ASH Clinical News June 2017 NEW #2 | Page 17

CLINICAL NEWS

The U . S . Food and Drug Administration ( FDA ) approved midostaurin in combination with 7 + 3 induction and consolidation chemotherapy with daunorubicin and cytarabine for the treatment of adult patients with newly diagnosed FLT3- mutated acute myeloid leukemia ( AML ), and as monotherapy for patients with aggressive systemic mastocytosis ( SM ) or SM with associated hematologic neoplasm or mast cell leukemia . Midostaurin was approved for use with a companion diagnostic tool , the LeukoStrat CDx FLT3 Mutation Assay , which is used to detect the FLT3 mutation in patients with AML .

Midostaurin is an oral , multitarget protein kinase inhibitor and the first FDA-approved targeted therapy to treat patients with AML . The approval was based on results from the randomized RATIFY trial , which evaluated the safety and efficacy of midostaurin in 717 patients who had not been treated previously for their FLT3-mutated AML . In the trial , patients who received midostaurin and chemotherapy had longer survival than those who received chemotherapy alone ; however , a specific median survival rate could not be reliably estimated . Midostaurin-treated patients also continued on the trial longer without certain complications ( including failure to achieve complete remission within 60 days of starting treatment , progression of leukemia , or death ) than patients who received chemotherapy alone ( median duration = 8.2 vs . 3 months ).

The most common adverse events ( AEs ) included febrile neutropenia , nausea , mucositis , vomiting , headache , petechiae , musculoskeletal pain , epistaxis , device-related infection , hyperglycemia , and upper respiratory tract infection . The FDA approval notes that midostaurin should not be used in women who are pregnant or breastfeeding , and patients who show signs or symptoms of pulmonary toxicity should stop using midostaurin .

Midostaurin was previously granted priority review , as well as fast-track and breakthrough-therapy designations .

Source : U . S . Food and Drug Administration news release , April 28 , 2017 .

The FDA accepted a supplemental new drug application of ibrutinib for patients with chronic graft-versus-host disease ( cGVHD ) who have not responded to ≥1 lines of systemic therapy .

The decision was based on data from the single arm , phase Ib / II PCYC-1129 trial , which was presented at the 2016 ASH Annual Meeting . In a cohort of 42 previously treated patients with cGVHD , ibrutinib was associated with an overall response rate of 67 percent and showed clinically meaningful and durable responses . Twenty-one percent of responders had a complete response ( CR ) and 45 percent had a partial response .

Patients were included in the study if they had not responded to ≤3 prior therapies for cGVHD and had either an erythematous rash on > 25 percent of their body surface area or a National Institutes of Health Oral Mucosal Score of > 4 .

Patients received oral ibrutinib 420 mg daily in combination with ongoing therapies , including corticosteroids and other immunosuppressants .

Most patients ( 71 %) had a sustained cGVHD response of at least 5 months . cGVHD response was observed across multiple organs : 56 percent ( n = 20 / 25 ) of patients with ≥2 involved organs at baseline responded in at least two organs , and 42 percent of patients with ≥3 involved organs at baseline responded in at least three organs .

In June 2016 , the FDA granted ibrutinib breakthrough-therapy and orphan drug designation as a potential treatment for cGVHD after failure of ≥1 lines of systemic therapy .

Source : Janssen Research & Development , LLC , news release , April 5 , 2017 .

The FDA granted marketing authorization to ipsogen JAK2 RGQ PCR Kit for the detection of JAK2 mutations . This is the first FDA-approved test to evaluate patients with suspected polycythemia vera ( PV ). The device is a qualitative in vitro diagnostic test for real-time polymerase chain reaction on the Rotor-Gene

Q MDx instrument to detect the JAK2 V617F / G1849T allele .

The marketing authorization was based on a clinical trial that included 216 individuals with suspected PV . The researchers compared the test characteristics of the ipsogen JAK2 RGQ PCR Kit with Sanger sequencing . The ipsogen JAK2 RGQ PCR Kit detected PV with 94.6 percent sensitivity and 98.1 percent specificity .

The test does not detect less common mutations associated with PV , including mutations in exon 12 , and should be used to diagnosis the disease in combination with an assessment of other known clinical , biologic , bone marrow histology , and cytogenetic criteria , according to the FDA .

Source : U . S . Food and Drug Administration news release , March 27 , 2017 .

The manufacturer of the investigational chimeric antigen receptor ( CAR ) T-cell therapy KTE-C19 reported that one patient enrolled in the safety expansion phase of the ZUMA-1 trial died from cerebral edema . The patient , who had refractory non-Hodgkin lymphoma ( NHL ), died in April . The FDA was notified , but the study was not placed on any clinical hold , according to Kite Pharmaceuticals , the drug ’ s manufacturer .

This is the first death from cerebral edema recorded in the KTE-C19 clinical trials program . In April , Kite Pharmaceuticals submitted a biologics license application to the FDA for KTE-C19 ( also called axicabtagene ciloleucel ) for the treatment of patients with aggressive NHL who cannot undergo hematopoietic cell transplantation , based on data from the ZUMA-1 trial . Three other deaths unrelated to disease progression have been recorded in the primary analysis of the ZUMA-1 trial ; two were judged to be treatment-related and none involved cerebral edema .

However , earlier this year , development of another experimental CAR T-cell therapy ( JCAR015 ) was discontinued after five patients with acute lymphocytic leukemia died from cerebral edema . The manufacturer , Juno Therapeutics , said its internal investigation identified multiple factors that increased the risk of severe toxic reactions among JCAR015-treated patients , including “ factors related to the product .”

Source : TheStreet . com , May 8 , 2017 .

The FDA is looking into 359 reports linking silicone and saline breast implants with development of anaplastic large cell lymphoma ( ALCL ), a rare type of NHL .

“ All of the information to date suggests that women with breast implants have a very low but increased risk of developing ALCL , compared with women who do not have breast implants ,” the FDA said in a statement .

The FDA started looking into the association in 2011 . ALCL can take approximately 10 years , on average , to develop after the implant is first inserted . The lymphoma usually develops in the area near the implant , although it can spread , according to researchers from the World Health Organization who published an article reporting their findings in Blood .

As of February 1 , 2017 , the FDA had received a total of 359 medical device reports ( MDRs ) of ALCL , including nine deaths . There are 231 reports that include information on the implant surface . Of those , 203 were textured implants and 28 smooth implants . Most of the reports contained no information about the surface textures of any previous implants .

“ Although it is rare , breast implantassociated ALCL appears to develop more frequently in women with textured implants than in women with smoothsurfaced implants ,” the agency ’ s report said . “ Before getting breast implants , make sure to talk to your health-care provider about the benefits and risks of textured-surface versus smooth-surfaced implants .”

Details on breast implant surface and fill type are limited . Although the MDR system is a valuable source of information , it may contain incomplete , inaccurate , untimely , unverified , or biased data , the FDA noted . In addition , the incidence or prevalence of an event cannot be determined from the MDR system because of potential underreporting , duplicate reporting of events , and lack of information about the total number of breast implants . ●

Sources : U . S . Food and Drug Administration news release , March 23 , 2017 ; Chalasani P , Go RS , Parsons B , Al-Hamadani M . Anaplastic large cell lymphoma of the breast : incidence , patterns of care , and outcome in the US population . Blood . 2015 ; 126:5035 .