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CLINICAL NEWS |
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of PTS ( primary endpoint ) as a Villalta score ≥5 ( score ranges from 0-33 , with higher scores indicating more severe PTS ) or an ulcer in the leg . Secondary efficacy outcomes included severity of PTS and patient-reported health-related quality of life .
One patient in the pharmacomechanical thrombolysis group was excluded from analysis ; five in the control group and 11 in the treatment cohort were
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excluded within seven days of randomization and were not included in perprotocol analysis .
The treatment cohort received pharmacomechanical thrombolysis a median of one day after randomization ( range not provided ), and the mean degree of thrombus removal was 76 percent ( mean pre-procedure Marder score = 11.4 ; mean post-procedural Marder score = 2.7 ; change = – 8.7 %; 95 % CI – 8.1 to – 9.4 ; p < 0.001 ).
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Over the 24-month period , 47 percent of patients in the treatment cohort ( n = 157 / 336 ) and 48 percent in the control group ( n = 171 / 355 ) developed PTS ( risk ratio = 0.96 ; 95 % CI 0.82-1.11 ; p = 0.56 ). Incidence of PTS was similar among prespecified subgroups , except for a suggestion that patients 65 years and older were less likely to benefit from pharmacomechanical thrombolysis than younger patients ( p = 0.04 ). |
Although patients in the pharmacomechanical thrombolysis group experienced less-severe PTS and lower venous clinical severity scores than the control group , there were also no between-group differences in change in venous diseasespecific quality of life ( p = 0.08 ) or general quality of life ( p = 0.37 ).
Six patients ( 1.7 %) in the pharmacomechanical thrombolysis group experienced major bleeding within 10 days
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product , 76 % and 73 %, respectively , completed the full course . Dose modification due to adverse reactions occurred in 74 % of the GAZYVA arm and 63 % of the rituximab product arm throughout study treatment , and discontinuation of any study drug due to adverse reactions occurred in 18 % and 15 %, respectively . Throughout treatment and follow-up , the most common adverse reactions ( incidence ≥ 20 %) observed at least 2 % more in the GAZYVA arm included infusion related reactions , neutropenia , upper respiratory tract infection , cough , constipation and diarrhea ( Table 8 ). Neutropenia , infusion related reactions , febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions ( incidence ≥ 5 %) observed more frequently in the GAZYVA arm . Table 8 Common Adverse Reactions ( ≥ 10 % Incidence and ≥ 2 % Greater in the GAZYVA Arm ) in Patients with Previously Untreated NHL ( GALLIUM )
Body System Adverse
Reactions a , b
GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 691
All Grades %
Grades 3 to 5 %
Rituximab product + chemotherapy followed by rituximab product monotherapy n = 694
All Grades %
Grades 3 to 5 %
Injury , Poisoning and Procedural Complications Infusion Related
72 12 60 8
Reaction c
Blood and Lymphatic System Disorders Neutropenia d 53 49 47 41
Thrombocytopenia d 14 7 8 3 Infections and Infestations
Upper Respiratory Tract Infection
50 3 43 1
Herpesvirus Infection
18 3 14 1
Pneumonia 14 7 12 6 Respiratory , Thoracic and Mediastinal Disorders Cough 35 < 1 28 < 1 Gastrointestinal Disorders Constipation 32 < 1 29 < 1 Diarrhea 30 3 26 2 Nervous System Disorders Headache 18 < 1 15 < 1 Musculoskeletal and Connective Tissue Disorders Arthralgia 16 0 14 < 1 Psychiatric Disorders Insomnia 15 < 1 12 < 1 Metabolism and Nutrition Disorders
Decreased Appetite
14 < 1 12 < 1
Skin and Subcutaneous Tissue Disorders Alopecia 13 0 10 < 1 Pruritus 11 < 1 9 0 a
Includes adverse reactions reported throughout study treatment and follow-up . b
Includes grouped preferred terms . c
Except where noted , individual events that meet the definition of “ infusion related reaction ” are excluded from Table 8 above , as they are already included in the group term “ Infusion Related Reaction ”. The most common individual terms within the group term “ Infusion Related Reaction ” in decreasing order of frequency are nausea , chills , pyrexia and vomiting . d
Includes adverse reactions reported as infusion related reactions .
