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Treatment of MDS in 2014 and Beyond Treatment goals in MDS
• Get rid of it May 17, 2014 • If you can’t do that, make life better and longer – Improve blood counts Gail J. Roboz, M.D. – Improve quality of life Director, Leukemia Program – Decrease time to progression/leukemia Associate Professor of Medicine
Hematopoietic Growth Factors: Hematopoietic Growth Factors: What are they? What are they? • Erythropoietin (EPO,Procrit®, Epogen®) – red • Synthetic versions of proteins normally • Granulocyte colony stimulating factor (GCSF, made in the body to stimulate growth of red Neupogen®) – white cells, white cells and platelets • Granulocyte-macrophage colony stimulating • Promote growth and differentiation factor (GM-CSF, Leukine®) – white • Thrombopoietin (TPO, romiplostim, Nplate®) – • Inhibitors of apoptosis (cell death) platelets • Darbepoietin (Aranesp®) • Peg-filgrastim (Neulasta®) • Note, these are not FDA-approved for MDS
Erythropoietin (epo) in MDS Erythropoietin (epo) in MDS
• Anemia is presents in >80% of MDS pts at dx • Often high endogenous epo levels • Transfusions help, but many issues • Many different doses and schedules • Recombinant EPO is FDA-approved for treating • Higher response rates with epo + G-CSF if anemia associated with kidney failure epo ≤500 mU/mL and transfusions <2 • Has been used since about 1990 in MDS U/month • Response rates in about 15-30% of patients • Poor probability of response if epo >500 • Many different studies including >1000 patients mU/mL and transfusions >2 U/month • Part of the NCCN MDS treatment guidelines
1. Casadevall N, et al. Blood. 2004;104:321-327. 2. Hellstrom-Lindberg E. Br J Haematol. 1995;89:67-71. 3. Hellstrom-Lindberg E, et al. Br J Haematol. 1997;99:344-351. 4. Ludwig H. Semin Oncol. 2002;29:45-54.
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Erythropoietin (epo) in MDS Problem
• Varying response criteria in clinical trials: usually • Studies of EPO in solid tumor patients showed complete response is increase in hgb to at least increased heart attacks, stroke, heart failure, blood 11.5 without transfusions, partial response clots, increased tumor growth, death, especially increase of hgb by at least 1.5 g/dl or reduction in when hgb >12 transfusion requirements • Responses usually in 12-16 weeks • Has resulted in concern for MDS patients, but NO DATA yet showing these effects in MDS patients • Generally well-tolerated • Side effects: hypertension, fever, headache, • Has had major effects on insurance coverage nausea, chest pain
EPO in MDS: Good or Bad? Stimulating White Blood Cells • Don’t treat the number, treat the patient • Will be difficult to do a study in MDS proving • Not for routine treatment EPO is safe, so concern will remain • Active infections, recurrent/resistant • Note: JCO study, Jadersten et al (vol 26, July infections, neutropenic fever 2008): Erythropoietin and granulocyte-colony stimulating factor treatment associated with • Can be combined with red cell growth improved survival in MDS factors to improve responses in some • Mostly low-risk patients patients • Erythroid response 39%, median duration 23 mos • Side effects: fever, bone pain, injection site • Improved survival in pts requiring fewer than 2 reactions units/month • Does stimulating white cells cause • No increased AML leukemia??
Romiplostim in MDS Summary Original Article Lenalidomide in the Myelodysplastic Syndrome • In patients receiving azacitidine, romiplostim vs with Chromosome 5q Deletion placebo: Alan List, M.D., Gordon Dewald, Ph.D., John Bennett, M.D., Aristotle Giagounidis, – increased PLT counts over time and increased M.D., Azra Raza, M.D., Eric Feldman, M.D., Bayard Powell, M.D., Peter Greenberg, M.D., Deborah Thomas, M.D., Richard Stone, M.D., Craig Reeder, M.D., Kenton PLT count nadir during treatment cycles Wride, M.S., John Patin, M.S., Michele Schmidt, R.N., Jerome Zeldis, M.D., Robert – reduced incidence of clinically significant Knight, M.D., for the Myelodysplastic Syndrome-003 Study Investigators thrombocytopenic events – reduced incidence of PLT transfusions – fewer Grade ≥ 3 bleeding events N Engl J Med • Romiplostim plus azacitidine well-tolerated Volume 355(14):1456-1465 October 5, 2006
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Kaplan-Meier Estimate of the Duration of Independence from Red-Cell Lenalidomide: Erythroid Response Data Transfusion
Data Parameter Del 5q (n=148)
Erythroid response Transfusion indep 99 (67%)* Minor (>50% ↓) 13 (9%) Median duration of transfusion independence † >104 wks
Median Hgb rise 5.4 g/dL (1.1–11.4) Median time to initial response 4.6 wk (1–49)
*P<0.001; †not reached at median follow-up of 104 wk 90% of responses occur within the first 3 months
List A et al. N Engl J Med 2006;355:1456-1465 List A et al. N Engl J Med 2006;355:1456-1465
Practical issues with lenalidomide Epigenetic Therapy
• CBC weekly for at least first 8 weeks, significant neutropenia and thrombocytopenia • Dose adjustments may be necessary for thrombocytopenia and neutropenia, but they may be indicative of response, especially in 5q- patients
Revlimid® (lenalidomide) prescribing information. Available at: www.celgene.com/PDF/RevlimidPI.pdf
CALGB 9221 Phase 3 Trial of Subcutaneous Randomized Study of Azacitidine in Azacitidine vs Supportive Care Patients With MDS: Results
Supportive Care
R ≥4 mo unless transformation to 1.0 AML, higher FAB type, (N=191) • CR = 7% A progressive BM failure, or death • PR = 16% N 0.8 Azacitidine RA D Supportive Care • Improved 37% RARS O A M S 0.6 RAEB Response*: Continue I S RAEB-T Z x 4 cycles E No response*: Off study 0.4 S CMML A T Azacitidine S (n=191) 0.2
I 75 mg/m2/day for 7 days every Survival Probability Probability Survival O 28 days N 0.0 0 6 12 18 24 30 36 42 48 54 *Not IWG response 4 week months 75 mg/m2/d SC x 7 days every month. Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440. Kornblith AB, et al. J Clin Oncol. 2002;20:2441-2452. Silverman et al. J Clin Oncol. 2002;20:2429
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Effect of Azacitidine on Azacitidine vs Supportive Care: Quality of Life and Transfusions Most Frequent Adverse Events (>30%) Improvement in: Adverse event Azacitidine (n=220), % Supportive care (n=92), % Nausea 70.5 17.4 – Fatigue Anemia 69.5 64.1 – Dyspnea Thrombocytopenia 65.5 45.7 – Physical functioning Vomiting 54.1 5.4 Pyrexia 51.8 30.4 – Positive affect Leukopenia 48.2 29.3 – Psychologic distress Diarrhea 36.4 14.1 45% became transfusion-independent Fatigue 35.9 25 Injection site erythema 35.0 0.0 9% had a 50% reduction in transfusions Constipation 33.6 6.5 Neutropenia 32.3 10.9
Silverman LR, et al. J Clin Oncol. 2002;20:2429- Ecchymosis 30.5 15.2 2440. Kornblith AB, et al. J Clin Oncol. 2002;20:2441- Silverman LR, et al. J Clin Oncol. 2002;20:2429-2440. 2452. Kaminskas E, et al. Clin Cancer Res. 2005;11:3604-3608.
Azacitidine vs. conventional care regimens
Azacitidine Treatment Prolongs Overall Survival in Higher-Risk MDS Patients Compared with Conventional Care Regimens: Results of the AZA-001 Phase III Study
P Fenaux, MD, GJ Mufti, MD, V Santini, MD, C Finelli, MD, A Giagounidis, MD, R Schoch, MD,A List, MD, S Gore, MD, J Seymour, MD, E Hellstrom-Lindberg, MD, J Bennett, MD, J Byrd, MD, J Backstrom, MD, L Zimmerman, BSN, D McKenzie, MS, CL Beach, PharmD and L Silverman, MD on behalf of the International Vidaza High-Risk MDS Survival Study Group
P et al. Lancet Oncology 2009;10(3):223-232.
