Benign Disorders. Loree Larratt, MD University of Alberta

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1 Benign Disorders Loree Larratt, MD University of Alberta

2 Disclosures Ad boards, honorarium: Alexion, Novartis, Lundbeck, Roche

3 Agenda Iron Overload CARE Iron Chelation Needs Assessment Program Update Myeloproliferative Neoplasms (MPN) Polycythemia Vera (PV) PNH

4 Iron Remains Important Education program Iron homeostasis Donnall Thomas Lecture Dr Ganz

5 Iron Chelation: Background/Impact When iron homeostasis is in balance, iron is absorbed from the diet (gut) at a rate equivalent to 1 2 mg/day. After absorption from the duodenum, iron enters the plasma where it is complexed with transferrin Transferrin-bound iron in the plasma is the main pool supplying iron to the erythron, which cycles mg of iron each day, as well as to hepatocytes and other parenchyma, which cycle around 10% of this amount. The erythron encompasses all circulating red blood cells, their precursors and the tissues that produce them When transferrin becomes completely saturated during conditions of iron overload, iron circulates in the bloodstream as extracellular non-transferrin-bound iron

6 M2.2 Imbalance of distribution and turnover of body iron with transfusion therapy Erythron Transfusions NTBI mg/day Parenchyma Transferrin Reticuloendothelial macrophages Hershko C et al. Ann NY Acad Sci 1998;850: Gut Iron balance is disturbed by blood transfusion because the body cannot remove the excess iron NTBI=non-transferrin-bound iron

7 M2.3 Iron overload leads to formation of NTBI Transferrin saturation due to frequent blood transfusions Subsequent formation of NTBI in plasma Uncontrolled iron loading of organs, such as: 100% Normal: No NTBI produced Iron overload Fe Fe Fe Fe Fe 30% Fe Fe Uncontrolled loading of of organs occurs can be when prevented reversed NTBI species with and reversed are chelation formed with chelation in therapy blood therapy NTBI=non-transferrin bound iron

8 Iron Chelation: ASH 2014 Abstract 52. Insights into Relationships Between Serum Ferritin and Liver Iron Concentration Trends during 12 Months of Iron Chelation Therapy with Deferasirox a Post-HocAnalysis from the Epic Study John B Porter, MD et al. Results: Of the 374 patients analyzed in the EPIC liver MRI substudy, 317 had TDT, of which 72.7% (n=226) had a serum ferritin response and 27.3% (n=85) had no response. After 1 year LIC decreased in approximately half of serum ferritin nonresponders (51.8%; n=44; Table) and in 79.6% of serum ferritin responders (n=180). Median (min, Q1, Q3, max) change in LIC (mg Fe/g dw) was 5.4 ( 38.5, 11.7, 0.9, 15.4) in serum ferritin responders and 0.2 ( 18.4, 2.6, 2.7, 19.6) in nonresponders. Median (range) transfusional iron intake (mg/kg/day) was similar in serum ferritin responders (0.30 [ ]) and nonresponders (0.37 [ ]). Median deferasirox dose (mg/kg/day) was higher in serum ferritin responders than nonresponders (28.1 [ ] vs 23.7 [ ]).

9 Iron Chelation: ASH 2014 Abstract Results con t: Evaluation of responses by baseline serum ferritin showed that a greater proportion of serum ferritin responders with baseline serum ferritin <4000 ng/ml also had decreased LIC (88.7% [n=102]; Table), compared with serum ferritin responders with baseline serum ferritin 4000 ng/ml (70.3% [n=78]). Serum ferritin baseline category had no effect on the proportion of patients who decreased LIC despite having no serum ferritin response (52.6% [n=30], <4000 ng/ml; 50.0% [n=14], 4000 ng/ml; Table). There was little change in median LIC in serum ferritin nonresponders after 1 year regardless of baseline serum ferritin value ( 0.3 [ ] for <4000 ng/ml and 0.2 [ ] for 4000 ng/ml). Assessment by change in serum ferritin and LIC quadrants indicated that patients without serum ferritin or LIC response had the lowest baseline median (range) serum ferritin and LIC (2155 [ ] ng/ml; 11.9 [ ] mg Fe/g dw; n=41), and received a lower median deferasirox dose (23.7 [ ] mg/kg/day). Overall, median LIC decrease (mg Fe/g dw) was smaller in patients with baseline serum ferritin <4000 ng/ml (n=172) than in those with serum ferritin 4000 ng/ml ( 2.8 [ ] vs 4.9 [ ]; n=139). Median iron intake was similar between groups.

