Symptomatic Splenomegaly Research Articles

A Phase 1/2 Study of NS-018, an Oral JAK2 Inhibitor, in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (pPV MF), or Post-Essential Thrombocythemia Myelofibrosis (pET MF)

Background:NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2).OBJECTIVE:The purpose of this study is to determine the safety, tolerability and efficacy of orally administered NS-018 in patients with PMF, post-PV MF, or post-ET MF.METHODS:This multicenter, Phase 1/2, 3+3 dose-escalation study of NS-018 enrolled patients with IPSS intermediate-1, intermediate-2, or high risk PMF, post-PV MF, or post-ET MF. The study drug, NS-018, was given orally either daily (QD) or twice daily (BID) in 28-day cycles. In Phase 1, changes in spleen size were assessed by manual palpation, quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF), and responses were assessed according to the IWG-MRT/ELN consensus criteria. Bone marrow fibrosis (BMF) was evaluated by biopsy, according to WHO criteria. Changes in grade of BM fibrosis from baseline were categorized as improvement, stabilization, or worsening. The Phase 1 portion of the study has been completed and data are presented here.RESULTS:In this Phase 1 study, 48 patients were enrolled across 10 dosing cohorts (75-400 mg QD/100-400 mg BID). Characteristics: 37 PMF, 5 post-PV MF, 6 post-ET MF with a median age (range) 69.5 yrs (38-83); M/F:29/19; 35 JAK2V617F+, and 23 previously treated with a different JAK2 inhibitor.At 400 mg QD/BID, NS-018 dosing was associated with drug-related neurologic adverse events (AEs) including dizziness, peripheral neuropathy, headache, disturbance in attention, vertigo, dysesthesia, paresthesia, aphasia, and nervous system disorder (not otherwise specified). The 300 mg QD dose was better tolerated than 250 mg BID or 300 mg BID, with fewer neurologic AEs, and was selected as the recommended phase 2 dose (RP2D).For the 48 phase 1 patients, reductions in MF-SAF score were observed for all symptoms after 3 cycles, including for patients with prior JAK2 inhibitor treatment. In all dose cohorts, ≥ 50% patients achieved ≥ 50% score reduction from baseline in night sweats, pruritus and bone pain after 1 cycle. Moreover, ≥ 50% patients achieved ≥ 50% score reduction from baseline in abdominal pain and inactivity after 3 cycles. In patients who had received prior JAK2 inhibitor, ≥ 50% patients achieved ≥ 50% score reduction from baseline in filling up quickly, inactivity, night sweats and quality of life after 3 cycles.Among 36 patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 20 (56%) showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 16 patients), including 9/19 (47%) patients with prior JAK2 treatment. According to IWG criteria, 14/36 (39%) patients showed splenic clinical improvement (CI) for ≥ 8 weeks, 4 had hemoglobin CI, and 1 had platelet CI.After 3 cycles of NS-018 treatment, 11/31 (37%) evaluable patients had a reduction in bone marrow fibrosis(BMF) by ≥ 1 grade. At any time during NS-018 treatment, 17/31 (55%) evaluable patients had a reduction in BMF by ≥ 1 grade. Overall, 23% (7/31) patients maintained improvement in BMF for ≥ 12 weeks. Reduction in BMF after 3 cycles was correlated with reduction in splenomegaly and hemoglobin responses.To date, 8 patients with prior JAK inhibitor treatment have been enrolled into the phase 2 portion of the trial. Updated Phase 2 data will presented at the meeting.CONCLUSIONS:The RP2D dose of NS-018 was 300 mg QD. This dose provided an acceptable safety and tolerability profile, and reduction in symptomatic splenomegaly. Phase 2 is ongoing and includes patients previously treated with other JAK2 inhibitors. DisclosuresTalpaz:ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding; Sanofi Aventis: Research Funding; Pfizer: Research Funding; Incyte: Research Funding. Ritchie:Incyte: Speakers Bureau; Celgene: Speakers Bureau. Odenike:Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI/Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Research Funding. Jamieson:GlaxoSmithKline: Research Funding; Johnson & Johnson: Research Funding. Stein:Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis Pharmaceuticals Corporation: Consultancy; Pfizer: Research Funding; CTI Biopharma: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Genentech: Research Funding.

Management of T-Cell Large Granular Lymphocyte Leukemia with Methotrexate or Cyclophosphamide

Background. T-Cell Large Granular Lymphocyte Leukemia (T-LGL Leukemia) is an extremely rare lymphoproliferative disorder which can originate from either mature T cells (CD3+) or natural killer cells (CD3-). T-LGL leukemia is a slowly progressing disease, rarely presenting with an aggressive course and in general patients have prolonged survival. Treatment is commonly monotherapy with methotrexate (with or without prednisone), cyclosporine, or cyclophosphamide. Herein we review our experience with the management of T-LGL in the last 15 years.Patients and Methods. We conducted a retrospective cohort study of all patients diagnosed with T-LGL at our center between 2000 and 2015. Patients were included if they had a positive study for T-Cell Receptor gene rearrangement. Response was evaluated using the criteria of Loughran et al (Leukemia 2015). Data was analyzed using descriptive statistics.Results. We included 23 patients, (16 male). All of the patients were caucasian with the exception of two. The average age at diagnosis is 65.1 years. Patients were treated for symptomatic cytopenias or splenomegaly with transfusions and/or chemotherapy. Six patients did not need any treatment. Fourteen of the 23 patients were treated with oral methotrexate monotherapy. The methotrexate dose ranged from 5mg/week to 15mg/week orally. Seven patients had a complete response, 2 had a partial response, 3 patients failed treatment, 1 patient was not evaluable, and 1 was stable. Four patients were treated with methotrexate and prednisone. Two patients obtained a complete response, with 1 partial response, and 1 patient was not evaluable due to the short duration of the prescription. Nine patients were treated with oral cyclophosphamide at doses of 50mg or 100mg po daily. Four patients achieved a complete response, 2 patients achieved a partial response, while the other 3 patients did not respond. Only 2 patients were treated with oral cyclosporine, at 400mg/day and at 500mg/day. One patient failed treatment while the other is still on therapy. Two patients died while on the study at 22 and 42 months, both deaths were due to other illnesses not associated with T-LGL Leukemia. The median time since diagnosis for the remaining patients is 41 months.Conclusion. T-LGL is a rare lymphoproliferative disorder. Most patients responded to simple oral therapy with methotrexate or cyclophosphamide and patients generally have prolonged survivals. DisclosuresLazo-Langner:Bayer: Honoraria; Pfizer: Honoraria. Kovacs:Daiichi Sankyo Pharma: Research Funding; LEO Pharma: Honoraria; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding.

