Combination Therapy Of Imatinib Research Articles

Cost-effectiveness analysis of imatinib versus dasatinib in the treatment of pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia when combined with conventional chemotherapy in China

BackgroundTyrosine kinase inhibitors combined with conventional chemotherapy (CC) in treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) has achieved promising efficacy and safety outcomes. The study was conducted to compare the cost-effectiveness between imatinib (HANSOH Pharma, Jiangsu, China) and dasatinib (CHIATAI TIANQING Pharma, Jiangsu, China) in treating pediatric Ph-positive ALL when combined with CC from the perspective of the health system in China.MethodsA Markov model was established to simulate a hypothetical cohort of pediatric Ph-positive ALL patients receiving imatinib or dasatinib, combined with CC. The model was designed using a 10-year horizon, a 3- month cycle, and a 5% discount rate. Three health states were included: alive with progression-free survival, progressed disease, and death. Patient characteristics and transition probabilities were estimated based on clinical trials. Other relevant data, such as direct treatment costs and health utility data were extracted from published literature and Sichuan Province’s centralized procurement and supervision platform. One-way sensitivity analysis and probabilistic sensitivity analysis were performed to assess the robustness of the results. The willingness-to-pay (WTP) was set as three times China’s GDP per capita in 2021.ResultsIn the base-case analysis, the total medical costs were $89,701 and $101,182, and the quality-adjusted life years (QALYs) gained were 1.99 and 2.70, for imatinib and dasatinib regimens, respectively. The incremental cost-effectiveness ratio for dasatinib versus imatinib was $16,170/QALY. The probabilistic sensitivity analysis indicated that treatment with dasatinib combined with CC achieved a 96.4% probability of cost-effectiveness at a WTP threshold of $37,765/QALY.ConclusionsDasatinib combined with CC is likely to be a cost-effective strategy compared to imatinib combination therapy for pediatric Ph-positive ALL in China at a WTP threshold of $37,765/QALY.

STABILITY ANALYSIS OF A MATHEMATICAL MODEL FOR CHRONIC MYELOID LEUKEMIA ERADICATION

We analyze a mathematical model for the treatment of chronic myeloid leukemia (CML). The model is designed for complete recovery of CML patients after treatment. The model developed in the paper [Bunimovich-Mendrazitsky S, Kronik N, Vainstein V, Optimization of interferon-alpha and imatinib combination therapy for CML: A modeling approach, Adv Theory Simul 2(1):1800081, 2018] introduced a combined treatment of CML based on imatinib therapy and immunotherapy. Immunotherapy based on Interferon alpha-2a (IFN-[Formula: see text]) affects stem and mature cancer cell mortality, and leads to outcome improvements in the combined therapy. The qualitative character of our results shows that additional therapy for the complete cure of CML patients is required. This additional treatment is tumor infiltrating lymphocytes (TIL) along with a combination imatinib and IFN-[Formula: see text] treatment. The model examines the interaction between CML cancer cells and effector cells, using an ODE system. Stability analysis of the model defines conditions when imatinib treatment might lead to the eradication of CML with IFN-[Formula: see text] and TIL. Three equilibria are investigated for the proposed model. Stability conditions for equilibria are formulated in terms of the linear matrix inequalities (LMIs).

Artemether and imatinib combination therapy against malaria infection

Artemisinin-based combination therapy (ACT) is recommended by the World Health Organization (WHO) as the first and second line of treatment for uncomplicated malaria caused by P. falciparum, as well as for chloroquine-resistant P. vivax malaria. Despite the large number of antimalarial drugs, there is no any ideal drug, since each individual combination of drugs or monotherapy have their own limitations, ranging from their triple (activity) in relation to certain forms of the development of Plasmodium in the human body, side effects, toxicity and resistance. During the course of the study carried out, the most promising compound-candidate was selected – imatinib, which is currently used as targeted therapy for a number of oncological diseases. The objective of this work is to evaluate the efficacy of the combined use of imatinib and artemether in vivo studies on the human malarial model – the rodent malaria parasites Plasmodium berghei. Dut to the optimally selected treatment scheme, it was possible to reduce the dosage of imatinib twice – to 0,25 mg/kg, and that of artemether three times – to 33 mg/kg. The use of this scheme made it possible to considerably reduce the toxic effect of these drugs due to the potentiation of antimalarial effect. Key words: malaria, drug resistance, telomerase inhibitors, imatinib, chemotherapy of malaria

