scholarly journals High-Dose Vincristine Sulfate Liposome Injection for Advanced, Relapsed, and Refractory Adult Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia

2013 ◽  
Vol 31 (6) ◽  
pp. 676-683 ◽  
Author(s):  
Susan O'Brien ◽  
Gary Schiller ◽  
John Lister ◽  
Lloyd Damon ◽  
Stuart Goldberg ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chemotherapy Resistance ◽  
High Dose ◽  
Rapid Progression ◽  
Target Tissue ◽  
Vincristine Sulfate ◽  
Pivotal Phase

Purpose 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. We evaluated high-dose VSLI 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). Patients and Methods 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 this pivotal phase II, multinational trial. Intravenous VSLI 2.25 mg/m2, 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). Results The CR/CRi rate was 20% and overall response rate was 35%. VSLI 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. VSLI was generally well tolerated and associated with a low 30-day mortality rate (12%). Conclusion High-dose VSLI monotherapy resulted in meaningful clinical outcomes including durable responses and bridging to HCT in advanced ALL settings. The toxicity profile of VSLI was predictable, manageable, and comparable to standard VCR despite the delivery of large, normally unachievable, individual and cumulative doses of VCR.

Neurotoxicity Profile of Vincristine Sulfate Liposome Injection (VSLI, Marqibo®) Monotherapy in Adults with Relapsed Acute Lymphoblastic Leukemia and Universal Prior Standard Vincristine Exposure

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3568-3568
Author(s):  
Steven R. Deitcher ◽  
Jeffrey A. Silverman
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Peripheral Neuropathy ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Dose Intensity ◽  
Vincristine Sulfate ◽  
Pivotal Phase ◽  
Serious Adverse Events

Abstract Abstract 3568 Background: VinCRIStine sulfate LIPOSOME injection (VSLI, Marqibo®) is a nanoparticle formulation of vincristine sulfate (VCR) that encapsulates the drug in long-circulating sphingomyelin and cholesterol liposomes. The unique pharmacologic properties of VSLI impart superior nonclinical efficacy and pharmacokinetic properties versus standard VCR. Decades of clinical experience with standard VCR has established peripheral neuropathy as the most notable toxicity and one that underpins the common practice of individual dose capping which limits cumulative dosing. We recently conducted clinical trials to support VSLI accelerated approval for the treatment of adults with relapsed and refractory Philadelphia chromosome negative acute lymphoblastic leukemia (ALL). Here we present data on the neurotoxicity profile of weekly VSLI at the approved dose. Methods: Eighty-three subjects received weekly VSLI 2.25 mg/m2as a 1-hour infusion, with no dose cap, for treatment of advanced, relapsed and/or refractory ALL; Sixty-five patients were enrolled in a pivotal, Phase 2 study and 18 patients were enrolled in an expanded cohort in a Phase 1 study. Signs and symptoms of peripheral neuropathy were proactively assessed using a detailed 15-point evaluation. The pooled data from these studies are the primary safety population for VSLI. Neurotoxicity data are presented here in comparison to two published studies that prospectively evaluated standard VCR induced peripheral neuropathy in patients with Hodgkin disease, non-Hodgkin lymphoma or acute lymphoblastic leukemia (Haim et al, Cancer 1994; 73:2515–2519 and Verstappen et al Neurology 2005; 64:1076–1077. Results: The median individual VSLI dose per infusion was 4.1 mg (range 3.1–5.5) and the median cumulative dose was 18.4 mg (range 3.5–70.1). All patients had prior exposure to VCR containing regimens that resulted in 80% of patients entering the studies with Grade 1 or Grade 2 residual neuropathy. The most common neurological adverse events were constipation (56.6%) and peripheral neuropathy (37.3%). Serious adverse events (SAEs) were reported in 76% of patients and were consistent with advanced ALL. The most frequently reported neuropathy-associated SAEs in patients treated with VSLI were peripheral neuropathy (4.8%) and constipation (3.6%). Incidence of paraesthesia, the only neuropathy uniformly reported across VSLI and VCR studies, was greater in the VCR studies than following much higher dosages and dose density (based on BSA of 1.8) of VSLI. Conclusions: Experience with VCR has established a clear relationship between dose intensity and symptoms of peripheral neuropathy. Administration of VSLI at a dose of 2.25 mg/m2with no dose cap did not result in any new or unexpected toxicity. Although neuropathy remains a significant toxicity associated with VSLI, the frequency and severity of neuropathic AEs was no greater than what would be expected from a standard VCR regimen. Despite administration of higher doses and dose density, incidence of peripheral neuropathy following exposure to VSLI was lower than previously reported with standard VCR. This is significant given that the individual and cumulative doses of VSLI were 2–3 fold greater than what is generally achieved with standard VCR. VSLI facilitates increasing the tolerable dose and dose density and may result in improved clinical response with similar or less toxicity than VCR. *On behalf of the RALLY trial investigators Disclosures: Deitcher: Talon Therapeutics: Employment, Equity Ownership. Silverman:Talon Therapeutics: Employment.

scholarly journals Impact of TKIs post–allogeneic hematopoietic cell transplantation in Philadelphia chromosome–positive ALL

Blood ◽  
2020 ◽  
Vol 136 (15) ◽  
pp. 1786-1789 ◽  
Author(s):  
Neeraj Saini ◽  
David Marin ◽  
Celina Ledesma ◽  
Ruby Delgado ◽  
Gabriela Rondon ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Cell Transplantation ◽  
Kinase Inhibitors ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Large Body ◽  
Prophylactic Use ◽  
Philadelphia Chromosome Positive

How to best use tyrosine kinase inhibitors (TKIs) of BCR-ABL after allogeneic stem cell transplantation for Philadelphia chromosome–positive acute lymphoblastic leukemia (ALL) is unknown but will almost certainly not be addressed by a definitive randomized trial. Saini and colleagues provide a large body of observational data to reinforce earlier circumstantial evidence favoring prophylactic use of TKIs for at least 2 years posttransplant.

scholarly journals Long-term remission of Philadelphia chromosome–positive acute lymphoblastic leukemia after allogeneic hematopoietic cell transplantation from matched sibling donors: a 20-year experience with the fractionated total body irradiation–etoposide regimen

Blood ◽  
2008 ◽  
Vol 112 (3) ◽  
pp. 903-909 ◽  
Author(s):  
Ginna G. Laport ◽  
Joseph C. Alvarnas ◽  
Joycelynne M. Palmer ◽  
David S. Snyder ◽  
Marilyn L. Slovak ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Lymphoblastic Leukemia ◽  
Total Body Irradiation ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Disease Status ◽  
Matched Sibling ◽  
Total Body

Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only known curative modality for patients with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). Sixty-seven patients with HLA-matched sibling donors received fractionated total body irradiation (FTBI) and high-dose VP16, whereas 11 patients received FTBI/VP16/cyclophosphamide, and 1 patient received FTBI/VP16/busulfan. The median age was 36 years. At the time of HCT, 49 patients (62%) were in first complete remission (CR1) and 30 patients (38%) were beyond CR1 (> CR1). The median follow-up was 75 months (range, 14-245 months). The 10-year overall survival for the CR1 and beyond CR1 patients was 54% and 29% (P = .01), respectively, and event-free survival was 48% and 26% (P = .02), respectively. There was no significant difference in relapse incidence (28% vs 41%, P = .28), but nonrelapse mortality was significantly higher in the beyond CR1 patients, (31% vs 54%, P = .03, respectively). By univariate analysis, factors affecting event-free and overall survival were white blood cell count at diagnosis (< 30 × 109/L vs > 30 × 109/L) and disease status (CR1 vs > CR1). The median time to relapse for CR1 and for beyond CR1 patients was 12 months and 9 months, respectively. Our results indicate that FTBI/VP16 with or without cyclophosphamide confers long-term survival in Ph+ ALL patients and that disease status at the time of HCT is an important predictor of outcome.

Time-Sequenced G-CSF (Lenograstim) for the Treatment of Adult Acute Lymphoblastic Leukemia - Seven Year Follow-Up of the Polish Adult Leukemia Group 4–96 Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2733-2733
Author(s):  
Sebastian Giebel ◽  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Slawomira Kyrcz-Krzemien ◽  
Andrzej Hellmann ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Chemotherapy Protocol ◽  
Adult Leukemia ◽  
Leukemia Group

