Complete Resolution Of Splenomegaly Research Articles

Safety and Efficacy of Ruxolitinib for the Final Enrollment of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis (N = 2233)

Safety and Efficacy of Ruxolitinib for the Final Enrollment of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis (N = 2233)

Bendamustine and Rituximab, as First Line Treatment, in Intermediate, High Risk Splenic Marginal Zone Lymphomas of Elderly Patients.

BackgroundSplenic marginal zone lymphoma (SMZL) is a chronic B-cell lymphoproliferative disorder, comprising less than 2% of non-Hodgkin’s lymphomas, and affecting mainly middle-aged and elderly patients with a median survival of >10 years. The typical clinical features of SMZL include splenomegaly. Treatment should be patient-tailored and can range from a ‘watchful waiting’ approach for asymptomatic patients without cytopenias to surgery, localized radiation therapy or immuno/chemotherapies. Recently, the combination of rituximab and Bendamustine (R-Benda) has been defined as highly active in patients with follicular lymphomas, but little is known about the efficacy of R-Benda in SMZL.Aim of the studyThe purpose of this retrospective study was to report our experience on the efficacy of R-Benda as first line treatment in 23 consecutive elderly SMZL patients.ResultsAll patients had a complete resolution of splenomegaly along with restoration of their blood counts. Nineteen patients (83%) achieved a complete response (CR) to therapy; three patients (13%) achieved a partial response (PR).Ten patients (43%) obtained molecular remission. Toxicities were mild and mainly haematological and result in dose reductions for fourteen patients.ConclusionsOur data suggest a high activity and good tolerance of R-Benda, despite dose reduction due to potential toxicity.

Safety and Efficacy of Ruxolitinib in an 1869-Patient Cohort of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis

Safety and Efficacy of Ruxolitinib in an 1869-Patient Cohort of JUMP: An Open-Label, Multicenter, Single-Arm, Expanded-Access Study in Patients with Myelofibrosis

A New Prognostic Model for Response in Myelofibrosis Patients Treated with JAK2 Inhibitors: A Study from Three US Academic Centers

Background: JAK2 inhibitors have been shown to improve symptoms and produce durable reductions in splenomegaly in patients with myelofibrosis (MF), and ruxolitinib has been shown to improve survival in MF patients (Cervantes et al., 2013; Verstovsek et al., 2013). Current prognostic models such as DIPSS plus (Gangat et al., 2011) predict survival in MF based on clinical, laboratory, and cytogenetic information, but their value in predicting clinical response or survival during treatment with JAK2 inhibitors remains unknown. We hypothesized that clinical features such as bone marrow fibrosis and splenomegaly may have independent effects on therapy response. Therefore, we conducted a retrospective analysis to create a new model to risk stratify patients with respect to their likelihood of responding to oral JAK2-inhibitor therapy.Methods: We studied a cohort of 203 patients with bone marrow biopsy-proven MF seen at University of Michigan, Stanford University, and Mayo Clinic in Scottsdale, AZ. These patients were all treated with ruxolitinib or an experimental JAK2 inhibitor. Our primary endpoint was defined as IWG-MRT criteria for splenic response by palpation (Tefferi et al., 2013). Response in patients with spleen size of less than 5 cm was defined as complete resolution of splenomegaly. Of the 203 patients studied, splenic response was evaluated after 3 months of therapy in 167 patients and after 6 months of therapy in 138 patients; 127 patients were in both groups. A logistic regression was performed to identify factors that would predict clinical response.Results: The following characteristics were significantly associated with spleen response at 3 and 6 months: initial spleen size, European consensus criteria grading of MF on bone marrow biopsy, initial DIPSS plus score, and initial WBC count. Cellularity on marrow biopsy was not significant. [Display omitted] We enriched a baseline logistic model of initial dose of oral JAK2 therapy and DIPSS plus score with additional prognostic factors. We found the following clinical characteristics to be jointly associated with splenic response: normalized initial dose of oral JAK2 inhibitor, initial spleen size, DIPSS plus score, degree of fibrosis by European consensus criteria. Duration of disease from time of diagnosis to time of treatment initiation was not prognostic for splenic response. [Display omitted] We used this model to calculate the probability of splenic response based on a risk score:Risk score = –1.18(Dose) + 0.09(Initial Spleen Size in cm) + 0.20(DIPSS-plus Points) +0.92 (if fibrosis is MF-3).The probability at 6 months can then be calculated from the risk score as follows: [1/(1+e(risk score-2.6))]. The figure demonstrates the prognostic gain of our model over a model based on DIPSS plus alone.Conclusion: With this observational study, we propose a predictive model which may serve as a clinical tool to identify which patients are most likely to benefit from JAK2 inhibitor-based therapies. Further validation in independent data sets will be required before this model can be more widely applied. [Display omitted] DisclosuresMesa:Incyte Corporation, CTI, NPS Pharma, Inc., Gilead Science Inc., Celgene: Research Funding. Gotlib:Incyte: Consultancy, Honoraria, Research Funding, Travel Reimbursement Other; Gilead: Research Funding; Sanofi: Research Funding; Novartis: Research Funding, Travel Reimbursement, Travel Reimbursement Other. Talpaz:ARIAD Pharmaceuticals, Inc., BMS, Sanofi, Incyte, Pfizer: Research Funding.

