BCR-ABL nuclear entrapment kills human CML cells: ex vivo study on 35 patients with the combination of imatinib mesylate and leptomycin B

The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.

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A novel mechanism for imatinib mesylate–induced cell death of BCR-ABL–positive human leukemic cells: caspase-independent, necrosis-like programmed cell death mediated by serine protease activity

Blood ◽

10.1182/blood-2003-05-1605 ◽

2004 ◽

Vol 103 (6) ◽

pp. 2299-2307 ◽

Cited By ~ 73

Author(s):

Masayuki Okada ◽

Souichi Adachi ◽

Tsuyoshi Imai ◽

Ken-ichiro Watanabe ◽

Shin-ya Toyokuni ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Serine Protease ◽

Imatinib Mesylate ◽

Protease Activity ◽

Kinase Inhibitor ◽

Leukemic Cells ◽

Endonuclease G ◽

Serine Protease Activity ◽

Human Leukemic Cells

Abstract Caspase-independent programmed cell death can exhibit either an apoptosis-like or a necrosis-like morphology. The ABL kinase inhibitor, imatinib mesylate, has been reported to induce apoptosis of BCR-ABL–positive cells in a caspase-dependent fashion. We investigated whether caspases alone were the mediators of imatinib mesylate–induced cell death. In contrast to previous reports, we found that a broad caspase inhibitor, zVAD-fmk, failed to prevent the death of imatinib mesylate–treated BCR-ABL–positive human leukemic cells. Moreover, zVAD-fmk–preincubated, imatinib mesylate–treated cells exhibited a necrosis-like morphology characterized by cellular pyknosis, cytoplasmic vacuolization, and the absence of nuclear signs of apoptosis. These cells manifested a loss of the mitochondrial transmembrane potential, indicating the mitochondrial involvement in this caspase-independent necrosis. We excluded the participation of several mitochondrial factors possibly involved in caspase-independent cell death such as apoptosis-inducing factor, endonuclease G, and reactive oxygen species. However, we observed the mitochondrial release of the serine protease Omi/HtrA2 into the cytosol of the cells treated with imatinib mesylate or zVAD-fmk plus imatinib mesylate. Furthermore, serine protease inhibitors prevented the caspase-independent necrosis. Taken together, our results suggest that imatinib mesylate induces a caspase-independent, necrosis-like programmed cell death mediated by the serine protease activity of Omi/HtrA2.

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The CNS is a sanctuary for leukemic cells in mice receiving imatinib mesylate for Bcr/Abl-induced leukemia

Blood ◽

10.1182/blood-2002-10-3059 ◽

2003 ◽

Vol 101 (12) ◽

pp. 5010-5013 ◽

Cited By ~ 68

Author(s):

Nicholas C. Wolff ◽

James A. Richardson ◽

Merrill Egorin ◽

Robert L. Ilaria

Keyword(s):

Imatinib Mesylate ◽

Kinase Inhibitor ◽

High Response Rate ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Murine Bone Marrow ◽

Systemic Control ◽

Therapeutic Doses ◽

The Impact ◽

Transplantation Model

AbstractThe chronic myelogenous leukemia (CML)–like myeloproliferative disorder observed in the BCR/ABL murine bone marrow transduction and transplantation model shares several features with the human disease, including a high response rate to the tyrosine kinase inhibitor imatinib mesylate (STI571). To study the impact of chronic imatinib mesylate treatment on the CML-like illness, mice were maintained on therapeutic doses of this drug and serially monitored. Unexpectedly, despite excellent systemic control of the CML-like illness, many of the mice developed progressive neurologic deficits after 2 to 4 months of imatinib mesylate therapy because of central nervous system (CNS) leukemia. Analysis of imatinib mesylate cerebral spinal fluid concentrations revealed levels 155- fold lower than in plasma. Thus, in the mouse, the limited ability of imatinib mesylate to cross the blood-brain barrier allowed the CNS to become a sanctuary for Bcr/Abl-induced leukemia. This model will be a useful tool for the future study of novel anti-CML drugs and in better defining the mechanisms for limited imatinib mesylate penetration into the CNS.

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Extracellular KIT receptor mutants, commonly found in core binding factor AML, are constitutively active and respond to imatinib mesylate

Blood ◽

10.1182/blood-2005-02-0583 ◽

2005 ◽

Vol 106 (12) ◽

pp. 3958-3961 ◽

Cited By ~ 58

Author(s):

Jörg Cammenga ◽

Stefan Horn ◽

Ulla Bergholz ◽

Gunhild Sommer ◽

Peter Besmer ◽

...

