multiple Sclerosis (MS) patients shows a clinical trend to a fast deterioration of disability despite the use of approved drugs. New immunosuppressive agents are currently employed only in the early phase of the disease but in almost 10% of patients they either do not show any clinical/ radiological improvement or have to be halted for different reasons. Autologous HSCT has been reported as a promising approach for MS patients unresponsive to the available therapies but long term clinical and laboratory follow-up with a stringent MRI monitoring are not yet available. We report here the long term follow-up of a prospective phase II multicenter trial of the Italian GITMO-Neuro cooperative network. Method 21 MS patients (4 Relapsing Remitting and 17 Secondary Progressive) were enrolled between 1999 and 2004 in a prospective trial, aimed to monitor both clinical outcome and MRI imaging. Patients were shown to be refractory to conventional treatments, had a EDSS between 5.0 and 6.5 and at least 1 Gadolinium (Gd) enhancing area in brain MRI. PBSC were mobilized with Cyclophosphamide (4g/m2 ) and Filgrastim; patients were conditioned with BEAM plus rabbit ATG (Thymoglobulin®, Genzyme) and infused with unmanipulated graft. The effect of HSCT was evaluated with serial monthly Gd-enhanced brain MRI for a pretreatment period of 3 months and compared with serial monthly Gd-enhanced MRI imaging for the following 6 months. Subsequently, MRI scans were carried out at, +9, +12, +18 + 24 and at the last follow-up. Clinical outcome was evaluated by both EDSS assessment and number of clinical relapses after the transplant. The same MRI scanning protocol was used at each neuroradiological examination: T1 and T2 total lesion load, new T2 lesions, new hypointense lesions, Gd enhancing activity and progression of brain atrophy were evaluated. Results All patients showed a sustained engraftment with modest early side effects, as previously reported (Saccardi R. et al. Blood 2005 105:2601-07). At a median follow up of 7 years (range 4-10 years) no late effects were reported. Two patients had a clinical relapse 5 years after the HSCT, spontaneously recovered. Nine patients showed a clinical progression at a median of 30 months (16 – 66) after transplant, while the others are either stable (7) or improved (5), as compared with baseline. No patients received any immunosuppressive treatment after HSCT. At MRI examination total lesion load assessed by T2 and T1 sequences remained stable through the follow-up, and only 5 new T2 lesions appeared after HSCT. No Gd enhancing activity was ever observed after transplantation in the examined cases. Brain atrophy progression was higher in the first 2 years after transplantation and then decreased significantly in the following years Conclusions The clinical and MRI results of this prospective study are extremely positive, considering that the majority of cases remained stable at a median of 7 years after transplantation. MRI activity, as evaluated with Gd enhancing areas and the appearance of new lesions, was absent or negligible. Also brain atrophy, rapidly progressing early after the transplant probably due to the suppression of the inflammation, was thereafter shown to be in the range of MS patients. The duration of the follow-up and the stringent MRI methodology provide an evidence of the efficacy of this procedure in this subset of aggressive MS patients. Disclosures No relevant conflicts of interest to declare.

Description: Fever, cutaneous rash, and hepatitis—for which an infectious cause was suspected—developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8–specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti–HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.

