FEATURE
Drawing First Blood
Dr . Erba : Of course , there are other clinical questions that also need to be resolved , such as how CPX-351 can be used in combination with other approved drugs . Should we add midostaurin ? Should we add gemtuzumab ozogamicin ?
Also , what do we do if a patient is not responding to CPX-351 induction ? Typically , with 7 + 3 chemotherapy , if the patient has cytoreduction at day 14 , he or she is supposed to get a reinduction , but what if a patient has no change in their BM after CPX-351 ? We don ’ t yet know what to do . Personally ,
I would switch them to a high-dose cytarabinecontaining regimen .
Dr . Stone : Yes , that ’ s another thing that ’ s never been proven for 7 + 3 treatment failures . I feel like the next step is 5 + 2 , but many people move to high-dose cytarabine .
Dr . Erba : In the pivotal trial , CPX-351 was administered in the inpatient setting for the vast majority of individuals ( 98 %). As consolidation , it was administered via 90-minute infusion , which could potentially be given in the outpatient setting .
Patients presenting with AML are often ill with neutropenia , are getting transfusions , or are in disseminated intravascular coagulation and need to be admitted . In patients who are not ill , though , there is a debate about whether CPX-351 can be given in the outpatient setting during induction . This approach would require close monitoring , and I recommend it only be used in a patient who can reliably get back to the hospital quickly because it is a myelosuppressive drug with a similar toxicity profile to 7 + 3 .
ADYNOVATE ® [ Antihemophilic Factor ( Recombinant ), PEGylated ] Lyophilized Powder for Solution For Intravenous Injection Brief Summary of Prescribing Information : Please see package insert for full Prescribing Information .
INDICATIONS AND USAGE
ADYNOVATE , Antihemophilic Factor ( Recombinant ), PEGylated , is a human antihemophilic factor indicated in children and adults with hemophilia A ( congenital factor VIII deficiency ) for :
• On-demand treatment and control of bleeding episodes
• Perioperative management
• Routine prophylaxis to reduce the frequency of bleeding episodes
Limitation of Use ADYNOVATE is not indicated for the treatment of von Willebrand disease . CONTRAINDICATIONS
ADYNOVATE is contraindicated in patients who have had prior anaphylactic reaction to ADYNOVATE , to the parent molecule ADVATE ® ( Antihemophilic Factor [ Recombinant ]), mouse or hamster protein , or excipients of ADYNOVATE ( e . g . Tris , mannitol , trehalose , glutathione , and / or polysorbate 80 ).
WARNINGS AND PRECAUTIONS Hypersensitivity Reactions
Hypersensitivity reactions are possible with ADYNOVATE . Allergic-type hypersensitivity reactions , including anaphylaxis , have been reported with other recombinant antihemophilic factor VIII products , including the parent molecule , ADVATE . Early signs of hypersensitivity reactions that can progress to anaphylaxis may include angioedema , chest tightness , dyspnea , wheezing , urticaria , and pruritus . Immediately discontinue administration and initiate appropriate treatment if hypersensitivity reactions occur .
Neutralizing Antibodies
Formation of neutralizing antibodies ( inhibitors ) to factor VIII can occur following administration of ADYNOVATE . Monitor patients regularly for the development of factor VIII inhibitors by appropriate clinical observations and laboratory tests . Perform an assay that measures factor VIII inhibitor concentration if the plasma factor VIII level fails to increase as expected , or if bleeding is not controlled with expected dose .
Monitoring Laboratory Tests
• Monitor plasma factor VIII activity by performing a validated one-stage clotting assay to confirm the adequate factor VIII levels have been achieved and maintained .
• Monitor for the development of factor VIII inhibitors . Perform the Bethesda inhibitor assay to determine if factor VIII inhibitor is present . If expected factor VIII activity plasma levels are not attained , or if bleeding is not controlled with the expected dose of ADYNOVATE , use Bethesda Units ( BU ) to determine inhibitor levels .
ADVERSE REACTIONS The most common adverse reactions ( ≥1 % of subjects ) reported in the clinical studies were headache and nausea .
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 clinical trials of another drug and may not reflect the rates observed in practice .
The safety of ADYNOVATE was evaluated in 237 previously treated patients ( PTPs ) and 6 previously untreated patients ( PUPs ) with severe hemophilia A ( factor VIII less than 1 % of normal ), who received at least one dose of ADYNOVATE in 3 completed multicenter , prospective , open label clinical studies and 4 ongoing clinical studies . The median duration of participation per subject was 401 ( min-max : 3-1034 ) days and the median number of exposure days to ADYNOVATE per subject was 111 ( min-max : 1-322 ). Table 1 lists the adverse reactions reported during clinical studies .
Table 1 : Adverse Reactions Reported for ADYNOVATE
MedDRA System Organ Class
Gastrointestinal Disorders Immune System Disorder Nervous System Disorders Skin and Subcutaneous Tissue Disorders Vascular Disorders
MedDRA Preferred Term
Number of Subjects n (%) ( N = 234 )
Rate of AEs per 100 Infusions ( N = 30865 )
Diarrhea |
1 ( 0.4 %) |
0.003 |
Nausea |
2 ( 0.8 %) |
0.006 |
Hypersensitivity a 1 ( 0.4 %) 0.003
Headache 5 ( 2.1 %) 0.026 Rash 1 ( 0.4 %) 0.003 Flushing 1 ( 0.4 %) 0.003 a
The event of hypersensitivity was a mild transient non-serious rash , occurring in one 2-year old patient who had developed a previous rash while on ADYNOVATE .
Two cases of acute pancreatitis , with no precipitating cause identified in one case , were reported in adults during an extension study of the clinical trial which evaluated 137 subjects . Administration of ADYNOVATE continued and both cases resolved .
Immunogenicity
The risk of the development of factor VIII inhibitors with the use of ADYNOVATE was evaluated in 3 completed and 4 ongoing clinical trials . Subjects consisted of adolescent and adult ( n = 148 with ≥150 prior EDs ) and pediatric PTPs [(< 6 years of age with ≥50 prior EDs ( n = 32 ), ≥6 years of age with ≥150 prior EDs ( n = 57 )], and pediatric PUPs ( n = 6 ). In 191 adult and pediatric PTPs who were treated for at least 50 exposure days with ADYNOVATE , the factor VIII inhibitor frequency was 0 ( 95 % CI of 0 to 0.019 ). One PUP subject from an ongoing study , who received at least one infusion of ADYNOVATE , developed neutralizing antibodies to factor VIII .
Immunogenicity also was evaluated by measuring the development of binding IgG and IgM antibodies against factor VIII , PEGylated ( PEG ) -factor VIII , PEG and Chinese hamster ovary ( CHO ) protein using validated ELISA assays . The majority of subjects ( 238 / 243 ) with at least one infusion of ADYNOVATE did not develop a persistent binding antibody response to any of these antigens . Twenty-eight subjects in total showed pre-existing antibodies to factor VIII ( n = 3 ), PEG-factor VIII ( n = 25 ) and / or PEG ( n = 3 ) prior to the first exposure to ADYNOVATE . Thirteen subjects who tested negative at screening developed transient antibodies against factor VIII ( n = 6 ), or PEG-FVIII ( n = 8 ) at one or two consecutive study visits . Antibodies were transient and not detectable at subsequent visits . Five subjects showed positive results for binding antibodies at study completion or at the time of data cutoff . Binding antibodies that were detected prior to exposure to ADYNOVATE , that transiently developed during the trial or were still detectable at study completion or data cutoff could not be correlated to any impaired treatment efficacy or altered PK parameters . There was no causal relationship between observed adverse events and binding antibodies except in one subject where a causal relationship cannot be ruled out based on available data . No subject had pre-existing or treatment-emergent antibodies to CHO protein .
The detection of antibodies that are reactive to factor VIII is highly dependent on many factors , including : the sensitivity and specificity of the assay , sample handling , timing of sample collection , concomitant medications and underlying disease . For these reasons , comparison of the incidence of antibodies to ADYNOVATE with the incidence of antibodies to other products may be misleading .
Baxalta , Advate , Adynovate , and Baxject are trademarks of Baxalta Incorporated , a wholly owned , indirect subsidiary of Shire plc .
Baxalta US Inc . Westlake Village , CA 91362 USA U . S . License No . 2020 Issued 12 / 2016 16I045-ADY-US S24588 01 / 17
Dr . Stone : However , the issue there is an important one that we often overlook : cost . This is an expensive drug . In many health-care systems , it makes a difference where such an expensive drug is administered . That ’ s owing to the vagaries of our health-care system . Although there may be patients who can receive CPX-351 safely in the clinic , we always want to make the choice that ’ s best for the patient , and cost to the patient is something we need to think about .
Dr . Erba : It ’ s unfortunate that we occasionally need to make decisions about what drugs we use in the inpatient setting based on diagnosisrelated group ( DRG ) payments and the cost of the intervention . If this drug was priced reasonably and did not eat up most of our DRG payments , I think the debate about which patients should receive it would be settled . ●
REFERENCES
1 . Lim WS , Tardi PG , Xie X , et al . Schedule- and dosedependency of CPX-351 , a synergistic fixed ratio cytarabine : daunorubicin formulation , in consolidation treatment against human leukemia xenografts . Leuk Lymphoma . 2010 ; 51:1536-42 .
2 . Lim WS , Tardi PG , Dos Santos N , et al . Leukemia-selective uptake and cytotoxicity of CPX-351 , a synergistic fixedratio cytarabine : daunorubicin formulation in bone marrow xenografts . Leuk Res . 2010 ; 34:1214-23 .
3 . Lancet JE , Cortes JE , Hogge DE , et al . Phase 2 trial of CPX- 351 , a fixed 5:1 molar ratio of cytarabine / daunorubicin , vs cytarabine / daunorubicin in older adults with untreated AML . Blood . 2014 ; 123:3239-46 .
4 . Lancet JE , Uy GL , Cortes JE , et al . Final results of a phase III randomized trial of CPX-351 versus 7 + 3 in older patients with newly diagnosed high risk ( secondary ) AML . Abstract # 7000 . Presented at the 2016 ASCO Annual Meeting , June 4 , 2016 ; Chicago , IL .
5 . Brunetti C , Anelli L , Zagaria A , et al . CPX-351 in acute myeloid leukemia : can a new formulation maximize the efficacy of old compounds ? Exp Rev Hematol . 2017 ; 10:853-62 .
6 . Arber DA , Orazi A , Hasserjian R , et al . The 2016 revision to the World Health Organization ( WHO ) classification of myeloid neoplasms and acute leukemia . Blood . 2016 ; 127:2391-405 .
March 2018