Patients Required Platelet Transfusions Research Articles

Romiplostim for the management of perioperative thrombocytopenia.

Thrombocytopenic patients requiring invasive surgery have few options to improve their platelet count preoperatively. This is a single-centre, retrospective review of thrombocytopenic patients receiving the thrombopoietin receptor agonist romiplostim perioperatively to allow for surgical interventions. Patient characteristics, romiplostim use, and surgical and safety outcomes (bleeding, thrombosis, transfusions) were collected and analysed. Forty-seven patients underwent 51 surgical procedures (ranging from total hip arthroplasty to open cardiac surgery) with romiplostim support. Thrombocytopenia aetiologies included immune thrombocytopenia, chronic liver disease, haematological malignancy, drug-related thrombocytopenia, and hereditary thrombocytopenia. Median (range) platelet counts improved, from 47×109 /l (9-120×109 /l) at romiplostim initiation to 164×109 /l (28-603×109 /l) at the time of surgery (P<0·0001). A dose of 3μg/kg per week for 2 doses increased the platelet count to >100×109 /l in 79% of patients within 14days. In 96% of cases, surgery proceeded on schedule without delay or cancellation. Four patients had bleeding events unrelated to thrombocytopenia and 1 patient developed deep venous thrombosis. Six patients required red cell transfusion and 3 patients required platelet transfusion perioperatively. In conclusion, romiplostim was effective in increasing platelet counts to allow surgery to proceed safely and on schedule. Bleeding and thromboembolic events were within acceptable limits for this surgical population.

Dengue fever during pregnancy.

ABSTRACTDengue fever during pregnancy is an expanding issue in Southeast Asia; however, the knowledge of adverse effects on mothers and neonates remains limited. Therefore, we aimed to determine the impact of dengue fever. The clinical information of 20 patients of dengue fever during pregnancy in Vietnam from January 1, 2015 to December 31, 2015 was collected and their outcomes were retrospectively investigated. A total of 18 patients (90%) presented with positivity of nonstructural protein 1, and a primary infection. Additionally, 4 patients (20%) had preterm deliveries and 1 (5%) had a stillborn child. All live-born neonates were discharged from the hospital uneventfully. Also, 6 patients (30%) required platelet transfusion and 3 of them received transfusion before delivery, but there were no maternal death. In addition, 3 cases of patients (15%) developed to postpartum hemorrhage (PPH), and their platelet concentrations were significantly lower than those of patients without PPH [90.0 (19.0 – 374.0) × 103 vs. 40.0 (12.0 – 57.0) × 103 cell/μl, p = 0.001]. In addition, patients with PPH also presented with elevated liver enzymes. Pregnant patients with low platelet counts should be recognized as being at high risk for PPH.

Romiplostim for Treatment and Prevention of Chemotherapy-Associated Thrombocytopenia

Introduction Romiplostim is a fusion protein agonist of the thrombopoietin receptor, approved by the US FDA for the treatment of immune thrombocytopenia (ITP) after failure of glucocorticoid therapy. This agent has been examined in other settings, including its use in the management of the thrombocytopenic surgical patient (Marshall et al., Transfusion 2015) and its use for the treatment of refractory aplastic anemia (Gill et al., Br J Haematol 2016). Thrombocytopenia is a complication of chemotherapy in cancer patients that may lead to treatment delays, dose reductions, and discontinuation of therapy (Kuter DJ, Oncology 2015). This study is a retrospective, single-center review of cancer patients who either developed thrombocytopenia as a result of chemotherapy or who had an underlying pre-existing thrombocytopenic disorder (such as ITP or chronic liver disease) who were supported with romiplostim during all or part of their chemotherapy. Methods We performed a retrospective review of patients with solid tumor malignancies who received at least two sequential weekly doses of romiplostim concurrently with chemotherapy. We collected patient demographics, dates and doses of romiplostim administration with corresponding platelet (Plt) counts, and outcomes of therapy, including ability of the treating oncologist to administer chemotherapy before initiating and during use of romiplostim as measured by number of treatment cycles administered, number and duration of delays in therapy, and number and extent of clinically necessary dose reductions. Results Review of pharmaceutical dispensation records from at our institution from January 1, 2010 through April 1, 2016 revealed 19 patients concurrently treated with romiplostim and chemotherapy, with 15 meeting our inclusion criteria (Table 1). At initiation of romiplostim, 40% of patients had a Plt count ≥75 x 109/L and 26.7% of patients had a Plt count ≥100 x 109/L, with a median Plt count of 72 x 109/L (range, 21-145 x 109/L). Patients were treated with weekly injections of romiplostim, with platelet count measured at the time of drug administration; the most common starting dose was 3 mcg/kg. The average duration of romiplostim therapy required to achieve a platelet count ≥75 x 109/L was 13.6 days, and the average time to achieve a platelet count ≥100 x 109/L was 21.1 days. During treatment with romiplostim, 85.3% and 73.2% of all platelet counts measured were ≥75 x 109/L and ≥100 x 109/L, respectively (Figure 1). All patients were able to receive two or more cycles (range, 2-18) of chemotherapy while on romiplostim. Twelve patients (80%) had delays in receiving antineoplastic therapy attributed to thrombocytopenia prior to initiation of romiplostim, with an average per-patient cumulative delay time of 4.7 weeks; 5 patients (33.3%) concurrently treated with romiplostim and chemotherapy had such delays (p=0.010 by Pearson's chi-squared test), with an average per-patient cumulative delay time of 1 week. Eleven patients (73.3%) required at least 1 dose-reduction in chemotherapy attributed to thrombocytopenia prior to initiation of romiplostim; 4 patients (26.7%) required at least 1 such dose-reduction while receiving romiplostim (p=0.011 by Pearson's chi-squared test). Three patients required platelet transfusion and 10 patients required red blood cell (RBC) transfusion while receiving romiplostim, though 8 of the patients received RBC transfusions only for chemotherapy-associated anemia or fatigue. While receiving romiplostim, no patient suffered a thrombotic event, and 3 patients suffered from bleeding (1 patient developed grade 1 mucosal bleeding and 2 patients developed grade 3 gastrointestinal bleeding). Conclusion In patients with solid tumor malignancies with chemotherapy-associated thrombocytopenia or who have co-existing thrombocytopenic disorders (such as ITP or chronic liver disease), this study provides evidence that romiplostim is safe and increases the platelet count sufficiently in a majority of patients to allow subsequent chemotherapy to be given at full dose and on schedule. Table 1 Patient Characteristics. Table 1. Patient Characteristics. Fgure 1 Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Fgure 1. Platelet Count Over Time. The dotted lines represent the platelet count trend of individual patients. The solid black line represents the platelet count trend of the study population (platelet counts averaged together over seven-day intervals). Disclosures Kuter: Protalex: Research Funding; ONO: Consultancy; Pfizer: Consultancy; 3SBios: Consultancy; Eisai: Consultancy; GlaxoSmithKline: Consultancy; Bristol-Myers Squibb: Research Funding; Genzyme: Consultancy; Shire: Consultancy; Amgen: Consultancy, Paid expert testimony; Shionogi: Consultancy; Rigel: Consultancy, Research Funding; Syntimmune: Consultancy; MedImmune: Consultancy; CRICO: Other: Paid expert testimony.

