Anemia Grade Research Articles

Comparison between helical tomotherapy and intensity-modulated radiotherapy on acute toxicity in patients with rectal cancer

Objective To compare acute toxicity for stage Ⅱ-Ⅲ patients with rectal cancer irradiated with helical tomotherapy (HT) and conventional five-field intensity-modulated radiotherapy (5-IMRT). Methods The data of 84 stage Ⅱ-Ⅲ patients with rectal adenocarcinoma treated with concurrent chemoradiotherapy (CRT) were retrospectively analyzed. 19 patients underwent postoperative CRT, and 65 patients underwent preoperative CRT. 43 patients received radiotherapy with HT and 41 patients with 5-IMRT. The delineation on clinical target volume (CTV) and gross tumor target (GTV) was similar for two groups. The CTV to plan tumor volume (PTV) margins were 1.0 cm for patients with 5-IMRT and 0.5 cm for patients with HT. For all patients, a dose of 45.0-50.4 Gy, in daily fractions of 1.8 Gy, was delivered to PTV. For 45 patients with high risk factors, simultaneous integrated boost (SIB) was given to the tumor or tumor bed of a total dose of 55.0-60.0 Gy, in daily fractions of 2.1-2.3 Gy. Before treatment, the patients treated with HT underwent scanning by the tomotherapy-integrated megavoltage computed tomography (MVCT) scan modality and were positioned by co-registration of these images to the original kilovoltage planning CT image set. Concurrent capecitabine every day 1 600 mg/m2, twice daily on every day in the week. Results The rates of grade ≥2 acute cystitis were 7.0 % (3 cases) in HT group and 2.4 % (1 case) in 5-IMRT group (P= 0.616), and ≥3 grade acute diarrhea were 4.7 % (2 cases) and 12.2 % (5 cases), respectively (P= 0.259). ≥2 grade leukopenia were 48.8 % (21 cases) and 19.5 % (8 cases), respectively (P= 0.005), ≥1 grade anemia were 34.9 % (15 cases) and 14.6 % (6 cases), respectively (P= 0.032), and ≥1 grade thrombocytopenia were 23.3 % (10 cases) and 14.6 % (6 cases), respectively (P= 0.314). Conclusions There is no significant difference in acute diarrhea and cystitis for patients treated with HT and 5-IMRT. Leukopenia and anemia in patients treated with HT are worse than those in patients with 5-IMRT, and thrombocytopenia is similar in the two groups. Key words: Rectal neoplasms; Chemoradiotherapy; Helical tomotherapy; Acute toxicity

A Phase II Study of S-1 for Previously Untreated Elderly Patients with Advanced Non-Small Cell Lung Cancer

Background: S-1, a novel oral fluoropyrimidine, is active in the treatment of non-small cell lung cancer (NSCLC). However, data on S-1 for elderly patients with NSCLC are insufficient. Methods: Eligibility criteria were no prior chemotherapy, stage IIIB or IV NSCLC, performance status 0-1, age >70 years, and adequate hematological, hepatic, and renal functions. Patients received S-1 (40 mg/m² twice a day) for 28 consecutive days. This schedule was repeated every 6 weeks. The primary end point was the tumor response rate. Results: Thirty-two patients were enrolled and 31 patients were evaluable for response. The patients' median age was 80 years (range: 71-88). The response rate was 22.6% (95% CI: 11-38). Neutropenia, anemia, thrombocytopenia, febrile neutropenia, and diarrhea of grade ≥3 occurred in 6, 6, 10, 3, and 3%, respectively. Conclusions: In elderly patients with previously untreated advanced NSCLC, S-1 appears to be well tolerated and demonstrates encouraging activity.

Significance of Red Cell Distribution Width in the Diagnosis of Iron Deficiency Anemia: An Observational Study from India

Objective: To study the importance of Red cell distribution width (RDW) and peripheral smear in Iron Deficiency anemia (IDA) and its correlation with various RBC indices. Method and material: Hundred cases of microcytic (MCV <80fl) anemia (Hb<11 gm %), diagnosed as IDA were enrolled in the study, after getting parental consent. These children's were evaluated for clinical examination, red cell indices, RDW, serum iron and serum total iron binding capacity (TIBC) and transferrin saturation and peripheral blood film (PBF) examination for red cell morphology. Results: The mean RDW in mild, moderate and severe grade of iron deficiency anemia were 16.83±1.24, 18.52%+1.54 and 21.4%+3.15 respectively. The RDW was high in 98% cases of IDA.As the severity of IDA increased the values of RDW increased, serum iron decreased (p<0.001), TIBC increased (p<0.001) and serum transferrin saturation decreased (p<0.001). There was progressive decrease in MCV with increase in severity of anemia and there was corresponding increase in RDW. In mild IDA, the sensitivity of RDW was found to be very high (91%) in comparison to PBF changes (43.47%) cases and was statistically highly significant (p<0.001). In moderate IDA and severe IDA the sensitivity of RDW & PBF changes both were found to be very high. The positive predictive value of RDW and peripheral blood film changes was (100%) in all grades of IDA. The negative predictive value of RDW in mild grade of IDA was 88.23% as compared to 53.57% in PBF. In moderate grade of IDA, NPV of RDW was 100% as compared to 83% in case of PBF. While in severe grade of IDA the NPV of RDW and PBF was recorded to be 100%. Conclusion: The RDW was found to be highly sensitive and effective tool for early diagnosis of mild iron deficiency anaemia therefore; it is recommended that the RDW can be used as an effective tool for the diagnosis of iron deficiency anaemia in early stages, in a large number of samples at major hospitals thereby reducing manpower and time consumption.

Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a retrospective case review.

