Vincristine Sulfate Liposome Injection (Marqibo)

Number: 0908

Policy

Aetna considers vincristine sulfate liposome injection (Marqibo) medically necessary for the treatment of relapsed or refractory acute lymphoblastic leukemia (ALL) as a single-agent therapy when either of the following criteria is met:

• Member has Philadelphia chromosome-negative ALL; or
• Member has Philadelphia chromosome-positive ALL refractory to tyrosine kinase inhibitors (TKIs).

Aetna considers continuation of vincristine sulfate liposome injection (Marqibo) medically necessary for members with ALL meeting initial selection criteria, and when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. 

Aetna considers vincristine sulfate liposome injection experimental and investigational for all other indications, including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Acute myeloid leukemia
• Adrenal cortical carcinoma
• AIDS-related Kaposi's sarcoma
• Anaplastic large cell lymphoma
• Angioimmunoblastic T-cell lymphoma
• Bone cancer
• Breast cancer
• Breast cancer brain metastases
• Choroid plexus tumors
• Chronic myelogenous leukemia
• Ependymoma
• Ewing's sarcoma
• Glioma
• Hodgkin lymphoma
• Kidney cancer
• Lung cancer
• Melanoma
• Multiple myeloma
• Neuroblastoma
• Non-Hodgkin’s lymphoma
• Oral mucositis
• Peripheral T-cell lymphoma
• Pleuropulmonary blastoma
• Primitive neuroectodermal tumor
• Retinoblastoma
• Rhabdomyosarcoma
• Soft tissue sarcoma
• Uveal melanoma
• Wilms tumor.

Dosing Recommendations

Vincristine sulfate liposome injection is available as the Marqibo Kit. The final drug product is prepared on site from the components in the Marqibo Kit. After preparation, each single-dose vial of Marqibo contains 5 mg/31 mL (0.16 mg/mL) vincristine sulfate for intravenous use only. Note: Marqibo (vincristine sulfate liposome injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage. 

The recommended dose of Marqibo (vincristine sulfate liposome injection) is 2.25 mg/m² intravenously over 1 hour once every 7 days.

Refer to the Full Prescribing Information for dose schedule modifications guidelines for individuals who experience peripheral neuropathy.

Source: Acrotech, 2020

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Marqibo is a vinca alkaloid indicated for the treatment of adult patients with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti-leukemia therapies (Acrotech, 2020).

Compendial Uses

• Single-agent therapy for relapsed/refractory Philadelphia chromosome-negative ALL (NCCN, 2020b).
• Single-agent therapy for relapsed/refractory Philadelphia-positive ALL refractory to TKIs (NCCN, 2020b).

Marqibo (vincristine sulfate liposome injection) is sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate for intravenous administration.

Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and rapid progression leading to death. Vincristine sulfate liposome injection (VSLI), sphingomyelin and cholesterol nanoparticle vincristine (VCR), facilitates VCR dose-intensification and densification plus enhances target tissue delivery.

In 2012, Marqibo (vincristine sulfate liposome injection) was approved by the U.S. Food and Drug Administration for the treatment adult patients with Philadelphia chromosome‐negative (Ph‐) acute lymphoblastic leukemia (ALL) in second or greater relapse or whose disease has progressed following two or more anti‐leukemia therapies. This indication was approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial(s) (Acrotech, 2020).

Marqibo (vincristine sulfate liposome injection) is contraindicated in patients with demyelating conditions, including Charcot-Marie-Tooth syndrome. Marqibo is also contraindicated in patients with hypersensitivity to vincristine sulfate or any of the other components of Marqibo, and it is contraindicated for intrathecal administration (Acrotech, 2020).

Black box warning includes that Marqibo is for intravenous use only, and fatal if given by other routes. Death has occurred with intrathecal use. Furthermore, Marqibo (vincristine sulfate liposome injection) has different dosage recommendations than vincristine sulfate injection. Verify drug name and dose prior to preparation and administration to avoid overdosage (Acrotech, 2020).

