Aetna considers omacetaxine mepesuccinate (Synribo) medically necessary for members with chronic myelogenous leukemia (CML) (see Appendix).
Aetna considers omacetaxine mepesuccinate experimental and investigational for all other indications including the following (not an all-inclusive list):
Synribo (omacetaxine) was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic or accelerated phase chronic myeloid leukemia (CML) with resistance and/or intolerance to 2 or more tyrosine kinase inhibitors (TKIs). This labeling states that this indication is based upon response rate. The labeling notes that there are no trials verifying an improvement in disease-related symptoms or increased survival with omacetaxine. Current guidelines from the National Comprehensive Cancer Network (NCCN, 2014) recommend Synribo in CML for patients with resistance and/or intolerance to 2 or more TKIs for chronic phase, disease progression in accelerated phase, and for post-transplant relapse.
Quintas-Cardama and Cortes (2008) stated that homoharringtonine (HHT), a natural alkaloid extracted from various Cephalotaxus species, exerts its anti-tumoral and anti-angiogenic activity through an inhibition of protein synthesis and the promotion of apoptosis. ChemGenex Pharmaceuticals Ltd, in collaboration with Stragen Group, is developing omacetaxine mepesuccinate, a semi-synthetic formulation of HHT, as a potential treatment for CML, myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). In pre-clinical studies, omacetaxine mepesuccinate induced apoptosis in leukemia cell lines. Results from phase II clinical trials revealed omacetaxine mepesuccinate to be active in patients with CML that was resistant to TKI therapy, including those patients who carry the BCR-ABL1T315I mutation, which is highly insensitive to the TKIs imatinib, nilotinib and dasatinib; the therapeutic was also generally well-tolerated. Phase II and III clinical trials have been underway to assess the activity of omacetaxine mepesuccinate, either alone or in combination with TKIs or other cytotoxic drugs, in patients with CML that is resistant to TKI therapy. Phase I and II clinical trials for omacetaxine mepesuccinate in the treatment of AML and MDS are also ongoing; intravenous, subcutaneous (SC) and oral formulations of the drug are being developed. The authors concluded that omacetaxine mepesuccinate appears to hold potential for the treatment of CML and, in particular, imatinib-resistant CML; the development of alternative formulations of the therapeutic further expands the potential for success in drug development.
Daver et al (2013) noted that HHT (omacetaxine mepesuccinateis) is an alkaloid inhibitor of protein synthesis with activity in myeloid malignancies. In a phase II clinical trial, these investigators reported the findings of a pilot study of HHT in MDS. Induction consisted of HHT at 2.5 mg/m(2) via continuous infusion for 7 days. Maintenance was given every 4 weeks. A total of 9 patients were enrolled: 5 with refractory anemia with excess blasts, 2 with refractory anemia with excess blasts in transformation, 1 each with refractory anemia and CML, respectively. Median age was 70 years (55 to 84) and 6 (66 %) were males. Per International Prognostic Scoring System (IPSS), 2 patients were intermediate-1, 5 intermediate-2 and 2 high-risk. Median chemotherapy courses were 1 (1 to 3). One patient (11 %) responded with complete hematological and cytogenetic remission after 1 course. Eight patients did not respond (4 had stable disease, 2 progressed to acute leukemia and 2 died during induction -- from aspergillus pneumonia and intra-cerebral hemorrhage, respectively). Grade 3/4 myelosuppression seen in 56 % (5/9). Serious non-hematological toxicities included 1 case of grade 4 left bundle branch heart block and 1 grade 3 nephrotoxicity. Median time between courses was 42 days (35 to 72 days). The authors concluded that HHT might have clinical activity in some patients with MDS.
