Scientists prove low cost arthritis drug can effectively treat blood cancer sufferers
Posted: Wed Sep 18, 2019 10:19 am
Sept. 16, 2019
by University of Sheffield
A simple arthritis drug could be an effective, low cost solution to treat patients with blood cancers such as polycythemia vera (PV) and essential thrombocythemia (ET), a breakthrough study by the University of Sheffield has shown.
This article has some rather fascinating implications, in my view...
I can still recall how I made my specialist Test me to see if what I was suffering from was actually Rheumatoid Arthritis (RA). However, those tests proved negative...
Just recently, I was also discussing this with another ET/MPN friend whose doctor had sent her for Arthritis tests too... Awaiting results when we last spoke about it.
This question about this RA drug, largely refers to treating of the inflammation being caused by a variety of chronic conditions, and it might just provide some of us MPN people with another alternative pharmaceutical treatment regime... (?)
Below, I have pasted the entire PDF from this study, and there are No Conflicts of Interest noted:
Low-dose methotrexate: potential clinical impact on haemato-logical and constitutional symptoms in myeloproliferativeneoplasms
(Thomaset al, 2015; Chinnaiyaet al,2017).
We recently identified low-dose methotrexate (MTX) as aJAK/STAT pathway inhibitor and have demonstrated its activity in humanised animal models of myeloproliferative neoplasms (MPNs)
Here, we describe a retrospective service evaluation of11 MPN patients treated with low-dose MTX for unrelated co-morbidities. Three showed haematological changes follow-ing initiation/interruption of MTX while standardised symptom assessments suggested that MTX-treated MPN patients suffer significantly decreased constitutional symptoms. Given the inflammatory nature of MPN symptoms we suggest that low-dose MTX may represent a low cost, safe and effective treatment for the wider MPN population and propose further studies to test this hypothesis.
Mutations that constitutively activate JAK/STAT signalling represent key drivers of MPNs and, consequently, pathway inhibitors, such as ruxolitinib, have been developed and licenced (Quintas-Cardama & Verstovsek, 2013). Previously identified as a JAK/STAT pathway inhibitor with efficacy in mouse MPN models (Thomaset al, 2015; Chinnaiyaet al,2017), the low cost, generic drug MTX is generally well tolerated with a favourable risk profile (Shindeet al, 2014).Patients’ perception of MPNs are largely shaped by constitutional symptoms. In order to capture their impact, standardised assessments ask patients to rate their fatigue, early satiety, abdominal discomfort, inactivity, problems with concentration, night sweats, pruritus, bone pain, fever and unintentional weight loss on a scale of 0 to 10, to give a total symptom score (TSS) between 0 and 100 (Emanuelet al,2012). Some of these symptoms are probably a consequence of increased pro-inflammatory cytokine levels resulting in long-term systemic inflammation (Barosiet al, 2017).
Given that many pro-inflammatory cytokines are themselves dependent on JAK/STAT signalling, inhibitors, such as ruxolitinib,offer both haematological and symptomatic control (Mesa et al, 2016).We set out to identify and evaluate serendipitous cases where MPN patients were co-incidentally treated with MTX for unrelated co-morbidities (termed MTX-MPN patients). Although interpretation is complicated by changes in conventional therapy, three cases in which MTX initiation/cessation demonstrated a potential haematological response in MPN patients were identified (detailed information on individual cases is provided in the Data S1).
Taken together, our data supports the potential effective-ness of low-dose MTX in MPNs. Although not conclusive,haematological data suggests MTX may complement/enhance the effectiveness of existing cytoreductive therapy while MTX alone may potentially contribute to a small reduction in platelet counts. In addition, low-dose MTX also appears to reduce the frequency and severity of constitutional symptoms. Despite the potential confounding influence of RA-associated inflammatory effects, patients reported statistically significantly lower TSS’s and decreases in the incidence and severity of individual symptoms (Fig 2; Table SI). We suggest that low-dose MTX may suppress the activity of pro-inflam-matory cytokines in MPN patients. Consistent with this hypothesis, symptoms associated with chronic inflammation appear to be most strongly reduced in MTX-MPN patients (Table SI). While absolute number of patients in this study were small, we did not identify any toxicities regarding MTX inan MPN context. Adverse events included transient renal impairment in Case 1 and intolerance in Case 3, however, no further adverse events have been identified in MTX-MPN patients taking HC over a collective 139 years of treatment. Overall, our results are consistent with, and expand on, a previous report describing two successfully treated MTX-MPN patients (Palandriet al, 2016). Current licencing for JAK inhibitors, such as ruxolitinib,excludes a large proportion of the MPN patient population. Furthermore, even where indicated, access is frequently...
