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VSLI offers exciting therapeutic option for relapsed, refractory ALL
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Debbie Blamble
A new formulation of vincristine, which received FDA approval in August, should be commercially available in the first quarter of 2013.
Vincristine sulfate liposome injection (Marqibo, Talon Therapeutics) — which has been under investigation for several years — is approved for the treatment of adults with Philadelphia chromosome-negative acute lymphoblastic leukemia in second or greater relapse, or in patients whose disease has progressed after two or more therapies.
This article will highlight the data that lead to the approval, as well as explain what distinguishes vincristine sulfate liposome injection (VSLI) from standard vincristine sulfate.
Rationale for development
Vincristine, a vinca alkaloid from the periwinkle plant, is a mainstay in the treatment of ALL and certain lymphomas.
Vincristine binds to tubulin, which leads to altered function of the microtubules and ultimately inhibits mitosis. This cell cycle-specific medication is highly active against the malignant lymphoid cell.
Disadvantages associated with standard vincristine include its short half-life as a cell cycle-specific agent, neurotoxicity and risk for extravasation. Neurotoxicity, a dose-limiting toxicity of vincristine, is caused by vincristine’s ability to alter the function of neuronal microtubules. The standard dose of vincristine is 1.4 mg/m2, which is capped at 2 mg to avoid toxicity. Despite the dosing cap, neurotoxicity continues to occur, and further dose reductions or dose omissions often are required.
Vincristine has been on the market for decades, and there is great familiarity with the product. Still, extravasations continue to occur. The desire for a medication that could maintain or increase the antileukemic activity of vincristine and potentially have a more favorable toxicity profile led to the development of VSLI. In addition, response to salvage therapies for ALL frequently is unsatisfactory. New agents are needed in the management of relapsed, refractory ALL.
VSLI
VSLI is a sphingomyelin/cholesterol liposome-encapsulated formulation of vincristine sulfate.
The goal of the new formulation, as with many liposomal products, was to provide targeted drug delivery and enhanced drug exposure to the malignant lymphoid cell. In preclinical models, this has been shown to be the case. In pharmacokinetic studies, the area under the curve (AUC) of VSLI is much higher, and the half-life is much longer than that which can be achieved with vincristine.
This formulation of the drug does not arrive ready to administer from the manufacturer. The product comes as a kit with three different vials for use in preparation: one vial of standard vincristine sulfate injection, one vial of sphingomyelin/cholesterol liposome injection and one vial of sodium phosphate injection.
The pharmacy must follow specific instructions to encapsulate vincristine into the liposome. Preparation of VSLI takes about 60 to 90 minutes, and it requires the use of a water bath. Therefore, administration of this medication should not be scheduled as the first appointment of the day. Prepared VSLI also has a relatively short stability and should be administered within 12 hours of initiating reconstitution.
Selected clinical trials
A multicenter phase 1/2 trial (VSLI-06) evaluated VSLI in adults with relapsed or refractory ALL, including lymphoblastic lymphoma and Burkitt’s leukemia/lymphoma. Researchers excluded patients if they had a history of grade-3 or grade-4 neuropathy from previous chemotherapy, persistent grade-2 or higher neuropathy or active neurologic disorders.
VSLI was administered once weekly over 60 minutes for 4 weeks to complete a cycle. Concurrent dexamethasone 40 mg (oral or IV) was administered on days 1 through 4 and days 11 through 14 of each cycle.
Because this was a dose-finding study, dose levels of VSLI ranged from 1.5 mg/m2 to 2.4 mg/m2, with no dose capping allowed. Up to 12 cycles could be administered in responding patients.
The investigators enrolled 36 patients (median age, 32 years) over approximately 4 years. All of the patients had received standard vincristine in previous regimens. VSLI was the first salvage attempt in 39% of patients, the second salvage attempt in 39% of patients and the third or greater salvage attempt in 22% of patients.
Seventy-five percent of patients completed at least one cycle. The overall response rate (CR + PR) in all patients who received at least one dose of VSLI was 22%; the CR rate was 19%. Researchers observed dose-limiting toxicity at the 2.4 mg/m2 dose level, so the maximum tolerated dose was determined to be 2.25 mg/m2. Notably, considering an average-sized adult, this dose represents approximately a 100% increase in vincristine delivery as compared with standard vincristine.
The most common toxicities were constipation (overall, 53%; grade 3/4, 6%), fatigue, peripheral neuropathy (overall, 55%; grade 3/4, 8%), anemia and pyrexia. Incidence of peripheral neuropathy was consistent across dose levels, but the overall incidence of constipation appeared to increase with increasing dose, reaching 60% at dose levels between 2.25 mg/m2 and 2.4 mg/m2. Cumulative exposure to VSLI appeared to be more closely associated with the incidence of peripheral neuropathy.