Clinical profile of dengue infection in pregnancy – A hospital-based study

Abstract Background Dengue is a major public health problem. The present study aimed to determine clinical profile of pregnant patients suffering from dengue. Methodology An observational study was conducted in the Obstetrics department of a tertiary care centre of Delhi, over 10 weeks (July to mid-September 2016). Pregnant patients suffering from dengue were included. Data was collected with basic demographic profile, historical details, investigations including platelet counts and maternal consequences. Results One hundred and twenty pregnant patients were admitted with fever, of which 25 (20.8%) had dengue. Eleven (44%) of these pregnant women were in 20–25 years age group, and 9 (36%) were in 25–30 years age group. Fever ( n = 22, 88%) and myalgia ( n = 20, 80%) were the most common presenting symptoms. Eighteen (72%) patients presented in third trimester. Thrombocytopenia was present in 60% cases. 12% dengue patients required platelet transfusion. 20% went into preterm labour and 8% had dengue haemorrhagic fever. Conclusion Fever and myalgias are the most common presenting symptoms of dengue in pregnancy. Dengue fever in pregnancy most often is treated conservatively. Preterm labour is a common complication in patients presenting in third trimester. Prompt diagnosis of pregnant women with dengue infection is necessary for effective management and better feto-maternal outcome.

Coagulation profile changes and safety of epidural analgesia after hepatectomy: a retrospective study.

We aimed to review post-hepatectomy coagulation profile changes, to assess outcomes of epidural catheter placement in post-hepatectomy patients, and to make justifications regarding use of epidural analgesia in patients undergoing hepatectomy. We performed a retrospective study of 141 patients undergoing liver resection at Brigham and Women's Hospital between January 1, 2007 and December 31, 2011. All patients were between 21 and 85 years old, with ASA physical status classification of II or III, and Child-Pugh scores ≤6. Patients undergoing laparoscopy or resection of less than three hepatic segments were excluded. We examined pre-operative hematocrit, platelet count, coagulation studies, and liver function tests, and trended values for 7 post-operative days. We examined frequency of epidural placement, use of peri-operative anticoagulation, and incidence of epidural-related complications. We demonstrated statistically significant decreases in hematocrit and platelet counts, as well as statistically significant increases in prothrombin time and international normalized ratio (INR) values. Thirty-two percent of patients required vitamin K or fresh frozen plasma to achieve an INR ≤1.3. No patient required platelet transfusion to achieve platelets ≥100,000 prior to catheter removal. Changes in post-operative partial thromboplastin time were not significant. Epidural catheters were placed in 90% of liver resections performed at our institution. We noted no epidural hematomas, even in the 7% of patients in whom the epidural catheter was inadvertently removed before coagulation criteria were met. The latter group was monitored with hourly neurologic exams for 24 h. Epidural analgesia may be safely used in patients undergoing major hepatic resection, providing that they have normal pre-operative coagulation and catheters are removed only when resection-induced perioperative coagulopathy has resolved or has been corrected.

Changing profile of Plasmodium vivax malaria

Background: Malaria, endemic in India, tends to be a major contributor to morbidity and mortality globally. Of the various species, Plasmodium Falciparum is associated with serious prognosis,(morbidity and mortality) in a sizeable number of patients. Chloroquine resistance was an important clinical issue; the current issue is that of an apparently changing scenario with rising number of P.Vivax malaria cases, associated with severity of complications. The observational study is aimed to find out whether there is change in P.Vivax malaria features and how it influences management. Methods & Materials: An observational study conducted at a teaching hospital in centralmetropolitanMumbai, India during the monsoon months (June-October 2013). Febrile patients admitted from the medical outdoor and emergency service form the basis of this study. Patients with moderate to severe degree fever, with chills, localized and generalized body ache, varying degrees of weakness/fatigue and malaise/lethargy, vomiting suspected clinically to be suffering from malaria were tested by peripheral smear examination/malaria specific Antigen. Other investigations included total and differential count, liver function testsmainly Serum Bilirubin, Transaminases, renal function tests (Serum Creatinine). Haemodynamic Instability (hypotension), thrombocytopenia withmanifest bleeding, affected renal function singly and in combination were the differentiating criteria towards critical care. Results: A total of 41 cases (29M, 12 F) of malaria were diagnosed39 were P.vivax and 2 were mixed malaria. As many as 32 patients were found to be thrombocytopenic (platelet count <1.5 lakhs), the range being from 12,000 to 1.4 lakhs/cumm. Seven patients (17%) presented with hypotension and required ICU monitoring. 14 patients (34%) had deranged liver function test mostly in the form of transaminitis and 3 cases with renal insufficiency.3 patient presentedwith bleeding. 7 patients required platelet transfusion (4 units each of Random Donor Platelet transfusion) and 1 patient required platelet transfusion twice. Patients who tested positive for Dengue Antigen fared poorly. Fluctuating and decreasing platelet countwithout bleeding contributed to prolongation of hospital stay. Conclusion: P.falciparum has been considered malignant malaria, P.vivax malaria particularly with thrombocytopenia has increased in incidence and is not considered benign any longer.

