Amantadine Associated Myoclonus: Case Report and Review of the Literature

Purpose: Amantadine is commonly used to treat Parkinson’s disease. A case of myoclonus and asterixis was associated with amantadine is reported. Case Summary: An 80-year-old man with Parkinson’s disease diagnosed in 2015 was started on amantadine for treatment of progressive tremor and orofacial dyskinesias induced by levodopa. He took amantadine 100mg orally daily for 7 days, then increased to 100mg twice a day thereafter. The patient complained of “worsening tremor” after 9 days and amantadine was decreased to 100mg daily. After 1 month on this dose, the patient reported that his “tremor” persisted and experienced visual hallucinations. His examination demonstrated diffuse myoclonus throughout his extremities and trunk, as well as asterixis when attempting to stand or holding his arms antigravity. Laboratory testing for renal and hepatic failure was unrevealing. Amantadine was reduced to 50mg daily for 4 days and then discontinued. Myoclonus resolved 3 days after discontinuation of amantadine. Conclusion: While amantadine-induced myoclonus is rare, health care providers should be vigilant in monitoring for signs and symptoms of myoclonus following amantadine initiation.

Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) < 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) < 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]

Successful Treatment of a Diamond-Blackfan Anemia (DBA) Patient with Eltrombopag

DBA is a rare bone marrow failure syndrome clinically defined by onset of hypoproliferative anemia in early childhood accompanied by a grossly normocellular bone marrow. With age, a significant fraction of patients progress to pancytopenia and a hypocellular bone marrow, with some increased risk of progression to leukemia. Autosomal dominant or sporadic heterozygous mutations in genes encoding for ribosomal subunit proteins have been etiologically linked to DBA. How loss of function mutations in ribosomal proteins results in selective loss of erythroid progenitors with variable severity is incompletely understood. Chronic transfusion therapy and corticosteroid treatment can alleviate anemia, but both cause severe long term toxicities. Hematopoietic stem cell transplantation, when available, is the only definitive treatment modality for the hematological manifestations, and the only known treatment for DBA patients once pancytopenia develops. Here we report on a 28 year old female patient diagnosed with DBA at age of one month based on clinical criteria. Recent mutational analysis identified a novel mutation in intron 4(c.356+3>C) of the RPS19 gene affecting a known splice donor site that has previously reported in DBA patients. She did not respond to corticosteroids and was maintained on transfusions. She failed various experimental therapies including danazol, hematopoietic growth factors including IL-3 and GM-CSF, and anti-thymocyte globulin/cyclosporine without sustained clinical response. After treatment with daclizumab in 2006 her transfusion requirements decreased for about 4 years. In 2012 she presented with progressive pancytopenia and hypocellular bone marrow without overt dysplasia, and normal cytogenetic analysis. She required red cell transfusions. The patient was enrolled in a clinical research protocol investigating the efficiency and safety of the thrombopoietin receptor agonist eltrombopag (EPAG) in patients with moderate aplastic anemia or those with bone marrow failure with unilineage cytopenia (ClinicalTrials.gov: NCT01328587). The study is designed as a non-randomized, phase II, dose modification study with the primary endpoint hematological response at 16 weeks. EPAG was administered at 50mg daily and escalated every 2 weeks by 25 mg to the maximal dose of 300mg daily. At response assessment the patient's hemoglobin (Hgb) improved from 7.0g/dl to 8.9g/dl and platelets from 112K/ul to 171k/ul. She required no further transfusions, and was deemed a responder. EPAG was subsequently continued at the same dose level for an additional 6 months when the peripheral cells counts peaked at Hgb 11.9g/dl, platelets 251K/ul, ANC 3.19 K/ul, and EPAG was discontinued for protocol-defined robust response. After discontinuation of EPAG the patient's hemoglobin steadily declined over a period of 8 months. EPAG was reinitiated at 300mg per protocol. Peripheral blood cell counts rapidly improved and the EPAG dose was slowly tapered. The patient is currently on EPAG 50mg daily with normal blood cell counts. We have not observed any EPAG related toxicities in our patient, and repeated cytogenetic studies on bone marrow documented a normal karyotype. To the best of our knowledge this is the first report documenting EPAG efficacy in a DBA patient. Trautman et al. (2012) previously reported a DBA patient that failed treatment with low dose EPAG after six months. Our observation warrants further systematic investigation of EPAG treatment for DBA patients within a clinical research study setting. Figure Figure. Disclosures Winkler: GSK/Novartis: Research Funding. Townsley:Novartis: Research Funding. Desmond:Novartis: Honoraria. Dumitriu:GSK/Novartis: Research Funding. Grasmeder:GSK/Novartis: Research Funding. Young:GSK/Novartis: Research Funding. Dunbar:GSK/Novartis: Research Funding.