Description: Abstract 246 Introduction. Chronic graft versus host disease (cGvHD) remains a serious and potentially lethal complication following allogeneic hemopoietic stem cell transplants (HSCT). Imatinib may be a treatment option, because of its inhibitory activity on platelet derived growth factor (PDGF)(Svegliati Blood 2007; 110:237). Last year we reported a first feasibility study in 19 patients, receiving Imatinib as compassionate use for refractory cGVHD, with encouraging results (Blood 2009;114:709). We have treated an additional 25 patients (with Imatinib supplied by Agenzia Italiana del Farmaco-AIFA) using similar inclusion/exclusion criteria, and are now reporting response rates on 44 patients, with a median follow up of 31 months. Patients and methods. Overall 44 patients with cGVHD, refractory to two or more lines of therapy, including steroids, have been consecutively enrolled: 29 were male and 15 female, with median age 38 years (range 10–67). Median duration of cGVHD was 35 (range 6–148) months and all patients received ≥2 lines of therapy, (22 previously treated with ECP and/or Rituximab). The main cGVH targets were represented by lung in 19 patients (Bronchiolitis Obliterans Pneumonia/fibrosis), skin in 38 (generalized scleroderma in 17 and localized in 21); 17 patients had Sicca Syndrome, 9 other visceral manifestations and one severe eosinophilic fasciitis. Imatinib administration was planned for a minimum of 6 months and all patients received the same schedule of Imatinib: in absence of severe toxicity the initial dose of 100 mg/day was increased to 200 mg/day and if no response occurred the dose was increased up to 400 mg/day. The median duration of treatment was 24 months (6-40) and 23 patients are still on Imatinib. Results: the treatment was well tolerated (41 patients were able to complete the treatment for at least 6 months) and we did not observe toxic deaths; the haematological toxicity was mild, only one patient developing a grade 3 anemia, while the main grade 3–4 extrahematological adverse events were infections (3 pneumonia and 1 John Cunningham Virus infection) or fluid retention (2 cases). The response rate (excluding minor responses), evaluated according to the NIH criteria, was 59%, both at 6 months and at 12 months after the start of treatment. In 5 patients we observed the relapse of the underlying disease, while two developed a second tumor (1 diffuse large cell lymphoma and 1 spinocellular carcinoma). With a median follow-up of 31 months (8-40) 33 patients are alive (OS=75 %) and 11 patients died: causes of death were the underlying disease (n=5), second tumour (n=2), and cGVHD (n=4) (2 due to GVHD progression and 2 due to infections). Twenty patients of the original 44 (45%) are still maintaining a response to Imatinib, without requiring additional treatment; 13/44 (29%) are recorded as responders, but, after further treatment. Purified immunoglobulins from 8 patients have now been evaluated for their ability to induce Reactive oxygen species (ROS) output in PDGF-R+ve murine fibroblasts, before and during Imatinib treatment, by using the same methodology previously published)(Svegliati Blood 2007;110:237); at baseline we confirmed the high ROS output in all evaluable patients; interestingly the IgG samples from 4 patients responding to Imatinib, showed a significantly reduced ability to increase ROS output; on the contrary 3 out of the 4 IgG samples from patients refractory to Imatinib, showed a persistence of the ability to trigger the ROS output during treatment with Imatinib. Conclusions In conclusion we can confirm safety and efficacy of Imatinib in this larger series of patients with steroid-refractory cGVHD, with promising OS. Whether this benefit is mainly due to the anti-fibrotic effect or to an immunomodulatory effect (or both) induced by Imatinib, remains to be determined. This work has been partly supported by AIFA. Disclosures: Leoni: Celgene: Honoraria.