Six weeks of zidovudine (ZDV) is recommended for postnatal prophylaxis of HIV-exposed infants, but combination antiretrovirals are indicated if HIV transmission risk is increased. We investigated the frequency and severity of adverse events (AE) in infants receiving multiple drug prophylaxis compared to ZDV alone. In this retrospective review of 148 HIV-exposed uninfected infants born between 1997–2009, we determined clinical and laboratory AE that occurred between days of life 8–42. Thirty-six infants received combination prophylaxis; among those, a three-drug regimen containing ZDV, lamivudine, and nevirapine was most common (53%). Rates of laboratory AE grade ≥1 were as follows for the combination prophylaxis and ZDV alone groups, respectively: neutropenia 55% and 39%; anemia 50% and 39%; thrombocytopenia 0 and 3%; elevated aspartate aminotransferase 3% and 3%; elevated alanine aminotransferase 0 and 1%; hyperbilirubinemia 19% and 42%. Anemia occurred more frequently in infants who received three-drug prophylaxis compared to infants who received ZDV alone (63% vs. 39%, p = 0.04); all anemia AE were grade 1 or 2 in the three-drug prophylaxis group. Overall, 75% of infants on combination prophylaxis and 66% of infants on ZDV alone developed grade ≥1 AE (p = 0.32), and 17% of infants in either group developed grade ≥3 AE. Stavudine was substituted for ZDV in 23 infants due to anemia or neutropenia. After this antiretroviral change, 50% of evaluable infants demonstrated improvement in AE grade, and 25% had no change. In conclusion, low grade anemia, neutropenia, and hyperbilirubinemia occurred frequently regardless of the prophylactic regimen, but serious AE were uncommon. Although most AE were typical of ZDV toxicity, the combination of ZDV with lamivudine and nevirapine resulted in an increased frequency of low-grade anemia. Further studies are needed to identify prophylactic regimens with less toxicity for infants born to HIV-infected mothers.

Prospective Study of I/V Iron Sucrose in Anemic Women and Its Effect

Objective: To determine different grades of anaemia, observe the effect of I/V sucrose in anaemic patients at different age groups, and to observe the combined effect of I/V iron sucrose and blood transfusion in anaemic patients to find out the impact of antenatal visits in improvement of anaemia in pregnant women presenting at Department of Obstetrics and Gynecology at Kamla Raja Hospital, Gwalior from 2007-2009. Methodology: 50 antenatal primipara patients’ with anaemia having haemoglobin (Hb)

A study on biochemical facet of anemia in cancers: A strong link between erythropoietin and tumor necrosis factor alpha in anemic cancer patients.

The three direct factors that could lead cancer patients to anemia, apart from therapy are iron deficiency, inflammatory cytokines surge and decreased erythropoietin (Epo). Our aim was to quantify biochemical and hematologic markers serum Epo, ferritin (Fe) and tumor necrosis factor-alpha (TNF-α) along with hemoglobin (Hb) to understand the associations between these factors, patient characteristics and anemia. The study group consisted of 100 anemic cancer patients and 80 controls. Biochemical marker levels were determined by the enzyme linked immunosorbent assay on an autoanalyser. Univarient analysis, t-test, ANOVA, Bonferroni test, linear regression was performed to find correlations and associations among various factors. The baseline serum Epo (153.07 ± 173.88 vs. 23.607 ± 36.462) and Fe levels (233.53 ± 257.12 vs. 23.06 ± 20.04) were adequately high in cases compared with that controls (P ≤ 0.001). Considerable raise in TNF-α levels was also observed (16.26 ± 13.44 vs. 11.2375 ± 4.84) (P = 0.001). TNF-α correlated positively (P = 0.022) with Epo and Fe (P = 0.000), which was also evident from large effect size of Epo (r2 = 0.414), TNF-α (r2 = 0.369), Hb (r2 = 0.226). Epo and Hb were negatively correlated (β = -0.375, P = 0.001) and Epo production was found to be appropriate for the degree of anemia (O/P ratio of 3.51 ± 1.26 vs. 1.43 ± 0.47). A strong association was seen between Hb, Epo and TNF-α in hematological and gynecological malignancies for different grades of anemia. Men were more prone to life-threatening anemia (13%) than women (9%). Anemia in cancers was not because of inadequate Epo or Fe levels, but because of improper Epo response. Further studies on molecular analysis of Epo, biochemical and molecular interplay between Epo and TNF-α could explain a rationale for anemia in cancers.

On-pump versus off-pump coronary artery bypass surgery in patients with preoperative anemia

ObjectivesThe study objective was to evaluate the effects on early outcome and midterm survival of performing coronary artery bypass grafting with the off-pump technique in comparison with cardiopulmonary bypass (on-pump) in patients with preoperative anemia. MethodsConsecutive adult anemic patients (preoperative hemoglobin <13.0 g/dL in men and <12.0 g/dL in women) resident in Puglia region who underwent isolated coronary artery bypass grafting between January 2011 and November 2013 were considered. Vital status was ascertained from the date of surgery to December 31, 2013. Odds ratio and hazard ratio (HR) were estimated. Propensity score methods were used to control for confounders. ResultsOf 939 anemic patients (234 female, aged 71 ± 9 years), 361 underwent operation with the off-pump technique and 578 underwent operation with the on-pump technique. Patients undergoing off-pump coronary artery bypass had a shorter intensive care unit length of stay, lower blood transfusion rate, and postoperative reduction in creatinine clearance. During a median follow-up of 18 months, 126 patients died: 46 in hospital (35 on-pump) and 80 after discharge (33 on-pump). In comparison with the off-pump technique, the on-pump technique had greater hospital mortality (odds ratio, 2.57; P = .028) and 30-day incidence of fatal events (HR, 2.67; P = .026). After a period without risk differences between groups (1-6 months; HR, 0.79; P = .618), a lower mortality in those undergoing the on-pump technique was detected (after 6 months HR, 0.35; P = .014). All results were confirmed in the 157 pairs of patients matched for propensity score, anemia grade, and surgery center. ConclusionsIn patients with low levels of preoperative hemoglobin, off-pump coronary artery bypass was associated with lower early morbidity and mortality but a greater risk of mortality during follow-up compared with on-pump coronary artery bypass.