Keyword(s):

Imatinib Mesylate ◽

Kinase Inhibitors ◽

Kinase Inhibitor ◽

Therapeutic Option ◽

Extracellular Domain ◽

Genetic Alterations ◽

Myelogenous Leukemia ◽

Core Binding Factor ◽

Kit Receptor ◽

Binding Factor

Multiple genetic alterations are required to induce acute myelogenous leukemia (AML). Mutations in the extracellular domain of the KIT receptor are almost exclusively found in patients with AML carrying translocations or inversions affecting members of the core binding factor (CBF) gene family and correlate with a high risk of relapse. We demonstrate that these complex insertion and deletion mutations lead to constitutive activation of the KIT receptor, which induces factor-independent growth of interleukin-3 (IL-3)–dependent cells. Mutation of the evolutionary conserved amino acid D419 within the extracellular domain was sufficient to constitutively activate the KIT receptor, although high expression levels were required. Dose-dependent growth inhibition and apoptosis were observed using either the protein tyrosine kinase inhibitor imatinib mesylate (STI571, Gleevec) or by blocking the phosphoinositide-3-kinase (PI3K)–AKT pathway. Our data show that the addition of kinase inhibitors to conventional chemotherapy might be a new therapeutic option for CBF-AML expressing mutant KIT.

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Several Bcr-Abl kinase domain mutants associated with imatinib mesylate resistance remain sensitive to imatinib

Blood ◽

10.1182/blood-2002-12-3659 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4611-4614 ◽

Cited By ~ 236

Author(s):

Amie S. Corbin ◽

Paul La Rosée ◽

Eric P. Stoffregen ◽

Brian J. Druker ◽

Michael W. Deininger

Keyword(s):

Imatinib Mesylate ◽

Kinase Inhibitor ◽

Blast Crisis ◽

Chronic Phase ◽

Kinase Domain ◽

Myelogenous Leukemia ◽

Imatinib Resistance ◽

Abl Kinase ◽

Cellular Assays ◽

Kinase Domain Mutations

Abstract Imatinib mesylate is a selective Bcr-Abl kinase inhibitor, effective in the treatment of chronic myelogenous leukemia. Most patients in chronic phase maintain durable responses; however, many in blast crisis fail to respond, or relapse quickly. Kinase domain mutations are the most commonly identified mechanism associated with relapse. Many of these mutations decrease the sensitivity of the Abl kinase to imatinib, thus accounting for resistance to imatinib. The role of other mutations in the emergence of resistance has not been established. Using biochemical and cellular assays, we analyzed the sensitivity of several mutants (Met244Val, Phe311Leu, Phe317Leu, Glu355Gly, Phe359Val, Val379Ile, Leu387Met, and His396Pro/Arg) to imatinib mesylate to better understand their role in mediating resistance.While some Abl mutations lead to imatinib resistance, many others are significantly, and some fully, inhibited. This study highlights the need for biochemical and biologic characterization, before a resistant phenotype can be ascribed to a mutant.

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Constitutive Activation of SRC-Family Kinases in Chronic Myelogenous Leukemia Patients Resistant to Imatinib Mesylate in the Absence of BCR-ABL Mutations: A Rationale for Use of SRC/ABL Dual Kinase Inhibitor-Based Therapy.

Blood ◽

10.1182/blood.v106.11.1087.1087 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1087-1087 ◽

Cited By ~ 1

Author(s):

Nicholas J. Donato ◽

Ji Wu ◽

Ling-Yuan Kong ◽

Feng Meng ◽

Francis Lee ◽

...

Keyword(s):

Cell Survival ◽

Imatinib Mesylate ◽

Src Family Kinases ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Imatinib Resistance ◽