Refractory Anemia with Ring Sideroblasts Associated with Marked Thrombocytosis Complicated by Massive Splenomegaly Treated with Lenalidomide Resulting in Resolution of Splenomegaly but Severe and Prolonged Pancytopenia

Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T) is a hematological malignancy that combines features of both a myeloproliferative and myelodysplastic disorder. There have been recent reports of the successful treatment of anemia in 2 patients with RARS-T with lenalidomide. Here we report the successful treatment of massive splenomegaly in a patient with a long history of RARS-T resulting in complete resolution of splenomegaly, but with prolonged severe cytopenias. We also report the acquisition of the t(3;12)(q26;p13) translocation previously described in cases of myelodysplasia and the potential for transformation to myelofibrosis.

Case Report of a Primary Splenic Marginal Zone Lymphoma Patient Presenting with Factor VII Inhibitor

AbstractAbstract 4927We present the case report of a 38 year old female presenting with primary splenic marginal zone lymphoma and a Factor VII inhibitor. She presented with pancytopenia (WBC 2.1 × 10@9/L, Hemoglobin 74 g/L, platelets 122× 10@9/L), an elevated INR 3.2 (0.8-1.2) and a normal aPTT 25 sec (22 - 36), and massive splenomegaly. Spleen measured 33 cm in length on coronal CT images. The liver was slightly prominent. There were no masses in liver or spleen, nor any abnormal adenopathy. Her IgM was elevated at 16.2 g/L(0.46-3.04), immunofixation positive for IgM Kappa. Bone marrow biopsy revealed patchy infiltrates of small lymphocytes strongly positive for CD 20. CD 5, Cyclin D1, CD10, CD23, CD138 and DBA44 were negative. Flow cytometry revealed a monoclonal infiltrate positive for CD19, CD20, FMC7, CD23, and kappa light chain restricted. Flow cytometry was negative for CD11c, CD25, and CD103. With this information, the diagnosis of primary splenic marginal zone lymphoma was made, despite the positive CD23 on flow cytometry. Splenectomy was not possible because of the coagulopathy.Mixing studies at 60 minutes did not correct the coagulopathy. Factor VII was low at 0.37 [0.5-2.0], Fibrinogen 2.78 g/L [2.00 - 4.00], Lupus anticoagulant was negative, Factor II 0.40 U/mL, [0.50-2.00], Factor V 0.37 U/mL [0.50– 2.00], Factor X 0.09 U/ml [0.50-2.00], and Factor VII inhibitor was elevated at 4.8 Bethesda units. Factor VII inhibitor showed cross reactivity with factors II, V, and VII.She was initially treated with fresh frozen plasma (> 8 units) and IV Vitamin K (10 units × 2) without correction of her INR. She underwent five days of plasma-pharesis with partial correction of her INR to 2.6.With concerns regarding bleeding risks, cytotoxic chemotherapy was avoided and patient was given single agent Rituximab at 375 mg/m2 for four weekly doses. The initial infusion was complicated with severe thrombocytopenia: 13,000 × 10@9. The platelet count recovered to > 75×10@9/L by day 4 post her first infusion. She received her second infusion on day 10. Her platelet count nadir was 50×10@9 this time. Her spleen had a remarkable response, shrinking to 15 cm below the costal angle following the first infusion and only splenic tip palpable by the fourth. Her INR continued to normalize and was at 1.4 by the end of the fourth cycle. The patient received four more weekly cycles of Rituximab with complete resolution of splenomegaly and coagulopathy. Following that the patient underwent splenectomy. Pathology on this spleen revealed no malignancy indicating complete remission to treatment. She received two years of maintenance Rituximab (one dose every 3 months) and remains disease free without recurrence of splenomegaly nor coagulopathy at 2.5 years followup.To our knowledge, only a handful of previous cases factor VII inhibitor have been reported. We report the successful management of a difficult case using anti-CD20 monoclonal antibody treatment alone. Disclosures:No relevant conflicts of interest to declare.

