Palpable Spleen Research Articles

A Multicenter, Open-Label, Pilot Study of Alisertib (MLN8237), a Novel Inhibitor of Aurora Kinase a, in Myelofibrosis

Background: Primary/Post-Essential/Post-Polycythemic Myelofibrosis (MF) is characterized by impaired maturation of GATA1 deficient megakaryocytes, which we hypothesize directly contribute to disease. (J Clin Invest 2017). The selective AURKA inhibitor alisertib (MLN8237) was shown to promote megakaryocytic maturation, amelioration of bone marrow fibrosis and lessen disease in animal models (Nat Med 2015).Methods: In an investigator sponsored multi-center pilot study (clinical trials.gov Identifier NCT 02530619), alisertib was administered to MF patients with at least DIPSS intermediate 1 risk who were in need of treatment, and were intolerant/refractory to or unlikely to benefit from JAK inhibitor therapy. Eligibility criteria also included an absolute neutrophil count ≥ 1 x109/L and platelet count ≥ 50 x109/L. Alisertib was provided by Takeda and administered at a dose of 50 mg by mouth twice daily for 7 days every three weeks. Adverse events (AEs) were monitored by common terminology criteria (Version 4.0). Laboratory correlative studies included assessment of the effects of alisertib and ruxolitinib on diagnostic samples and evaluation of changes in megakaryocytes and GATA1 expression in the bone marrow with therapy.Results:i) Patient characteristicsAs of June 2017, 19 patients (63% males; median age 72 years) have been enrolled, including 68% primary MF and 32% post PV/ET MF; 26% were DIPSS high and 74% intermediate-risk.11 (89%) patients had abnormal karyotype, including 7(64%) with unfavorable risk. Driver mutational frequencies were JAK2 58%, CALR 32%, and MPL 10%. Prior treatments included JAK inhibitors in 68% of patients.13 (68%) patients remain on treatment (median number of cycles=4; range 1-16). Median follow up of patients that were alive was 5 months (range; 1-10 months).ii) Safety dataTreatment related grade 4 hematological AEs included neutropenia, lymphopenia and thrombocytopenia seen in one patient each (5%). Grade 3 related hematological AEs included lymphopenia (n=4; 21%), anemia (n=3, 16%), febrile neutropenia (n=2, 11%), thrombocytopenia (n=1; 5%). The incidence of grade 3 related non- hematological AEs was as follows- vertigo (n=1; 5%), diarrhea (n=1; 5%); elevated lipase, alanine aminotransferase, and creatinine in one patient (5%) each. There was one unrelated grade 5 event -pneumonia with renal failure.iii)Preliminary efficacy dataa) Spleen response : 11(58%) patients had palpable splenomegaly ≥ 5 cm at time of study entry; 3 (27%) achieved ≥ 50% reduction in palpable spleen size.b) Erythroid response: 8 (62%) patients were transfusion dependent at baseline, of which none achieved transfusion independence. One patient displayed a durable rise in hemoglobin of ≥ 1g/dl.c) Leukocytosis/Thrombocytosis/Leukoerythroblastosis/LDH responses: 6 (32%) patients presented with leukocytosis and all (100%) had resolution of leukocytosis with treatment. Two patients (11%) had baseline thrombocytosis and both displayed ≥ 50% reduction in platelet count. Ten patients (53%) demonstrated leukoerythroblastosis and 2 (20%) displayed ≥ 50% improvement. All 19 patients had increased serum lactate dehydrogenase levels at time of study entry and 6 (32%) displayed ≥ 50% reduction with treatment.d) Symptom response: Of the 9 patients with constitutional symptoms at presentation, 5 (56%) reported improvement/resolution of symptoms. Moreover, 4 of 16 (25%) patients with at least moderate symptom burden achieved ≥ 50% reduction in the MF-SAF score.iv) Correlative studies: Alisertib, but not ruxolitinib, robustly promoted polyploidization and apoptosis of megakaryocytes derived from patient CD34+ cells at diagnosis. Morphological analysis of bone marrow revealed that alisertib led to improved megakaryocyte morphology and restoration of GATA1 staining (Figure 1).Conclusions: In this study we have reproduced, in the setting of a clinical trial, our previous preclinical observations that alisertib appears to normalize megakaryopoiesis in the MPNs. The reduction in peripheral counts is consistent with studies that suggest atypical MF megakaryocytes promote expansion of leukocytes. Although Alisertib had limited activity beyond demonstrated myelosuppressive activity in patients treated an average of four cycles, it was relatively safe. Updated results including overall response assessment and bone marrow review will be presented. [Display omitted] DisclosuresWatts:Jazz Pharmaceuticals: Consultancy, Speakers Bureau. Altman:Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Giles:Novartis: Consultancy, Research Funding.