Fig 1.Graphs illustrating three individual case reports showing the changes in haematocrit [Hct (%), red squares], white blood cell count [WBC(9109/l), green], haemoglobin [Hb (g/l), black] and platelet count [Plt (9109/l), purple] over time for the three case studies discussed. Periodsduring which patients were treated with low-dose methotrexate (MTX) are shown by the pink bars. [Colour figure can be viewed at wileyonlineli-brary.com]Correspondence2ª2019 British Society for Haematology and John Wiley & Sons Ltd
...restricted by financial and cost-effectiveness concerns (Wadeet al, 2013), significant side effects and progressive loss inefficacy (Passamonti & Maffioli, 2018). By contrast, long-term low-dose MTX in RA patients is well tolerated and associated with defined, and generally mild/moderate, adverse events (Shindeet al, 2014). Given this background, we suggest that haematologically controlled MPN patients suffering constitutional symptoms may benefit from low-doseMTX–although further prospective studies are required.
The severity and incidence of MPN-associated constitutional symptoms in MTX-treated MPN patients compared to historic control populations (Emanuel et al., 2012).
(A) Mean and standard deviation of the Total Symptom Score (TSS) are plotted for historic populations (grey)and methotrexate (MTX)-treated myeloproliferative neoplasm (MPN) patients (black).
(B) The incidence of the indicated symptoms (i.e. the per-centage of all patients reporting a score>0) in MTX-treated polycythaemia vera (MTX PV; dark green) and MTX-treated essential thrombocythaemia (MTX ET; dark red) relative to historic values (light green and light red respectively).
(C,D) Mean and standard deviation of individual symptom scores reported by MTX-treated MPN patients (black) and historic populations (grey) for both PV (C) and ET (D).
[Colourfigure can be viewed at wileyonlinelibrary.com]Correspondenceª2019 British Society for Haematology and John Wiley & Sons Ltd3
Acknowledgements
The authors would like to thank Sheffield Hospitals Charity for partial support. SF and NS undertook the research study and collected data. MZ and RL undertook data analysis. ST,NS, AM, JAS, MPZ provided clinical and intellectual insights and prepared the manuscript.
REFERENCE
Sebastian Francis Sally Thomas Robert Luben Nikolaos Sousos Adam Mead John A. Snowden Martin P. Zeidler. 2019. "Low‐dose methotrexate: potential clinical impact on haematological and constitutional symptoms in myeloproliferative neoplasms"
First published: 16 September 2019
https://doi.org/10.1111/bjh.16193
PDF Link:
https://onlinelibrary.wiley.com/doi/epd ... /bjh.16193
by University of Sheffield
A simple arthritis drug could be an effective, low cost solution to treat patients with blood cancers such as polycythemia vera (PV) and essential thrombocythemia (ET), a breakthrough study by the University of Sheffield has shown.
This article has some rather fascinating implications, in my view...
I can still recall how I made my specialist Test me to see if what I was suffering from was actually Rheumatoid Arthritis (RA). However, those tests proved negative...
Just recently, I was also discussing this with another ET/MPN friend whose doctor had sent her for Arthritis tests too... Awaiting results when we last spoke about it.
This question about this RA drug, largely refers to treating of the inflammation being caused by a variety of chronic conditions, and it might just provide some of us MPN people with another alternative pharmaceutical treatment regime... (?)
Below, I have pasted the entire PDF from this study, and there are No Conflicts of Interest noted:
Low-dose methotrexate: potential clinical impact on haemato-logical and constitutional symptoms in myeloproliferativeneoplasms
(Thomaset al, 2015; Chinnaiyaet al,2017).