10 Iron Chelation: ASH 2014 Abstract Conclusions: A decrease in LIC was seen in ~80% of serum ferritin responders after 1 year of deferasirox; a greater proportion of serum ferritin responders (88%) decreased LIC when baseline serum ferritin was <4000 ng/ml. Importantly, among patients with no serum ferritin response up to half may be responding with respect to iron balance, indicating that a lack of serum ferritin response should be interpreted with caution. However, since a decrease in serum ferritin predicts a decrease in LIC in 80% of patients, MRI measurement (where available) should be prioritized for patients with serum ferritin increase/no change. Serum ferritin response can help predict LIC response, but in some patients treated with deferasirox, serum ferritin may not accurately reflect removal of iron from the body.

11 Iron Chelation Therapy: CARE Needs Assessment

12 CARE Iron Chelation Needs Assessment The CARE Hematology Faculty, led by Drs. Richard Wells and Richard Ward, developed a Pan-Canadian needs assessment that focused on screening, diagnosis and treatment of chronic iron overload. The Faculty thought this was an important concept to consider as it is often unrecognised/underappreciated and there are serious risks associated with iron overload if left untreated. This needs assessment questionnaire was sent to 250 hematologists from all regions of Canada. Targeted mostly academic centres who may have more interest/experience treating iron overload 44 physicians responded to the questionnaire to date Of the 44 responders, 37 were from academic centres

13 Key Takeaways 93% of responders manage patients with iron overload. Iron chelation is a serious condition that can lead to liver damage, infections, diabetes, and cardiovascular issues. Due to its severity, it is important that patients, especially within these specific disease categories, are given treatment when they experience an iron overload. Consensus that iron overload is understood and there are risks associated with not treating patients with iron overload.

14 To what extent do you agree that (1-strongly disagree, 3-neutral, 5-strongly agree): Thalassemia major Iron chelation is important in terms of patient outcomes Enough patients receive iron chelation therapy n=33 0% 3% 0% 33% 64% 16% 6% 31% 34% 13% To what extent do you agree that (1-strongly disagree, 3-neutral, 5-strongly agree): Chronic Iron Overload (eg. MDS) Iron chelation is important in terms of patient outcomes Enough Patients receive iron chelation n=43 therapy % 11% 9% 56% 22% 12% 17% 40% 21% 10%

15 Results: With both thalassemia major and chronic iron overload, almost all patients agree patient outcomes are important. However, a large proportion of responders do not agree or are unsure whether enough patients receive therapy. Discussion: There seems to be disconnect between the need and supply of chelation therapy as patient outcomes are important to specialists however over half of responders do not agree that enough patients are receiving iron chelation therapy.

16 Are there risks associated with not treating patients with iron chelation therapy? Yes No n=36 94% 6%

17 Results: Almost all (94%) practitioners indicated there are risks with not treating patients with iron chelation therapy. Discussion: Physicians recognize the risk of not treating patients with iron chelation therapy. Highlighting the patient groups and risk factors to look for will be important so that patients are provided with optimal treatment to prevent further issues.

18 What barriers do you face in your practice for prescribing iron chelation therapy? (Please select all that apply) Reimbursement and insurance n=43, r=67 Lack of evidence base Too few therapy options Knowledge gap Too little time to supervise and monitor 40% 18% 18% 10% 10% 3% None

19 Results: 40% stated reimbursement & insurance are the key barriers to prescribing iron chelation therapy. This trend was consistent among all provinces. Quebec responders selected lack of evidence base as one of the top barrier they face in prescribing iron chelation therapy, while responders from Alberta believe there are too few options (only 3) for therapy available. Among those who treat less patients with thalassemia major, knowledge was not identified as a barrier, which is surprising. These results may suggest that physicians are knowledgeable about therapy, there is just a barrier in terms of funding for therapy. Responders who see <25 MDS patients each year indicated there are barriers with each of the listed factors. This suggests that all of these factors need to be addressed in order for chelation therapy to be adequately prescribed. Discussion: Reimbursement and access to oral therapies can be time consuming and difficult to navigate. There are forms available to make this process easier, however, knowledge on the best way to approach them may be limited.

20 Please rate how strongly you believe the evidence is for iron chelation therapy in the following condition: (1-low, 3-neutral, 5-high) Thalassemia Major Thalassemia Intermedia Transfused Sickle Cell Myelodyplastic Stem Cell Allogenic Stem Cell Hereditary Hemochromatosi N= 44 s % 0% 0% 5% 95% 0% 7% 26% 30% 37% 0% 0% 18% 30% 48% 5% 12% 21% 44% 19% 19% 24% 40% 14% 2% 34% 30% 18% 5% 14%

21 Results: The results are pretty consistent for each question and may reflect the lack of data rather than respondants certainty about the data. All responders agreed that it should be used for patients with thalassemia major, however support is slightly lower for thalassemia intermedia (68% agreed, 26% were neutral), transfused sickle cell disease (78% agreed, 18% were neutral), and myelodysplastic syndrome (63%, 21% were neutral). Responders were less sure of the evidence available for patients receiving allogeneic stem cell transplants (ASCT) (40% 'unsure'), and did not believe there was strong evidence for patients with hereditary hemochromatosis.