Overall Survival: Azacitidine vs CCR Important features of this trial ITT Population Log-Rank p=0.0001 1.0 HR = 0.58 [95% CI: 0.43, 0.77] Deaths: AZA = 82, CCR = 113 • 79 sites in 15 countries 0.9 0.8 Difference: 9.4 months • Median age 69 years (38-88) 0.7 • 113 pts (32%) met WHO criteria for AML 0.6 50.8% 0.5 24.4 months • 18 pts with IPSS Int-1 0.4 15 months 26.2% • 8 patients sent for allo transplant (did not 0.3 AZA Proportion Surviving Proportion 0.2 CCR affect overall survival) 0.1 0.0 • Azacitidine given for median 9 cycles 0 5 10 15 20 25 30 35 40 Time (months) from Randomization
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Secondary endpoints also Further analysis of AZA-001 favored aza • OS better for AZA in all cytogenetic subgroups, esp - • AZA better survival and better tolerated than 7/del7q LDAC (Fenaux, Br J Hematol 2010) • Time to AML 17.8 mos AZA, 11.5 mos CCR, p<0.0001 • Older pts with 20-30% blasts improved OS with AZA (Fenaux, JCO 2010) • Improved RBC Transfusion Independence with AZA • Ongoing treatment with AZA beyond time of – 45% with AZA vs 11% with CCR, p<0.0001 first response improved quality of response • Infections Requiring IV Antimicrobials (Silverman, Cancer 2011) – Reduced by 33% with AZA vs CCR
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Decitabine in MDS Phase III Study of Decitabine in Myelodysplastic Syndrome • Nucleoside analogue (5-aza-2’- Open-label, 1:1 randomized, multi-center study in the US and Canada
deoxycytidine) R A Decitabine + Supportive • FDA approved on 5/2/06 for: N Care* D – Previously treated and untreated MDS Stratification (N = 89) Eligible O Patients • IPSS Classification – De novo and secondary MDS (N = 170) M • Prior Chemotherapy I • Study Center – All FAB subtypes Z E – IPSS Int-1, Int-2, and high-risk groups Supportive Care* D (N = 81)
*Antibiotics, Growth Factors and/or Transfusions Schedule: 15 mg/m2 IV 3 hour infusion q 8 hrs x 3 days 27 Kantarjian et al, Cancer. 2006 Apr 15;106(8):1794-803
Phase III Decitabine vs. ECOG PHASE III Decitabine vs. Best Supportive Care Supportive Care • Complete remission 9% • Cytogenetic remission 35% vs.10% • Hematologic improvement 13% vs. 7% • Overall improvement 30% vs. 7% • Trend toward longer time to AML/death
Lübbert M et al. JCO 2011;29:1987-1996
29 ©2011 by American Society of Clinical Oncology
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Optimizing treatment with Allogeneic Stem Cell Transplantation hypomethylating agents • Can we predict who will respond? • The only potentially curative treatment • How do we select which one for which • Almost always recommended for high-risk patient? MDS patients <60 years • Combinations? • Can definitely be done for patients >60 years • Can we predict resistance? • Recent data suggest survival benefit for • Can we predict who should get ongoing cycles patients 60-70 years, but still controversial and who should stop?
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Supportive Care Moderate transfusion requirement: 2 units / month 24 units / year • Anti-microbial agents ~ 100 units / 4 years • Blood transfusions High transfusion requirement: • ? Iron chelation 4 units / month 200–250 mg 48 units / year iron ~ 100 units / 2 years
100 units: ≥ 20 g iron
Normal body iron: 3-4 g
Courtesy of E. Rachmilewitz
Excess Iron is deposited in multiple organs, resulting in organ damage Ok, so how do we know if Iron overload Chelation aims: there’s too much iron? Capacity of serum transferrin to bind iron is exceeded
preventing LPI NTBI circulates in the plasma; formation Labile forms of NTBI (e.g. LPI) enter cells and raise the levels of & LCI accumulation labile cell iron (LCI)
Excess iron promotes the generation of free Insoluble iron complexes are deposited hydroxyl radicals, propagators of oxygen- in body tissues and end-organ toxicity related tissue damage occurs
Liver cirrhosis/ Endocrine Cardiac failure Diabetes mellitus Infertility disturbances → fibrosis/cancer growth failure
LPI = labile plasma iron.
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Assessing Iron Overload Complications of iron
• Serum ferritin concentration overload: keep in mind… – Used in clinical practice globally • Most of the data are from children with • Liver biopsy thalassemia: severe anemia, chronic – Gold standard for kids, not feasible in most transfusions starting at age 1 MDS • Iron-related heart disease most common • Magnetic resonance imaging (MRI) cause of death – Investigational, potential for broad access • Clear evidence that chelation with – T2* cardiac MRI deferoxamine improved survival and helped • Magnetic susceptometry (SQUID) liver and endocrine complications – Investigational, very limited access
Deferoxamine (Desferal®) The $6 billion question • Most clinical experience, dosing and administration well- known • Reduces morbidity and mortality for sure in kids with thal, • Does this mean iron overload is bad for less clear in adults everyone and chelation (treatment to Challenges of therapy get rid of iron) is good for everyone at – Subcutaneous or IV administration risk of iron overload? – Continuous 12-hour infusion 5 - 7 days/week rec’d – Infusion-site reactions and pain – Eye and ear side effects, need periodic exams – Infectious complications – High degree of noncompliance
• Survival correlated with compliance .
