Phase II Pilot Study of Imatinib Mesylate Combined with Induction Chemotherapy in Blast-Phase CML and Ph+ ALL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4682-4682
Author(s):  
Jason Lickliter ◽  
Chris Arthur ◽  
James D’Rozario ◽  
Chi-hung Hui ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Massive Hemoptysis ◽  
Acute Leukemias ◽  
Western Blots ◽  
Expression Levels

Abstract CML in blast crisis (BC) and Philadelphia chromosome-positive (Ph+) ALL are incurable with conventional chemotherapy and in most cases respond only transiently to the Bcr-Abl kinase inhibitor imatinib mesylate. We hypothesized that pretreatment with imatinib would overcome inherent drug resistance to induction chemotherapy mediated by Bcr-Abl, and evaluated the combination in 17 patients with Ph+ acute leukemias (5 CML in BC, 6 de-novo Ph+ ALL, 6 relapsed Ph+ ALL). All patients received a 1-week prephase of imatinib alone at 600 mg daily. In CML in BC and relapsed Ph+ ALL, imatinib was continued concomitantly with induction chemotherapy (standard-dose idarubicin/ara-C with vincristine/prednisone added for lymphoid leukemias) for an additional week. Imatinib was then ceased, but recommenced as a single agent after blood-count recovery. Patients with de-novo Ph+ ALL received the imatinib prephase and then commenced the French LALA94 protocol without concomitant imatinib. Neutrophils recovered to ≥ 1.0 x 109/L at a median of day 28 (range 21–56) of induction chemotherapy. During induction, 1 patient died from sepsis and multi-organ failure, and 1 patient died on day 7 from CNS leukemia. Subsequently, 1 patient died on day 37 from massive hemoptysis and 1 patient developed pulmonary fibrosis and died on day 144. Among 14 evaluable patients, combined imatinib and chemotherapy induction resulted in 9 (64%) complete hematological responses and there were 5 complete and 3 major cytogenetic responses. Notably, 2 out of 3 patients with CML in myeloid BC achieved major cytogenetic responses. The in-vivo effects of imatinib on Bcr-Abl activity were monitored in leukemic blasts during the imatinib-only prephase. Western blots revealed a decrease in CrkL phosphorylation to < 25% of the pretreatment level in peripheral-blood samples from 5 out of 6 evaluable cases and in marrow samples from 1 of 2 evaluable cases. Bcl-xL expression levels revealed no consistent in-vivo responses to imatinib. However, all 7 cases evaluable for Bcl-2 protein showed strong expression levels, which were unaffected by imatinib in 5 cases and decreased in 2 cases. Imatinib potently inhibited Bcr-Abl activity in vivo in Ph+ acute leukemic blasts and its combination with induction chemotherapy was tolerable and shows promising activity.

scholarly journals Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 700-711 ◽  
Author(s):  
P Bettelheim ◽  
P Valent ◽  
M Andreeff ◽  
A Tafuri ◽  
J Haimi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Gm Csf ◽  
Cell Counts ◽  
Macrophage Colony Stimulating Factor ◽  
De Novo Aml ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Based on in vitro data suggesting that recombinant human granulocyte- macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara- C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.

Acute promielocytic leukemia: 14 years experience at the University Hospital, San Juan, Puerto Rico

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e18006-e18006
Author(s):  
A. T. Lopez-Enriquez
Keyword(s):  
Complete Remission ◽  
Induction Chemotherapy ◽  
Remission Rate ◽  
Single Agent ◽  
Receptor Site ◽  
Early Death ◽  
University Hospital ◽  
High Dose ◽  
Chromosome 15 ◽  
Acute Leukemias