A Phase-Ib/II Study of Ruxolitinib Plus Pomalidomide in Myelofibrosis

Background: Myelofibrosis (MF) patients (pts) frequently suffer from constitutional symptoms, splenomegaly, and cytopenia. While ruxolitinib (RUX) is available for the treatment of symptomatic splenomegaly and constitutional symptoms in MF, therapeutic options for the treatment of cytopenia are limited. Recent data indicate that the immunomodulatory drug pomalidomide (POM) may improve anemia and thrombocytopenia in a subset of MF pts (e.g. Tefferi et al., J Clin Oncol 2009). We designed a single arm, multicenter phase-Ib/II combination study of RUX and POM (MPNSG-0212 trial, NCT01644110) to evaluate potential synergistic effects of both drugs in MF.Study Design: Primary endpoints are response rate after 12 treatment cycles (28 days each) according to IWG-MRT criteria (Tefferi et al., Blood 2006) and achievement of red blood cell (RBC) transfusion independence (Gale et al., Leuk Res 2011). Secondary endpoints are safety, quality of life, progression-free survival, and overall survival. Main inclusion criterion is pre-treated or untreated primary or secondary (post-ET / post-PV) MF with anemia (Hb <10 g/dL and/or RBC transfusion dependency). Key exclusion criteria are suitability for allotransplant, low platelet count (<100 /nL), and severe neutropenia (ANC <0.5 /nL). While POM is given at the fixed dosage of 0.5 mg QD, RUX is started at 10 mg BID with dose modifications being allowed to optimize efficacy and to manage myelosuppression. According to a Simon´s two-stage design, recruitment will be extended to a total number of 72 pts if response is achieved in a minimum of 12/37 pts tested initially.Results: Safety of the combination therapy was evaluated favorably by an independent safety monitoring committee after treatment of the first 6 pts as reported previously (Stegelmann et al, ASH 2014). Here, we present follow-up data from 25 pts. Median age of the study population was 75 years (range 51-82). Ten of 25 pts (40%) had one or more previous therapies. The most frequent previous drugs were hydroxyurea (n=6), ruxolitinib (n=3), EPO (n=2), pomalidomide (n=2), and steroids (n=2). Median Hb at study entry was 8.6 g/dL (range 6.8-10.6); 6 pts (24%) were RBC transfusion dependent. Median spleen size measured by ultrasound was 18 cm (range 13-28). Eight pts (32%) were intermediate-1, 10 pts (40%) intermediate-2, and 7 pts (28%) high-risk according to the dynamic international prognostic scoring system (DIPSS). Mutation frequencies of JAK2 V617F, MPL W515L, and CALR exon 9 were 72%, 12%, and 16%, respectively. ASXL1 was mutated in 5 pts (20%). Regarding safety, 287 adverse events (AE) of any grade (CTCAE 1-5) were recorded. Among these, worsening of anemia (°3/°4) was the most frequent AE (n=35 in 9 pts), followed by musculoskeletal pain (n=25 in 6 pts; °1-°3), and constitutional symptoms (n=13 in 2 pts; °1-°3). In total, 11 serious AE (SAE) CTCAE °2-5 were recorded. While 9 SAE (pneumonia °3, n=3; cardiac decompensation °5, malignant melanoma °2, septic shock °5, syncope °3, and TIA °2, worsening of general condition °3, n=1 each) were considered non-related to the study drugs, 2 SAE (hemoglobin °4, neuropathy °3) were considered related. Of note, neuropathy resolved after end of study. Treatment interruptions and dose reductions of RUX were uncommon. RUX could be step-wise increased to 15 or 20 mg BID in 10 pts (40%). Median time on treatment was 8 28-days cycles (range 1-13) in 24 pts, while one patient has not yet started therapy; 14 pts (56%) are still on study treatment. A total of 10 pts (40%) discontinued, due to death (n=2), no response after 12 cycles (n=5), or withdrawal of informed consent (n=3). Within this short observation time, 3 pts experienced ´clinical improvement´ (CI) according to IWG-MRT criteria in the following categories: i) spleen reduction, ii) spleen reduction + increase of Hb, and iii) increase of both Hb and ANC. RBC transfusion independency criteria have not yet been fulfilled in transfusion dependent pts. None of the study pts progressed during treatment.Conclusions: Taking into account that the majority of study pts were pre-treated and at advanced risk, the combination therapy of RUX and POM was well tolerated and is feasible. First efficacy evaluation shows that clinical improvement regarding reduction of splenomegaly and improvement of cytopenia is achieved in a subset of MF pts. Recruitment of the study continues. An update on safety and efficacy will be presented at the meeting. DisclosuresHochhaus:ARIAD: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Schlenk:Arog: Honoraria, Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Boehringer-Ingelheim: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Teva: Honoraria, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Hairy Cell Leukemia Variant Has Similar Survival to Classical Disease Despite Poorer Responses to Initial Therapy: A 30-Year Experience from Memorial Sloan Kettering Cancer Center