Abstract The goal of the study was to evaluate long-term outcome of patients treated within 4–96 trial by the Polish Adult Leukemia Group (PALG). Sixty four patients with newly diagnosed acute lymphoblastic leukemia (ALL) (median age 26 years, range 16–58) were randomly assigned to receive chemotherapy alone (n=31) or chemotherapy and glucosylated G-CSF (lenograstim) (n=33). Both groups were well-balanced in terms of age, initial WBC, immunophenotype and bcr/abl positivity. Induction therapy consisted of epirubicin+vincristin (Epi/Vcr) on days 1, 8, 15, 22, prednisone on days 1–28, L-asparaginase 8 doses starting from day 13; consolidation treatment included twice methotrexate+etoposide (Mtx/Vep), twice high dose cytarabine and cyclophosphamide (HDAraC/Ctx), CNS irradiation and intrathecal Mtx. In T-derived ALL, additional HDAraC/Ctx was administered instead of the first Mtx/HDAraC. During induction patients received G-CSF 150 μg/m2 sc. on days 2–6, 9–13, 16–20, 23-until the neutrophil recovery &gt;1.0x109/L, starting 36 hours after Epi/Vcr, finishing 48 hours before the next dose; in consolidation - following each HDAraC/Ctx course on days 5–16. High risk patients having a donor were performed allogeneic hematopoietic cell transplantation in first complete remission, whereas those without a donor were given autologous transplant. At seven years the overall survival rate equalled 42% for G-CSF group and 24% for the controls (p=0.11). There was also a trend to higher probability of leukemia-free survival in advantage of patients receiving the cytokine (38% vs. 20%, p=0.17). The above differences might have resulted from: 1) Higher CR rate in the G-CSF group compared to the controls (94% vs. 87%), 2) Better adherence to the chemotherapy protocol (faster completion of induction-consolidation programme by 19 days, p=0.005, less dose reductions or delays), which in turn might have influenced the risk of relapse. We conclude that time sequenced G-CSF administration may improve long-term outcome of adult ALL patients although the study including larger population is required to confirm this hypothesis.

Minimal Residual Disease Status Is the Most Important Preditive Factor in Adults with Acute Lymphoblastic Leukemia. Prospective, Multicenter PALG 4-2002 MRD Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2821-2821 ◽  
Author(s):  
Jerzy Holowiecki ◽  
Malgorzata Krawczyk-Kulis ◽  
Sebastian Giebel ◽  
Krystyna Jagoda ◽  
Beata Stella-Holowiecka ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Disease Status ◽  
High Dose ◽  
Risk Criteria ◽  
Minimal Residual

Abstract Current therapeutic protocols for adult acute lymphoblastic leukemia (ALL) take into account the risk of relapse, in order adjust the treatment intensity to individual patient needs. It is postulated that in addition to “classical” risk criteria the status of minimal residual disease (MRD) should be considered for treatment decisions. The aim of this study was to prospectively evaluate the feasibility and prognostic significance of MRD detected with the use of immunophenotyping for outcome of ALL patients treated according to 4-2002 protocol of the Polish Adult Leukemia Group (PALG). Induction therapy included PDN, Asp and 4x epirubicin+VCR. Consolidation consisted of 2x high-dose AraC+Cy, 2x Mtx+Vep, 6MP, and CNS prophylaxis. Patients stratified to high risk (HR) group according to “classical” criteria based on those formerly developed by GMALL (bcr/abl(+), WBC>30 G/L, prepreB, early or mature T phenotype, age>35y, or prolonged time to achieve CR) were further referred for hematopoietic cell transplantation (HCT), whereas those assigned to standard risk (SR) group were treated with maintenance for 2 years. MRD was tested at the level of 0.1% after completion of induction and consolidation therapy in patients achieving CR, employing multicolor flow-cytometry, including a new “empty spaces” method taking into account an individual pattern of antigen expression on blast cells. 165 ALL pts (B-lineage 79%, T-lineage 21%), aged 29 y (17–60) were included. CR rate equaled 85,5%. 23% of CR pts were assigned to SR, 77%- to HR according to classical criteria. MRD evaluation was possible in all but 8 pts. After induction 37% of CR pts were found MRD(+). Among those who remained in CR, MRD after consolidation was detected in 26% of cases. 64% of patients were MRD(−) at both time-points, whereas in the remaining 36% of cases MRD was detected at least once. MRD status affected both relapse incidence (RI) and leukemia-free survival (LFS). After 3 years the RI was higher for pts with MRD(+) vs. MRD(−) if assessed after induction (82%vs.29%,p=0.00007) and after consolidation (62%vs.41%,p=0.05). For pts with MRD(−) at both study end-points the probability of LFS was 65% whereas for those with MRD(+) after either induction and/or consolidation − 26% (p=0.008). In the respective subgroups RI equaled 28% and 73% (p=0.004). The difference was observed for patients assigned to SR group (20%vs.92%,p=0.01) as well as to HR group (33%vs.70%,p=0.05). In a multivariate analysis including classical risk criteria the MRD status remained the only significant factor predictive for RI (HR: 2.5(1.3–4.8),p=0.006) and LFS (HR: 2.1(1.2–3.9),p=0.01). We conclude that immunophenotyping employing “empty spaces” method is feasible for MRD evaluation in adults with ALL. MRD stzatus after induction and consolidation is the most important predictive factor for RI and LFS. Based on our findings patients with MRD detected after induction and/or consolidation should be offered intensified treatment with the use of HCT irrespective of the absence of other risk factors.

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