Warnings and precautions of vincristine sulfate liposome injection (Marqibo) include:

• Extravasation Tissue Injury: Extravasation causes tissue injury. If suspected, discontinue infusion immediately and consider local treatment measures.
• Neurologic Toxicity: Monitor patients for peripheral motor and sensory, central and autonomic neuropathy. Patients with preexisting severe neuropathy should be treated with Marqibo only after careful risk-benefit assessment. Interrupt, dose reduce, or discontinue Marqibo based on severity.
• Myelosuppression: Neutropenia, thrombocytopenia, or anemia may occur. Monitor blood counts prior to each dose of Marqibo. Consider Marqibo dose delay or reduction, as well as supportive care measures for grade 3 or 4 reactions.
• Tumor Lysis Syndrome: Anticipate, monitor for, and manage.
• Constipation and Bowel Obstruction: Institute a prophylactic bowel regimen to prevent potential constipation, bowel obstruction, and/or paralytic ileus. Use additional laxative products as needed.
• Fatigue: Severe fatigue can occur. Consider dose delay, reduction or discontinuation as appropriate.
• Hepatic Toxicity: Fatal liver toxicity and increased AST occurred. Monitor hepatic function tests. Interrupt or dose reduce as appropriate.
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception.

Most common adverse reactions (incidence ≥ 30%) are constipation, nausea, pyrexia, fatigue, peripheral neuropathy, febrile neutropenia, diarrhea, anemia, decreased appetite, and insomnia (Acrotech, 2020).

O'Brien, et al. (2013) evaluated high-dose vincristine sulfate liposome injection (Marqibo) monotherapy in adults with Philadelphia chromosome (Ph) -negative ALL that was multiply relapsed, relapsed and refractory to reinduction, and/or relapsed after hematopoietic cell transplantation (HCT). Sixty-five adults with Ph-negative ALL in second or greater relapse or whose disease had progressed following two or more leukemia therapies were treated in a phase II, multinational trial. Intravenous vincristine sulfate liposome injection 2.25 mg/m(2), without dose capping, was administered once per week until response, progression, toxicity, or pursuit of HCT. The primary end point was achievement of complete response (CR) or CR with incomplete hematologic recovery (CRi). The CR/CRi rate was 20% and overall response rate was 35%. Vincristine sulfate liposome injection monotherapy was effective as third-, fourth-, and fifth-line therapy and in patients refractory to other single- and multiagent reinduction therapies. Median CR/CRi duration was 23 weeks (range, 5 to 66 weeks); 12 patients bridged to a post-VSLI HCT, and five patients were long-term survivors. The investigators stated that vincristine sulfate liposome injection was generally well tolerated and associated with a low 30-day mortality rate (12%). The investigators concluded that hgh-dose vincristine sulfate liposome injection monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of vincristine sulfate liposome injection was predictable, manageable, and comparable to standard vincristine despite the delivery of large, normally unachievable, individual and cumulative doses of vincristine.

Breast Cancer

Zeng and colleagues (2015) noted that standard chemotherapy cannot eradicate triple-negative breast cancer (TNBC) while the residual cancer cells readily form the vasculogenic mimicry (VM) channels, which lead to the relapse of cancer after treatment. In this study, the functional VCR plus dasatinib liposomes, modified by a targeting molecule DSPE-PEG2000-c(RGDyK), were fabricated to address this issue.  The studies were performed on TNBC MDA-MB-231 cells and MDA-MB-231 xenografts in nude mice.  The liposomes exhibited the superior performances in the following aspects: the enhancement of cellular uptake via targeted action; the induction of apoptosis via activation of caspase 8, 9, and 3, increased expression of Bax, decreased expression of Mcl-1, and generation of reactive oxygen species (ROS); and the deletion of VM channels via inhibitions on the VM channel indicators, which consisted of vascular endothelial-cadherin (VE-Cad), focal adhesion kinase (FAK), phosphatidylinositide 3-kinase (PI3K), and matrix metallopeptidases (MMP-2, and MMP-9).  Furthermore, the liposomes displayed the prolonged circulation time in the blood, the increased accumulation in tumor tissue, and the improved therapeutic efficacy along with deletion of VM channels in the TNBC-bearing mice.  The authors concluded that the nano-structured functional drug-loaded liposomes may provide a promising strategy for the treatment of invasive TNBC along with deletion of VM channels.