Effect of Losartan and Atenolol on Lung Function Status in Newly Diagnosed Essential Hypertensive Patients

Introduction: Essential hypertension is associated with altered pulmonary function. Antihypertensive medication and lung function are also associated. Losartan (angiotensin II receptor blocker) and atenolol (beta blocker) are commonly used antihypertensive drugs.Objective: To evaluate the effects of antihypertensive drugs on lung function status in patients with essential hypertension.Methods: This prospective observational study was carried out in the Department of Physiology of Bangabandhu Sheikh Mujib Medical University (BSMMU), Shahbag, Dhaka, from July 2012 to June 2013 on 100 newly diagnosed essential hypertensive patients who had not received any antihypertensive medications. They were selected from the Out Patient Department (OPD) of Cardiology unit, BSMMU, Dhaka. The study sbujects of age between 30-55 were allocated in group B. Based on prescribed treatment, these study subjects were divided into two groups - B1 and B2. B1 included 50 patients who received losartan 50mg daily and B2 included 50 patients who received atenolol 50mg daily. Again basing on duration of treatment group B1 was divided into B1a (newly diagnosed hypertensive patients before treatment), B1b (after 3 months of medication with losartan) and B1c (after 6 months medication with losartan). Similarly group B2 was divided into B2a, B2b, and B2c. For assessing lung function status, FVC, FEV1 and PEFR were measured with acomputer based Spirometer. Age, sex and BMI matched 50 apparently healthy normotensive subjects were also studied as control (group A). Data were compared among subjects of different groups. For statistical analysis independent sample ‘t’ test and paired sample ‘t’ test were performed.Results: Mean systolic blood pressure and diastolic blood pressure were significantly higher and mean FVC, FEV1 and PEFR were significantly lower in newly diagnosed hypertensive patients in comparison with that of healthy normotensive subjects. Mean FVC and FEV1 were found significantly higher in the group taking losartan for 6 months when compared to newly diagnosed hypertensive patients but lower than those of controls. In addition, mean FVC and FEV1 were found significantly lower in the group taking atenolol for 6 months when compared to newly diagnosed hypertensive patients and those of controls.Conclusion: Reduced lung function occurs in newly diagnosed essential hypertensive patients which improves by treatment with losartan but decreases after treatment with atenolol.Journal of Armed Forces Medical College Bangladesh Vol.10(2) 2014

A Final Report: Phase I/II Study of Sequential Azacitidine and Lenalidomide in Patients with Higher-Risk Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML)

Hypomethylating agents (HMAs) are currently the front-line therapeutic choice for patients with higher risk MDS, and also frequently employed in elderly AML or in AML patients not otherwise eligible for standard intensive therapy. A number of combination strategies are under development to improve the results of HMA monotherapy. Given the single-agent activity of both azacitidine (AZA) and lenalidomide (LEN) in patients with MDS and AML, a scientific rationale exists to explore this therapeutic combination strategy. Previous studies have evaluated the combination of AZA and lenalidomide in this population with encouraging results, using lenalidomide at doses ranging from 5 to 50mg daily over 5 to 28 days per cycle. The optimal dose and schedule for this combination remains unknown. We report our completed Phase I/II study of sequential AZA and lenalidomide in 88 patients with high-risk MDS and AML. Phase I eligibility included relapsed/refractory AML or MDS patients with bone marrow blasts >10%. Phase II eligibility included untreated high-risk MDS, or AML with 20-30% blasts. All subjects were registered into the RevAssist® program. Median age was 67 (range 32–88). Per WHO criteria, there were 42 MDS patients (48%), 3 (3%) with CMML-2, 20 (23%) with RAEB-T (i.e. 20-30% bone marrow blasts), and 23 patients (26%) with AML (>30% blasts). All subjects received 75mg/m²/day AZA days 1-5 of each 28-day cycle. LEN was administered orally for 5 or 10 days, starting on day 6 per cycle. 28 patients in the Phase I and 60 in the Phase II portion were treated. In the Phase I portion, 7 levels of LEN were evaluated with the following doses and schedules: 10mg x 5 days (n=5), 15mg x 5 days (n=3), 20mg x 5 days (n=3), 25mg x 5 days (n=3), 50mg x 5 days (n=4), 75mg x 5 days (n=3), and 75mg x 10 days (n=7). The initial Phase II starting dose was LEN 50mg daily x 10 days, however due to myelosuppression and infections with repeated cycles in the first 20 Phase II subjects, the Phase II dose was amended to LEN 25mg daily x 5 days, and another 40 patients were evaluated. In the entire cohort, overall response rate (ORR) was 35% (31/88) (15 CR; 16 CR with incomplete count recovery (CRi)), with median overall survival (OS) of 33 weeks (range 1-172). Phase I ORR was 14% (4/28) and Phase II ORR was 45% (27/60). Of the 40 patients receiving the optimal Phase II dose, ORR was 55% (22/40), with 75 week median OS. In responding patients (n=31), the median response duration was 29 weeks (range 2 - 127 weeks), with a median overall survival that has not been reached with a median follow-up time of 57 weeks (Figure 1). 13 of the 31 responding patients (42%) proceeded with stem cell transplant, of which 10 patients continue in a sustained remission. In a cohort of 25 molecularly annotated patients (Table 1), 5 of 9 (56%) TP53-mutant patients, all with complex cytogenetics, achieved CR/CRi. By multivariate analysis, treatment was associated with worse OS in patients with bone marrow blasts > 30% (HR 4.5, 95% CI 2.4 – 8.5, p < 0.001), complex cytogenetics (HR 3.4, 95% CI 1.8 – 6.2, p < 0.001), and lenalidomide dose (HR 2.2, 95% CI 1.1-4.4, p = 0.03). In conclusion, we identify the combination of AZA 75mg/m²/day on days 1-5 with 25mg LEN on days 6-10 over a 28-day cycle as an effective front-line regimen for high-risk MDS and AML with up to 30% blasts. Responses are rapid with a median of 2 cycles for response, durable, and treatment with this dosing schedule is well tolerated. Figure 1: Overall survival of responders (n=31) Figure 1:. Overall survival of responders (n=31) Figure 2: Somatic mutations, cytogenetics and response in the annotated subset of 25 patients Figure 2:. Somatic mutations, cytogenetics and response in the annotated subset of 25 patients Disclosures Garcia-Manero: Celgene: Research Funding.