A Phase I Study of LBH589, a Novel Histone Deacetylase Inhibitor in Patients with Primary Myelofibrosis (PMF) and Post-Polycythemia/Essential Thrombocythemia Myelofibrosis (Post-PV/ET MF).

Abstract 308 Background:Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by progressive constitutional symptoms, cytopenias, splenomegaly and constitutive mobilization of CD34+ cells. The JAK2V617F mutation is present in approximately 50% of MF patients and the mutational burden has been used as a surrogate marker of disease burden and treatment response. LBH589 (Panobinostat), is a novel histone deacetylase inhibitor (HDACi) with potent inhibitory activity against HDAC and HSP90. CXCR4 has previously shown to be down-regulated in PMF CD34+ cells but can be up-regulated by in vitro treatment with sequential chromatin modifying agents (CMA). In addition, the number of JAK2V617F + progenitor cells (PC) can be reduced by treatment of MF CD34+ cells with CMA. (Shi et al, Cancer Research 67: 6417, 2007) Our working hypothesis is that restoration of CXCR4 expression by PMF CD34+ cells would redirect these cells to the bone marrow niche and reduce extramedullary hematopoiesis and promote elimination of MF PC. In order to test this hypothesis, a series of preclinical studies with purified CD34+ cells isolated from peripheral blood of untreated PMF patients were performed. Cells were cultured with SCF, IL-3, FLT3 and TPO ± LBH589 for 2 days and assayed for total number of cells, CD34+ cells, and % CD34+ cells expressing CXCR4. Both total and CD34+ cell numbers were reduced following LBH589 treatment. CXCR4 expression by cultured CD34+ PMF cells was up-regulated in the presence of LBH589. Cells were placed in semi-solid culture and hematopoietic colonies were enumerated, plucked and genotyped for JAK2V617F. CD34+ cells from 2 of 4 PMF patients treated with LBH589 had a decrease in the number of JAK2V617F homozygous colonies. Based on these data, we are presently conducting an ongoing investigator initiated phase I/II study of LBH589 in patients with MF at our institution. Methods:Patients with Lille class I/II PMF, post-ET/PV MF, collectively referred to as MF were eligible if they had an ANC >1000 and platelet count > 60,000. The primary endpoint of the study is to assess the safety and tolerability of LBH589. Secondary endpoints include measurement of clinical response as assessed by IWG-MRT criteria and assessment of change in JAK2V617F burden, histone acetylation, peripheral blood CD34+ cell number and cytogenetics. DLT was defined as an AE that occurred in the first 28 days on study and judged unrelated to disease progression, intercurrent illness or concomitant medications. AEs were graded by CTCAEv3.0 criteria. LBH589 was given to patients in the first cohort at an oral dose of 20mg TIW and the second cohort at 30mg TIW for 28 days and were eligible to receive additional cycles if no DLT was seen. Results:A total of 12 patients (6 in cohort 1 and 6 in cohort 2) have been enrolled and 8 patients (6 in cohort 1 and 2 in cohort 2) are evaluable to date. Thrombocytopenia is the only DLT observed as of yet and was seen in 2 patients. Grade 3 soft tissue hemorrhage requiring platelet and red blood cell transfusion occurred in a single patient in the first cohort who developed worsening thrombocytopenia from a baseline count of 61,000. In the second cohort at a 30mg TIW dose, Grade 3 thrombocytopenia occurred in 1 patient with a baseline normal platelet count after only 3 doses and resolved within 1 week off the drug. Grade 3 anemia is the only other hematologic AE seen in subsequent cycles in 25% of patients (2/8; a patient in both cohorts). The most common non-hematologic AEs noted were grade 1 nausea, fatigue, diarrhea and musculoskeletal pain. Two patients in cohort 1 have had a greater than 50% reduction in spleen size. One of these patients has also had a significant reduction in RBC transfusion requirements and has complete resolution of splenomegaly at 7 months. By IWG consensus criteria for treatment response, 2 patients (1 JAK2V617F + and 1 -) experienced clinical improvement and 4 patients had stable disease. Conclusion:Treatment of MF patients with LBH589 is associated with acceptable hematologic and non-hematologic toxicity and can result in clinical improvement in patients with advanced MF. Based on these observations, LBH589, an oral HDACi, appears to be a promising new agent for the treatment of both JAK2V617F positive and negative MF. Accrual continues in the phase I portion of this study and data on the effects of LBH589 on a variety of biomarkers including JAK2V617F allele burden, will be presented at the meeting. Disclosures:Off Label Use: LBH589, panobinostat, is a novel oral histone deacetylase inhibitor that is being investigated in myelofibrosis to reverse the splenomegaly and improve cytopenias as well to modulate the JAK2V617F allele burden and potentially change the natural history of the disease. .