Breast Cancer Brain Metastases

Shad and associates (2018) noted that in women, breast cancer is the most common cancer diagnosis and 2nd commonest cause of cancer death.  More than 50 % of breast cancer patients will develop metastases to the bone, liver, lung, or brain.  Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative.  Within the realm of chemotherapy, the past 10 years has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms.  These investigators provided a historical overview of BCBM chemotherapy, reviewed the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin-dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM, tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM, re-purposed cytotoxic chemotherapy for triple negative BCBM, and the utilization of these new agents and formulations in ongoing clinical trials.  The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials were also discussed.  The authors concluded that these new treatments provide a promising outlook in the treatment of BCBM; and vincristine was one of the keywords listed in this study.

Combination of Blinatumomab and Vincristine Sulfate Liposome Injection for the Treatment of Relapsed Philadelphia Chromosome Positive B-cell Acute Lymphoblastic Leukemia

McCusker and colleagues (2018) stated that relapsed Philadelphia chromosome (Ph) positive ALL is an aggressive lymphoid malignancy with a poor prognosis and no randomized studies demonstrating superiority of any single salvage regimen.  These researchers presented the case of a 33-year old woman with relapsed Ph positive precursor (pre) B-cell ALL with rapidly rising peripheral blasts while on blinatumomab monotherapy initially, but ultimately responded with the addition of vincristine sulfate liposome injection (VSLI).  Ponatinib was added later when it became available for the patient, and she ultimately achieved a complete remission.  The authors concluded that further study is needed to examine mechanisms of potential synergy, and the safety and efficacy of the combination of blinatumomab and VSLI.

Glioma

Zhang and colleagues (2017) stated that therapeutic outcome for the treatment of glioma was often limited due to drug resistance and low permeability of drug across the multiple physiological barriers, including the blood-brain barrier (BBB), and the blood-tumor barrier (BTB). In order to overcome these hurdles, these researchers designed T7 and DA7R dual peptides-modified liposomes (abbreviated as T7/DA7R-LS) to efficiently co-deliver doxorubicin (DOX) and VCR to glioma in this study.  T7 is a 7-peptide ligand of transferrin receptors (TfR) capable of circumventing the BBB and then targeting glioma.  DA7R is a d-peptide ligand of vascular endothelial growth factor receptor 2 (VEGFR 2) over-expressed on angiogenesis, presenting excellent glioma-homing property.  By combining the dual-targeting delivery effect, the dual-modified liposomes displayed higher glioma localization than that of single ligand-modified liposomes or free drug.  After loading with DOX and VCR, T7/DA7R-LS showed the most favorable anti-glioma effect in-vivo.  The authors concluded that this dual-targeting, co-delivery strategy provided a potential method for improving brain drug delivery and anti-glioma treatment efficacy.

Melanoma

Song and associates (2015) stated that cancer initiating cells (CIC) are tumorigenic cancer cells that have properties similar to normal stem cells. CD20 is a phenotype of melanoma CIC that is responsible for melanoma drug resistance.  Vincristine is commonly used in melanoma therapy; however, it has been found ineffective against CIC.  To target CD20+ melanoma CIC, theseresearchers prepared VCR-containing immuno-liposomes that were conjugated to CD20 antibodies (VCR-Lip-CD20).  The drug release profile and the antibody-mediated targeting of the immuno-liposomes were optimized to target CD20+ melanoma CIC.  The immuno-liposomes had desirable particle size (163 nm), drug encapsulation efficiency (91.8 %), and drug release profile.  These researchers demonstrated that these immuno-liposomes could successfully target more than 55 % of CD20+ Chinese Hamster Ovary cells (CHO-CD20) even when the CHO-CD20 cells accounted for only 0.1 % of a mixed population of CHO-CD20 and CHO cells.  After treating WM266-4 melanoma mammospheres for 96 hours, the IC50 values (the drug dose causing 50 % growth inhibition) of the drug delivered in VCR-Lip-CD20, VCR-Lip (VCR liposomes), and VCR were found to be 53.42, 98.99, and 99.09 μg/ml, respectively, suggesting that VCR-Lip-CD20 was 1.85 times more effective than VCR-Lip and VCR.  VCR-Lip-CD20 could almost completely remove the tumorigenic ability of WM266-4 mammospheres in-vivo, and showed the best therapeutic effect in WM266-4 melanoma xenograft mice.  The authors concluded that VCR-Lip-CD20 could selectively kill CD20+ melanoma CIC in populations of WM266-4 cells both in-vitro and in-vivo; they demonstrated that VCR-Lip-CD20 has the potential to efficiently target and kill CD20+ melanoma CIC.