Therapeutic potential of bone marrow-derived mesenchymal stem cells and imatinib in a rat model of liver fibrosis

Considering the global increase in the prevalence of hepatic fibrosis and ineffective disease treatment, novel therapies are urgently needed. The current study is focused on comparing the therapeutic effects of mesenchymal stem cells (MSC)/imatinib combination therapy to single (MSCs or imatinib) therapy, in a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis. Using rats, hepatic fibrosis was induced by injection of CCL4. Rats were divided into 5 groups: CCL4-induced hepatic fibrosis, phosphate buffered saline (PBS) treatment (vehicle control), Bone marrow-MSCs (BM_MSCs), imatinib, and bone marrow-MSCs/imatinib co-treatment. The therapeutic impact of these approaches was determined using histopathology, sirius-red staining, serum markers, and qRT-PCR for over expression of matrix components. IHC and Western blot were conducted for further confirmation of the results. Single treatment with MSCs or imatinib and the combination therapy, all significantly reduced serum levels of ALT, AST, and ALP concomitant with down-regulation of α-SMA, pro-collagen I, pro-collagen III, collagen IV, and laminin. A significant reduction of ECM components deposits and a decrease in α-SMA expression were detected in all treatment groups. Pathological observations demonstrated that 20% and 40% of the rats in the MSC and MSC/imatinib group were in grade F0 respectively, while 80% of the rats of the imatinib group were in grade 2. Even though all treatment strategies studied resulted in an equally potent reduction in the mRNA and protein expression levels of pro-fibrotic markers, in aspect of pathological observations, our results demonstrate the highest therapeutic potential of utilizing combination of BM-MSCs and imatinib.

The potentiation of menadione on imatinib by downregulation of ABCB1 expression.

Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukaemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

With the introduction of tyrosine kinase inhibitors (TKIs) in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the prognosis of patients has improved dramatically. Currently, the standard of care in the frontline setting for fit patients is TKI in combination with chemotherapy. Age-adjusted chemotherapy or corticosteroids alone have been used with TKIs in elderly patients with comorbidities with modest long-term benefit. The primary goal of treatment is the achievement of early deep molecular remission as the achievement of complete molecular remission (CMR) at 3months has been demonstrated to be predictive of higher long-term survival. The probability of attaining this goal by a more potent TKIs like dasatinib or ponatinib is higher, thus we recommend the use of second- or third-generation TKIs over imatinib. Clinicians should be aware of possible fatal cardiovascular events mainly related to ponatinib. Allogeneic hematopoietic stem cell transplantation (alloHSCT) should still be considered in first remission, especially for younger patients treated with imatinib combination therapy. A subset of patients achieving CMR at 3months may be able to continue consolidation and maintenance with chemotherapy and TKI without the need for alloHSCT. Because of higher risk of relapses in the central nervous system, intrathecal chemoprophylaxis is mandatory for all patients. New strategies incorporating novel agents, such as antibody-drug conjugates, bispecific monoclonal antibodies, potent TKIs, and CAR T cells are under investigation.

Optimization of Interferon–Alpha and Imatinib Combination Therapy for Chronic Myeloid Leukemia: A Modeling Approach

AbstractChronic myeloid leukemia (CML) in its chronic phase is treated with imatinib, with an attempt at discontinuation after at least three years of therapy in patients with deep molecular responses. Following the attempted discontinuation, approximately half of the patients regress and need to return to the imatinib treatment. Interferon‐alpha monotherapy results in a cure in only a small percentage of patients. The combination of both drugs is simulated to optimize the treatment with respect to duration and schedule. This is achieved through a mathematical model in which three cell types are described: leukemic stem cells, mature leukemic cells, and CML‐cytotoxic‐lymphocyte (CML‐CTL) cells. The model is simulated in silico, under different combination treatment regimens of imatinib and interferon‐alpha. It is observed that a low level of CML‐CTL cells causes failure of the combination treatment; an intermediate level of CML‐CTL produces mixed results for the success of the combination treatment; a high level of CML‐CTL cells promotes the success of the combination treatment. According to the model, treatment can lead to low‐level persistence of CML stem cells after treatment discontinuation, even in the absence of acquired drug resistance. The model defines conditions under which imatinib‐interferon‐alpha treatment leads to CML eradication.

