You Make the Call : Readers ’ Response
We asked , and you answered ! Here are a few responses from this month ’ s “ You Make the Call .”
For the full description of the clinical dilemma , and to see how the expert responded , turn to page 64 .
Clinical Dilemma :
I have a patient at 37 weeks of her fourth pregnancy . She has a history of type 2A von Willebrand disease ( vWD ), requiring Humate-P replacement in the prior two deliveries and other bleeding occasions ( epistaxis , hematuria , and heavy menses prior to last pregnancy ). She will undergo vaginal induction delivery in two weeks . She weighs 161 pounds .
Her current values are as follows : PT , PTT , and fibrinogen are normal ; factor VIII ( FVIII ) is 96 percent ; von Willebrand factor ( vWF ) antigen is 113 percent ; and vWF activity is 34 percent . My recommendations include keeping activity level at 100 percent prior to delivery and three days postpartum , Humate-P 2,400 units 30 minutes prior to epidural , then the same dose every 12 hours for three days followed by Humate-P 1,450 units daily
Summary of Clinical Trial Experience in Diffuse Large B-Cell Lymphoma ( DLBCL )
The data in Table 2 were obtained in the MabEASE study , a comparative , randomized , parallel-group , multicenter study to investigate the efficacy of RITUXAN HYCELA ( 1,400 mg rituximab and 23,400 Units hyaluronidase human ; n = 369 ) versus 375 mg / m 2 a rituximab product by intravenous infusion ( n = 203 ) both in combination with CHOP ( R-CHOP ) in previously untreated patients with CD20-positive DLBCL .
Eighty two percent of patients receiving RITUXAN HYCELA or rituximab completed all 8 cycles of study treatment . In both RITUXAN HYCELA and rituximab treatment groups , patients experienced 4.9 months median duration of rituximab exposure in each arm .
The demographic characteristics were balanced between the two treatment groups . Most patients were Caucasian ( 79 %) and more than half ( 54 %) were male . The study population had a median age of 64 years ( 61 % of patients aged ≥ 60 years ) with median BSA of 1.83 m 2 ( 1.83 and 1.84 m 2 for RITUXAN HYCELA and rituximab groups , respectively ).
The incidences of adverse reactions of any grade ( RITUXAN HYCELA [ 94 %] vs . rituximab [ 92 %]) ( Table 2 ), Grade 3 – 4 adverse reactions ( RITUXAN HYCELA [ 63 %] vs . rituximab [ 57 %]), and serious adverse reactions ( RITUXAN HYCELA [ 42 %] vs . rituximab [ 37 %]) were generally comparable between the two treatment groups . The common adverse reactions ( occurring in ≥ 20 % of patients in any treatment group ) were neutropenia , alopecia , nausea , and anemia .
A total of 91 patients ( 16 %) died , including 58 / 369 patients ( 16 %) in RITUXAN HYCELA and 33 / 203 patients ( 16 %) in rituximab . Of these patients , 44 patients ( 29 patients RITUXAN HYCELA [ 8 %] vs . 15 patients rituximab [ 7 %]) died due to adverse reactions and 35 patients ( 22 patients RITUXAN HYCELA [ 6 %] vs . 13 patients rituximab [ 6 %]) died due to disease progression . Pneumonia ( 4 patients RITUXAN HYCELA vs . 1 patient rituximab ), septic shock ( 2 patients RITUXAN HYCELA vs . 3 patients rituximab ), and cardiac arrest ( 1 patient RITUXAN HYCELA vs . 3 patients rituximab ) were the most common adverse reactions leading to death .
The incidence of administration-related reactions was balanced between the RITUXAN HYCELA and rituximab groups ( 28 % vs . 29 %). Grade 1 – 2 ARRs constituted 97 % of the overall ARRs for the RITUXAN HYCELA arm and 80 % for the rituximab arm . Of the reported ARRs , local cutaneous reactions with RITUXAN HYCELA were reported in 17 patients . These events resolved within a median of 2 days from the onset ( range 1 to 32 days ). Majority of these reactions were Grade 1 and 2 and were observed in 16 patients ( 4 %).