e18006 Background: Acute promielocytic leukemias (APL) are a unique example in carcinogenesis, of maturation arrest at the promielocytic stage, associated with a chromosomal reciprocal translocation of a portion of chromosome 15 and 17 with the formation of fusion proteins between the PML gene and the alpha-retinoic acid receptor site. Methods: Since 1994 when transretinoic acid (ATRA) became available to us, we developed a protocol incorporating this drug to the standard regime of induction chemotherapy for acute leukemias used in our institution of 7 days of continuous infusion of cytosine arabinoside (Ara-C) and three days of daunorubicine (7+3), starting the ATRA on day 14 at 45 mg/m2 and continued daily for 120 days. Two to three more courses of consolidation with high-dose Ara-C, Ara-C with daunorubicine or daunorubicine alone where given. Results: We have treated 91 patients with APL since 1994 up to November 2008. Eighty-nine (89) patients received 7+3+ATRA. Nineteen of eighty-nine (19/89) died early in the first two weeks of treatment mainly secondary to bleeding and sepsis for a 21% early death rate. Sixty-seven of seventy (67/70) patients went into complete remission for a 98% rate. Four patients developed ATRA syndrome; three early pulmonary syndromes with one death, and the other two responded to steroids and went into remission. A fourth developed increased intracranial pressure two weeks on ATRA, resolved on steroids, Diamox, and continued on a lower ATRA dose. Fifty-three (53) has remained in complete remission with a range of 6months to 14 years, for a rate of 76%. Seventeen (17) patients or 25% (17/70) relapsed within the first 2 years of treatment. Thirteen of 17 (13/17) relapsed after receiving Dauno x3 x3 as consolidation chemotherapy for a 76% relapsed rate. Conclusions: The initial high early mortality needs to be addressed with a more aggressive support system. A 98% complete remission rate for induction chemotherapy is extraordinary, no ATRA syndrome when started on day 14 of treatment, reducing further morbidity and mortality. Daunorubicine as a single agent in consolidation is inappropriate in our population. No significant financial relationships to disclose.

Biological and Molecular Evidences for the Antitumor Potential of EGb 761 in Glioma Cells In Vitro and In Vivo

2021 ◽  
Vol 15 (5) ◽  
pp. 685-692
Author(s):  
Xin Sui ◽  
Jia Zhou ◽  
Yan Xu ◽  
Yuchen Wang ◽  
Guangfu Lv ◽  
...  
Keyword(s):  
Growth Factor ◽  
Caspase 3 ◽  
Glioma Cells ◽  
Signalling Pathway ◽  
Migration And Invasion ◽  
Egb 761 ◽  
Western Blots ◽  
Expression Levels

EGb 761, the standardized extract from the Ginkgo biloba leaves, has therapeutic effect on many diseases. However, its mechanisms on glioma remain to be fully established. This study aims to investigate the possible effects of EGb 761 on glioma cells, to explore its potential mechanism. The glioma cells SHG44 and U251 were used as materials, the proliferation, migration and invasion were assessed by the MTT, the scratch-wound and Transwell assays were performed respectively. Levels of insulin-like growth factor-1, Bcl-2, p53, Smad2/3, Bax, cleaved caspase-3 and p-Smad2/3 were determined by western blots. The development and progression of U251 glioma cell were measured in vivo, and the apoptosis was evaluated. The results showed that EGb 761 could inhibit the proliferation, migration, and invasion of SHG-44 and U251 cells in vitro. Meanwhile, the expression levels of IGF-1 and Bcl-2, and the transforming growth factor-β (TGF-β) signaling were inhibited. In contrast, the expression levels of p53, Bax, and cleaved caspase-3 were increased significantly. In conclusion, this study suggested that EGb 761 could suppress the growth of glioma cells in vitro and in vivo, possibly by inhibiting the TGF-β signalling pathway and activating the p53 signalling pathway.

AMN107, Novel Aminopyrimidine Inhibitor of Bcr-Abl, Is Significantly More Potent Than Imatinib Mesylate Against Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2737-2737
Author(s):  
Mirna Golemovic ◽  
Miloslav Beran ◽  
Francis Giles ◽  
Taghi Manshouri ◽  
Deborah Thomas ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cell Line ◽  
Imatinib Mesylate ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Imatinib Treatment ◽  
Significant Activity ◽  
Mts Assay