The combination therapy of imatinib and dasatinib achieves longterm molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia.

For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

(720) - Combination Therapy Using Imatinib and Vatalanib Improves the Long-Term Outcome After Rat Lung Transplantation

Purpose: Chronic allograft rejection (CR) is the main risk factor after lung transplantation (LTx). According to the pathogenesis of idiopathic pulmonary fibrosis it was speculated that epithelial/endothelial -mesenchymal transition might be responsible for the development of bronchiolitis obliterans (BO) and vasculopathy. Imatinib and Valalanib, two different inhibitors of receptor tyrosin kinases, prevented the development of inflammation-driven experimental fibrosis. The aim was to confirm the efficacy of the combination therapy of imatinib and vatalanib in a rat LTx model to attenuate the development of CR. Methods: To evaluate the antifibrotic effects of imatinib (20 mg/kg/day i.g.) and vatalanib (20 mg/kg/day i.g) after LTx, a rat model of left lung allotransplantation (F344-to-WKY) was used. Allogenic transplanted rats were treated with imatinib/vatalanib from day 0 to 20/60 (n= 12). Non-treated animals were used as a reference (n= 16). Results: In the none-treated reference group, severe acute rejection (ISHLT-A4) and lymphocytic bronchiolitis (ISHLT-B2R) was seen on day 20 after LTx and resulted in chronic rejection (ISHLT-C2R/D2R) on day 60. In 40% of the allografts, dual application of imatinib and vatalanib reduced severe acute rejection (ISHLT-A3/B1R). In the long-term follow up, two allografts developed severe chronic rejection (ISHLT-C2R/D2R). The remaining four allografts showed no evidence of BO, vasculopathy or interstitial fibrosis (ISHLT-C0/D0). Two of these allografts demonstrated slight signs of peribronchiolar/perivascular fibrosis of the medium-sized bronchioles and vessels. Conclusion: In Conclusion, we speculate that a dual inhibition of the platedderived growth factor by imatinib and the vascular endothelial growth factor by vatalanib might be effective to slow down CR after LTx. Thus, the combination of different RTK-Inhibitors might be an interesting tool for patients after LTx to reduce CR.

The interferon-alpha revival in CML.

Interferon-alpha (IFNα) was once the standard of frontline treatment for chronic myeloid leukemia (CML). Its pleiotropic mechanism of action in CML includes immune activation and specific targeting of CML stem cells. Early studies of IFNα in CML demonstrated that patients in chronic phase could attain extremely stable remissions, which correlated with long-term survival. Some patients even sustained their remission after discontinuing therapy, but the mechanism underlying this phenomenon is not well understood. Today, BCR-ABL tyrosine kinase inhibitors (TKIs), such as imatinib, induce remarkable responses in CML patients and have become the mainstay of CML therapy. Although TKIs target the pathogenic BCR-ABL protein in CML, they cannot fully eradicate CML stem cells. Some of the clinical trials testing IFNα plus imatinib combination therapy suggest that addition of IFNα increases the speed and rate of responses with imatinib therapy. However, the undesirable side effects of IFNα can make this therapy difficult to deliver, and the optimal therapeutic window for using IFNα in combination therapy is unknown. Further studies are needed to clarify the best niche for IFNα use in CML.