Open Label Phase I Study of Single Agent Oral RG7388 (idasanutlin) in Patients with Polycythemia Vera and Essential Thrombocythemia

Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are associated with an increased risk of thrombosis, progression to myelofibrosis (MF) and significant symptom burden. While hydroxyurea, interferon, and JAK2 inhibitors are used to treat these myeloproliferative neoplasms (MPNs), hematopoietic stem cell-depleting therapies may result in an alternative mechanism to alter disease course and improve outcome. MDM2, a negative regulator of P53, is overexpressed in CD34+ MPN cells harboring wild type P53. It is the target of idasanutlin (IDA), an oral MDM2 antagonist that results in up-regulation of P53 and down-stream activators of apoptosis. Preclinical data from our laboratory group supports the clinical evaluation of IDA in patients (pts) with ET/PV (Lu et al Blood. 2014;124(5):771-9). We evaluated the safety and tolerability of IDA in a phase I dose escalation trial of pts with JAK2V617F-positive ET or PV [NCT02407080].Methods: 13 pts (1 withdrew prior to treatment) resistant/intolerant to hydroxyurea and/or interferon therapy and without prior JAK2 inhibitor therapy were enrolled in a single institution phase I trial of oral IDA at two dose levels of 100 mg and 150 mg daily for five consecutive days and repeated every 28 day cycles. The first cycle consisted of 56 days for the evaluation of dose limiting toxicities (DLT). A DLT was defined as any non-hematologic AE of grade 3+ or a hematologic AE of grade 2+ thrombocytopenia, or grade 3+ neutropenia or anemia. The absence of DLT in the initial cohort of 100 mg daily in 3 evaluable pts allowed for dose escalation in a new cohort to 150 mg and after a total of 6 pts were treated at this level an additional 3 pts were treated at 100mg to complete the intended study. Pts that did not attain at least a partial response (PR) by modified European LeukemiaNet (ELN) criteria after cycle 6 and met eligibility were able to continue receiving IDA in combination with pegylated interferon-α (PEG) at 45ug weekly. Correlative studies included baseline mutational profiling, MDM2 protein levels, changes in serum MIC-1 levels and JAK2V617F variant allele frequency (VAF) with therapy.Results: 12 pts (6 at 100 mg; 6 at 150 mg) were treated and their baseline characteristics are shown in Table 1. Pts received a median of 7 cycles (range, 1-12) over a median of 33 weeks (range, 8-107) on study. Three pts discontinued treatment due to pt decision (n=2) and physician decision (n=1). A DLT was not identified for either dose level during cycle 1, and no hematologic treatment emergent adverse events (TEAE) were seen at any time point. Table 2 shows the non-hematologic TEAEs that occurred in at least 2 pts regardless of attribution. Grade 3 fatigue (n=1) and grade 3 headache (n=1) were the only significant TEAE noted at any time on study (both in 100mg cohort). The overall response rate by modified ELN criteria by cycle 7 for the 9 evaluable pts was 7/9 (78%). 7 of 10 (70%) evaluable pts achieved a ≥50% improvement in total symptom score (TSS) from baseline. There were no thrombotic or major hemorrhagic episodes, or progression to MF. Bone marrow pathologic response was assessed in 2 pts after 5 cycles. One case showed histological improvement, with normalization of overall marrow cellularity and megakaryocyte number, and less pronounced megakaryocytic atypia. The median JAK2V617F VAF at baseline, 7 cycles, and 9 cycles of therapy was 45% (n=12), 12% (n=6) and 13% (n=6), respectively. One pt was eligible to receive combination therapy and achieved phlebotomy freedom, normalization of palpable spleen (baseline 18cm), leukocyte count (baseline 44 x109/L), and PV-related symptoms by cycle 8. This pt also attained a 20% reduction in JAK2V617F VAF.The percentage of mononuclear cells expressing MDM2 was dramatically increased as compared to normal controls (p=0.01) (Figure 1). Serum levels of MIC-1 was used to assess pharmacodynamic effects of IDA therapy. Serum MIC-1 levels were elevated (~ 5 fold) after 5 days of administration of IDA in 85% of the pts (Figure 2), indicating activation of P53 by the low doses of IDA administered. Persistent elevation in MIC-1 levels was observed on day 15 in 6 of the 12 pts treated.Conclusion: IDA is well tolerated and demonstrates a clear signal of clinical activity in pts with therapy refractory PV. Correlatives support on-target activity. Mature follow up on the entire cohort will be presented. A multicenter phase II trial of IDA at a dose of 150 mg is underway [Display omitted] DisclosuresMascarenhas:CTI Biopharma: Research Funding; Janssen: Research Funding; Promedior: Research Funding; Novartis: Other: DSMB member , Research Funding; Merck: Research Funding; Incyte: Other: Clinical Trial Steering Committee , Research Funding.

A phase 3, randomized, double-blind, placebo-controlled study of ruxolitinib plus parsaclisib in patients with JAK- and PI3K-inhibitor treatment-naïve myelofibrosis.