Kinase Activation ◽

Abl Kinase ◽

Lyn Kinase ◽

Imatinib Resistant

Abstract BCR-ABL is an unregulated tyrosine kinase expressed as a consequence of a reciprocal chromosomal translocation that is common in chronic myelogenous and acute lymphocytic leukemia. BCR-ABL induces transformation of hematopoetic stem cells through tyrosine phosphorylation of multiple substrates. The src-family kinases (SFKs), Lyn and Hck, are highly activated by BCR-ABL in leukemic cells and recent studies suggest that they are substrates and essential mediators of BCR-ABL signal transduction and transformation. In cells selected for resistance to the BCR-ABL inhibitor, imatinib mesylate, Lyn kinase is overexpressed and its activation is not dependent on or regulated by BCR-ABL, suggesting that autonomous regulation of SFKs may play a role in imatinib resistant. In this report, activation of Lyn and Hck was compared in CML specimens derived from imatinib responsive and resistant patients that did not express a mutant BCR-ABL protein as their primary mediator of resistance. In imatinib sensitive cell lines and specimens derived from imatinib responsive CML patients imatinib effectively reduced activation of both BCR-ABL and SFKs. However, in multiple specimens from resistant patients, imatinib reduced BCR-ABL kinase activation but failed to reduce SFK activation. The dual ABL/SRC inhibitor, BMS-354825, blocked activation of both BCR-ABL and SFKs expressed in leukemic cells and correlated with clinical responsiveness to this agent. Animal models demonstrated that loss of imatinib-mediated inhibition of Lyn kinase activation significantly impaired its anti-tumor activity which was recovered by treatment with BMS-354825. Direct silencing of Lyn or Hck reduced CML cell survival in imatinib resistant patient specimens and cell models, suggesting a direct role for these kinases in cell survival. Our results show that SFK activation is mediated by BCR-ABL in imatinib responsive cells but these kinases escape control by BCR-ABL in CML patients that develop imatinib resistance in the absence of BCR-ABL point mutations. This form of resistance can effectively be overcome by BMS-354825 through its dual SRC and ABL kinase inhibitory activities. Dual specificity kinase inhibitors may be indicated for the treatment and prevention of imatinib resistance in CML when it is associated with constitutively activated src-family kinases.

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Imatinib Resistance Restoration with Antioxidants and Immunomodulation in Patients with Chronic Myelogenous Leukemia (CML).

Blood ◽

10.1182/blood.v108.11.4818.4818 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4818-4818

Author(s):

Eugene McPherson ◽

R. Shuklar ◽

S.Y. Huang ◽

M. Grimbel ◽

E. Hazel

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Chronic Myelogenous Leukemia ◽

Reductase Inhibitor ◽

Kinase Inhibitor ◽

Myelogenous Leukemia ◽

Leukemic Cells ◽

Hmg Coa Reductase ◽

Hmg Coa Reductase Inhibitor ◽

Coa Reductase

Abstract Imatinib mesylate (IM) is potent BCR/abl tyrosine kinase inhibitor in patients with chronic myelogenous leukemia (CML). It has remarkable frontline clinical effects in this disease, however, the leukemic cells become resistant to IM in both chronic and blast phases. BCR/abl kinase can induce reactive oxygen species (ROS) and promote self-mutation which subsequently render IM to resistance and failure to eliminate all leukemia cells. This mechanism of resistance in IM (mutation) is caused by oxidant damage to DNA with kinase domain mutations, reduced IM binding and kinase inhibition. Antioxidants (ascorbic acid, etc.) may help overcome IM resistance and restore sensitivity to IM via suppression of transcription factor Nrf2 that regulates the gene expression gammaglutamylcysteine ((g-GCS), the rate-limiting enzyme in glutathione (GSH) biosynthesis and detoxification. P-glycoprotein (P-gp) drug efflux can also exist and complete molecular response relapse occurs. Leukemic cells that are P-gp positive, and P-gp dependent decline of intracellular IM levels are associated with retained phosphorylation pattern of BCR/abl and loss of IM effect on apoptosis and cellular proliferation. Modulation of P-gp with HMG-CoA reductase inhibitor simvastatin may help restore IM cytotoxicity. We present a case of an 80+ year old female with CML-chronic phase-II (CML-CP-II) with concommitant cormorbidities of CAD, unstable angina, hypertension, and dyslipidemia treated with aspirin, simvastatin and started on IM 400mg daily. After two months of therapy she developed grade 3 neutropenia, lower extremity edemia, nausea/vomiting and fluid retention requiring IM interruption and supportive care with growth factors. IM dose reduction to 300mg daily and simvastatin 10 mg every other day. Soluble interleukin-2 receptor (sIL-2R) levels were elevated and trending down once proinflammatory cytokines were modulated. Real-time BCR-ABL/abl-PCR ratio increased insignificantly from 0.001% to 0.003%. Betacarotene level significantly decreased to 4, ascorbic level within normal limits, VEGF remained < 31 pg/ml (normal 31–86 pg/ml), fibrinogen level 309.90 mg/dl (normal 162–431), ESR 15 mm/hr, C-reactive protein 5.55 mg/dl and sIL-2R increased to > 3,000 U/mL (normal 200– 1100 U/mL). Betacarotene and ascorbic antioxidants dosage were increased and immunomodulation of preinflammatory cytokines ROS, sIL-2R and betacarotene normalized, 512 and 44 respectively. Serial measurement of BCR-ABL/abl ratio did not exceed 0.02% on three occasions or 0.05% on two occasions, therefore no molecular relapse and persistent low levels of BCR-ABL/abl ratio with no hematologic or cytogenetic relapse. We felt that an acute coronary syndrome with perturbation of CML with some IM resistance was developed. CONCLUSION: IM, a tyrosine kinase inhibitor may develop resistance when leukemic cells are positive with P-gp and oxidative stress increase ROS along with decreases in IM intracellular levels. Modulation by HMG -CoA reductase inhibitor (simvastatin) via a mechanism of inhibition of P-gp transport and antioxidants reduction of BCR/abl mutagenesis may allow IM to efficently restore normal hematopoiesis in CML patients.