Description: Abstract 3558 Poster Board III-495 We recently reported in a pilot study, including 19 adult and pediatric patients affected by refractory cGvHD with fibrotic features, that the administration of Imatinib at low dose was well tolerated and effective, achieving an overall response rate (ORR) of 79% at 6 months; the response has been evaluated according to the modified Curiel Criteria. We report here the preliminary results of an Italian GITMO Multicenter study, aimed to confirm these promising data. Main objective of this study was to assess the response rate, evaluated according to the stringent criteria suggested by the NIH Consensus Conference for cGVHD and to confirm the safety of low dose Imatinib in this setting. Secondary objectives were both clinical and biological: 1-to evaluate the clinical outcome (OS at 1 and 2 years) and quality of life; 2-to test a reliable technique for screening these patients for the presence of stimulating anti-PDGFR antibodies before and after the end of Imatinib treatment. The study was planned as phase 2 trial (optimal two stages Simon design), and enrolled 24 patients with cGVHD, refractory to two or more lines of therapy, including steroids. Nine Italian Centres enrolled 24 adults patients, starting from February 2008 to August 2009; 18 patients are now evaluable for toxicity and for the response at 3 and 6 months; 13 were male and 5 female; the median age was 47 years (range 31-62). The median duration of cGVH was 36 (range 3-148) months and all patients received 2 or more lines of therapy; the main cGVH target was represented by lung in 9 patients (5 patients had severe abnormalities of the functional tests with compromised Lung Functional Score), skin in 8 patients and bowel in 8 patients. Most patients had multi-organ involvement. The treatment with Imatinib was planned for a minimum of 6 months, starting at the initial dose of 100 mg/day, then increasing the dose to 200 mg/day until 3rd month; if no response and in absence of severe toxicity, patients were allowed to receive 400 mg/day until 6th month. The response has been defined as CR or PR, and was evaluated after 3 and 6 months of therapy; the kind of response (CR or PR) was defined according to the Curiel criteria, integrated by the criteria suggested by the NIH Consensus Conference for cGVHD. Results the treatment was well tolerated (all patients were able to complete the treatment for at least 6 months) and we did not observe toxic deaths; the toxicity was mild (no grade 3-4 toxicities have been reported) and 3 Severe Adverse Events have been reported (3 cases of pneumonia), probably related to the immunesuppression due to cGVHD instead to the Imatinib treatment. The ORR at 3 months was 72% and 56% at 6 months (9 PR and 1CR); 3 patients were able to stop or significantly decrease steroids. With a median follow-up of 6 months 15 out of the 18 evaluable patients are alive while 3 died of progressive cGVHD. The preliminary results of this multicenter study confirm that low-dose Imatinib is safe and effective in patients affected by refractory cGVHD; the slightly lower response rate observed at 6 months, compared to the previous study probably reflects the different population enrolled: older patients in the present study (the median age was 47, compared to 27 in the previous study; absence of pediatric patients who showed the best responses), most of them with lung involvement (9) and 5 with severe impairment of Lung Functional Score. These data encourage the use of Thyrosin Kinase Inhibitors in patients with refractory cGVHD and the evaluation of these drugs in phase 3 trials; furthermore the extensive evaluation of biological activity of these drugs could be able to select those patients who could benefit of this approach. This study was supported by the Italian medicines Agency (AIFA) within the independent drug research program contract no. FARM7ZWZ7Y. Disclosures: Off Label Use: yes we report the results obtained with Imatinib off-label in patients with refractory cGVHD.

Description: Fever, cutaneous rash, and hepatitis—for which an infectious cause was suspected—developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8–specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti–HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.

Description: The majority of patients with multiple myeloma are not eligible for curative treatments because of advanced age at diagnosis or contraindications to high-dose chemotherapy. Several anti-myeloma agents and other supportive medications, generally provided on outpatient basis, have shown to improve overall survival and quality of life even in the setting of unfit and fragile patients. Frequent accesses to day-hospital or outpatient clinic may however cause discomfort and unease in myeloma patients presenting vertebral lesions, bone pain, severe immunodeficiency and comorbidities. In our department a hospital-based home care service supported by the fundraising organisation A.I.L. (Italian Association against Leukemia-Lymphoma-Myeloma) is active in order to assist hematology patients who have poor performance status and fulfil other inclusion criteria (appropriate home logistics, caregiver availability and trainability, distance from hospital within 20 km, cooperation with general practitioners, community nurses and on-call doctors). Through a 9-yrs period (July 1999 – June 2008) 53 patients (male=26, female=27) affected by multiple myeloma have been enrolled in a domiciliary program of supportive and palliative care agreed by the hospital Division of Hematology, the Community Health Trust and the local section of the Italian Association against Leukemia-Lymphoma-Myeloma (A.I.L.). All patients were stage II or III according to Salmon-Durie classification. ECOG performance status was 2.8 on average. Median age was 76 years (under 60 years=4 patients, between 60 and 70 yrs=11 pts, between 70 and 80 yrs=17 pts, over 80 yrs=21 pts). At the time they were referred to the service, 14 patients were in terminal phase of disease with a life expectancy of about 3 months; 35 patients presented progressive disease after at least one previous therapy; there were also 4 patients undergoing transplant-based therapeutic programs and discharged early from the ward. Patients were generally followed-up on weekly-basis for collection of blood samples, clinical assessment and intravenous therapies (bisphosphonates, blood and platelet transfusions, anti-myeloma agents, antimicrobials, immunoglobulins). Median duration of a home care cycle was 323 days, with significant differences among the three groups of patients (in terminal phase=84 days, in progressive disease=466 days, in causal treatment=55 days). Excluding 4 ongoing patients, the end of home care resulted in 15 patients deceased at home (37%) and 26 died as inpatients (63%) while 8 patients were referred back to day hospital or ward. Urgent hospital admissions were 66, corresponding to an average of 1.25 admissions per home care cycle: main reasons were infection and fever, cardiopulmonary complications, renal failure, major bleeding and caregiver burnout. Once-monthly bisphosphonate treatment regarded 31 patients for a total of 332 infusions (pamidronate=191, zoledronic acid=141). Blood transfusions were provided to 22 patients for a total of 202 erythrocyte units while 8 patients required platelet transfusions (82 bags). Although most patients were off-therapy or in treatment with oral drugs, several novel and conventional anti-myeloma agents were administered intravenously at home in monotherapy or in combination, such as bortezomib, dexamethazone, vincristine, cyclophosphamide, carmustine, doxorubicine. No serious adverse event was reported as direct consequence of home intravenous therapies. Home care has achieved a relevant role in the global management of patients with blood malignancies improving quality of life and reducing health care costs. Thanks to our operating model, characterized by the presence of a full-time specialist team and by a careful selection of patients, home care of unfit patients with multiple myeloma represents a valid integration to the standard in-hospital hematology services. Many issues remain open, such as cost analysis, quality-of-life assessment, legislation on domiciliary medications, role of fundraising organisations and recognition in public health system.

Description: Abstract 334 Background: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease believed to be mediated by autoreactive lymphocytes that invade the Central Nervous System and cause oligodendrocyte, axonal and neuronal damage as well as glial scarring.to and resulting in demyelination, neuronal death and brain atrophy. Hematopoietic Stem Cell Transplantation (HSCT) has been tried in the last 15 years as a therapeutic option in patients with a poor prognosis autoimmune disease not responding to conventional treatments. Worldwide ≥600 patients with MS have been treated with HSCT, most of them having been recruited in small, single center, phase 1–2 uncontrolled trials. Clinical and MRI outcomes from case series reports or Registry-based analyses suggest that a major response is achieved in most patients; quality and duration of response are better in patients transplanted earlier in the relapsing-remitting phase. The intensity of the immunosuppression from transplant treatment may be determined by several factors, such as the use of chemotherapy in the mobilization regimen, the intensity of the conditioning regimen and ex-vivo T-cell depletion. Methods: We report here the Italian multi-center experience on 74 MS patients treated with AHSCT between 1996 and 2008, all mobilized with Cyclophosphamide/G-CSF and conditioned with BEAM and rabbit ATG. Clinical and MRI outcomes were reported to the Italian Registry; the median follow-up is 48.3 (range 30–210) months. All patients clinically deteriorated in the year prior to HSCT, with an increase of Extended Disability Scale (EDSS) of at least one point (average EDSS change=1.5 points, range=1–9), Results: Two patients (3.3%) died for transplant-related causes. At 5 years after the transplant, 66% of patients remained stable or improved. Progression free survival (PFS) was slightly better in relapsing-remitting (RR) (5 years PFS=71%) than in secondary-progressive (SP) forms (5 years PFS=62%, p=0.28). Amongst patients with a follow up longer than 1 year, 8 out of 25 RR subjects (31%) had a 6–12 months confirmed EDSS improvement 〉 1 point as compared to 1 out of 36 (3%) SP patients (p=0.009), Figure 1. Out of 18 cases with a follow up longer than 7 years, 8 (44%) remained stable or had a sustained improvement whilst 10 (56%), after an initial period of stabilization or improvement with a median duration of 3.5 years, showed a slow progression of disability. Conclusions: This study shows in a large cohort of patients with a long follow-up that AHSCT with BEAM/ATG conditioning regimen has a profound effect in suppressing disease progression in aggressive MS cases, unresponsive to conventional therapies. Indeed it results in a sustained improvement of the disability, free of immunosuppression, in a significant amount of RR patients. Clinical improvement is scarcely reported in MS literature as it is rather infrequent with conventional treatments; nevertheless it results in a stable increase of the quality of the life in this subset of young patients and should be considered in the choice of a therapeutic strategy in the early phase of MS. Disclosures: Cuneo: Roche: Consultancy, Speakers Bureau.

Description: Although the evidence available associating bisphosphonates (BP) with osteonecrosis of the jaw (ONJ) is far from conclusive, the growing literature reports strongly suggest a strict relationship between them. The real frequency of this complication is unknown because of the recent observation of this condition, the bias related to retrospective studies and the wide-spread use of this supportive therapy. Aims of this research were to look for additional risk factors for developing ONJ and to determine the frequency of this event in the subgroup of patients affected by Multiple Myeloma (MM) treated with BP. We asked 49 GISL centers to participate in a retrospective multicenter study filling out a form containing several queries, including sex and age, anamnesis for smoke habit, anemia and thrombotic events, type and time of neoplasia diagnosis, treatment and neoplasia status, odonthoiatric anamnesis, type and duration of therapy with BP, microbial isolation in site of lesion, specific treatment for osteonecrosis, number of patients (pts) affected by MM treated with BP from 2002 to 2005. Fifteen centers decided to participate in the study and 12 had cases of osteonecrosis. ONJ was reported in 19 pts. Sixty % were females and the median age was 65 ys. Sixteen had MM, 1 breast cancer, 1 prostatic cancer, 1 osteoporosis steroid related. Median time from diagnosis of cancer was 54 months and median duration of treatment with BP was 34 months. Thirteen events manifested between 20 and 60 months. Of the 19 pts, 8 had received zolendronate, 2 pamidronate and 9 both drugs. None had radiotherapy on head and neck, while two received total body irradiation. In these two cases, ONJ was associated with necrosis of the pelvis. The 2 solid tumors were treated with ormonal therapy. All MM pts had received one or more line of treatment including, VAD, MP, steroids and thalidomide alone or in combination, as well as high dose melphalan, as part of autologous bone marrow transplant. ONJ involved the mandible in 14 pts, the maxilla in 3 and both in 2. Symptoms included local pain and discomfort. In 17 cases CT scan was the strumental procedure used to identifiy the lesion. In 14 pts biopsy was performed excluding localization of neoplasia in 11 cases. Microbiological evaluation of the lesion was positive in 11 pts, with 6 cases of Actynomices. In 12 patients ONJ was apparently spontaneous; in 7 occurred after dental procedures. Parodonthopaties were present in 10 pts. In 11 cases ONJ was complicated by fistula, exposed bone or abscess. BP were stopped in 17 pts. Antibiothic therapy was administered in 17 cases; 7 pts underwent hyperbaric oxygen therapy and 8 surgical debridement. Several pts improved but none were cured. Considering only the MM subgroup 16 cases of ONJ were identified among 888 pts treated with BP between 2002 and 2005, with a frequency of 1.8%. Utilizing the data collected by our retrospective study a fine statistical analysis is not applicable. However, in MM pts the frequency of steroid treatment, parodonthopaties and anemia was particularly high, respectively 100%, 56%, and 56%, supporting the idea that these are additional risk factors for developing ONJ.