Table 2 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated DLBCL Receiving RITUXAN HYCELA or Rituximab in Combination with CHOP
Body System / Adverse Reactions
RITUXAN HYCELA + CHOP ( n = 369 )
All AEs %
Grade 3 – 4 %
Rituximab + CHOP ( n = 203 )
All AEs %
Grade 3 – 4 %
Gastrointestinal Disorders |
Nausea |
22 |
< 1 |
24 |
< 1 |
Constipation |
15 |
< 1 |
17 |
< 1 |
Diarrhea |
14 |
1 |
10 |
1 |
Vomiting |
11 |
< 1 |
8 |
< 1 |
Abdominal Pain |
7 |
< 1 |
7 |
< 1 |
Stomatitis |
6 |
< 1 |
5 |
0 |
Dyspepsia |
5 |
0 |
7 |
0 |
General Disorders and |
Administration Site Conditions |
Fatigue |
19 |
1 |
15 |
1 |
Pyrexia |
13 |
< 1 |
13 |
0 |
Asthenia |
11 |
< 1 |
12 |
< 1 |
Mucosal Inflammation |
8 |
< 1 |
8 |
1 |
Edema Peripheral 8 |
< 1 |
4 |
0 |
Infections |
|
|
|
Pneumonia |
7 |
3 |
4 |
2 |
Blood and Lymphatic System Disorders |
Neutropenia |
31 |
25 |
29 |
19 |
Anemia |
23 |
5 |
21 |
4 |
Febrile Neutropenia |
14 |
14 |
12 |
11 |
Leukopenia |
7 |
3 |
7 |
3 |
Lymphopenia |
5 |
1 |
6 |
3 |
Table 2 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated DLBCL Receiving RITUXAN HYCELA or Rituximab in Combination with CHOP ( cont ’ d )
Body System / Adverse Reactions
RITUXAN HYCELA + CHOP ( n = 369 )
All AEs %
Grade 3 – 4 %
Rituximab + CHOP ( n = 203 )
All AEs %
Grade 3 – 4 %
Investigations Neutrophil Count Decreased |
14 |
11 |
14 |
11 |
White Blood Cell Count Decreased |
7 |
4 |
7 |
5 |
Weight Decreased 8 |
< 1 |
4 |
< 1 |
Lymphocyte Count |
|
|
|
Decreased |
5 |
2 |
3 |
2 |
Metabolism and Nutrition Disorders |
Decreased Appetite 8 |
< 1 |
9 |
< 1 |
Nervous System Disorders |
Neuropathy |
Peripheral |
12 |
< 1 |
12 |
0 |
Paresthesia |
9 |
< 1 |
6 |
0 |
Headache |
6 |
0 |
7 |
0 |
Skin and Subcutaneous Tissue Disorders |
Alopecia |
24 |
0 |
24 |
0 |
Respiratory , Thoracic and |
Mediastinal Disorders |
Cough |
11 |
< 1 |
9 |
0 |
Dyspnea |
6 |
0 |
4 |
< 1 |
Psychiatric Disorders |
Insomnia |
7 |
< 1 |
6 |
< 1 |
Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia
The data in Table 3 were obtained in part 2 of the SAWYER study , a two-part , comparative , randomized , parallel-group , multicenter study of RITUXAN HYCELA versus a rituximab product by intravenous infusion both in combination with fludarabine and cyclophosphamide ( FC ) chemotherapy in patients with previously untreated CLL .
The safety analysis population in part 2 of the study included 85 patients receiving RITUXAN HYCELA ( 1,600 mg rituximab / 26,800 Units hyaluronidase human ) and 89 patients receiving 500 mg / m 2 rituximab . In both RITUXAN HYCELA and rituximab groups , patients had similar median duration of rituximab exposure ( 4.9 vs . 4.7 months ). The majority of patients received all 6 cycles of study treatment ( 86 % RITUXAN HYCELA vs . 81 % rituximab ).
The patient population was predominantly Caucasian ( 96 %), male ( 65 %), with a median age of 60 years and median BSA of 1.9 m 2 ( 1.97 and 1.86 m 2 for the RITUXAN HYCELA and intravenous rituximab groups , respectively ). Overall , the treatment groups were balanced with respect to demographic characteristics , with the exception of more males in the RITUXAN HYCELA arm ( 71 % RITUXAN HYCELA vs . 60 % rituximab ). Baseline disease characteristics were similar between the two groups . Over half of the patients ( 62 %) had Binet Stage B disease and the majority had typical CLL characterizations ( 93 %), with median time from first CLL diagnosis to randomization being 18.5 months .
