ASH Clinical News ACN_4.8_Final_digital | Page 46

On Location Conference Coverage

Manipulating Natural Killer Cells to Fight Myeloma

Using cord blood – derived natural killer ( NK ) cells in hematopoietic cell transplantation ( HCT ) appears to enhance the effectiveness of the transplant in patients with myeloma , according to updated results from a phase II trial . More than three-quarters of participants ( n = 26 / 33 ) experienced at least a very good partial response ( VGPR ) at day 100 , the study ’ s primary endpoint .
Nina Shah , MD , from the University of California San
Francisco and Helen Diller Family Comprehensive Cancer Center , shared the findings at the 2018 ASCO Annual Meeting , reporting that using cord blood – derived allogeneic NK cells in the setting of high-dose melphalan and autologous HCT is “ a promising adjunct immunotherapy .”
“ Patients who undergo HCT have long-term remission , suggesting an immune-mediated graft-versusmyeloma effect , so we ’ ve been interested in NK cells [ for this patient population ],” she explained . “ Cord blood is a known source of hematopoietic cells that is immediately available , does not require donor manipulation , and has more flexibility in matching .”
The trial included 33 adults ( median age = 59 years ; range = 25-72 years ) with symptomatic MM who were considered eligible for autologous HCT . Participants were also required to have at least a 4 / 6 HLA-matched cord
BESPONSA ( inotuzumab ozogamicin ) for injection , for intravenous use
Initial U . S . Approval : 2017
Brief Summary of Prescribing Information
WARNING : HEPATOTOXICITY , INCLUDING HEPATIC VENO-OCCLUSIVE DISEASE ( VOD ) ( ALSO KNOWN AS SINUSOIDAL OBSTRUCTION SYNDROME and INCREASED RISK OF POST-HEMATOPOIETIC STEM CELL TRANSPLANT ( HSCT ) NON-RELAPSE MORTALITY
HEPATOTOXICITY , INCLUDING VOD
• Hepatotoxicity , including fatal and life-threatening VOD occurred in patients with relapsed or refractory acute lymphoblastic leukemia ( ALL ) who received BESPONSA . The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment ; use of HSCT conditioning regimens containing 2 alkylating agents and last total bilirubin level ≥ upper limit of normal ( ULN ) before HSCT were significantly associated with an increased risk of VOD .
• Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease , prior HSCT , increased age , later salvage lines , and a greater number of BESPONSA treatment cycles .
• Elevation of liver tests may require dosing interruption , dose reduction , or permanent discontinuation of BESPONSA . Permanently discontinue treatment if VOD occurs . If severe VOD occurs , treat according to standard medical practice .
INCREASED RISK OF POST-HSCT NON-RELAPSE MORTALITY
• There was higher post-HSCT non-relapse mortality rate in patients receiving BESPONSA , resulting in a higher Day 100 post-HSCT mortality rate .
1 . INDICATIONS AND USAGE BESPONSA is indicated for the treatment of adults with relapsed or refractory B-cell precursor ALL .
5 . WARNINGS AND PRECAUTIONS
5.1 Hepatotoxicity , Including Hepatic VOD ( also known as Sinusoidal Obstruction Syndrome [ SOS ]) In the INO-VATE ALL trial , hepatotoxicity , including severe , life-threatening , and sometimes fatal hepatic VOD was observed in 23 / 164 patients ( 14 %) in the BESPONSA arm during or following treatment or following a HSCT after completion of treatment . VOD was reported up to 56 days after the last dose during treatment or during follow-up without an intervening HSCT . The median time from subsequent HSCT to onset of VOD was 15 days ( range : 3-57 days ). In the BESPONSA arm , among the 79 patients who proceeded to a subsequent HSCT , VOD was reported in 18 / 79 patients ( 23 %), and among all 164 patients treated , VOD was reported in 5 / 164 patients ( 3 %) during study therapy or in follow-up without an intervening HSCT . The risk of VOD was greater in patients who underwent HSCT after BESPONSA treatment ; use of HSCT conditioning regimens containing 2 alkylating agents ( e . g ., busulfan in combination with other alkylating agents ) and last total bilirubin level ≥ ULN before HSCT are significantly associated with an increased risk of VOD . Other risk factors for VOD in patients treated with BESPONSA included ongoing or prior liver disease , prior HSCT , increased age , later salvage lines , and a greater number of BESPONSA treatment cycles . Patients who have experienced prior VOD or have serious ongoing hepatic liver disease ( e . g ., cirrhosis , nodular regenerative hyperplasia , active hepatitis ) are at an increased risk for worsening of liver disease , including developing VOD , following treatment with BESPONSA . Monitor closely for signs and symptoms of VOD ; these may include elevations in total bilirubin , hepatomegaly ( which may be painful ), rapid weight gain , and ascites . Due to the risk of VOD , for patients proceeding to HSCT , the recommended duration of treatment with BESPONSA is 2 cycles ; a third cycle may be considered for those patients who do not achieve a CR or CRi and MRD negativity after 2 cycles . For patients who proceed to HSCT , monitor liver tests closely during the first month post-HSCT , then less frequently thereafter , according to standard medical practice . In the INO-VATE ALL trial , increases in liver tests were reported . Grade 3 / 4 AST , ALT , and total bilirubin abnormal liver tests occurred in 7 / 160 ( 4 %), 7 / 161 ( 4 %), and 8 / 161 patients ( 5 %), respectively . In all patients , monitor liver tests , including ALT , AST , total bilirubin , and alkaline phosphatase , prior to and following each dose of BESPONSA . Elevations of liver tests may require dosing interruption , dose reduction , or permanent discontinuation of BESPONSA . 