Immature Platelet Fraction: Coming of Age of an Underutilized Test in the Setting of Thrombotic Thrombocytopenic Purpura

Copyright: © 2014 Maitta RW, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Circulating immature platelets, also known as the immature platelet fraction (IPF), is the term that defines much larger platelets that have been recently released from the bone marrow. IPF have a greater RNA content, are measured by automated hematology analyzers equipped with a reticulocyte detection channel, and are reported as percentage of the total platelet count (%-IPF) [1]. It is well accepted that a high %-IPF is usually found in either consumptive or recovering thrombocytopenic disorders [2], while a low %-IPF is characteristic of bone marrow suppression disorders [3]. However, little was known until recently about their biology compared to mature platelets. A recent report by our group indicates that immature platelets differ from mature ones in that they have a longer lifespan, may be able to continue expanding during storage and that this expansion is significantly reduced by irradiation [4]. The latter is of major importance since it indicates that immature platelets are biosynthetically active and opens the possibility to research further these blood elements for transfusion support of patients needing platelets. Indeed in young pediatric patients who have received stem cell transplantations, a recent study reported that transfusion of IPF-rich platelet units significantly reduced the overall number of platelet transfusions required by these children compared to those receiving IPF-poor units [5]. Considering the increased longevity and distinct biology of immature platelets, these preliminary findings suggest that larger randomized trials ought to be performed to address if the concentration of immature platelets in a platelet product can further benefit patients requiring platelet transfusions.

Use and Delivery of Blood Platelet to the National Blood Transfusion Center (NBTC) of Cote d’Ivoire

Objectives: To know the use of blood platelets and their delivery by the National Blood Transfusion Center of Cote d’Ivoire; describe the socio-demographic characteristics of patients receiving transfusion of blood platelets; specify the platelets order history(old or new command); to assess the delivery of platelets by the National blood Transfusion Center (NBTC) and then specify the group of patients requiring blood transfusion of platelets at the National blood Transfusion Center of Cote d’Ivoire. This was a descriptive cross-sectional study that concerned the period from 01 November to 30 November 2012. It was a comprehensive study that involved 36 controls platelet registered to the NBTC during the defined period. Of the 36 orders of platelets retained the age group 0-10 years was the most frequent with 33.3 % of cases. There were 63.9 % men and 32.6 % women. Pupils and students predominated with 30.5 % of cases. Most orders platelets came equally to Cocody Teaching Hospital and Yopougon Teaching Hospital with 30.5%. Services leading orders platelets were hematology services with 22.2% and pediatrics with 16, 6 %.In 33.3% of cases, patients requiring platelet transfusion lived in Yopougon. Among orders platelets, news represented 58.3 %. The delivery of blood platelets by the National Blood Transfusion Center was three days or more in most cases with 44.4 % and patients requiring platelet transfusion were in 38.9 % of cases of group O Rh positive. At the end of our study, we can remember that most orders platelets come from hematology and pediatrics services of CocodyTeachingHospital and YopougonTeachingHospital. These orders are made primarily of platelets for patients of group O Rh positive and issued by theNBTCwithin3 days or more in most cases.

Platelet function normalization after a prasugrel loading‐dose: time‐dependent effect of platelet supplementation

Hemostatic benefits of platelet transfusions in thienopyridine-treated acute coronary syndrome (ACS) patients may be compromised by residual metabolite in circulation. To estimate the earliest time after a prasugrel loading-dose when added platelets are no longer inhibited by prasugrel's active metabolite. Baseline platelet reactivity of healthy subjects (n=25, 30 ± 5 years, 68% male) on ASA 325 mg was tested using maximum platelet aggregation (MPA, ADP 20 μm) and VerifyNow(®) P2Y12 and was followed by a 60 mg prasugrel loading-dose. At 2, 6, 12 and 24 h post-dose, fresh concentrated platelets from untreated donors were added ex-vivo to subjects' blood, raising platelet counts by 0% (control), 40%, 60% and 80%. To estimate the earliest time when prasugrel's active metabolite's inhibitory effect on the added platelets ceases, platelet function in supplemented samples was compared across time-points to identify the time when effect of supplementation on platelet function stabilized (i.e. the increase in platelet reactivity was statistically similar to that at the next time-point). Supplemented samples showed concentration-dependent increases in platelet reactivity vs. respective controls by both MPA and VerifyNow(®) at all assessment time-points. For each supplementation level, platelet reactivity showed a sharp increase from 2 to 6 h but was stable (P=NS) between 6 and 12 h. The earliest measured time when supplemented platelets were not inhibited by circulating active metabolite of prasugrel was 6 h after a prasugrel loading-dose. These findings may have important implications for prasugrel-treated ACS patients requiring platelet transfusions during surgery.

Splenectomy for Massive Splenomegaly Associated with Myelofibrosis: Outcomes From 63 Patients At Mayo Clinic.