Incidence of Chemotherapy Induced Anemia in Patients Diagnosed with Solid Tumors

Background: Anemia is a common complication of cancer and its treatment, causing fatigue, drowsiness, depression, dyspnoea, tachycardia, dizziness and reduced quality of life. Yet, little data exist on the burden of chemotherapy induced anemia (CIA) in current oncology practice.Methods: Patients diagnosed with incident cancers of breast, lung, colon/rectum, stomach and ovary who received chemotherapy were identified from Kaiser Permanente Southern California Health Plan (2010-2012). Patients who had a diagnosis of myelodysplastic syndrome or anemia before chemotherapy (i.e., diagnosis of inherited anemia or hemoglobin measurement <10g/dl within 3 months of chemotherapy) were excluded. We also excluded patients who received a transfusion within 2 weeks or radiation within 4 months prior to chemotherapy initiation, or who had bone marrow transplantation within 12 months prior to chemotherapy or during chemotherapy. All clinical data were collected from the health plan’s electronic medical records. Anemia was classified as grade 1: 10 g/dL to lower limit of normal (14 g/dL for men and <12 g/dL for women) ; grade 2: 8.0-9.9 g/dL; grade 3: 6.5-7.9 g/dL; and grade 4: <6.5 g/dL. The type of anemia was determined based on mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH). Incidence proportions of patients developing CIA and 95% confidence intervals were calculated overall and by CIA severity and type, as well as by stage at cancer diagnosis, and by chemotherapy regimen and cycle.Results: A total of 4426 patients who received chemotherapy were included. The mean age was 59.3 years. Across cancers, 3962 (89.5%) patients developed anemia during the course of chemotherapy (58% grade 1, 34% grade 2, 8% grade 3 and <1% grade 4; normocytic 85%, macrocytic 10%, microcytic 5%; normochromic 47%, hyperchromic 44%, hypochromic 9%; Table 1). The incidence proportion of grade 2+ anemia ranged from 26.3% in colorectal cancer patients to 59.2% in ovarian cancer patients. The risk of grade 2+ anemia was greater in stage IV (49%), compared with 29% in stage I. The risk of severe anemia (grade 3+, Hb<8 g/dL) was highest in patients with ovarian cancer (16.9%), and lowest in patients with colorectal cancer (4%). The incidence of grade 2+ anemia during the course of chemotherapy varied from 18.2% in breast cancer patients treated with TC (CYCLOPHOSPHAMIDE|DOCETAXEL) regimen to 59.7% in patients with ovarian cancer receiving Carbo-Tax (carboplatin + paclitaxel) regimen (Figure 1).Conclusion: Our study suggested that the burden of anemia remained high in patients with solid tumors receiving chemotherapy. The risk of anemia is greater in patients with distant metastasis. The incidence of anemia varied significantly by chemotherapy regimens. [Display omitted] [Display omitted] DisclosuresXu:Amgen: Employment, Equity Ownership. Xu:Amgen Inc.: Research Funding. Page:Amgen Inc.: Employment, Equity Ownership. Sattayapiwat:Amgen Inc.: Research Funding. Rodriguez:Amgen Inc.: Research Funding. Chao:Amgen Inc.: Research Funding.

A Phase 1/2, Open-Label, Dose-Escalation, Multi-Center Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Orally Administered NS-018 in Patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (postPV MF), or Post-Essential Thrombocythemia Myelofibrosis (postET MF)

Background: NS-018 is an oral, selective, small molecule inhibitor of Janus kinase 2 (JAK2). Pre-clinically NS-018 inhibited JAK2 kinase with an IC50 value in the subnanomolar range and demonstrated splenomegaly reduction at low doses in a JAK2V617F-bearing mouse model (Blood Cancer J 2011; 1: e29.).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, postPV MF, or postET MF. Patients were ≥ 18 years, had ECOG PS ≤ 2 and required therapy but were not required to have splenomegaly in Phase 1. NS-018 was dosed orally daily (QD) or twice daily (BID) in 28-day cycles. Responses were assessed according to IWG consensus criteria, changes in spleen size by manual palpation and quality of life with the Myelofibrosis Symptom Assessment Form (MF-SAF). The Phase 1 portion of the study completed enrollment and is presented here.Results:Patients: 42 patients were enrolled across 10 cohorts. Patient characteristics: 33 PMF, 5 postPV MF, 4 postET MF; median age (range) 69 yrs (43-83); M/F:28/14; 31 JAK2V617F+, and 17 previously treated with a different JAK inhibitor.Dosing and tolerability: Dose levels included 75, 125, 200, 300 and 400 mg QD and 100, 200, 250, 300 and 400 mg BID. Systemic exposures based on Cmax were approximately dose proportional across the tested range from 75 to 400 mg.The recommended Phase 2 dose (RP2D) was 300 mg BID, based on drug-related neurological adverse events (AEs) at 400 mg BID including dizziness (Grade 2 or 3), dysphagia (Grade 2) or hypoesthesia (Grade 1) in one patient each that led to dose reduction or drug discontinuation.Study drug-related serious AEs (SAEs) included non-cardiac chest pain (Grade 2, 200 and 300 mg BID), lower GI hemorrhage (Grade 3, 300mg BID), paresthesia (Grade 3, 300mg BID), increased lipase (Grade 2, 300mg BID), and dizziness (Grade 3, 400 mg BID) in one patient each.For the 300 mg BID cohort (n=11), the most frequent drug-related AEs across all grades were nausea (Grade 1, 18%), decreased platelet count (≤ Grade 2, 18%), and dizziness (≤ Grade 2, 27%); Grade 3 related AEs included anemia, lower GI bleed, leukopenia, neutropenia or paresthesia (1 patient each, 9%); and no Grade 4 AEs.Overall, 22 patients (52%) discontinued treatment due to AEs (n=7), progressive disease (PD) (n=7), or MD/patient decision (n=8). The AEs leading to discontinuation included thrombocytopenia (Grade 4), transient ischemic attack (Grade 2), muscle contraction involuntary (Grade 2), light headedness (Grade 1), insomnia (Grade 1), hemolytic anemia (Grade 3), dizziness (Grade 2), dysphagia (Grade 2), and hypoesthesia (Grade 1). Nine patients had a hemoglobin decrease ≥ 2 g/dL and 8 patients a platelet decrease ≥ 50%.Responses: Of 33 evaluable patients with baseline splenomegaly ≥ 5 cm and treatment for ≥ 1 cycle, 16 (48%) patients showed ≥ 50% reduction in spleen size (confirmed for ≥ 8 weeks in 11 patients). In addition, 11 patients showed splenic clinical improvement (CI, for ≥ 8 weeks), 3 patients hemoglobin CI, and 2 patients platelet CI. Median (range) time to splenic response and duration of response: 1.5 cycle (1-12) and 4.5 cycles (1-29). Splenic reductions ≥50% are shown in the Table for the specified patient groups. Changes in MF-SAF and PK and PD results will be presented.TableSplenic reduction(in evaluable patients)All doses16/33 (48%)300mg BID3/6 (50%)300mg QD4/7 (57%)Prior different JAK inhibitor treated8/16 (50%)Conclusions: The dose of NS-018 determined to be the RP2D in Phase 1 was 300 mg BID. This dose provided a durable dosing schedule with an acceptable safety profile, and was associated with splenic size reduction and clinical improvements. The Phase 2 portion of the study is ongoing and includes only patients previously treated with a different JAK inhibitor. DisclosuresVerstovsek:NS Pharma, Inc: Research Funding. Talpaz:Ariad, BMS, Sanofi, Pfizer, Incyte: Research Funding. Ritchie:Celgene, Incyte: Speakers Bureau. Odenike:Suneisis Pharmaceuticals, Incyte, Sanofi-Aventis, Algeta Pharmaceuticals, Spectrum Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Jamieson:Roche, Johnson&Johnson, CTI: Research Funding. Stein:Incyte Corporation: Honoraria, Speakers Bureau; Sanofi Oncology: Honoraria. Tomonori:NS Pharma, Inc.: Employment. Mesa:Incyte, CTI, NS Pharma, Inc., Gilead, Celgene: Research Funding.

