High-Dose Vincristine Sulfate Liposome Injection (Marqibo®) Is Not Associated With Clinically Meaningful Hematologic Toxicity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2676-2676
Author(s):  
Olivia R. Deitcher ◽  
John Glaspy ◽  
Rene Gonzalez ◽  
Takami Sato ◽  
Agop Bedikian ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
The United States ◽  
Cumulative Exposure ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Median Dose ◽  
Vincristine Sulfate

Abstract Background The treatment of hematologic malignancy patients with heavily pre-treated, advanced, relapsed, or refractory disease and those with advanced age, active infection, cardiovascular disease, recent surgery, or poor performance status may require therapies with limited hematologic toxicity and associated peripheral blood cytopenias. Cancer and concomitant chemotherapy related anemia, neutropenia, and thrombocytopenia in patients with hematologic malignancy complicate evaluation of hematologic toxicity related to new drugs. Vincristine sulfate liposome injection (VSLI; Marqibo®) is a new drug developed to optimize vincristine (VCR) pharmacokinetics and facilitate VCR dose-intensification and densification. VSLI is active in untreated and relapsed lymphomas, and was recently approved in the United States for relapsed and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. Methods We assessed the hematologic toxicity of VSLI 2.25 mg/m2 administered every 14 days (Cohort 1) or 7 days (Cohort 2) in 54 patients with metastatic uveal melanoma, a cancer not known to involve the bone marrow. Cohort 1 patients could have received 1 prior systemic therapy. Cohort 2 patients must not have received any prior systemic chemotherapy, immunotherapy, cancer vaccine, or hepatic arterial chemotherapy for metastatic disease. Results Patients in Cohort 2 received a higher median number of VSLI doses (6 vs. 4) over a shorter median time period (5.7 weeks vs. 8.7 weeks) resulting in a larger median cumulative exposure (22.6 mg vs. 17.7 mg) and near doubling of median dose density (4.0 mg/week vs. 2.2 mg/week) compared to patients in Cohort 1. Despite greater VSLI exposure and dose density, Cohort 2 had a smaller decrease from baseline in median neutrophil count and greater increase from baseline in median platelet count compared to Cohort 1. Both Cohorts experienced similar gradual decreases in hemoglobin concentration over time that were attributed to cancer-associated anemia and frequent blood sampling. Hematologic adverse events (AEs) were uncommon and mostly Grade 1 or 2. There were no Grade 4 hematologic AEs. Conclusions VSLI at its approved dose resulted in a low incidence of clinically meaningful hematologic toxicity. A near doubling of median dose density did not have an impact on the reported incidence and severity of hematologic AEs. VSLI may be well suited for use alone or in combination with myelosuppresive drugs and in patients unable to tolerate peripheral blood cytopenias. Disclosures: Silverman: Talon Therapeutics: Employment. Deitcher:Talon Therapeutics: Employment, Equity Ownership.

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.

scholarly journals Sustained long-term hematopoiesis after myeloablative therapy with peripheral blood progenitor cell support

Blood ◽  
1995 ◽  
Vol 85 (12) ◽  
pp. 3754-3761 ◽  
Author(s):  
R Haas ◽  
B Witt ◽  
R Mohle ◽  
H Goldschmidt ◽  
S Hohaus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Peripheral Blood ◽  
Progenitor Cell ◽  
Lymphoblastic Leukemia ◽  
Peripheral Blood Progenitor Cell ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Platelet Recovery ◽  
Cd34 Cells

