Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) in Combination with UK ALL-R3 Induction Chemotherapy for Children, Adolescents and Young Adults with Relapsed Acute Lymphoblastic Leukemia (ALL): A Therapeutic Advances in Childhood Leukemia and Lymphoma (TACL) Consortium Trial

Introduction: Vincristine intensification has the potential to improve outcomes in ALL, but severe neurotoxicity has prohibited escalation beyond standard capped doses. Vincristine sulfate liposome injection, VSLI (Marqibo®) is a liposomal formulation of aqueous vincristine that optimizes pharmacokinetics, prolongs circulating half-life, increases tissue penetration, and may be better tolerated than standard vincristine. VSLI received accelerated FDA approval for adults with relapsed/refractory (r/r) ALL, at a dose of 2.25 mg/m 2/dose without a dose cap. A phase I trial of VSLI in children and young adults with r/r ALL demonstrated safety, tolerability, and evidence for single-agent activity (Shah NN, et al. Pediatric Blood Cancer, 2016). Studies of VSLI with combination chemotherapy in children have not been conducted. With emerging data supporting improved outcomes for patients (pts) with r/r ALL who proceed to immunotherapy with low-burden disease, identifying safe and effective reinduction regimens to reduce disease burden remains a priority. Methods: This multicenter pilot study conducted through the TACL consortium was designed to assess safety and feasibility of VSLI as replacement for standard vincristine with combination chemotherapy for individuals between the ages of 2-21 years with r/r ALL. Two dose levels of VSLI were utilized without a dose cap: Dose level 1 (DL1) 1.5 mg/m 2/dose; and Dose level 2 (DL2) 2.0 mg/m 2/dose. Treatment success was determined by both 1) the absence of a dose-limiting toxicity (DLT) (as defined by any > Grade 3 regimen related non-hematologic toxicity which precluded completion of the pre-specified treatment course or from proceeding to subsequent therapy within 7 weeks) and 2) completion of the prescribed treatment regimen. Adverse event grading was based on CTCAE v4.03. Bone marrow aspirate was used for standard morphologic assessment of response with central flow cytometric analysis for minimal residual disease (MRD) determination with a cut-off of <0.01% of mononuclear cells considered as MRD negative. This analysis reports the toxicities and feasibilities for Cohort A which constituted the 4-drug UK ALL-R3 induction regimen consisting of VSLI, dexamethasone, mitoxantrone, and asparaginase (pegaspargase or Erwinia). Results: A total of 10 pts with r/r B-ALL, median age 13.4 (range 5.0-17.3 years) were treated on Cohort A. Pts were heavily pre-treated, with 3 having relapsed after prior allogeneic stem cell transplantation; 8 of 10 had an M3 marrow (>/= 25% blasts). The first 4 pts were treated at DL1. All 4 were evaluable for toxicity and response and met the criteria for treatment success, facilitating dose escalation to DL2. At DL2, 4 pts were treated, with 2 experiencing DLT, including one grade (Gr) 5 event (Table 1). Two additional pts were subsequently treated at DL1 and achieved treatment success, confirming safety and feasibility of DL1 with a VSLI dose of 1.5 mg/m 2 in combination with UK ALL-R3 4-drug induction. Nine of 10 (90%) pts achieved a morphologic complete remission (CR), 5 of which were MRD negative. The median VSLI dose administered at DL1 was 2.3 mg (range, 1.8-3.2 mg) and at DL2 was 2.2 mg (range, 1.5-3.3 mg) demonstrating the feasibility of dosing beyond the standard vincristine dose-cap of 2 mg. Transient aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations were seen in 8 pts, 6 of whom had a grade 1-2 toxicity. Gr 3 hepatic toxicities were seen in 3 pts: 1 each with ALT elevation and hyperbilirubinemia; ALT and AST elevation; gamma-glutamyl transferase elevation. Toxicities were generally consistent with the UK ALL-R3 regimen. Conclusions: In children with r/r ALL, the combination of UK ALL-R3 with VSLI was highly effective with an acceptable safety profile. DL1 (1.5 mg/m 2/dose) was found to be the maximum tolerated dose in combination with this intensive re-induction regimen. The trial continues to enroll at DL1 in the expansion phase to obtain additional safety and response data with this 4-drug regimen. Additionally, 2 cohorts have been added to gain further experience with VSLI in combination with 3-drug induction (Cohort B: UK ALL-R3 without mitoxantrone) and with ALL maintenance chemotherapy (Cohort C: dexamethasone, methotrexate, mercaptopurine). VSLI has potential as a vincristine dose-intensification strategy in combination with reinduction chemotherapy for r/r ALL in pediatric patients. Figure 1 Figure 1. Disclosures Hermiston: Novartis: Consultancy; Sobi: Consultancy. Whitlock: Amgen; Jazz Pharmaceuticals: Honoraria; Novartis: Research Funding; Sobi Pharmaceuticals: Consultancy. Silverman: Takeda, Servier, Syndax, Jazz Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Wayne: Spectrum/Acrotech: Research Funding; KITE/Gilead: Research Funding.