Abstract Imatinib mesylate is effective against Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) but, when used as a single agent, responses are transient and most patients relapse within 4–6 months. AMN107 is a novel oral aminopyrimidine ATP-competitive inhibitor of the protein tyrosine kinase activity of Bcr-Abl. Following oral administration to animals, AMN107 is well absorbed, has a good pharmacokinetic profile, and is well tolerated. The activity of AMN107, relative to imatinib, in both Ph-positive (Z-119 and Z-181) and Ph-negative (Z-138) ALL cell lines was studied. Z-119 and Z-181 cells were derived from Ph-positive ALL patients and retained typical B-cell characteristics and phenotypes of the original leukemia, including cytogenetic abnormality t(9;22) and p190 Bcr/Abl kinase. Z-138, a Ph-negative cell line, was derived from a patient with chronic lymphocytic leukemia and supervening ALL. Treatment with AMN107 or imatinib for 3 days (MTS assay) inhibited proliferation of Z-119 cells with the IC50 values of 19.3 nM and 620.0 nM, respectively, revealing AMN107 to be 32 fold more potent than imatinib. Treatment of Z-181 cell line lasted for 4 days (MTS assay) because of lower growth rate of these cells: IC50 for AMN107 and imatinib were 1.6 nM and 63.9 nM, respectively, showing AMN107 to be 40 fold more potent than imatinib. Neither drug showed activity against Ph-negative Z-138 cells. We also compared the activity of AMN107 in Ph-positive ALL cell lines expressing p190 Bcr/Abl protein to that in Ph-positive chronic myeloid leukemia cell lines KBM5 and KBM7 expressing p210 Bcr/Abl protein. The activity was similar with IC50 in KBM5 cells of 11.3 nM and in KBM7 cells of 4.3 nM. In experiments focused on cell cycle analysis we found that at equipotent doses (as determined by MTS assay) both drugs induced cell accumulation in G0/G1 phase in Z-119 but not in Z-181. We demonstrated that increasing equipotent concentrations of AMN107 and imatinib induced activation of caspase-3 that resulted in apoptosis, as assessed by propidium iodide staining, in Z-119 cells, while Z-181 cells showed lack of apoptotic response. Following treatment with a broad range of AMN107 and imatinib doses for 3 hrs, Bcr/Abl expression and phosphorylation were determined in Z-119 cells by immunoprecipitation and Western blotting: Bcr/Abl phosphorylation was inhibited completely with AMN107 at 125.0 nM, and with imatinib at 2500 nM, confirming again the higher potency of AMN107. Finally, similar differential effect of AMN107 and imatinib on Bcr/Abl protein expression and phosphorylation was observed in leukemic cells obtained from blood of Ph-positive ALL patients. We conclude that AMN107 has significant activity against Ph-positive ALL cells and warrants investigation in patients with Ph-positive ALL.

Treatment of Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) with Concurrent Chemotherapy and Imatinib Mesylate.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4483-4483 ◽  
Author(s):  
Josep-Maria Ribera ◽  
Albert Oriol ◽  
Marcos Gonzalez ◽  
Maria-Belen Vidriales ◽  
Blanca Xicoy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Imatinib Mesylate ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Prospective Trial ◽  
Philadelphia Chromosome ◽  
Concurrent Chemotherapy ◽  
Newly Diagnosed ◽  
Family Donor

