Literature Scan |
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DVT ,” explained Suresh Vedantham , MD , of Washington University in St . Louis , Missouri , and co-authors . “ We hypothesized that pharmacomechanical thrombolysis would reduce this percentage to 20 percent or lower ,” but nearly half of patients enrolled in the multicenter , open-label trial still developed PTS within 24 months of DVT .
The ATTRACT ( Acute Venous Thrombosis : Thrombus Removal with
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Adjunctive Catheter-Directed Thrombolysis ) trial included 692 patients with symptomatic proximal DVT involving the femoral , common femoral , or iliac vein . Patients were excluded if they were symptomatic for > 14 days , were at high risk for bleeding , had active cancer , had PTS , or had ipsilateral DVT in the previous two years .
Between December 2009 and December 2014 , patients were stratified based on
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thrombus extent ( i . e ., whether thrombosis involved the common femoral or iliac vein or not ), then randomized 1:1 to receive pharmacomechanical thrombolysis ( n = 336 ; median age = 52 years ; range = 41-62 years ) or no procedural intervention ( control ; n = 355 ; median age = 53 years ; range = 43-62 years ).
Participants in both cohorts received initial and long-term anticoagulation consistent with published guidelines ( including
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rivaroxaban when it became available ) and received sized-to-fit , knee-high , elastic compression stockings at the 10-day follow-up visit and every six months .
In the pharmacomechanical thrombolysis group , recombinant tissue plasminogen activator < 35 mg was administered into the thrombus .
Researchers assessed outcomes at 10 and 30 days , as well as six , 12 , 18 , and 24 months . They defined the development
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rates in Stage 1 . In addition to the adverse reactions observed in Stage 2 , in Stage 1 back pain ( 5 % vs . 2 %), anemia ( 12 % vs . 10 %) and cough ( 10 % vs . 7 %) were observed at a higher incidence in the obinutuzumab treated patients . The incidence of Grade 3 to 4 back pain (< 1 % vs . 0 %), cough ( 0 % vs . < 1 %) and anemia ( 5 % vs . 4 %) was similar in both treatment arms . With regard to laboratory abnormalities , in Stage 1 hyperkalemia ( 33 % vs . 18 %), creatinine increased ( 30 % vs . 20 %) and alkaline phosphatase increased ( 18 % vs . 11 %) were observed at a higher incidence in patients treated with obinutuzumab with similar incidences of Grade 3 to 4 abnormalities between the two arms .
Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil ( 6 cycles of 28 days each in total ). In the last 140 patients enrolled , the first dose of GAZYVA was split between day 1 ( 100 mg ) and day 2 ( 900 mg ) [ see Dosage and Administration ( 2.1 )]. In total , 81 % of patients received all 6 cycles ( of 28 days each ) of GAZYVA-based therapy .
The most common adverse reactions ( incidence ≥ 10 %) observed in patients with CLL in the GAZYVA containing arm were infusion reactions , neutropenia , thrombocytopenia , anemia , pyrexia , cough , nausea , and diarrhea .
The most common Grade 3 to 4 adverse reactions ( incidence ≥ 10 %) observed in patients with CLL in the GAZYVA containing arm were neutropenia , infusion reactions , and thrombocytopenia . Table 4 Summary of Adverse Reactions Reported in ≥ 5 % of Patients with CLL and at Least 2 % Greater in the GAZYVA Treated Arm ( Stage 2 )
Body System Adverse Reactions
GAZYVA + Chlorambucil n = 336
All Grades %
Grades 3 to 4 %
Rituximab product + Chlorambucil n = 321
All Grades %
Grades 3 to 4 %
Injury , Poisoning and Procedural Complications |
Infusion Related |
66 |
20 |
38 |
4 |
Reaction |
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Blood and Lymphatic System Disorders a |
Neutropenia |
38 |
33 |
32 |
28 |
Thrombocytopenia |
14 |
10 |
7 |
3 |
Leukopenia |
6 |
4 |
2 |
< 1 |
General Disorders and Administration Site Conditions |
Pyrexia |
9 |
< 1 |
7 |
< 1 |
Gastrointestinal Disorders |
Diarrhea |
10 |
2 |
8 |
< 1 |
Constipation |
8 |
0 |
5 |
0 |
Infections and Infestations |
Nasopharyngitis |
6 |
< 1 |
3 |
0 |
Urinary Tract |
5 |
1 |
2 |
< 1 |
Infection |
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a
Adverse reactions reported under “ Blood and lymphatic system
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disorders ” reflect those reported by investigator as clinically significant . |
Table 5 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5 % of Patients with CLL and at Least 2 % Greater in the GAZYVA Treated Arm ( Stage 2 )
Laboratory Abnormalities
GAZYVA + Chlorambucil n = 336
All Grades %
Grades 3 to 4 %
Rituximab product + Chlorambucil n = 321
All Grades %
Grades 3 to 4 %
Hematology Neutropenia |
76 |
46 |
69 |
41 |
Lymphopenia |
80 |
39 |
50 |
16 |
Leukopenia |
84 |
35 |
62 |
16 |
Thrombocytopenia 48 |
13 |
40 |
8 |
Anemia |
39 |
10 |
37 |
10 |
Chemistry Hypocalcemia |
37 |
3 |
32 |
< 1 |
Hypokalemia |
14 |
1 |
10 |
< 1 |
Hyponatremia |
26 |
7 |
18 |
2 |
AST / SGOT |
27 |
2 |
21 |
< 1 |
increased |
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ALT / SGPT |
28 |
2 |
21 |
1 |
increased |
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Hypoalbuminemia |
23 |
< 1 |
16 |
< 1 |
Summary of Clinical Trial Experience in Non-Hodgkin Lymphoma
GADOLIN The GADOLIN study evaluated safety in 392 patients with relapsed or refractory NHL , including FL ( 81 %), small lymphocytic lymphoma and marginal zone lymphoma ( a disease for which GAZYVA is not indicated ), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen . In the population of patients with FL , the profile of adverse reactions was consistent with the overall NHL population . Patients were treated with either GAZYVA in combination with bendamustine , followed by GAZYVA monotherapy in patients that have not progressed , or with bendamustine alone .