The combination therapy of imatinib and dasatinib achieves long-term molecular response in two imatinib-resistant and dasatinibintolerant patients with advanced chronic myeloid leukemia

For patients with chronic myeloid leukemia (CML) failing imatinib therapy, second-generation tyrosine kinase inhibitors (TKIs) are recommended. Here, we describe two patients with advanced CML who failed imatinib therapy and did not tolerate the recommended dose of dasatinib, but then achieved a major molecular response with the combination of imatinib and dasatinib with no significant extramedullary toxicity. Our observations suggest that combination of TKIs may provide an additive/synergistic antileukemic effect.

Successful Antemortem Diagnosis and Treatment of Pulmonary Tumor Thrombotic Microangiopathy

Pulmonary tumor thrombotic microangiopathy (PTTM) is a fatal cancer-related complication with rapid progression. Although the underlying molecular mechanisms of PTTM remain unclear, platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) may play important roles in the pathogenesis of PTTM. We herein report a case of PTTM that was diagnosed antemortem by pathology using pulmonary wedge aspiration. The patient was treated with a combination therapy of imatinib (PDGF receptor antagonist), bevacizumab (VEGF receptor inhibitor), S-1, and cisplatin. These findings suggest that molecular-target drugs are effective for the treatment of PTTM.

Optimizing the selection of kinase inhibitors for chronic myeloid leukemia patients

Long-term follow-up of clinical studies has demonstrated the efficacy of imatinib therapy in newly diagnosed chronic phase-chronic myeloid leukemia patients (CML). However, recent updates of two separate randomized Phase III studies demonstrated higher complete cytogenetic and major molecular response rates with dasatinib and nilotinib compared with imatinib 400 mg/day. Hence, for newly diagnosed chronic phase-CML patients there are multiple treatment options, including standard-dose imatinib, high-dose imatinib, and combination therapy of imatinib and interferon, dasatinib and nilotinib. This article critically analyzes the current literature and provides guidelines for the management of newly diagnosed CML. Disease and therapy-related prognostic factors, which may aid in the selection of therapeutic strategies to enable optimal treatment outcomes, are discussed. In addition, we provide commentary on the therapeutic options for patients who fail imatinib therapy.

A case of myeloid neoplasm associated with eosinophilia and KIAA1509-PDGFRβ responsive to combination treatment with imatinib mesylate and prednisolone

A 41-year-old woman presented with dyspnoea, persistent leucocytosis and eosinophilia for 8 months. High-resolution computed tomography scan and pathology of bronchoalveolar lavage confirmed the diagnosis of hypereosinophilic pneumonitis. The patient was treated with prednisolone (0·5-1 mg/kg/day) for more than 20 weeks under the impression of hypereosinophilic syndrome, but without improvement of leucocytosis and eosinophilia. The bone marrow aspiration smear disclosed hypercellular marrow with myeloid hyperplasia and eosinophilia. The fusion gene detection was positive for KIAA1509-PDGFRβ. Myeloid neoplasm associated with eosinophilia and abnormality of PDGFRβ was then diagnosed (Tefferi A, Vardiman JW, Leukemia, 22, 2008, 14). The tyrosine kinase inhibitor, imatinib mesylate (Glivec; 200 mg/day), was administered along with prednisolone (0·25-1 mg/kg/day). White blood cell (WBC) count decreased from 49,500/μL to 17,200/μL, and eosinophil count decreased from 1932/μL to 35/μL, which represent percentage dropped from 7·7%> to 0·2%. Withdrawal of prednisolone was done to avoid adverse events. However, absolute eosinophil count increased progressively despite the continue administration of imatinib and negative detection PDGFRβ fusion gene. The patient then received combination therapy of imatinib and prednisolone again. WBC and absolute eosinophil were normalized subsequently. We had discontinued the prednisolone one more time, and rebound of eosinophilia was seen again. The phenomenon of rebounding of eosinophilia was observed in two subsequent withdrawals of prednisolone. Either steroid or imatinib mesylate alone failed to achieve complete haematological response. A synergistic effect of imatinib and steroid is postulated.

