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CLINICAL NEWS |
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cytogenetic abnormalities were complex karyotypes ( 44 %) and isolated abnormalities of chromosome 7 ( 28 %).
Researchers performed WES at the time of diagnosis on bone marrow ( BM ) mononuclear cells ( MNC ; n = 6 ) or PB MNC ( n = 1 ). WES revealed a median of 27 somatically acquired mutations ( range = 9-29 mutations ). TP53 was the most common mutation among seven patients who developed tMN after AHCT ( n = 4 ).
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“ We observed that tMNs are characterized by significantly increased mutation load , [ compared with ] de novo myelodysplastic syndromes ( MDS ),” the authors wrote . For de novo MDS , there was no correlation between Revised International Prognostic Scoring System assessment and total number of mutations ( median = 12 for both very low / low and intermediate / high ; p = 0.9266 ). However , there was a significantly higher number of mutations |
identified in tMN versus de novo MDS ( median = 27 vs . 12 ; p = 0.001 ).
The researchers also performed a mutational signature analysis ( n = 7 for tMN and n = 11 for de novo MDS ) and observed that “ the mutations found in tMN did not carry a clear aging-signature , unlike the mutations found in de novo MDS , indicating a different mutational mechanism .”
Clonal hematopoiesis of indeterminate potential ( CHIP ) at the time of AHCT
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was demonstrated in seven of 10 cases ( 70 %), and variant allele frequencies ( VAFs ) ranged between 0.1 and 8 percent . “ Our data suggest that determination of CHIP following AHCT becomes even more important when there is the intention to treat the patient with agents that could impose an extra selective pressure on the hematopoietic system ,” the authors concluded .
Next , researchers tracked all mutations
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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
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