P0244OVERTURNING THE CONVENTIONAL PYRAMID OF AL AMYLOIDOSIS MANAGEMENT: DARATUMUMAB ADMINISTERED AS MONOTHERAPY IN SEVERE PATIENTS WITH BIOPSY PROVEN RENAL INVOLVEMENT

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Dario Roccatello ◽  
Roberta Fenoglio ◽  
Elena Rubini ◽  
Carla Naretto ◽  
Simone Baldovino ◽  
...  
Keyword(s):  
Cell Clone ◽  
Therapeutic Option ◽  
Renal Involvement ◽  
Single Agent ◽  
Treatment Protocol ◽  
Infusion Reaction ◽  
Current Treatment ◽  
Al Amyloidosis ◽  
Human Antibody ◽  
Antibody Testing

Abstract Background and Aims Immunoglobulin light chain amyloidosis (AL) with multi-organ involvement is characterized by poor outcome. Current treatment of AL targeting the underlying plasma cell clone has been adapted from the multiple myeloma (MM). Novel powerful drugs are expanding the therapeutic options. Daratumumab is a first-in-class anti-CD38 human antibody (IgG1κ) which proved to be effective in combination with bortezomib in MM refractory to conventional bortezomib-based regimens. Its effectiveness as a single agent and its safety in the treatment of AL amyloidosis is under study. Aim of the study: This study reports the experience with Daratumumab monotherapy in a series of severe patients with AL amyloidosis and multiorgan and biopsy-proven renal involvement. Method Five patients (2 males and 3 females), mean age 64 years (range 52-69) were treated with Daratumumab following antibody testing and extended RBC antigen phenotyping. Treatment protocol was as follows: 16 mg/kg Daratumumab i.v. administered weekly for 8 weeks, then 8 times every two weeks, and then monthly for 1 year. Premedication included oral paracetamol, and i.v. chlorphenamine and methylprednisolone. Results In patient #1, in dialysis, who was refractory to conventional therapies Daratumumab administration resulted in normalization of the FLC ratio with disappearance of serum M-component and Bence-Jones (BJ) proteinuria. In patient #2 who had a relapsing disease, Daratumumab treatment resulted in a rapid decrease of proteinuria (from 6.8 to 2.7gr/24 hours at the 16th dose) and N-terminal propeptide (NT-pro-BNP) levels (from 1844 pg/ml to 330 pg/ml) with disappearance of serum M-component and BJ proteinuria and normalization of the FLC ratio. Patient #3 was treated front-line. He had an impressive decrease of proteinuria from 9.3 to 2.2 gr/24 hrs and NT-proBNP levels (from 850 pg/ml to 225 pg/ml) with normalization of FLC ratio and disappearance of serum M-component. In patient #4, who was intolerant to conventional regimens, Daratumumab therapy resulted in decrease in proteinuria, disappearance of serum M-component and improvement in the FLC ratio, which were paralleled by a reduction of NT-proBNP levels. Patient #5 had a relapsing disease. Daratumumab achieved a decrease of proteinuria (from 2.5 to 1 gr/24 hrs9, a decrease of serum M-component with increase of FLC ratio (0.29, nv: 0.31 – 1.56). This was the only patient who experienced an infusion reaction during the first dose (grade 1). The 4 patients with still preserved renal function also showed renal response with sCr improvement or stabilization and a decrease in proteinuria levels These data were paralleled by the reduction of NT-proBNP values in the 3 patients with cardiac involvement. Conclusion Daratumumab monotherapy resulted in the disappearance of M-proteins in every patient with FLC ratio normalization in 4 out of 5 subjects and impressive decrease of proteinuria and pro-BNP values proving to be an effective therapeutic option for pretreated/naïve patients with severe AL with renal involvement.

scholarly journals Daratumumab Monotherapy in Severe Patients with AL Amyloidosis and Biopsy-Proven Renal Involvement: A Real Life Experience