Combination of Autohemotherapy and Vincristine Sulfate in Treatment of Canine Transmissible Venereal Tumor in Bitches in Mozambique

Background: Canine transmissible venereal tumor (TVT) is a tumor of round cells. Vincristine sulfate is the most effective for TVT. Alternatively, hemotherapy is an alternative therapy that consists of the administration of autologous blood and the positive effects are associated with an immunomodulatory effect. Since chemotherapy has some collateral effects, it is necessary to study another treatment with minimal side effects. In this context, this report case aimed to describe the use of autohemotherapy associated with vincristine sulfate for treating a transmissible venereal tumor in the vulvar mucosa of 7 adult bitches, being the first case report in Mozambique, Africa.Case: Seven adult bitches, median size, were referred to the School Veterinary Hospital, School of Veterinary, Eduardo Mondlane University, Maputo, Mozambique, Africa, with a diagnosis of TVT in the vulvar mucosa. All bitches were treated weekly with autohemotherapy and vincristine sulfate for 21 days. The parameters assessed included clinical and TVT macroscopic examination, complete blood count, serum biochemical examination and urinalysis, and were evaluated 60-min before each treatment. No clinical side effects were identified during the treatments. Color, appearance and tumor size were changed during the treatment period, and all bitches showed complete remission of the tumor 21 days after the beginning of treatment or after the third therapeutic session. The values of the complete blood count, serum biochemical and urinalysis did not demonstrate significant variations throughout the evaluated time-points. The TVT cytopathological classification was lymphocytic (42.9 %), plasmacytic (28.6 %) and lymphoplasmacytic (28.6 %). Discussion: The aims of this report were to describe the combination of autohemotherapy and vincristine sulfate for treating the transmissible venereal tumor located in the vulvar mucosa of adult bitches, through clinical and laboratory evaluation, and was not identified side and significant hematological changes. The novelty of this case report was associated with the use of adult bitches with TVT in the vulvar mucosa. Other authors conducted a similar study however with male dog with TVT identified at the base of the penis. The complete remission of the tumor after 3 applications and the absence of side effects showed the effectiveness of this treatment compared with use of chemotherapy without autohemotherapy. In contrast, dogs diagnosed with TVT and treated with vincristine sulfate showed complete remission after 4 treatment sessions However, the use of autohemotherapy alone for treating extragenital TVT in bitches did not induce complete remission after 6 weekly treatments. Doses and administration of autologous blood and vincristine sulfate were in accordance with the recommendations of the literature, and were determined according to body mass. Other routes of administration through the cephalic vein were also used and showed complete remission after 4 treatments. The decrease in size tumor associated with the changes in appearance and color was associated with regression of the TVT. The connective tissue isolating groups of cells identified in the literature were not confirmed in this report, probably due to the phase of the progression of the tumor. The highest percentage of animals with lymphocytoid TVT was different from the literature, which referred to the predominance of the plasmacytoid pattern. The combination of autohemotherapy and vincristine sulfate every 7 days encouraged complete remission of TVT in the vulvar mucosa of adult median size bitches after 3 sessions.

Comparison between hematological and biochemical changes caused by conventional and metronomic chemotherapies in the treatment of canine transmissible venereal tumor

ABSTRACT: This study aimed to report the hematological and biochemical changes caused by conventional and metronomic chemotherapies, using vincristine sulfate to treat canine Transmissible Venereal Tumor (TVT). Twelve dogs were selected, six of them for the group receiving conventional chemotherapy (G1), and six dogs for the group receiving metronomic chemotherapy (G2). The G1 group received vincristine sulfate once a week at the dose of 0.75mg/m² until the tumor had disappeared with treatment, and the G2 group was treated with vincristine sulfate three times a week at the dose of 0.25mg/m2 until the tumor had disappeared. Before and after chemotherapy treatment, hematological and biochemical blood tests were performed to evaluate the main alterations caused by both chemotherapeutic models. Dogs undergoing conventional chemotherapy had significant leukocyte changes (p<0.05), causing neutropenia and leukopenia. In dogs undergoing metronomic chemotherapy, leukocytes remained within the reference range. Half of the dogs in group G1 had normochromic, normocytic anemia. The only biochemical alteration observed was the increase of urea in group G2. Thus, metronomic chemotherapy for the treatment of TVT with vincristine sulfate proved to be an excellent method for treatment, with fewer adverse effects, especially in maintaining the leukogram of dogs within normal range and reducing the number of anemia in animals during treatment.