Abstract Imatinib mesylate as a single agent has modest activity in refractory/relapsed Ph-positive ALL. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL was explored. Nineteen patients (pts) with de novo Ph-positive ALL were included in a prospective trial. Induction chemotherapy consisted of imatinib mesylate (400 mg/d, p.o.) and VCR (1.5mg/m2/wk), DNR (60 mg/m2/wk) and PDN (60mg/m2/d) for 4 weeks if adequate bone marrow response (<5% blast cells) at day +14 was observed. If not mitoxantrone (12 mg/m2, d15, 16, 17) and HD-ARAC (1,000mg/m2/12h d 18, 19) were administered. Consolidation chemotherapy (C1) included imatinib mesylate and MP, HD-MTX (1.5 g/m2), VM-26 and ARA-C. Pts with a HLA-identical family or MUD donor were submitted to SCT. IF no MUD donor was found a second consolidation cycle (C2) with imatinib mesylate, VCR, DNR, DXM and CPM was administered. Pts without family donor or with no MUD donor after 6 mo. of active search were submitted to autologous SCT. After SCT imatinib mesylate was administered from the sustained hematological recovery to the eventual relapse or at least up to 1 yr. of continuous molecular remission. Sequential MRD study was performed by cytofluorometry and quantitative RT-PCR. Up to July 2004, 19 pts (10 males, mean [SD] age 43[12] yr., range 17–62, p190bcr-abl in 75% of the cases) were included. One pt is still on treatment, 1 died in induction because of infection, 1 was refractory and the remaining 16 (89%) attained CR. Slow bone marrow response was observed in 4 out of 14 evaluable pts. Three patients have relapsed before SCT, 8 are on consolidation therapy and SCT was performed in 5 (3 from family donor and 2 MUD). 1 pt died after SCT and no relapses after SCT have been observed to date (range 1–6 months from SCT). With a median follow-up of 5 (0.2–14) mo., 3 pts have died, 2 are alive in second CR and 13 are in first CR, with a median DFS of 8 mo. and an OS probability of 66±30%. Levels of BCR-ABL/GUS x100 less than 0.05 were observed in 6/12 (50%) pts at the end of induction therapy. There was a further 1–2 log median reduction of BCR/ABL transcripts at the end of C1, (BCR-ABL/GUS x100 less than 0.05 in 5/6 cases). No additional reduction of transcripts was observed between C1 and SCT. A good correlation between molecular and cytofluorometric MRD data was observed. Use of concurrent chemotherapy and imatinib mesylate in newly diagnosed Ph-positive ALL pts is feasible and the preliminary data are promising in terms of high rate of clinical and molecular CR. Continued accrual and longer follow-up of the current cohort is needed.

Outcome with the Hyper-CVAD and Imatinib Mesylate Regimen in Philadelphia (Ph) Positive Acute Lymphocytic Leukemia (ALL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1830-1830 ◽  
Author(s):  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Jorge Cortes ◽  
Susan O’Brien ◽  
Francis Giles ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Single Agent ◽  
Disease Free Survival ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant

Abstract In Ph+ ALL, complete remission (CR) rates with intensive chemotherapy such hyper-CVAD is 90%, but most patients (pts) relapse within a median time of 16 months [Kantarjian et al, JCO18:547, 2000; Kantarjian et al, Cancer101:2788, 2004]. Single agent therapy with the tyrosine kinase inhibitor imatinib mesylate in relapsed or refractory Ph+ ALL or chronic myelogenous leukemia in lymphoid blast phase yielded CR rates of 20% with rapid disease recurrence. A phase II clinical trial of concurrent hyper-CVAD and imatinib was designed to improve these results, with the initial regimen of imatinib 400 mg orally daily days 1–14 of each course (fractionated cyclophosphamide, vincristine [VCR], doxorubicin and dexamethasone alternating with high dose methotrexate and cytarabine) followed by imatinib, VCR and prednisone maintenance with intensifications months 6 and 13. Allogeneic stem cell transplant (SCT) was performed in CR if feasible. Preliminary results of first 20 pts treated were encouraging [Thomas et al, Blood103:4396, 2004]. Recent modifications included increasing dosing of imatinib to 600 mg daily days 1–14 of course 1, then daily if tolerated with courses 2–8. Maintenance was extended to 24 months with imatinib indefinitely. To date, 43 pts with Ph+ ALL have been treated from April 2004 to July 2005. Thirty-six pts had active disease, either untreated (n=31) or refractory (n=1) to one induction course without imatinib; 7 pts were in CR after one induction course without imatinib. Of 35 evaluable pts, 33 (94%) achieved CR (1 induction death, 1 failed to meet platelet criteria for CR). Median days to response was 21 days. 13 pts underwent allogeneic SCT within a median of 3 months from start of therapy (range, 1–12). After a median follow-up of 3 yrs (range 1–48 months), 1 primary refractory pt relapsed at 12 months, 1 de novo pt had isolated CNS relapse, 2 pts relapsed after allogeneic SCT (no post SCT imatinib) and 2 pts changed therapy for persistent Ph+ metaphases (1 relapsing). Deaths in CR included 5 older pts without allogeneic SCT (1 osteomyelitis, 1 mucormycosis, 1 C. difficile colitis, 1 sudden death, 1 GNR sepsis) and 4 pts after allogeneic SCT (3 graft-versus-host disease, 1 GNR sepsis). Outcome with the hyper-CVAD and imatinib regimen continues to demonstrate favorable disease-free survival rates compared with hyper-CVAD alone, particularly for the de novo group. Use of higher dose imatinib concurrently appears to be feasible. Molecular response rates appear to be improved with the higher dose imatinib; additional accrual will be required to assess impact of modifications, including role of allogeneic SCT.