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Imatinib Increases Cytotoxicity of Melphalan and Their Combination Allows An Efficient Killing of CML Cells.

Blood ◽

10.1182/blood.v114.22.4254.4254 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4254-4254

Author(s):

Cesarina Giallongo ◽

Piera La Cava ◽

Daniele Tibullo ◽

Nunziatina Parrinello ◽

Provvidenza Guagliardo ◽

...

Keyword(s):

Dna Damage ◽

Drug Resistance ◽

Dna Repair ◽

Conflicts Of Interest ◽

Leukemic Cells ◽

Proliferative Potential ◽

Cell Accumulation ◽

M Phase ◽

Pre Treatment ◽

Human Leukemic Cells

Abstract Abstract 4254 BCR/ABL-positive cells are relatively resistant to chemotherapy and, in order to evaluate the effect of Imatinib (IM) in reverting drug-resistance, we evaluated on K562 the toxicity of 1 h exposure to cytosine arabinoside (ARA-C) 20 μM, hydroxyurea (HU) 100 μM, and melphalan (MEL) 20 μM, after a pre-treatment of 24 h with 1 μM IM. The doses of the drugs were similar to that achieved in the plasma after standard chemoterapeutic treatment. Cell viability was evaluated by ATP-lite at 24, 48 and 72 hs from beginning of drug-free condition. The combinations of IM plus MEL induced the highest cytotoxicity (P<0,001 at 24, 48 and 72 hs vs MEL alone) indicating that pre-treatment with IM increased K562 exposition to the genotoxic damage of MEL. We next analyzed effects on cell cycle and DNA damage by alkaline comet assay induced by this drug combination and we observed that DNA damage peaked at 48 h with IM/MEL combination. In addition, flow cytometry analysis showed that IM/MEL combination reduced the cell accumulation in G2/M phase induced by MEL (P<0.001 vs MEL), thus reducing the ability to DNA repair and recovery. These data indicate that inhibition of BCR/ABL activity by IM increased cell cytotoxicity of MEL by reducing the effectiveness of the DNA-repair pathways and decreasing the time for DNA repair at the G2/M checkpoint.. To ascertain that these results were linked to BCR/ABL inhibition, TonB.210, a cell line where the BCR-ABL expression is inducible by doxycycline (DOX), were treated in the same conditions. Only TonB.210 cultured with DOX were insensitive to MEL while IM/MEL combination reverted these drug resistance (P<0,001). In the final step we studied the sequential association IM/MEL on the proliferative potential of myeloid progenitors of 6 CML patients at diagnosis. IM/MEL combination increased the reduction of the overall number of colonies in comparison to IM alone (P<0.05 vs IM). In addition, the analysis on CFU-GM and BFU-E colonies by qRT-PCR demonstrated that the IM/MEL combination led to the highest reduction in the number of BCR/ABL positive colonies (P<0.01 vs IM). Therefore, our data indicate that the pre-inhibition of BCR/ABL activity by IM increases the toxicity of MEL and allows an efficient killing of human leukemic cells, thus suggesting new therapeutic combinations for CML patients Disclosures: No relevant conflicts of interest to declare.

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GADD45a Is a Tumor Suppressor In BCR-ABL-Driven Leukemogenesis

Blood ◽

10.1182/blood.v122.21.1467.1467 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1467-1467

Author(s):

Kaushiki Mukherjee ◽

Xiaojin Sha ◽

Ravi Bhatia ◽

Tomasz Skorski ◽

Barbara Hoffman ◽

...