TPS7058 Background: Ruxolitinib (JAK1/JAK2 inhibitor) significantly improves outcomes in patients with myelofibrosis (MF); however, a subset of patients may experience a suboptimal response. Recent phase 2 data showed that addition of PI3Kδ inhibitor parsaclisib to ruxolitinib monotherapy resulted in additional alleviation of MF symptoms and splenomegaly in patients with MF (Yacoub. EHA2020. S216). This phase 3, randomized, double-blind study (INCB 50465-313; NCT04551066), evaluates the combination of ruxolitinib and parsaclisib in patients with MF who are naïve to Janus kinase (JAK) and PI3K inhibitor therapies. Methods: Eligible patients are aged ≥18 years with a diagnosis of primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, have a Dynamic International Prognostic Scoring System (DIPSS; Passamonti. Blood. 2010;115:1703-1708) risk category of at least Intermediate (INT)-1, palpable spleen ≥5 cm below left subcostal margin; total symptom score ≥10 at screening, ECOG PS 0–2, and life expectancy ≥24 weeks. Patients will be excluded if they previously received therapy with any JAK inhibitor, any PI3K inhibitor, any experimental or standard drug therapy for MF ≤3 months of first study dose and/or lack of recovery from all toxicities related to previous therapies to grade ≤1, have recent history of inadequate bone marrow reserve (eg, platelet count = 50×109/L) or have inadequate liver or renal function at screening. Approximately 440 patients will be randomized (1:1) to ruxolitinib plus parsaclisib 5 mg QD or ruxolitinib plus matching placebo, with stratification at randomization by DIPSS risk category (high vs INT-2 vs INT-1) and platelet count (≥100×109/L vs 50 to = 100×109/L inclusive). Treatment will begin on Day 1, with starting ruxolitinib dose level determined by baseline platelet count, and will continue as long as treatment is tolerated and discontinuation criteria are not met. When the last enrolled patient has completed 24 weeks of treatment, the study will be unblinded and patients randomized to ruxolitinib plus placebo who have adequate hematology parameters will be able to crossover to receive parsaclisib together with continued ruxolitinib. The primary objective is the evaluation and comparison of spleen volume at Week 24 for patients who received ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Secondary objectives include evaluation and comparison of patient-reported MF symptoms, overall survival, time to onset and duration of response in spleen volume, and safety and tolerability for ruxolitinib plus parsaclisib versus ruxolitinib plus placebo. Sites are opening across the United States, Europe, Asia, and New Zealand. Clinical trial information: NCT04551066.

Efficacy and safety of a novel dosing strategy for ruxolitinib in the treatment of patients with myelofibrosis and anemia: the REALISE phase 2 study

Anemia is a frequent manifestation of myelofibrosis (MF) and there is an unmet need for effective treatments in anemic MF patients. The REALISE phase 2 study (NCT02966353) evaluated the efficacy and safety of a novel ruxolitinib dosing strategy with a reduced starting dose with delayed up-titration in anemic MF patients. Fifty-one patients with primary MF (66.7%), post-essential thrombocythemia MF (21.6%), or post-polycythemia vera MF (11.8%) with palpable splenomegaly and hemoglobin <10 g/dl were included. Median age was 67 (45–88) years, 41.2% were female, and 18% were transfusion-dependent. Patients received 10 mg ruxolitinib b.i.d. for the first 12 weeks, then up-titrations of up to 25 mg b.i.d. were permitted, based on efficacy and platelet counts. Overall, 70% of patients achieved a ≥50% reduction in palpable spleen length at any time during the study. The most frequent adverse events leading to dose interruption/adjustment were thrombocytopenia (17.6%) and anemia (11.8%). Patients who had a dose increase had greater spleen size and higher white blood cell counts at baseline. Median hemoglobin levels remained stable and transfusion requirements did not increase compared with baseline. These results reinforce the notion that it is unnecessary to delay or withhold ruxolitinib because of co-existent or treatment-emergent anemia.

Splenomegaly

Key Points A palpable spleen may be normal, especially in neonates and infants.Because an enlarged spleen can extend into the pelvis, palpation should begin in the right lower quadrant and move across the abdomen toward the left upper quadrant.Viral infection is the most common cause of splenomegaly in children.Splenomegaly from sequestration crisis in patients with sickle cell disease and following abdominal trauma are emergencies.