Infusion related reactions are defined as any related adverse reaction that occurred during or within 24 hours of infusion . Neutropenia includes neutropenia , agranulocytosis , febrile neutropenia , granulocytopenia and neutrophil count decreased ; febrile neutropenia includes febrile neutropenia , neutropenic infection , neutropenic sepsis , and febrile bone marrow aplasia . Thrombocytopenia includes thrombocytopenia and platelet count decreased . Upper respiratory tract infection includes upper respiratory tract congestion , upper respiratory tract inflammation , sinusitis bacterial , upper respiratory tract infection bacterial , pharyngitis streptococcal , sinusitis fungal , upper respiratory fungal infection , acute sinusitis , chronic sinusitis , laryngitis , nasopharyngitis , pharyngitis , rhinitis , sinusitis , tonsillitis , upper respiratory tract infection , rhinovirus infection , viral pharyngitis , viral rhinitis , viral upper respiratory tract infection . Herpesvirus infection includes genital herpes , genital herpes zoster , herpes dermatitis , herpes ophthalmic , herpes simplex , herpes simplex pharyngitis , herpes virus infection , herpes zoster , herpes zoster disseminated , herpes zoster infection neurological , herpes zoster oticus , nasal herpes , ophthalmic herpes simplex , ophthalmic herpes zoster , oral herpes , varicella , varicella zoster virus infection . Pneumonia includes pneumonia bacterial , pneumonia haemophilus , pneumonia pneumococcal , pneumonia fungal , pneumocystis jirovecii infection , pneumocystis jirovecii pneumonia , atypical pneumonia , lung infection , pneumonia , pneumonia aspiration , lung infiltration . Cough includes cough , productive cough , upperairway cough syndrome . Diarrhea includes diarrhea , defecation urgency , frequent bowel movement , gastroenteritis , gastroenteritis viral . Headache includes cluster headache , headache , sinus headache , tension headache , migraine . Insomnia includes initial insomnia , insomnia , sleep disorder . Pruritus includes pruritus and pruritus generalized .
During the monotherapy period , the common adverse reactions ( incidence ≥ 10 %) observed at least 2 % more with GAZYVA were upper respiratory tract infection ( 40 %), cough ( 23 %), musculoskeletal pain ( 20 %), neutropenia ( 19 %) and herpesvirus infection ( 13 %). Table 9 summarizes treatment-emergent laboratory abnormalities during treatment and follow-up . The Grade 3 to 4 abnormalities reported at least 2 % more in the GAZYVA arm were lymphopenia , leukopenia , neutropenia , thrombocytopenia and hyperuricemia . Patients in the GAZYVA arm , as compared to the rituximab product arm , had higher incidences of Grade 4 neutropenia ( 38 % vs . 30 %, respectively ), Grade 4 lymphopenia ( 33 % vs . 22 %), and Grade 4 leukopenia ( 17 % vs . 12 %).
Table 9 Common New or Worsening Laboratory Abnormalities ( ≥ 10 % Incidence and ≥ 2 % Greater in the GAZYVA Arm ) in Patients with Previously Untreated NHL ( GALLIUM )
Laboratory
Abnormalities a
GAZYVA + chemotherapy followed by GAZYVA monotherapy n = 691
All Grades %
Grades 3 to 4 %
Rituximab product + chemotherapy followed by rituximab product monotherapy n = 694
All Grades %
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Grades 3 to 4 %
Hematology |
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Lymphopenia |
97 |
83 |
95 |
67 |
Leukopenia |
92 |
49 |
89 |
39 |
Neutropenia |
84 |
59 |
76 |
50 |
Thrombocytopenia |
68 |
11 |
50 |
4 |
Chemistry |
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ALT / SGPT |
50 |
3 |
43 |
2 |
increased |
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AST / SGOT |
44 |
1 |
41 |
1 |
increased |
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Hypophosphatemia 36 |
5 |
33 |
5 |
Hypoalbuminemia |
33 |
1 |
25 |
1 |
Hypoproteinemia |
32 |
0 |
30 |
0 |
Hypocalcemia |
32 |
1 |
26 |
1 |
Hyperuricemia |
28 |
28 |
22 |
22 |
Hyponatremia |
26 |
4 |
20 |
3 |
Hyperkalemia |
23 |
1 |
17 |
1 |
Hypernatremia |
16 |
< 1 |
13 |
0 |
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a
Includes lab abnormalities , reported throughout treatment and followup
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, that were new or worsening , or worsening from baseline unknown . |
In the monotherapy phase , new-onset Grade 3 or 4 neutropenia was reported in 21 % of patients in the GAZYVA arm ( Grade 4 , 10 %) and 17 % of patients in the rituximab product arm ( Grade 4 , 9 %). Infusion Reactions : Chronic Lymphocytic Leukemia The incidence of infusion reactions in the CLL11 study was 65 % with the first infusion of GAZYVA . The incidence of Grade 3 or 4 infusion reactions was 20 % with 7 % of patients discontinuing therapy . The incidence of reactions with subsequent infusions was 3 % with the second 1000 mg and < 1 % thereafter . No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused . Of the first 53 patients receiving GAZYVA in CLL11 , 47 ( 89 %) experienced an infusion reaction . After this experience , study protocol modifications were made to require pre-medication with a corticosteroid , antihistamine , and acetaminophen . The first dose was also divided into two infusions ( 100 mg on day 1 and 900 mg on day 2 ). For the 140 patients for whom these mitigation measures were implemented , 74 patients ( 53 %) experienced a reaction with the first 1000 mg ( 64 patients on day 1 , 3 patients on day 2 , and 7 patients on both days ) and < 3 % thereafter [ see Dosage and Administration ( 2 )].
