Human herpesvirus 8 (HHV-8

Summary The role of Ann Arbor staging in determining treatment intensity after achieving a negative positron emission tomography (PET) has not been established in classical Hodgkin lymphoma (cHL). Patients with stage I–IV cHL, received three cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and an interim PET scan (PET3). PET3‐negative patients received no further therapy. PET3‐positive patients received three additional cycles of ABVD plus involved‐field radiation therapy or salvage chemotherapy, if refractory to ABVD, and were re‐evaluated by PET scan (PET6). Study endpoints were 3‐year progression‐free survival (PFS) and overall survival (OS) rates. Two hundred and thirty‐nine patients with early‐stage and 138 with advanced‐stage were evaluable. Overall, 260 patients (70%) were PET3‐negative and had higher 3‐year PFS (90% vs. 65%; P < 0·0001) and OS (98% vs. 92%; P = 0·007) rates than PET3‐positive patients. All PET3‐negative patients, regardless of disease stage at diagnosis, achieved similarly good PFS (90–91%; P = 0·76) and OS (97–99%). The only independent prognostic factor for PFS was PET3‐negativity (Hazard ratio 3·8; 95% confidence interval 2·4–6·3; P < 0·0001). This study suggests that cHL patients who achieve a negative PET3 following ABVD have an excellent outcome, regardless of stage at diagnosis. An appropriately powered, phase III trial will be necessary to confirm these findings.

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PET CT adapted treatment for first line Hodgkin Lymphoma has been widely studied in the last decades. Long-term follow-up is important to judge both efficacy and safety of this approach.Patients and Methods: We analyzed updated follow-up data on all patients (pts.) treated within the LH-05 GATLA trial. Newly diagnosed pts. with HL Stages I-IV were included. All patients received 3 ABVD and were evaluated with a PET-CT (PET-CT+3). Pts. with a negative PET-CT+3 (DS 1 and 2) were considered in metabolic CR and received no further therapy. Pts with DS 3 and 4 completed 6 ABVD and IFRT on PET-CT positive areas. Pts with progressive disease (DS 5) after 3 ABVD received salvage chemotherapy. With a median age of 35 yrs., 300 presented with localized stage and 190 with advanced stage. Results:In LH-05 of all pts. 338 (69%) achieved CR with negative PET-CT+3, 152 (31 %) were PET-CT+3 positive. With a median follow up of 120 months the EFS and OS for all pts. at 5 years is 79.2% and 94.3% respectively. Pts with negative PET-CT+3 had an EFS of 89% and 80% for localized and advanced stage, compared to 63% for 276 -SUPPLEMENT ABSTRACTS all pts. with positive PET-CT+3 (p < 0.0001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET+3. This last parameter together with age were the only ones with statistical significance (p = 0.001 and 0.046 respectively). Stage at diagnosis was not significant.With long term follow up the OS at 5 years is 97.3% and 87.3% for all PET+3 negative vs PET+3 positive pts.When comparing the results LH-05 with our previous clinical trial (LH-96) there is no difference in EFS and OS at 5 years but in LH-05 only 31% received more than 3 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This PET adapted approach reduces exposure to chemo and radiotherapy with no negative effect on long term outcome. Conclusion:This long term follow up data support the PET-CT adapted approach for all stages of HL after a short course of ABVD. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS.Treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3 regardless their stage at diagnosis. Nevertheless, this long term follow up demonstrated that there is still room for improvement trying to identify PET-CT+3 negative patients that will relapse and escalating treatment in PET-CT+3 positive patients to improve outcome. GATLA is designing a trial with the aim to improve these two different risk groups.

1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively (<0.001). Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Background: 90Y-ibritumomab tiuxetan (Zevamab®; ZEV; Bayer-Schering Pharma- Argentina) has been approved for the treatment of relapsed, refractory and transformed (high grade) follicular lymphomas. Methods: Between Sep. 2005 and Feb. 2008, 45 patients (pts) [22 F & 23 M; median age 62 yrs (45–83)] with refractory/relapsed lymphoma were enrolled. Diagnoses: 37 follicular lymphoma (FL), 5 were mantle cell lymphoma (ML) and 3 transformed lymphoma (TL); 18 pts had bulky disease, 8 had bone marrow involvement and 21 had stage III–IV disease. Median time from diagnosis was 5 yrs (0.5– 29). Twenty two pts had received 1–2 previous treatments, and 23 pts had received 3–5 previous treatments including 5 pts with autologous bone marrow transplantation. All had previously received anti-CD20 monoclonal antibody therapy. Six pts received previous radiotherapy. ZEV was administered at 0.3 or 0.4 mCi, based on initial platelet count. Seven days before, and the same day of the ZEV administration, pts received standard rituximab 250 mg/m2. In 3 pt, ZEV was part of the conditioning regimen of autologous bone marrow transplantation. Results: Forty pts were evaluable for response: 34 (86%) pts responded – 19 CR (48%), 15 PR (38%). Overall survival and PFS for the entire group at 18 months was 63% and 37% respectively, with a median follow-up of 12 months (1–29 months). Of the 45 patients, 5 pts (11%) had died before third month and response was not assessed, 6 pts (13%) did not respond, 3 (7%) died with response from other causes, 14 pts (31%) responded and subsequently relapsed. Finally 17 pts (38%) continue to be in response, 9 (20%) lasting more than twelve months (long lasting responders). Slight differences in duration of response and survival were observed between FL vs ML and TL favouring FL (RR 2.047). Forty six per cent of pts required filgrastim for neutropenia, 24% required platelet transfusions, 22% had neutropenia plus fever and were admitted for complicated pancytopenia, and 20% required red blood cells transfusion. Two patient died 30 & 40 days after treatment with hypoplastic bone marrow complicated with sepsis in the post autologous bone marrow transplantation period. Four pts with previous bone marrow transplantation required filgrastim, transfusions and 2/3 had febrile neutropenia. Conclusion: Our experience with ZEV in relapsed and refractory FL shows 48 % CR. Even heavily treated pts that had previous bone marrow transplantation were able to receive ZEV, although they required extra support. Our experience supports the use of ZEV in relapsed and refractory lymphomas even after autologous bone marrow transplantation.

The radionucleid conjugate with monoclonal antibodies (antiCD20/90Y-ibritumomab tiuxetan) have been approved for the treatment of relapsed, refractory and transformed (high grade) follicular lymphomas. Between September 2005 and August 2007, 41 patients with refractory/relapsed lymphoma were enrolled. Median age was 62 yrs old (45–83). Twenty were women and 21 were men. Thirty three were follicular and 5 were mantle cell lymphoma and 3 transformed lymphoma. Eighteen patients had bulky disease, 8 had bone marrow involvement and 21 had stage III-IV disease. Median time from diagnosis was 5 years (0.5–29). Twenty one had received 1–2 previous treatments, and 20 pts had received 3–5 previous treatments including 5 pts with autologous bone marrow transplantation. All had previously received anti-CD20 monoclonal antibody therapy. Six pts received previous radiotherapy. 90Y-Ibritumomab (Zevamab™ Bayer-Schering Argentina) was administered at 0.3 or 0.4 mCi, based on initial platelet count. Seven days before, and on the same day of the immunoconjugate administration, pts received rituximab 250 mg/m2. Thirty eight were evaluable for response. Thirty four (89%) pts responded: 20 CR (53%) and 14 PR (36%). With a median follow-up of 10 months, 60% of pts were expected to continue in CR at 18 months. Overall survival at the same period for the entire group was 89%. Nineteen pts (46%) required filgrastim administration for neutropenia, Ten pts (24%) required platelet transfusions, 10 pts had neutropenia plus fever and they had to be admitted for complicated pancytopenia, 8 pts required red blood cells transfusion. Two patient died 30 and 40 days after treatment with hypoplastic bone marrow complicated with septicemia and in the post autologous bone marrow transplantation period, respectively. Four pts with previous bone marrow transplantation, required filgrastim, transfusions and 2/3 had febrile neutropenia. Our experience with 90Y-ibritumomab in relapsed and refractory folicullar lymphoma shows 53% CR. Even heavily treated pts, that had previous bone marrow transplantation were able to receive the radioimmunoconjugate, although they required extra support. Our experience favours the use of 90Y-Ibritumomab tiuxetan in relapsed and refractory lymphomas even if they had received previous autologous bone marrow transplantation.