The phase 2, multicenter, international RALLY trial evaluated single-agent VSLI at the previously determined maximum tolerated dose (2.25 mg/m2) in patients with Philadelphia-negative ALL who had experienced at least two relapses or had failed at least two prior lines of therapy. Patients with Burkitt’s leukemia/lymphoma were excluded. Patients had to have achieved a CR to at least one prior regimen. Patients were treated with single-agent VSLI 2.25 mg/m2 IV over 60 minutes every 7 days. Concomitant corticosteroids were not allowed beyond day 5.
Sixty-five patients (median age, 31 years) received at least one dose of VSLI. Of them, 48% had failed a prior hematopoietic stem cell transplant (HSCT). All patients had been previously exposed to standard vincristine, and 80% had residual neuropathy. The overall response rate (CR + PR) was 29%, with a 20% CR rate. Twelve patients were able to proceed to a potentially curative HSCT. The most common toxicities were peripheral neuropathy, constipation, anorexia, diarrhea, nausea, fever and febrile neutropenia.
A role in therapy
Similar to standard vincristine, VSLI is very active against malignant lymphoid cells. However, standard vincristine is seldom used as a single agent in the management of ALL. This likely will be the case with VSLI.
An ongoing phase 3 trial is evaluating a VSLI-based combination chemotherapy regimen in elderly patients with newly diagnosed ALL. Although VSLI neurotoxicity appears to be similar to that seen with standard vincristine, it will be interesting to see how the toxicity profile of VSLI changes in previously untreated patients.
Additional trials of VSLI have been conducted in the lymphoma population. In fact, several of the initial investigations with VSLI were conducted in patients with non-Hodgkin’s lymphoma.
Researchers in one phase 2 study that enrolled patients with previously untreated NHL substituted VSLI for standard vincristine in the CHOP regimen. A VSLI dose of 2 mg/m2 IV every 21 days was used, and neuropathy was described as generally mild (grade 1 or 2).
A phase 3 trial in elderly adults with newly diagnosed, aggressive NHL is being conducted by the German High-Grade Non-Hodgkin’s Lymphoma Study Group. Pediatric studies have been conducted and are ongoing, as well. VSLI also is being studied in malignant melanoma.
Despite the difference in the formulation, VSLI still has many of the same warnings and precautions that one encounters with vincristine. Considering the means of administration — 1-hour IV infusion via a mini-bag — accidental intrathecal administration of VSLI should not be a concern. However, extravasation is still a potential adverse event, and appropriate precautions should be taken.
Source: Blamble D
Patients should be educated about the possibility of peripheral neuropathy and encouraged to report such symptoms to their providers. Similar to vincristine, the incidence of neuropathy is a cumulative toxicity. The prescribing information for VSLI has recommended dose modifications for VSLI-related peripheral neuropathy (see Table 1).
Constipation also is quite common. Patients should be given dietary recommendations to avoid constipation, as well as stool softeners and laxatives as needed.
Source: Blamble D
Table 2 lists the most commonly reported grade 3 or higher toxicities seen in the ALL clinical trials.
Conclusions
VSLI offers a new therapeutic option for patients with relapsed or refractory ALL. The liposomal formulation improves the pharmacokinetic profile of the cell cycle-specific active drug, vincristine, by allowing increased dose intensity and drug exposure.
The FDA-approved dosing is 2.25 mg/m2 IV over 1 hour once every 7 days. The dose is not capped. The preparation procedure and the associated time needed should be taken into account when scheduling patients to receive the drug.
Although currently only indicated as a single agent in the setting of second-line or greater therapy for ALL, it will be exciting to see data from ongoing clinical trials of combination therapy and in other disease states. The side effect profile is similar to the parent drug, although VSLI may be better tolerated in less heavily pretreated patients. At this time, patients receiving VSLI should be educated similarly to vincristine with regard to adverse effects.
References:
Deitcher OR. Blood. 2011;118:Abstract 2592.
Marqibo [prescribing information]. South San Francisco, CA: Talon Therapeutics, Inc.; 2012.
O’Brien S. Blood. 2010;116:Abstract 2143.
Rodriguez MA. Cancer. 2009;115:3475-3482.
Thomas DA. Cancer. 2009;115:5490-5498.
For more information:
Debbie Blamble, PharmD, BCOP, is an oncology clinical pharmacy specialist at The University of Texas MD Anderson Cancer Center. She may be reached at The University of Texas MD Anderson Cancer Center, Division of Pharmacy, 1515 Holcombe Blvd., Houston, TX 77030; email: dblamble@mdanderson.org.
Disclosure: Blamble reports no relevant financial disclosures.