Clinical evaluation of acute respiratory distress and chest wheezing in infants

Background: Differentiating acute respiratory distress and wheezing in infants is difficult due to similar clinical presentations. Therefore, it is of utmost importance to diagnose and differentiate bronchopneumonia, bronchiolitis, and bronchial asthma on the basis of clinical parameters in infants. Materials and Methods: One hundred infants with fever, cough, and increased respiratory distress with wheezing were included, and detailed clinical history, allergic disorder, immunization status were collected. Study cases were diagnosed as bronchopneumonia, bronchiolitis, or bronchial asthma based on clinical criteria, and a suitable treatment regimen was provided. Chi-square test, Fisher's exact test, and two-sample proportion test were used to analyze the data. Results: Among 100 cases, 50% of cases were of bronchopneumonia, whereas 36% and 14% of cases were of bronchiolitis and bronchial asthma. A significant difference was observed among them for the history of wheezing (P = 2.839e-12), presentation of various signs and symptoms (P = 0.00), and treatment regimens. The odds of occurrence of bronchopneumonia was more with the signs of flaring of alae nasi and palpable liver (OR=[0.62–4.32]; and [0.63–4.14]). For bronchiolitis also, it was higher if they showed signs of tachycardia, pallor, and reduced breathing sounds (OR = [0.96–6.8679]; [0.44–2.76]; and [0.70–5.44]). Furthermore, for bronchial asthma, it was higher if it presented the signs of tachycardia, cyanosis, reduced breathing sounds, palpable spleen, etc., (OR = [0.90–16.18]; [1.93–36.50]; [0.43–6.92]; and [0.17–11.52]). Ampicillin and gentamicin treatment regimen for bronchopneumonia; salbutamol and intravenous fluids for bronchiolitis; and steroids and salbutamol for bronchial asthma were the choice of treatment. Conclusion: The study demonstrated the differential diagnosis of bronchopneumonia, bronchiolitis, and bronchial asthma based on clinical features and will be useful in the rational management of these conditions.

Prenatal Diagnosis of Type 1c Choledochal Cysts in 1 Month Old Baby

Choledochal cysts (CCs) are congenital dilatations of extrahepatic and/or intrahepatic bile ducts. It is a rare biliary entity, in the Asian population, the incidence can be as high as 1:1000 live. We reported case of One-month old baby girl with yellowish skin and acholic stool the baby has been suspected with anechoic abdominal mass at 17 weeks of gestational age using fetal ultrasound. From physical examination, jaundice was seen on the sclera and all over the body. The bowel sound was normal, without distention, without palpable liver nor spleen. The mass was not palpable either. Aspartate transaminase serum (AST), alanine aminotransferase serum (ALT), gamma glutamyl tranferase (GGT), bilirubin level was increased. Ultrasound was performed and revealed extrahepatic dilation to form a saccus in the proximal CBD, according to the picture of type 1 choledocal cyst. The surgeon performed cyst excision and hepatoduodenostomy procedure and found choledochal cyst. Histopathologic examination from cyst confirmed the choledochal cyst. The patient was discharged in good condition. We conclude that Type I choledochal cysts can be identified prenatally during a detailed fetal sonogram. The newborn should be investigated to confirm the diagnosis and undergo cyst excision promptly to reduce the potential for complications.

Splenomegaly: Epidemiological, Clinical and Therapeutic Aspects in Children in the Pediatric Surgery in the General Surgery Department of Ignace Deen National Hospital

The objective of this study was to contribute to the study of splenomegaly in children under the age of 15 in the Pediatric Surgery Unit of the General Surgery Department of Ignace Deen National Hospital. Methodology: This was a retrospective descriptive study lasting 5 years from January 1, 2011 to December 31, 2015 on children with splenomegaly in the pediatric surgery unit of the general surgery department of the hospital national Ignace-Deen. Results: Splenomegaly represented 1.24% of surgical pathologies during our study. Both sexes were concerned with a male predominance in 52.63%; the sex ratio was 1.11. The 10-14 age group was the most affected (47.37%); The average age of our cases was 9.5 years with extremes of 3 years and 15 years. Abdominal pain associated with an abdominal mass and fever were the main reasons for consultation (100%), followed by physical asthenia and anorexia (78.94%). 63.15% of our diagnosed cases were stage IV of the Hackett classification, followed by stage III (31.57%) and stage V (5.26%). Conclusion: Any palpable spleen must in fact be considered as pathological. The conditions causing splenomegaly are multiple in tropical countries, their frequency varies from one country to another.

First Line Treatment with Hydroxyurea in Patients with Policitemia Vera: Evaluation of Efficacy in the Current Clinical Practice Beyond ELN Criteria

First Line Treatment with Hydroxyurea in Patients with Policitemia Vera: Evaluation of Efficacy in the Current Clinical Practice Beyond ELN Criteria

Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis

Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with Myelofibrosis

Spinal Cord Compression in Patients with Acute Myeloid and Lymphoid Leukemia

Introduction Acute leukemias can be divided into acute myeloid leukemia and acute lymphoblastic leukemia. Common presentations of acute leukemia include fever, symptoms of anemia, bleeding, bone pain palpable Lymph nodes or spleen and symptoms due inflation or leukocystasis. Extramedullary mass is rare and can be of myeloid tissue and known as Chloroma or myeloid (granulocytic) sarcoma which one of the WHO classifications for acute myeloid leukemia. Common sites of occurrence are skin, sinuses, bone and other. It's rarely involve central nervous system. Spinal cord involvement usually manifest as epidural mass causing cord compression. Spinal epidural tumor with acute leukemia and myeloid sarcoma is rare and can be found in 3-9% in patients with leukemia. In this review we decide to review the cases of spinal cord compression caused by acute myeloid leukemia (including Chloroma) and acute lymphoblastic leukemia due to the significance of such presentation in addition to reports that Myeloid sarcoma of the spine has very poor prognosis Methodology: We have reviewed the literature using: PubMed, google scholar, Scopus for patient with spinal cord compression and acute leukemia. We used the search term and synonyms : : acute myeloid leukemia , acute myelocytic leukemia , acute monocytic leukemia , acute lymphoblastic leukemia , acute lymphoid leukemia, chloroma , myeloid sarcoma ,granulocytic sarcoma, spinal cord compression .We included adult patients above 18 years old only cases we exclude pediatrics cases and cases of chronic leukemia's and other myeloproliferative disorders as well as cases of central nervous system involvement other than spinal cord Results We gathered the information from 98 cases with general demographics, presentation, image modality, cytogenetics and molecular in addition to management and outcome. We have found mean age for the patients is 38 years old with male predominance with 70% of the cases. The most presenting symptom was back pain in around 75% of the cases. Neurological findings showed sensory loss and parapreresis in most of the documented cases. MRI was most performed modality of imaging 63% followed by Computed tomography(CT) 15 % and then myelogram 13 %, which is least used due to invasive nature and before the era of MRI. The most common affected site on spinal cord were thoracic followed by lumbar. Cytogenetics and molecular data was not reported in most of the cases. Patients were treated with either steroids or surgery or radiotherapy and or chemotherapy while few underwent bone marrow transplant, but the most common approach was surgery+ radiotherapy + chemotherapy combination. Steroids used in most of the cases especially in the cases of acute lymphoblastic leukemia and dexamethasone was the steroids of the choice mainly. The outcome of the patients were variable, 30 % were alive at the time of the reports 30 % died and 30 % between relapse and complete remission. Conclusions Acute leukemia can be presented as mass causing spinal cord compression which is very serious. There are is no standardized management of patients with acute leukemia who presented with spinal cord compression nether guidelines or steps to follow. Some reports speculated also specific morphology and cytogenetics association with predisposition to have Extramedullary mass, however there lack of reporting of such a valuable information. Large studies including all adjusted variables required to determine if spinal cord compression presentation can be an independent risk facto or not Effective diagnosis and prompt action should take place. Figure Disclosures No relevant conflicts of interest to declare.

Differential Treatment Strategy in Polycythemia Vera Patients with Stable Suboptimal Response to Hydroxyurea: Clinical Correlations and Impact on Survival

Differential Treatment Strategy in Polycythemia Vera Patients with Stable Suboptimal Response to Hydroxyurea: Clinical Correlations and Impact on Survival

Real-World Investigation of Spleen, Symptom, and Hematologic Response in Patients with Myelofibrosis Treated with First-Line Ruxolitinib