We recently identified low-dose methotrexate (MTX) as aJAK/STAT pathway inhibitor and have demonstrated its activity in humanised animal models of myeloproliferative neoplasms (MPNs)
Here, we describe a retrospective service evaluation of11 MPN patients treated with low-dose MTX for unrelated co-morbidities. Three showed haematological changes follow-ing initiation/interruption of MTX while standardised symptom assessments suggested that MTX-treated MPN patients suffer significantly decreased constitutional symptoms. Given the inflammatory nature of MPN symptoms we suggest that low-dose MTX may represent a low cost, safe and effective treatment for the wider MPN population and propose further studies to test this hypothesis.
Mutations that constitutively activate JAK/STAT signalling represent key drivers of MPNs and, consequently, pathway inhibitors, such as ruxolitinib, have been developed and licenced (Quintas-Cardama & Verstovsek, 2013). Previously identified as a JAK/STAT pathway inhibitor with efficacy in mouse MPN models (Thomaset al, 2015; Chinnaiyaet al,2017), the low cost, generic drug MTX is generally well tolerated with a favourable risk profile (Shindeet al, 2014).Patients’ perception of MPNs are largely shaped by constitutional symptoms. In order to capture their impact, standardised assessments ask patients to rate their fatigue, early satiety, abdominal discomfort, inactivity, problems with concentration, night sweats, pruritus, bone pain, fever and unintentional weight loss on a scale of 0 to 10, to give a total symptom score (TSS) between 0 and 100 (Emanuelet al,2012). Some of these symptoms are probably a consequence of increased pro-inflammatory cytokine levels resulting in long-term systemic inflammation (Barosiet al, 2017).
Given that many pro-inflammatory cytokines are themselves dependent on JAK/STAT signalling, inhibitors, such as ruxolitinib,offer both haematological and symptomatic control (Mesa et al, 2016).We set out to identify and evaluate serendipitous cases where MPN patients were co-incidentally treated with MTX for unrelated co-morbidities (termed MTX-MPN patients). Although interpretation is complicated by changes in conventional therapy, three cases in which MTX initiation/cessation demonstrated a potential haematological response in MPN patients were identified (detailed information on individual cases is provided in the Data S1).
Case 1, a 56-year-old male, was diagnosed with rheumatoid arthritis (RA) in 2013 andJAK2V617F-positive polycythaemia vera (PV) in April 2015 (Fig 1A). MTX was stopped due to renal impairment in June 2016 and soon afterwards, the patient complained of pruritus. Haematocrit rapidly increased to 51% and the patient required venesection despite continuing hydroxycarbamide (HC) treatment. Subsequently, MTX was restarted in August 2016 and constitutional symptoms resolved, while HC was increased in September 2016 and haematological values rapidly normalised.
Case 2 (Fig 1B) is a 62-year-old male diagnosed withJAK2V617F-positive essential thrombocythaemia (ET) in May 2013 with a platelet count of 916x109/l. Treatment withHC 1000 mg/day maintained stable values, although the platelet count remained>400x109/l. In April 2016, the patient was diagnosed with RA and started on MTX, increasing to20 mg/week by August 2016. The combination of MTX and unchanged HC markedly reduced the platelet count to<400x109/l without apparent toxicity.
We also examined the impact of low-dose MTX on constitutional symptoms reported by three PV and eight ET patients as assessed by MPN-10 scoring. Overall, we found that patients taking low-dose MTX reported statistically significantly lower and less variable MPN10 total symptom scores compared to historic controls (Emanuelet al, 2012)(Fig 2A). When considered individually, most symptoms were less prevalent in MTX-MPN patients (Fig 2B) with lower mean scores in 9 of 10 symptoms in PV and for all symptoms in ET (Fig 2C,D). In particular, values for night sweats and fever were reduced in both diseases, while significant reductions in abdominal discomfort, pruritus and bone pain are reported by ET patients (Table SI).correspondenceª 2019 British Society for Haematology and John Wiley & Sons Ltddoi: 10.1111/bjh.16193Case 3 is an 81-year-old female diagnosed withJAK2V617F-positive ET in October 2012 (Fig 1C). At the time of ET diagnosis long standing psoriasis had flared and low-doseMTX treatment was being initiated at 10 mg/week. After 9 months MTX was stopped. During MTX treatment the rising platelet trend reduced slightly, although absolute numbers remained>600x109/l. Subsequently, HC achieved rapid reduction in platelet numbers. In early 2013, a psoriasis flare prompted reintroduction of MTX and HC was stopped. During this period, the platelet count increased to 544x109/l. In late 2013, HC was reintroduced and achieved a stable response.