Nemunaitis et al (2013) stated that omacetaxine mepesuccinate is a first-in-class cephalotaxine demonstrating clinical activity in CML. A SC formulation demonstrated efficacy and safety in phase I/II trials in patients previously treated with greater than or equal to 1 TKI. These researchers evaluated pharmacokinetics and safety of SC omacetaxine in patients with advanced cancers. Omacetaxine 1.25 mg/m(2) SC was administered BID, days 1 to 14 every 28 days for 2 cycles, until disease progression or unacceptable toxicity. Blood and urine were collected to measure omacetaxine concentrations and inactive metabolites. Adverse events, including QT interval prolongation, were recorded. Tumor response was assessed at cycle 2 completion. Pharmacokinetic parameters were estimated from cycle 1, day 1 data in 21 patients with solid tumors or hematologic malignancies and cycle 1, day 11 data in 10 patients. Omacetaxine was rapidly absorbed, with mean peak plasma concentrations observed within 1 hour, and widely distributed, as evidenced by an apparent volume of distribution of 126.8 L/m(2). Plasma concentration versus time data demonstrated bi-exponential decay; mean steady-state terminal half-life was 7 hours. Concentrations of inactive metabolites 4'-DMHHT and cephalotaxine were approximately 10 % of omacetaxine and undetectable in most patients, respectively. Urinary excretion of unchanged omacetaxine accounted for less than 15 % of the dose. Grade 3/4 drug-related adverse events included thrombocytopenia (48 %) and neutropenia (33 %). Two grade 2 increases in QTc interval (greater than 470 ms) were observed and were not correlated with omacetaxine plasma concentration. No objective responses were observed. The authors concluded that omacetaxine is well-absorbed after SC administration. Therapeutic plasma concentrations were achieved with 1.25 mg/m(2) BID, supporting clinical development of this dose and schedule.
Shim et al (2014) noted that anti-cancer chemotherapy usually involves the administration of several anti-cancer drugs that differ in their action mechanisms. These researchers examined if the combination of omacetaxine mepesuccinate (OMT) and doxorubicin (DOX) could show synergism, and whether the liposomal co-delivery of these 2 drugs could enhance their anti-tumor effects in cervical carcinoma model. OMT-loaded liposomes (OL) were prepared by loading the drug in the lipid bilayers. OL were then electrostatically complexed with DOX, yielding double-loaded liposomes (DOL). DOX-loaded liposomes (DL) were formulated by electrostatic interaction with negatively charged empty liposomes (EL). The combination index (CI) values were calculated to evaluate the synergism of the 2 drugs. In-vitro anti-tumor effects against HeLa cells were measured using CCK-8, calcein staining, and crystal violet staining. In-vivo anti-tumor effects of various liposomes were tested using HeLa cell-bearing mice. Combination of DOX and OMT had ratio-dependent synergistic activities, with very strong synergism observed at a molar ratio of 4:1 (DOX:OMT). The sizes of EL, DL, OL, and DOL did not significantly differ, but the zeta potentials of DL and DOL were slightly higher than those of OL and EL. In-vitro, DOL showed higher anti-tumor activity than OL, DL or EL in cervical carcinoma HeLa cells. In-vivo, unlike other liposomes, DOL reduced the tumor growths by 98.6 % and 97.3 % relative to the untreated control on day 15 and 25 after the cessation of treatment, respectively. The authors concluded that these results suggested that liposomal co-delivery of DOX and OMT could synergistically potentiate anti-tumor effects.
In a meta-analysis, Kantarjian et al (2015) provided an overview on the effectiveness of HHT combination regimens to treat AML. Because most of these studies were performed in China, Chinese published clinical studies were used for the analysis. A search for studies from 2006 to 2013 of regimens containing HHT for AML treatment was performed using published studies and Chinese databases in Mandarin. The complete response (CR) and overall response (OR) rates were analyzed, and the fixed effects model and random effects model (REM) were calculated. The heterogeneity of the studies was calculated using Q homogeneity statistics. The meta-analysis included 21 studies (n = 1,310, n = 229 pediatric, and n = 216 elderly). Homoharringtonine was given in combination with cytarabine, daunorubicin, idarubicin, aclacinomycin, mitoxantrone, or granulocyte colony-stimulating factor. Heterogeneity was seen in all analyzed pools, but it was most pronounced in retrospective studies. Overall, the REM showed a CR rate of 65.2 %. However, in studies in which HHT-containing regimens were compared to regimens without HHT, the CR rates were 69.1 % in randomized trials and 62.8 % in retrospective studies. Additionally, in studies with exclusively elderly patients, the CR rate was considerably lower than it was for the studies with mixed age populations (47.5 % versus 65.2 %). The authors concluded that higher overall CR rates for HHT-containing regimens in AML treatment in the Chinese studies suggested that HHT could be an active agent in the management of AML. Moreover, they stated that additional clinical trials are needed to evaluate the effectiveness of HHT in the treatment of AML.
Renal Cell Carcinoma:
Wolff et al (2015) noted that renal cell carcinoma (RCC) accounts for 85 % of primary renal neoplasms, and is rarely curable when metastatic. Approximately 70 % of RCCs are clear-cell type (ccRCC), and in greater than 80 % the von Hippel-Lindau (VHL) gene is mutated or silenced. These researchers developed a novel, high-content, screening strategy for the identification of small molecules that are synthetic lethal with genes mutated in cancer. In this strategy, the screen and counter-screen are conducted simultaneously by differentially labeling mutant and reconstituted isogenic tumor cell line pairs with different fluorochromes and using a highly sensitive high-throughput imaging-based platform. This approach minimizes confounding factors from sequential screening, and more accurately replicates the in-vivo cancer setting where cancer cells are adjacent to normal cells. A screen of approximately 12,800 small molecules identified HHT, an FDA-approved drug for treating CML, as a VHL-synthetic lethal agent in ccRCC. Homoharringtonine induced apoptosis in VHL-mutant, but not VHL-reconstituted, ccRCC cells, and inhibited tumor growth in 30 % of VHL-mutant patient-derived ccRCC tumorgraft lines tested. Building on a novel screening strategy and utilizing a validated RCC tumorgraft model recapitulating the genetics and drug responsiveness of human RCC, these studies identified HHT as a potential therapeutic agent for a subset of VHL-deficient ccRCCs.
Synribo is considered medically necessary for members who meet the following criteria:
Table: Tyrosine Kinase Inhibitors (TKIs)
|CPT Codes / HCPCS Codes / ICD-10 Codes|
|Information in the [brackets] below has been added for clarification purposes.  Codes requiring a 7th character are represented by "+":|
|ICD-10 codes will become effective as of October 1, 2015:|
|Other CPT codes related to the CPB:|
|96372||Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular|
|96401||Chemotherapy administration, subcutaneous|
|HCPCS Codes covered if selection criteria are met:|
|J9262||Injection, omacetaxine mepesuccinate, 0.01 mg|
|ICD-10 codes covered if selection criteria are met:|
|C92.10 - C92.22||Chronic myeloid leukemia|
|ICD-10 codes not covered for indications listed in the CPB:|
|C11.0 - C11.9||Malignant neoplasm of nasopharynx|
|C15.3 - C15.9||Malignant neoplasm of esophagus|
|C16.0 - C16.9||Malignant neoplasm of stomach|
|C18.0 - C18.9||Malignant neoplasm of colon|
|C19 - C21.8||Malignant neoplasm of rectosigmoid junction, rectum, anus and anal canal|
|C22.1||Intrahepatic bile duct carcinoma|
|C23 - C24.9||Malignant neoplasm of gall bladder and other and unspecified parts of biliary tract|
|C25.0 - C25.9||Malignant neoplasm of pancreas|
|C31.0 - C31.9||Malignant neoplasm of accessory sinuses (paranasal)|
|C33 - C34.92||Malignant neoplasm trachea, bronchus, and lung|
|C37||Malignant neoplasm of thymus|
|C40.00 - C41.9||Malignant neoplasm of bone and articular cartilage|
|C43.0 - C43.9||Malignant melanoma of skin|
|C47.0 - C47.9
C49.0 - C49.9
|Malignant neoplasm of peripheral nerves, autonomic nervous system, connective and soft tissue|
|C50.011 - C50.929||Malignant neoplasm of breast|
|C46.1||Kaposi's sarcoma of soft tissue|
|C53.0 - C53.9||Malignant neoplasm of cervix uteri|
|C54.0 - C54.9||Malignant neoplasm of corpus uteri|
|C57.00 - C57.02||Malignant neoplasm of fallopian tube|
|C61||Malignant neoplasm of prostate|
|C64.1 - C66.9
C68.0 - C68.9
|Malignant neoplasm of kidney and other and unspecified urinary organs|
|C70.0 - C70.9||Malignant neoplasm of meninges|
|C71.0 - C71.9||Malignant neoplasm of brain|
|C72.0 - C72.9||Malignant neoplasm of spinal cord, cranial nerves and other parts of central nervous system|
|C73||Malignant neoplasm of thyroid gland|
|C92.00 - C92.02
C92.40 - C92.A2
|Acute myeloid leukemia|
|D46.0 - D46.9||Myelodysplastic syndromes|