Effects of CYT387, a Potent Novel JAK2 Inhibitor on JAK2-V617F Induced MPD

Background: The V617F mutation of JAK2 (JAK2-V617F) is present in almost all patients with polycythemia vera (PV), and approximately 50% of patients with essential thrombocythemia and idiopathic myelofibrosis. JAK2-V617F leads to constitutive activation of the JAK2 kinase, causing cytokine independent growth in cell lines and development of a PV-like MPD in mice. Targeting JAK2-V617F may be therapeutically useful. We tested CYT387, a novel small molecule inhibitor of JAK2, in a variety of cells, and in a murine MPD model.Methods: Specificity profiling was performed using in vitro kinase assays on the Upstate and Invitrogen platforms. Cell lines (n=26) were cultured in graded concentrations of CYT387 and cell proliferation was measured by MTT assay after 72 hours. For in vivo experiments bone marrow from 5-FU treated BalB/C mice was infected with a retrovirus expressing JAK2-V617F and GFP and transplanted into lethally irradiated recipients. Upon development of MPD CYT387 was initiated at doses of 25mg/kg (low dose) and 50mg/kg (high dose) twice daily by oral gavage. Mice were followed by blood counts and inspection. At 60 days treatment was stopped and a subset of mice was euthanized for detailed autopsy, histopathology and FACS analysis of hematopoietic cells. Accompanying experiments included pharmacokinetic and pharmacodynamic studies.Results: In kinase assays CYT387 inhibited JAK1 and JAK2 with an IC50 of 11 and 18nM, while JAK3 was much less sensitive (IC50:155nM). Upon screening >100 additional kinases significant activity (IC50<100nM) was seen only for CDK1 and TBK1. CYT387 inhibited the growth of hematopoietic cell lines expressing JAK2-V617F with IC50 values between 0.5 and 1.5 microM. Similar values were seen in IL3, GM-CSF and IL-6-dependent lines, CMK cells (which carry A572V of JAK3), Molm14 cells (FLT3-ITD-positive) and several lines engineered to express BCR-ABL. In contrast, IC50 for most other hematopoietic and non-hematopoietic lines was >5 microM. In mice treated with high dose CYT387 hematocrit and white cell counts normalized, while they remained mildly elevated in the low dose group. On autopsy high dose mice showed almost complete resolution of splenomegaly with partially restored architecture, and reduced bone marrow fibrosis (but not cellularity), while the effects of low dose CY387 were less pronounced. FACS analysis of peripheral blood cells confirmed dose- and time-dependent inhibition of JAK2 signal transduction. A detailed analysis of spleen and bone marrow revealed a reduction (but not elimination) of MPD cells (GFP+), with partial normalization of progenitor cell distribution and differentiation. No significant weight loss or other toxicity was observed. Drug was stopped in two mice each from the low and high dose groups, with normal blood counts after 60 days of treatment. All 4 animals relapsed with MPD within 2 weeks.Conclusions:CYT387, which structure will be presented, is a pyrimidine derivative with low nanomolar activity against JAK1/2 in biochemical assays and a very narrow scope of additional targets.CYT387 inhibits the growth of JAK2-dependent cell lines in the high nanomolar – low micromolar dose range.CYT387 is active in a murine model of JAK2-V617F-positive MPD, with normalization of blood counts and spleen size, without apparent toxicity.However, residual disease remained detectable and relapse occurred upon discontinuation of drug, reminiscent of preliminary data from studies of JAK2 inhibitors in humans. Studies to evaluate cytokine profiles are ongoing and will be presented.

Rituximab monotherapy is highly effective in splenic marginal zone lymphoma

Splenectomy has traditionally been considered as a standard first line treatment for splenic marginal zone lymphoma (SMZL) conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of this retrospective study was to report our experience on the efficacy of Rituximab as first line treatment in 16 consecutive SMZL patients, diagnosed in our department. The diagnosis was established using standard criteria. Patients' median age was 57 years (range, 48-78). Prior to treatment initiation all patients had splenomegaly, nine had anemia, five lymphocytosis, five neutropenia and six thrombocytopenia. Rituximab was administered at a dose of 375 mg/m2/week for 6 consecutive weeks. The overall response rate was 100%. After treatment, all patients had a complete resolution of splenomegaly along with restoration of their blood counts. Eleven patients (69%) achieved a CR, three (19%) unconfirmed CR and two (12%) a PR. Among the complete responders seven patients had also a molecular remission. The median time to clinical response was 3 weeks (range, 2-6). Rituximab maintenance was given to 12 patients. Eleven of them had no evidence of disease progression after a median follow-up time of 28.5 months (range, 14-36), while two out of four patients who did not receive maintenance, relapsed 7 and 24 months after the completion of induction treatment. Median follow-up time for the entire series was 29.5 months (range, 15-81). No deaths were recorded during the follow-up period. Therapy was well tolerated. The present study demonstrates that rituximab is an effective treatment for SMZL and could be considered as a substitute or alternative to splenectomy.

PD166326, a novel tyrosine kinase inhibitor, has greater antileukemic activity than imatinib mesylate in a murine model of chronic myeloid leukemia

AbstractImatinib mesylate is highly effective in newly diagnosed chronic myeloid leukemia (CML), but BCR/ABL (breakpoint cluster region/abelson murine leukemia)–positive progenitors persist in most patients with CML treated with imatinib mesylate, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and antileukemic properties of PD166326, one of the most potent members of the pyridopyrimidine class of protein tyrosine kinase inhibitors. In mice with the CML-like disease, PD166326 rapidly inhibited Bcr/Abl kinase activity after a single oral dose and demonstrated marked antileukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a white blood cell (WBC) count less than 20.0 × 109/L (20 000/μL) at necropsy, compared with only 8% of imatinib mesylate–treated animals. Further, two thirds of PD166326-treated animals had complete resolution of splenomegaly, compared with none of the imatinib mesylate–treated animals. Consistent with its more potent antileukemic effect in vivo, PD166326 was also superior to imatinib mesylate in inhibiting the constitutive tyrosine phosphorylation of numerous leukemia-cell proteins, including the src family member Lyn. PD166326 also prolonged the survival of mice with imatinib mesylate–resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective antileukemic activity. Clinical development of PD166326 or a related analog may lead to more effective drugs for the treatment of de novo and imatinib mesylate–resistant CML.

Imatinib Mesylate Therapy for Patients (pts) with Polycythemia Vera (PV).

Imatinib is a potent inhibitor of tyrosine kinases, including abl, c-kit, and platelet-derived growth factor receptor (PDGFR). A role for PDGF in PV has been suspected, and direct inhibition of PV colonies with imatinib has been reported. We initiated a phase II trial of imatinib in pts with PV diagnosed by the Polycythemia Vera Study Group criteria. Pts were treated with imatinib at 400 mg daily; if no significant response after 1 month (mo) of therapy, the dose could be escalated to 800 mg daily. Hydroxyurea could be used only during the first mo of therapy, but anagrelide was allowed at any time. 9 patients have been treated (6 male, 3 female). Median age was 51 years (yrs) (range 28 to 72 yrs); median duration of PV was 8 years (range 1/4–35 years). ECOG performance status was 0 for 2 pts and 1 for 7 pts. Most common symptoms included fatigue (n=7), intractable pruritus (n=5) and headache (n=4). 4 pts had splenomegaly, 1 had hepatomegaly, and 1 had prior splenectomy. All patients were dependent on repeated phlebotomies. All pts had diploid cytogenetics except one who had 20q− (prior therapy with 32 P). FISH and PCR confirmed absence of Bcr-Abl translocation. After a median follow-up of 4 mo (range, 2 to 37 mo), 3 pts have ≥50% reduction in phlebotomy requirements. These include one pt with complete remission defined as hemoglobin &lt; 14 g/dl, no phlebotomies and complete resolution of splenomegaly. Pruritus improved significantly in 3 pts; fatigue improved in 3 pts, headache and visual symptoms improved in one pt each. The dose of imatinib was increased to 800 mg in 3 pts. Grade 3 diarrhea and liver dysfunction occurred in 1 pt requiring dose reduction to 300 mg daily. Grade 2 toxicities included edema (n=2), rash (n=1), bone pain (n=1) and diarrhea (n=1). We conclude that imatinib has activity in PV, leading to improved symptoms and decreased phlebotomy requirements.