Introduction: Relief of symptoms and splenomegaly are important treatment goals for all patients with myelofibrosis (MF). Until 2019, ruxolitinib (RUX) was the only FDA-approved therapy for the treatment of intermediate- or high-risk MF. This study sought to explore real-world treatment patterns and clinical outcomes, including spleen response, hematologic response, and patient symptomology during first-line (1L) RUX therapy to describe the unmet need in RUX-treated patients with MF. Methods: A retrospective, multisite (US community oncology practices) medical chart review of patients with MF who initiated 1L RUX between January 2015 and December 2017 was undertaken. Patient demographic and clinical characteristics at initiation of RUX, and RUX dosing and dose modifications were abstracted. In addition, at the initiation of RUX and every patient visit during the first 6 months of therapy, physicians abstracted data on spleen size, symptom burden, and hematologic parameters. We assessed the rate of dose modifications (decrease or increase) during the first 6 months of therapy and subsequently compared patients who dose modified to those who did not (stable dose). Univariate comparisons between cohorts of baseline characteristics were performed (chi-square and t-tests). Time to treatment discontinuation was described. The proportion of patients with spleen length reduction, palpable spleen resolution, resolution of ≥ 1 baseline symptom, and platelet decrease to &amp;lt; 100 × 109/L at 6 months following RUX initiation was described and compared between dose-modified and stable-dose cohorts. The Kaplan-Meier method was used to estimate these proportions; patients were censored on their date of treatment discontinuation if the outcome had not occurred. Results: Data for 152 patients were collected from 37 different sites across the USA (South 43.2%, Northeast 21.6%, Midwest 18.9%, West 16.2%). Mean follow-up was 26 months from initiation of 1L RUX; 29% of patients were deceased at the time of data abstraction. Overall, 69 patients (45.4%) were not initiated on the recommended dose of RUX based on their platelet count according to US package insert. Forty-five patients (29.6%) were dose modified during the first 6 months of therapy including 39 with dose decreases and 7 with dose increases (1 patient had both a decrease and increase). Physicians reported the most common reason (76.9%) for dose reduction was a hemoglobin level of 8-10 g/dL or platelet count 50-75 × 109/L. The most common reason (57.1%) for dose increase was provider decision to start on a low dose and titrate to a therapeutic dose. Mean age at diagnosis was significantly higher in the dose-modified subgroup (70 vs 62 years, P &amp;lt; 0.01) compared to the stable-dose subgroup, while platelets at the time of RUX initiation were significantly lower (246 vs 326 × 109 /L, P = 0.03); no other baseline factors were associated with dose modification during the study period. At the time of chart data abstraction, 57.0% of stable-dose and 66.7% of dose-modified patients had discontinued RUX. Among stable-dose and dose-modified patients who had discontinued RUX, the median time to discontinuation was 10.7 and 10.0 months, respectively, while duration of treatment for patients still receiving RUX was 26.4 and 28.6 months, respectively. At 6 months, while not statistically significant, a lower proportion of patients in the dose-modified cohort achieved spleen length reduction by palpation (57.9% vs 65.6%; P = 0.710) and resolution of splenomegaly (39.1% vs 49.3%; P = 0.090) (Figure, panel A). A lower proportion of patients in the dose-modified cohort had resolution of ≥ 1 baseline symptom (19.9% vs 39.1%; P = 0.003) (Figure, panel B). Among patients with ≥ 100 × 109/L platelets at baseline, a significantly higher proportion of patients in the dose-modified cohort had platelets decrease to &amp;lt; 100 × 109/L during 1L RUX treatment (66.0% vs 16.7%; P &amp;lt; 0.001) (Figure, panel C). Conclusions: Dose modifications occurred in nearly one third of 1L RUX-treated patients, with the majority requiring a dose decrease. Patients with dose modifications were less likely to have improved splenomegaly or symptom burden and experienced significantly lower platelet counts than those who maintained a stable dose of RUX during the first 6 months of therapy. These findings identify a population of RUX-treated patients with a significant need for alternative MF treatments. Figure Disclosures Kish: Cardinal Health: Current Employment, Current equity holder in publicly-traded company. Kee:Bristol Myers Squibb: Current Employment. Abraham:BMS: Current Employment, Current equity holder in publicly-traded company. Copher:Bristol Myers Squibb: Current Employment. Miller:Cardinal Health: Current Employment. Gerds:Imago Biosciences: Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Sierra Oncology: Research Funding; Incyte Corporation: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding.