2020 ◽  
Vol 9 (10) ◽  
pp. 3232 ◽  
Author(s):  
Dario Roccatello ◽  
Roberta Fenoglio ◽  
Carla Naretto ◽  
Simone Baldovino ◽  
Savino Sciascia ◽  
...  
Keyword(s):  
Life Experience ◽  
Cell Clone ◽  
Renal Involvement ◽  
Single Agent ◽  
Real Life ◽  
Clinical Results ◽  
Current Treatment ◽  
Clinical Activity ◽  
Al Amyloidosis ◽  
M Proteins

Objectives: This paper aims to describe the clinical experience with Daratumumab (DARA), a first-in-class anti-CD38 human monoclonal IgG1κ antibody monotherapy, in severe patients with AL and biopsy-proven renal involvement. Immunoglobulin light chain (AL) amyloidosis with multi-organ involvement is characterized by short survival. Novel powerful drugs are expanding the therapeutic options. Current treatment of AL amyloidosis, which has been adopted from multiple myeloma (MM), is based on chemotherapy targeting the underlying plasma cell clone. DARA is effective in treating MM. The clinical activity and toxicity profile of DARA as a single agent in the treatment of AL amyloidosis is currently under evaluation. Patients and Methods: DARA was administered in a series of patients with severe AL amyloidosis and biopsy-proven renal involvement. Five patients(mean age 64.2 years) were treated. One patient was refractory and one intolerant to conventional bortezomib-based therapy, two were treated with DARA for relapsing disease, and one was treated front-line. Results: Data showed that DARA monotherapy resulted in good clinical results, with the disappearance of M-proteins in four out of five patients and with serum free light chains (sFLC) ratio normalization in three out of four and a remarkable amelioration in the remaining patient. The four patients with still preserved renal function at baseline also showed serum creatinine stabilization or improvement and a decrease in proteinuria. These data were paralleled by the reduction of the N-terminal prohormone of brain natriuretic peptide (NT pro-BNP)values. Conclusions: Our data show that monotherapy with DARA had significant clinical efficacy in pretreated/naïve patients with severe AL amyloidosis and biopsy-proven renal involvement.

scholarly journals Clonal plasma cells in AL amyloidosis are dependent on pro survival BCL-2 family proteins and sensitive to BH3 mimetics

2019 ◽  
Author(s):  
Cameron Fraser ◽  
Adam Presser ◽  
Vaishali Sanchorawala ◽  
Shayna Sarosiek ◽  
Kristopher Sarosiek
Keyword(s):  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Plasma Cells ◽  
Alkylating Agents ◽  
Single Agent ◽  
Current Treatment ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Current Standard ◽  
Bh3 Mimetics

Immunoglobulin light chain (AL) amyloidosis is a protein misfolding disorder characterized by the production of amyloidogenic immunoglobulin light chains by clonal populations of plasma cells. These abnormal light chains misfold and accumulate as amyloid fibrils in healthy tissues causing devastating multi-organ dysfunction that is rapidly fatal. Current treatment regimens, which include proteasome inhibitors, alkylating agents, and immunomodulatory agents, were developed for the treatment of the more common plasma cell disease, multiple myeloma, and have limited efficacy in AL amyloidosis as demonstrated by the median survival of 2-3 years. The recent development of novel small-molecule inhibitors of the major pro-survival proteins from the apoptosis-regulating BCL-2 family has created an opportunity to therapeutically target abnormal cell populations, yet identifying the extent of these dependencies and how to target them clinically has thus far been challenging. Using bone marrow-derived plasma cells from 45 patients with AL amyloidosis, we find that clonal plasma cells are highly primed to undergo apoptosis and exhibit strong dependencies on pro-survival BCL-2 family proteins. Specifically, we find that clonal plasma cells in a majority of patients are highly dependent on the pro-survival protein MCL-1 and undergo apoptosis when treated with an MCL-1 inhibitor as a single agent. In addition, BCL-2 inhibition sensitizes clonal plasma cells to several current standard of care therapies. Our results suggest that BH3 mimetics, when deployed rationally, may be highly effective therapies for AL amyloidosis.

scholarly journals AL amyloidosis: advances in diagnostics and treatment

2018 ◽  
Vol 34 (9) ◽  
pp. 1460-1466 ◽  
Author(s):  
Romana Ryšavá
Keyword(s):  
Therapeutic Option ◽  
Systemic Disease ◽  
Treatment Options ◽  
Renal Involvement ◽  
Deposition Process ◽  
High Dose ◽  
Al Amyloidosis ◽  
Primary Amyloidosis ◽  
Formalin Fixed Paraffin Embedded ◽  
High Dose Melphalan

