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detected by WES at tMN diagnosis ( n = 7 cases ) using targeted deep sequencing . Transformation from MDS to acute myeloid leukemia ( AML ) was accompanied by the acquisition of mutations .
Four years post-AHCT , all mutations present at AML diagnosis could be detected at VAFs of 12 to 25 percent . Reconstruction of clonal patterns based on VAFs showed that pre-malignant clones can be present more than seven years before tMN diagnosis .
The researchers also examined the presence of high p53-protein expressing cells ( p53 ++) for specific tMN cases . Patients who displayed 5 percent or greater p53 ++ cells had confirmed TP53 mutation . Pre-leukemic biopsies were evaluated for p53 expression , and in all cases clear clusters of p53 ++ cells were detected up to three years prior to tMN diagnosis , which demonstrates that “ small pre-leukemic clones are present
in the BM of patients years before tMN diagnosis .”
Treatment also impacted mutations , “ by both causing stabilization or outgrowth of pre-leukemic clones ,” the authors noted .
“ The presence of CHIP may be correlated to a more general dysfunction of the HSC compartment and the surrounding microenvironment that may favor the outgrowth of pre-leukemic clones ,” the researchers concluded . “ Our
results would argue for regular monitoring of patients ’ PB counts following AHCT .”
The study is limited by its small patient population . Also , this analysis was restricted to WES-identified mutations that could be confirmed by targeted deep sequencing ; considering all mutations found by wholegenome sequencing may identify different mutational profiles .
“ Future research , preferentially based
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 %
Grades 3 to 4 %
Hematology
Lymphopenia
97
83
95
67
Leukopenia
92
49
89
39
Neutropenia
84
59
76
50
Thrombocytopenia
68
11
50
4
Chemistry
ALT / SGPT
50
3
43
2
increased
AST / SGOT
44
1
41
1
increased
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
a
Includes lab abnormalities , reported throughout treatment and followup
, 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 .