Non-Hodgkin Lymphoma Overall , 69 % of patients in the GADOLIN study experienced an infusion reaction ( all grades ) during treatment with GAZYVA in combination with bendamustine . The incidence of Grade 3 to 4 infusion reactions in GADOLIN was 11 %. In Cycle 1 , the incidence of infusion reactions ( all grades ) was 55 % in patients receiving GAZYVA in combination with bendamustine with Grade 3 to 4 infusion reactions reported in 9 %. In patients receiving GAZYVA in combination with bendamustine , the incidence of infusion reactions was highest on Day 1 ( 38 %), and gradually decreased on Days 2 , 8 and 15 ( 25 %, 7 % and 4 %, respectively ). During Cycle 2 , the incidence of infusion reactions was 24 % in patients receiving GAZYVA in combination with bendamustine and decreased with subsequent cycles . During GAZYVA monotherapy in GADOLIN , infusion reactions ( all grades ) were observed in 8 % of patients . No Grade 3 to 4 infusion reactions were reported during GAZYVA monotherapy . Overall , 2 % of patients in GADOLIN experienced an infusion reaction leading to discontinuation of GAZYVA . In GALLIUM , 72 % of patients in the GAZYVA treated arm experienced an infusion reaction ( all grades ). The incidence of Grade 3 to 4 infusion reactions for these patients was 12 %. In Cycle 1 , the incidence of infusion reactions ( all grades ) was 62 % in the GAZYVA treated arm with Grade 3 to 4 infusion reactions reported in 10 %. The incidence of infusion reactions ( all grades ) was highest on Day 1 ( 60 %), and decreased on Days 8 and 15 ( 9 % and 6 %, respectively ). During Cycle 2 , the incidence of infusion reactions ( all grades ) in the GAZYVA treated arm was 13 % and decreased with subsequent cycles . During GAZYVA monotherapy treatment in GALLIUM , infusion reactions ( all grades ) were observed in 9 % of patients . Overall , 1 % of patients in GALLIUM experienced an infusion reaction leading to discontinuation of GAZYVA . Neutropenia : Chronic Lymphocytic Leukemia The incidence of neutropenia reported as an adverse reaction in CLL11 was 38 % in the GAZYVA treated arm and 32 % in the rituximab product treated arm , with the incidence of serious adverse reactions being 1 % and < 1 %, respectively ( Table 4 ). Cases of late-onset neutropenia ( occurring 28 days after completion of treatment or later ) were 16 % in the GAZYVA treated arm and 12 % in the rituximab product treated arm . Non-Hodgkin Lymphoma The incidence of neutropenia in GADOLIN was higher in the GAZYVA plus bendamustine arm ( 38 %) compared to the arm treated with bendamustine alone ( 32 %). Cases of prolonged neutropenia ( 3 %) and late onset neutropenia ( 7 %) were also reported in the GAZYVA plus bendamustine arm . The incidence of neutropenia was higher during treatment with GAZYVA in combination with bendamustine ( 31 %) compared to the GAZYVA monotherapy treatment phase ( 12 %). The incidence of neutropenia in GALLIUM was higher in the GAZYVA treated arm ( 53 %) compared to the rituximab product treated arm ( 47 %). Cases of prolonged neutropenia ( 1 %) and late onset neutropenia ( 4 %) were also reported in the GAZYVA treated arm . The incidence of neutropenia was higher during treatment with GAZYVA in combination with chemotherapy ( 45 %) compared to the GAZYVA monotherapy treatment phase ( 20 %). Infection : Chronic Lymphocytic Leukemia The incidence of infections was similar between GAZYVA and rituximab product treated arms . Thirty-eight percent of patients in the GAZYVA treated arm and 37 % in the rituximab product treated arm experienced an infection , with Grade 3 to 4 rates being 11 % and 13 %, respectively . Fatal events were reported in 1 % of patients in both arms . Non-Hodgkin Lymphoma The incidence of infection in GADOLIN was 66 % in the GAZYVA plus bendamustine arm and 56 % in the bendamustine arm , with Grade 3 to 4 events reported in 16 % and 14 %, respectively . Fatal events were reported in 3 % of patients in the GAZYVA plus bendamustine arm and 4 % in the bendamustine arm . The incidence of infections in GALLIUM was 82 % in the GAZYVA treated arm and 73 % in the rituximab product treated arm , with Grade 3 to 4 events reported in 21 % and 17 %, respectively . In the GAZYVA arm , fatal infections occurred in 2 % of patients compared to < 1 % in the rituximab product arm .