First Line BR in Chronic Lymphocytic Leukemia Patients: Interim Results of Russian Norma Trial

CLL is the disease of the elderly. Many CLL pts have high comorbidity burden, which makes them ineligible for intensive chemotherapy regimens like FCR. Recently, DCLLSG CLL10 trial proved comparable efficacy of BR and FCR regimens, but better tolerability of BR. It is thus conceivable that BR is a good treatment alternative for slow-go pts, particularly those with advanced chronic kidney disease.In February 2012 a Russian prospective multicenter observational non-interventional clinical study of BR use in previously untreated CLL pts in routine clinical practice was initiated (BEN-001, NORMA). There are no strict incl./excl. criteria in this study, facilitating unbiased analysis of efficacy and toxicity under real world conditions. Here we report our preliminary results.Materials and methodsBy the time of writing (30 Jun 2014) 123 pts have been included by 25 participating centers. 68 pts have completed therapy and another 28 have completed at least 3 cycles. 55 pts continue treatment. Median duration of observation is 13 mos.Patient characteristics are as follows: median age 59 years (39–79); M-to-F ratio 1.7:1; Binet stage (А/B/C) - 13%/68%/19%; CD38-pos. 30%; IGHV-UM/M ratio 2.1:1; FISH (del13q/del11q/del17p/tri12) - 46%/41%/8%/17%; mut. NOTCH1 - 7%. Also, two FISH abnormalities were detected in 23% pts, three in 2% and four in 1%. IGHV stereotypy was found in 18% of analyzed cases. Median ECOG status was 1 (1-3). Median CIRS score was 3 (0-11), 20% pts had CIRS ≥6. CKD (stage II/III-IV) was documented in 53%/27% pts, 43% pts had GFR <70 ml/min. Enlargement of abdominal lymph nodes was seen in 52% pts.Rituximab and bendamustine were given in standard doses of 375/500 mg/m2 and 90 mg/m2 respectively. As per IWCLL recommendations remissions were confirmed by CT and BM MRD evaluation was done after 3 cycles and at least 2 mos after the last therapy cycle. MRD was evaluated by flow cytometry according to ERIC protocol. Data was entered to eCRF by investigators and centrally analyzed.ResultsData on response after 3 cycles is available for 79 pts. Of these 40.5% had CR and 53% had PR. Another 3 pts had progression and 1 ptn had SD. 14% of CRs were MRD-negative. All 4 refractory pts had del17p and IGHV-UM. Ptn with SD after 3 cycles developed progressive disease at final restaging.Of 68 pts who completed all 6 cycles data on response is currently available for 48 pts. Of these 42 (87.5%) had CR and 5 (10.4%) had PR. Among pts with confirmed CR 25 underwent MRD evaluation, giving 13 MRD-neg. and 12 MRD-pos. responses.MRD evaluation after 6 cycles of therapy was done in 33 pts. All MRD-negative pts (n=13) were in CR group, all of them having had MRD levels <10-2 after 3 cycles (4 pts had MRD-neg. already at that time). Among MRD-positive pts (n=20) 12 had CR and 8 had PR. Notably, all of them had MRD levels ≥10-2 (average 10-1) after 3 cycles. In general, the speed of tumor clone eradication, as measured by MRD level after 3 cycles of therapy, correlated well with further response to therapy (р=.0001). TableMRD levels<10-4≥10-4–< 10-2≥10-2After 3 cycles, N pts.4920After 6 cycles, N pts.13155There was no statistically significant difference in response rates among pts younger and older than 60 (р>.05), those with CIRS ≥6 and <6 (р>.05), those with early (A) and advanced (B+C) disease stages (р>.05); those with (GFR<70 ml/min) and without (GFR≥70 ml/min) meaningful renal dysfunction (р>.05).With regard to toxicity, only 4 cases of anemia grade II, 2 cases of thrombocytopenia grade II and 14 cases of neutropenia grade III-IV were reported. In addition there were 14 cases of infections with the need of systemic antibacterial or antiviral treatment, particularly one case of HBV reactivation. Mild to moderate skin reactions were seen in 7 pts. Two pts had grade II hepatotoxicity.ConclusionsOur preliminary results show outstanding clinical efficacy of BR regimen in 1st line treatment of CLL as the majority of our pts completed therapy with CR. Notably, response rates were not inferior in pts with advanced age, disease stage or high comorbidity burden. All refractory pts had known adverse biological factors like del17p and IGHV-UM haplotype. Reported toxicity was very low. Particularly, pts with renal dysfunction tolerated therapy equally well. One important consideration for the future is that MRD level <10-2 as early as after 3 treatment cycles is a robust predictor for MRD negativity after completion of therapy.ClinicalTrials.gov id NCT02110394 DisclosuresNo relevant conflicts of interest to declare.

Occult Iron Deficiency Might be an Important Factor in MPN Patients with Myeloproliferative Neoplasms (MPN) Treated with Ruxolitinib. a Single Centre Experience

Myelofibrosis (MF) is manifested as primary myelofibrosis or post-essential thrombocythemia myelofibrosis (PET-MF), or post-polycythemia vera myelofibrosis (PPVMF). The JAK2 V617F a gain of function somatic mutation is present in approximately 50% of patients (pts) with MF. This and related mutations result in an exaggerated JAK2 signaling and they are the mechanistic cause of Ph(-) myeloproliferative neoplasms (MPN). Ruxolitinib, an oral JAK inhibitor was approved by FDA and EMEA as treatment of myelofibrosis in 201. Clinical trials have demonstrated its effectiveness and that the response rate its independent of the JAK2 mutation status or MPN subtype, , being anemia and thrombocytopenia the most common adverse events that rarely lead to drug discontinuation. In phase I/II clinical trials, in pts who were transfusion independent at baseline, new onset anemia occurred in 23% and was dose dependent, up to 20% of patients required transfusions at higher doses. It was not reported whether any specific MF subtype developed more severe anemia. Hematological toxicity in the placebo-controlled COMFORT-I study revealed grade 3 or 4 anemia in 34.2% and 11.0% of those treated with ruxolitinib and only in 15.9% and 3.3% of placebo-treated patients. The frequency of severe anemia grades 3 and 4 was higher if the initial hemoglobin (Hb) was under 10g/dl. The anemia can be managed effectively with dose modifications, temporary treatment interruptions, as well as red blood cell transfusions and/or erithropoyetin administration Aim: To describe hematological toxicity management on MF pts treated with ruxolitinib Methods: Descriptive, retrospective analysis addressing the anemia safety profile of five MF patients (WHO criteria) treated with ruxolitinib with a median age of 68.2 years. One patient had PMF, 3 had PPV-MF and 1 had PET-MF. One of them required transfusion support, and two of them who had documented iron deficiency, were treated with iron supplementation with marked improvement (Table 1) without requiring dose reduction. Abstract 5564. TableGenderAgeDiagnosisDate of DxDate start TxDose start TxBaseline Hb (gr/dL)Anemia (&gt; 2 gr/dL)Time of tx until anemiaIron SupplementationTransfusion supportAnemia OutcomeFemale79PPV MF04-feb-0522-nov-1220 mg/BID14.4Yes8 weeksYesNoImprovedFemale49PET MF01-Dec-9815-Jan-1320 mg/BID16.6YesYesNoImprovedFemale79PPV-MF07-mar-9613-may-1320 mg/BID14.4NoN/AN/AN/AN/AFemale85PPV-MF01-abr-0902-sep-1315 mg/BID13.3NoN/ANoN/AN/AMale79PMF04-jul-1312-ago-1310 mg/BID8.5Yes16 weeksYesYesImproved Conclusion: Use of ruxolitinib in clinical practice requires careful monitoring of anemia, which is a common side effect that might require dose reduction or hematological support with blood transfusions and erithropoyetin. As PPVMF patients are frequently iron deficient we postulate that the identification and treatment of iron deficiency in patients with secondary myelofibrosis is an important issue as it may ameliorate the anemia, avoiding transfusions, Ruxolitinib discontinuation and therefore improving the treatment outcome. This very provocative observation warrants further investigations addressing this issue. Disclosures No relevant conflicts of interest to declare.

Ibrutinib, Single Agent or in Combination with Dexamethasone, in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma (MM): Preliminary Phase 2 Results

Introduction: Multiple myeloma (MM) remains an incurable disease in need of new therapies with unique targets. Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase (BTK), an essential enzyme in the B-cell receptor signaling pathway. While BTK is essential for the development and function of B cells and is down-regulated in plasma cells, the expression of BTK in malignant plasma cells is increased 4-fold and comparable to BTK expression levels in chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). In addition, pre-clinical models show that BTK inhibition with ibrutinib led to direct inhibition of both osteoclast bone resorption and the release of osteoclast-derived tumor growth factors (Tai et al, Blood 2012). Taken together these data suggest that ibrutinib may have a role in the treatment of MM.Methods: This open label phase 2 dose escalation study was designed to enroll patients in 4 cohorts (Figure) to evaluate efficacy (≥MR) and secondary endpoints of safety, PK, ORR and DOR. Patients must have had documented non-responsive/progressive disease at the time of study entry following at least 2 prior lines of therapy including at least one immunomodulatory agent. Efficacy and safety were assessed at 4 weeks intervals using the IMWG response criteria for efficacy assessments (Rajkumar et al, Blood 2011), while safety was assessed according to CTCAE v4.0 criteria.Results: As of 15 May 2014 and a median follow up of 15.2 months, 69 patients with a median age of 64 years (range 43-81) were dosed, of which 20% had either a del 17p or p53 deletion. The number of median prior therapies was 4 (range, 2-14), 41% had ≥ 5 prior therapies and 80% had undergone autologous stem cell transplant. Sixty-two percent of patients were refractory to their last line of therapy and of the 65 patients that had received prior therapy with both an immunomodulatory agent and a proteasome inhibitor, 44% were refractory to both.Anti-tumor activity was noted across all cohorts. The highest activity with a clinical benefit rate (CBR) of 25% including 1 PR, 4 MR and 5 sustained (>4 cycles) SD was observed in Cohort 4. (Table) This led to expansion of Cohort 4 per protocol design. In Cohorts 1 and 3, 14 patients had dex added following PD, resulting in 1 PR and 9 SD.Overall, 57% experienced a Grade 3 or higher adverse event. The most commonly reported non-hematologic toxicities (any grade) were diarrhea (51%), fatigue (41%), nausea (35%), dizziness (25%), and muscle spasms (23%). The majority were Grade 1 and 2. Myelosuppression had a reported overall incidence of any grade anemia (29%), thrombocytopenia (23%), and neutropenia (7%) with 16%, 9% and 4% being Grade 3, respectively. There were no clinically meaningful differences among dose levels. Twenty-three patients experienced a SAE for a total of 47 reported events with 16 assessed as possibly/definitely related to ibrutinib per investigator. At least one dose modification occurred in 22% of patients, with 6 discontinuing due to an adverse event.At the time of the data cut-off 7 patients remain on study treatment. The most common reason for treatment discontinuation was PD in 47% of patients, with additional patients discontinuing due to investigator discretion (18%), patient decision (7%) and non-compliance (3%).Conclusions: In this heavily pre-treated patient population ibrutinib, as a single agent and in combination with dex, demonstrated evidence of anti-tumor activity. There was a trend toward improved efficacy (≥MR) in Cohort 4 and treatment was well tolerated with manageable toxicities. Ongoing correlative studies are being conducted to determine changes in cytokines, chemokines and indices of bone metabolism and to determine the effect of dex, a known CYP3A4/5 inducer, on the pharmacokinetic profile of ibrutinib. In addition, ibrutinib is currently being evaluated in combination with carfilzomib in an ongoing Phase1/2b study. (NCT01962792) [Display omitted] TableConfirmed Response by Assigned TreatmentCohortResponse, n (%)1 (n=13)2 (n=18)3 (n=18)4 (n=20)PR11-1MR1--4SD ≥ 4 cycles2465SD < 4 cycles5641PD4575Not evaluable-214Not evaluable – no post-baseline assessments [Display omitted] DisclosuresOff Label Use: Discussion of efficacy and safety data with ibrutinib as single-agent and in combination with dexamethasone in patients with relapsed and relapsed/refractory multiple myeloma treated in a phase 2 clinical trial. Huff:Celgene, Millenium: Consultancy. Bensinger:Pharmacyclics, Novartis, Celgene, Millenium, Sanofi, Acetylon: Consultancy, Research Funding. Siegel:Celgene, Millennium, Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Jagannath:Celgene, BMS, Jansen, Sanofi-Aventis: Honoraria. Lebovic:Onyx, Celgene: Speakers Bureau. Anderson:Celgene, Millenium, Onyx, : Speakers Bureau. Elias:Pharmacyclics, Inc.: Employment. Clow:Pharmacyclics, Inc.: Employment. Fardis:Pharmacyclics: Employment. Graef:Pharmacyclics: Employment. Bilotti:Pharmacyclics: Employment. Richardson:Celgene, Millennium, Johnson&Johnson: Membership on an entity’s Board of Directors or advisory committees.

Tratamiento con cloramfenicol de casos de bartonellosis aguda (enfermedad de Carrión) en período de inicio

Cuatro pacientes atacados de Bartonellosis aguda (Fiebre grave de Carrión), en su período de inicio (fiebre ligera anemia y escasas formas bacilares de la Bartonella bacilliformis) fueron tratados con Cloramfenicol. El Cloramfenicol se mostró eficaz en todos los casos. La fiebre cayó entre 24 y 48 horas; las bartonellas desaparecieron entre 24 y 48 horas. Como el tratamiento ha sido llevado a cabo en período de inicio de la enfermedad los resultados obtenidos tienen gran valor demostrativo; no ocurrió la anemia grave que usualmente se produce en casos no tratados. Se produjo recaidas en un caso; élla fue tratado con éxito con el mismo antibiótico. La eficacia del Cloramfenicol contra la Bartonella bacilliformis y contra las bacterias del género Salmonella, los cuales frecuentemente producen graves infecciones secundarias, muy a menudo de curso fatal, hacen del Cloramfenicol el mejor antibiótico para el tratamiento de la Bartonellosis aguda.

Erythropoietin treatment in patients with myelodysplastic syndromes and type 2 diabetes.

The aim of the present study was to assess the role of a concomitant type 2 diabetes as a potentially negative factor in the management of low-risk myelodysplastic syndrome (MDS) patients treated with high-dose (40,000 UI s.c. 2 times/week) recombinant human erythropoietin (EPO) alpha (rHuEPO alpha). One hundred and forty patients (M/F 69/71, median age 76, interquartile range [IR] 68-81) were included in the analysis: 27/140 (19.2%) had a concomitant type 2 diabetes. No difference was reported between patients with and without diabetes as to the grade of anemia, the EPO endogenous levels and the need for transfusional requirement at baseline. Erythroid response was achieved in 79/140 patients (56.4%): factors associated with response were lower EPO levels (P < 0.0001), higher baseline Hb levels (P < 0.0001) and transfusion independence (P < 0.0001). Diabetes was not predictive of response: 17/27 (62.9%) patients with diabetes were responsive to high-dose EPO compared with 62/113 (54.8%) patients without diabetes (P = 0.446). This was confirmed in multivariate analysis, controlling for the effects of Hb levels, transfusion-dependence and serum EPO levels. No difference was observed in relapse rate, response duration and OS between patients with and without diabetes. Concomitant type 2 diabetes was not a major concern in the management of MDS patients.