22 Discussion: Among responders, there seems to be strong support/understanding of the evidence towards using iron chelation therapy for thalassemia major. It is not surprising that there is less confidence in the other areas as there is less clinical data available. Patients with thalassemia must have many blood transfusions as a form of treatment, making iron overload and the need for chelation common. It is important to reinforce this practice for conditions where patients may receive some transfusions over a longer period of time. The challenge is knowing who should be receiving iron chelation therapy in disease categories where transfusion is not commonly used.

23 Which investigations do you routinely use to aid the decision? Transfusion History Serum Ferritin Liver MRI Cardiac MRI Other (Please Specify) 37% 39% 16% 8% 0% N= 43, R=106

24 Results: Transfusion History (37%) and Serum Ferritin (39%) are the most common methods used in making a decision about requiring iron chelation therapy. Liver MRI (16%) and Cardiac MRI (8%) are less likely to be used, which is expected as MRI is not a validated tool used in MDS iron management. A cross-analysis was performed based on those who treat a low vs. high amount of thalassemia patients. Data showed that experts (treating over 75 patients), rely on only transfusion history and serum ferritin levels to make decisions. This is consistent with physicians that treat less than 25 patients, as they also rely mostly on transfusion history and serum ferritin levels. There are more responders who treat more patients with MDS than with thalassemia. When the same cross-analysis was done, data showed that among responders who have more than 70 patients, the most important decision making test (by far) was serum ferritin. Those with less experience (less than 25 patients), tended to choose both serum ferritin and transfusion history equally.

25 Discussion: Serum ferritin level is an easy method to monitor for iron chelation as it readily available and inexpensive. Transfusion history is also an easy way to determine if a patient needs iron chelation therapy as blood transfusions contain approximately 250 mg of iron/unit, which can cause iron overload to develop quickly or over time. Having access to these tests are important for identifying/diagnosing these complications to ensure adequate therapy is being given to prevent further issues. It is not surprising that MRI was not rated highly in this question, as MRI is not a validated tool for MDS patients

26 What levels of iron overload do you aim to target with chelation? (Choose all that apply) Serum Ferritin <1000 Liver iron Concentratio n <7mg/gm dw Cardiac t2>20ms No Specific Values Serum Ferritin <500 Liver iron <3 mg/gm dw 37% 9% 12% 5% 30% 7% 0% N=44, r=57 Other

27 Results: A variation can be seen with response to this question; 37% of responders said that they aim to target serum ferritin levels less than 1000, and 30% responders saying that they would target levels less than 500. There was no trend among responses for physicians who treat a low vs. high amount of thalassemia major, or MDS patients. The general consensus is that serum ferritin, whether it be <500 or <1000, are the most common levels of iron overload that are aimed for. Discussion: Serum ferritin was identified as the main investigation used when deciding on whether to give iron chelation therapy. However, when asked which levels were used when determining this, the majority of responders were split between <1000 and <500. Many institution protocols to initiate iron chelation therapy aim to initiate therapy when serum ferritin hit high levels (ie. ~1500). The trigger for initiating ICT is not equal to the target SF in MDS we typically initiate ICT when SF>1000 and aim to reduce to and maintain at that level.

28 CARE Iron Chelation Needs Assessment: Next Steps All questions and responder feedback will be compiled in a CARE Hema-TIMES publication Also included will be additional thoughts/perspectives from the CARE Faculty members This publication will be sent out as a supplement to the CARE at ASH 2014 Conference Report For more information on CARE Hematology initiatives, or if you would like to fill out a questionnaire please visit the CARE website at

29 MPN: Background/Impact MPNs have long thought to be the different forms of the same disease. The discovery of the JAK2V617F mutation demonstrated that it is the principal common clonal event in MPN However, this does not explain all cases of MPN Results from ASH 2013 (Abstracts LBA-1, and -2) highlighted the need for molecular biology laboratories to add exon 9 deletions in calreticulin in cases of presumed MPN without JAK2V617F mutation. Differences in disease characteristics between patients with different clonal events suggests that disease severity might by impacted and that the diagnostic clonal event could actually have a predictive value

30 Pre read Blood dec education program Therapy for myeloproliferative neoplasms: when, which agent and who Geyer and mesa

31 MPN: ASH 2014 Abstract 160. Type II Inhibition of JAK2 with NVP-CHZ868 Reverses Type I JAK Inhibitor Persistence and Demonstrates Increased Efficacy in MPN Models Sara C Meyer, MD, PhD et al. Results: MPN cells can acquire persistence to ruxolitinib and other type I JAK inhibitors which bind the active conformation of JAK2, and that JAK2 inhibitor persistence is associated with reactivation of JAK-STAT signaling and with heterodimerization between activated JAK2 and JAK1/TYK2, consistent with activation of JAK2 in trans by other JAK kinases. It was found that MPN cells which were persistent to one JAK inhibitor were insensitive to the other JAK inhibitors, suggesting that the mechanisms which limit overall efficacy of ruxolitinib will limit the efficacy of other JAK inhibitors in clinical development. We hypothesized that novel, type II JAK inhibitors that interact with and inhibit JAK2 in the inactive conformation might retain activity in JAK inhibitor persistent cells and show increased efficacy in murine MPN models.