Patients randomized to the GAZYVA + bendamustine arm received three weekly 1000 mg doses of GAZYVA in the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with bendamustine 90 mg / m 2 on Days 1 and 2 in all 6 cycles . Patient randomized to the bendamustine alone arm received 120 mg / m 2 on Days 1 and 2 . This regimen continued for 6 cycles of 28 days in duration . For patients who did not progress on GAZYVA in combination with bendamustine , a single dose of 1000 mg GAZYVA monotherapy was given every two months until progression or for a maximum of two years . During combination therapy with GAZYVA and bendamustine , 79 % of patients received all 6 treatment cycles of GAZYVA and 76 % received all 6 treatment cycles of bendamustine compared to 67 % of patients in the bendamustine alone arm .
The most common adverse reactions ( incidence ≥ 10 %) observed in GADOLIN in the GAZYVA containing arm were infusion reactions , neutropenia , nausea , fatigue , cough , diarrhea , constipation , pyrexia , thrombocytopenia , vomiting , upper respiratory tract infection , decreased appetite , arthralgia , sinusitis , anemia , asthenia and urinary tract infection .
The most common Grade 3 to 4 adverse reactions ( incidence ≥ 10 %) observed in GADOLIN in the GAZYVA containing arm were neutropenia , thrombocytopenia and infusion reactions .
Table 6 Summary of Adverse Reactions Reported in ≥ 5 % of Patients with Relapsed or Refractory NHL and at Least 2 % Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arm ( GADOLIN )
Body System Adverse Reactions
GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 194
All Grades %
Grades 3 to 4 %
Bendamustine n = 198
Print-only content
All Grades %
Grades 3 to 4 %
Injury , Poisoning and Procedural Complications |
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Infusion Related
69
11
63
6
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Reaction a |
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Blood and Lymphatic System Disorders |
Neutropenia |
35 |
33 |
28 |
26 |
Gastrointestinal Disorders |
Constipation |
19 |
0 |
16 |
0 |
Dyspepsia |
5 |
0 |
3 |
0 |
General Disorders and Administration Site Conditions |
Pyrexia |
18 |
1 |
14 |
0 |
Asthenia |
11 |
1 |
8 |
0 |
Infections and Infestations |
Upper |
13 |
2 |
8 |
1 |
Respiratory Tract Infection |
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Sinusitis |
12 |
1 |
5 |
0 |
Urinary Tract |
10 |
3 |
6 |
0 |
Infection |
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Nasopharyngitis |
9 |
0 |
4 |
0 |
Musculoskeletal and Connective Tissue Disorders |
Arthralgia |
12 |
0 |
5 |
0 |
Pain in Extremity |
9 |
1 |
4 |
0 |
Respiratory , Thoracic and Mediastinal Disorders |
Cough |
26 |
0 |
17 |
0 |
Nasal Congestion |
7 |
0 |
2 |
0 |
Skin and Subcutaneous Tissue Disorders |
Pruritus |
9 |
0 |
6 |
0 |
a
Defined as any related adverse reaction that occurred during or within 24 hours of infusion .