Life threatening fulminant peritonitis following spontaneous mid-trimester abortion

An un-booked, thirty year second gravida from lower socioeconomic class, labourer by occupation ,residing in rural area was admitted with history of spontaneous abortion at 24 weeks of gestation at home. It was attended by untrained person .Patient developed distension of abdomen, breathlessness and high grade fever following day of abortion.. On examination, her general condition was poor. She had severe anaemia, tachycardia ,tachypnoea and high grade fever. She was ill-nourished with BMI of 16.Her abdomen was grossly distended up to xiphi-sternum giving rise to cardio-respiratory embarrassment. The abdomen was tense with cystic feel suggestive of either gross ascitis or a big ovarian cyst of 32 weeks size pregnant uterus. Patient underwent exploratory laparotomy with the provisional diagnosis of peritonitis or ruptured ovarian tumour. Laparotomy revealed four to five litres of thin watery, extremely foul smelling, purulent fluid in the abdominal cavity.There was no bowel injury. After through peritoneal lavage and after keeping peritoneal drain, abdomen was closed with tension sutures. Patient received fourth generation higher antibiotics, blood transfusions , intravenous albumin. Post operative period was relatively smooth. Patient went home after twelve days of admission.The case is presented because of its rarity in regards to primary aetiology ie spontaneous abortion, severity of sepsis, short duration of symptoms , clinical and radiological diagnostic dilemma and successful team efforts that saved the life.

Intermediate Results of Treatment of Primary Mediastinal Large В-Cell Lymphoma with Da-Epoch-R Regimen

ABSTRACT Aim: To estimate efficacy and toxicity of R-DA-EPOCH regimen in patients with primary mediastinal (thymic) large B-cell lymphoma (PMBL). Methods: The studied group included 22 patients with newly diagnosed PMBL. Median age was 34 years, 16 were females (72,8%) and 6 were mails (27,2%). Primary and post treatment assessment of disease included PET/CT or CT of neck, chest, abdomen and pelvic. In 61,5% of patient was early stage (І-ІІ) of disease, 93,3% of patients had greatest size of the tumor mass in mediastinum more than 10 cm. The tumor pleurisy, pericarditis and lungs lesions were revealed in 46,5%, 52% and 30,7%, respectively. All patients received 6 cycles of R-DA-EPOCH regimen. Patients who achieved complete metabolic response received mediastinal radiation therapy (30 Gy) or were under observation. Results: Response assessment performed after the completion of 6th cycles of chemotherapy. 19 patients have already completed treatment plan. 2 patients were exclude from study due to diseases progression (one of them had CNS lesion after 3rd cycle of chemotherapy, second patient had rapid increase of mediastinal mass after 6 cycle). Overall response rate was 89,4%. Complete response was achieved in 14 patients (73,6%). PET/CT was performed in 16 patients. Complete morphologic regression but with residual metabolic activity of residual mass was revealed in 5 patients (31,3%). Treatment was associated with moderate hematological toxicity: anemia grade 4 observed in one case (5,2%), febrile neutropenia requiring hospitalization in 2 patients (10,5%), and one of them had infection associated with venous port. Thrombocytopenia grade 3-4 was not observed. All detected cases of non-hematological toxicity were grade 1 or 2. Diarrhea, nausea, stomatitis, neuropathy were observed in 5,2%, 10,5%, 36,8% and in 31,6% of cases, respectively. Conclusions: Our results indicate that R-DA-EPOCH has a high cure rate in patients with PMBL, which allows to achieve good response in 89,4% cases. Such treatment associated with moderate hematological and non-hematological toxicity. Further continuation of study is needed to estimate and analyze long-term results of therapy. Disclosure: All authors have declared no conflicts of interest.

A Phase II evaluation of ixabepilone (IND #59699, NSC #710428) in the treatment of recurrent or persistent leiomyosarcoma of the uterus: An NRG Oncology/Gynecologic Oncology Group Study

ObjectiveThe combination of gemcitabine and docetaxel is the standard first-line therapy for recurrent or metastatic uterine leiomyosarcoma. There is no standard second-line therapy. Ixabepilone is a semi-synthetic analog of epothilone B that binds to the same site on beta tubulin as paclitaxel and may be a more potent polymerizer of tubulin. We sought to determine the activity of ixabepilone as a single agent as second-line treatment for patients with metastatic uterine leiomyosarcoma who had received taxane based therapy. MethodsEligible women with unresectable uterine leiomyosarcoma progressing after prior cytotoxic therapy containing a taxane were treated with ixabepilone 40mg/m2 on day one of a 21day cycle. Patients with prior pelvic radiation were treated without dose reduction. Response Evaluation Criteria in Solid Tumors (RECIST) response was assessed by computed tomography (CT). ResultsTwenty-three of 26 women were evaluable (two wrong histology, one never treated) with two of 23 receiving 1cycle of therapy. There were no complete or partial responses. Stable disease (SD) was seen in four patients (17.4%, median 3.4months). Seventeen patients (73.9%) had increasing disease (PD) and two patients were inevaluable per RECIST. One patient had SD over 6cycles of treatment. Median PFS for all 23 patients was 1.4months and overall survival was 7.0months. The predominant grade 3 or 4 toxicity was uncomplicated myelosuppression: neutropenia grade 3 (13%), grade 4 (17%), and anemia grade 3 (22%). ConclusionIxabepilone as a single agent is not an active second-line therapy for uterine leiomyosarcoma previously treated with a taxane.