Few studies have compared treatment outcomes and disease complications between classical and variant hairy cell leukemia (HCL).We reviewed records of patients (pts) with HCL treated at Memorial Sloan Kettering Cancer Center between 1983 and 2013 and identified 331 pts. To reduce bias we limited analysis to the 183 pts who were reviewed and treated at MSKCC within 3 months of diagnosis (table 1).The median follow-up was 46.8 months. Median overall survival (OS) for the entire cohort was not reached and 5 and 10 year OS was 94% and 83% respectively. Median OS for classical and variant HCL was not reached in either group (Fig 1) while 5 and 10 year OS appeared equal. The time to next treatment (TNT) following initial therapy was longer for classical HCL (Fig 2). Pts with classical HCL were also more likely to achieve remission with first therapy and required fewer individual lines of therapy (Table 1). Cladribine was used first line in 122 pts and resulted in a median TNT of 138 months (97.1-NA), pentostatin was used in 9 pts and resulted in similar remission duration as cladribine with TNT of 81 months (80.5-NA) (p=0.82). 5 pts had abnormal cytogenetics at diagnosis and this did not influence OS when compared to the 62 pts who had a normal karyotype with estimated 5 year OS of 100% and 97%, respectively.31 pts required treatment for disease relapse. The median time to 3rd therapy was not reached however 72% and 52% of all pts were estimated to require a 3rd treatment at 5 and 10 years, respectively. Cladribine was used to treat 1st relapse in 18 pts while 5 were treated with the combination of cladribine and rituximab. This resulted in a median TNT of 66.3 (37.2-NA) months in the cladribine group, median TNT was not reached for the combination group. We found that initial treatment of HCL with cladribine appeared to result in a longer disease remission when compared with the second treatment with a median TNT of 138 and 66 months respectively. 22 pts died during follow up, with 2 deaths due to HCL, 6 due to secondary malignancy, the remainder were unknown.27 Secondary cancers were identified the most common were non-melanoma skin cancer (5), prostate cancer (5), melanoma (4) and other lymphoproliferative disorders (4). The most common reasons for needing retreatment varied depending on disease type with the recurrence of cytopenias accounting for 23/25 pts with classical HCL and only 1 with variant HCL. Symptomatic splenomegaly prompted re-treatment in 4/5 with variant and 3/25 classical HCL. B symptoms were uncommon occurring in 1 pt with classical and 1 with variant disease at relapse. The major complication of 1st therapy was febrile neutropenia necessitating admission for intravenous antibiotics, which occurred in 40/139 pts. There were no mortalities due to bacterial sepsis following 1st therapy.We conclude that OS of pts with HCL variant is equal to that of classical disease; however patients with classical HCL have a far longer duration of first remission and a greater chance of complete remission. Patients with variant HCL have different clinical features at relapse and appear to require more lines of therapy to maintain disease control. We found that responses to cladribine following first treatment appear longer than for second treatment. The combination of cladribine and rituximab may result in a longer second remission. We did not find a higher incidence of secondary malignancy in patients with variant HCL.Table 1Comparison of patients with classical and variant HCL.Classical HCL (N=146)Variant HCL (N=10)Median age (range)52 (27-84)67 (39-78)P=0.005Men (%)114 (78%)6 (60%)Median WBC at diagnosis3.7x10^9/L9.7x10^9/LCD25 expression146/1460/10BRAF* (V600E mutated/ assessed)3/61/2Number needing therapy10910Indication for re-treatment255Cytopenia23/251/5splenomegaly3/254/25Median OSNot reachedNot reached5 year OS94%100%10 year OS84%67%TNT following 1st treatment (months)12020P=0.002CR to 1st therapy87/1095/10Median number of therapies (range)1 (0-7)4 (2-7)Splenectomy13Secondary cancers270Deaths151*BRAF mutation was infrequently assessed as we analyzed patients up to 2013. [Display omitted] [Display omitted] DisclosuresPark:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy.

Isolated Extrapulmonary Hepatic and Splenic Sarcoidosis With Hepatomegaly and Symptomatic Massive Splenomegaly

A 28-year-old white male with a history of chronic abdominal pain, GERD and IV drug abuse presented to the Emergency Department complaining of fatigue, abdominal pain, nausea and vomiting for 3-4 months, and rapid weight loss of 90 lbs. CT scan of his abdomen revealed hepatosplenomegaly, portal hypertension and portacaval lymphadenopathy. Initial labs were remarkable for pancytopenia, elevated serum creatinine of 2.9, elevated serum calcium of 12.7, elevated AST of 69 and ALT of 65, and alkaline phosphatase of 506. Hepatitis C antibody was positive with a negative viral load. Due to the concern for underlying malignant process, he underwent endoscopic ultrasound with periportal lymph node biopsy which was nondiagnostic. SPEP was unremarkable, alpha-1 antitrypsin was normal, ferritin was mildly elevated, ceruloplasmin was elevated, ANA was negative, antimitochondrial antibodies weakly positive, ANCA negative, anti-smooth muscle antibody moderately to strongly positive, light chains elevated, the CMV and EBV viral load were negative, HIV was negative, and ACE level was elevated. Pt then underwent bone marrow biopsy, no evidence of a lymphoproliferative disorder was found. Subsequently, a liver biopsy and splenectomy was performed. Pathology revealed diffuse non-necrotizing granulomatous inflammation consistent with sarcoidosis of both the liver and spleen, and a diagnosis of extrapulmonary sarcoidosis was made. Resected spleen weighed 2,022 g easily meeting criteria for massive splenomegaly by weight. Pathology also revealed stage 2-3 fibrosis of the liver, iron staining and AFB staining was negative for mycobacteria in both organs. Pt never had any pulmonary symptoms and multiple chest x-rays failed to demonstrate the hallmark hilar lymphadenopathy and reticular opacities of pulmonary sarcoidosis. Sarcoidosis is a disease of unknown origin, characterized by noncaseating granulomas in involved organs with pulmonary involvement in 90% of cases. Isolated extrapulmonary disease is rare, occuring in only 10% of cases. This patient's presentation with symptomatic massive splenomegaly and pancytopenia in the setting of isolated hepatic and splenic sarcoidosis is very rare. After nearly a month long hospitalization, he was discharged on ursodiol. On follow up, he was then transitioned to prednisone and later to methotrexate with the discontinuation of prednisone due to an elevation in his LFTs. As a result of his treatment, the patient gained back some weight, his liver enzymes decreased to AST of 97 and ALT of 89, alkaline phosphatase decreased to 305, and his pancytopenia completely resolved.Figure 1

Patient reported outcomes after splenectomy in patients with symptomatic splenomegaly

CONCLUSIONS: Implementation of a comprehensive ERP in major AWR was not associated with any adverse effects. Multimodal perioperative pain management, oral opioid receptor blockade and early feeding strategies resulted in accelerated intestinal recovery, shorter hospitalizations and fewer readmissions. The use of our ERP appears to result in improved outcomes in patients undergoing complex open AWRs.

Ruxolitinib treatment for myelofibrosis: Efficacy and tolerability in routine practice

Ruxolitinib has been shown in two randomized clinical trials to be effective in alleviating systemic symptoms and reducing spleen size in patients with myelofibrosis (MF). We retrospectively evaluated efficacy and tolerability of ruxolitinib in a cohort of unselected MF patients treated in routine clinical practice. One hundred and two patients who began ruxolitinib therapy were identified in 13 participating centers. Ninety three of the patients receiving ruxolitinib for at least 3 months were evaluated for treatment efficacy and toxicity. Median age at ruxolitinib initiation was 67 years. Indications for treatment were constitutional symptoms (15%), symptomatic splenomegaly (6%) or both (76%). Two patients received ruxolitinib for other indications. The median initial ruxolitinib dose was 30mg/day. Median duration of therapy was 11 months. Eighty two patients (88.2%) responded to therapy, 76 (84.4%) patients had improvement in constitutional symptoms and 60 patients (70.6%) had reduction in spleen length. While on ruxolitinib, 30% of patients had grade 3–4 anemia and 12.9% of patients had grade 3–4 thrombocytopenia. Thirteen patients (14%) discontinued therapy. This analysis of a cohort of MF patients treated with ruxolitinib in routine clinical practice demonstrates the efficacy and tolerability of this drug outside of a highly monitored clinical trial setting.