Keyword(s):

Tumor Suppressor ◽

Kinase Inhibitor ◽

Conflicts Of Interest ◽

Multiple Stressors ◽

Blast Crisis ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Pcr Analysis ◽

M Cell ◽

Number Of Patients

Abstract The BCR-ABL fusion oncogene which encodes a fused deregulated tyrosine kinase causes chronic myelogenous leukemia (CML) in humans. Imatinib, a small molecule ABL kinase inhibitor has been highly effective in treating chronic phase (CP) CML patients. However, a substantial number of patients undergo relapse due to development of resistance to imatinib therapy that leads to blast crisis (BC-CML), which is invariably fatal within weeks to months. Additional genetic aberrations assist in progression and identification of key players that are responsible for transformation is of utmost importance from a therapeutic point of view. Growth arrest DNA damage 45a (Gadd45a) gene, a member in the gadd45 family of genes including Gadd45b & Gadd45g, was identified as a myeloid differentiation primary response gene. There is evidence consistent with it’s involvement in G2/M cell cycle arrest and apoptosis in response to multiple stressors, including genotoxic and oncogenic stress. To investigate the effect of Gadd45a in the development of CML, adaptive bone marrow transplantation experiments with either wild type or Gadd45a null myeloid progenitors expressing 210-kD BCR-ABL fusion oncoprotein revealed that loss of Gadd45a accelerated BCR-ABL driven CML resulting in the development of a more aggressive AML/BC like disease. Recent newly obtained data indicate that number of Gadd45a deficient Leukemic stem cells (LSC) harboring BCR-ABL increased as disease progressed confirming Gadd45a as a crucial tumor suppressor in CML. Recent data also indicate, that transformed Gadd45a deficient progenitors exhibit increased proliferation and decreased apoptosis, associated with enhanced PI3K-AKT-mTOR-4E-BP1 signaling and upregulated oncogenic p30C/EBPα. More importantly, newly obtained data indicate that Gadd45a transcript levels in peripheral blood of human blast crisis (BC-CML) samples was found to be reduced compared to accelerated phase (AP-CML), chronic phase (CP-CML) and normal controls, assessed by Quantitative real time PCR analysis. Collectivly these data strongly suggest that Gadd45a expression is a novel prognostic indicator of CML progression, implicating Gadd45a as a downregulated target of BCR-ABL associated with progression to more aggressive stages. To conclude, our findings provide novel evidence that Gadd45a functions as a suppressor of BCR/ABL driven myeloid leukemogenesis, & that suppresion of Gadd45a is associated with CML progression. These data provide the impetus to further elucidate the role Gadd45a plays in suppressing the development of CML, and explore how its loss contributes to the progression of CML to more aggressive leukemic phenotypes. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v106.11.1830.1830 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1830-1830 ◽

Cited By ~ 2

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.

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Imatinib Mesylate Discontinuation in Patients with Chronic Myelogenous Leukemia in Complete Molecular Remission: An Update Follow Up.

Blood ◽

10.1182/blood.v108.11.2154.2154 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2154-2154 ◽

Cited By ~ 1

Author(s):

Francois-Xavier Mahon ◽

Francoise Huguet ◽

Gabriel Etienne ◽

Delphine Réa ◽

Jean-Michel Cayuela ◽

...

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Kinase Inhibitor ◽

Residual Disease ◽

Quantitative Polymerase Chain Reaction ◽

Leukemic Cell ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Molecular Remission

Abstract The BCR-ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec) induces complete cytogenetic responses (CCR) in more than 85% of patients with chronic myelogenous leukemia (CML). However, patients in CCR relapse after imatinib interruption in case of detectable residual disease. In fact, less than 10% of patients achieve a molecular remission, defined by an undetectable residual disease using real time quantitative polymerase chain reaction (RTQ-PCR). We previously reported the outcome of CML patients in CCR after cessation of interferon-alpha during the pre-imatinib era. Seven (all with a negative PCR) out of 15 patients did not relapse (J Clin. Oncol.,20,2002:214–220). In the present study, we address the issue of the discontinuation of imatinib in CML with undetectable residual disease for more than 2 years in 15 patients. The median duration of RTQ-PCR negativity and imatinib therapy were respectively 32 months (24–46) and 45 months (32–56) before imatinib interruption. Eight patients displayed a molecular relapse with a detectable BCR-ABL transcript appearance between the first 6 months. Imatinib was then re-introduced and led to a novel molecular response in most patients. Seven other patients have still an undetectable level of BCR-ABL transcript after a median follow up of 20 months (9–24). With the assumption that the doubling time of a proliferative CML cell is 8 days, it will take a maximum of 6 months if only one leukemic cell persists and proliferates to reach 107 cells i.e corresponding to a residual disease detectable by RTQ-PCR. Relapses observed within 6 months may reflect the kinetic of undetectable dividing CML cells. Those cells may be eradicated or controlled in long term non relapsing patients described in our study.

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