5.2 Increased Risk of Post-Transplant Non-Relapse Mortality In the INO-VATE ALL trial , a higher post-HSCT non-relapse mortality rate was observed in patients receiving BESPONSA compared to the Investigator ’ s choice of chemotherapy arm ( standard chemotherapy [ SC ]), resulting in a higher Day 100 post-HSCT mortality rate . Overall , 79 / 164 patients ( 48 %) in the BESPONSA arm and 35 / 162 patients ( 22 %) in the SC arm had a follow-up HSCT . The post-HSCT non-relapse mortality rate was 31 / 79 ( 39 %) and 8 / 35 ( 23 %) in the BESPONSA arm compared to the SC arm , respectively . In the BESPONSA arm , the most common causes of post-HSCT non-relapse mortality included VOD and infections . Five of the 18 VOD events that occurred post-HSCT were fatal . In the BESPONSA arm , among patients with ongoing VOD at time of death , 6 patients died due to multiorgan failure ( MOF ) or infection ( 3 patients died due to MOF , 2 patients died due to infection , and 1 patient died due to MOF and infection ). Monitor closely for toxicities post-HSCT , including signs and symptoms of infection and VOD . 5.3 Myelosuppression In the INO-VATE ALL trial , myelosuppression was observed in patients receiving BESPONSA . Thrombocytopenia and neutropenia were reported in 83 / 164 patients ( 51 %) and 81 / 164 patients ( 49 %), respectively . Grade 3 thrombocytopenia and neutropenia were reported in 23 / 164 patients ( 14 %) and 33 / 164 patients ( 20 %), respectively . Grade 4 thrombocytopenia and neutropenia were reported in 46 / 164 patients ( 28 %) and 45 / 164 patients ( 27 %), respectively . Febrile neutropenia , which may be life-threatening , was reported in 43 / 164 patients ( 26 %). For patients who were in CR or CRi at the end of treatment , the recovery of platelets counts to > 50,000 / mm 3 was later than 45 days after the last dose in 15 / 164 patients ( 9 %) who received BESPONSA and 3 / 162 patients ( 2 %) who received SC . Complications associated with myelosuppression ( including infections and bleeding / hemorrhagic events ) were observed in patients receiving BESPONSA . Infections , including serious infections , some of which were life-threatening or fatal , were reported in 79 / 164 patients ( 48 %). Fatal infections , including pneumonia , neutropenic sepsis , sepsis , septic shock , and pseudomonal sepsis , were reported in 8 / 164 patients ( 5 %). Bacterial , viral , and fungal infections were reported . Hemorrhagic events were reported in 54 / 164 patients ( 33 %). Grade 3 or 4 hemorrhagic events were reported in 8 / 164 patients ( 5 %). One Grade 5 ( fatal ) hemorrhagic event ( intra-abdominal hemorrhage ) was reported in 1 / 164 patients ( 1 %). The most common hemorrhagic event was epistaxis which was reported in 24 / 164 patients ( 15 %). Monitor complete blood counts prior to each dose of BESPONSA and monitor for signs and symptoms of infection , bleeding / hemorrhage , or other effects of myelosuppression during treatment with BESPONSA . As appropriate , administer prophylactic anti-infectives and employ surveillance testing during and after treatment with BESPONSA . Management of severe infection , bleeding / hemorrhage , or other effects of myelosuppression , including severe neutropenia or thrombocytopenia , may require dosing interruption , dose reduction , or permanent discontinuation of BESPONSA . 5.4 Infusion Related Reactions In the INO-VATE ALL trial , infusion related reactions were observed in patients who received BESPONSA . Infusion related reactions ( all Grade 2 ) were reported in 4 / 164 patients ( 2 %). Infusion related reactions generally occurred in Cycle 1 shortly after the end of the BESPONSA infusion and resolved spontaneously or with medical management . Premedicate with a corticosteroid , antipyretic , and antihistamine prior to dosing . Monitor patients closely during and for at least 1 hour after the end of infusion for the potential onset of infusion related reactions , including symptoms such as fever , chills , rash , or breathing problems . Interrupt infusion and institute appropriate medical management if an infusion related reaction occurs . Depending on the severity of the infusion related reaction , consider discontinuation of the infusion or administration of steroids and antihistamines . For severe or life-threatening infusion reactions , permanently discontinue BESPONSA . 5.5 QT Interval Prolongation In the INO-VATE ALL trial , increases in QT interval corrected for heart rate using Fridericia ’ s formula ( QTcF ) of ≥ to 60 msec from baseline were measured in 4 / 162 patients ( 3 %). No patients had QTcF values greater than 500 msec . Grade 2 QT prolongation was reported in 2 / 164 patients ( 1 %). No ≥ Grade 3 QT prolongation or events of Torsade de Pointes were reported . Administer BESPONSA with caution in patients who have a history of or predisposition for QTc prolongation , who are taking medicinal products that are known to prolong QT interval , and in patients with electrolyte disturbances . Obtain electrocardiograms ( ECGs ) and electrolytes prior to the start of treatment , after initiation of any drug known to prolong QTc , and periodically monitor as clinically indicated during treatment . 5.6 Embryo-Fetal Toxicity BESPONSA can cause embryo-fetal harm when administered to a pregnant woman . In animal studies , inotuzumab ozogamicin caused embryo-fetal toxicities , starting at a dose that was approximately 0.4 times the exposure in patients at the maximum recommended dose , based on the area under the concentration-time curve ( AUC ). Advise females of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 8 months after the final dose of BESPONSA . Advise males with female partners of reproductive potential to use effective contraception during treatment with BESPONSA and for at least 5 months after the last dose of BESPONSA . Apprise pregnant women of the potential risk to the fetus . Advise women to contact their healthcare provider if they become pregnant or if pregnancy is suspected during treatment with BESPONSA .