scholarly journals INNO-406, a novel BCR-ABL/Lyn dual tyrosine kinase inhibitor, suppresses the growth of Ph+ leukemia cells in the central nervous system, and cyclosporine A augments its in vivo activity

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 306-314 ◽  
Author(s):  
Asumi Yokota ◽  
Shinya Kimura ◽  
Satohiro Masuda ◽  
Eishi Ashihara ◽  
Junya Kuroda ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Imatinib Mesylate ◽  
Cyclosporine A ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
P Glycoprotein ◽  
Cns Relapse

Abstract Central nervous system (CNS) relapse accompanying the prolonged administration of imatinib mesylate has recently become apparent as an impediment to the therapy of Philadelphia chromosome–positive (Ph+) leukemia. CNS relapse may be explained by limited penetration of imatinib mesylate into the cerebrospinal fluid because of the presence of P-glycoprotein at the blood-brain barrier. To overcome imatinib mesylate–resistance mechanisms such as bcr-abl amplification, mutations within the ABL kinase domain, and activation of Lyn, we developed a dual BCR-ABL/Lyn inhibitor, INNO-406 (formerly NS-187), which is 25 to 55 times more potent than imatinib mesylate in vitro and at least 10 times more potent in vivo. The aim of this study was to investigate the efficacy of INNO-406 in treating CNS Ph+ leukemia. We found that INNO-406, like imatinib mesylate, is a substrate for P-glycoprotein. The concentrations of INNO-406 in the CNS were about 10% of those in the plasma. However, this residual concentration was enough to inhibit the growth of Ph+ leukemic cells which expressed not only wild-type but also mutated BCR-ABL in the murine CNS. Furthermore, cyclosporine A, a P-glycoprotein inhibitor, augmented the in vivo activity of INNO-406 against CNS Ph+ leukemia. These findings indicate that INNO-406 is a promising agent for the treatment of CNS Ph+ leukemia.

scholarly journals Recombinant human granulocyte-macrophage colony-stimulating factor in combination with standard induction chemotherapy in de novo acute myeloid leukemia

Blood ◽  
1991 ◽  
Vol 77 (4) ◽  
pp. 700-711 ◽  
Author(s):  
P Bettelheim ◽  
P Valent ◽  
M Andreeff ◽  
A Tafuri ◽  
J Haimi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Gm Csf ◽  
Cell Counts ◽  
Macrophage Colony Stimulating Factor ◽  
De Novo Aml ◽  
Macrophage Colony ◽  
Stimulating Factor