New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera.

New and treatment-relevant risk stratification for thrombosis in essential thrombocythemia and polycythemia vera.

A Sinister Cause of Hematemesis

Question: A 52-year-old man with myelofibrosis presented to the emergency room with hematemesis. Earlier that day, he had experienced cough, rhinorrhea, and pharyngitis. On the evening of admission, he vomited blood, prompting him to seek medical attention. He denied fevers, chills, chest pain, abdominal pain, melena, hematochezia, prior history of upper gastrointestinal bleeding, nonsteroidal anti-inflammatory drug ingestion, or alcohol abuse. He was afebrile and hemodynamically stable. Physical examination was significant for splenomegaly and brown, guaiac-positive stool. His abdomen was nontender and nondistended without overt evidence of hepatomegaly. Pertinent laboratory results were as follows: blood urea nitrogen, 34 mg/dL; International Normalized Ratio, 1.3; white blood cell count 4.6 K/μL; platelets, 194 K/μL; and hemoglobin, 12.5 g/dL, which decreased to 9.6 g/dL on repeat 6 hours later. On presentation, he was given an intravenous bolus of esomeprazole 80 mg and initiated on an intravenous esomeprazole drip at 8 mg/h. An urgent upper endoscopy revealed isolated gastric varices with recent evidence of bleeding (Figure A, yellow arrow). He was given a bolus of intravenous octreotide 50 μg followed by an intravenous octreotide drip at 50 μg/h and ceftriaxone 1 g/d. The patient was transferred to the intensive care unit for further monitoring. What was the cause of this patient’s gastric varices (GV) and what is the next appropriate step? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. CT of the abdomen and pelvis revealed marked splenomegaly and prominent gastric (Figure B, C, arrow), paragastric, splenic, and mesenteric varices (Figure B, C, arrowhead). The patient underwent a liver biopsy, which revealed extramedullary hematopoiesis without evidence of fibrosis or nodular regenerative hyperplasia. Measurement of hepatic venous pressure gradient was 8 mmHg, confirming absence of right-sided portal hypertension. In our patient, sinistral portal hypertension and gastric variceal bleeding occurred secondary to splenomegaly from increased splenic blood flow owing to myelofibrosis-induced extramedullary hematopoiesis. Isolated GV are less prevalent than esophageal or gastroesophageal varices. Our patient had type 1 varices (IGV1), which are confined to the fundus. A common cause of IGV1 is splenic vein thrombosis and this diagnosis should be excluded. Initial management of gastric variceal bleed includes antibiotics, vasoactive drugs, and selective transfusion.1Garcia-Pagan J.C. Barrufet M. Cardenas A. et al.Management of gastric varices.Clin Gastroenterol Hepatol. 2014; 12: 919-928Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Beyond this initial management, studies have documented the use of splenectomy, splenic embolization, endoscopic variceal obturation (EVO) using tissue adhesives such as cyanoacrylate (CA), endoscopic injection sclerotherapy (EIS), variceal band ligation (EBL), transjugular intrahepatic portosystemic shunt and balloon-occluded retrograde transvenous obliteration.2Goh B.K. Chen J.J. Tan H.K. et al.Acute variceal bleed in a patient with idiopathic myelofibrosis successfully treated with endoscopic variceal band ligation.Dig Dis Sci. 2007; 52: 173-175Crossref PubMed Scopus (2) Google Scholar CA has demonstrated higher hemostasis and lower rebleeding rates compared with EBL and EIS. A recent study has shown that endoscopic ultrasonographic (EUS)-guided therapy for fundal varices with CA and coils may improve efficacy and decrease embolization of glue.3Binmoeller K.F. Weilert F. Shah J.N. et al.EUS-guided transesophageal treatment of gastric fundal varices with combined coiling and cyanoacrylate glue injection (with videos).Gastrointest Endosc. 2011; 74: 1019-1025Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar CA is not currently available in the United States. However, many experts agree that, in patients with bleeding gastric fundal varices, the use of CA is preferred where available, with EBL as an alternative.1Garcia-Pagan J.C. Barrufet M. Cardenas A. et al.Management of gastric varices.Clin Gastroenterol Hepatol. 2014; 12: 919-928Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar Splenectomy can be definitive treatment in patients with GV associated with sinistral portal hypertension.1Garcia-Pagan J.C. Barrufet M. Cardenas A. et al.Management of gastric varices.Clin Gastroenterol Hepatol. 2014; 12: 919-928Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar In patients with myelofibrosis and splenomegaly, splenectomy is reserved for those with drug-refractory, symptomatic splenomegaly associated with frequent transfusions, portal hypertension, or severe thrombocytopenia. In our patient, splenectomy was chosen over EVO or transjugular intrahepatic portosystemic shunt owing to lack of available CA in the United States and the lack of elevated right-sided portal pressures. Postoperatively, his white blood cell count was 6.7 K/μL and platelet count was 279 K/μL. He received low-molecular-weight heparin for splenic and portal vein thrombosis, as well as hydrea and interferon. Repeat endoscopy 1 year after surgery showed no evidence of any varices. This case highlights the need for larger scale, randomized, controlled trials to guide management of gastric variceal bleeding. In addition, not all effective endoscopic and interventional techniques to treat GV are widely available, making it difficult for providers to follow current recommendations.

Adaptive splenic radiotherapy for symptomatic splenomegaly management in myeloproliferative disorders.

Symptomatic, massive splenomegaly is a debilitating complication of myeloproliferative disorders. In the study, we evaluated the use of a contemporary, individualized radiotherapeutic approach for splenic irradiation, including 3-dimensional computed tomography-based treatment planning, individualized treatment margins based on splenic motion assessment, online setup verification with volumetric image guidance at each fraction, and adaptive radiation treatment planning to account for changes in splenic size during the fractionated radiotherapy course. Between December 2008 and January 2014, 18 patients (13 males, 5 females) with myeloproliferative disorders referred to Gulhane Military Medical Academy Radiation Oncology Department underwent 22 courses of splenic irradiation using 3-dimensional computed tomography-based treatment planning and volumetric image guidance for palliation of symptomatic splenomegaly. Median age was 64 years (range 28-79). Significant pain relief was achieved in 20 of the 22 splenic irradiation courses (90.9%). Improvement in hematological parameters was achieved in 8 of the 11 splenic irradiation courses applied for cytopenia (72.7%). At least a 50% reduction in splenic size was achieved in 18 of the 22 splenic irradiation courses (81.8%). Toxicity was manageable with supportive treatment including antiemetics and platelet or red blood cell transfusions. Splenic irradiation with a contemporary radiotherapeutic approach offers safe and effective palliation of symptomatic splenomegaly in myeloproliferative disorders.