A phase II open-label randomized multicenter trial of TSU-68 in combination with S-1 and oxaliplatin versus S-1 in combination with oxaliplatin in patients with metastatic colorectal cancer

Colorectal cancer (CRC) is the fourth leading cause of cancer-related deaths worldwide. The combination of oxaliplatin-based treatments (oxaliplatin plus infusional 5-fluorouracil and leucovorin [FOLFOX] or oxaliplatin plus capecitabine [CapeOX]) and bevacizumab is a standard chemotherapy regimen for metastatic CRC (mCRC). However, several clinical studies that tested S-1 plus oxaliplatin (SOX) indicate that SOX is also a treatment option for mCRC. TSU-68 is an oral compound that inhibits vascular endothelial growth factor receptor and platelet-derived growth factor receptor. The recommended dose of TSU-68 + SOX was previously determined in a phase I study of mCRC patients. The goal of this trial was to evaluate the efficacy of TSU-68 in combination with SOX. This open-label multicenter randomized phase II trial was performed in Korea. Treatment-naive mCRC patients with a performance status of 0 or 1 were randomized in a 1:1 ratio to receive either TSU-68 + SOX or SOX alone. The primary endpoint was progression-free survival (PFS). A total of 105 patients (TSU-68 + SOX, 52 patients; SOX alone, 53 patients) were randomized. The median PFS was 7.0 months in the TSU-68 + SOX group (hazard ratio [HR], 1.057) and 7.2 months in the SOX group (p = 0.8401). The most frequent grade 3 and 4 adverse events were thrombocytopenia (9.6 % [TSU-68 + SOX] vs. 26.4 % [SOX]), neutropenia (13.5 % [TSU-68 + SOX] vs. 15.1 % [SOX]), and anemia (3.8 % [TSU-68 + SOX] vs. 13.2 % [SOX]). We observed a difference between the 2 groups for all grades of anemia (15.4 % [TSU-68 + SOX] vs. 32.1 % [SOX]), diarrhea (30.8 % [TSU-68 + SOX] vs. 47.2 % [SOX]), vomiting (50.0 % [TSU-68 + SOX] vs. 26.4 % [SOX]), and chromaturia (23.1 % [TSU-68 + SOX] vs. 0.0 % [SOX]). Analysis using a Cox proportional hazard model showed that baseline interleukin 6 (IL-6) levels were associated with a survival benefit of TSU-68 (p = 0.012). TSU-68 + SOX had a favorable safety profile. However, TSU-68 did not have a synergistic effect on the efficacy of SOX. The baseline serum IL-6 level could be a prognostic factor for TSU-68 efficacy.

DIFFERENCES OF TUMOR MASSES AND HEMOGLOBIN LEVELS IN CERVICAL CANCER SQUAMOUS CELL TYPE PATIENTS TREATED WITH COMBINATION OF PACLITAXEL AND CARBOPLATIN CHEMOTHERAPY

Background: Paclitaxel and carboplatin are standard operating procedure for chemotherapy treatment of cervical cancer squamous cell carcinoma at Sanglah General Hospital, Bali-Indonesia. Chemotherapy improves outcome of cancer treatment. However, chemotherapy brings also a variety of adverse effects and complications. This study aims to evaluate the therapeutic and adverse effects of chemotherapy in patients with squamous cell cervical cancer. Methods: This is a case study of six patients with cervical cancer underwent chemotherapy paclitaxel and carboplatin 3-series at Sanglah General Hospital, Bali-Indonesia during January to November 2013. The therapeutic effect of chemotherapy was assessed from cervical cancer tumor mass measured before and after chemotherapy 3-series. The adverse effect of chemotherapy was determined from hemoglobin levels measured before and after chemotherapy. Data were analyzed using a paired t-test with a level of confidence of 95% using the SPSS to find out the differences. Results : In this study we found that there is a difference between tumor mass pre and post 3 series chemotherapy within p < 0.05. In term of toxic effect, we also obtained that there were difference of hemoglobin between pre and post of treatment within p < 0.05. Conclusion : Paclitaxel carboplatin as a chemotherapy drug in patients with cervical cancer is highly recomended when seen from the effects of reduced tumor size, and has a low side effect of anemia (anemia grade 1).

Variation of adverse drug reaction profile of platinum-based chemotherapy with body mass index in patients with solid tumors: an observational study.

Objectives:Toxicity of cancer chemotherapy may be affected by nutritional status of patients which is reflected in the body mass index (BMI). We sought to assess whether the adverse drug reaction (ADR) profile of platinum-based chemotherapy varies with BMI status.Materials and Methods:Adult patients of either sex, suffering from a solid tumor (lung, head and neck, ovary, gall bladder, stomach, colon) and started on platinum-based chemotherapy as initial treatment were included. BMI at chemotherapy commencement was obtained from medical records. Events were recorded and graded as per Eastern Co-operative Oncology Group Common Toxicity Criteria-patients’ complaints; clinically evident signs and laboratory reports were considered. Frequencies of individual adverse events were compared between low BMI (<18.5 kg/m2) and satisfactory BMI groups. Similar comparisons were done for events with grades 2 or 3 severities.Results:A total of 50 patients were observed over a 3-month period of whom 17 (34%) belonged to the low BMI group. Nausea, vomiting, diarrhea, stomatitis, anemia, alopecia, tinnitus and paresthesia were the commonly observed ADRs. The frequencies of anemia (P = 0.152) and vomiting (P = 0.140) and severity of grades of nausea (P = 0.066), anemia (P = 0.120) and paresthesia (P = 0.128) showed a higher trend in the low BMI group though differences were not statistically significant. The frequencies of tinnitus (P = 0.021) and paresthesia overall (P = 0.036) were significantly higher in the low BMI group.Conclusion:ADR profile of primary platinum-based chemotherapy appears to be partly influenced by BMI. This suggests the importance of maintaining adequate nutrition in patients and the need for greater vigilance in those with low BMI.