Hydroxyurea to Reduce Stroke Risk in Tanzanian Children with Sickle Cell Anemia

Introduction: Sickle cell anemia (SCA) is highly prevalent in sub-Saharan Africa with &amp;gt;300,000 annual births, and substantial morbidity and mortality due to limited resources. The burden of stroke in this population is of particular concern, given the devastating clinical and neurocognitive sequelae of these events. Hydroxyurea, a potent disease modifying therapy for SCA, is safe and feasible for low-resource and malarial endemic countries within sub-Saharan Africa and when used at maximum tolerated dose (MTD), decreases the incidence of acute painful vaso-occlusive events, infections, malaria, transfusions, hospitalizations, and death. Whether hydroxyurea can prevent primary stroke in SCA within Africa has not yet been determined, due in part to lack of stroke screening programs using transcranial Doppler (TCD) ultrasonography. If effective, hydroxyurea would have even more therapeutic benefits for children with SCA, particularly in settings where blood is not available, affordable, or safe. We designed the Stroke Prevention with Hydroxyurea Enabled through Research and Education (SPHERE) trial to determine the stroke risk among Tanzanian children using TCD screening and to investigate the effects of hydroxyurea to reduce that risk. Methods: The SPHERE trial (NCT03948867) is a single center prospective phase 2 open-label screening and treatment pilot study at Bugando Medical Centre, a teaching and referral hospital in Mwanza, Tanzania. Children 2-16 years old with SCA consented to TCD screening by locally trained and certified examiners; recent febrile illness, red cell transfusion, or hospitalization were temporary exclusions. Study participants with maximum Time-Averaged Mean Velocity (TAMV) on TCD exam categorized as conditional (170-199 cm/sec) or abnormal (≥200 cm/sec) are offered hydroxyurea with escalation to MTD, while those with normal TCD screening exams will be rescreened annually. Hydroxyurea is initiated at ~20 mg/kg/day using 500 mg capsules and a weekly dosing calculator, then escalated every 8 weeks by 5 mg/kg/day up to 35 mg/kg/day. Children on hydroxyurea are seen monthly during dose escalation and every 3 months after reaching MTD. The primary endpoint is change in TCD velocity after 12 months of hydroxyurea therapy. Secondary endpoints include changes in splenic volume and filtrative function; change in renal function; incidence of infection, especially malaria; hydroxyurea pharmacokinetics; and genetic modifiers of disease including pharmacogenomics. Results: From April 2019 to April 2020, a total of 202 children underwent TCD screening, exceeding the projected enrollment pace and goal (Figure). The average age (mean ± SD) at enrollment was 6.8 ± 3.5 years, and 53% were female. A majority had previous dactylitis (75%), painful vaso-occlusive episode (93%), blood transfusion (68%), and malaria (89%). Recurrent hospitalization was common with 30% having &amp;gt;5 previous hospitalizations. Only 4% had previously used hydroxyurea. Baseline labs included hemoglobin = 7.8 ± 1.3 g/dL, HbF = 9.3 ± 5.4 %, and ANC = 5.5 ± 2.4 x 109/L. Baseline assessment revealed a palpable spleen in 46 children (23%), and most of these (29) were ≥5 cm below the costal margin. Abdominal ultrasonography documented splenic tissue in 91% of children with an average volume of 101 ± 123 mL (range 8-1045). TCD examinations were performed in all children at enrollment with average TAMV of 148 ± 27 cm/sec [median 144, IQR 130-169 cm/sec] with 76% normal, 21% conditional, 2% abnormal, and 1% inadequate exams. Of 47 children eligible for hydroxyurea for elevated TCD velocities, 45 successfully initiated treatment, while 1 lived too far away for regular visits, and 1 had low blood counts from acute splenic sequestration and died before initiating study treatment. Conclusion: Children with SCA in Tanzania have a high risk for primary stroke. Identification of elevated TCD velocities through screening by local trained certified examiners, coupled with initiation of hydroxyurea treatment with dose escalation to MTD, offers a feasible and affordable means by which to lower TCD velocities and reduce primary stroke risk. Now fully enrolled, SPHERE has built local clinical capacity, research infrastructure and high-quality TCD screening, and will prospectively determine the benefits of hydroxyurea for stroke prevention, as a prelude for expanding hydroxyurea access for children with SCA in Tanzania. Figure Disclosures No relevant conflicts of interest to declare.

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Clinical Characteristics and Treatment Patterns By Risk Stratification in Patients with Essential Thrombocythemia: An Analysis of the MOST Study

Low-dose ruxolitinib shows effective in treating myelofibrosis.

The aim of this study was to investigate the effect of low-dose ruxolitinib (daily dose ≤ 10 mg) for the treatment of myelofibrosis (MF). A retrospective analysis was performed on a total of 88 patients with myeloproliferative neoplasm-associated MF (MPN-MF) who were diagnosed and treated in West China Hospital, Sichuan University, China. A total of 44 MPN-MF patients received a low dose of ruxolitinib (daily dose ≤ 10 mg), while another 44 patients received 10-25 mg twice daily. Low-dose ruxolitinib treatment resulted in slow, but gradual spleen response. Compared with baseline, the mean changes in palpable spleen length in the low- and high-dose groups were -26.9 and -49.0% after 12 weeks of treatment, respectively, and -46.7 and -64.1% after 48 weeks of treatment, respectively. In the low dose group, the median myeloproliferative neoplasm symptom assessment form (MPN-SAF) total symptom score (TSS) decreased by 37.8 and 35.9% at the 12 weeks and 48 weeks after treatment, respectively. No statistical difference was observed in MPN-SAF TSS among different dose groups. After 48 weeks of treatment, bone marrow (BM) fibrosis improved in 43.3% (13/30) of evaluated patients and was stable in 56.7% (17/30) patients. In the low-dose treated group, BM fibrosis improved in 50% patients and was stable in remaining 50%. Low-dose ruxolitinib is effective in treating MF.

MPN-183: Preliminary Gastrointestinal Safety and Tolerability of Fedratinib from the Phase IIIb FREEDOM Trial in Patients with Intermediate- or High-Risk Myelofibrosis Previously Treated with Ruxolitinib