Quantitative T2*MRI for Bone Marrow Iron Overload Assessment in Thalassemia Major and Intemedia Patients

Introduction. Multiecho T2* MRI is a well-established technique for cardiac and hepatic iron overload assessment, but there are limited data on its potential to quantify iron in other organs. The aims of this study were to describe for the first time the T2* values of the bone marrow in patients with thalassemia major (TM) and intermedia (TI) and to investigate the correlation between bone marrow T2* and iron deposition in myocardium and liver.Methods. 283 TM patients (32.25±8.28 years, 144 females) and 46 TI patients (38.30±8.73 years, 17 females) enrolled in the Myocardial Iron Overload in Thalassemia (MIOT) network underwent MRI. For the measurement of iron overload, multiecho T2* sequences were used. Bone marrow T2* values were obtained on a circular regions of interest (ROI) located in the visible body of the first or second lumbar vertebra. The left ventricle was segmented into a 16-segments standardized model and the T2* value on each segment was calculated as well as the global value. In the liver the T2* value was assessed in a single ROI defined in a homogeneous area of the parenchyma]and it was converted into liver iron concentration (LIC).Results. Bone marrow T2* values were significantly lower in TM than in TI patients (7.65±6.29 vs 13.22±6.01 ms; P<0.0001). Bone marrow T2* values were significantly lower in females than in males in both the diseases (Figure 1), but they increased with age in a significant manner only in TM (R=0.343, P<0.0001).In TM bone marrow T2* values were weakly associated with global heart T2* values (R=0.143; P=0.016) and negatively correlated with LIC values (R=-0.439; P<0.0001) and mean serum ferritin levels (R=-0.582; P<0.0001).In TI no association was present between bone marrow and global heart T2* value, but bone marrow T2* values were negatively correlated with LIC values (R=-0.273; P=0.046) and mean serum ferritin levels (R=-0.569; P<0.0001).One hundred and sixty-six TM patients (58.7%) were splenectomised and splenectomised TM patients showed significant higher bone marrow T2* values than non-splenectomised patients (9.78±6.78 ms vs 4.61±3.85 ms, P<0.0001). The difference remained significant also correcting for the age, significantly higher in splenectomised patients.Fourty TI patients (87.0%) were splenectomised and bone marrow T2* were comparable between splenectomised and non-splenectomised TI patients (13.46±6.26 ms vs 11.61±4.05 ms, P=0.493).Conclusions. In both TM and TI groups, males showed significantly higher T2* values. This difference may be due to the fact that the male sex is associated with severely low bone mass , which can influence the T2* values. Bone marrow T2* values were associated with heart T2* values only in TM, maybe because in TI cardiac iron overload was not common. In both TM and TI a positive correlation was found between hepatic and bone marrow siderosis. Splenectomised TM patients showed higher bone marrow T2* values, probably due to the fact that splenectomy is generally performed in patients with hypersplenism to reduce transfusion requirements. Conversely, bone marrow T2* values were comparable in splenectomised and non-splenectomised TI patients. In fact, the current indications for splenectomy in TI include growth retardation, leukopenia, thrombocytopenia, increased transfusion demand, symptomatic splenomegaly. Moreover the transfusion iron intake is significantly lower in TI. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ruxolitinib Treatment for Myelofibrosis: Efficacy and Tolerability in a Real-World Setting

Introduction: Ruxolitinib has been shown in two randomized clinical trials (RCTs) to be effective in alleviating systemic symptoms and effecting a reduction in spleen size in patients with myelofibrosis (MF). However, JAK2 allele burden is not significantly impacted by this drug and there is no consistent salutary effect on marrow fibrosis or definite improvement in overall survival. Currently, the goals of Ruxolitinib treatment remain palliative. We sought to determine the efficacy and tolerability of Ruxolitinib in a cohort of unselected patients with MF treated in routine clinical practice.Methods: MF patients treated with Ruxolitinib for at least 3 months in 13 participating centers that are members of the Israel Myeloproliferative Neoplasm (MPN) Working Group were identified. The following demographic and clinical data were analyzed: the form of MF [primary (PMF), post polycythemic myelofibrosis (PPVMF), post essential thrombocytosis myelofibrosis (PETMF)], duration of MPN, indication for treatment, initial dose, dose reduction, hematologic toxicity, response to therapy and withdrawal of treatment.Results: One hundred and two patients from 13 centers that began Ruxolitinib between January 2012 and April 2014 were identified. Ninety three patients who were treated for more than 3 months were included in the analysis. Median age at diagnosis was 59 years (range 25-84), 57 % were males. PMF was the diagnosis in 44 patients (47.3%), PPVMF in 29 (31.2%) and PETMF in 17 (18.3%). The median duration of disease was 5 years (range 3 months-35 years) for the entire cohort. Median age at Ruxolitinib initiation was 67 years (range 32-84). Seventy two (78.3%) patients received cytoreductive therapies for MF prior to Ruxolitinib. Indications for treatment were constitutional symptoms only in 14 patients (15%), symptomatic splenomegaly only in 6 patients (6%) and both in 71 patients(76%). Two patients received Ruxolitinib for other indications (non-constitutional symptoms and refractory thrombocytosis). The median initial dose of Ruxolitinib was 30 mg per day (range 10-40mg). Median duration of Ruxolitinib therapy was 11 months (range 3-31 months). Eighty two patients (88.2%) responded to therapy, 76 (84.4%) patients had improvement in constitutional symptoms and 60 patients (70.6%) had reduction in spleen length. While on Ruxolitinib, 60 patients (64%) had a nadir hemoglobin level of less than 10g/dL, 43 patients (46%) had a nadir platelet count of less than 100 x 109/µL and in 12 of them (12.9%) a platelet nadir was less than 50 x 109/µL. Twenty one patients (22.6%) needed packed red blood cell (PRBC) transfusion in the 2 months preceding Ruxolitinib initiation and they received a median of 2.5 units (range 1-8), while 27 patients (29.1%) needed PRBC transfusion in the first 2 months after starting treatment and they received a median of 4 units (range 1-8). Thirty five patients required dose reduction of Ruxolitinib and 14 (15.2%) discontinued their therapy. Univariate analysis revealed that response to Ruxolitinib occurred in patients with a lower white blood cell (WBC) count (median 9.7 x 103/µL vs 21.5 x 103/µL; P=0.033), a greater degree of splenomegaly (median 12 vs 4 cm below costal margin; P=0.001) and hepatomegaly (median 4 vs 0 cm below costal margin; P=0.011). In multivariate analysis, the degree of splenomegaly was found to be predictive of response to treatment (odds ratio=1.263, p=0.03 and 95% CI=1.08-1.476) while there was a trend to improved response in patients with a lower WBC (p=0.074).Conclusions: The present analysis of a cohort of MF patients treated with Ruxolitinib in routine clinical practice has demonstrated the efficacy and tolerability of this drug outside of a highly monitored RCT setting. Data of this sort are currently sparse, and emanate mainly from single-center reports. Our study performed in 13 academic and community hospitals provides real-life evaluation of the utility of Ruxolitinib and factors associated with response to treatment. DisclosuresNo relevant conflicts of interest to declare.