A retrospective analysis of long-term hematopoiesis was performed in a group of 145 consecutive patients who had received high-dose therapy with peripheral blood progenitor cell (PBPC) support between May 1985 and December 1993. Twenty-two patients had acute myelogenous leukemia, nine had acute lymphoblastic leukemia, 43 had Hodgkin's disease, 57 had non- Hodgkin's lymphoma, and 14 patients had multiple myeloma. Eighty-four patients were male and 61 female, with a median age of 37 years (range, 16 to 58 years). In 46 patients, PBPC were collected after cytotoxic chemotherapy alone, while 99 patients received cytokines either during steady-state hematopoiesis or post-chemotherapy. Sixty patients were treated with dose-escalated polychemotherapy, and 85 patients had a conditioning therapy including hyperfractionated total body irradiation at a total dose of 14.4 Gy. The duration of severe pancytopenia posttransplantation was inversely related to the number of reinfused granulocyte-macrophage colony-forming units (CFU-GM) and CD34+ cells. Threshold quantities of 2.5 x 10(6) CD34+ cells per kilogram or 12.0 x 10(4) CFU-GM per kilogram became evident and were associated with rapid neutrophil and platelet recovery within less than 18 and 14 days, respectively. These numbers were also predictive for long-term reconstitution, indicating that normal blood counts are likely to be achieved within less than 10 months after transplantation. Conversely, 12 patients were autografted with a median of 1.75 x 10(4) CFU-GM per kilogram resulting in delayed recovery to platelet counts of greater than 150 x 10(9)/L between 1 and 6 years. Our study includes bone marrow examinations in 50 patients performed at a median follow-up time of 10 months (range, 1 to 85 months) posttransplantation. A comparison with normal volunteers showed a 3.2-fold smaller proportion of bone marrow CD34+ cells, which was paralleled by an even more pronounced reduction in the plating efficiency of CFU-GM and burst-forming unit-erythroid. No secondary graft failure was observed, even in patients autografted with relatively low numbers of progenitor cells. This suggests that either the pretransplant regimens were not myeloablative, allowing autochthonous recovery, or that a small number of cells capable of perpetual self-renewal were included in the autograft products.

scholarly journals Co-infusion of high-dose haploidentical donor cells and CD19-targeted CART cells achieves complete remission, successful donor engraftment and significant CART amplification in advanced ALL

2020 ◽  
Vol 12 ◽  
pp. 175883592092760 ◽  
Author(s):  
Changlin Yu ◽  
Bo Cai ◽  
Yao Wang ◽  
Zhiqiang Wu ◽  
Kaixun Hu ◽  
...  
Keyword(s):  
Complete Remission ◽  
B Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Lymphoblastic Leukemia ◽  
Human Leukocyte ◽  
High Dose ◽  
Peripheral Blood Mononuclear ◽  
Grade Ii

Autologous CD19-targeted chimeric antigen receptor-modified T cells (CD19-CART) remarkably improved the outcome of patients with advanced B-cell acute lymphoblastic leukemia (B-ALL). However, the application and outcomes of allogeneic CART cells is still uncertain. Two patients with advanced B-ALL were enrolled to receive a co-infusion of high-dose human leukocyte antigen-haploidentical donor granulocyte colony-stimulating factor mobilized peripheral blood mononuclear cells (GPBMCs; 21.01–25.34 × 108/kg) and the same donor-derived CD19-targeted CART cells (8.44–22.19 × 106/kg) without additional in vitro gene-editing following a reinduction chemotherapy as precondition. They achieved complete remission and full donor chimerism (FDC) with ongoing 20- and 4-month leukemia-free survival. A significant amplification of donor CART cells was detected in peripheral blood and/or cerebrospinal fluid and was associated with the formation of FDC. The highest amount of copies of the donor CART cells reached 4962 per µg of genomic DNA (gDNA) and 2449 per µg of gDNA, and the longest persistence was 20 months associated with B cell aplasia. Two patients experienced Grade II or III cytokine release syndromes and developed controllable Grade II intestinal acute graft-versus-host disease (GVHD) or limited chronic oral GVHD. High-dose donor GPBMC infusion may enhance amplification and persistence of haploidentical CD19-targeted CART cells, suggesting an alternative therapy for advanced B-ALL patients.

A Multicenter Phase II Study Using a Dose Intensified Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1858-1858 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Lewis B. Silverman ◽  
Stephen Couban ◽  
Suzanne Dahlberg ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Demographic Data ◽  
Philadelphia Chromosome ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Childhood All

Abstract Background: In children with ALL, current chemotherapy regimens produce an event-free survival (EFS) of greater than 80%. Adults with ALL have a much poorer prognosis, with EFS rates of 30–40%. Recent retrospective studies suggest that young adult patients may have superior outcomes when treated on more intensive pediatric regimens, but prospective studies are lacking. A phase II trial was performed in an effort to determine if an intensive pediatric regimen can be administered to adults with ALL. Methods: The therapeutic backbone of this protocol is based upon the high-risk arm of the DFCI Childhood ALL Consortium Protocol 00–01. Patients with newly diagnosed ALL were enrolled and received intensive multiagent remission induction chemotherapy, which included doxorubicin, prednisone, vincristine, high-dose methotrexate, high-dose asparaginase, and triple intrathecal therapy. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of 3 week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 weeks of high-dose asparaginase that was individually dosed in order to maintain asparagine depletion. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 years from an established complete remission (CR). Results: 71 patients have been enrolled to date. Although there was no initial upper age restriction, the protocol was amended to include only patients between the ages of 18–50 with de novo ALL; this amendment excluded 4 patients from the analysis. Two patients were enrolled but never received therapy. Demographic data are available for 61 evaluable patients. The median age was 28 years, (range, 18–50), 65% were male, 75% had B-lineage phenotype, and 13% were Philadelphia chromosome positive. In the 54 patients for whom response data was available, the 4 week CR rate was 82%. Among the patients who had the opportunity to complete Intensification therapy, asparaginase data was available for 23 patients, 18 (78%) of whom completed all 30 weeks. One death occurred during induction therapy from sepsis. Four patients developed grade 3 pancreatitis and one patient died of grade 5 pancreatitis. The latter case represented the only remission death on study. There were two cases of osteonecrosis, 10 cases of thrombosis/embolism and 12 cases of neutropenic infection that occurred during the post-remission period. At the median follow-up time of 18.4 months, the estimated EFS is 75% (95%CI: 61–89%) and the overall survival is 79% (95%CI: 65–93%). Conclusions: These results suggest that administration of a dose intensified pediatric-like strategy is feasible. Although the high EFS rate requires longer follow up and larger confirmatory studies, such intensive treatment of young adults with ALL could represent a major therapeutic advance.

Autologous Stem Cell Transplantation (SCT) Following Sequential Chemotherapy and Imatinib for Adults with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) — CALGB Study 10001.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2869-2869 ◽  
Author(s):  
Meir Wetzler ◽  
Wendy Stock ◽  
Kathleen A. Donohue ◽  
Kouros Owzar ◽  
Dorie A. Sher ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leukemia Cell ◽  
High Dose ◽  
Time Interval ◽  
Rt Pcr ◽  
Sequential Chemotherapy ◽  
Hematopoietic Stem

Abstract Imatinib, given sequentially or concomitantly with chemotherapy, now plays an important role in the frontline treatment of Ph+ ALL. Once in morphologic and cytogenetic remission, most patients are recommended to undergo allogeneic SCT. However, many patients lack an HLA-matched donor. No data have yet shown a benefit from autologous SCT in this disease. We hypothesized that sequential chemotherapy and imatinib would result in greater leukemia cell cytoreduction than previously achieved with chemotherapy alone, thereby allowing collection of large numbers of normal hematopoietic stem cells from the blood uncontaminated by residual Ph+ lymphoblasts. Thus, patients without matched sibling donors could undergo autologous SCT with a lower likelihood of relapse. Patients 15–59 years old with Ph+ ALL who had a CR or PR after one cycle of a 4 or 5-drug induction regimen were eligible. Imatinib 400 mg BID was then given for 4 weeks. Central nervous system prophylaxis was given with 3 weekly doses of high-dose systemic and intrathecal methotrexate, followed by another 4 weeks of imatinib. Patients with donors then received allogeneic SCT after 13.2 Gy fractionated total body irradiation (FTBI) and etoposide (60 mg/kg × 1). Those without donors received high-dose cytarabine (2 gm/m2 every 12 hours × 8), etoposide (10 mg/kg/day × 4), and G-CSF (10 mcg/kg) for stem cell mobilization and leukapheresis, followed by autologous SCT after 13.2 Gy FTBI, etoposide (60 mg/kg × 1) and cyclophosphamide (100 mg/kg × 1). Imatinib was held during the transplant period but resumed for maintenance until patients were RT-PCR negative for 12 months. To date, 35 patients have enrolled; 31 were in complete and 4 in partial morphologic remission following induction. Data are available on 16 patients who have completed their SCT so far. The median age at study entry was 41 years for the 8 allogeneic SCT patients (range, 27–54) and 47 years (range, 24–56) for the 8 autologous SCT patients. The time interval between achievement of remission and initiation of either an allogeneic SCT (109 days, range 99–132) or stem cell collection (119 days, range 98–158) was similar between the two groups. The median autologous CD34+ cell yield by leukapheresis was 67.1 × 106/kg (range, 34.8 – 309.8). Peripheral blood stem cells have been assayed from 5 patients by RT-PCR with a sensitivity of 1:105-106; 4 were negative for BCR-ABL. Median time to autologous engraftment was 29 days (range, 28–35). Two patients have relapsed at 334 and 475 days, and 6 are in continuous major molecular remission (≥3 log reduction from pretreatment level) at a median of 487 days (range, 197 – 923). Sequential chemotherapy and imatinib yields RT-PCR negative CD34+ leukapheresis products, allowing autologous SCT for patients without donors. Engraftment is not compromised. Post-transplant imatinib is tolerable. Molecular data on minimal residual disease following induction and pre- and post-autologous SCT will be presented. As patients continue to be accrued, longer follow-up will allow comparison of outcomes between patients who underwent autologous versus allogeneic SCT for Ph+ ALL in first CR.

Phase II Study of Combination of the HyperCVAD Regimen with Dasatinib in Patients with Philadelphia Chromosome (Ph) or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Myeloid Leukemia (CML-LB).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2814-2814 ◽  
Author(s):  
Farhad Ravandi ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinical Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Platelet Recovery

Abstract Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL and resulted in eradication of minimal residual disease and durable remissions without allogeneic stem cell transplant in some patients (Thomas D, Blood, 2004; Yanada M, JCO, 2006; Wassmann B, Blood, 2006; de Labarthe A, Blood, 2007). The dual Src and Abl inhibitor dasatinib has a significantly higher in vitro kinase inhibition against BCR-ABL and has demonstrated potent clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL with over 50% complete cytogenetic responses (CG CR) in phase I and II trials but with median progression free survival of only 3 to 4 months. We are conducting a phase II trial in which patients with newly diagnosed or relapsed Ph+ ALL or CML-LB receive dasatinib 50 mg po bid for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continue to receive maintenance dasatinib 50 mg po bid daily and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 15 newly diagnosed patients with Ph+ ALL (cohort I) and 4 patients with relapsed Ph+ ALL or CML-LB (cohort II) have received a median of 4 cycles (range 1 – 8); 4 patients are receiving maintenance in CR. Median age for cohort I is 55 years (range 23 – 79) and for cohort II, 43 years (range 26 – 69); 13 and 3 patients were older than 50 years, respectively. Median WBC at diagnosis for cohort I was 4.3 × 109/L (range, 0.8 – 203.4 x 109/L). Three patients had CNS involvement. Fourteen and 3 patients in the 2 cohorts are evaluable for response to induction; 2 are too early. Thirteen patients (93%) in cohort I and all evaluable patients in cohort II have achieved CR after the first cycle; 1 patient in cohort I died on day 20 from infections before response assessment; her bone marrow exam on day 14 showed no detectable disease. Ten of 11 (91%) patients in cohort I have achieved CG CR after 1 cycle; 3 are too early. Three of 4 patients in cohort II have achieved CG CR after 1 cycle; 1 had a new CG abnormality and 1 is too early. Six patients have achieved complete molecular remission after the first cycle with the lowest BCR-ABL/ABL in the other patients ranging from 0.01 to 1.91. Median time to neutrophil and platelet recovery for cohort I is 18 and 25 days and for cohort II 18.5 and 30.5 days. Grade 3 and 4 toxicity has included 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and acute renal failure unrelated to treatment. With a median follow up of 4 months (range, 0 – 10), 15 patients are alive and in CR; 1 died at induction, 1 died in CR from an unrelated cardiac event, and 2 are too early. No patient has relapsed and no patient has received an allogeneic transplant. We conclude that the combination of the hyperCVAD regimen with dasatinib is feasible and can achieve early molecular remissions in patients with Ph+ ALL and CML-LB.

A Multicenter Phase II Study Using a Dose Intensified Pediatric Regimen in Adults with Untreated Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 587-587 ◽  
Author(s):  
Daniel J. DeAngelo ◽  
Suzanne Dahlberg ◽  
Lewis B. Silverman ◽  
Stephen Couban ◽  
Philip C. Amrein ◽  
...  
Keyword(s):  
Young Adults ◽  
Phase Ii ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Treatment Strategies ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Childhood All

Abstract Background: Current chemotherapy regimens in children with ALL produce event-free survival (EFS) rates of greater than 80%. In contrast, adults with ALL have a much poorer prognosis, with EFS rates of 30–40%. Recent retrospective studies suggest that young adults may have superior outcomes when treated with intensive pediatric regimens. Unfortunately, prospective studies are lacking. This phase II trial was performed to determine if an intensive pediatric regimen could be administered to adults with ALL. Methods: The therapeutic backbone of this protocol is based on the high-risk arm of the DFCI Childhood ALL Consortium Protocol 00-01. Patients with newly diagnosed ALL received induction chemotherapy, which included doxorubicin, prednisone, vincristine, high-dose methotrexate, L-asparaginase (L-asp), and triple intrathecal therapy. CNS prophylaxis included triple intrathecal therapy and cranial radiation. Intensification therapy consisted of ten 3-week courses of doxorubicin, vincristine, dexamethasone, 6-mercaptopurine and 30 weeks of L-asp that was dosed to maintain asparagine depletion, defined as an L-asp level between 0.1 and 0.14. Continuation therapy consisted of 3 week courses of vincristine, dexamethasone, methotrexate and 6-mercaptopurine for a total of 2 years from an established complete remission (CR). Results: 89 patients have been enrolled and treated to date. The first 75 eligible patients were used for this analysis, 73 of whom had on-study data. Although there was no initial upper age restriction, the protocol was amended to include only patients between the ages of 18–50 with de novo ALL, which excluded 4 patients from the analysis. The median age was 28 years, (range, 18–50), 60% were male, 74% had B-lineage phenotype, and 20% were Philadelphia chromosome positive. The CR rate after 4 weeks was 84%. 39 patients had the opportunity to complete L-asp intensification therapy, and 27 (69%) completed all 30 weeks. The median L-asp dose was 16,582 U/m2 (starting dose was 12,500 U/m2). One death occurred during induction therapy (sepsis). Nine patients developed pancreatitis, one of whom died. This last case represented the only remission death on study. Two patients developed osteonecrosis, 14 thrombosis/embolism and 23 neutropenic infection during the post-remission period. With a median follow-up time of 15.3 months, the estimated 2-yr EFS is 72.5% (95%CI: 61–84%) and the estimated 2-yr overall survival (OS) is 77.1% (95%CI: 67–95%). Conclusions: The administration of a dose intensified pediatric regimen to adults with ALL is feasible. Although the high EFS and OS rates require longer follow up, such intensive treatment strategies for young adults with ALL could represent a major therapeutic advance.

Trends in Survival after Diagnosis with Hematologic Malignancy in Adolescence or Young Adulthood in the United States, 1981- 2005

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 877-877
Author(s):  
Dianne Pulte ◽  
Adam Gondos ◽  
Hermann Brenner
Keyword(s):  
21St Century ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Relative Survival ◽  
Hematologic Malignancies ◽  
The United States ◽  
Acute Leukemias ◽  
Period Analysis ◽  
Early 21St Century ◽  
Survival Expectations

Abstract Background: There are few population based studies of long-term survival of adolescents and young adults (AYA) with hematologic malignancies, mostly pertaining to patients diagnosed in the 1990s or earlier. Traditionally, survival in AYA with hematologic malignancies has been worse than survival for children with similar malignancies. Here, we use period analysis to obtain up-to-date information on survival expectations of AYA diagnosed with hematologic malignancies through the early 21st century. Methods: Period analysis was used to calculate 5- and 10-year relative survival for AYA aged 15–24 diagnosed with hematologic malignancies for five calendar periods from 1981–85 to 2001–2005, using data from the Surveillance, Epidemiology, and End Results (SEER) database. Results: Data from 9836 patients aged 15–24 included in the SEER database who were diagnosed with Hodgkin’s lymphoma (HL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML), and chronic myelocytic leukemia (CML) were analyzed. HL was the most common malignancy, accounting for about 50% of all hematologic maligancies in each calendar period examined. Survival strongly improved for each of the five hematologic malignancies. Increases in 10-year relative survival were as follows: HL, from 80.4 to 93.4%; NHL, from 55.6 to 76.2%; ALL, from 30.5 to 52.1%; AML, from 15.2 to 45.1%; CML, from 0 to 74.5% (p<0.0001 in all cases, see table). However, while survival improved steadily throughout the period examined for the lymphomas and CML, survival was stable during the late 1990s and early 21st century for the acute leukemias. Survival has not improved for AML since 1990–95 or for ALL since 1996–2000 (see table). Discussion: Survival expectations for AYA with hematologic malignancies have strongly improved since the 1980s. However, with the exception of HL, survival rates have not reached the levels observed for children diagnosed with the same malignancies. In particular, 10-year survival in children aged 10–14 with ALL was over 75% for the 2000–04 period1 compared to about 50% for AYA in 2001–05. Similarly, 10-year survival for children aged 0–14 diagnosed with acute non-lymphoblastic leukemia was about 60% in the 2000–04 period compared with less than 50% for AYA with AML in the 2001–05 period. Some caution must be used when comparing survival in AYA versus in children since survival estimates for children are for absolute survival, while those for AYA are for relative survival. However, relative survival in children and AYA is close to 100%, making the comparison relatively straightforward. Furthermore, survival estimates for the acute leukemias have not improved since the 1990s while survival for children continued to improve during the early 21st century. Reasons for the poorer survival observed may include differences in the biology of the malignancies, poorer compliance in AYA, differences in treatment protocols in children versus AYA, lower availability of clinical trials in AYA than in children, and low rates of health insurance in AYA patients, particularly after age 18. Further examination of the reasons for the poorer outcomes observed for AYA with acute leukemias may clarify this issue. 1 Pulte D, Gondos A, Brenner H. Trends in 5- and 10-year survival after diagnosis with childhood hematologic malignancies in the United States, 1990–2004. Accepted JNCI 7/08. Table: 10-year relative survival 1981–85 to 2001–05 by hematologic malignancy Diagnosis 1981– 85 1986–90 1991–95 1996–2000 2001–05 Diff1 p-val2 PE3 SE4 PE SE PE SE PE SE PE SE 1 Difference in survival, 1981–85 versus 2001–05. 2 P-value for trend. 3 Point estimate 4 Standard error HL 80.4 1.5 82.6 1.4 86.9 1.2 88.9 1.2 93.4 1.0 +13.0 <0.0001 NHL 55.6 3.1 59.9 2.9 62.7 2.7 67.9 2.6 76.2 2.3 +20.6 <0.0001 ALL 30.5 4.1 35.8 4.0 42.1 3.9 51.6 3.9 52.1 3.7 +21.6 <0.0001 AML 15.2 3.4 22.3 4.1 43.6 4.7 39.5 4.0 45.1 4.0 +29.9 <0.0001 CML 0 0 22.5 6.5 20.8 6.5 41.4 7.9 74.5 7.6 +74.5 <0.0001

Marqibo® (vincristine sulfate liposomes injection; VSLI) Optimizes the Dosing, Delivery, and Pharmacokinetic (PK) Profile of Vincristine Sulfate (VCR) In Adults with Relapsed and Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2142-2142 ◽  
Author(s):  
Jeffrey A Silverman ◽  
Walter E. Aulitzky ◽  
John Lister ◽  
Lori Maness ◽  
Gary J Schiller ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Specific Activity ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Full Blood Count ◽  
National Study ◽  
Vincristine Sulfate ◽  
Dose Intensification ◽  
The Mean