32 Results cont. MPN: ASH 2014 Abstract Type II inhibition with CHZ868 completely suppressed JAK-STAT signaling in type I JAK inhibitor-persistent cells, and prevented heterodimeric activation of JAK2 by JAK1 and TYK2. Most importantly, JAK2/MPL-mutant cells which were insensitive to type I JAK inhibitors remained highly sensitive to CHZ868, demonstrating that type I JAK inhibitor persistence does not confer resistance to type II inhibitors. CHZ868 resulted in significant reductions of mutant allele burden (mean allele burden reduction 49%) in the Jak2V617F model. Conclusions: Taken together, our data demonstrate that a spectrum of type I JAK inhibitors induce JAK inhibitor persistence, by a similar mechanism of JAK2 transactivation as observed with ruxolitinib. By contrast, type II JAK inhibition with CHZ868 remains highly active in JAK inhibitor persistent cells, and shows increased activity in murine MPN models. These data demonstrate that novel JAK inhibitors can increase target inhibition and therapeutic efficacy and should be pursued as an approach to improve outcomes for MPN patients.

33 Polycythemia vera (PV) Polycythemia vera (PV) is a myeloproliferative neoplasm driven by JAK/STAT activation and is associated with erythrocytosis and a broad symptom burden that may negatively impact patient quality of life (QoL). Hydroxyurea (HU) is often used as first-line therapy for high-risk patients but may not effectively control or reduce symptom burden.

34 PV: ASH 2014 Abstract 709. Changes in Quality of Life and Disease-Related Symptoms in Patients with Polycythemia Vera Receiving Ruxolitinib (RUX) or Best Available Therapy (BAT): RESPONSE Trial Results Ruben Mesa, MD et al. Results: At Week 32, a higher proportion of patients in the RUX vs the BAT arms had a 50% improvement in MPN-SAF TSS (49% vs 5%, respectively) and MPN-SAF symptom cluster scores (cytokine, 64% vs 11%; hyperviscosity, 37% vs 13%; splenomegaly, 62% vs 17%). Median percentage changes in individual symptom scores are from baseline at Week 32 on the 5 items of the PSIS indicated that the severity of pruritus and its interference on daily life improved with RUX (range, 1.5 to 2.2) and was unchanged/worsened with BAT (range, 0.1 to 0.3).

35 PV: ASH 2014 Abstract Results cont: Treatment with RUX vs BAT was associated with improved mean changes from baseline at Week 32 on EORTC QLQ-C30 symptom subscales, functional subscales, and Global Health Status/QOL; 46% of RUX patients versus 10% of BAT patients achieved an MID in Global Health Status/QOL. At Week 32, RUX patients were more likely to rate their global impression of symptom changes as very much improved or much improved (67%) vs BAT patients (13%). Conclusions: In patients with PV who were resistant to or intolerant of HU, treatment with RUX was associated with greater and clinically meaningful improvements in PV-related symptom burden and QoL measures compared with BAT.

36 PNH Number of interesting posters Canadian Initiative with PNH Network with centers of excellence across Canada

37 1532 Detection of PNH in patients in patients with Idiopathic VTE Lazo=Lagner et al London ont Prevalance of PNH.002% but vte in PNH 25-33% Thrombosis clinic 394 pt 388 samples for flow 2 pt found no cytopenias no hemolysis

38 4280 Clinical & Immunological Characterization of Coversin a novel small protein inhibitor of C5 Volution pharmacyticals Alt to eculuzimab Overcomes resistance sc

39 4817 Novel Small Molecule Inhibitor Targeting Complement Factor D for PNH Morgan et al Extravascular hemolysis an issue for a small percentage of pnh pt on eculuzimab This is an oral agent which block rate limiting enzyme of alternative pathway

40 4398 Long term outcomes of allo sct in pt with PNH and AA Korean registry 27 pt 20 aa/pnh 7 classic PNH Clone median 46% wbc 15.6%rbc Results comparable to SAA 5 y OS 90% cmp to aa alone Pnh cone disappears by 1.8 mo

41 Thank you! Enjoy San Francisco and ASH 2014