Introduction MF is a myeloproliferative neoplasm characterized by bone marrow fibrosis, splenomegaly, cytopenias and constitutional symptoms. Since the identification of JAK2V617F mutation and development of anti JAK molecules, the course of the disease has changed. Ruxolitinib is a JAK1 and JAK2 inhibitor recently approved for patients (pts) with primary and secondary MF. In Argentina, pts could access the ruxolitinib through CUP. Analysis of this multicenter protocol provides a preliminary data set, follow up and efficacy results. Objectives To assess the efficacy (reduction in spleen size/improvement in constitutional symptoms) and toxicity. To investigate risk groups modifications during follow-up. Methods In Argentina, 36 pts with myelofibrosis, including primary MF (PMF) and post polycythemia vera (PPV) received ruxolitinib through CUP regardless of JAK2 mutational status. Study period: September 2011 to June 2013. The participating physicians provided information of the disease characteristics by completing a data form. Splenomegaly was evaluated by physical exam, and constitutional symptoms were categorized as present or absent. Retrospective analysis was performed based on data at baseline (n 36), after 3 months (n 30), 6 months (n 24) and 12 months (n 14). Results Median follow-up is 10 months (1-20). The median age is 65 years (30-79), 64% were men and 36% women.  There were 72% positive for the JAK2 V617F mutation, 69% had PMF and 31% Post-PV. At admission 89% of pts had received ≥1 lines of therapy for MF prior to ruxolitinib: hydroxyurea 77%, thalidomide 26%, erythropoietin 23%, others: corticosteroids, interferon, anagrelide, danazol, busulfan, splenic radiation, cytarabine, and 6-mercaptopurine. The distribution of risk category according to DIPSS was: 61% high, 19% Intermediate 2, 17% Intermediate 1, and 3% low. Median value for spleen size was 15 cm (4-33) below the costal margin. Constitutional symptoms were present in 71% of the patients and 33% were transfusion dependent. ECOG (Eastern Cooperative Oncology Group) was zero 28%, one 44%, two 22%, three 3%, and four 3%. The median hemoglobin, leucocytes and platelets was 10 g/dl (4.8-15.2); 13, 4 x 109/L (3.6-64) and 217 x 109/L (75-850), respectively. Peripheral blood blasts ≥ 1% in 44% of pts. Ruxolitinib therapy was initiated at 40 mg/d in 16 pts (50%), 30 mg/day in 9 pts (28%), and at a lower dose in the minority of pts. The median value for spleen size at 3, 6 and 12 months was 10, 8 and 6.5 cm, representing decrease of 20%, 41% and 42% from baseline, respectively (fig 1.). In 13 of 29 pts (45%) spleen size decreased ≥ 50% in 3 months. Constitutional symptoms not present at 3, 6 and 12 months in 79%, 100% and 87% of pts, respectively. Improvement in ECOG class was noted in 73%, 69 % and 73% at the above mentioned time points, respectively. Persistence of transfusion dependence at 3, 6 and 12 months was seen in 33, 24 and 27% of the patients. Hemoglobin median levels during treatment (g/dL): at baseline 10.1, at 3 months 8.5, at 6 months 9.7, and at 12 months 9.5. During follow-up, 27% pts shifted to a lower risk group, 2 pts (7%) to a higher group due to worsening anemia, and 67% did not change its category. Hematologic adverse events (AE) were anemia and thrombocytopenia in 8 pts (Grade 1 and Grade 3 according to CTCAE v4.0), 31% of pts required dose adjustment. There were no suspensions of medication because of cytopenia. Others AE > 10% were: headache, musculoskeletal pain, and diarrhea (<G3). Treatment was discontinued in 7 pts (MF progression n= 2, tuberculosis n=1, death n=4 non related to ruxolitinib). Conclusion Ruxolitinib is an effective therapy that reduced spleen size and improved constitutional symptoms with an acceptable toxicity profile in this group of pts. During follow up at 12 months, a quarter of pts shifted to a lower risk group. Our data is consistent with previous reports Disclosures: Barreyro: GSK: Employment. Enrico:Bristol Myers Squibb: Speakers Bureau; Pfizer: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Lanari Zubiaur:Novartis: Membership on an entity’s Board of Directors or advisory committees. Pavlovsky:Novartis: Consultancy. Sackmann:Novartis: Membership on an entity’s Board of Directors or advisory committees. Bengió:Novartis: Member advisory Board Myelofibrosis Other.