Abstract AL amyloidosis (light chain; previously also called primary amyloidosis) is a systemic disease characterized by an amyloid deposition process affecting many organs, and which still has unsatisfactory survival of patients. The monoclonal light chains kappa (κ) or lambda (λ) or their fragments form the fibrils that deposit and accumulate in different tissues. Renal involvement is very frequent in AL amyloidosis and can lead to the development of nephrotic syndrome followed by renal failure in some cases. AL amyloidosis ultimately leads to destruction of tissues and progressive disease. With recent advances in the treatment, the importance of an early diagnosis of amyloidosis and correct assessment of its type is high. Histologic confirmation is based on Congo red detection of amyloid deposits in tissues but AL amyloidosis must also be distinguished from other systemic forms of amyloidoses with renal involvement, such as AA amyloidosis, amyloidosis with heavy chain deposition, fibrinogen Aα or ALECT2 (leukocyte chemotactic factor 2) deposition. Immunofluorescence (IF) plays a key role here. IF on formalin-fixed paraffin-embedded tissue after protease digestion, immunohistochemistry or laser microdissection with mass spectrometry should complete the diagnosis in unclear cases. Standard treatment with melphalan and prednisolone or with cyclophosphamide and dexamethasone has been replaced with newer drugs used for the treatment of multiple myeloma—bortezomib, carfilzomib and ixazomib or thalidomide, lenalidomide and pomalidomide. High-dose melphalan supported by autologous stem cell transplantation remains the therapeutic option for patients with low-risk status. These new treatment options prolong survival from months to years and improve the prognosis in a majority of patients.

scholarly journals Light chain amyloidosis

2018 ◽  
Vol 10 (1) ◽  
pp. e2018022 ◽  
Author(s):  
Paolo Milani ◽  
Giampaolo Merlini ◽  
Giovanni Palladini
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Molecular Mechanisms ◽  
Cell Clone ◽  
Renal Involvement ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Cardiac Damage ◽  
Risk Patients

Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic lights chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. This needs be risk adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.

Venetoclax induces sustained complete responses in refractory/relapsed patients with cardiac AL amyloidosis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19538-e19538 ◽  
Author(s):  
Fabien Le Bras ◽  
Jehan Dupuis ◽  
François Lemonnier ◽  
Silvia Oghina ◽  
Diane Bodez ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Influenza Infection ◽  
Single Agent ◽  
Complete Response ◽  
Median Number ◽  
Al Amyloidosis ◽  
Duration Of Treatment ◽  
Systemic Involvement ◽  
Academic Center ◽  
Heavily Pretreated

e19538 Background: Venetoclax (VEN) is an orally bioavailable small molecule inhibitor of the anti-apoptotic protein BCL-2 and has been shown to have efficacy against myeloma (MM), particularly in patients that harbor t(11;14). Approximately, 50% of AL amyloidosis patients will exhibit t(11;14) making VEN an attractive therapeutic option. Methods: We here report the results of a retrospective analysis of a monocentric series of refractory/relapsed (R/R) patients (pts) heavily pretreated with cardiac AL amyloidosis treated in a french academic center. VEN was given daily alone or in association with dexamethasone (DEX), with or without bortezomib (BTZ). Treatment was planned to be administered until progression. Results: Between February 2017 and January 2019, 7 consecutive R/R pts have been treated. All had received previous BTZ and daratumumab (DARA) containing regimen. Baseline characteristics were: median age: 72.7 years (range 40-84), Mayo Clinic stage: stage I in 2 pts, stage II in 3 and stage IIIA in 2. All patients but one had in addition to cardiac deposit, systemic involvement including kidney, joint, neurologic, gastro-intestinal tract, lymph node and muscle. All but one pts were refractory to their last treatment consisting of DARA-DEX with or without IMID. The t(11;14) translocation was present in 5 pts, absent in 1 and undetermined in 1 pts. Two pts had concomitant MM at diagnosis. Median number of previous line treatments was 4 (3-5). Five patients received VEN- BTZ- DEX as described in MM (PMID: 28847998), 1 with DEX and 1 as monotherapy. Five pts received 400 mg/d, one 200 mg/d and one 100 mg/d. Median duration of treatment was 76 days (30-713). All patients but one are still on treatment. One patient treated with 400 mg/d had a dose reduction to 100 mg/d due to grade 2 diarrhea. Four patients received at least 2 cycles and were evaluable for response. One 84 y old patient in stable disease after 1 cycle died due to influenza infection. 2 patients received only one cycle of treatment. Hematological complete response occurred in 2/4 (50%) patients, after 63 and 27 days. Interestingly, responses were sustained as the 2 responders were still on therapy after 76 and 713 days. This later patient, refractory to 2 previous lines had a cardiac and neurologic response. The 2 responding patients had proven t(11:14). Conclusions: On this limited series of heavily pretreated patients with R/R AL cardiac amyloidosis VEN used as a single agent or in combination can induce prolonged response and seems a promising drug with an acceptable safety profile in patients with t(11;14).

