Teniposide in the treatment of leukemia: a case study of conflicting priorities in the development of drugs for fatal diseases.

1988 ◽  
Vol 6 (2) ◽  
pp. 351-379 ◽  
Author(s):  
J L Grem ◽  
D F Hoth ◽  
B Leyland-Jones ◽  
S A King ◽  
R S Ungerleider ◽  
...  
Keyword(s):  
Individual Component ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Cure Rate ◽  
Front Line ◽  
Preclinical Models ◽  
Investigational Agent ◽  
Highly Active ◽  
Heavily Pretreated

Teniposide, a semisynthetic epipodophyllotoxin, was found to be highly active against murine leukemias, and the combination of teniposide with cytosine arabinoside (ara-C) was curative in murine leukemia models. The antitumor activity in preclinical models prompted introduction of teniposide into the clinic in 1971. Although teniposide as a single agent rarely produced a complete remission in heavily pretreated leukemia patients, teniposide plus ara-C produced complete remissions in some patients with refractory and relapsed acute lymphoblastic leukemia (ALL). Innovative front-line and salvage regimens using teniposide have been developed that incorporate a multi-drug strategy with early intensification, rotation of drug combinations in maintenance, and regional therapy in an effort to improve the cure rate in leukemia. However, as the complexity of these regimens increases, the contribution of an individual component such as teniposide becomes less clear. Although some of these regimens for newly diagnosed and relapsed ALL are now thought to represent the best available therapy, teniposide remains an investigational agent. In this review, we outline and discuss the conflicts arising from the need to answer drug-specific issues, and, at the same time, facilitate the implementation of innovative, curative regimens.

Remarkable Activity of Bortezomib Combined with Chemotherapy in a Phase I Study of Relapsed Childhood Acute Lymphoblastic Leukemia (ALL). A Report from the Therapeutic Advances in Childhood Leukemia (TACL) Consortium.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1919-1919 ◽  
Author(s):  
Yoav H. Messinger ◽  
Paul S. Gaynon ◽  
Elizabeth Raetz ◽  
Raymond Hutchinson ◽  
Steven DuBois ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Dose Level ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Chemotherapy Drugs ◽  
Highly Active ◽  
Heavily Pretreated ◽  
Drug Induction

Abstract The outcome of relapsed ALL remains very poor, and many re-induction regimens are highly toxic. We report here the Phase I component of a Phase I/II study of bortezomib added to 4-drug induction with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin in children with relapsed ALL. A total of 10 patients were enrolled, 5 in 1st marrow relapse (2 early and 3 late relapses) and 5 in 2nd or subsequent relapse. Four patients were enrolled at dose level 1 (1 mg/m2) to obtain 3 evaluable patients. One patient was inevaluable for toxicity because of an error in dexamethasone doses and was removed after 8 days. No dose-limiting toxicity (DLT) was observed. Six patients were enrolled at dose level 2 (1.3 mg/m2), the standard single agent dose. One patient had a DLT (hypophosphatemia and rhabdomyolysis) after1 dose of bortezomib, and that patient died from diffuse zygomyces infection by day 17. Five additional patients were enrolled with no further DLT’s. As planned, no further dose escalation was pursued. The regimen had predictable toxicity related to the chemotherapy drugs. Only 2 patients had mild peripheral neuropathy (grades 1 and 2). Seven of the10 patients (70%) achieved a CR, and 1/10 had bone marrow CR with persistent central nervous system (CNS) leukemia despite weekly intrathecal (IT) methotrexate, for a total of 80% bone marrow CR rate. In conclusion: the combination of bortezomib with 4 standard drugs is highly active with acceptable toxicity in heavily pretreated relapsed pediatric ALL patients. We are expanding the MTD cohort for a phase II estimate, and intend to report updated results at the ASH meeting. Day 1 2 4 8 11 14 15 18 22 29 - 35 Bortezomib (1 or 1.3 mg/m2) B B B B Evaluate Vincristine (1.5 mg/m2) V V V V Doxorubicin (60 mg/m2) Dox Dexamethasone (10 mg/m2) x 14 days —— —— —— —— —— —> PEG-Asparaginase (2500 U/ m2) PEG PEG PEG PEG IT Ara-C ITA CNS Negative: IT Methotrexate ITM CNS Positive: IT Triples ITT ITT ITT

Phase II Study of Clofarabine in Pediatric Patients With Refractory or Relapsed Acute Lymphoblastic Leukemia

2006 ◽  
Vol 24 (12) ◽  
pp. 1917-1923 ◽  
Author(s):  
Sima Jeha ◽  
Paul S. Gaynon ◽  
Bassem I. Razzouk ◽  
Janet Franklin ◽  
Richard Kadota ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase Ii ◽  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Median Number ◽  
Open Label ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Heavily Pretreated