Complete Clinical, Histopathologic and Molecular Remission of Primary Myelofibrosis with Long-Term Treatment with the JAK1/2 Inhibitor Ruxolitinib

The JAK1/2 inhibitor ruxolitinib (RUX) is effective in decreasing symptomatic splenomegaly, and constitutional symptoms in patients with myelofibrosis (MF). Long-term data suggest that treatment with RUX is associated with a survival benefit, and may delay/reverse bone marrow fibrosis. Further, a ≥ 20% reduction in JAK2 V617F allele burden with RUX has been described (Vannucchi et al. Blood. 2012). Yet, many uncertainties surrounding the full clinical potential of RUX persist. The conceivable disease-modifying impact including the achievement of a JAK2 V617F molecular remission under sustained JAK1/JAK2 inhibition in a patient with primary myelofibrosis (PMF) is presented.Patient and Methods: the diagnosis of JAK2 V617F-positive PMF according to the 2008 WHO criteria was made in a 50-years old caucasian male in February 2009. On the first consultation in November, 2009, he complained of fatigue and night sweats. Spleen was 12 cm below costal margin by palpation. Laboratory results were: Hb 153 g/L, WBC 18.9 x109/L, platelets 268 x109/L, peripheral blasts 2%, a leucoerythroblastic blood picture, LDH 10.6 µkat/L [2.8x upper limit of normal]. With an IPSS of 2 points (night sweats and peripheral blasts > 1%) the IPSS risk category for survival was intermediate-II. After signing informed consent, the patient was included in the phase 3, multicenter COMFORT-II trial and randomized to treatment with RUX at a dose of 20mg bid based on platelets count. By week (w) 4, the dose was increased to 25mg bid per protocol (< 40% reduction is palpable spleen length). For efficacy and safety evaluations, serial clinical, spleen volume [by magnetic resonance imaging (MRI)], blood picture, blood chemistry, bone marrow trephine biopsy, and JAK2 V617F allele burden from both peripheral blood samples as well as bone marrow assessments were conducted. The histology of the biopsies was evaluated according to the WHO criteria by experienced pathologists (Table). The JAK2 V617F allele burden was measured from blood samples using allele-specific oligonucleotide quantitative real-time polymerase chain reaction (qPCR) with a dynamic detection range from 0.1 to100% mutated allele (Lange et al. Haematologica 2013) and from bone marrow samples via qPCR followed by pyrosequencing for determining the allelic burden with a sensitivity of 5% of mutated DNA. If necessary, blocking of the non-mutated allele for sensitivity enhancement from 5% up to 0,001% of mutated DNA was done (Siebolts et al. J Clin Pathol 2010).Results: After a follow-up of 240 weeks, treatment with 25mg bid is ongoing. No dose modification/interruption because of adverse events was required. Clinical response was rapid with a 52% reduction in baseline spleen volume from 3.77 L to 1.8 L and improvement in constitutional symptoms at w 12. This was followed by a further decline in spleen volume. By w 216, spleen volume was 0.5 L which corresponded to 85.5% reduction from baseline (Figure). WBC and LDH normalized by w 24 and w 84 respectively. Histologic improvement in marrow cellularity, megakaryocytic, and granulocytic lineages was first evident at w 126 with further reversal of MF-related abnormalities including marrow fibrosis by w 216 (Table). JAK2 V617F allele burden of < 10% in a peripheral blood sample and < 1% in the bone marrow were first documented at w 108 and w 132 respectively. As of w 216, an allele burden <1% was sustained in both blood and marrow samples (Figure). Conclusions: The rapid symptomatic improvement with ruxolitinib could be followed by a considerable MF-modifying response with the potential to alter the course of disease and prognosis. Unlike targeted therapy for chronic myeloid leukemia, ruxolitinib-delivered molecular and histologic remissions could be gradual, and progressive. Whether such deep long-term responses are dose-dependent is not yet known. Thus, the full potential of a sustained JAK1/JAK2 inhibition needs to be elucidated by carefully analyzing the possible correlation between dose, short-term spleen responses and long-term molecular and histologic responses; both in retro- and prospective studies.Changes in marrow histology and spleen volume under ruxolitinib Table 1Marrow Cellularity %MegakaryocyteGranulocytic ProliferationG:EMarrow Fibrosis (EUMNET)Spleen volume (L)ProliferationAtypiaBaseline100%+++++++++8:1PMF13.8Week 4880%+++++++5:1PMF21.2Week 12630%+++-1:3PMF10.6Week 21640%-+-3:1PMF00.5 [Display omitted] DisclosuresAl-Ali:Novartis: Honoraria, Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding. Prashanth:Novartis: Employment. Niederwieser:Novartis: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Gentium: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

Low-dose splenic irradiation in symptomatic congestive splenomegaly: report of five cases with literature data

BackgroundTo show effectiveness of low-dose splenic irradiation in symptomatic congestive splenomegaly.MethodsFive patients were referred to our department for symptomatic congestive splenomegaly within three years. Primary diseases were autoimmune hepatitis with liver cirrhosis (n = 2), cystic fibrosis (n = 1), granulomatous liver disease (n = 1) and Werlhof disease with liver cirrhosis (n = 1). Mean age was 54 years (range: 36–67). Patients received splenic irradiation with a total dose of 3 Gy (single dose: 0.5 Gy). One patient was re-irradiated after long-term failure with the same treatment schedule.ResultsIn four patients long term relief of splenic pain could be observed during the follow-up time of median 20 (range: 2–36) months. Four patients showed haematological response after irradiation with an increase of erythrocytes, leucocytes and/or platelets. A slightly decrease in spleen size was found in two patients.ConclusionsLow-dose splenic irradiation in symptomatic congestive splenomegaly is feasible and perhaps as effective as in lympho-and myeloproliferative malignancies regarding pain relief and haematological response.