scholarly journals Monoclonal gammapathy of renal significance (MGRS) at the current state: terminology, diagnosis and treatment

2020 ◽  
Vol 92 (6) ◽  
pp. 15-22
Author(s):  
Lidia V. Lysenko (Kozlovskaya) ◽  
Vilen V. Rameev ◽  
Tatyana V. Androsova
Keyword(s):  
Monoclonal Gammopathy ◽  
Multidisciplinary Approach ◽  
Cell Clone ◽  
Current Treatment ◽  
Al Amyloidosis ◽  
Monoclonal Immunoglobulin ◽  
Current State ◽  
Monoclonal Gammapathy ◽  
Amyloid Nephropathy

In this article we discussed the current state of monoclonal gammapathy of renal significance (Monoclonal Gammopathy of Renal Significance MGRS) and revealed problems of B-cell clone secreting nephrotoxic monoclonal immunoglobulin identification. We followed 276 patients with monoclonal gammapathy including patients with non-amyloid nephropathy. The majority of patients had systemic AL-amyloidosis. We established better survival of the treated patients with systemic AL-amyloidosis in comparison with retrospective untreated cohort. We considered current treatment of patients with non-amyloid nephropathy and focused on the crucial role of multidisciplinary approach in management of these patients.

Biweekly Bortezomib Is More Efficacious Than Weekly Bortezomib When Used As First Line In Patients With Systemic AL Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1981-1981
Author(s):  
Sajitha Sachchithanantham ◽  
Shameem Mahmood ◽  
Rabya Sayed ◽  
Ketna Patel ◽  
Marianna Fontana ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Data ◽  
Renal Involvement ◽  
Single Agent ◽  
Response Assessment ◽  
Al Amyloidosis ◽  
Significant Prognostic Factor ◽  
First Line ◽  
Haematological Response ◽  
Line Therapy