AbstractAbstract 2848 Background:Massive splenomegaly (MS) (>1500 grams) is a rare and overtly symptomatic manifestation of myelofibrosis. While splenectomy may provide palliation, the procedure may be technically difficult and lead to high operative risks. We retrospectively analyzed myelofibrosis patients who underwent splenectomy for MS to analyze complications and outcomes. Methods:Retrospective chart review of all patients with myelofibrosis at our institution who underwent splenectomy for MS between 1998 and 2006 was performed. MS was defined as post-operative spleen weight measured to be more than 1500 grams. A total of 63 patients with MS had splenectomy for palliation of pressure symptoms or transfusion requiring cytopenias during that time period. Kaplan Meier statistics and log rank test were used for survival analysis. Results:Mean age of the study patients was 64.9 ± 9.5 years and 56% of those were males. Commonest pre-splenectomy symptoms were left upper quadrant abdominal discomfort (85.7%), fatigue (81%), early satiety (76.2%), anorexia (54%) and weight loss (39.7%). Packed red blood cell and platelet transfusions were required pre-operatively in 36/63 (57.1%) and 10/63 (15.9%) of patients, respectively. Median spleen weight was 2805 (range 1540 – 13085) grams. Perioperative complications occurred in 15 patients (23.8%) including infection (= 4 patients [6.3 %]), thrombosis (= 6 patients [9.5%]), or bleeding (= 9 patients [14.3%]), 2 of which (3.2% of all patients) were fatal.Median post-splenectomy survival (PSS) of these patients was 16.4 (0–110) months and 5 year PSS was 20%. Excluding patients lost to follow up, 43/55 (78.2%), 33/55 (60%) and 26/54 (48.1%) patients were alive at 6 months, 1 year and 2 years after splenectomy, respectively. At 1 year, out of 33 alive patients, 24 (72.7%) patients had relief of pressure symptoms. Out of 36 patients who were red cell transfusion dependent pre-splenectomy, 13 were alive and 6/13 (46.2%) patients were transfusion independent at 1 year. Similarly, out for 10 patients requiring platelet transfusions pre-operatively, 5 were alive and 3/5 (60%) were transfusion independent after 1 year follow up.PSS after splenectomy for MS was decreased in patients that required pre-operative packed red cell transfusions (median 9.3 months vs. 32.1 months, p= 0.033) (Fig 1), but not affected by other factors including age (>64 years), pre-operative thrombocytopenia (<100 × 109/uL), prolonged operative time (>90 minutes) or larger spleen size (>2800 grams). Conclusions:Splenectomy is relatively safe and effective palliative treatment for pressure related symptoms and refractory cytopenias related to MS in patients with myelofibrosis. Pre-operative anemia requiring red cell transfusions may predict advanced disease and is associated with inferior PSS. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase II study of short CHOP-rituximab combination with early consolidation with ibritumomab-tiuxetan-Y90 (IT-Y90) in non-pretreated patients age 65 to 80 with CD20+ diffuse large B-cell lymphoma (DLBCL).

6633 Background: IT-Y90was approved in follicular lymphoma, and some data indicates that it could be used in DLBCL. It has been reported that early TEP-TDM negativity is associated with a longer survival in DLBCL, which suggest that these patients could benefit of a less intensive protocol. Methods: We conducted an international, open-label, phase II non-randomised study, in patients aged between 65 and 80 with age-adjusted (aa) IPI score of 0 and 1 and CD20+ DLBCL. The primary objective was to evaluate the efficacy of 3 cycles of RCHOP14 followed by, in case of complete response (CR), an injection of IT-Y90. Results: Thirty patients (M/F= 1) were included. Median age was 72.6 years (range 65 - 80). Patients had a stage III/IV, elevated LDH and IPI=1 in 38%, 16.6 and 57% respectively. 25 patients received the full treatment. Five obtained an uncomplete FDG-PET response and were excluded after 2 RCHOP cycles. 23 patients received the full IT-Y90 dosage (0.4mCi/Kg) and two received the attenuated dosage (0.3mCi/Kg). Mean treatment time was 54 days (median 52; min 48-max 69). The CR rate after RCHOP treatment was 85% [95% CI: 65-94]. No treatment-related deaths occurred. Grade III-IV neutropenia and thrombocytopenia was observed in 45% and 4%, respectively. Five patients experienced at least one febrile neutropenia. After IT-Y90, mean duration time for platelets &lt;50G/l was 2.08 weeks (median 2; min 0-max 5). Two patients required platelet transfusion. With a median follow-up of 29.5 months [95% CI: 23-39], the estimated 3-year PFS was 90% [95% CI: 80-100] and the 3-year OS was 100% [95% CI: 100-100]. Among patients treated with 90Y-IT, only 3 relapsed were recorded (at 6, 16 and 24 months). Conclusions: this study suggested the feasibility, and efficacy of a short regimen including one injection of IT-Y90for selected DLBCL in complete response after 3 cycles of RCHOP14. This results need to be confirmed by further studies.

5q-syndrome in Japan

5q-syndrome is a form of refractory anemia that occurs predominantly in females and is characterized by pronounced macrocytosis, frequent erythroblastopenia, absent or mild leukopenia, normal or elevated platelet counts, abnormal large monolobulate megakaryocytes with eccentric nuclei, typically normal bone marrow blast percentage, isolated deletion of the long arm of chromosome 5, rare progression to acute myeloid leukemia (AML), and prolonged survival [1]. Patients with 5q-syndrome are severely anemic, and show transfusion dependency at presentation; therefore, iron overload is an important prognostic factor for 5q-syndrome. 5q-syndrome patients demonstrate clear geographic, racial, ethnic, age, and gender variation in both incidence and mortality [2, 3]. 5q-syndrome is rare among Japanese MDS patients, and to our knowledge no study of Japanese 5q-syndrome patient series has been reported. To this end, we sought to characterize Japanese 5q-syndrome patients with, on the verge of the lenalidomide era in Japan, an emphasis on iron overload. Data from 21 5q-syndrome patients were obtained from a previous study [2]. Four patients were newly diagnosed, and were recruited into this study from the Japanese Cooperative Study Group for Intractable Bone Marrow Diseases. 5q-syndrome patients were assessed by (1) the international prognostic scoring system (IPSS), World Health Organization (WHO) classification-based prognostic scoring system (WPSS) [4, 5], and (2) degree of cytopenia, transfusion dependency, and iron overload. The median age of patients with 5q-syndrome was 67 years, and the male-to-female ratio was 11/14, which was in agreement with the well-known female predominance of 5q-syndrome. All cases had anemia, with median red blood cell count and hemoglobin level of 2.25 9 10/ll and 7.5 g/dl, respectively. Median neutrophil and platelet counts were 1624/ll and 25.2 9 10/ll, respectively. All cases were diagnosed as having refractory anemia (RA), according to the FAB classification. Thirteen patients were classified as low-risk, and 12 were classified as Int-1, following the IPSS scale. Eight patients were sorted to very low risk and 17 were classified as low-risk of WPSS classification. Seventeen patients (68%) required red blood cell transfusion more than once in the 8-week period, indicating transfusion dependency. In contrast, none of the patients required platelet transfusion. The degree of iron overload was estimated by serum ferritin concentration. Serum ferritin concentration at diagnosis ranged from 64.3 to 9114.5 ng/ml (median 252.7 ng/ml; Table 1). Additional data were obtained from 14 patients concerning maximum ferritin concentrations during their clinical courses, which ranged from 511 to 16470 ng/ml (median 1291 ng/ml; Table 1). UPN 1 and 14 showed ECG abnormality, heart failure and hepatic insufficiency. Five patients (20%) received iron chelating agents. UPN 1, 9, 14 and 18 died, and the causes of death were as follows: cardiac failure owing to hemochromatosis (UPN1 and UPN14), severe infection (UPN9) and neurogenic tumor (UPN18). None of the patients progressed to acute leukemia. On behalf of the Japanese Cooperative Study Group for Intractable Bone Marrow Diseases.

Infection-Related Transient Loss of Response and Other Early Side Effects in Chronic ITP during Treatment with Thrombopoietin Mimetics

Background: The new thrombopoietin mimetics (TM) romiplostim (Nplate®) and eltrombopag (Revolade®) have been demonstrated to increase platelet counts in the majority of patients with chronic autoimmune thrombocytopenia (ITP). Platelet counts in chronic ITP may fluctuate significantly due to infections, but it is unknown if this holds true in patients being treated with TM. Patients and Methods: 13 adult patients with refractory chronic ITP were treated with the new TM. 10 patients were only treated with eltrombopag, 2 were initially treated with eltrombopag and subsequently switched to romiplostim, and 1 patient was only treated with romiplostim. Results: Ten patients responded to eltrombopag, and 4 of these patients experienced a transient loss of response following infection. Two patients developed bleeding symptoms, with 1 of these patients requiring platelet transfusion. All 3 patients treated with romiplostim responded, and 1 of these patients experienced also a transient loss of response following infections. Conclusions: Patients receiving treatment with TM may experience adverse platelet count fluctuations during infections.

Transfusional requirements for escharectomy in burned children

Early excision has considerably improved outcome in extensive burns, but massive resections usually mean copious bleeding that must be conveniently corrected. The purpose of this study was to measure blood component use during escharectomies in children. All pediatric patients with acute burns excised at the Burn Unit of the Hospital Garrahan during one year were included. Volume of blood component used during and immediately after surgery was analyzed and related to percent excised, time post-burn, and the coexistence of infection and autograft at the time of excision. Ninety-four surgeries in 51 children aged 0-14 years with total burned body surface areas of 5-80% who underwent resections of 3-70% were studied. Total blood use (intra + post-operatively) was 2.07 ml/kg/%excised for red blood cells (60% during surgery) and 0.7 ml/kg/% excised for plasma. Only 12% of patients required platelet transfusion. There was no significant requirement variation with the existence of infection, grafting or time post-burn. Approximately 2 ml/kg/% excised of red blood cells (2/3 for surgery) and 1 ml/kg/% excised of plasma are needed for escharectomies in children. The need for platelets must be judged considering the individual patient.

Sequential Approach with Bortezomib as Induction Before Autologous Transplantation, Followed by Lenalidomide as Consolidation-Maintenance in Untreated Multiple Myeloma Patients.

Abstract 3419Poster Board III-307 BackgroundBortezomib induction before autologous stem cell transplantation (ASCT) has shown its efficacy in newly diagnosed multiple myeloma (MM) patients, both in association with dexamethasone alone (Harousseau JL, et al. Blood 110, 2007, abstr 450) and in combination with doxorubicin and dexamethasone (Popat R, et al. Br J Haematol 141:512-516, 2008). Lenalidomide, a less toxic and more potent thalidomide-derivative, lacks the neurotoxic effects of the parent drug and represents an optimal agent to include in maintenance regimens. AimsThese observations provided the rationale for investigating a sequential approach including bortezomib as induction and lenalidomide as consolidation-maintenance in MM patients undergoing ASCT. MethodsA hundred and two newly diagnosed patients aged 65–75 years were enrolled in 17 Italian centers. Induction (PAD) included four 21-day cycles of bortezomib (1.3 mg/m2 days 1,4,8,11), pegylated-liposomal-doxorubicin (30 mg/m2 day 4), and dexamethasone (40 mg/day: cycle 1, days 1–4, 8–11, 15–18; cycles 2–4, days 1–4). Autologous transplantation was tandem melphalan 100 mg/m2 (MEL100) followed by stem-cell support. After ASCT, patients received consolidation with four 28-day cycles of lenalidomide (25 mg/day days 1–21 every 28 days) plus prednisone (50 mg every other day) (LP), followed by maintenance (L) with lenalidomide alone (10 mg/day days 1–21 every 28 days) until relapse. Primary endpoints were safety (incidence of grade 3–4 adverse events [AEs]) and efficacy (response rate). Secondary endpoints were progression-free survival (PFS) and overall survival (OS). Time-to-event estimates analysis was performed using the Kaplan-Meier method. ResultsVery good partial response (VGPR) or better was 58% after PAD induction and increased to 82% after MEL100 and to 86% during LP-L. Complete response (CR) rate was 13% after PAD induction, increased to 38% after MEL100 and to 66% during LP-L. After a median follow-up of 2 years, the 2-year PFS was 69%, the 2-year time-to-progression was 75% and the 2-year OS was 86%. During PAD induction, main grade 3–4 AEs were thrombocytopenia (17%), neutropenia (10%), peripheral neuropathy (16%), and pneumonia (10%); treatment-related mortality was 3%. During consolidation-maintenance grade 3–4 AEs included neutropenia (16%), thrombocytopenia (6%), pneumonia (5%), and cutaneous rash (4%). Consolidation-maintenance treatment was well tolerated: only 4% of patients required Granulocyte-colony stimulating factor support and no patient required platelet transfusion; dermatological toxicity was easily manageable with dose-reduction and supportive therapy; no treatment-related deaths were reported. Updated results will be presented at the meeting. ConclusionThis is the first phase II study in newly diagnosed MM patients to date, where a sequential approach including bortezomib as induction, and lenalidomide as post ASCT consolidation-maintenance was explored. Treatment was correlated with an increase in response rate and in the depth of response (CR rate) and was generally well tolerated. These data suggest that this is a safe and effective regimen for newly diagnosed MM patients. Randomized trials are needed to confirm these results. DisclosuresPatriarca:Celgene: Honoraria; Janssen Cilag: Honoraria. Bringhen:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Janssen Cilag : Consultant, advisory committee, Research Funding; Celgene: Consultant, advisory committee, Research Funding; Pharmion: Consultant, advisory committee, Research Funding. Palumbo:Celgene: Honoraria; Janssen Cilag: Honoraria.

Paroxysmal Nocturnal Hemoglobinuria and Pregnancy: The French Experience.

Abstract 1984Poster Board I-1006Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired stem cell disorder characterized by hemolytic anemia, bone marrow failure and venous thromboembolism. PNH and pregnancy is associated with an increased risk of complications for both mother and foetus with high maternal and foetal mortality rates (around 10%, Fieni et al, Obst and Gynecol survey, 2006). However, the literature about PNH and pregnancy is scarce. We took advantage of the French PNH registry to systematically review all cases of pregnancy between 1978 and 2008. We thus identified 27 pregnancies occurring in 22 patients. The median age was 21 years (17-41) at PNH diagnosis and 27 years (21-38) at pregnancy. Pregnancy occurred mainly in women who were already diagnosed with PNH (n=20) with a median time of 70.4 months (1-192) between PNH diagnosis and pregnancy. The PNH diagnosis was also made during pregnancy for 4 patients (2 cytopenias and 2 hemolytic anemia). For the remaining 3 cases, PNH diagnosis was made after pregnancy with strong evidence of PNH history during pregnancy. Among the 27 pregnancies, 2 ended in therapeutic abortion and one was complicated by severe intrauterine foetal growth restriction leading to foetal death at 27 weeks of amenorrhea. Twenty four pregnancies gave birth to live newborns. The foetal mortality was 4%. Delivery was preterm in 29% of cases and therapeutically induced in 70% (half cases delivered by caesarean section). Birth weight was less than 3 kg in 53% of cases with one case of high prematurity. During pregnancy, minor maternal complications (not requiring hospitalization and/or intensive care) occurred in all but one of the 22 documented cases and consisted mostly in cytopenias requiring transfusions (14/22). Anemia (Hb<10 g/dl) occurred in 18/22 cases (82%) with 10 patients requiring red blood cell transfusions. Thrombocytopenia (<80.000/mm3) was observed in 16/21 cases (76%), with 10 patients requiring platelet transfusions. Arterial hypertension and diabetes occurred in 6/24 and in 1/24 women, respectively. Major maternal complications during pregnancy were observed in 8% of the patients (n=2/25, aplastic anemia). In one case, the onset of aplastic anemia allowed the diagnosis of PNH at 5 months of pregnancy while in the other case, it was a relapse of a previously treated disease. We did not observe any thrombotic events during pregnancy. Most severe complications appeared in the immediate post partum (PP) period with an incidence rate of 32%. Three thrombotic events were recorded (12.5%): 2 cerebral venous thromboses occurred in the first month of PP, one associated with maternal death. One patient experienced a Budd-Chiari syndrome leading to death at one month PP. Maternal mortality rate in post partum was 8.3%. Other maternal major complications during post partum were hemorrhagic delivery (n=2), febrile neutropenia (n=1), HELLP syndrome (n=1) and hemolysis (n=1). After delivery, two patients experienced late major thrombotic events at 7 and 9 months PP (mesenteric venous thrombosis and cerebral thrombotic event). Concerning thrombosis prophylaxis, 13/24 pregnancies (54%) were accompanied by prophylactic anticoagulation with half of them started during the first or second trimester. In all documented cases, anticoagulation was continued during at least 1 month PP. The 3 post partum thrombotic events appeared in 3 patients whom at least 1 was anticoagulated (one without anticoagulation, one unknown). In conclusion, we confirmed that pregnancy during PNH is associated with an increased risk of complications for both mother and foetus with maternal and foetal mortality rates of 8.3% and 4%, respectively. However, those rates are lower than those previously described in the literature probably because of the preferentially report of selective dramatic cases. Thrombotic events are still the main fatal complication in this context, occurring preferentially during the post partum period. Young women patients with PNH must be informed about the high risk of complications during and after pregnancy. Prophylactic anticoagulation should be started from the sixth month and continued at least until six weeks post partum. Anticoagulation is not always enough to prevent thrombotic complications raising the potential role of Eculizumab in this situation. Disclosures:No relevant conflicts of interest to declare.

Immune Ablation Using Cyclophosphamide without Stem Cell Rescue for Intractable Multiple Sclerosis and Its Variants

Background: Multiple sclerosis (MS) is the most common progressively disabling neurologic disease of young adults worldwide. MS is a cytotoxic T Cell mediated disease with autoimmune-driven destruction occurring most actively in the early stages. Immune suppression with high dose steroids, cyclophosphamide (CTX), cladribine, and mitoxantrone has demonstrated benefit in intractable, more progressive or frequently relapsing patients, both on clinical and MRI parameters. In particular, non-ablative doses of CTX appear to stabilize progressive MS for one year or longer and were most effective earlier in the course of the disease. In aggressive MS deletion of cytotoxic T cells through immune ablation may offer a more durable remission than standard immune suppression. Due to aldehyde dehydrogenase mediated resistance of CD34+ cells to CTX, hematopoietic reconstitution without hematopoietic stem cell rescue is possible and could eliminate the need for stem cell mobilization which has been associated with disease flare and potential re-infusion of T-cells.Objective: To assess the safety and efficacy of immunoablation using CTX without hematologic stem cell rescue for intractable relapsing progressive multiple sclerosis failing standard immune modulation or immune suppression.Patients and Methods: Eight patients (median age = 29, range 24–37, men = 2, women = 6) between January 2005 and July 2008 underwent immunoablation with high dose CTX (HD-CTX) at 50 mg per kg per day intravenously for four consecutive days. Adequate hydration and forced diuresis were implemented to prevent hemorrhagic cystitis. G-CSF was started 6 days after the last dose of chemotherapy at 5 mcg/kg per day until the absolute neutrophil count was > 1000 per UL for two consecutive days. Red cell transfusions were administered to maintain hemoglobin of > 8 gm/dl and platelet transfusions were given to patients with < 10 Th/ul or to patients with active bleeding regardless of their platelet count. Clinical, laboratory, and MRI monitoring was scheduled at 3–6 month intervals over 24 months.Results: Eight patients have been treated with HD-CTX since 2005 and six of these patients have been monitored for more than 2 years. Hematologic complications included grade 4 neutropenia in all patients (duration 9–18 days), grade 4 thrombocytopenia in all patients (duration 3–13 days in 5 patients; 3 patients were discharged prior to platelet recovery), and grade 3 anemia in 6 patients (duration 1–9 days). All 8 patients required platelet transfusion (mean = 3.85 units, range 1–13 units) and 7 patients required PRBC transfusion (mean = 1.625 units, range 0–4 units). Non-hematologic grade 3 or 4 complications included grade 3 neutropenic fever in 7 patients, grade 3 hematuria in 2 patients and CTX-induced cardiotoxity with troponin elevation and infective endocarditis in 1 patient. 1 pt had a dystonic reaction to compazine.All patients have demonstrated improvements ranging from halting progression of MS clinically and radiologically to dramatic reductions of neurologic deficits, except in two patients whose disease reprogressed after 20 months of stability. One of these two patients demonstrated only subclinical disease activity on brain MRI without clinical correlates whereas the other experienced two milder clinical exacerbations. The latter has begun therapy with natalizumab, and the same has been recommended for the former. Given the refractory nature of these patients' MS prior to therapy, the absence of further disease activity has been remarkable.Conclusions: Immunoablation with HD-CTX without stem cell rescue in patients with intractable MS represents a reasonable treatment option. These patients had significant improvements ranging from amelioration to stabilization of the disease course as well as reduction of disabilities. HD-CTX was tolerable with acceptable side effects and full hematologic recovery without the use of stem cell rescue. This is particularly important in patients with MS because of the associated disease flare and potential re-infusion of T-cells with stem cell mobilization. More data is needed and this clinical trial continues to accrue patients.

Oral Melphalan, Prednisone, and Lenalidomide for Newly Diagnosed Multiple Myeloma Patients: Kinetics of Neutropenia/Thrombocytopenia and Time to Event Results

Background: The association of Melphalan, Prednisone and Lenalidomide (MPR) has shown significant anti-myeloma activity in newly diagnosed Multiple Myeloma (MM) patients. In this phase I/II study, the more frequent adverse events were neutropenia and thrombocytopenia. Non-hematologic toxicities were unusual.Methods: We analyzed the kinetics and risk factors for neutropenia and thrombocytopenia in 21 patients (median age 69 years) who received nine four-week cycles of MPR at the maximum tolerated dose (melphalan 0.18 mg/Kg d 1–4, lenalidomide 10 mg d 1–21, prednisone 2 mg/Kg d 1–4, followed by maintenance period with lenalidomide 10 mg/day for 21 days every 4 weeks). We also up-dated efficacy end-point. At the occurrence of grade-3 neutropenia, G-CSF was administered for 5–7 days. The occurrence of grade-4 neutropenia despite G-CSF administration or any other grade-4 hematological toxicities required withholding of treatment and subsequent dose reduction at the start of the following cycle. A new cycle was allowed if the neutrophil count was >1×109/L and platelet count >50×109/L. A delay of 2 weeks was allowed, a delay beyond 2 weeks required dose reduction and a delay beyond 4 weeks required therapy discontinuation.Results: Grade-3 neutropenia occurred in 38.1% of patients, grade-4 neutropenia in 14.2% of patients, but febrile neutropenia was 9.5%. G-CSF was administered in 42.3% of patients. The mean neutrophil count at the start of each MPR cycle was 2.69 × 109/L (SD 1.4). The mean neutrophil count at nadir (day 15–21) of each cycle was 1.43 × 109/L (SD 1.0). The incidence and depth of neutropenia did not increase with the number of cycles. The mean neutrophil count during maintenance was 2.11 × 109/L (SD 1.0).Grade-3 thrombocytopenia occurred in 14.2% of patients and grade-4 thrombocytopenia in 9.5%; one patient required platelet transfusion. The mean platelet count at the start of each MPR cycle was 174 × 109/L (SD 63.9). The mean platelet count at nadir (day 15–21) of each cycle was 121 × 109/L (SD 56.3). Thrombocytopenia was more pronounced after 9 cycles of treatment. The mean platelet count after 9 cycles was 109 × 109/L (SD 53). The mean platelet count at the end of 6 months of lenalidomide maintenance therapy was 158 × 109/L (SD 79.2).One patient required lenalidomide dose reduction for severe neutropenia. Three patients discontinuated therapy for severe thrombocytopenia and neutropenia. Grade 3–4 hematologic toxicity was more frequent in patients with low baseline neutrophil count and in those with Bence-Jones myeloma. Neutropenic fever (9.5%), cutaneous reaction (9.5%), thromboembolism (4.8%) were the most frequent grade 3–4 non-hematologic adverse events.After a median follow-up of 29.5 months, the median time-to-progression was 28.5 months, the median progression-free survival was 28.5 months and the 2-years overall survival was 90.5%. No death was reported in the first 18 months of treatment.Conclusions: MPR is a promising first line regimen for elderly MM patients. Hematologic adverse events were frequent but manageable with the use of G-CSF.

