ALBERT

Description: In 1999, recombinant factor VIIa (rFVIIa, NovoSeven®) received FDA approval with recommended dosing of 90 mcg/kg every 2 hours. Individual case reports and small series have described the use of rFVIIa at doses ≥ 270 mcg/kg and 3 randomized trials have suggested that one bolus dose of rFVIIa at 270 mcg/kg provides equivalent efficacy and safety when compared to the conventional regimen of three doses of 90 mcg/kg over 6 hrs. The extent to which higher doses of rFVIIa have been used in clinical practice in the US is unknown. The HTRS registry records data regarding the treatment of acute bleeding episodes in those with hemophilia A or B and related hemorrhagic disorders with special emphasis on outcomes in individuals with congenital hemophilia complicated by alloantibody inhibitors; From over 5,000 evaluable bleeding episodes reported between January 2004 and March 2008, all episodes treated with at least one dose of ≥ 250 mcg/kg rFVIIa were examined for their initial and total dose, number of doses, and number of days on rFVIIa therapy. The efficacy of two treatment regimens was assessed: an initial high dose ≥250 mcg/kg followed by “as needed” lower doses; some of these only required a single high dose; and initial smaller doses of rFVIIa or aPCC followed by a≥250 mcg/kg dose for salvage. Of 2,532 bleeds treated with rFVIIa, 153 bleeds treated with at least one dose ≥ 250 mcg/kg were reported in 21 individuals with either congenital hemophilia A (n=17) or B (n=4) with alloantibody inhibitors. These 153 bleeding episodes required 1642 doses of rFVIIa of which 358 doses were ≥ 250 mcg/kg. The mean patient age was 12.6 years (0.9– 41.7 years). Mean titers of anti-FVIII and anti-FIX alloantibodies were 104.6 BU (0–683) and 0.9 BU (0–5.6), respectively. Bleed sites were in joints (102 bleeds, 67%), muscles (31 bleeds, 20%), mucosal surfaces (7 bleeds, 5%), and subcutaneous areas (6 bleeds, 4%). Bleeds were treated mainly in the home (78%). Of 153 bleeding episodes treated with at least one dose ≥ 250 mcg/kg rFVIIa, 80 had at least one dose ≥ 270 mcg/kg, and 49 had at least one dose ≥ 300 mcg/kg. For the whole group, mean (median, range) total dose was 1835 (867, 250–27323) mcg/kg with 10.4 (4, 1–201) doses over 3.8 (2.0, 1–79) days. Half of the doses received for these bleeds were ≥ 250 mcg/kg, and 79.1% had an initial dose of ≥ 250 mcg/kg. For those receiving a dose of ≥250 mcg/kg, there were 14.5 (4, 1–157) doses prior to the dose of ≥ 250 mcg/kg. Efficacy was 90% in 147 bleeds where rFVIIa was used as primary treatment and 100% in 6 bleeds where rFVIIa was used after a mean 154 U/kg (2.0 doses) of aPCC. Efficacy was 90% for joint bleeds and 94% for muscle bleeds. There were 15 episodes of presumed efficacy where documentation did not indicate bleeding stopped, but no other medications were recorded, resulting in adjusted overall efficacy of 100%. There were 9 patients with 23 bleeding episodes treated with a single dose of ≥ 250 mcg/kg, including mostly joint bleeds (10 spontaneous, 7 traumatic), and mostly home treatment (21). Dosing was 307 ± 62.1 (300, 250–500) mcg/kg and in 91% physicians reported “bleeding stopped” (remaining 2 had no other doses or medications). Cumulative exposure in this group was 157 doses of 250–269 mcg/kg, 70 doses of 270–299 mcg/kg, and 131 of 300–500 mcg/kg. There were no serious adverse drug related events or thrombotic complications reported after treatment of these bleeding episodes. The 2004–2008 data from HTRS provides the largest single source of data on the safety and efficacy of higher doses of rFVIIa administered to reverse moderate to severe bleeds in a broad cohort of inhibitor patients with hemophilia. Efficacy was consistent for both intra-articular or muscle bleeds in a home setting and rFVIIa was an effective single hemostatic agent in this context so the administration of additional replacement products was unnecessary. Importantly, rFVIIa ≥250 mcg/kg was not associated with any serious adverse drug reactions or thrombogenicity. These data support the feasibility of an initial high dose of rFVIIa for treatment of bleeds in inhibitor patients and justifies the conduct of a prospective, randomized clinical trial to confirm these observations.

