scholarly journals Venetoclax-Ponatinib for T315I/Compound-Mutated Ph+Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3395-3395
Author(s):  
Huafeng Wang ◽  
Jiejing Qian ◽  
Chang Yang ◽  
Yi Zhang ◽  
Yungui Wang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Treatment Group ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Tumor Lysis Syndrome ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Molecular Remission ◽  
Grade 3

Abstract The outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have greatly improved in tyrosine kinase inhibitors (TKIs) era and is just moving to a chemo-free era using dasatinib and blinatumomab (Foà R, N Engl J Med. 2020; Ravandi F, Blood. 2019). However, the outcome of T315I/compound-mutated Ph+ ALL patients is dismal (Cortes JE, N Engl J Med. 2013), representing an unmet need. Recently, Scherr et al reported the curative potential of venetoclax-TKIs-dexamethasone in a BCR-ABL+ mouse model (Scherr M, Leukemia. 2019). Here, we firstly reported outcome of 19 T315I/compound-mutated relapsed/refractory （R/R）Ph+ ALL patients treated with venetoclax(100mg d1, 200mg d2, 400mg d3-28), ponatinib (45mg d1-28) and dexamethasone (0.15mg/kg d1-21,0.075mg/kg d22-28）(VPD regimen) (Figure 1A) between January 2020 and May 2021. They had already received a median of 3 lines of salvage therapy. After one cycle, 17 patients (89.5%) achieved CR/CRi [13 minimal residual disease (MRD)--negative by flow cytometry;11 major molecular remission (MMR);8 complete molecular remission (CMR)] (Figure 1B). Subsequently relapse occurred in 1/6 [allogeneic hematopoietic cell transplantation (allo-HSCT) group)] and 7/11 (VDP consolidation group). At a median follow-up of 259 days, the median EFS and OS of patients from the starting VPD treatment was 242 and 400 days. Adverse events of VPD regimen were listed in Figure 1C. Grade 3-4 neutropenia, anemia and thrombocytopenia occurred in 73.7%,36.8% and 52.6% patients. 5.3% and 16% patients have grade 3-4 rash and infection separately. No tumor lysis syndrome or death occurred. 7/19 patients were treated safety outpatient. Moreover, venetoclax had a strong synergistic effect with ponatinib and dexamethasone on inducing apoptosis of primary blast cells and BaF3 cells expressing p190 BCR/ABL with T315I-mutation in vitro, with a combination index of 0.019 when the suppressing rate is 0.05, while the effect was significant decreased when ponatinib was replaced by dasatinib (Figure 1D-F), a prominent change of mitochondrial membrane potential as well as the cleavage of PARP were also observed in triple-combination treatment group (Figure 1G-H). For T315I/compound-mutated Ph+ ALL, VPD regimen exhibited 89.5% CR/CRi rate, with deep molecular remission (57.9% MMR), while ponatinib alone showed 41% hematologic response (Cortes JE, N Engl J Med. 2013), which supported by the preclinical data suggesting TKIs and venetoclax are highly synergistic in BCR-ABL + cells in vitro (Scherr M, Leukemia. 2019). 7/11 and 1/6 patients subsequently relapsed in continuous VPD and allo-HSCT postremission treatment group separately, suggested bridging to allo-HSCT after remission is warranted. Moreover, novel compounds such as blinatumomab showed a preliminary efficacy (Couturier MA, Leuk Lymphoma. 2021). In summary, VPD regimen provides a novel treatment for T315I/compound-mutated R/R Ph+ALL under a complete oral and chemo-free model. A clinical trial also using similar VPD regimen for treatment of R/R Ph+ ALL is ongoing now (Short NJ, Am J Hematol. 2021). Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Pegasperagase Toxicity in Adult Patients with Acute Lymphoblastic Leukemia: A Single Center Experience Comparing Patients Older and Younger Than 35 Years of Age

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5067-5067
Author(s):  
Jun H Choi ◽  
Jacques Azzi ◽  
Tsivia Hochman ◽  
Mary Lynn R. Nierodzik ◽  
Shella Saint Fleur-Lominy ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Adverse Events ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Adult Population ◽  
Prospective Trial ◽  
Philadelphia Chromosome ◽  
Treatment Protocol ◽  
Adult Patients ◽  
Grade 3

Background: The treatment paradigm of adult patients with acute lymphoblastic leukemia (ALL) is primarily derived from successful pediatric chemotherapy regimens. Pegasparagase (PEG) is a key component of pediatric therapy and is the backbone of cytotoxic ALL regimens. However, among the adult population the use of PEG has been limited by the difficulty in tolerating prolonged asparagine depletion. Hepatotoxicity is among the most common adverse events reported with the use of PEG, with grade 3/4 hepatotoxicity seen in 20% of young adults compared to 40-60% of older adults. Incorporating PEG into the treatment of ALL patients under 40 remains an accepted practice despite some studies that report up to 75% of patients have grade 3/4 adverse events as a result of asparagine depletion. In a study of 85 patients with ALL, 3-year overall survival (OS) was significantly different between patients older and younger than 35 (52% vs 83% p = 0.003). Whether this difference is due to PEG toxicity or to other factors remains to be determined. At NYU hospitals, PEG-containing protocols are frequently deployed to treat adult ALL. In our study, we sought to look at the difference in PEG toxicity and response rate (RR) in patients older and younger than 35 and whether these toxicities contributed to a delay in subsequent treatments and to a worse outcome. Methods: We conducted a retrospective chart review of patients older than 18 diagnosed with ALL or lymphoblastic lymphoma, who received at least 1 dose of PEG at our institution between 2014 and 2018. All patients received PEG as part of their first line treatment protocol. Our main objective was to compare the tolerability and toxicity profile of intravenous PEG in patients ≥35 years old versus <35. Our secondary objective was to investigate its effects on chemotherapy delay, RR, and relapse rate. Results: Out of a total of 50 patients, 23 were age ≥ 35 (46%). Mean age was 34.4 (Range: 18.9-63.1). The 2 groups shared similar distributions in gender, race, and Philadelphia chromosome (Ph) subtypes (Table 1). The older group received significantly less PEG, 5114.8 vs. 25353.7 units (p=0.0007) and 1.65 vs. 3.59 doses (p<0.0001) compared to the younger group. Grade 1-4 toxicity profiles were similar as both groups had high hepatotoxicity rates: transaminitis 100% vs. 89% (p=0.079) and hyperbilirubinemia 78% vs. 78% (p=0.104) in the older vs younger group, respectively. Grade 3-4 hepatotoxicity was significantly more pronounced in patients ≥35 years old (transaminitis 65% vs. 33% [p=0.0245], hyperbilirubinemia 48 vs. 15% [p=0.0111]). Coagulopathy rates evaluated with hypofibrinogenemia and thrombosis were similar between the older and the younger groups at 52% vs. 44% [p=0.104] and 17% vs. 7%, [p=0.855], respectively, and the frequency of pancreatitis and anaphylaxis were 4% vs. 18.5% (p=0.422) and 0% vs. 14.8% (p=0.115), respectively. In the older group, only 13% completed the planned PEG dosages compared to 59% in the younger group (p=0.0008), and delay in other chemotherapy by more than 30 days due to PEG hepatotoxicity occurred in 55% of older patients compared to 22% of younger patients (p=0.02). MRD negativity rate after induction was similar in the older and younger group (50% vs. 60% [p=0.491], respectively), but the 12-month relapse free survival was significantly lower in the older group (41%, [95% CI: 55.7%-89%] vs. 77%, [95% CI: 21%-61%], p=0.022) (Figure 1). Conclusions: Patients aged ≥ 35 received significantly less PEG during their treatments but were more likely to develop severe grade 3-4 hepatotoxicity compared to their younger counterparts. The response rates were similar with comparable MRD negativity rates after induction regardless of total amount of PEG administered. However, relapse occurred more frequently in the older group, possibly resulting from more frequent delays in administering other chemotherapy agents due to PEG toxicity. Incorporation of PEG is important in the treatment of ALL but should be used with caution in patients ≥35 years old, and will likely require dose and schedule modifications. A larger prospective trial investigating adequate dosing and scheduling of PEG in this age group is warranted, specifically comparing delays in chemotherapy, relapse, and survival rates in regimens with and without PEG. Disclosures No relevant conflicts of interest to declare.

scholarly journals Phloridzin Docosahexaenoate (PZ-DHA) : A Novel Naturally Derived Drug Active in T-Cell Acute Lymphoblastic Leukemia (T-ALL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5197-5197
Author(s):  
Niroshaathevi Arumuggam ◽  
Nicole Melong ◽  
Catherine K.L. Too ◽  
Jason N. Berman ◽  
H.P. Vasantha Rupasinghe
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Xenograft Model ◽  
Jurkat Cells ◽  
Interferon Α ◽  
Omega 3 ◽  
Cell Acute Lymphoblastic Leukemia

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignant disease that accounts for about 15% of pediatric and 25% of adult ALL. Although risk stratification has provided more tailored therapy and improved the overall survival of T-ALL patients, clinical challenges such as suboptimal drug responses, morbidity from drug toxicities, and drug resistance still exist. Plant polyphenols have therapeutic efficacy as pharmacological adjuvants to help overcome these challenges. They can be acylated with fatty acids to overcome issues concerning bioavailability, such as poor intestinal absorption and low metabolic stability. Phloridzin (PZ), a flavonoid found in apple peels, was acylated with an omega-3 fatty acid, docosahexaenoic acid (DHA), to generate a novel ester called phloridzin docosahexaenoate (PZ-DHA). The cytotoxic effect of PZ-DHA was studied in the human Jurkat T-ALL cell line. PZ-DHA significantly reduced the viability and cellular ATP levels of treated cells. PZ-DHA was found to selectively induce apoptosis in Jurkat cells, while sparing normal murine T-cells. Apoptosis was further confirmed by demonstrating the ability of PZ-DHA to induce morphological alterations, DNA fragmentation, caspase activation, and the release of intracellular lactate dehydrogenase. PZ-DHA also significantly inhibited cell division in Jurkat cells. Furthermore, interferon-α-induced phosphorylation of the transcription factor, STAT3, was downregulated following PZ-DHA treatment. The in vitro efficacy of PZ-DHA was recapitulated in vivo in an established zebrafish xenograft model, where the proliferation of transplanted Jurkat cells was inhibited when PZ-DHA was added to the embryo water. Overall, these findings provide evidence for PZ-DHA as a novel therapeutic agent with activity in T-ALL. Studies examining the effect of PZ-DHA on patient-derived ALL cells engrafted in zebrafish are currently underway. Disclosures No relevant conflicts of interest to declare.

scholarly journals Axitinib in Ponatinib-Resistant B-Cell Acute Lymphoblastic Leukemia Harboring a T315L Mutation

2020 ◽  
Vol 21 (24) ◽  
pp. 9724
Author(s):  
Valentina Giudice ◽  
Andrea Ghelli Luserna di Rorà ◽  
Bianca Serio ◽  
Roberto Guariglia ◽  
Maria Benedetta Giannini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Acute Lymphoblastic Leukemia ◽  
Randomized Clinical Trials ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Fatal Outcome ◽  
Philadelphia Chromosome ◽  
Dose Finding ◽  
Third Generation

Adult acute lymphoblastic leukemia (ALL) with BCR-ABL1 rearrangement (Philadelphia chromosome, Ph) is a hematological aggressive disease with a fatal outcome in more than 50% of cases. Tyrosine kinase inhibitors (TKIs) targeting the activity of BCR-ABL1 protein have improved the prognosis; however, relapses are frequent because of acquired somatic mutations in the BCR-ABL1 kinase domain causing resistance to first, second and third generation TKIs. Axitinib has shown in vitro and ex vivo activity in blocking ABL1; however, clinical trials exploring its efficacy in ALL are missing. Here, we presented a 77-year-old male with a diagnosis of Ph positive ALL resistant to ponatinib and carrying a rare threonine to leucine (T315L) mutation on BCR-ABL1 gene. The patient was treated with axitinib at 5 mg/twice daily as salvage therapy showing an immediate although transient benefit with an overall survival of 9.3 months. Further dose-finding and randomized clinical trials are required to assess the real efficacy of axitinib for adult Ph positive ALL resistant to third generation TKIs.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Herve Dombret ◽  
O.G. Ottmann ◽  
G. Rosti ◽  
B. Simonsson ◽  
R.A. Larson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
Hematologic Response ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Transient Responses to Notch and Tlx1/Hox11 Inhibition In T-Cell Acute Lymphoblastic Leukemia/Lymphoma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1026-1026
Author(s):  
Erica A. Lehotzky ◽  
Mark Y. Chiang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Line ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Leukemia Cells ◽  
Inhibitory Effects ◽  
Notch Inhibition

Abstract Abstract 1026 Despite numerous advances in the past few decades, treatment of acute lymphoblastic leukemia/lymphoma (ALL) remains a common and considerable challenge. Further efforts to define the molecular lesions that drive ALL are needed to improve clinical management. The Hox subfamily of T-cell ALL (T-ALL) represents 30–40% of pediatric and adult cases. TLX1/HOX11 is the prototypical member of the Hox group. To generate a resource for developing targeted therapies for Hox T-ALLs, we developed a doxycycline-regulated mouse model of Tlx1-initiated T-ALL. Dysregulated thymic expression of Tlx1 induces T-ALL after ∼5-7 months with penetrance of 15–60%. The lymphoblasts are arrested at the early CD4+/CD8+/CD24hi stage of T-cell development, similar to human T-ALLs of the TLX1 subtype. Spontaneous activation of the Notch1 oncogene occurred in the tumors. In about two-thirds of samples, Notch was activated through acquired mutations in the heterodimerization and PEST domains that resemble the Notch1 mutations found in human patients. Inhibition of Notch signaling with g-secretase inhibitors completely abrogated cell line growth and induced apoptosis. Notch inhibition also transiently delayed leukemia progression by ∼17 days in vivo. In contrast, suppression of Tlx1 expression had more moderate inhibitory effects on cell line growth in vitro. However, suppression of Tlx1 expression in transgenic mice transiently delayed leukemia progression by ∼11 days. Tlx1 suppression had the strongest inhibitory effects on expression of CCR7 and lymph node size. These effects were fully reversed with ectopic expression of Tlx1. These data show that Tlx1 can convert normal thymocytes into leukemia cells, but the leukemia cells are not fully dependent on continued Tlx1 expression. The leukemia cells recruit secondary factors and pathways such as Notch and c-Myc to sustain growth and survival. Our study highlights a strong resiliency of T-ALL cells to both Tlx1 and Notch inhibition. Our study has important implications for targeting these pathways for the treatment of T-ALL. Disclosures: No relevant conflicts of interest to declare.

Outcome After First Relapse In Adult Patients with Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3084-3084
Author(s):  
Shinichi Kako ◽  
Heiwa Kanamori ◽  
Naoki Kobayashi ◽  
Akio Shigematsu ◽  
Yasuhito Nannya ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Salvage Chemotherapy ◽  
Adult Patients ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
First Relapse

Abstract Abstract 3084 With modern intensive chemotherapy, 78% to 93% of adult patients with acute lymphoblastic leukemia (ALL) achieve complete remission (CR). However, the disease-free survival rate is only 30% to 40% due to the high rate of relapse. A part of relapsed patients can achieve second remission (CR2) with salvage therapy, and allogeneic hematopoietic stem cell transplantation (HSCT) in CR2 will be the only curative strategy. Prognosis after relapse in adult patients with ALL is considered to be extremely poor, but reports as to the outcome after relapse have been limited. To elucidate the outcome of relapsed patients and prognostic factors after relapse, we retrospectively collected and analyzed clinical data from 69 institutions in Japan on patients with Philadelphia-chromosome (Ph) negative ALL, aged 16–65 years, who relapsed after first CR (CR1) between 1998 and 2008. A total of 332 patients were included in this study. The median age of them was 35 years, and 165 patients were male. Median duration of CR1 was 290 days (range 15–7162 days), and median follow-up time after relapse was 319 days (range 3–3689 days). Fifty-eight and 4 of them relapsed after allogeneic and autologous HSCT in CR1, respectively. The overall survival (OS) rate was not significantly different between patients who relapsed after allogeneic HSCT in CR1 and those who relapsed after chemotherapy only (50.0% vs. 43.4% at 1 year and 10.6% vs. 16.3% at 5 year, respectively). Among 270 patients who relapsed after chemotherapy only, 234 patients received salvage chemotherapy after relapse, and 123 patients achieved CR2 (52.5%). Sixty-two patients out of those 123 patients underwent allogeneic HSCT in CR2. Median duration between the achievement of CR2 with salvage chemotherapy and allogeneic HSCT in CR2 was 76 days. OS rate was significantly better in patients who underwent allogeneic HSCT in CR2 following salvage chemotherapy than those who did not (74.1% vs. 55.1% at 1 year and 44.7% vs. 11.6% at 5 year, respectively) by a landmark analysis limiting patients who were surviving without disease at 76 days after the achievement of CR2. In multivariate analysis of factors that included allogeneic HSCT in CR2 following salvage chemotherapy as a time-dependent covariate, lower white blood cell count at relapse (less than 10000/μl) and allogeneic HSCT in CR2 were associated with better OS rate among patients who achieved CR2 following salvage chemotherapy. Forty-six patients underwent allogeneic HSCT in non-CR after receiving salvage chemotherapy. A part of them survived long, and 5 year OS rate was 20.9%. In conclusion, the prognosis of adult patients with relapsed Ph-negative ALL is poor. Allogeneic HSCT after first relapse could improve the prognosis. Disclosures: No relevant conflicts of interest to declare.

Final Report of a Phase I/II Study of Hyper-CVAD Plus RAD001 (Everolimus) in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3567-3567
Author(s):  
Yanis Boumber ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
Michael E. Rytting ◽  
Marian R Love ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Mtor Inhibitors ◽  
Median Number ◽  
Mtor Signaling ◽  
Final Report ◽  
Grade 3

Abstract Abstract 3567 Background: Acute lymphoblastic leukemia (ALL) is an aggressive lymphoproliferative disorder, responsive to frontline standard induction and consolidation chemotherapy. However, the prognosis of patients (pts) with relapsed/refractory ALL is extremely poor. Deregulation of the PI3K/Akt/mTOR signal transduction pathway is central to leukemic cell growth, proliferation and survival, and has been implicated in ALL pathogenesis. In a recent phase II study of pts with relapsed/refractory non-Hodgkin lymphoma, single agent mTOR inhibitor everolimus showed ORR 30% and acceptable toxicity in 77 heavily pretreated pts (Witzig TE et al, Leukemia 2011; 25,341–7). The purpose of this study was to establish the safety and efficacy of everolimus in combination with hyper-CVAD in pts with relapsed/refractory ALL, and to study effects of everolimus on AKT/mTOR signaling in ALL blasts. Methods: In this single center phase I/II study, pts aged 10 years or older with relapsed/refractory ALL or lymphoblastic lymphoma were treated with oral everolimus at a daily dose of 5 mg or 10 mg in combination with the standard hyper-CVAD regimen (Kantarjian HM et al, J Clin Oncol. 2000 Feb;18(3):547–61) until disease progression or unacceptable toxicity. Primary endpoints were to establish safety (after 2 cycles) and efficacy. Secondary endpoints included assessments of pharmacodynamics and pharmacokinetics. Results: Twelve pts have been enrolled and are evaluable for response. Median was age 24 years (range, 11–59). Five pts had T-ALL and 7 had Philadelphia chromosome negative precursor-B-ALL. Median number of prior treatments was 2 (range, 1–4); 5 pts were 1st salvage attempts. Three pts received everolimus 5 mg/day and 9 were treated with 10 mg/day continuously in combination with hyper-CVAD. Median number of cycles given was 2 (range, 1–4). Median follow-up was 12 months (range, 7–23). Three pts achieved CR (all were 1st salvage attempts) and 1 patient had CRi (second salvage); 2 pts achieved PR. No responses were seen beyond second salvage. Of the 9 pts completing 2 cycles, both EFS and OS were not reached for 3 pts in the 1st salvage, and were 8.5 weeks and 18.5 weeks respectively for pts in second salvage and beyond (P=.01 and P=0.04). Of the 12 pts (including 3 only treated with one cycle), both EFS and OS were not reached for 3 pts in the 1st salvage, and were 10 weeks and 18 weeks respectively for pts in second salvage and beyond (P=0.17 and P=0.05). Treatment-related toxicities in the 9 pts evaluable for MTD (completed 2 cycles) included 3 episodes of grade 3 mucositis, which was a dose-limiting toxicity, 3 episodes of grade 4 infections (sepsis) and 9 episodes of grade 3 infections (neutropenic fever, pneumonia, bacteremia). There was no deaths on-study. Inhibition of mTOR signaling (p-pS6K) was observed in 5 of 8 (62%) patient samples tested, at both the 5 and 10 mg dose levels, suggesting that 5 mg is sufficient to block the pathway. Lack of inhibition of p-pEBP1 and pAKT argues for potential benefit of second generation mTOR inhibitors or dual PI3K/mTOR inhibitors. Conclusions: We conclude that administration of hyper-CVAD plus everolimus is well-tolerated. The study warrants further investigation of next generation mTOR inhibitors in combination with hyper-CVAD for ALL in relapsed and frontline settings. Disclosures: Cortes: Novartis: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document