The incidences of adverse reactions were balanced between the two treatment groups ( 96 % RITUXAN HYCELA vs . 91 % rituximab ), and the common adverse reactions ( occurring in ≥ 20 % of patients in any arm ) were infections , neutropenia , nausea , thrombocytopenia , pyrexia , anemia , vomiting , and injection site erythema . The incidences of Grade 3 – 4 adverse reactions were also balanced between the two treatment groups ( 69 % RITUXAN HYCELA vs . 71 % rituximab ). The incidence of serious adverse reactions was 29 % for RITUXAN HYCELA and 33 % for rituximab . The incidence of administrationrelated reactions was 44 % for RITUXAN HYCELA and 45 % for rituximab ). Of the reported ARRs , local cutaneous reactions with RITUXAN HYCELA were reported in 15 patients . These events resolved within a median of 6 days from the onset ( range 3 to 29 days ). Majority of these reactions were Grade 1 and 2 and were observed in 14 patients ( 16 %).
A total of 9 patients ( 5 %) died , including 5 patients in the RITUXAN HYCELA group and 4 patients in the rituximab group . In the RITUXAN HYCELA group , 1 patient died due to herpes zoster infection , 1 patient died as a result of progressive multifocal leukoencephalopathy ( PML ) ( considered by the investigator as related to rituximab ), and 3 patients died due to disease progression . In the rituximab group , 2 patients died due to diarrhea and listeriosis and 2 patients died due to disease progression .
Table 3 : Incidence of Adverse Reactions in ≥ 5 % of Patients with Previously Untreated CLL Receiving RITUXAN HYCELA or Rituximab in Combination with FC
Body System / Adverse Reactions
RITUXAN HYCELA + FC ( n = 85 )
All AEs %
Grade 3 – 4 %
All AEs %
Rituximab + FC ( n = 89 )
Grade 3 – 4 %
Gastrointestinal Disorders |
Nausea |
38 |
1 |
35 |
0 |
Vomiting |
21 |
2 |
22 |
1 |
Diarrhea |
12 |
0 |
11 |
3 |
Abdominal Pain |
9 |
0 |
6 |
0 |
Constipation |
8 |
0 |
8 |
0 |
General Disorders and |
Administration Site Conditions |
Pyrexia |
32 |
5 |
25 |
1 |
Injection Site Erythema |
26 |
2 |
0 |
0 |
Injection Site Pain 16 |
1 |
0 |
0 |
Chills |
13 |
0 |
10 |
1 |
Fatigue |
11 |
0 |
10 |
0 |
Asthenia |
8 |
1 |
17 |
2 |
Infections Upper Respiratory Tract Infection |
13 |
0 |
12 |
1 |
Respiratory Tract Infection |
8 |
1 |
4 |
1 |
Bronchitis |
7 |
0 |
6 |
0 |
Urinary Tract Infection |
2 |
0 |
8 |
1 |
Pneumonia |
2 |
2 |
6 |
2 |
Blood and Lymphatic System Disorders |
Neutropenia |
65 |
56 |
58 |
52 |
Thrombocytopenia 24 |
6 |
26 |
9 |
Leukopenia |
19 |
14 |
16 |
12 |
Anemia |
13 |
5 |
24 |
9 |
Febrile Neutropenia 11 |
8 |
8 |
8 |
Musculoskeletal and |
|
|
|
Connective Tissue Disorders |
Arthralgia |
9 |
0 |
1 |
0 |
Pain In Extremity |
7 |
1 |
2 |
0 |
Bone Pain |
6 |
0 |
2 |
0 |
Nervous System Disorders |
Headache |
7 |
0 |
9 |
0 |
Skin and Subcutaneous Tissue Disorders |
Erythema |
15 |
0 |
7 |
0 |
Rash |
12 |
0 |
10 |
1 |
Pruritus |
8 |
0 |
4 |
0 |
Respiratory , Thoracic and Mediastinal Disorders |
Cough |
13 |
0 |
11 |
0 |
Oropharyngeal Pain 6 |
0 |
3 |
0 |
Dyspnea |
4 |
0 |
8 |
1 |
Psychiatric Disorders |
Insomnia |
1 |
0 |
7 |
0 |
Vascular Disorders |
Hypotension |
1 |
0 |
7 |
1 |
Hypertension |
0 |
0 |
6 |
1 |
6.2 Immunogenicity As with all therapeutic proteins , there is potential for immunogenicity . The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay . Additionally , the observed incidence of antibody ( including neutralizing antibody ) positivity in an assay may be influenced by several factors including assay methodology , sample handling , timing of sample collection , concomitant medications , and underlying disease . For these reasons , comparison of the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading .
In the SABRINA study , where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP , the incidence of treatment-induced / enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group ( 2.0 % RITUXAN HYCELA vs . 1.5 % rituximab ). The incidence of treatment-induced / enhanced anti-recombinant human hyaluronidase antibodies was 13 % in the RITUXAN HYCELA group compared with 8 % in the rituximab group , and the overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies