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Filippo Ballerini - One of the best experts on this subject based on the ideXlab platform.
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Liposomal Daunorubicin, fludarabine, and cytarabine (FLAD) as bridge therapy to stem cell transplant in relapsed and refractory acute leukemia
Annals of hematology, 2014Co-Authors: Enrico De Astis, Marino Clavio, Maurizio Miglino, Anna Maria Raiola, Anna Ghiso, Fabio Guolo, Paola Minetto, Federica Galaverna, Carmen Di Grazia, Filippo BalleriniAbstract:Therapeutic options for patients with relapsed or refractory acute leukemia are still undefined and often unsatisfactory. We report the outcome of 79 patients with relapsed-refractory acute leukemia treated with fludarabine, cytarabine, and Liposomal Daunorubicin (FLAD regimen) followed by hematopoietic stem cell transplantation (HSCT), when clinically indicated, between May 2000 and January 2013. Forty-one patients had acute myeloid leukemia (AML), and 38 had acute lymphoblastic leukemia (ALL). Two patients with myeloid blast crises of CML and three with lymphoid blast crises were included in the AML and ALL subgroups, respectively. Median age was 48 years (range 13–77). FLAD was well tolerated with negligible, nonhematological toxicity. Six patients (7.5 %) died before response evaluation. Forty-seven patients achieved hematologic complete response (CR). Complete remission rate was 53 and 65 % among AML and ALL patients, respectively. No CR was recorded among 11 refractory AML patients. Twenty-four patients (30 %) underwent HSCT. Nine patients received stem cells from an HLA identical sibling, and 15 from an alternative donor (3 unrelated matched, 12 haploidentical sibling). Median overall survival in AML and ALL patients receiving FLAD therapy was 9 and 8 months, respectively. A 5-year projected OS for patients receiving the whole program (FLAD + HSCT) was 24 % for AML patients (median survival 43 months), 28 % for ALL patients treated in relapse (median survival 15 months), and 0 % for ALL patients treated for refractory disease. In this paper, we show that FLAD seems to be an effective bridge therapy to HSCT for a part of poor prognosis acute leukemia patients. However, prospective studies are needed to confirm our results.
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Combination of Liposomal Daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia
Annals of Hematology, 2004Co-Authors: Marino Clavio, Claudia Venturino, Ivana Pierri, Alberto Garrone, Maurizio Miglino, Letizia Canepa, Enrico Balleari, Manuela Balocco, Gian Luca Michelis, Filippo BalleriniAbstract:Sixty-two patients with high-risk acute leukemia were treated with the FLAD regimen [3 days of treatment with fludarabine 30 mg/m^2, cytarabine (AraC) 2 g/m^2, and Liposomal Daunorubicin 80 mg/m^2]. The acute myeloid leukemia (AML) patients were either refractory to standard induction regimens (8), were in first or second relapse (13), or received therapy as first-line treatment [21 patients, 16 were above 60 years of age and 5 had post-myelodysplastic syndrome (MDS) AML]. The acute lymphoblastic leukemia (ALL) patients were treated for relapsed (7) or refractory disease (10). Three patients had chronic myeloid leukemia (CML) in the blastic phase. FLAD was well tolerated by most patients. Ten major infectious complications were recorded while no signs of cardiac toxicity were observed. Five patients (8%) died before day 28 with hypocellular marrow, mainly of infection or hemorrhage, and response could not be evaluated. Complete response rate was 62% and 69% among AML patients treated at diagnosis or for relapsed disease, respectively, and 59% among the ALL patients. Furthermore, FLAD managed to overcome the negative impact of poor prognosis karyotype in ALL patients, since five of the seven patients with t(9;22) or complex karyotype achieved complete remission (CR). Nine patients underwent bone marrow transplantation (BMT). Among the AML patients who were treated at diagnosis or for relapse, the median duration of CR was 7 months (range: 2–18) and 8 months (range: 2–26), respectively. Median survival among these patients was 8 (range: 1–40) and 12 (range: 1–30) months, respectively. Similar values were found in ALL patients. In conclusion, FLAD may be an effective alternative treatment for patients with relapsed AML and for patients with ALL who failed first-line therapy.
Jorge E. Cortes - One of the best experts on this subject based on the ideXlab platform.
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A randomized trial of Liposomal Daunorubicin and cytarabine versus Liposomal Daunorubicin and topotecan with or without thalidomide as initial therapy for patients with poor prognosis acute myelogenous leukemia or myelodysplastic syndrome.
Cancer, 2003Co-Authors: Jorge E. Cortes, Francis J. Giles, Hagop M. Kantarjian, Maher Albitar, Deborah A. Thomas, Stefan Faderl, Charles Koller, Guillermo Garcia-manero, Michael Andreeff, Susan O'brienAbstract:BACKGROUND Because angiogenesis may play a role in the pathogenesis of acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), and thalidomide (Th) has shown significant anti-angiogenic activity, this study was designed to investigate the potential role of Th in the treatment of patients with AML and MDS and the possible role of a non–ara-C-containing regimen. METHODS Adults with AML or high-risk MDS and cytogenetic abnormalities other than inv (16), t(8;21), -Y or -X were randomized to receive Liposomal Daunorubicin (DNX) and ara-C (DA) or DNX and topotecan (DT). Within each arm, patients were randomized to receive chemotherapy alone (DA or DT) or with thalidomide (DATh or DTTh). Vascular endothelial growth factor (VEGF) plasma levels and microvascular density was measured before and after therapy. Eighty-four patients (median age, 65 years; range, 27–84 years) were treated. RESULTS None of 11 patients treated with DT or DTTh responded and these arms were closed. Seventeen of 37 patients treated with DA and 15 of 36 treated with DATh achieved an early complete remission. Median complete response duration was 38 and 34 weeks (P = 0.57) and median survival 35 and 28 weeks (P = 0.15), respectively. Patients with high pretreatment VEGF levels had an inferior survival. There was no significant difference in the changes in VEGF levels or microvascular density after treatment in patients who did versus those who did not receive thalidomide. CONCLUSIONS The authors concluded that thalidomide in combination with chemotherapy does not result in clinical benefit in patients with AML or high-risk MDS. Cancer 2003;97:1234–41. © 2003 American Cancer Society. DOI 10.1002/cncr.11180
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High-dose Liposomal Daunorubicin and high-dose cytarabine combination in patients with refractory or relapsed acute myelogenous leukemia
Cancer, 2001Co-Authors: Jorge E. Cortes, Francis J. Giles, Susan O'brien, Elihu H. Estey, Michael J. Keating, Deborah A. Thomas, Charles Koller, Yu Shen, Miloslav Beran, Hagop M. KantarjianAbstract:BACKGROUND Liposomal encapsulation of Daunorubicin (DaunoXome, DNX; Nexstar Pharmaceutical, Boulder, CO) changes the pharmacology profile to increase delivery to tumor sites and decrease toxicity. The authors investigated the effect of Daunorubicin in combination with ara-C in patients with refractory or recurring acute myelogenous leukemia (AML). PATIENTS AND METHODS Sixty-two patients with refractory or recurring AML received escalating doses of Daunorubicin of 75, 100, 125, or 135 mg/m2 daily for 3 days together with ara-C 1 g/m2 intravenous continuous infusion daily for 4 days. RESULTS Eighteen patients (29%) achieved a complete remission (CR) and 7 (11%) a hematologic improvement (i.e., met all criteria for CR except for platelet count < 100 × 109/L) for an overall response rate of 40%. The dose-limiting toxicity was mucositis in 4 in 9 (44%) patients treated at the 150 mg/m2 dose level, but minimal at 125 mg/m2 (2 of 32, 6%) or 135 mg/m2 (1 of 13, 8%). Cardiotoxicity Grade 2 was observed in 4 patients (6%) and Grade 3 or higher in 4 patients (6%). The median CR duration was 63 weeks, and overall survival rate was 25 weeks, with 28% patients alive after 1 year. CONCLUSIONS The combination of DNX (or Liposomal Daunorubicin) and ara-C has significant antileukemia activity with acceptable toxicity. Further studies are warranted to investigate the role of high-dose anthracyclines in frontline AML therapy. Cancer 2001;92:7–14. © 2001 American Cancer Society.
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palmar plantar erythrodysesthesia syndrome associated with Liposomal Daunorubicin
Pharmacotherapy, 2000Co-Authors: Yuk Fung Hui, Jorge E. CortesAbstract:Daunorubicin and doxorubicin are anthracyclines that have efficacy against malignancies such as breast cancer, lung cancer, lymphoma, and leukemia. Their adverse effects are similar. The most serious is cardiotoxicity, which often limits the total cumulative dose that can be administered. Introduction of a Liposomal formulation for both agents allows tumor selectivity by accumulating the drug in tumor tissue, thus increasing the tolerated dose. Liposomal doxorubicin is commonly associated with palmar-plantar erythrodysesthesia syndrome (PPES), although no reports of PPES were found in the literature related to Liposomal Daunorubicin (L-DNR). Two patients developed PPES while receiving high-dose L-DNR. The symptoms were self-limiting and resolved within a few weeks.
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Palmar‐Plantar Erythrodysesthesia Syndrome Associated with Liposomal Daunorubicin
Pharmacotherapy, 2000Co-Authors: Yuk Fung Hui, Jorge E. CortesAbstract:Daunorubicin and doxorubicin are anthracyclines that have efficacy against malignancies such as breast cancer, lung cancer, lymphoma, and leukemia. Their adverse effects are similar. The most serious is cardiotoxicity, which often limits the total cumulative dose that can be administered. Introduction of a Liposomal formulation for both agents allows tumor selectivity by accumulating the drug in tumor tissue, thus increasing the tolerated dose. Liposomal doxorubicin is commonly associated with palmar-plantar erythrodysesthesia syndrome (PPES), although no reports of PPES were found in the literature related to Liposomal Daunorubicin (L-DNR). Two patients developed PPES while receiving high-dose L-DNR. The symptoms were self-limiting and resolved within a few weeks.
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Phase I study of Liposomal Daunorubicin in patients with acute leukemia
Investigational new drugs, 1999Co-Authors: Jorge E. Cortes, Francis J. Giles, Susan O'brien, Elihu H. Estey, Michael J. Keating, Hagop M. KantarjianAbstract:The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of Liposomal Daunorubicin (Daunoxome® DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m2 on each cycle, to a total dose of 225, 300, 450, and 600 mg/m2, respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3–4) in 3 of 5 patients treated at 200 mg/m2, 2 of 9 treated at 150 mg/m2 and 1 of 6 at 100 mg/m2. Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m2 and has significant anti-leukemia activity.
Domenico Russo - One of the best experts on this subject based on the ideXlab platform.
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Disposition of Liposomal Daunorubicin During Cotreatment with Cytarabine in Patients with Leukaemia
Clinical Pharmacokinetics, 2003Co-Authors: Federico Pea, Domenico Russo, Mariagrazia Michieli, Daniela Damiani, Renato Fanin, Angela Michelutti, Teresa Michelutti, Stefano Piccolrovazzi, Michele Baccarani, Mario FurlanutAbstract:Objective: To investigate the pharmacokinetics and pharmacodynamics of Liposomal Daunorubicin (DaunoXome™) 80 or 100 mg/m^2 on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia. Design: Unblinded pharmacokinetic-pharmacodynamic study. Participants: Twenty-three adult patients with acute leukaemia. Methods: Blood, bone marrow and urine samples were collected at appropriate intervals on days 1–6. Total Daunorubicin and Daunorubicinol concentrations in plasma, bone marrow, peripheral blood cells and urine were measured by high performance liquid chromatography. Results: Liposomal Daunorubicin exhibited a markedly different pharmacokinetic behaviour from the free drug due to a slow distribution of the Liposomal moiety into the body. The ratio of area under the concentration-time curve (AUC) for metabolite to parent drug was lower for Liposomal Daunorubicin than for free Daunorubicin, mainly due to higher concentrations of the parent drug in plasma, whereas Daunorubicinol exposure was more or less comparable, if not higher. After Liposomal Daunorubicin at both 80 and 100 mg/m^2, total Daunorubicin concentrations in leukaemic cells were at least similar to those observed for free Daunorubicin, and significant accumulation was also observed in bone marrow blast cells. Nineteen of 23 patients obtained a complete remission, although 13 had P-glycoprotein-overexpressing blast cells. Grade 3–4 mucositis was found only in three patients with very high AUCs for total Daunorubicin and Daunorubicinol. Conclusions: Liposomal Daunorubicin at both 80 and 100 mg/m^2 in combination with cytarabine may represent a valid treatment for high-risk acute leukaemia. Liposomal Daunorubicin may be helpful in overcoming multidrug resistance, since it shows significant accumulation into tumour target cells, irrespective of P-glycoprotein expression. The tolerability profile suggests that toxicity may be related to exposure to both the parent drug and the metabolite.
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Disposition of Liposomal Daunorubicin during cotreatment with cytarabine in patients with leukaemia.
Clinical pharmacokinetics, 2003Co-Authors: Federico Pea, Domenico Russo, Mariagrazia Michieli, Daniela Damiani, Renato Fanin, Angela Michelutti, Teresa Michelutti, Stefano Piccolrovazzi, Michele Baccarani, Mario FurlanutAbstract:Objective: To investigate the pharmacokinetics and pharmacodynamics of Liposomal Daunorubicin (DaunoXome™) 80 or 100 mg/m2 on days 1, 2 and 3 coadministered with standard or high-dose cytarabine to patients with poor-risk acute leukaemia.
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Liposomal Daunorubicin (DaunoXome) for treatment of poor-risk acute leukemia
Annals of hematology, 2002Co-Authors: Domenico Russo, Mariagrazia Michieli, Teresa Michelutti, Pier Paolo Piccaluga, Giuseppe Visani, Ivana Pierri, Luigi Gugliotta, Alessandro Bonini, Marco Gobbi, Mario TiribelliAbstract:Toxicity limits the use of anthracyclines in elderly sick patients and in heavily pretreated patients. Since the Liposomal preparation of Daunorubicin (DNR) (DaunoXome, or DNX) is expected to be less toxic than conventional DNR, we tested DNX combined with high-dose arabinosyl cytosine (HDAC) in 42 adult poor-risk acute leukemia patients. Thirty-one patients had acute non-lymphocytic leukemia (ANLL). Of these, 12 patients were newly diagnosed but were not eligible for standard induction treatment, 13 were in first relapse, and 6 were in second or subsequent relapse. Eleven patients had acute lymphocytic leukemia (ALL), in first (eight cases) or second (three cases) relapse. DNX was given i.v. in three doses of 80 or 100 mg/m2 each (days 1–3) by a 60-min infusion in glucose 5%, followed by a 4-h infusion of HDAC 2 g/m2 (days 1–5). Among 31 ANLL patients there were 16 (51%) complete remissions (CR), 5 deaths during induction, and 10 failures. Among 11 ALL patients there were 10 CRs and 1 failure. The response rate was not affected by the overexpression of MDR-related proteins (PgP, MRP-1, and LRP). Non-hemopoietic toxicity was negligible, with no intestinal toxicity and only one case of gram-negative bacteremia. We conclude that DNX, in combination with HDAC, is an effective treatment for poor-risk adult AL. Because of the low non-hematologic toxicity, it can be used to reinduce remission in poor-risk patients who are candidates for allogeneic bone marrow transplantation. The high CR rate observed in ALL requires confirmation.
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Liposomal Daunorubicin plasmatic and renal disposition in patients with acute leukemia.
Cancer chemotherapy and pharmacology, 2000Co-Authors: Federico Pea, Domenico Russo, Mariagrazia Michieli, Daniela Damiani, Michele Baccarani, Massimo Baraldo, Anna Ermacora, Mario FurlanutAbstract:Liposomal formulations of anthracyclines have been developed to increase their delivery to solid tumors while reducing toxicity in normal tissues. DaunoXome (DNX, NeXstar) is a Liposomal-encapsulated preparation of Daunorubicin registered for treatment of Kaposi's sarcoma that during prior in vitro studies showed a toxicity to leukemic cells at least comparable to that of free Daunorubicin. The aim of our study was to determine DNX pharmacokinetics in 11 poor-risk patients with acute leukemia treated with DNX 60 mg/m2 IV on days 1, 3, and 5. Blood and urine samples were collected at appropriate intervals after each of the three DNX administrations. The total amount of Daunorubicin (free and entrapped) (t-DNR) and of its metabolite Daunorubicinol (DNRol) was assayed by HPLC. The main pharmacokinetic parameters (t1/2α 4.54 ± 0.87 h; Vdss 2.88 ± 0.93 l/m2; Cl 0.47 ± 0.26 l/h/m2) showed that in patients with acute leukemia Liposomal-entrapped Daunorubicin pharmacokinetics greatly differed from that observed for the conventional formulation. In fact, DNX produced mean plasma AUC levels (t-DNR AUC0–∞ 456.27 ± 182.64 μg/ml/h) about 100- to 200-fold greater than those reported for the free drug at comparable doses due to a very much lower total body clearance. Volume of distribution at steady state was 200- to 500-fold lower than for the free drug. Plasma AUC of DNRol (17.62 ± 7.13 μg/ml · h) was similar to or even greater than that observed with free Daunorubicin for comparable doses. Cumulative urinary excretion showed that about 6% and 12% of the total dose of DNX administered was excreted in urine as Daunorubicin and Daunorubicinol, respectively. No major toxicity was encountered. Therefore, pharmacokinetic characteristics suggest that DNX may be more convenient than free Daunorubicin in the treatment of acute leukemia. In fact, Liposomal formulation may allow a reduction of Daunorubicin captation in normal tissues, thus minimizing toxicity at least for the parent drug, and guarantee an unimpeded access to leukemic cells in the bloodstream and bone marrow, thus theoretically improving efficacy.
Stephanie B. Tsai - One of the best experts on this subject based on the ideXlab platform.
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Liposomal Daunorubicin cytarabine as a bridge to second allogeneic transplant for early relapses after first allograft for acute myelogenous leukemia myelodysplastic syndrome
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Daulath Singh, Nasheed Hossain, Scott E. Smith, Patrick J. Stiff, Patrick Hagen, Stephanie B. TsaiAbstract:Introduction Liposomal Daunorubicin/cytarabine (Vyxeos® or lipo-CD) is a dual drug Liposomal encapsulation, delivering these drugs at a fixed 1:5 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, lipo-CD pts had improved survival and remission rates in a pivotal phase III study, with more reaching allogeneic transplantation (HCT), with lower post-HCT mortality and improved survival. With its enhanced pharmacokinetics, lipo-CD may provide a potent bridge to second transplant for early relapses after HCT. Here, we report our experience. Methods We retrospectively reviewed recipients of lipo-CD at our institution since FDA approval 8/2017. Of 23 pts, 8 relapsed Results Median age was 60 yrs. They received 1-4 lines of therapy (median 2) prior to first HCT with 5/8 pts having received 7+3 (cytarabine 100-200mg/m2 × 7 days + dauno 60-90mg/m2 × 3 days). 6 had adverse cytogenetics/genomic profiles. 7/8 had AML and 1 high grade MDS. Pts relapsed at 2 to 7 mo (median 4 mo) after first HCT, and all 8 received full lipo-CD induction (dauno 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy. [Table] 7/8 had Day 14 bone marrow biopsies: 3 were clear, 2 had >80% cytoreduction, and 2 had similar blast count. 3 with persistent disease underwent re-induction with lipo-CD (Days 1 and 3). All successfully proceeded to second transplant at 15-70 days after lipo-CD: 7 with same donor after melphalan 140mg/m2, and 1 from a different donor after busulfan/fludarabine. Tacrolimus was started on day + 7 and discontinued at day + 28 if no GVHD. 4/8 remain alive. 2 relapsed at 3 and 6 months post-HCT and are remarkably in CR at 19 and 16 mo after second transplant despite isolated CNS relapses, which were successfully treated. The other two relapsed at 2 and 3 mo post-HCT and are alive after second transplant. Conclusion Outpatient lipo-CD as a bridge to second transplant is feasible and effective in treating AML/MDS with early relapse after first HCT. While preliminary, survival appears favorable to that reported (14-23% at 1 year) in this very poor risk group, including those with adverse cytogenetics. Prospective multi-center trials are planned.
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Liposomal Daunorubicin/Cytarabine As a Bridge to Second Allogeneic Transplant for Early Relapses after First Allograft for Acute Myelogenous Leukemia/Myelodysplastic Syndrome
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Daulath Singh, Patrick A. Hagen, Nasheed Hossain, Scott E. Smith, Patrick J. Stiff, Stephanie B. TsaiAbstract:Introduction Liposomal Daunorubicin/cytarabine (Vyxeos® or lipo-CD) is a dual drug Liposomal encapsulation, delivering these drugs at a fixed 1:5 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, lipo-CD pts had improved survival and remission rates in a pivotal phase III study, with more reaching allogeneic transplantation (HCT), with lower post-HCT mortality and improved survival. With its enhanced pharmacokinetics, lipo-CD may provide a potent bridge to second transplant for early relapses after HCT. Here, we report our experience. Methods We retrospectively reviewed recipients of lipo-CD at our institution since FDA approval 8/2017. Of 23 pts, 8 relapsed Results Median age was 60 yrs. They received 1-4 lines of therapy (median 2) prior to first HCT with 5/8 pts having received 7+3 (cytarabine 100-200mg/m2 × 7 days + dauno 60-90mg/m2 × 3 days). 6 had adverse cytogenetics/genomic profiles. 7/8 had AML and 1 high grade MDS. Pts relapsed at 2 to 7 mo (median 4 mo) after first HCT, and all 8 received full lipo-CD induction (dauno 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy. [Table] 7/8 had Day 14 bone marrow biopsies: 3 were clear, 2 had >80% cytoreduction, and 2 had similar blast count. 3 with persistent disease underwent re-induction with lipo-CD (Days 1 and 3). All successfully proceeded to second transplant at 15-70 days after lipo-CD: 7 with same donor after melphalan 140mg/m2, and 1 from a different donor after busulfan/fludarabine. Tacrolimus was started on day + 7 and discontinued at day + 28 if no GVHD. 4/8 remain alive. 2 relapsed at 3 and 6 months post-HCT and are remarkably in CR at 19 and 16 mo after second transplant despite isolated CNS relapses, which were successfully treated. The other two relapsed at 2 and 3 mo post-HCT and are alive after second transplant. Conclusion Outpatient lipo-CD as a bridge to second transplant is feasible and effective in treating AML/MDS with early relapse after first HCT. While preliminary, survival appears favorable to that reported (14-23% at 1 year) in this very poor risk group, including those with adverse cytogenetics. Prospective multi-center trials are planned.
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Liposomal Daunorubicin/Cytarabine As a Bridge to Donor Lymphocyte Infusion or Allogeneic Stem Cell Transplantation for High-Risk Acute Myelogenous Leukemia
Blood, 2019Co-Authors: Daulath Singh, Patrick A. Hagen, Nasheed Hossain, Scott E. Smith, Patrick J. Stiff, Stephanie B. TsaiAbstract:Introduction: Liposomal Daunorubicin/cytarabine (Vyxeos®) is a dual drug Liposomal encapsulation of cytarabine and Daunorubicin, delivering drugs at a fixed 5:1 synergistic ratio for a longer therapeutic period. Compared to standard 7+3, Liposomal cytarabine/Daunorubicin (lipo-cytara/dauno) patients had improved survival and remission rates in a pivotal phase III study of elder adults with high-risk acute myelogenous leukemia (AML). Furthermore, more lipo-cytara/dauno patients went to allogeneic stem cell transplantation (HCT), with lower mortality and improved survival compared to those induced with 7+3. With its enhanced pharmacokinetics, lipo-cytara/dauno may provide a potent bridge to transplant. We report our experience using lipo-cytara/dauno as a bridge to same donor lymphocyte infusion (DLI) or different donor HCT in high-risk AML. Methods: We retrospectively reviewed all patients who received lipo-cytara/dauno at our institution since the FDA approval in August 2017. Of the 21 patients who have been treated, 9 received it as a bridge to cell therapy. All patients received the drug by usual means under the FDA label. Results: The median age of the 9 patients who received lipo-cytara/dauno as a bridge to cell therapy was 59 years. Seven were male, and two were female. Patients had had 1-4 prior lines of chemotherapy (median 2) with 7 of 9 patients having received prior standard 7+3 induction (cytarabine 100-200 mg/m2 x 7 days infusion and Daunorubicin 60-90 mg/m2 x 3 days). Most had adverse cytogenetics, and all 9 patients received full lipo-cytara/dauno induction (Daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on Days 1, 3, and 5) as outpatient therapy [Table]. Of the 9 patients, 6 had AML with very early relapse after HCT, with median time to relapse of 4 months (range 3 to 7 months). All 6 successfully proceeded to their planned cell infusion: 5 received same donor DLI after melphalan at 140 mg/m2, and 1 underwent second HCT from a different donor with busulfan/fludarabine conditioning at Days 15-40 after lipo-cytara/dauno. Of the remaining 3, two had relapsed AML after an initial remission (one was in first complete remission (CR1) for 3 months after 7+3/midostaurin induction and the other was in CR1 for 7 months after 7+3 induction/high dose cytarabine consolidation) and one had primary refractory disease (PREF) after 7+3 and azacitidine/venetoclax induction regimens. All 3 successfully underwent first HCT at Days 15-100 days after lipo-cytara/dauno bridge. The PREF patient received fludarabine/cyclophosphamide/TBI conditioning followed by matched unrelated donor transplant. Of the 2 with relapsed AML after initial remission, one received busulfan/fludarabine/thiotepa conditioning followed by umbilical cord stem cell transplantation and the other patient received fludarabine/cyclophosphamide/TBI conditioning prior to matched related donor transplant. Six of 9 had Day 14 bone marrow biopsies after lipo-cytara/dauno: 2 were in CR, 2 had >80% cytoreduction, and 2 had similar blast count. Three with persistent disease underwent reinduction with lipo-cytara/dauno (Days 1 and 3) and proceeded straight to cell therapy after. Median days to hospitalization after outpatient lipo-cytara/dauno was 6 days (range 3 to 14 days). Four out of 9 patients remain alive. Two were very early post HCT relapses (relapsed at 3 and 6 months post-HCT), both of which are remarkably in CR at 14 and 17 months after second cell therapy. Interestingly, both had CNS relapse, which were successfully treated, and both remain alive and in remission today. The other two had relapsed AML and PREF AML and underwent first HCT after lipo-cytara/dauno bridge. They remain alive and in remission at 1 and 8 months. Conclusion: In this retrospective study, outpatient lipo-cytara/dauno as a bridge to cell therapy is feasible and effective in very high-risk AML with no other viable options. While preliminary, survival appears favorable to that reported elsewhere at 14-23% at 1 year in this poor risk group, including those with adverse cytogenetic and/or very early post-HCT relapse. Prospective multi-center trials are planned to further evaluate lipo-cytara/dauno as a bridge to DLI/HCT in those with early relapse post-HCT and in those with refractory disease, with therapy to include CNS prophylaxis. Disclosures Stiff: Gilead/Kite Pharma: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Gamida-Cell: Research Funding; Incyte: Research Funding; Cellectar: Research Funding; Unum: Research Funding. Tsai:Jazz pharmaceuticals: Speakers Bureau; Jazz pharmaceuticals: Consultancy.
Esther E Freeman - One of the best experts on this subject based on the ideXlab platform.
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The Cochrane Library - Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults.
The Cochrane database of systematic reviews, 2014Co-Authors: Oluwatoyin F Gbabe, Charles I Okwundu, Martin Dedicoat, Esther E FreemanAbstract:Background Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.Objectives To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.Selection criteria Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.Data collection and analysis Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.Main results We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing Liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus Liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated Liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated Liposomal doxorubicin versus Liposomal Daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing Liposomal Daunorubicin to ABV, there was no significant difference with the use of Liposomal Daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from Liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.Authors' conclusions The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between Liposomal doxorubicin, Liposomal Daunorubicin and paclitaxel.
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treatment of severe or progressive kaposi s sarcoma in hiv infected adults
Cochrane Database of Systematic Reviews, 2014Co-Authors: Oluwatoyin F Gbabe, Charles I Okwundu, Martin Dedicoat, Esther E FreemanAbstract:Background Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients.Objectives To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma.Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014.Selection criteria Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens.Data collection and analysis Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens.Main results We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing Liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus Liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated Liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated Liposomal doxorubicin versus Liposomal Daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing Liposomal Daunorubicin to ABV, there was no significant difference with the use of Liposomal Daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from Liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events.Authors' conclusions The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between Liposomal doxorubicin, Liposomal Daunorubicin and paclitaxel.
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Treatment of severe or progressive Kaposi's sarcoma in HIV-infected adults.
The Cochrane database of systematic reviews, 2014Co-Authors: Oluwatoyin F Gbabe, Charles I Okwundu, Martin Dedicoat, Esther E FreemanAbstract:Kaposi's sarcoma remains the most common cancer in Sub-Saharan Africa and the second most common cancer in HIV-infected patients worldwide. Since the introduction of highly active antiretroviral therapy (HAART), there has been a decline in its incidence.However, Kaposi's sarcoma continues to be diagnosed in HIV-infected patients. To assess the added advantage of chemotherapy plus HAART compared to HAART alone; and the advantages of different chemotherapy regimens in HAART and HAART naive HIV infected adults with severe or progressive Kaposi's sarcoma. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and , GATEWAY, the WHO Clinical Trials Registry Platform and the US National Institutes of Health's ClinicalTrials.gov for ongoing trials and the Aegis archive of HIV/AIDS for conference abstracts. An updated search was conducted in July 2014. Randomised trials and observational studies evaluating the effects of any chemotherapeutic regimen in combination with HAART compared to HAART alone, chemotherapy versus HAART, and comparisons between different chemotherapy regimens. Two review authors assessed the studies independently and extracted outcome data.We used the risk ratio (RR) with a 95% confidence interval (CI) as the measure of effect.We did not conduct meta-analysis as none of the included trials assessed identical chemotherapy regimens. We included six randomised trials and three observational studies involving 792 HIV-infected adults with severe Kaposi's sarcoma.Seven studies included patients with a mix of mild to moderate (T0) and severe (T1) Kaposi's sarcoma. However, this review was restricted to the subset of participants with severe Kaposi's sarcoma disease.Studies comparing HAART plus chemotherapy to HAART alone showed the following: one trial comparing HAART plus doxorubicin,bleomycin and vincristine (ABV) to HAART alone showed a significant reduction in disease progression in the HAART plus ABV group (RR 0.10; 95% CI 0.01 to 0.75, 100 participants); there was no statistically significant reduction in mortality and no difference in adverse events. A cohort study comparing Liposomal anthracyclines plus HAART to HAART alone showed a non-statistically significant reduction in Kaposi's sarcoma immune reconstitution inflammatory syndrome in patients that received HAART plus Liposomal anthracyclines (RR 0.49; 95% CI 0.16 to 1.55, 129 participants).Studies comparing HAART plus chemotherapy to HAART plus a different chemotherapy regimen showed the following: one trial involving 49 participants and comparing paclitaxel versus pegylated Liposomal doxorubicin in patients on HAART showed no difference in disease progression. Another trial involving 46 patients and comparing pegylated Liposomal doxorubicin versus Liposomal Daunorubicin showed no participants with progressive Kaposi's sarcoma disease in either group.Studies comparing different chemotherapy regimens in patients from the pre-HAART era showed the following: in the single RCT comparing Liposomal Daunorubicin to ABV, there was no significant difference with the use of Liposomal Daunorubicin compared to ABV in disease progression (RR 0.78; 95% CI 0.34 to 1.82, 227 participants) and overall response rate. Another trial involving 178 participants and comparing oral etoposide versus ABV demonstrated no difference in mortality in either group. A non-randomised trial comparing bleomycin alone to ABV demonstrated a higher median survival time in the ABV group; there was also a non-statistically significant reduction in adverse events and disease progression in the ABV group (RR 11; 95% CI 0.67 to 179.29, 24 participants).An additional non-randomised study showed a non-statistically significant overall mortality benefit from Liposomal doxorubicin as compared to conservative management consisting of either bleomycin plus vinblastine, vincristine or single-agent antiretroviral therapy alone (RR 0.93; 95% CI 0.75 to 1.15, 29 participants). The overall quality of evidence can be described as moderate quality. The quality of evidence was downgraded due to the small size of many of the included studies and small number of events. The findings from this review suggest that HAART plus chemotherapy may be beneficial in reducing disease progression compared to HAART alone in patients with severe or progressive Kaposi's sarcoma. For patients on HAART, when choosing from different chemotherapy regimens, there was no observed difference between Liposomal doxorubicin, Liposomal Daunorubicin and paclitaxel.