Rhabdomyosarcoma

Roveri and co-workers (2017) attempted to improve VCR-based rhabdomyosarcoma (RMS) therapy by encapsulating the drug into liposomes. A targeting strategy was attempted to enhance tumor accumulation.  VCR was loaded in control and peptide-decorated liposomes via an active method.  The interaction of an RMS-specific peptide with the presumed target furin and the cellular uptake of both liposomal groups were studied in-vitro.  Pharmacokinetics and bio-distribution of VCR-containing liposomes were assessed in an RMS xenograft mouse model.  Liposomes ensured high VCR concentration in plasma and in the tumor.  Peptide-decorated liposomes showed modest uptake in RMS cells.  The authors concluded that the investigated peptide-modified liposomal formulation may not be optimal for furin-mediated RMS targeting.  Nevertheless, VCR-loaded liposomes could serve as a delivery platform for experimental RMS

Other Experimental Indications

There are clinical trials on the use of vincristine sulfate liposome for the treatment of various malignancies including acute myeloid leukemia, adrenal cortical carcinoma, AIDS-related Kaposi's sarcoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, bone cancer, choroid plexus tumors, chronic myelogenous leukemia, ependymoma, Ewing's sarcoma, Hodgkin lymphoma, kidney cancer, lung cancer, multiple myeloma, neuroblastoma, non-Hodgkin’s lymphoma, oral mucositis, peripheral T-cell lymphoma, pleuropulmonary blastoma, primitive neuroectodermal tumor, retinoblastoma, soft tissue sarcoma, uveal melanoma, and Wilms tumor.

Table: CPT Codes / HCPCS Codes / ICD-9 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
HCPCS codes covered if selection criteria are met :
J9371	Injection, vincristine sulfate liposome, 1 mg
ICD-10 codes covered if selection criteria are met :
C91.00	Acute lymphoblastic leukemia not having achieved remission
C91.02	Acute lymphoblastic leukemia, in relapse
ICD-10 codes not covered for indications listed in the CPB:
C34.0 - C34.9	Malignant neoplasm of bronchus and lung [including pleuropulmonary blastoma]
C40.0 - C41.9	Malignant neoplasm of bone and cartilage [including Ewing's sarcoma]
C43.0 - C43.9	Malignant melanoma of skin
C46.0 - C46.9	Kaposi's sarcoma [AIDS-related]
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue [rhabdomyosarcoma] [soft tissue sarcoma]
C50.011 - C50.929	Malignant neoplasm of breast
C64.1 - C65.9	Malignant neoplasm of kidney and renal pelvis [including Wilms tumor]
C69.20 - C69.22	Malignant melanoma of retina [retinoblastoma]
C69.4	Malignant melanoma of ciliary body [uveal melanoma]
C71. 0 - C71.9	Malignant neoplasm of brain [choroid plexus tumors] [ependymoma] [glioma] [primitive neuroectodermal tumor]
C74.00 - C74.92	Malignant neoplasm of adrenal gland [adrenal cortical carcinoma] [neuroblastoma]
C79.31	Secondary malignant neoplasm of brain [breast cancer brain metastases]
C81.00 - C81.99	Hodgkin lymphoma
C84.40 - C84.49	Peripheral T-cell lymphoma, not classified
C85.10 - C85.99	Other specified and unspecified types of non-Hodgkin's lymphoma
C86.50 - C86.59	Angioimmunoblastic T-cell lymphoma
C84.60 - C84.69	Anaplastic large cell lymphoma, ALK positive
C84.70 - C84.79	Anaplastic large cell lymphoma, ALK negative
C90.00 - C90.02	Multiple myeloma
C92.10 - C92.19	Chronic myelogenous leukemia, BCR/ABL-positive
C92.60 - C92.69	Acute myeloid leukemia with11q23-abnormality
C92.A0 - C92.A2	Acute myeloid leukemia with multilineage dyslasia
C94.00 - C94.02	Acute erythroid leukemia
C94.20 - C92.22	Acute megakaryoblastic leukemia
D33.2	Benign neoplasm of brain, unspecified [ependymoma]
D43.2	Neoplasm of uncertain behavior of brain [ependymoma] [glioma]
K12.30 - K12.39	Oral mucositis (ulcerative)

The above policy is based on the following references: