Temsirolimus combined with etoposide and cyclophosphamide for relapsed/refractory acute lymphoblastic leukemia: Therapeutic advances in Childhood Leukemia Consortium (TACL 2014-001) trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10512-10512
Author(s):  
Susan R. Rheingold ◽  
Lewis B. Silverman ◽  
James A. Whitlock ◽  
Richard Sposto ◽  
Eric S. Schafer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Complete Response ◽  
Pi3k Pathway ◽  
Critical Pathway ◽  
Pathway Inhibition

10512 Background: PI3K/mTOR signaling, a critical pathway in cell proliferation, metabolism, and apoptosis, is often dysregulated in acute lymphoblastic leukemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus combined with etoposide and cyclophosphamide was performed in children with relapsed/refractory (r/r) ALL. Methods: Temsirolimus was administered intravenously (IV) on days 1 and 8 with cyclophosphamide 440 mg/m2 and etoposide 100 mg/m2 IV daily days 1-5. The starting dose level (DL) of temsirolimus was 7.5 mg/m2 (DL1) with escalation to 10 mg/m2 (DL2), 15 mg/m2 (DL3), and 25 mg/m2 (DL4). MRD was performed centrally. PI3K pathway inhibition was measured by phosphoflow cytometry (PFC) analysis of peripheral blood (PB) from treated patients (pts). Results: Sixteen heavily pretreated r/r ALL pts ages 2-19 years with marrow blasts > 25% were enrolled; 15 were evaluable [10 B-ALL/5 T-ALL]. One dose-limiting toxicity (DLT) of grade (Gr) 4 pleural and pericardial effusions with pneumonitis/lung infection leading to Gr 5 cardiorespiratory arrest occurred in a pt treated at DL3. No further DLTs were seen in the DL3 expansion and DL4 cohorts. Gr 3/4 non-hematologic toxicities occurring in ≥ 3 pts included febrile neutropenia, elevated ALT, hypokalemia, mucositis, and tumor lysis syndrome and were independent of dose. Of 15 evaluable pts, 4 (27%; 2 B-ALL/2 T-ALL) had a complete response (CR) after cycle 1, comprised of 1 pt at each DL. Three had MRD < 0.01%. Three pts (20%; 2 B-ALL/1 T-ALL) had partial response (PR). Overall response rate (CR+PR = ORR) was 47%. Pharmacodynamic PFC studies compared phosphoprotein levels pre (day 0) and post treatment (days 3-5) in 9 consenting pts with available PB. All tested pts showed basal activation of PI3K pathway signaling. Dose-dependent inhibition of mTOR targets phosphorylated (p) S6 and/or p4EBP1 was observed in 9/9 and 6/9 pts, respectively, following temsirolimus and chemotherapy treatment. Various patterns of compensatory upregulation of pPI3K, pmTOR, pAkt, and/or pERK was observed. Conclusions: Temsirolimus at 25 mg/m2 combined with salvage etoposide and cyclophosphamide has an acceptable safety profile in high-risk pediatric patients with r/r ALL. Responses were observed at all DLs. mTOR target inhibition was achieved and appeared to correlate with dose level. Future testing of other PI3K/mTOR pathway inhibitors in combination with chemotherapy may be warranted with a goal of further increasing response in r/r ALL. Clinical trial information: NCT01614197.

Phase 1 Study of Weekly Vincristine Sulfate (VCR) Liposomes Injection (VSLI, Marqibo™) Plus Dexamethasone in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2930-2930 ◽  
Author(s):  
Deborah A. Thomas ◽  
Hagop M Kantarjian ◽  
Wendy Stock ◽  
Leonard Heffner ◽  
Sue Hirabayashi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Dose Level ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Pharmacokinetic Studies ◽  
Cell Transplant ◽  
Motor Neuropathy ◽  
Vincristine Sulfate ◽  
Total N

Abstract Novel formulations of standard chemotherapy allowing increased drug delivery without additional toxicity may improve outcomes for patients with relapsed or refractory acute lymphoblastic leukemia (ALL). Vincristine sulfate liposomes injection (VSLI, Marqibo®) is VCR encapsulated in sphingomyelin (55%)/cholesterol (45%) nanoparticle liposomes called Optisomes™. Pharmacokinetic studies have shown that the altered distribution and elimination phases of VSLI may lead to increased VCR exposure compared to traditional VCR, and may account for the increased efficacy observed in preclinical models. Activity of VCR is dose and time-dependent, but neurotoxicity limits dosing to 1.4 mg/m2 (capped at 2.0 mg). VSLI, however, may be given without dose capping. We conducted a phase 1, open-label, dose-escalation study of VSLI in adults with relapsed or refractory ALL to determine the safety, maximum tolerated dose (MTD), and activity of this formulation. Subjects received VSLI intravenously weekly at doses of 1.5, 1.825, 2.0, 2.25 or 2.4 mg/m2. Dexamethasone 40 mg was given days 1–4 and 11–14 of each 4 week cycle. Thirtysix eligible subjects, all of whom had been previously treated with VCR, received at least 1 dose of VSLI. All were Philadelphia chromosome negative except for one. Median number of doses received for all subjects was 4; total medium cumulative dose was 9.09 mg/m2 (19.20 mg). MTD of VSLI was 2.25 mg/m2 based on dose-limiting toxicities of grade 3 motor neuropathy, grade 4 seizure and grade 4 hepatotoxicity observed in 1 subject each at the 2.4 mg/m2 dose level. The most common toxicities (constipation [67%], fatigue [61%], pyrexia [50%], anemia [50%], peripheral neuropathy [50%; mostly grade 1–2]) were as expected. Complete response (CR) was achieved in 7 of 36 (19%) subjects based on intent to treat analysis (Table). Overall response rate (including 1 PR) was 22%. Four subjects (11%) achieved hematologic improvement, 13 (36%) had stable disease, and 9 (25%) progressed. CR rate was 29% for the 7 subjects treated with VSLI as second salvage. Five of 7 subjects who achieved CR were able to undergo allogeneic stem cell transplant (SCT). In conclusion, VSLI appears to be an effective therapeutic option which may permit potentially curative SCT. A phase 2 international multi-center trial of single agent VSLI in subjects with relapsed ALL is currently accruing. Table. VSLI Clinical Activity (CR) by Dose Level and Salvage Status 1.5 mg/m2 n = 5 1.825 mg/m2 n = 3 2 mg/m2 n = 3 2.25 mg/m2 n = 18 2.4 mg/m2 n = 7 Total n = 36 1st salvage 1/1 0/1 -- 2/7 1/4 4/13 (31) 2nd or later salvage 1/4 1/2 0/3 1/11 0/3 3/23 (13)

Potent Efficacy of Combined PI3K/mTOR and JAK or SRC/ABL Inhibition in Philadelphia Chromosome-like Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 798-798 ◽  
Author(s):  
Sarah K Tasian ◽  
Yong Li ◽  
Feng Shen ◽  
Theresa Ryan ◽  
Tiffaney L Vincent ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Acute Lymphoblastic Leukemia ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Pi3k Pathway ◽  
Vehicle Treatment ◽  
Pathway Inhibition ◽  
Pdx Models ◽  
Phosphoflow Cytometry

Abstract Background. Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with genomic alterations that activate JAK/STAT and PI3K/Akt/mTOR signal transduction and with poor clinical outcomes. Therapeutic disruption of PI3K pathway signaling in Ph-like ALL has been minimally investigated to date, however. We hypothesized that PI3K isoform-selective or dual PI3K pathway protein inhibition would robustly inhibit Ph-like ALL proliferation in vivoand abrogate aberrant signaling. Methods. NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were engrafted with primary CRLF2/JAK-mutant or ABL/PDGFR-mutant Ph-like ALL specimens (Table 1) and treated with inhibitors of PI3K? (BYL719), PI3K? (idelalisib), PI3K/mTOR (gedatolisib), TORC1/TORC2 (AZD2014) or with vehicle. Treated patient-derived xenograft (PDX) models were assessed for pharmacodynamic inhibition of signal transduction phosphoproteins at 72 hours by phosphoflow cytometry and for residual ALL in murine spleens after 3-4 weeks of inhibitor or vehicle treatment by quantitative flow cytometry. Subsequent studies tested the efficacy of gedatolisib with the JAK1/2 inhibitor ruxolitinib (CRLF2/JAK-mutant models) or gedatolisib with the SRC/ABL inhibitor dasatinib (ABL/PDGFR-mutant models). Table 1. Genomic characteristics of Ph-like ALL specimens utilized for PDX studies. USI Disease status CRLF2/JAK alterations ABL/PDGFR alterations PALTWS D IGH@-CRLF2* PAMDKS D IGH@-CRLF2, JAK2R683G PAMDRM D IGH@-CRLF2,JAK2GPinsR683 ALL121 R IGH@-CRLF2, JAK2R683G ALL4364 R P2RY8-CRLF2, JAK2R683G PAKMVD D JAK1 S646F PAKYEP D BCR-JAK2 PAKKCA D EBF1-PDGFRB PAKVKK D NUP214-ABL1 PANSFD D ETV6-ABL1 USI = unique specimen identifier. D = de novo, R = relapse. * non-Ph-like by prediction analysis of microarrays. Results. All tested PDX models demonstrated inhibition of leukemia proliferation and abrogation of activated signaling with PI3K pathway inhibition. Gedatolisib treatment resulted in near-eradication of leukemia in CRLF2/JAK-mutant models (n=7) with mean 92.2% (range 86.0-99.4%) leukemia reduction vs vehicle treatment (p<0.0001), as well as prolonged animal survival (p<0.005). Gedatolisib also inhibited leukemia proliferation in ABL/PDGFR-mutant models (n=3) with mean 66.9 (range 42.0-87.6) leukemia reduction vs vehicle controls (p<0.0001). BYL719, idelalisib, and AZD2014 monotherapy decreased ALL burden in JAK-mutant models with mean 52.7% (range 27.5-72.9%), 41.6% (range 22.6-53.1%), and 56.3% (range 20.1-88.7%) reduction, respectively. These three inhibitors had variable potency in ABL/PDGFR-mutant models with 39.1% (range 11.4-71.2%) ALL reduction with BYL719, 0.4% (range -25.2-13.9%) reduction with idelalisib, and 14.5% (range -15.5-30.7%) reduction with AZD2014 treatment vs vehicle controls. Leukemias with greatest basal signaling activation measured by phosphoflow cytometry demonstrated greatest leukemia reduction with PI3K pathway inhibition in the treatment studies, suggesting that basal phosphoprotein levels may be predictive biomarkers of response. Given the recently reported efficacy of JAK inhibition in CRLF2/JAK-mutant and SRC/ABL inhibition in ABL/PDGFR-mutant Ph-like ALL PDX models, we hypothesized that dual pathway inhibition would be more effective than monotherapy. Indeed, simultaneous treatment with gedatolisib and ruxolitinib additively or synergistically reduced ALL burden in all tested CRLF2/JAK-mutant models vs gedatolisib or ruxolitinib monotherapy (p<0.001). Similarly, combined gedatolisib and dasatinib treatment induced markedly greater anti-leukemia efficacy in ABL/PDGFR-mutant models vs. either inhibitor alone (p<0.001). Conclusions. PI3K pathway inhibition is a biochemically relevant therapeutic approach for Ph-like ALL. Dual PI3K/mTOR inhibition with gedatolisib monotherapy potently inhibited leukemia proliferation and demonstrated additive or synergistic activity in combination with JAK or SRC/ABL inhibition in JAK-mutant or ABL/PDGFR-mutant Ph-like ALL, respectively. These data provide compelling rationale for testing combinations of signal transduction inhibitors without or with cytotoxic chemotherapy in children and adults with Ph-like ALL. Disclosures Off Label Use:preclinical testing of signal transaction inhibitors in Ph-like ALL models. Teachey:Novartis:Research Funding. Maude:Novartis:Consultancy, Research Funding. Perl:Actinium Pharmaceuticals:Consultancy; Asana Biosciences:Consultancy; Arog Pharmaceuticals:Consultancy; Ambit/Daichi Sankyo:Consultancy; Astellas US Pharma Inc.:Consultancy. Hunger:Sigma Tau:Consultancy; Jazz Pharmaceuticals:Consultancy; Spectrum Pharmaceuticals:Consultancy; Merck:Equity Ownership. Grupp:Novartis:Consultancy, Research Funding.

scholarly journals Bortezomib with chemotherapy is highly active in advanced B-precursor acute lymphoblastic leukemia: Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 285-290 ◽  
Author(s):  
Yoav H. Messinger ◽  
Paul S. Gaynon ◽  
Richard Sposto ◽  
Jeannette van der Giessen ◽  
Elena Eckroth ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Bacterial Infections ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Platelet Recovery ◽  
Highly Active ◽  
Early Closure ◽  
Grade 3

Abstract Therapy of relapsed pediatric acute lymphoblastic leukemia (ALL) is hampered by low remission rates and high toxicity, especially in second and subsequent relapses. Our phase 1 study, T2005-003, showed that the combination of bortezomib with vincristine, dexamethasone, pegylated asparaginase, and doxorubicin had acceptable toxicity. We report the phase 2 expansion of this combination in patients with relapsed ALL who failed 2-3 previous regimens. Twenty-two patients with relapsed ALL were treated with bortezomib combined with this regimen; their ages ranged from 1 to 22 years, and they had either B-precursor ALL (n = 20) or T-cell ALL (n = 2). Grade 3 peripheral neuropathy developed in 2 (9%) patients. After 3 patients died from bacterial infections, treatment with vancomycin, levofloxacin, and voriconazole prophylaxis resulted in no further infectious mortality in the last 6 patients. Fourteen patients achieved complete remission (CR), and 2 achieved CR without platelet recovery, for an overall 73% response rate, meeting predefined criteria allowing for early closure. B-precursor patients faired best, with 16 of 20 (80%) CR + CR without platelet recovery, whereas the 2 patients with T-cell ALL did not respond. Thus, this combination of bortezomib with chemotherapy is active in B-precursor ALL, and prophylactic antibiotics may be useful in reducing mortality. Bortezomib merits further evaluation in combination therapy in pediatric B-precursor ALL. This study is registered at http://www.clinicaltrials.gov as NCT00440726.

scholarly journals Acute leukemia of childhood: A single institution's experience

2005 ◽  
Vol 57 (1) ◽  
pp. 11-17 ◽  
Author(s):  
Bojana Slavkovic ◽  
Marija Guc-Scekic ◽  
Gordana Bunjevacki ◽  
S. Djuricic ◽  
Aleksandra Krstic ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Acute Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Rearrangements ◽  
Age Distribution ◽  
Normal Karyotype ◽  
Mediterranean Countries ◽  
B Lineage ◽  
Childhood Acute Leukemia

The aim of this study was to investigate distribution of immunophenotypic and cytogenetic features of childhood acute leukemia (AL) in the cohort of 239 newly diagnosed patients registered at the leading pediatric oncohematology center in the country during a six-year period (1996-2002). With approximately 60-70% of all childhood AL cases in Serbia and Montenegro being diagnosed and treated in this institution the used data represent a valid research sample to draw conclusions for entire country. On the basis of five phenotypic markers, the distribution of immunological subtypes was as follows: 169 (70.7%) expressed B-cell marker CD19 (137 were CD10 positive and 32 CD10 negative), 37 (15.5%) belonged to T-lineage acute lymphoblastic leukemia (T-ALL) (cyCD3 positive), and 33 (13.8%) were acute myeloblastic leukemia (AML) (CD13 positive and/or CD33 positive in the absence of lymphoid-associated antigens). The ratio of males and females was 1.5:1. Most of the cases were between the ages of 2 and 4, and were predominantly B-lineage acute lymphoblastic leukemia (B-ALL) cases. Another peak of age distribution was observed at the age of 7. The frequency of T-ALL (18% of ALL) was similar to that reported for Mediterranean countries: France (19.4%), Greece (28.1%), Southern Italy (28.3%), and Bulgaria (28.0%). Cytogenetic analyses were performed in 193 patients: 164 ALL and 29 AML. Normal karyotype was found in 57% of ALL and in 55% of AML patients, while cytogenetic abnormalities including structural, numerical, and complex chromosomal rearrangements were found in 43% of ALL and in 45% of AML patients. Our results represent a contribution to epidemiological aspects of childhood leukemia studies.

scholarly journals ACUTE LYMPHOBLASTIC LEUKEMIA EXPERIENCE: EPIDEMIOLOGY AND OUTCOME OF TWO DIFFERENT REGIMENS

2013 ◽  
Vol 5 (1) ◽  
pp. e2013024 ◽  
Author(s):  
Salah Abbasi ◽  
Faten Maleha ◽  
Muhannad Shobaki
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Medical Records ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Complete Response ◽  
Cancer Center ◽  
Poor Prognostic Factor ◽  
Minimal Residual Disease Monitoring ◽  
Adult Acute Lymphoblastic Leukemia

Objectives. Accurate data about adult acute lymphoblastic leukemia (ALL) are lacking. We aim to assess demographics, prognostic factors, and outcome of ALL therapy at King Hussein Cancer Center (KHCC) in Jordan, and to compare the efficacy of two protocols.Methods. We reviewed medical records of adults diagnosed and treated for ALL at KHCC from January, 2006 to December, 2010.Results. Over a 5-year period, 108 patients with ALL were treated (66 with the Hyper-CVAD regimen, and 42 with the CALGB 8811 regimen). Median age at diagnosis was 33 years, with 63% males. The most common immunophenotype was CD10-positive common ALL, and 16% have BCR-ABL translocation. Complete response (CR) rate was 88%. After a median follow-up of 32 months (range, 10-72 months), the median survival (MS) was 30 months, and CR duration (CRD) was 28 months. In the multivariate analysis, the presence of BCR-ABL translocation was the only poor prognostic factor with lower MS of 23 months (p<0.01). There was no difference in MS or CRD between the two used regimens.Conclusion. International protocols for adult ALL were successfully applied to our patients. There is no difference in efficacy between Hyper-CVAD and CALGB 8811 regimens. Future protocols for adult ALL should incorporate new targeted agents and minimal residual disease monitoring to improve outcome.

Dural Venous Sinus Thrombosis in Acute Lymphoblastic Leukemia

PEDIATRICS ◽  
1980 ◽  
Vol 66 (6) ◽  
pp. 943-947
Author(s):  
Lawrence A. Lockman ◽  
Angeline Mastri ◽  
John R. Priest ◽  
Mark Nesbit
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Childhood Leukemia ◽  
Sinus Thrombosis ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Intracerebral Hematoma ◽  
Sagittal Sinus ◽  
Dural Venous Sinus ◽  
Dural Venous Sinus Thrombosis ◽  
Sagittal Sinus Thrombosis

Three children with acute lymphoblastic leukemia developed sagittal sinus thrombosis. One patient was in peripheral remission. One patient survived. In neither patient who died were the walls of the dural sinuses infiltrated with leukemic cells. Attention is drawn to this potentially treatable cause of central nervous system symptoms in childhood leukemia. Angiography is the diagnostic test of choice and can also demonstrate intracerebral hematoma and subdural hematoma, if present. Sinus thrombosis can occur either during exacerbation or remission of the basic leukemic process. The possibility that chemotherapeutic techniques predispose toward this complication is raised.

MALIGNANCY MASQUERADING AS JOINT INFECTION- A CASE REPORT

2021 ◽  
pp. 36-36
Author(s):  
Aparna C Babu ◽  
B. Manohar
Keyword(s):  
Case Report ◽  
Acute Lymphoblastic Leukemia ◽  
Childhood Leukemia ◽  
Lymphoblastic Leukemia ◽  
Joint Infection ◽  
Joint Effusion ◽  
Childhood Cancers ◽  
Prolonged Fever ◽  
Hematological Disorder ◽  
Common Malignancy

ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) is the most common malignancy in children. It accounts for 25% of all childhood cancers and approximately 75% of all cases of childhood leukemia. ALL presents usually with fever, lassitude, pallor, bone pains+/- bleeds. Here, we present a case of a child presenting with prolonged fever and swelling and pain in joints. Child was initially diagnosed as one hematological disorder and presented with joint effusion within a week.

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