Abstract Bortezomib based chemotherapy (especially cyclophosphamide-bortezomib-dexamethasone – CVD) has been increasingly adopted as front line therapy for treatment of patients with systemic AL amyloidosis. The phase II prospective study of single agent Bortezomib in relapsed setting, suggested both once weekly or biweekly Bortezomib are equally effective. Based on a risk adapted model, in the UK, weekly Bortezomib (usually as part of CVD) is often used to reduce toxicity and improve tolerability. We report the outcomes of 115 patients diagnosed with systemic AL amyloidosis at the National Amyloidosis centre between 2010-2012 followed up prospectively as a part of the ALChemy observational study and received Bortezomib based first line therapy either on biweekly or weekly regimens. 75% of these patients had cardiac involvement and 73% renal involvement. Haematological response and survival were analysed in the context of Bortezomib regimen used. Further analysis was also performed in patients matched for cardiac staging. 79% patients received CVD regime and 82% had Dexamethasone with their Bortezomib. Response and survival data was available on all 115 patients; 3 patients lacking dosing details were excluded from the dosing analysis. 89% had measurable disease for response assessment analysis. 63% patients had once and 37% had twice weekly Bortezomib. 74% of patient received their Bortezomib intravenously and 26% subcutaneously. 17% of patients had only received a maximum of 1 cycle of which 58% (10% of total cohort) had died within 4 weeks of commencing chemotherapy. On an intention to treat analysis, haematological response was achieved in 59% of weekly and 72% receiving biweekly regimes - 45% achieved a VGPR or better (38% of weekly and 58% of biweekly patients, fisher’s exact p=0.061). 94% responses were achieved within the first three cycles (57% of the weekly and 64% of the biweekly) - 25% responders (14% of weekly and 19% of biweekly) had achieved their best response by end of cycle 1 and 67% ( 44% of weekly and 39% of biweekly) by cycle 2 and 94% (57% weekly and 64% biweekly) by cycle 3 (Figure1). Median OS for patients treated with Bortezomib was 73.5months. The 2 year survival rate for patients achieving a VRPR or better, PR or NR are 87%, 64% and 31% respectively. Median OS for the group treated on a weekly regimen was 27.2 months and those treated biweekly was not reached (p=0.020), (figure 2). The 2 and 4 year survival is 59%, 47% for weekly treated and 77% (both), for biweekly treated groups respectively. For patients who were matched for mayo cardiac stage (n=38 in each group), the median OS was not reached in either group. The overall survival was superior in the group receiving the biweekly regimen with survival at 2 and 4 years of 78% (both) compared to 72% and 55% in the weekly group. In the matched group, patients with Mayo stage 3 disease (n=15 in each group) had not reached their median OS when receiving biweekly regimen but those who received weekly regimen had a median OS of 27.2 months (p=0.574). On a multivariate analysis, NT-proBNP >8500ng/L remained the only statistically significant prognostic factor. In summary, patients treated with biweekly Bortezomib regimen appear to have a 20% higher rate of achieving a VGPR or better and have a superior overall survival compared to those treated on the less intensive weekly regimen. Better criteria for patient selection are needed to allow more patients to receive Bortezomib on the more potent biweekly regimen at least for the first three cycles to achieve a rapid deep clonal response. Disclosures: Wechalekar: Jansen Cilag: Honoraria.

The Use of Mesenchymal Stem Cells and their Derived Extracellular Vesicles in Cardiovascular Disease Treatment

2020 ◽  
Vol 15 (7) ◽  
pp. 623-638
Author(s):  
Saeideh Gholamzadeh Khoei ◽  
Fateme Karimi Dermani ◽  
Sara Malih ◽  
Nashmin Fayazi ◽  
Mohsen Sheykhhasan
Keyword(s):  
Cardiovascular Disease ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Adult Stem Cells ◽  
Heart Diseases ◽  
Therapeutic Option ◽  
Current Treatment ◽  
Treatment Modalities ◽  
Cellular Source

Background: Cardiovascular disease (CVD), including disorders of cardiac muscle and vascular, is the major cause of death globally. Many unsuccessful attempts have been made to intervene in the disease's pathogenesis and treatment. Stem cell-based therapies, as a regeneration strategy, cast a new hope for CVD treatment. One of the most well-known stem cells is mesenchymal stem cells (MSCs), classified as one of the adult stem cells and can be obtained from different tissues. These cells have superior properties, such as proliferation and highly specialized differentiation. On the other hand, they have the potential to modulate the immune system and anti-inflammatory activity. One of their most important features is the secreting the extracellular vesicles (EVs) like exosomes (EXOs) as an intercellular communication system mediating the different physiological and pathophysiological affairs. Methods: In this review study, the importance of MSC and its secretory exosomes for the treatment of heart disease has been together and specifically addressed and the use of these promising natural and accessible agents is predicted to replace the current treatment modalities even faster than we imagine. Results: MSC derived EXOs by providing a pro-regenerative condition allowing innate stem cells to repair damaged tissues successfully. As a result, MSCs are considered as the appropriate cellular source in regenerative medicine. In the plethora of experiments, MSCs and MSC-EXOs have been used for the treatment and regeneration of heart diseases and myocardial lesions. Conclusions: Administration of MSCs has been provided a replacement therapeutic option for heart regeneration, obtaining great attention among the basic researcher and the medical doctors.