Home Management of Unfit Patients with Multiple Myeloma: An Italian Single-Center Experience

The majority of patients with multiple myeloma are not eligible for curative treatments because of advanced age at diagnosis or contraindications to high-dose chemotherapy. Several anti-myeloma agents and other supportive medications, generally provided on outpatient basis, have shown to improve overall survival and quality of life even in the setting of unfit and fragile patients. Frequent accesses to day-hospital or outpatient clinic may however cause discomfort and unease in myeloma patients presenting vertebral lesions, bone pain, severe immunodeficiency and comorbidities. In our department a hospital-based home care service supported by the fundraising organisation A.I.L. (Italian Association against Leukemia-Lymphoma-Myeloma) is active in order to assist hematology patients who have poor performance status and fulfil other inclusion criteria (appropriate home logistics, caregiver availability and trainability, distance from hospital within 20 km, cooperation with general practitioners, community nurses and on-call doctors). Through a 9-yrs period (July 1999 – June 2008) 53 patients (male=26, female=27) affected by multiple myeloma have been enrolled in a domiciliary program of supportive and palliative care agreed by the hospital Division of Hematology, the Community Health Trust and the local section of the Italian Association against Leukemia-Lymphoma-Myeloma (A.I.L.).All patients were stage II or III according to Salmon-Durie classification. ECOG performance status was 2.8 on average. Median age was 76 years (under 60 years=4 patients, between 60 and 70 yrs=11 pts, between 70 and 80 yrs=17 pts, over 80 yrs=21 pts). At the time they were referred to the service, 14 patients were in terminal phase of disease with a life expectancy of about 3 months; 35 patients presented progressive disease after at least one previous therapy; there were also 4 patients undergoing transplant-based therapeutic programs and discharged early from the ward.Patients were generally followed-up on weekly-basis for collection of blood samples, clinical assessment and intravenous therapies (bisphosphonates, blood and platelet transfusions, anti-myeloma agents, antimicrobials, immunoglobulins). Median duration of a home care cycle was 323 days, with significant differences among the three groups of patients (in terminal phase=84 days, in progressive disease=466 days, in causal treatment=55 days). Excluding 4 ongoing patients, the end of home care resulted in 15 patients deceased at home (37%) and 26 died as inpatients (63%) while 8 patients were referred back to day hospital or ward. Urgent hospital admissions were 66, corresponding to an average of 1.25 admissions per home care cycle: main reasons were infection and fever, cardiopulmonary complications, renal failure, major bleeding and caregiver burnout. Once-monthly bisphosphonate treatment regarded 31 patients for a total of 332 infusions (pamidronate=191, zoledronic acid=141). Blood transfusions were provided to 22 patients for a total of 202 erythrocyte units while 8 patients required platelet transfusions (82 bags). Although most patients were off-therapy or in treatment with oral drugs, several novel and conventional anti-myeloma agents were administered intravenously at home in monotherapy or in combination, such as bortezomib, dexamethazone, vincristine, cyclophosphamide, carmustine, doxorubicine. No serious adverse event was reported as direct consequence of home intravenous therapies.Home care has achieved a relevant role in the global management of patients with blood malignancies improving quality of life and reducing health care costs. Thanks to our operating model, characterized by the presence of a full-time specialist team and by a careful selection of patients, home care of unfit patients with multiple myeloma represents a valid integration to the standard in-hospital hematology services. Many issues remain open, such as cost analysis, quality-of-life assessment, legislation on domiciliary medications, role of fundraising organisations and recognition in public health system.

Melphalan 200 Mg/m2 (Mel200) Versus Melphalan 100 Mg/m2 (Mel100) in Newly Diagnosed Myeloma Patients: A Prospective, Randomized Phase III Study

Background. Several trials have shown the superiority of high-dose melphalan (usually 200 mg/m2, MEL200) versus standard therapy in myeloma patients. Intermediate-dose melphalan (100 mg/m2, MEL100) was also superior to the standard dose, but MEL100 has not been clinically compared with MEL200 in a randomized study. In this prospective, randomized, phase III trial, we compared the efficacy and toxicity of MEL200 and MEL100.Aims. The primary end points were complete remission (CR) rate, event-free survival (EFS) and incidence of gastrointestinal toxicity, infections and treatment-related mortality (TRM).Methods. Inclusion criteria were previously untreated myeloma, aged ≤ 65 and Durie and Salmon stage II or III. Exclusion criteria were abnormal pulmonar, cardiac, liver and renal function, HBV, HCV, or HIV positivity, concomitant cancer or psychiatric disease. The institutional review board approved the protocol and written informed consent was obtained from all patients. All patients received 2 cycles of 28-day-dexamethasone- doxorubicin-vincristine (doxorubicin 50 mg/m2 day 1, vincristine 1 mg day 1, dexamethasone 40 mg days 1–4) and 2 cycles of cyclophosphamide (4 g/m2, day 1) followed by stem cell harvest. MEL200 patients was conditioned with 2 cycles of melphalan 200 mg/m2 and MEL100 patients with 2 courses of melphalan 100 mg/m2. All MEL courses were followed by stem cell reinfusion.Results. Two-hundred and ninety-eight patients (median age 57) were randomly assigned either to MEL200 (149 patients) or to MEL100 (149 patients). All patients were evaluated for response, EFS and OS in intention-to-treat analysis. Patient characteristics were similar in both groups with the exception of chromosomal 13 deletion, present in 69% of MEL200 and 45% of MEL100 patients (p=0.02). Ninety-six patients completed tandem MEL200; 103 tandem MEL100. The very good partial response rate was higher in MEL200 group (37% versus 21%, p=0.003), but CR was 15% in the MEL200 group and 8% in the MEL100 group (p=0.07). The median follow-up for censored patients was 40.5 months. The 4-years EFS was 44.5% in the MEL200 and 18.3% in the MEL100 group (HR=0.71, 95% CI 0.53–0.95, p=0.02). The 5-years overall survival (OS) was 59.2% in the MEL200 and 44.7% in the MEL100 group (HR=0.78, 95% CI 0.52–1.16, p=0.22). Duration of grade 4 neutropenia and thrombocytopenia was comparable, but a higher proportion of MEL200 patients required platelet transfusions (p=0.002). Grade 3–4 non-hematologic adverse events were reported in 38% of MEL200 patients and in 19% of MEL100 patients (p<0.0001). The incidence of grade 3–4 mucositis was 16% after MEL200 and 3% after MEL100 (p<0.0001). The incidence of severe gastrointestinal toxicity was 19% after MEL200 and 2% after MEL100 (p<0.0001). The incidence of grade 3–4 infections and of TRM was similar in both groups.Conclusions. In conclusion, MEL200 resulted in a significantly higher very good partial response rate. This translated in a superior EFS, but not OS. Mel200 was associated with less gastrointestinal toxicity, including mucositis.