Mycophenolate Mofetil and Thrombopoietin Receptor Agonists in the Treatment of Refractory Thrombocytopenia in Patients with Autoimmune Lymphoproliferative Syndrome

Abstract 2218 Autoimmune lymphoproliferative syndrome (ALPS), often due to an inherited defect in the FAS gene, presents with chronic non-malignant lymphadenopathy, splenomegaly, and autoimmune cytopenias (Oliveira JB et al. “Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop”. Blood. 2010 Oct 7;116(14):e35-40). Thrombocytopenia has been noted in approximately 23% of ALPS patients. These patients, especially those with massive splenomegaly and hypersplenism, are often refractory to standard dose short-term corticosteroid regimens and intravenous immunoglobulins (IVIG). Mycophenolate mofetil (MMF) has been used for persistent thrombocytopenia as a steroid sparing long-term measure in 40 out of 245 ALPS patients in our cohort. The median age at initiation of MMF was 10.5 years (range 7 months to 43 years) with an average follow-up of 3.8 years on MMF (range 3 months to 11 years). Here we share our experience over the last 7 months related to the use of thrombopoietin receptor agonists in 3 ALPS patients who have persistent, severe, MMF-refractory thrombocytopenia (platelets <10,000/uL) (Figure). Patient 1 is a 21 year old man with ALPS-FAS and splenomegaly who has been on MMF for 2 years. He presented with monthly episodes of thrombocytopenia requiring high dose corticosteroids and IVIG followed by four weeks of rituximab and daily prednisone without any durable improvement in his thrombocytopenia. He was started on eltrombopag 50mg daily and was able to taper off prednisone in one month with sustained stable platelet count. Three months after starting eltrombopag, he was able to survive surgical intervention for a spontaneous pneumothorax while on eltrombopag and MMF. Patient 2 is an 18 year old woman with ALPS-FAS and surgical asplenia who has been on MMF for approximately 7 years. She began having significant, symptomatic thrombocytopenia refractory to high-dose corticosteroids with transient responses to IVIG. She was started on eltrombopag 50mg daily with MMF and initially responded. However, when MMF was discontinued her platelet count plummeted. Despite reinitiating MMF, her platelet counts never recovered on eltrombopag and she continued to require monthly IVIG. She was eventually switched to romiplostim, and was incrementally increased to the maximum dose of 10mcg/kg/week. Her platelet counts continue to fluctuate, but she has not required any IVIG in over one month. Patient 3 is a 19 year old man with ALPS-U and surgical asplenia who has been on MMF for the last 9 years. During the past year he has had episodes of symptomatic thrombocytopenia requiring monthly courses of high dose corticosteroids and IVIG. After initiation of eltrombopag, he had a significant rise in his platelet counts. However, upon discontinuation of MMF, his platelet counts plummeted. MMF was restarted and he was trialed on multiple, different eltrombopag dosing regimens leading to supratherapeutic responses with platelet counts over 1,000,000/uL. Eltrombopag was held during these periods to allow for the significant thrombocytosis to resolve, but withholding eltrombopag led to platelet counts to eventually fall precipitously. Furthermore, he also developed severe headaches due to MMF and MMF had to be discontinued. After multiple dosing regimens, he eventually maintained a stable platelet count on eltrombopag 50mg daily for 5 days alternating with eltrombopag 25mg for 2 days without the concomitant use of MMF. Recently, there has been increasing evidence supporting the use of thrombopoietin receptor agonists in the treatment of refractory immune thrombocytopenia. MMF continues to be well tolerated as a long-term corticosteroid sparing drug for patients with ALPS complicated by chronic, refractory thrombocytopenia. Our preliminary experience suggests that there may be a role for thrombopoietin receptor agonists, most likely in combination with an immunosuppressive agent such as MMF, in the treatment of refractory thrombocytopenia in patients with ALPS. However, schedule and duration of therapy with this class of drugs needs further long term evaluation. Disclosures: No relevant conflicts of interest to declare.