Successful outcome of postsplenectomy chemotherapy in an acute myeloid leukemia patient with massive bilharzial splenomegaly

Bilharzial hepatic fibrosis is usually accompanied by marked enlargement of the spleen. Schistosoma hematobium and Schistosoma mansoni infestation is endemic in Africa and southern part of Saudi Arabia. Patients with acute myeloid leukemia (AML) present with clinical features resulting from bone marrow failure, symptoms resulting from organ infiltration with leukemic cells (including splenomegaly), or both. Co-occurrence of bilharzial splenomegaly and AML is intuitively possible. Spontaneous splenic rupture has been reported to be catastrophic in both conditions and rarely splenic rupture may be the first manifestation of AML. Splenectomy is a considerable option in symptomatic splenomegaly in schistosomiasis. An enlarged spleen may also serve as a sanctuary site for residual leukemic cells after chemotherapy. Splenectomy has been reported in pediatric AML after chemotherapy and selected adult patients with myelodysplastic syndrome and myeloproliferative neoplasm (MPN). However, to the best of our knowledge, this is the first report of successful outcome of splenectomy prior to induction chemotherapy in an AML patient who presented with huge symptomatic splenomegaly due to past history of schistosomiasis, had also shown refractoriness to platelet transfusion due to hypersplenism and vaginal bleeding. Splenectomy in such a scenario was a difficult decision but was feasible with adequate expertise, vigilance and blood products availability. The patient is alive in complete remission with good performance status more than 2½ years after therapy.

Single-Fraction Radiotherapy for Palliation of Myelofibrosis-Related Extremity Pain Syndrome

Polycythemia vera is a type of myeloproliferative disorder known to progress tomyelofibrosis (MF), with a conversion rate of 10%e20% after a latency of 10e20 years. MF also can have a de novo presentation. Many symptoms that affect quality of life are associated with MF, including fatigue, fever, pruritus, night sweats, symptomatic splenomegaly, weight loss, and bone pain. Extramedullary hematopoiesis, blood cell formation, and clumping outside of the bone marrow and peripheral blood are hallmarks of MF. Extramedullary hematopoiesis involving the spleen, lung, liver, and bone is well described and a potential source of intractable pain resulting in a decreased quality of life for symptomatic MF patients. Approximately 50% of these patients will experience bone pain as either a presenting or late feature. Bone pain in these patients is poorly understood. Pain may be related to periostitis and the subsequent increased vascularity. Hematopoiesis and osteosclerosis also have been attributed as sources of this bone pain. Radiation use in MF has been shown to offer palliation for pain in spleen, liver, lung, and spine related to extramedullary hematopoiesis.

Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with the JAK1 and JAK2 inhibitor ruxolitinib

The Janus-activated kinase 1 (JAK1) and JAK2 inhibitor ruxolitinib is effective in decreasing symptomatic splenomegaly and myelofibrosis (MF)-related symptoms. However, allogeneic hematopoietic cell transplantation (HCT) remains the only curative option. We evaluated the impact of ruxolitinib on the outcome after HCT. A cohort of 14 patients (median age 58 years) received a subsequent graft from related (n=3) and unrelated (n=11) donors after a median exposure of 6.5 months to ruxolitinib. At HCT, MF risk for survival according to the International Prognostic Scoring System was intermediate-2 or high risk in 86% of patients. Under ruxolitinib, MF-related symptoms were ameliorated in 10 (71.4%) patients and the palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. Engraftment occurred in 13 (93%) patients. Acute GvHD grade-III occurred in 2 (14%) patients. Median follow-up was 9 months. Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively. Through the anti-JAK-mediated reduction in both cytokines and splenomegaly as well as improvement in performance status, ruxolitinib might improve outcome after allogeneic HCT in patients with MF. The downregulation of inflammatory cytokines might have a beneficial impact on graft failure and acute GvHD.

Update On The Long-Term Efficacy and Safety Of Momelotinib, a JAK1 and JAK2 Inhibitor, For The Treatment Of Myelofibrosis

BackgroundMomelotinib (MMB, GS-0387, CYT387) is a JAK1 and JAK2 inhibitor under investigation for the treatment of myelofibrosis. Preliminary results of a phase I/II core study (n=166) were previously reported. Subjects who achieved at least stable disease in the core study could continue MMB treatment in an extension study (n=120). Final data from the phase I/II core study and updated data from the extension study are presented. MethodsSubjects with myelofibrosis categorized as IPSS intermediate-2 or high risk, or intermediate-1 risk with symptomatic splenomegaly or hepatomegaly and/or unresponsive to available therapy, were enrolled. Following a dose escalation phase, subjects were treated on a dose expansion phase in the core study with MMB at either 150 mg or 300 mg once-daily, or 150 mg twice-daily for 9 months. In the extension study, MMB was at the same dose the subject tolerated and derived clinical benefit from in the core study. Clinical responses were adjudicated according to IWG-MRT criteria.Spleen Response was defined as ≥ 50% reduction in palpable splenomegaly that lasted ≥ 8 weeks (wks) for baseline splenomegaly ≥ 10 cm, plus resolution of palpable splenomegaly that lasted ≥ 8 wks for baseline splenomegaly > 5 to < 10 cm. Anemia Response was defined as transfusion-free interval of ≥ 12 wks for baseline transfusion dependence, plus ≥ 2 g/dL rise in hemoglobin (Hb) for baseline transfusion independence and Hb < 10 g/dL. Baseline transfusion dependence was defined as ≥ 2U RBC transfusion in the 30 days prior to first dose of MMB or identified as transfusion dependent in medical history. ResultsAs of April 2013, 58 of 120 subjects remained on treatment in the open-label extension study, with median treatment duration of 507 days (range 23-1036) for both core and extension studies. Based on interim analysis, the most common reasons for discontinuation from the extension study were disease progression (n=13), investigator's decision (n=12), and consent withdrawal (n=10), with 2 drug-related adverse events (both peripheral neuropathy) that led to study discontinuation.Efficacy data for the core and extension studies are depicted in table below.TableNumber of Subjects (%)Total enrollment166 (100)Spleen ResponseBaseline palpable splenomegaly > 5 cm148 (89)≥ 50% reduction in palpable splenomegaly that lasted ≥ 8 weeks for baseline splenomegaly ≥ 10 cm: A (A/148)51 (34)Resolution of palpable splenomegaly that lasts ≥ 8 weeks for baseline splenomegaly > 5 and < 10 cm: B (B/148)6 (4)Spleen Response A + B (A + B/148)57 (39)Anemia ResponseTransfusion dependent at baseline72 (43)Achieved transfusion independence on study for 12 weeks among those who were transfusion dependent at baseline: C (C/72)49 (68)Transfusion independent with Hb < 10 g/dL at baseline39 (24)Transfusion independent with Hb < 10 g/dL at baseline and has rise in Hb ≥ 2 g/dL on study for 8 weeks: D (D/39)10 (26)Anemia Response C + D (C + D/111)59 (53)Median time to onset of Spleen Response was not yet reached (range 6-693 days), median duration of Spleen Response was 324 days (range 56-936). Median duration of 12-week transfusion independence was not yet reached (91-987 days), median duration of Anemia Response was not yet reached (57-987). Constitutional symptoms assessment at 3 months for the core study showed ≥ 50% improvement in 72%, 46%, 77%, 100%, and 74% of subjects with pruritis, cough, bone pain, fever, and night sweats respectively.Most common Grade 3 or 4 treatment-related events were thrombocytopenia (29%), neutropenia (5%), and elevated lipase (4%) without clinical pancreatitis. Peripheral neuropathy was reported by 38% of subjects, all ≤ Grade 2, with 17 subjects experiencing neuropathy at baseline. Four subjects transformed into acute leukemia (1 in core study, 3 in extension study). There was no treatment-related death. ConclusionProlonged administration of MMB for treatment of myelofibrosis is well tolerated and has an acceptable safety profile. MMB is efficacious in durably reducing myelofibrosis-related splenomegaly as well as improving transfusion requirement and disease-related symptoms. These data form the basis for the phase 3 randomized study of MMB in myelofibrosis. Disclosures:Gupta:Novartis: Lecture fee, Lecture fee Other; Novartis: Consultancy; Incyte: Consultancy; Novartis: Research Funding; Incyte: Research Funding. Bavisotto:YM Biosciences: Consultancy. Kawashima:Gilead Sciences: Employment. Lee:Gilead Sciences: Employment. Kowalski:Gilead Sciences: Employment. Deng:Gilead Sciences: Employment. Niforos:Gilead Sciences: Employment.

