The SOLVO MDQ Kit™

 

SOLVO MDQ Kit™ is the first commercially available CE-IVD approved clinical diagnostic kit for the detection of MDR protein function (MDR1, MRP1, and BCRP) by quantitative flow cytometry.

Learn more about how your patients can benefit from MDR protein function determination.

 

Autoimmune Diseases

Learn more about the application of SOLVO MDQ KitTM in Rheumatoid Arthritis

Hematologic Malignancies

Learn more about the application of SOLVO MDQ KitTM in Hematologic Malignancies

MDQuest Ltd.

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For clinical hematologists

 

In acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL), MultiDrug Resistance (MDR) protein function measured in white blood cells correlates with disease prognosis (prognostic marker) and inefficiency of certain therapies (predictive marker). Moreover, MDR protein function is an independent biomarker in AML. Functional measurement of MDR1, BCRP, and MRP1 with the SOLVO MDQ KitTM allows patient risk stratification and can help choose a tailored treatment strategy contributing to better patient outcomes and quality of care.

 

Page content:

I. Need for biomarkers in disease management

II. MDR proteins as biomarkers

III. Clinical utility of the SOLVO MDQ KitTM

IV. Availability

 

I. Need for biomarkers in disease management

 

AML

40–50% of patients belong to the cytogenetically normal AML (CN-AML) (1). The prognosis and therapy prediction in this patient group improved significantly with the discovery of new molecular genetic mutations such as FLT3, NMP1, CEBPA. These frequent mutations made possible the risk stratification of patients as they have been identified as the most powerful prognostic markers for outcome (2,3). Mutations as predictive markers indicate a treatment benefit in patients with these markers and can be used to guide clinical decision-making (4).
Despite the numerous novel drugs, such as purine analogues and intensification of initial treatment to improve outcome, (5,6) the standard induction treatment (cytarabine and anthracycline, known as the '7+3' regimen) remains the first choice (7-9). At standard induction therapy the rate of complete remission (CR) is about 60–80% in younger patients, whereas the overall survival (OS) is only 40-45% at 5 years; in patients above 60 years CR is significantly lower (40–55%) associated with poor long-term survival rates (10).
With regard to the post remission therapy of AML, retrospective studies suggest that cytogenetic and molecular genetic abnormalities in younger patients allow the choice of a tailored approach between conventional chemotherapy, allogeneic hematopoietic stem cell transplantation, or investigational agents (7-9).

 

CLL

Similarly to AML, several new molecular prognostic markers (e.g. IgvH, CD38, zap70, chromosomal abnormality) have been discovered and numerous studies have shown their utility in risk stratification and treatment decisions.

An outstanding milestone was the report of the GCLLSG-CLL-8 phase III trial (by German CLL Study Group), in which chemoimmunotherapy (Fludarabine, Cyclophosphamide, Rituximab – FCR group) has been compared with chemotherapy (Fludarabine, Cyclophosphamide – FC group), the previous 'gold standard' of care, in order to evaluate the clinical efficacy of different regimens in previously untreated CLL patients (11). The progression-free duration and OS were longer in the FCR than in the FC group, suggesting that the FCR treatment as first-line regimen has advantage for patients who have no severe co-morbidity or contraindications to this therapy. However, in cases with "primary resistance" (~10%),significant co-morbidity, or 17p deletion chromosomal abnormality the response rate was very poor with conventional chemotherapy (12).

 

II. MDR proteins as biomarkers 

 

The phenomenon of multidrug resistance (MDR) has been confirmed in hematological malignancies, where the frequency of efflux transporter (e.g. P-glycoprotein, MRP1, BCRP) mediated drug resistance was about 40% (13).

Since the beginning of the 90’s, several in vitro studies have verified the role of MDR proteins in chemoresistance. These studies focused on drugs used in AML and CLL to investigate whether they are substrates of drug efflux pumps. It was assumed that impaired therapeutic efficacy can be associated with the efflux pump function. Latest scientific evidence suggests that the role of MDR proteins in tumour biology is not restricted to the efflux of cytotoxic drugs, but they might also play a role in some important signalling pathways (13).

 

In vitro data

A number of cytostatic drugs applied in AML or CLL, such as daunorubicin or cyclophosphamide appear to be substrates of these efflux transporters confirmed by in vitro assays (15).

Table I. Clinically relevant efflux transporters and drug interactions based on in vitro assays

Common name (ABC code)

Pharmacologic substrate

P-gp, MDR1 (ABCB1)

Daunorubicin, Doxorubicin, Etoposide, Vincristine, Vinblastine, Mitoxantrone, Cyclophosphamide

BCRP (ABCG2)

Daunorubicin, Doxorubicin, Mitoxantrone, Etoposide

MRP1 (ABCC1)

Daunorubicin, Etoposide, Vincristine, Vinblastine, Cyclophosphamide, Chlorambucil

 

Clinical data in AML

Over the past two decades, several trials have studied the role and possible predictive or prognostic value of MDR proteins associated with therapy resistance or poor outcome. The methods included the measurement of functional activity or expression of the MDR transporters at mRNA or protein level. Numerous evidence shows that beside the most studied MDR1 (16, 17) and BCRP proteins even MRP1 protein has some clinical relevance in AML (18-21).