Based on in vitro data suggesting that recombinant human granulocyte- macrophage colony-stimulating factor (rhGM-CSF) is capable of stimulating acute myeloid leukemia (AML) blast cells to become more sensitive to cell-cycle-specific drugs we conducted a phase I/II study in de novo AML patients (pts). rhGM-CSF (250 micrograms/m2/d, continuous intravenous infusion) was administered in 18 pts suffering from de novo AML in combination with standard induction chemotherapy (3 + 7 = daunorubicin 45 mg/m2 days 1 through 3, cytosine-arabinoside [Ara- C] 200 mg/m2 continuous infusion days 1 through 7). GM-CSF was started 48 or 24 hours before chemotherapy (prephase) in 14 pts. In four pts with high white blood cell counts (WBC) rhGM-CSF was started after chemotherapy-induced cell reduction (WBC less than 30,000/mm3). During prephase GM-CSF induced an increase in neutrophil and blast cell counts in 13 of 14 and 10 of 14 pts, respectively. In vivo recruitment of leukemic cells into drug-sensitive phases of the cell cycle could be demonstrated by multiparameter cell-cycle analyses in peripheral blood (n = 7) and bone marrow (n = 4) specimens. On day 14, complete aplasia was evident in 17 of 18 pts. GM-CSF was administered until recovery from chemotherapy-induced myelosuppression (absolute neutrophil counts, [ANC] greater than 500/mm3). Fifteen pts (83%) achieved complete remission, 12 did so with one cycle. A shorter duration of neutropenia was evident in these pts compared with historical controls (n = 39), (ANC greater than 500/mm3, day 22.5 +/- 3.4 v 25.2 +/- 3.7, P less than .05). Three pts achieved complete remission after a second cycle (same combination of rhGM-CSF and 3 + 7). Two pts died during bone marrow aplasia because of invasive pulmonary aspergillosis. Clinical side effects possibly related to GM-CSF, mainly fever, diarrhea, and weight gain were mild and tolerable (World Health Organization toxicity grade less than or equal to 2). Together, rhGM-CSF recruits kinetically quiescient AML cells in vivo to enter drug-sensitive phases of the cell cycle and promotes early myeloid recovery from aplasia after exposure to standard induction chemotherapy for AML.

Simultaneous Administration of AMN107 and Imatinib in the Treatment of Imatinib-Sensitive and Imatinib-Resistant Chronic Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 694-694 ◽  
Author(s):  
James D. Griffin ◽  
Ellen L. Weisberg
Keyword(s):  
Cell Lines ◽  
Synergistic Effects ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Wild Type ◽  
Imatinib Resistant

Abstract Chronic myelogenous leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) are caused by the Bcr-Abl tyrosine kinase oncogene. The Abl inhibitor imatinib is an effective, frontline therapy for early, chronic phase CML. However, accelerated or blast crisis phase CML and Ph+ ALL patients often relapse because of drug resistance that results from the emergence of imatinib-resistant point mutations within the Bcr-Abl kinase domain. The aminopyrimidine ATP-competitive inhibitor, AMN107, was designed to fit into the ATP-binding site of the Bcr-Abl protein in such a way as to exhibit higher efficacy against imatinib-resistant Bcr-Abl point mutants. AMN107 is active against many imatinib-resistant Bcr-Abl mutants in vitro and in vivo, and is significantly more potent than imatinib against wild-type Bcr-Abl. AMN107 is currently showing promise in phase I/II clinical trials involving CML patients who are unresponsive to imatinib, and thus could potentially be used as a single agent in selected patients resistant or intolerant to imatinib. Alternatively, the use of more than one inhibitor of Abl should effectively lower the number of residual Bcr-Abl-expressing cells having the potential to undergo mutation, and therefore could potentially suppress the emergence of drug-resistant Bcr-Abl mutations. Thus, AMN107 and imatinib could be administered together to achieve higher responsiveness in CML patients. In the current study, we investigated the combination of imatinib and AMN107 in a panel of wild-type and imatinib-resistant Bcr-Abl-expressing cell lines, including 32D.p210, K562, F486S-Ba/F3, F317L-Ba/F3, M351T-Ba/F3, and T315I-Ba/F3. We found evidence of additive to synergistic effects in several of the cell lines examined. In addition, the combination of AMN107 and imatinib was studied in vivo using a bioluminescent Bcr-Abl model of CML. Mice harboring murine 32D.p210 cells engineered to stably express firefly luciferase were treated with vehicle, AMN107 alone (15mg/kg), imatinib alone (75mg/kg), or both AMN107 and imatinib at their respective doses. Mice treated with both agents were observed to carry an overall lower tumor burden (as measured by levels of total body bioluminescence and percent spleen weights) than vehicle-treated mice and mice treated with each agent alone. These results suggest that the combination of imatinib and AMN107 may be a more effective treatment for CML than either agent alone.