During the monotherapy period with GAZYVA , the most common adverse reactions ( incidence ≥ 5 %) in GADOLIN were cough ( 15 %), upper respiratory tract infections ( 12 %), neutropenia ( 11 %), sinusitis ( 10 %), diarrhea ( 8 %), infusion related reactions ( 8 %), nausea ( 8 %), fatigue ( 8 %), bronchitis ( 7 %), arthralgia ( 7 %), pyrexia ( 6 %), nasopharyngitis ( 6 %), and urinary tract infection ( 6 %). Grade 3 to 4 adverse reactions during the monotherapy period included neutropenia ( 10 %) and , at 1 % each , anemia , febrile neutropenia , thrombocytopenia , sepsis , upper respiratory tract infection , and urinary tract infection .
Table 7 Post-Baseline Laboratory Abnormalities by CTCAE Grade in ≥ 5 % of Patients with Relapsed or Refractory NHL and at Least 2 % Greater in the GAZYVA plus Bendamustine Followed by GAZYVA Monotherapy Treated Arm a ( GADOLIN )
Laboratory Abnormalities
GAZYVA + Bendamustine followed by GAZYVA monotherapy n = 194
All Grades %
Grades 3 to 4 %
Bendamustine n = 198
All Grades %
Grades 3 to 4 %
Hematology |
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Neutropenia |
75 |
52 |
77 |
42 |
Leukopenia |
86 |
47 |
88 |
34 |
Lymphopenia |
99 |
93 |
99 |
85 |
Chemistry |
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Hypocalcemia |
38 |
2 |
26 |
2 |
Hypophosphatemia 41 |
7 |
38 |
7 |
ALT / SGPT |
35 |
1 |
31 |
4 |
increased |
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Elevated |
87 |
4 |
92 |
2 |
creatinine |
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Creatinine |
58 |
6 |
61 |
4 |
clearance |
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decreased |
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a
Two percent different in either the All Grades or Grade 3 to 4 Lab
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Abnormalities . |
In the monotherapy phase of treatment with GAZYVA , the most frequently reported hematological laboratory abnormalities ( incidence ≥ 20 %) were lymphopenia ( 80 %), leukopenia ( 63 %), low hemoglobin ( 50 %), neutropenia ( 46 %) and thrombocytopenia ( 35 %). The most frequently reported hematological Grade 3 to 4 laboratory abnormalities ( incidence ≥ 1 %) during the monotherapy period were lymphopenia ( 52 %), neutropenia ( 27 %), leukopenia ( 20 %) and thrombocytopenia ( 4 %). In the monotherapy phase of treatment with GAZYVA , the most frequently reported chemistry laboratory abnormalities ( incidence ≥ 20 %) were elevated creatinine ( 69 %), decreased creatinine clearance ( CrCl ; 43 %), hypophosphatemia ( 25 %), AST / SGOT increased ( 24 %) and ALT / SGPT increased ( 21 %). The most frequently reported chemistry Grade 3 to 4 laboratory abnormalities ( incidence ≥ 1 %) during the monotherapy period were hypophosphatemia ( 5 %), hyponatremia ( 3 %) and decreased CrCl ( 1 %). GALLIUM A randomized , open-label multicenter trial ( GALLIUM ) evaluated the safety of GAZYVA as compared to rituximab product in 1385 patients with previously untreated follicular lymphoma ( 86 %) or marginal zone lymphoma ( 14 %). Patients received chemotherapy ( bendamustine , CHOP , or CVP ) combined with either GAZYVA ( 691 patients ) or rituximab product ( 694 patients ), followed in responding patients by GAZYVA or rituximab product monotherapy every two months until disease progression or for a maximum of two years . The study excluded patients having an absolute neutrophil count ( ANC ) < 1500 / μL , platelets < 75,000 / μL , CrCl < 40 mL / min and , unless attributable to lymphoma , hepatic transaminases > 2.5 x upper limit of normal . The median age was 60 ( range : 23-88 ), 47 % were male , 82 % were white , and 97 % had an ECOG performance status of 0 or 1 . The chemotherapy was bendamustine in 59 %, CHOP in 31 % and CVP in 10 % of patients . Following combination therapy , 624 patients ( 90 %) in the GAZYVA arm and 612 patients ( 88 %) in the rituximab product arm received monotherapy . Serious adverse reactions occurred in 50 % of patients on the GAZYVA arm and 43 % of patients on the rituximab product arm . Fatal adverse reactions were reported during treatment in 3 % in the GAZYVA arm and 2 % in the rituximab product arm , most often from infections in the GAZYVA arm . During treatment and follow-up combined , fatal adverse reactions were reported in 5 % of the GAZYVA arm and 4 % of the rituximab product arm , with infections and second malignancies being leading causes . In the GAZYVA arm , fatal infections occurred in 2 % of patients compared to < 1 % in the rituximab product arm . During combination therapy , 93 % of patients received all treatment cycles in the GAZYVA arm , and 92 % received all treatment cycles in the rituximab product arm . Of the responding patients who began monotherapy with GAZYVA or rituximab