Taken together, our data supports the potential effective-ness of low-dose MTX in MPNs. Although not conclusive,haematological data suggests MTX may complement/enhance the effectiveness of existing cytoreductive therapy while MTX alone may potentially contribute to a small reduction in platelet counts. In addition, low-dose MTX also appears to reduce the frequency and severity of constitutional symptoms. Despite the potential confounding influence of RA-associated inflammatory effects, patients reported statistically significantly lower TSS’s and decreases in the incidence and severity of individual symptoms (Fig 2; Table SI). We suggest that low-dose MTX may suppress the activity of pro-inflam-matory cytokines in MPN patients. Consistent with this hypothesis, symptoms associated with chronic inflammation appear to be most strongly reduced in MTX-MPN patients (Table SI). While absolute number of patients in this study were small, we did not identify any toxicities regarding MTX inan MPN context. Adverse events included transient renal impairment in Case 1 and intolerance in Case 3, however, no further adverse events have been identified in MTX-MPN patients taking HC over a collective 139 years of treatment. Overall, our results are consistent with, and expand on, a previous report describing two successfully treated MTX-MPN patients (Palandriet al, 2016). Current licencing for JAK inhibitors, such as ruxolitinib,excludes a large proportion of the MPN patient population. Furthermore, even where indicated, access is frequently...
Fig 1.Graphs illustrating three individual case reports showing the changes in haematocrit [Hct (%), red squares], white blood cell count [WBC(9109/l), green], haemoglobin [Hb (g/l), black] and platelet count [Plt (9109/l), purple] over time for the three case studies discussed. Periodsduring which patients were treated with low-dose methotrexate (MTX) are shown by the pink bars. [Colour figure can be viewed at wileyonlineli-brary.com]Correspondence2ª2019 British Society for Haematology and John Wiley & Sons Ltd
...restricted by financial and cost-effectiveness concerns (Wadeet al, 2013), significant side effects and progressive loss inefficacy (Passamonti & Maffioli, 2018). By contrast, long-term low-dose MTX in RA patients is well tolerated and associated with defined, and generally mild/moderate, adverse events (Shindeet al, 2014). Given this background, we suggest that haematologically controlled MPN patients suffering constitutional symptoms may benefit from low-doseMTX–although further prospective studies are required.
The severity and incidence of MPN-associated constitutional symptoms in MTX-treated MPN patients compared to historic control populations (Emanuel et al., 2012).
(A) Mean and standard deviation of the Total Symptom Score (TSS) are plotted for historic populations (grey)and methotrexate (MTX)-treated myeloproliferative neoplasm (MPN) patients (black).
(B) The incidence of the indicated symptoms (i.e. the per-centage of all patients reporting a score>0) in MTX-treated polycythaemia vera (MTX PV; dark green) and MTX-treated essential thrombocythaemia (MTX ET; dark red) relative to historic values (light green and light red respectively).
(C,D) Mean and standard deviation of individual symptom scores reported by MTX-treated MPN patients (black) and historic populations (grey) for both PV (C) and ET (D).
[Colourfigure can be viewed at wileyonlinelibrary.com]Correspondenceª2019 British Society for Haematology and John Wiley & Sons Ltd3
Acknowledgements
The authors would like to thank Sheffield Hospitals Charity for partial support. SF and NS undertook the research study and collected data. MZ and RL undertook data analysis. ST,NS, AM, JAS, MPZ provided clinical and intellectual insights and prepared the manuscript.
REFERENCE
Sebastian Francis Sally Thomas Robert Luben Nikolaos Sousos Adam Mead John A. Snowden Martin P. Zeidler. 2019. "Low‐dose methotrexate: potential clinical impact on haematological and constitutional symptoms in myeloproliferative neoplasms"
First published: 16 September 2019
https://doi.org/10.1111/bjh.16193
PDF Link:
https://onlinelibrary.wiley.com/doi/epd ... /bjh.16193