scholarly journals Novel therapeutic interventions towards improved management of septic arthritis

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jian Wang ◽  
Liucai Wang
Keyword(s):  
Antibiotic Therapy ◽  
Septic Arthritis ◽  
Clinical Success ◽  
Treatment Protocol ◽  
Current Treatment ◽  
Therapeutic Interventions ◽  
Medical Emergency ◽  
Success Rates ◽  
Joint Infections ◽  
Novel Therapeutic

AbstractSeptic arthritis (SA) represents a medical emergency that needs immediate diagnosis and urgent treatment. Despite aggressive treatment and rapid diagnosis of the causative agent, the mortality and lifelong disability, associated with septic arthritis remain high as close to 11%. Moreover, with the rise in drug resistance, the rates of failure of conventional antibiotic therapy have also increased. Among the etiological agents frequently isolated from cases of septic arthritis, Staphylococcus aureus emerges as a dominating pathogen, and to worsen, the rise in methicillin-resistant S. aureus (MRSA) isolates in bone and joint infections is worrisome. MRSA associated cases of septic arthritis exhibit higher mortality, longer hospital stay, and higher treatment failure with poorer clinical outcomes as compared to cases caused by the sensitive strain i.e methicillin-sensitive S. aureus (MSSA).In addition to this, equal or even greater damage is imposed by the exacerbated immune response mounted by the patient’s body in a futile attempt to eradicate the bacteria. The antibiotic therapy may not be sufficient enough to control the progression of damage to the joint involved thus, adding to higher mortality and disability rates despite the prompt and timely start of treatment. This situation implies that efforts and focus towards studying/understanding new strategies for improved management of sepsis arthritis is prudent and worth exploring.The review article aims to give a complete insight into the new therapeutic approaches studied by workers lately in this field. To the best of our knowledge studies highlighting the novel therapeutic strategies against septic arthritis are limited in the literature, although articles on pathogenic mechanism and choice of antibiotics for therapy, current treatment algorithms followed have been discussed by workers in the past. The present study presents and discusses the new alternative approaches, their mechanism of action, proof of concept, and work done so far towards their clinical success. This will surely help to enlighten the researchers with comprehensive knowledge of the new interventions that can be used as an adjunct therapy along with conventional treatment protocol for improved success rates.

scholarly journals Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

Antioxidants ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 74 ◽  
Author(s):  
Marta Romo-González ◽  
Sara Moreno-Paz ◽  
Violeta García-Hernández ◽  
Fermín Sánchez-Guijo ◽  
Ángel Hernández-Hernández
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Therapeutic Option ◽  
Single Agent ◽  
Signaling Cascade ◽  
Xanthine Oxidoreductase

Chronic myeloid leukemia (CML) is characterized by the expression of the oncogenic kinase BCR-ABL. Although tyrosine kinase inhibitors (TKIs) against BCR-ABL represent the standard therapeutic option for CML, resistances to TKIs can be a serious problem. Thus, the search for novel therapeutic approaches is still needed. CML cells show an increased ROS production, which is required for maintaining the BCR-ABL signaling cascade active. In line with that, reducing ROS levels could be an interesting therapeutic strategy for the clinical management of resistant CML. To analyze the therapeutic potential of xanthine oxidoreductase (XOR) in CML, we tested the effect of XOR inhibitor allopurinol. Here, we show for the first time the therapeutic potential of allopurinol against BCR-ABL-positive CML cells. Allopurinol reduces the proliferation and clonogenic ability of the CML model cell lines K562 and KCL22. More importantly, the combination of allopurinol with imatinib or nilotinib reduced cell proliferation in a synergistic manner. Moreover, the co-treatment arms hampered cell clonogenic capacity and induced cell death more strongly than each single-agent arm. The reduction of intracellular ROS levels and the attenuation of the BCR-ABL signaling cascade may explain these effects. Finally, the self-renewal potential of primary bone marrow cells from CML patients was also severely reduced especially by the combination of allopurinol with TKIs. In summary, here we show that XOR inhibition is an interesting therapeutic option for CML, which can enhance the effectiveness of the TKIs currently used in clinics.

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