6 . ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the label : Hepatotoxicity , including hepatic VOD . Increased risk of post-transplant non-relapse mortality . Myelosuppression . Infusion related reactions . QT interval prolongation 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . The adverse reactions described in this section reflect exposure to BESPONSA in 164 patients with relapsed or refractory ALL who participated in a randomized clinical study of BESPONSA versus SC ( fludarabine + cytarabine + granulocyte colony-stimulating factor [ FLAG ], mitoxantrone + cytarabine [ MXN / Ara-C ], or high dose cytarabine [ HIDAC ]) ( INO-VATE ALL Trial [ NCT01564784 ]). Of the 164 patients who received BESPONSA , the median age was 47 years ( range : 18-78 years ), 56 % were male , 68 % had received 1 prior treatment regimen for ALL , 31 % had received 2 prior treatment regimens for ALL , 68 % were White , 19 % were Asian , and 2 % were Black . In patients who received BESPONSA , the median duration of treatment was 8.9 weeks ( range : 0.1-26.4 weeks ), with a median of 3 treatment cycles started in each patient . In patients who received SC , the median duration of treatment was 0.9 weeks ( range : 0.1-15.6 weeks ), with a median of 1 treatment cycle started in each patient . In patients who received BESPONSA , the most common ( ≥ 20 %) adverse reactions were thrombocytopenia , neutropenia , infection , anemia , leukopenia , fatigue , hemorrhage , pyrexia , nausea , headache , febrile neutropenia , transaminases increased , abdominal pain , gamma-glutamyltransferase increased , and hyperbilirubinemia . In patients who received BESPONSA , the most common ( ≥ 2 %) serious adverse reactions were infection , febrile neutropenia , hemorrhage , abdominal pain , pyrexia , VOD , and fatigue . In patients who received BESPONSA , the most common ( ≥ 2 %) adverse reactions reported as the reason for permanent discontinuation were infection ( 6 %), thrombocytopenia ( 2 %), hyperbilirubinemia ( 2 %), transaminases increased ( 2 %), and hemorrhage ( 2 %); the most common ( ≥ 5 %) adverse reactions reported as the reason for dosing interruption were neutropenia ( 17 %), infection ( 10 %), thrombocytopenia ( 10 %), transaminases increased ( 6 %), and febrile neutropenia ( 5 %); and the most common ( ≥ 1 %) adverse reactions reported as the reason for dose reduction were neutropenia ( 1 %), thrombocytopenia ( 1 %), and transaminases increased ( 1 %). VOD was reported in 23 / 164 patients ( 14 %) who received BESPONSA during or following treatment or following a HSCT after completion of treatment .
Adverse Reactions ( All Grades [%]; ≥Grade 3 [%]) With ≥10 % Incidence a in Patients With Relapsed or Refractory B-Cell Precursor ALL Who Received BESPONSA ( N = 164 ) were infection b ( 48 ; 28 ), thrombocytopenia c ( 51 ; 42 ), neutropenia d ( 49 ; 48 ), anemia e ( 36 ; 24 ), leukopenia f ( 35 ; 33 ), febrile neutropenia ( 26 ; 26 ), lymphopenia g ( 18 ; 16 ), decreased appetite ( 12 ; 1 ), headache h ( 28 ; 2 ), hemorrhage i ( 33 ; 5 ), nausea ( 31 ; 2 ), abdominal pain j ( 23 ; 3 ), diarrhea ( 17 ; 1 ), constipation ( 16 ; 0 ), vomiting ( 15 ; 1 ), stomatitis k ( 13 ; 2 ), hyperbilirubinemia ( 21 ; 5 ), fatigue l ( 35 ; 5 ), pyrexia ( 32 ; 3 ), chills ( 11 ; 0 ), transaminases increased m ( 26 ; 7 ), gamma-glutamyltransferase increased ( 21 ; 10 ), and alkaline phosphatase increased ( 13 ; 2 ).
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