Splenectomy Is Still a Valid Option For Splenic Marginal Zone Lymphoma

IntroductionSplenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoma characterized by splenomegaly, frequent moderate lymphocytosis with or without villous morphology and possible involvement of various organs, especially the bone marrow (BM). Diagnosis is classically based on the spleen histology, but it can be made on the BM biopsy, based on the typical intrasinusoidal cell infiltration pattern and immunohistochemistry. Different therapeutic options are available, but to date there are no conclusive comparative data. Patients and methodsWe retrospectively analyzed 83 consecutive patients with a diagnosis of SMZL observed at our Institution between 1999 and 2013. The diagnosis was based on the BM biopsy in 79 patients; the BM was negative in 4 patients. Diagnosis was histologically confirmed on the spleen in 27 patients who underwent splenectomy. Patients presented a median age of 72.5 years (range 38-84); 43 were males. The median spleen size at diagnosis was 145 mm, ranging from 100 to 300 mm. The majority of patients were stage IV at diagnosis for BM infiltration (95%); B symptoms were present in 4 of them (4.8%). Forty-two patients (50.6%) had a lymphocytosis at diagnosis and 13 (15.6%) presented an IPI score higher than 3. Thirty-five of them (42%) had a MZL BM infiltration superior to 30% of the total bone cellularity. Forty-two patients (50.6%) underwent a watch and wait policy (WW), while 41 (49.4%) were treated within 6 months from diagnosis, mainly because of symptomatic splenomegaly; in these patients, treatment consisted of splenectomy, chemotherapy or chemotherapy plus immunotherapy with Rituximab. The features of patients submitted to WW with respect to patients treated at diagnosis were comparable for the various parameters mentioned above, except for spleen size (higher in patients treated at presentation) and lymphocyte count (higher in patients who were observed). After a median follow-up of 64 months, the overall median survival was 96%. Among the 42 WW patients, 18 (42.8%) are still untreated after a median follow-up of 57.5 months, while 24 (57.2%) have required therapy; the median treatment-free interval in these patients was 25.5 months. Concerning the 41 patients who underwent treatment at diagnosis, after a median follow-up of 50 months, 13 (31.7%) have required a subsequent second-line treatment. The interval between first-line approach and re-treatment in patients treated at diagnosis was 30 months. Overall, 27 patients were treated with splenectomy only (either at diagnosis or after a WW period): only 6 of them (22%) had a subsequent progression after a median latency of 42 months; 26 were treated with chemotherapy alone (alkylating agents in the majority of them, combination therapy in a minority): 15 of them (60%) had a subsequent relapse or progression after a median of 9 months; 12 patients received a Rituximab-containing regimen: of these, only 2 (16%) have so far required a second-line therapy after 10 and 26 months respectively. ConclusionsThe WW policy is a valid option for asymptomatic patients: in these patients, after 4.5 years from diagnosis more than 40% is still untreated. In patients requiring treatment, splenectomy alone is followed in the majority of patients by a long period of good disease control: only 22% required a second-line therapy after 3.5 years. The addiction of Rituximab to chemotherapy seems to reduce the probability of relapse and to prolong the response duration. However, these preliminary data need to be confirmed by larger studies. Disclosures:No relevant conflicts of interest to declare.

The New Landscape of Therapy for Myelofibrosis

The landscape of therapy for myelofibrosis (MF) is evolving at a pace not previously seen for this clonal myeloproliferative neoplasm. The discovery of the JAK2 V617F mutation in 2005 has led to the rapid development of therapy specifically developed for afflicted MF patients. Indeed, the successful phase III studies of ruxolitinib demonstrating improved symptomatic burden, splenomegaly and survival led to the first approved myelofibrosis drug in the United States and Europe. Multiple additional JAK2 inhibitors are currently in or nearing phase III testing, including SAR302503 (fedratinib), SB1518 (pacritinib) and CYT387 (momelotinib), seeking to offer incremental benefits to ruxolitinib in regards to cytopenias or other disease features. In parallel, phase III testing of pomalidomide is ongoing, with the goal of solidifying the role of immunomodulatory therapy in MF-associated anemia. Multiple single agents strategies are ongoing with histone deacetylase inhibitors, hedgehog inhibitors and hypomethylation agents. Incremental advances are further sought, either in additive or synergistic fashion, from combination strategies of ruxolitinib with multiple different approaches ranging from allogeneic stem cell transplant to current therapies mitigating anemia and further impacting the bone marrow microenvironment or histology. Transitioning from a pre-2011 era devoid of approved MF therapies to one of multiple agents that target not only disease course but symptomatic burden has indeed changed the platform from which MF providers are able to launch individualized treatment plans. In this article, we discuss the diagnostic and therapeutic milestones achieved through MF research and review the emerging pharmacologic agents on the treatment horizon.