Description: Acquired hemophilia A (AH) is a rare disorder marked by the development of autoantibodies to factor VIII. Patients present with a prolonged aPTT that does not correct with mixing and clinically evident bleeding. HRS and its successor, HTRS, have maintained a registry to study treatment strategies for acute bleeds in hemophilia and related disorders. Data from the HRS (1999–2003) and HTRS (2004–2008) registries were examined to identify acute bleeding episodes in patients with AH. In total, 49 patients were identified with AH, 28 of whom had 50 acute bleeding episodes recorded. 23 (46%) of such bleeds were treated with recombinant Factor VIIa (rFVIIa) alone, 9 (18%) with rFVIIa and other hemostatic agents, 12 (24%) with other hemostatic agents alone, 1 did not require treatment, and 5 no treatment information recorded. Of patients with bleeding episodes and recorded demographic information, there were 22 males and 12 females; 38 were Caucasian and 7 African American. Mean (median) age at time of the acute bleed was 69 (72) years for patients ever treated with rFVIIa and 66 (70) years for those treated exclusively with other agents. Remaining data are presented as mean (median, mode) unless otherwise indicated. For those ever treated with rFVIIa, the initial dose was 98 (100, 90) mcg/kg, mean treatment dose was 95 (100, 90) mcg/kg, and total cumulative treatment dose was 2520 (702, 300) mcg/kg. The highest single bolus dose given was 160 mcg/kg. There was no significant variation in initial or mean dose over the 9-year data collection period. The total number of doses of rFVIIa was 27 (7, 3) over a mean of 5.2 (1, 1) days for total treatment duration of 6.8 (2.5, 1) days per bleeding episode. Treatment within the first 24 hrs was a mean of 478 (311, 300) mcg/kg representing 63% (81%, 100%) of total rFVIIa dose. True efficacy was difficult to assess in this registry. As rated by the physician for the primary outcome of the bleed stopped at 72 hrs, efficacy was 64%. However, in 9 additional bleeding episodes (32%), documentation of efficacy was unclear. In 4 the dose of rFVIIa was not increased and no other hemostatic agents were given, 2 switched from porcine FVIII (pFVIII) to rFVIIa and 3 switched from rFVIIa to other agents, including aPCC (after a single inadequate 30 mcg/kg dose of rFVIIa), pFVIII and plasma derived FVIII (pdFVIII), for an overall efficacy rate of 82%. One patient with preeclampsia and bleeding after a Caesarean section experienced transient neurologic symptoms after receiving rFVIIa 90 mcg/kg q2h for 113 consecutive doses; brain MRI showed multifocal ischemia. Patients who did not receive rFVIIa were treated with pFVIII (7 bleeds, 58%), aPCC (4 bleeds, 33%) and pdFVIII concentrate (1 bleed, 8%) for a mean of 12 (8, 6) days. Efficacy as rated by the physician for the outcome of bleed stopped at 72 hrs was 55% in those specified (4/7 bleeds treated with pFVIII, 1/4 aPCC and 1/1 pdFVIII). In 5 bleeding episodes (45%), documentation of efficacy was unclear. While registry data can only show the treatment reported in selected bleeds captured, HRS-HTRS demonstrates rFVIIa efficacy similar to prior reports in the AH population. rFVIIa dosing was consistent over time with most patients receiving ~100 mcg/kg for 7 doses. Despite publication on higher dosing regimens in patients with congenital hemophilia, there were no documented doses above 160 mcg/kg in this series. Although rFVIIa is approved for use every 2–3 hrs, the data indicate that dosing was generally at more prolonged intervals, and often over long periods of time. In the absence of randomized prospective studies and the limited number of evaluable patients with this rare disorder, this registry data provide proof of principle that rFVIIa is an effective and safe treatment for acute bleeding episodes in AH. As this registry was originally intended in part to track the safety of rFVIIa, these derived data may be somewhat biased and selective. Nevertheless, they are certainly indicative that rapid and safe hemostasis can be achieved in an aging adult population where thrombogenicity of hemostatic agents is of major concern. This registry will continue to collect data on AH patients to determine whether dose, dosing interval and dosing frequency trends are maintained as experience with rFVIIa expands. Definitive comparative safety and efficacy data with various hemostatic agents in AH ideally will require prospective randomized trials, which will be challenging in such a rare disorder.

Description: In 1999, the Hemophilia Research Society established a registry to collect information on individuals diagnosed with bleeding disorders and on their bleeding episodes. Concurrently, the prospective database was intended to serve as a mechanism to satisfy the post-marketing surveillance requirements of the FDA to assess the safety and efficacy of rFVIIa (NovoSeven®, Novo Nordisk A/S) administered to individuals with congenital hemophilia complicated by alloantibody inhibitors to FVIII or FIX. On January 1, 2004, the database format was re-launched on a 2nd generation web-based platform and designated as the HTRS Registry. No data were transferred between databases. This study examines the data captured in the HTRS registry from January 2004-December 2007. The HTRS registry is a web-based single database with 11 component forms and 1564 fields. Any sites or physicians affiliated with the HTRS can participate in the registry after obtaining IRB approval and providing patients with an informed consent to capture de-identified information. Over this interval, 83 sites were IRB approved to participate, and all but 11 entered some data. Assessment of the accuracy and validity of the data contained in the registry was performed by an independent third party as part of an audit in early 2008. Overall there are 2,081 patient registration records in the HTRS database. Of these, 373 patients with ongoing treatment required merger of their data from the initial HRS Registry. A sub-cohort audit of all patients in the HTRS registry indicated that the diagnosis and inhibitor status and elements of the demographic information were accurate in 43/43 patient charts examined. The largest group of patients represent those with congenital hemophilia (Total, 1,432; A, 1,145; B, 287) and congenital hemophilia with inhibitors (Total, 354; A, 321; B, 33). Other common diagnoses were von Willebrand Disease (497), acquired hemophilia (48), congenital FVII deficiency (30), and inherited qualitative platelet disorders (29). A total of 5,144 bleeding events were captured for 473 patients, including 3,445 bleeds in congenital hemophilia, and 3,007 in 354 patients with alloantibody inhibitors. There were 2,532 bleeds in 293 patients in whom rFVIIa was administered alone or in combination with other agents. These included 2,099 bleeds in patients with congenital hemophilia, of which 1,702 were in 117 patients with inhibitors to FVIII or FIX. Recombinant FVIIa use was also reported in other patient groups, including congenital hemophilia without inhibitors (397 bleeds), congenital FVII deficiency (54), acquired hemophilia (38), Glanzmann’s thrombasthenia (23), and von Willebrand disease (9). A total of 18 serious adverse events were reported in the registry and forwarded to the manufacturer(s) regardless of relationship to therapy. In the United States (US) clinical research efforts have been focused primarily on evidence based outcomes and development of new therapeutic agents in large disease populations. For rare disorders, such as hemophilia complicated by alloantibody inhibitors, this is not practical or statistically conclusive. An alternative approach to understanding the safety and efficacy of new therapeutic agents in so-called “orphan diseases” involves the analysis of the “collective” experience of patients included in a longitudinal database. This is a labor intensive endeavor, which in the US has been subjugated to the need to deliver care to patients in a rapid fashion with limited infrastructure support. Thus, the documentation of prescribing habits, response to varying treatment modalities, and the reporting of adverse events have lagged. This is in contrast to many national health care systems outside the US, which mandate and finance such activities. The HTRS registry represents an industry- funded effort to satisfy a FDA mandate to monitor the longitudinal safety and efficacy of a clotting factor replacement product for alloantibody inhibitor patients. However, the supervision and oversight of the registry are based in an independent cooperative clinical research group, the HTRS. The significant amount of data accumulated over a 4 year period in the HTRS database will provide insight and important “signals” into current treatment practices and the safety and efficacy of treatment modalities, particularly for more severe bleeds that are treated in an HTC setting.

Description: Background: Autologous stem cell transplantation (ASCT) plays an important role in the treatment of multiple myeloma (MM) patients (pts). In this report, we describe the longterm outcome of cohort of 185 pts with newly diagnosed symptomatic MM treated with ASCT. Median follow-up from the start of therapy was 102.8 months (range 67.2–150.4). We have specifically analyzed benefit from the newer drugs used in the relapsed setting. Methods: A total of 185 MM pts underwent ASCT in the clinical trial 4W of Czech Myeloma Group in 18 centres in Czech Republic and Slovak Republic between 1996 and 2001. The conditioning regimen was high dose melphalan (200mg/m2) in all pts. At diagnosis of MM 72.4% (134/185) of pts had stage III according to Durie- Salmon, 18.4% (34/185) stage II and 9.2% (17/185) stage I. Clinical stages according to ISS were the following: stage 1 in 42.5% (74/174) of pts, stage 2 in 36.8% (64/174) and stage 3 in 20.7% (36/174) pts. Types of monoclonal immunoglobulin were as following: 67.6% (125/185) IgG, 21.1% (39/185) IgA, 9.7% (18/185) light chain, 1.6% (3/185) IgD. Renal insufficiency was presented in 5.9% (11/185) of pts. Median age at transplantation was 54.8 years (range: 28.3–69.2). When the symptomatic relapse of MM after ASCT was occurred, 34.6% (45/130) of pts were treated by conventional chemotherapy (CC) alone, 22.3% (29/130) by thalidomide based regimen, 10.7% (14/130) by bortezomib based regimen, 22.3% (29/130) pts underwent re-transplantation and 10% (13/130) of pts received combination of newer drugs and re-transplantation. Results: Following ASCT, overall response rate (ORR) was 93.5% (173/185), 29.2% (54/185) of pts were in CR, 38.4% (71/185) of pts were in VGPR, 25.9% (48/185) of pts in PR. Median of overall survival (OS) from start of treatment was 77.9 months (9.6 – 147.3), median of TTP was 39.8 months (7.0–146.9). Total of 23.2% (43/185) of pts are alive and disease free, 20.5% (38/185) of pts are alive with relapse and 56.3% (104/185) of pts died with median follow-up 8.3 years from the start of therapy. Significant prognostic parameters for better OS after ASCT were: ISS stage 〈 III (p

Description: The recommended dose of recombinant factor VIIa (rFVIIa, NovoSeven®) is 90 mcg/kg every 2–3 hours. The Home Treatment Study demonstrated an average of 2.2 doses of 90 mcg/kg were required to treat mild to moderate bleeds. Since it is recognized that a single dose administered shortly after a bleed, if equally effective, would be more convenient and possibly could reduce bleeding morbidity, this study examined the experience registered with the use of single rFVIIa doses in the United States. The HTRS database contains patient data relating to hemophilia treatment and related disorders, and in particular the treatment of acute bleeding episodes in individuals with hemophilia complicated by anti-factor VIII (FVIII) or IX (FIX) alloantibody inhibitors. Between January 2004 and March 2008, the database contained information on over 5,000 bleeding episodes. The data for patients receiving only a single bolus intravenous dose of rFVIIa and no additional treatment were evaluated. The parameters assessed included patient demographics, bleed location, bleed type (specifically joint and muscle bleeds), and dose. Of 2,532 patients who received rFVIIa, 70 with congenital hemophilia A (n=63) or B (n=7) and inhibitors experienced 508 bleeding episodes that were treated solely with a single dose of rFVIIa. The mean (median, range) age at the time of bleed was 12.7 years (8.2, 0.6–60.4). Mean titers for anti-FVIII and anti-FIX were 62.2 BU (15.0, 0–1408) and 6.8 BU (1.3, 0–31.7), respectively. The bleed sites recorded were joints (271 bleeds [53%], including 55 in target joints [20.2% of joint bleeds]), muscle (78, 15%), mucosal (45, 9%), intracranial (25, 5%), and subcutaneous (21, 4%). Joint bleeds occurred primarily in the ankles (124 bleeds), elbows (61 bleeds) and knees (53 bleeds). For 508 bleeds treated with a single dose of rFVIIa, the mean (median, range) dose was 119.5 mcg/kg (100, 25–500) with 20 of those doses ≥270 mcg/kg. Patients with joint bleeds were treated with 123.1 mcg/kg (100, 25–500), target joint bleeds with 155.3 (140, 50–393), and those with the muscle bleeds received 120.1 mcg/kg (100, 50–500). The most common single dose regimen overall and for the joint and muscle bleeds was 90 mcg/kg rFVIIa. The majority of bleeds (424, 82.7%) were treated at home, but bleeds were also treated at Hemophilia Treatment Centers (61, 12.0%) and in the emergency room (15, 3.0%). Overall, physician reported “bleeding stopped” in 97% of the 494 bleeds, 97% of hemarthroses, 96% of target joint hemarthroses and 96% of muscle bleeds. For the remaining 14 episodes, although documentation did not indicate “bleeding stopped”, no other medications were recorded. There were no serious adverse drug reactions. Registry data can only demonstrate the treatment reported in selected bleeds captured, and the analysis here specifically examined bleeds treated with only a single dose either because of bleed resolution or by physician/patient choice. The data analyzed here demonstrate single doses of rFVIIa of up to 500 mcg/kg (mean 119 mcg/kg) for mild to moderate bleeds effectively resolved bleeds in 97%, including hemarthrosis, target joints hemarthrosis, and muscle bleeds. These data support the possibility that rFVIIa can be administered in a single bolus dose with equivalent or superior efficacy as multiple lower doses for bleeding episodes treated as part of a home therapy regimen. While 3 randomized trials have examined the equivalence of a single dose of 270 mcg/kg with 3 doses of 90 mcg/kg, these data suggest that single doses of rFVIIa therapy in the real world often were empirically titrated on a patient specific basis, according to the severity and site of the bleeding episode. These registry data provide justification for prospective, randomized, single dose titration trials of rFVIIa or future analogues.