BUT… Critical questions… • Limited evidence showing that iron causes • Does iron overload shorten survival in clinically significant organ damage in MDS MDS? Maybe patients • Does iron overload hasten transformation to • Unclear how to measure iron overload leukemia? Maybe (ferritin, transferrin saturation, NTBI, liver • Does iron overload worsen hematopoiesis? biopsy, SQID, liver MRI, cardiac T2* MRI) Maybe • No prospective data demonstrating that • Does iron overload worsen outcomes of chelation improves survival stem cell transplantation by increasing • Unclear which chelator to use infections and/or VOD? Probably (deferoxamine, deferiprone, deferasirox) • Does chelation treatment get rid of excess and how to measure efficacy iron? Seems to
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So, now what do I do? Consider… Proposed treatment algorithm for patients with MDS • Transfusion-dependent patients with IPSS low or int-1 MDS (or WHO RA, RARS, 5q- syndrome) Low-risk High-risk (IPSS low, INT-1) (IPSS INT-2, high) • Life expectancy > 1 year (BM blasts < 10%) (BM blasts > 10%) • Serum ferritin > 1000 g/L or evidence of Any age Age < 60 Age ≥ 60 • Iron chelation • Intensive • MTI (5- iron-related organ damage; target serum • Growth factors chemotherapy AZA/decitabine) ferritin < 1000 (Epo + G-CSF) • MTI (5-AZA/decitabine) • Clinical trial • MTI (5-AZA/decitabine) • Clinical trial • Intensive • Higher risk MDS patients who are candidates • Lenalidomide (5q-) chemotherapy1 for stem cell transplant • Immunemodulation • Clinical trial 1Consider in younger • Deferoxamine or deferasirox with close patients with diploid cytogenetics clinical and lab monitoring 2 Consider earlier in ’ Failure/ younger patients • Don t just use deferoxamine at times of Progression transfusion Atallah. Cancer Inv. 2008;26:208-16 Allo SCT
Selected Trials at Conclusions Weill Cornell - NYP • Treatment options for MDS better than 10 • Vosaroxin for patients previously treated with years ago, but much work still needed aza or dac • Interesting new drugs, but no magic bullet yet • SGI-110 for patients previously treated with • Features of personalized medicine starting to aza or dac take shape • Rigosertib for patients previously treated with • Need to optimize stem cell transplantation aza or dac • CLINICAL TRIALS • Azacitidine + pracinostat/placebo for patients with untreated int-2 or high-risk MDS
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Reassurance with Personalization Personalized Medicine: What Does it Mean? • We will get to know everything about you • Your medical issues • Your family • Your pets • Your hobbies • YOU as a person
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But, can we cure with personalization? Messed up pathways (an organic chemistry nightmare) • Using advanced technologies to identify specific characteristics of an individual’s Glucose Cytosol cancer cells Acetyl CoA Citrate Citrate OAA
Malate Isocitrate Isocitrate • NADP+ αKG Succinate Mutations NAD+ NADP+ IDH1 DNMT3A mutation 0 C0 Fumarate IDH3 IDH2 2 2 CO2+NADPH NADPH NADPH+CO2 +CO2 DNMTs Succinate αKG αKG Cytosine 5-methylcytosine 5-hydroxymethylcytosine • Signaling pathways NADPH TET1, TET2, TET3 IDH2 mutant NADPH SAM NADP+ Glutamine IDH1 mutant TET2 mutant Mitochondrion 2HG NADP+ • A unique ‘fingerprint’ competitive inhibition Glutamine 2HG oncometabolite • Then, just find the right drug, right? multiple conversions
We need personalized medicine, IMPORTANT CHANGES not anecdotal medicine • One patient per regimen doesn’t work • New, broad consent forms for diagnostic • Start with a treatment backbone, then tailor material: don’t throw science in the garbage • Novel and efficient clinical trial designs (literally!) • Novel drug development strategies • Expanded biobanking with clinical annotation • Clinical trials for newly diagnosed and relapsed • Change the culture: none of this will work if patients AND for those in remission patients don’t participate • Study the cured patients: why are some cured, while others are not?
CRUSHMDS.ORG
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The Weill Cornell – NYPH Leukemia Program
Gail J. Roboz, M.D. Eric J. Feldman, M.D. Ellen K. Ritchie, M.D. Joseph Scandura, M.D. Pinkal Desai, M.D. Sangmin Lee, M.D. Richard T. Silver, M.D. Jeffrey Ball, M.D. Cindy Ippolitti, Pharm.D. Sandra Allen-Bard, N.P. Maureen Thyne, P.A. Jenny Park, N.P. Laboratory Collaborators: Tania Curcio, N.P. .Monica Guzman, Ph.D. Yulia Dault, R.N. .Ari Melnick, M.D. Jeremy Heinerich, PA-C .Ross Levine, M.D. .Joseph Scandura, M.D. Jessica Markis, R.N. 56
I’d be happy to see you at Weill Cornell/NYP!
Weill Cornell Medical Center The New York Presbyterian Hospital 525 East 68th Street New York, NY (646) 962-2700
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