scholarly journals Quantitative Assessment of Indoleamine 2,3-Dioxygenase (IDO) Expression at Diagnosis Predicts Clinical Outcome in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5261-5261
Author(s):  
Sarah Parisi ◽  
Simone Ragaini ◽  
Darina Ocadlikova ◽  
Mariangela Lecciso ◽  
Giovanni Marconi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Outcome ◽  
Mrna Expression ◽  
Board Of Directors ◽  
Induction Chemotherapy ◽  
De Novo ◽  
Advisory Committees ◽  
Secondary Aml ◽  
Expression Levels ◽  
Mrna Expression Levels

Abstract Introduction Indoleamine 2,3-dioxygenase (IDO) is an intracellular heme-containing enzyme that catalyzes the initial rate-limiting step in tryptophan degradation along the kynurenine pathway. IDO is physiologically expressed by a wide variety of human cells in response to several stimuli and it is known to have a crucial role in the induction of immune tolerance during pregnancy, infections, transplantation, autoimmunity and tumors. IDO-mediated tryptophan degradation results in inhibition of T-cell proliferation, increase of T-cell apoptosis and T-reg induction. Several studies demonstrated that IDO production can induce the increase of Regulatory T-cells (Tregs) directly through the conversion of CD25- into CD25+ T cells, even in acute myeloid leukemia (AML) patients. IDO expression can be considered a novel mechanism of leukemia escape from immune control and its inhibition may represent an antileukemia therapeutic strategy. Aim of our work is to analyze IDO mRNA expression in a cohort of AML patients and to investigate the presence of any significant correlation between IDO expression and standard prognostic factors or clinical outcome. Methods We analyzed a cohort of 68 adult patients aged 18 years or older, who were diagnosed with de novo or secondary AML. IDO mRNA expression was evaluated by Real-Time (RT)-PCR in blood bone marrow and peripheral blood samples at diagnosis. Patients were then retrospectively stratified according to standard risk factors at diagnosis and to IDO mRNA expression levels. Results Median age of analyzed patients was 57 years (range 21-76). Fifty-nine out of 68 patients (87%) had de novo AML, whereas 9 out of 68 patients (13%) had secondary AML. A comprehensive risk assessment was available for 61 patients. Among these 61 patients who were evaluable for risk stratification, 13 patients (21%) resulted to have a favorable risk AML, 30 (49%) had an intermediate risk AML and 17 patients (30%) were stratified as high-risk AML. Sixty out of 68 patients received intensive, standard, induction chemotherapy regimens. The remaining 8 patients were not candidate to receive intensive chemotherapy mainly because of comorbidities. Twenty-three out of 68 patients (34%) were considered eligible for allogeneic stem cells transplantation (alloSCT) as consolidation therapy, after obtaining complete remission with standard chemotherapy. IDO expression in peripheral blood (PB) samples was between 0.07 and 4272.26 (median 5.60). Conversely, IDO expression in bone marrow (BM) samples was between 0.17 and 243.16 (median 1.21). Our data did not establish any significant correlation between IDO expression and leukemia risk factors at diagnosis, in particular cytogenetics, de novo or secondary AML, leukocytosis. Among the 60 patients who received induction chemotherapy, 35 achieved morphological complete remission (CR), 24 did not respond and 1 patient was not evaluable for response. Response to induction chemotherapy was not influenced by IDO mRNA expression levels. Interestingly, among patients undergoing alloSCT, high levels of IDO mRNA expression in PB samples negatively correlated with patients' overall survival. In particular, high IDO expression of more than 10 was associated with worse overall survival after alloSCT even when adjusted by patients' age and disease status at transplant (log rank P=0.02) (Fig.1). With the limitations of the low number of patients, these results from the group of transplanted patients were not likely due to differences in the incidence and severity of graft-versus-host-disease, whereas high IDO mRNA expression level was predictive of increased incidence of relapse. Conclusions This work suggests that IDO mRNA expression levels can be considered as predictive of AML outcome, independently from other risk factors at diagnosis. In our set, higher level of IDO mRNA expression at diagnosis was correlated with worse clinical outcome in patients undergoing alloSCT. Larger studies are warranted in order to establish the real predictive role of IDO mRNA expression in influencing AML outcome. Disclosures Cavo: Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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