In recent years, several trials reconfirmed the correlation between MDR transporters and clinical outcome (22-24). One study has evaluated the impact of MDR1 and BCRP expression on fludarabine included in the induction treatment (25): the results showed that fludarabine increased the remission rate in MDR1+ AML but could not prevent the relapse in BCRP+ cases. The same study group investigated the frequency and correlation between BCRP expression and FLT3-ITD mutation, as the latter is an established prognostic factor (26): this group concluded that BCRP+/ FLT3-ITD+ co-expression is common in AML and predicts a bad prognosis for patients.

Recent studies established the correlation between the high MDR1 expression and low CR rate (27) or between MDR1/BCRP overexpression and shorter OS (28-30).

Very recent data showed that the activity of MDR proteins is an independent prognostic factor in AML without cytogenetic abnormalities (CN-AML) (31).

 

Clinical data in CLL

The predictive relevance of MDR protein function in CLL is limited. Although the overexpression of MDR1 is found to be very common (48%-73%) in CLL patients, it is difficult to establish the causality between the actual MDR activity and patient response because the patients had taken several chemotherapeutic drugs. The nature of the relationship between disease staging and previous treatments is under investigation, especially when compared to AML (32-36).

 

III. Clinical utility of the SOLVO MDQ KitTM

 

There are three different approaches to detect MDR proteins, but functional tests are regarded to be more useful than gene- or protein expression measurements because pump activity reveals the property of the proteins (37). The SOLVO MDQ KitTMis designed to determine the functional activity of the three clinically most relevant drug efflux proteins (MDR1, MRP1, and BCRP) in white blood cells, in a fast, quantitative, and standardized way.

 

1. Forecasting disease prognosis in CN-AML patients

Multiple clinical data suggest that the MDR protein function may be an independent prognostic marker in AML for the intermediate prognostic group, especially in cases without cytogenetic abnormalities, providing additional value to molecular genetic markers allowing better risk stratification of the CN-AML patients. Presence of elevated MDR activity related to any of the three drug efflux pumps MDR1, MRP1 or BCRP detected alone or simultaneously is seen as a negative prognostic marker.

 

2. Predicting the success of fludarabine-based induction therapy in AML patients

MDR protein function (MDR1, BCRP) may be a predictive marker in cases where fludarabine-based induction therapy is applied.

 

3. Guiding therapy decisions in certain CLL patients

For those CLL patients, who do not fit the criteria to undergo the first line FCR therapeutic regimen, have relapsed, or have a refractory disease MDR activity may help with further therapeutic considerations especially in the absence of other bad prognostic factors.

 

Figures 1-5. MDR activities in Acute Myleoid Leukemia on CD45+ cells

 

AML graf 1 crop

 

AML Oldal 2

             AML Oldal 4

 

AML Oldal 3

              AML Oldal 5

IV. Availability

PRODUCT SIZE CAT. NO.
SOLVO MDQ Kit™ 10 assays MDQ0101D

 

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Disclaimer: Our value proposition is based on expert opinion and the best available evidence. However this publication is an informative document intended for informational purposes only and does not constitute medical practice nor medical advice.


 

 

1. Schlenk NEJM 2008

2. Vardiman Blood 2009

3. Döhner Hematology 2011

4. Schlenk Curr Opin Hematol 2009

5. Fernandez New Eng J Med 2009

6. Löwenberg New Eng J Med 2011

7. Döhner Blood 2010

8. Roboz Hematology 2011

9. Rosenblat Hematol Oncol Clin N Am 2011

10. Kumar Genes & Cancer 2011

11. Hallek Lancet 2010

12. Hillmen Hematology 2011

13. Leonard The Oncologist 2003

14. Fletcher Nat Rev Cancer 2010

15. Polli J Pharm Exp Ther 2001 

Özvegy Biochem Res Commun 2001, Matsson J, Pharmacol Exp Ther 2007 , Zheng LS PLoS, One. 2009 , Renes J Br J Pharmacol 1999Schrenk Toxicol Lett 2001, Wang Acta, Pharmacol Sin 2001, Zaman FEBS Lett 1996Paumi J Biol Chem 2001 

16. Legrand Blood 2001

17. van den Heuvel‐Eibrink Leukemia 2001
18. Sonneveld J Int Med 2000
19. van der Kolk Blood 2002
20. van der Pol Hematologica 2003
21. Benderra Clin Cancer Res 2005
22. Ho Exp Hematol 2008
23. van den Heuvel‐Eibrink Ann Hematol 2007
24. Malagola Br J Hematol 2007 
25. Damiani Leukemia Res 2010
26. Tiribelli M Cancer 2011 
27. Marie JP Clin Oncol 2010
28. Ahn Am J Hematol 2011
29. Grundy BMC Cancer 2011
30. Marzac Hematologica 2011
31. Hirsch Hematologica 2012
32. Friedenberg Leuk Lymph 1999
33. Grey Leuk Res 1999
34. Svoboda‐Beusan Haematologica 2000
35. Consoli BJH 2002
36. Matsunaga Int J CLin Oncol 2003
37. Kappelmayer J Curr Med Chem 2007