Context: Fedratinib is a selective JAK2/FLT3 inhibitor shown to induce spleen responses and symptom improvement in patients with myelofibrosis. Gastrointestinal (GI) events including nausea, vomiting, and diarrhea, were the most common adverse events (AEs) in fedratinib clinical trials, and were most frequent during early treatment. The JAK1/2 inhibitor, ruxolitinib, has demonstrated efficacy in patients with myelofibrosis; however, many patients discontinue ruxolitinib due to loss of response or drug-related cytopenias. The ongoing, single-arm, phase IIIb FREEDOM study evaluates fedratinib in myelofibrosis patients previously treated with ruxolitinib. FREEDOM includes prospective mitigation strategies for managing GI events. Objective: Review the frequency, severity, and mitigation of GI events during early fedratinib treatment in FREEDOM. Methods: Eligible patients are aged ≥18 years, with intermediate- or high-risk MF, ECOG-PS score 0-2, platelet count ≥50 × 109/L, and splenomegaly ≥ 450cm3 or palpable spleen > 5 cm below LCM; and had previously received ruxolitinib for ≥3 months (or ≥28 days with intolerance). Patients receive fedratinib 400 mg/day in continuous 28-day cycles. Study design includes mitigation strategies (prophylaxis, symptomatic treatment, dosing modifications, dosing with food) for managing GI toxicities. AEs are evaluated in all treated patients. Results: At data cutoff (26-Mar-2020), 22 patients had enrolled; 4 patients discontinued (none due to GI-related events). Median age was 68.5 years (range, 49-80). All patients had received ≥3 months of prior ruxolitinib treatment; the most common reason for ruxolitinib discontinuation was relapse (27%). Median fedratinib treatment duration was 18.6 weeks (1.6-48); 10 patients (46%) received >6 fedratinib cycles. Diarrhea, vomiting, and nausea occurred in 32%, 18%, and 14% of patients, respectively; none of these events were grade 3-4 or required dose modification or discontinuation. 12 patients (55%) received ondansetron and 6 (27%) received loperamide. Conclusions: Fedratinib was generally well tolerated. In similar patients receiving fedratinib 400 mg/day (starting dose) in the phase II JAKARTA2 study, which did not prespecify mitigation for GI events, rates of diarrhea, nausea, and vomiting through end-of-cycle 6, ranged from 41% to 62%. Early data from the FREEDOM study suggest frequency and severity of GI events may be reduced via mitigation strategies. Study enrollment is ongoing.

Annals for Educators - 1 September 2020.

Annals for Educators - 1 September 2020.

Malnutrition, Its Attributes, and Impact on Quality of Life: An Epidemiological Study among β-Thalassemia Major Children.

BackgroundIndia is home to a large number of thalassemic children. Despite malnutrition being an essential determinant of their therapeutic goals and quality of life (QoL), it was hardly ever explored. With this background, this study aimed to estimate the proportion of β-thalassemia major (β-TM) children experiencing malnutrition, its attributes, and impact on their QoL.MethodsThis cross-sectional, hospital-based, analytical observational study was conducted among 328 β-TM children attending the thalassemia day care unit of a medical college from May 2016 to April 2017, with a structured schedule. Data were analyzed following appropriate statistical methods using SPSS statistical package ver. 16.0 (SPSS Inc., Chicago, IL, USA).ResultsAmong the study participants, 48.2% were malnourished with a mean body mass index of 13.9 kg/m2 . In the multivariable logistic regression model, participants’ age (adjusted odds ratio [AOR], 1.15; 95% confidence interval [CI], 1.02–1.29), caste (AOR, 2.11; 95% CI, 1.23–3.60), mothers’ educational level (AOR, 2.05; 95% CI, 1.22– 3.44), blood transfusion frequency (AOR, 1.25; 95% CI, 1.16–1.31), and palpable spleen size (AOR, 1.22; 95% CI, 1.08–1.37) were significant predictors of malnutrition after adjusting for pre-transfusion hemoglobin level and hemolytic facies status. In multiple linear regression analysis, malnutrition negatively impacted total QoL (unstandardized beta [standard error], -4.4 [1.7]; P=0.009) and various domains of the study participants except the social and school domains adjusted for age, sex, caste, place of residence, parents’ educational level, and socioeconomic status.ConclusionAlmost half of the study participants had malnutrition. Malnutrition had a negative impact on their QoL.

Essential Thrombocythemia Masquerading as Henoch–Schonlein Purpura in a 9-year-old Child

Leukocytoclastic vasculitis (LCV) is a complex group of conditions which are characterized by vascular damage and neutrophilic infiltrates. LCV in children is usually considered as a part of connective tissue diseases, autoimmune disorders, and primary systemic vasculitis such as systemic lupus erythematosus (SLE) or Henoch–Schonlein purpura (HSP). We herein describe a 9-year-old child with fever, arthritis, diffuse abdominal pain, and palpable purpura over the lower limbs, who was initially diagnosed to have HSP based on the European League Against Rheumatism criteria. He also had thrombocytosis which was attributed to HSP. The skin biopsy showed LCV, providing corroborative evidence of HSP in this setting. Due to severe abdominal pain, prednisolone was prescribed, and resolution of symptoms occurred. There was no hepatosplenomegaly, anemia, polycythemia, or lymphadenopathy at this juncture. On follow-up, however, the thrombocytosis worsened (2000 × 109/L) with appearance of a palpable spleen. Further investigations revealed essential thrombocythemia (ET) as the etiology of LCV in this child. The learning point in this case report is the emphasis on consideration of inclusion of malignancies in the spectrum of LCV in children, besides the usual differential diagnosis such as HSP or SLE, especially when accompanied by worsening thrombocytosis. ET has not been reported in the constellation of malignancies described in association with LCV in the literature.