Abstract Abstract 2142 Background: VCR is an important component of the treatment of ALL, non-Hodgkin lymphoma, Hodgkin's disease, multiple myeloma, and other adult and childhood cancers. In part, because of the cell cycle specific activity of VCR, its anti-cancer activity is believed to be very exposure time and concentration dependent. Standard dosing of conventional VCR (1.4 mg/m2 with a 2 mg cap) is limited because of early onset peripheral neuropathy and fails to achieve sustained VCR delivery. VSLI (Marqibo) is a nano-particle encapsulated formulation of VCR designed to facilitate dose intensification, prolonged drug delivery and enhanced cancer penetration and concentration. Methods: In a pivotal, Phase 2, multi-national study (RALLY Trial), 65 adults with Philadelphia chromosome negative ALL who were either in second or greater relapse or who had progressed after two or more prior lines of treatment received single-agent intravenous VSLI 2.25 mg/m2 (without any dose cap) weekly over 1 hour as salvage therapy. First-dose PK was investigated in a representative subset of 13 study subjects. Blood for analysis was collected at 8 time points ranging from 5 minutes to 48 hours following infusion. Total VCR plasma levels were determined by HPLC-MS/MS. PK parameters were calculated with Phoenix WinNonlin. Results: The PK subject subset had a median body surface area (BSA) of 1.92 m2 (range 1.47 to 2.45 m2) and received a median VSLI dose (VCR component) of 4.32 mg (range 3.3 to 5.51 mg). Based on BSA and the 2 mg dose cap, all subjects in this study group would have been dosed with 2.0 mg of conventional VCR. The median cumulative induction dose of VSLI (VCR component) that was administered in this study was 18.8 mg (range 3.5 to 70.1 mg). Total VCR plasma concentration decreased rapidly from Cmax after the VSLI infusion in 5 subjects (38%); 8 subjects (62%) exhibited a delay of 4 to 10 hours before the total VCR plasma concentration began to decrease. The calculated Tmax was 1.3 ± 0.4 hours (range 1.1 to 2.0 hours). The Cmax was 1214 ± 233 ng/mL (range 919 to 1720 ng/mL). The apparent mean half-life was 7.1 ± 3.2 hours. The mean AUCinf was 13,993 ± 6,588 ng hr/mL with a range from 7,167 to 27,233 ng hr/mL. The mean clearance (CL) was 6.4 ± 2.6 mL/min. The mean volume of distribution (Vd) was 0.051 ± 0.018 L/Kg. There were no significant differences in the PK parameters between the male and female subjects participating in this study. The table below presents VSLI PK parameters in addition to historical PK parameters for conventional VCR dosed at 2 mg. Conclusions: VSLI clearly provides dose intensification and prolonged VCR delivery compared to conventional, non-encapsulated VCR. VSLI, as dosed in this adult ALL clinical trial, delivered individual and cumulative amounts of VCR that exceed those achievable with standard and approved dosing of conventional VCR. This translated into a median dose intensification of 116% (range 65 to 176 percent) calculated as the percent change in VSLI dose from a standard VCR dose. This dose intensification is believed to have contributed to the 35% overall response rate including 20% complete responses (with or without full blood count recovery) reported in this heavily pre-treated, multiply-relapsed/refractory population without apparent enhanced toxicity [J Clin Oncol 28:15s, 2010 (suppl; abst 6507)]. VSLI has a distinctly different PK profile than conventional VCR. The larger VSLI Cmax and AUCinf reflect the dose intensification afforded by a larger mg/m2 dose and lack of dose capping. Even in the absence of dose capping, the 2.25 mg/m2 VSLI dose represents a 61% dose escalation above conventional VCR. While Cmax and AUCinf are dose-dependent PK parameters, the observed differences between VSLI and VCR control cannot be explained by dose alone. The larger AUCinf also reflects prolonged circulation afforded by the sphingomyelin:cholesterol liposome encapsulation. The modest VSLI mean CL and small Vd reflect the retention of encapsulated VCR within the plasma compartment for an extended period of time so that VCR can better penetrate and accumulate in sites of cancer through fenestrated vasculature. The enhanced delivery of encapsulated VCR contributes to maintenance of VCR concentrations above the effective concentration. Disclosures: Silverman: Hana Biosciences: Employment. Deitcher: Hana Biosciences: Employment.

Sign in / Sign up

Export Citation Format

Share Document