Complete Hematologic Response and Cytogenetic Remission after Imatinib and Dexamethasone Treatment of a Ph+ Precursor B-cell Acute Lymphoblastic Leukemia in Renal Transplantation Patient

In this report, we present a case of a patient with Philadelphia chromosome-positive (Ph+) B-cell acute lymphoblastic leukemia after renal transplantation. The patient, a 65-year-old man, had received a kidney transplantation 20 years prior to diagnosis with Ph+ precursor B-cell ALL. Because he was refractory to intensive chemotherapy and had refused to receive additional intensive chemotherapy, he was treated with imatinib and dexamethasone. While this patient experienced a complete hematologic and cytogenetic response, he did not show a complete molecular remission. Eighty days after imatinib combination therapy, the patient relapsed and died from intracerebral hemorrhage.

MEK inhibitor enhances the inhibitory effect of imatinib on pancreatic cancer cell growth

Imatinib mesylate (imatinib) inhibits the c-Kit-dependent tyrosine kinase activities and highly effective in the treatment of CML and GIST patients. Although pancreatic cancer is reported to express c-Kit, imatinib does not effectively inhibit pancreatic cancer cell growth at physiological concentrations. Therefore, we investigated the mechanism of resistance of pancreatic cancer to imatinib treatment. Imatinib inhibited growth of pancreatic cancer cell lines in concentration and time-dependent fashion regardless of c-Kit expression. However, 5 μM imatinib, which is almost a mean maximal plasma concentration in clinical setting, failed to suppress pancreatic cancer cell growth. Western blot analysis demonstrated that 5 μM imatinib treatment for 1 h activated the MEK–MAPK pathway and the activation was independent of Ras activation. Administration of 5 μM imatinib and 1 μM U0126 (MEK inhibitor) significantly suppressed pancreatic cell growth. Our results indicate that a combination therapy of imatinib and MEK inhibitor can be a new therapeutic strategy to suppress the progression of pancreatic cancer.

Comparison of Combination Therapy of Imatinib with Trisenox Versus Imatinib Monotherapy for Chronic Myeloid Leukemia Patients in Chronic Phase.

Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients.Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),–defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),–defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively.Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.

Zoledronate Inhibits Leukemia Growth in Bone Marrow and Synergizes with Imatinib Mesylate Against Ph+ Primary Leukemic Cells.

Imatinib mesylate has drastically changed Philadelphia chromosome positive (Ph+) leukemia treatment. However, remissions induced in advanced phase Ph+ leukemias tend to be short-lived even treated with imatinib. Combined therapy of imatinib with an agent which inhibits downstream signaling of BCR/ABL such as Ras is intriguing. Phase I studies of farnesyl transferase inhibitors (FTIs), which targeted farnesylation of Ras, with imatinib against Ph+ leukemias demonstrated limited combination effects. We previously reported that the third-generation bisphosphonates (BPs) zoledronate (ZOL) synergized with imatinib mesylate to inhibit Ph+ leukemia. BPs which inhibit both farnesylation and geranylgeranylation of Ras proteins may be more potent than FTIs. However, three important questions have remained unanswered to promote this attractive combination to a clinical trial. Concentrations of 20-30 μM ZOL are required in vitro to induce apoptosis in leukemic cell lines. However, peak serum concentrations after infusion of 4 mg ZOL were 1–2 μM. Therefore, it is important to investigate how ZOL achieves effective concentrations in vivo. The second is whether ZOL augments the effects of imatinib against not only cell lines but also primary cells from Ph+ leukemia patients. In addition, the safety of this combination therapy must be established, because the dose of ZOL used in our previous study was high compared with clinical doses administered for inhibition of bone lesions. To answer these questions, we herein investigated about the combination therapy of ZOL plus imatinib using NOD/SCID mice engrafted with primary Ph+ leukemic cells with or without mutations in the ATP binding site. ZOL inhibited the geranylgeranylation of Ras proteins of leukemic cells in bone marrow but not in peripheral blood, indicating that sufficient concentration of ZOL could be achieved in bone marrow. ZOL synergized with imatinib to enhance survival of mice engrafted with primary Ph+ leukemic cells without mutations and this combination was well-tolerated without any severe adverse effects. These findings suggest that ZOL inhibits leukemia growth in bone marrow and the combination of ZOL plus imatinib is a potential therapy for Ph+ leukemia patients.