Purpose To evaluate the efficacy and safety of clofarabine, a novel deoxyadenosine analog, in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL). Patients and Methods In a phase II, open-label, multicenter study, 61 pediatric patients with refractory or relapsed ALL received clofarabine 52 mg/m2 intravenously over 2 hours daily for 5 days, every 2 to 6 weeks. The median age was 12 years (range, 1 to 20 years), and the median number of prior regimens was three (range, two to six regimens). Results The response rate was 30%, consisting of seven complete remissions (CR), five CRs without platelet recovery (CRp), and six partial remissions. Remissions were durable enough to allow patients to proceed to hematopoietic stem-cell transplantation (HSCT) after clofarabine. Median CR duration in patients who did not receive HSCT was 6 weeks, with four patients maintaining CR or CRp for 8 weeks or more (8+, 12, 37+, and 48 weeks) on clofarabine therapy alone. The most common adverse events of grade ≥ 3 were febrile neutropenia, anorexia, hypotension, and nausea. Conclusion Clofarabine is active as a single agent in pediatric patients with multiple relapsed or refractory ALL. The toxicity profile is as expected in this heavily pretreated patient population. Studies exploring rational combinations of clofarabine with other agents are ongoing in an effort to maximize clinical benefit.

A Review of Nelarabine in the Treatment of T-cell Lymphoblastic Leukemia/Lymphoma

2009 ◽  
Vol 1 ◽  
pp. CMT.S1954 ◽  
Author(s):  
Francisco J. Hernandez-Ilizaliturri ◽  
Myron S. Czuczman
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Salvage Chemotherapy ◽  
Lymphocytic Leukemia ◽  
Front Line ◽  
Chemotherapy Agent ◽  
Purine Analogs ◽  
Dismal Prognosis ◽  
Anti Tumor Activity

Patients with relapsed/refractory T-cell acute lymphocytic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) have a dismal prognosis. Prior to the development of novel purine analogs, salvage chemotherapy was of limited efficacy. Nelarabine, and more recently, clofarabine and forodesine have demonstrated significant anti-tumor activity in relapsed/refractory T-ALL and T-LBL. As a single agent, nelarabine induces response rates in between 33% to 50% of adult or pediatric patients with T-ALL/T-LBL, respectively. On the other hand, limited activity was observed in mature T-cell neoplasms. Significant neurotoxicity has been the major obstacle for the further clinical development of nelarabine. Alternative dose-schedules for administration have been evaluated with some degree of success. Ongoing clinical studies are integrating nelarabine in the front-line chemotherapy regimens for patients with T-ALL/T-LBL in pediatric and young adult patients. The current work summarizes the pre-clinical and clinical evaluation of nelarabine, a chemotherapy agent whose development demonstrates that industry, government agencies, and academia can effectively collaborate together to improve the patient outcomes with highly resistant/refractory rare hematological malignancies.

Combinations of the Selective Phosphatidylinositol 3-Kinase-Delta (PI3Kdelta) Inhibitor GS–1101 (CAL-101) with Rituximab and/or Bendamustine Are Tolerable and Highly Active in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL): Results From a Phase I Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 191-191 ◽  
Author(s):  
Steven E. Coutre ◽  
John P. Leonard ◽  
Richard R. Furman ◽  
Jacqueline C. Barrientos ◽  
Sven de Vos ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Lymphocytic Leukemia ◽  
Tumor Control ◽  
Prior Therapy ◽  
Highly Active ◽  
Heavily Pretreated

Abstract Abstract 191 Introduction: PI3Kdelta drives proliferation and survival in malignant B-cells. GS-1101 is an orally bioavailable, small-molecule inhibitor of PI3Kdelta that has shown considerable monotherapy activity when given at dose levels of 3100 mg BID in patients with heavily pretreated CLL. Methods and Patients: This Phase 1 combination study has evaluated repeated 28-day cycles of GS-1101 in combination with rituximab and/or bendamustine in patients with previously treated CLL. GS-1101 was administered starting on Day 1 of Cycle 1 with rituximab (R) (375 mg/m2 given weekly for 8 doses) (GS-1101/R regimen), with bendamustine (B) (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/B regimen), or in combination with R (375 mg/m2, on Day 1 of each cycle for 6 cycles) and B (90 mg/m2 given on Days 1 and 2 of each cycle for 6 cycles) (GS-1101/BR regimen). Initial cohorts of patients received a GS-1101 dose of 100 mg/dose BID in the GR or GB regimens. Thereafter, all patients received a GS-1101 dose of 150 mg/dose BID. Tumor response was evaluated according to standard criteria (Hallek 2008). Chemokine/cytokine plasma levels were assessed at baseline and on Day 28 of therapy using multiplexed bead suspension arrays. Results: The study enrolled a total of 51 patients with CLL. Patient characteristics and safety and efficacy results are depicted in the table The majority of patients had bulky adenopathy and had undergone extensive prior therapy, with virtually all patients receiving prior rituximab and many receiving prior bendamustine. Grade 33 adverse events and lab abnormalities were generally consistent with those expected with each of the single agents. Lymph node shrinkage was rapid, and almost all evaluable patients had reductions in lymphadenopathy. As reported by investigators, the overall response rates (ORR) for the GS-1101/R, GS-1101/B, and GS-1101/BR regimens were 78%, 82% and 87%, respectively. With a minimum follow-up of 340 weeks for all regimens, 1-year progression-free survival (PFS) rates were 74%, 88% and 87% in the GS-1101/R, GS-1101/B, and GS-1101/BR treatment groups, respectively. Disease-associated chemokines/cytokines were commonly elevated at baseline and were significantly reduced by GS-1101-based combination treatment. Conclusions: A favorable safety profile and lack of overlapping toxicities allows the oral PI3Kdelta inhibitor, GS-1101, to be delivered at the full single-agent starting dose when coadministered with chemoimmunotherapies in heavily pretreated patients with CLL. GS-1101-based combination therapies with rituximab and/or bendamustine offer major and rapid reductions in lymphadenopathy and durable tumor control. Based on these results, Phase 3 trials evaluating the efficacy of GS-1101 in combination with R or BR have been initiated (NCT01539512 [GS-1101/placebo+R], NCT01569295 [GS-1101/placebo+BR]). Disclosures: Coutre: Gilead: Consultancy. Off Label Use: Phase 1 trial of GS-1101 (CAL-101)-based combination therapy. Leonard:Gileade: Consultancy. Barrientos:Gilead: Research Funding. de Vos:Gilead: Consultancy. Sharman:Gilead: Honoraria, Research Funding. Holes:Gilead: Employment. Lannutti:Gilead Sciences Inc: Employment. Johnson:Gilead Sciences: Employment. Miller:Gilead: Employment. Jahn:Gilead: Employment.

A phase II study of the tolerability and activity of weekly vincristine sulfate liposomes injection (VSLI) in adults with Philadelphia chromosome-negative (Ph-) acute lymphoblastic leukemia (ALL) in second relapse or progressing following two antileukemia treatment lines

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7046-7046
Author(s):  
L. T. Heffner ◽  
L. E. Damon ◽  
M. L. Larson ◽  
G. Schiller ◽  
W. Stock ◽  
...  
Keyword(s):  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Hormone Secretion ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Population Data ◽  
Maximum Tolerated Dose ◽  
Vincristine Sulfate ◽  
Inappropriate Antidiuretic Hormone Secretion ◽  
Heavily Pretreated

7046 Background: VSLI (Marqibo) is a nanoparticle formulation of vincristine sulfate (VCR) encapsulated in sphingomyelin/cholesterol liposomes called Optisomes. The optisomal formulation lends itself to an improved pharmacokinetic profile and enhanced tumor penetration and concentration. Preclinical studies of VSLI showed enhanced efficacy versus standard VCR in a variety of solid and hematologic malignancies. VSLI has a maximum tolerated dose of 2.25 mg/m2 with no dose cap, while conventional VCR is dosed at 1.4 mg/m2 with a 2 mg dose cap. A previous study in relapsed ALL showed a complete response rate of 19%, warranting further study. Methods: Eligible adult subjects received single agent intravenous VSLI at a dose of 2.25 mg/m2 weekly with no dose cap. This international, multicenter, single-arm study will enroll approximately 56 subjects. Major endpoints include response rate and overall survival (OS). An interim analysis was planned following enrollment of 29 evaluable subjects. Results: 29 heavily pretreated subjects received ≥ 1 dose of VSLI. To date, at least 9 of 29 subjects had clearing of leukemic blasts and achievement of an M1 bone marrow. Based on preliminary data, the median OS is estimated to be 7.5 months (95% CI: 4.7–10.5) using the Kaplan-Meier method. The most frequent related adverse event (AE) was peripheral neuropathy (PN) (48%), half of which was grade 3. No grade 4 PN was reported. Six subjects had 8 treatment-associated grade 4 AEs of neutropenia (4), thrombocytopenia (2), anemia (1), and inappropriate antidiuretic hormone secretion (1). Conclusions: These results are encouraging, as VSLI was given as a single agent to a heavily pretreated patient population who nearly universally received prior VCR. This population typically has a very low response rate to anti-leukemia therapies. Early OS data compares favorably to an historical median OS of ∼ 2 months (8.7 weeks) in a second salvage population (data on file, M. D. Anderson). VSLI was well tolerated in these patients in the context of universal prior vincristine treatment. [Table: see text]

Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10512-10512 ◽  
Author(s):  
Deepa Bhojwani ◽  
Richard Sposto ◽  
Nirali Shah ◽  
Vilmarie Rodriguez ◽  
Maureen Megan O'Brien ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Sinusoidal Obstruction Syndrome ◽  
Cell Transplant ◽  
Inotuzumab Ozogamicin ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Heavily Pretreated ◽  
Grade 3

10512 Background: Inotuzumab ozogamicin (InO), a CD22-targeting antibody linked to calicheamicin demonstrated exceptional activity in R/R ALL in adults. InO has been available to pediatric patients with R/R ALL via a compassionate access program. Methods: Participating international pediatric oncology centers received IRB approval to submit retrospective demographic, outcome and toxicity data on pediatric patients who received at least one dose of InO. Results: Thirty-four patients, age 2.3-21.4 yrs (median 11.7) received 1-4 cycles (3 weekly doses) of InO. Patients were heavily pretreated in 1st-5threlapse; 28 were refractory to their preceding regimen. Thirteen patients had prior hematopoietic stem cell transplant (HSCT), 27 received prior CD19 and 8 prior CD22-directed therapy. Pre-InO disease was M3 ( > 25% blasts) in 26 patients, M2 (5-25%) in 3, and MRD only in 5 (1 with extramedullary disease). Of 29 patients with M2/M3 disease at baseline, 18 (62%) achieved a complete remission (CR), 13 of whom were MRD negative. Post-InO, 15 patients proceeded to HSCT and 5 to CAR T-cell therapy. Alterations in CD22 expression at subsequent relapse were noted in two patients with available blasts samples. No deaths were attributed to InO during therapy. The incidence of grade 3/4 infections was 38% and were of the expected types. Grade 1-4 hepatic toxicity was noted in 11/34 (32%) patients, primarily asymptomatic elevations in transaminases/bilirubin. There was no sinusoidal obstruction syndrome (SOS) during InO therapy but 8/15 patients who received HSCT post-InO developed SOS. One patient died from SOS, but the others recovered. The incidence of SOS was higher in patients who had undergone prior HSCT (6/8) versus no prior HSCT (2/7). SIRS (1), neurotoxicity (2) and hemorrhage (3) were infrequent. Three patients had musculoskeletal pain associated with edema. Conclusions: Single agent InO had a CR rate of 62% in heavily pretreated pediatric patients. Toxicities were similar to adults with hepatic and infectious toxicity being the most common. Overall InO was well tolerated, but the incidence of SOS was high in patients who underwent HSCT post-InO, particularly in those who had undergone a prior HSCT.

Infectious complications in a child with acute lymphoblastic leukemia (case study)

Pediatru ro ◽  
2018 ◽  
Vol 4 (52) ◽  
pp. 47
Author(s):  
Mihaela Smărăndoiu ◽  
Ruxandra Vidlescu ◽  
Cristian Scurtu ◽  
Doiniţa Sfrijan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Infectious Complications

scholarly journals Scalable information-theoretic path planning for a rover-helicopter team in uncertain environments

2021 ◽  
Vol 18 (2) ◽  
pp. 172988142199958
Author(s):  
Larkin Folsom ◽  
Masahiro Ono ◽  
Kyohei Otsu ◽  
Hyoshin Park
Keyword(s):  
Path Planning ◽  
Lower Risk ◽  
Information Gain ◽  
Probability Distributions ◽  
Single Agent ◽  
Uncertain Environments ◽  
Information Theoretic ◽  
Highly Correlated ◽  
Naive Approach

Mission-critical exploration of uncertain environments requires reliable and robust mechanisms for achieving information gain. Typical measures of information gain such as Shannon entropy and KL divergence are unable to distinguish between different bimodal probability distributions or introduce bias toward one mode of a bimodal probability distribution. The use of a standard deviation (SD) metric reduces bias while retaining the ability to distinguish between higher and lower risk distributions. Areas of high SD can be safely explored through observation with an autonomous Mars Helicopter allowing safer and faster path plans for ground-based rovers. First, this study presents a single-agent information-theoretic utility-based path planning method for a highly correlated uncertain environment. Then, an information-theoretic two-stage multiagent rapidly exploring random tree framework is presented, which guides Mars helicopter through regions of high SD to reduce uncertainty for the rover. In a Monte Carlo simulation, we compare our information-theoretic framework with a rover-only approach and a naive approach, in which the helicopter scouts ahead of the rover along its planned path. Finally, the model is demonstrated in a case study on the Jezero region of Mars. Results show that the information-theoretic helicopter improves the travel time for the rover on average when compared with the rover alone or with the helicopter scouting ahead along the rover’s initially planned route.

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