Treatment-related Adverse Effects in MDS: Managing Them Before They Derail Therapy Amy E. DeZern, MD, MHS Assistant Professor of Oncology and Medicine Department of Hematologic Malignancies Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland

Learning Objectives Recognize key treatment-related adverse effects experienced by patients with MDS Describe toxicity mitigation strategies, including dose- modifications and supportive care Outline proactive monitoring strategies for patients receiving therapy for MDS

Myelodysplastic Syndromes A group of heterogeneous clonal hematopoietic cell NEOPLASMS Overall incidence: ~5 per 100,000 = most common myeloid neoplasm Median age >60 years (70% >50 years) Rollison DE, et al. Blood. 2008;112:45-52.

Steensma DP. Leuk Lymphoma. 2016;57(1):17-20.

Thrombopoietin agonists Hypomethylating agents Lower Risk MDS [IPSS (score ≤1.0) or IPSS-R (score ≤4.0)] Treatment Paradigm - 2016 Symptomatic Cytopenias (+ Del5q) Symptomatic Cytopenias (No Del5q) Anemia Thrombocytopenia Pancytopenia Lenalidomide ESAs Transfusions Transfusions Thrombopoietin agonists Clinical trial Transfusions ATG Clinical trial No response or loss of response Lenalidomide Hypomethylating agents Clinical trial Allogeneic HSCT DeZern AE. Hematology Am Soc Hematol Educ Program. 2015;2015:308-316.

Higher Risk MDS [IPSS (score ≥1. 5) or IPSS-R (score ≥4 Higher Risk MDS [IPSS (score ≥1.5) or IPSS-R (score ≥4.5)] Treatment Paradigm - 2016 HR MDS diagnosis: Discussion of goals Not candidate for HSCT Candidate for HSCT Initiate HMA alone or on clinical trial x ≥6 cycles HLA typing Older patients, complex karyotype Younger patients, higher blast % Hematologic improvement No response Initiate HMA alone or on clinical trial until HSCT Induction chemotherapy Continue HMA until loss of response Clinical trial or supportive care HSCT DeZern AE. Hematology Am Soc Hematol Educ Program. 2015;2015:308-316.

Considerations Disease characteristics Goals of therapy Keeping low-risk disease low risk vs overly toxic therapy Treatment administrative characteristics Treatment pharmacology characteristics Therapy can initially worsen patients’ clinical condition Avoid discontinuation of therapy before achieving benefit Patient characteristics Age and frailty are relative but organs do have chronologic age Expectation management Hematologic and non-hematologic AEs usually decrease in frequency as therapy continues Severe to us vs severe to patient Kurtin S, et al. Clin J Oncol Nurs. 2012 Jun; 16 Suppl.

Growth Factors in Lower Risk Disease First line based on Nordic model Majority of responses occur within 8-12 weeks Fixed-dose versus weight-based EPO regimen IRON and TESTOSTERONE Studies of EPO* in solid tumor patients showed increased heart attacks, stroke, heart failure, blood clots, increased tumor growth, death, especially when hgb >12 Has resulted in concern for MDS patients, but NO DATA yet showing these effects in MDS patients NOT FDA approved; major effects on insurance coverage *EPO is not FDA approved for this use in the United States Park S, et al. Blood. 2008;111(2):574-582.; Jädersten M, et al. J Clin Oncol. 2008;26(21):3607-3613.; Hellström-Lindberg E, et al. Br J Hematol. 2003; 120:1037-1046.; Bennett CL, et al. Semin Thromb Hemost. 2012;38(8):783-796.; Bennett CL, et al. JAMA. 2008;299(8):914-924.; Bohlius J, et al. Lancet. 2009;373(9674):1532-1542.; Glaspy J, et al. Br J Cancer. 2010;102(2):301-315.; Tonelli M, et al. CMAJ. 2009;180(11):E62-E71.; Hershman DL, et al. J Oncol Pract. 2014;10(4):264-269.

Growth Factors in Lower Risk Disease White cell growth factors: Not routine – DON’T treat the number, treat the patient Active infections Recurrent/resistant infections Neutropenic fever Can be combined with red cell growth factors to improve responses in some patients Side effects: fever, bone pain, injection site reactions Does stimulating white blood cells cause leukemia Pegfilgrastim requires less frequent dosing, but administration to patients with MDS has been associated with leukemoid reactions and splenic rupture The standard 6 mg post-chemotherapy dose of pegfilgrastim may be too high for many patients with MDS; in my experience, patients seem to tolerate 1 mg or 2 mg subcutaneously every 1 to 3 weeks better than 6 mg, and most have a suitable increment in neutrophil count with this dose National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 1.2016.

Growth Factors in Lower Risk Disease Platelet growth factors: Not routine – DON’T treat the number, treat the patient Bleeding history Single-digit platelets Romiplostim*: azacitidine Rx patients romiplostim vs placebo Less bleeding events Does stimulating platelets cause leukemia?? *Romiplostim is not FDA approved for this use in the United States National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 1.2016.

Lenalidomide in IPSS Low/Int-1-risk MDS With del(5q): MDS 002/003 Without del(5q) refractory to ESAs Therapy=10 mg daily po (102 patients) or 10 mg po x 21day (46 patients) Therapy=10 mg daily po or PBO (239 patients: LEN=160, PBO=79) RESPONSE LEN 28d LEN 21d RBC-TI 70% 61% 67% no longer needed transfusion by week 24 No significant difference in response rate between the two treatment schedules (P=.26) Median time to transfusion independence was 4.6 weeks (range, 1 to 49) RESPONSE LEN PBO RBC-TI ≥56 d 26.9 % 2.5% Duration in weeks of TI 32.9 NE RBC-TI ≥168 d 17.5% Of responders, 90% responded in 16 weeks (4 cycles!) Median duration of response 32.9 weeks (20.7-71.1) List A, et al. N Engl J Med. 2006;355:1456-465.; Santini V, et al. J Clin Oncol. 2016 Jun 27.

Most Frequently Observed Hematologic Adverse Events: del 5q MDS Safety Data Grade 3 or 4 Neutropenia 55% Thrombocytopenia 44% Anemia NOS 7% Leukopenia NOS 6% Grade 3 or 4 febrile neutropenia reported in 4.1% (6/148) of MDS patients In registration trial, G-CSFs were permitted for patients who developed neutropenia or fever in association with neutropenia Patients may require the use of blood product support and/or growth factors RASH NOT reported here but as high as 20% in other trials List A, et al. N Engl J Med. 2006;355:1456-1465.

Lenalidomide Rash An analysis of the Celgene Global Drug Safety database showed that non-serious rash was the leading cause of permanent early discontinuation of LEN in patients with MDS treated in the post- marketing setting Tinsley SM, et al. Clin Lymphoma Myeloma Leuk. 2015;15 Suppl:S64-69.

Lenalidomide in Renal impairment Dose Mild (80 > CLcr ≥50 mL/min) 10 mg (full dose) every 24 h Moderate (30 ≤ CLcr <50 mL/min) 5 mg every 24 h Severe (CLcr <30 mL/min, not requiring dialysis) 5 mg every 48 h ESRD (CLcr <30 mL/min, requiring dialysis) 5 mg three times a week after each dialysis Chen N, et al. J Clin Pharmacol. 2007;47:1466-1475.

Neutropenia Due to Lenalidomide ANC <1000 ANC <500 Interrupt therapy Introduce GCSF Temporarily discontinue therapy or delay After 1 week of cessation, ANC improves to >750 After 1 week of cessation, ANC <750 Monitor Monitor Resume but with dose reduction Giagounides A, et al. Ann Hematol. 2008:87(5):345-352.

Lenalidomide Diarrhea Diarrhea is a frequent problem and may impact on a patient’s quality of life Patients with known lactose intolerance should add lactase to their diet Lenalidomide capsules contain small amounts of lactose Loperamide, diphenoxylate hydrochloride/atropine sulfate, papaveretum bromide, uzara root extract, and tincture of opium Colesevelam* (extrapolated from MM patients)   *Colesevelam is not FDA approved for this use in the United States Pawlyn C, et al. Blood. 2014;124(15):2467-2468.; Giagounidis A, et al. Ann Hematol. 2008;87(5):345-352.

Dose Modifications of LEN Retrospective, real-world, claims database review 529 patients treated with lenalidomide N=245 (46%) had lenalidomide dose modifications 135 had >1 change 201 patients had >1 dose interruption 91 patients had BOTH N=284 (54%) did not have dose modifications Dose modifications also associated with improved: Median time to progression: 20.6 mos vs 13.7 mos [Adjusted HR=0.703 (95% CI: 0.541–0.914) (P=.008)] Increased time to AML (P=.018) Increased time to next therapy (P=.002) Increased time to high-risk disease (P=.042) DeZern AE, et al. Blood. 2015;126(23):Abstract 3286.

AZA-001: Azacitidine Only Drug Proven to Prolong Survival 1.0 5 10 15 20 25 30 35 40 Mos From Randomization 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 Proportion Surviving Conventional care regimens Azacitidine HR: 0.58 (95% CI: 0.43-0.77; log-rank P=.0001) Median OS 24.5 months Median OS 15 months Fenaux P, et al. Lancet Oncol. 2009;10(3):223-232.

Decitabine Compared to BSC Higher-risk MDS: DAC Median OS 10.1 vs 8.5 months (P=.38) Median PFS 6.6 vs 3.0 months (P=.004) Lübbert M, et al. J Clin Oncol. 2011;29(15):1987-1996.

AZA vs DAC Intensity of therapy is greater with the commonly used 5-day DAC regimen, compared with the 7-day 75 mg/m2/d AZA regimen Two outpatient regimens are not dose-equivalent Febrile neutropenia was higher in 5-day DAC trials (ID03-0180 and DACO-020) 7-day AZA trials (CALGB 9221 or AZA-001) no significant difference in the rate of febrile neutropenia between patients treated with AZA vs patients on supportive care alone Rate of response to DAC may be quicker 82% of patients who would ultimately respond to DAC in DACO-020 (ADOPT) had experienced an initial response by the end of two cycles 75% of responders showing improvement by cycle 4 of AZA in CALGB 9221 81% showing improvement after 6 cycles in AZA-001 Kantarjian H, et al. Blood. 2007;109:52-57.; Steensma DP, et al. J Clin Oncol. 2009;27:3842-3848.; WijerMans PW, et al. Blood. 2008;112:226.; Deeg HJ. Hematology Am Soc Hematol Educ Program. 2005:167-173.; WijerMans P, et al. J Clin Oncol. 2000;18;956-962.; Silverman LR, et al. J Clin Oncol. 2006;24:3895-3903.; Steensma DP, et al. Hematol Oncol Clin North Am. 2010;24(2):389-406.

Injection Site Reactions In the AZA-001 trial, injection site redness was reported by 43% of patients, and other injection site reactions were reported by 29% of patients The pharmacokinetics of intravenous azacitidine are almost identical to those of subcutaneous azacitidine AZA001 SQ Murray C, et al. Can Oncol Nurs J. 2012;22(4):222-234.

Infections Infection = most frequent serious adverse event Also most common cause of death in MDS in patients not undergoing treatment Febrile episodes occur in patients receiving only supportive care at an average rate of approximately one episode per 250 days Not possible to distinguish treatment- related infection from infection caused by the underlying disease Sébert M, et al. ASH 2014. Abstract 1917.; Caira M, et al. Expert Rev Hematol. 2016;9(6):607-614.; Sullivan LR, et al. Transplant Infect Dis. 2013;15(6):652-657.; Falantes JF, et al. Clin Lymphoma Myeloma Leuk. 2014;14(1):80-86.; Voso MT, et al. Eur J Haematol. 2016;96(4):344-351.; Merkel D, et al. Am J Hematology. 2013;88(2):130-134.

Prophylactic Antibiotics No randomized data exists to make formal recommendation for any of these interventions NCCN guidelines: Antibiotics are recommended for bacterial infections, but no routine prophylaxis is recommended except in patients with recurrent infections Isolated neutropenia in patients not receiving therapy are not at significantly increased risk of infection Commonly used in the context of active therapy Fluoroquinolones Acyclovir or valacyclovir Antifungal - azoles Greenberg PL, et al. J Natl Compr Canc Netw. 2015;13(3):261-272.

Renal Impairment No initial AZA dose adjustment in patients with renal impairment is required AZA is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK If creatinine or blood urea nitrogen increases, or if serum bicarbonate decreases, the prescribing information suggests that, for the next cycle, the dose be reduced by 50% or delayed (or both) until values return to normal or baseline Anecdotally try to avoid (per previous trial criteria) in Cr >1.8 or greater than 50% increase from baseline Douvaili E, et al. Leuk Res. 2013;37:889-893.; Laille E, et al. Pharmacotherapy. 2014;34(5):440-451.

Debilitating Fatigue The most common symptom reported by patients with MDS ‒ regardless of whether they are receiving treatment QUALMS study looking at QoL shows fatigue is big limitation in these patients Fatigue also has been reported commonly as an adverse event in clinical trials of hypomethylating agents Challenging symptom to address Encourage patients to remain as active as possible physically Abel GA, et al. Haematologica. 2016;101(6):781-788.; Fenaux P, et al. Lancet Oncol. 2009;10(3):223-232.; Cooper MR, et al. Ann Pharmacother. 2009;43:721-725.7

Debilitating Fatigue Modafinil*= non-habit forming centrally acting wakefulness-inducing agent encouraging results in MDS and cancer-related fatigue Not reimbursed by insurance companies when used off-label in other settings such as cancer-associated fatigue Strong potential for a placebo effect Controlled trials will be necessary before formal recommendation Methylphenidate† also is employed to treat fatigue Costs less than modafinil Central nervous system overstimulation can be problematic *Modafinil is not FDA approved for this use in the United States; †Methylphenidate is not FDA approved for this use in the United States Abel GA, et al. Haematologica. 2016;101(6):781-788.; Fenaux P, et al. Lancet Oncol. 2009;10(3):223-232.; Cooper MR, et al. Ann Pharmacother. 2009;43:721-725.7

Monitoring During Treatment: Real-world Recommendations Testing Role Recommendation Comments Creatinine Renal function Every 4 weeks in patients aged 65 years and older CBC Blood counts, disease and therapy effects Weekly monitoring of full blood count mandatory for the first 2 months (it may be continued for 5 months) Biweekly or monthly monitoring should be considered thereafter, depending on hematological status TSH Thyroid function Monitor every other month during the course of treatment Hypothyroidism reported in ~7% of patients on LEN almost exclusively of autoimmune cause Testosterone Male gonadal function In case of loss of response during LEN treatment Deficiency can cause worsening anemia Ferritin Iron overload Quarterly if consistent transfusion dependence or on chelation Bone marrow Disease assessment At commencement of therapy and as clinically indicated thereafter In case of loss of response to rule out progressive disease or cytogenetic evolution Digoxin Lithium Therapeutic drug monitoring Ensure levels at goal Can be recommendation to primary prescribing physician Garcia-Manero G. Am J Hematol. 2015;90(9):831-841.

Supportive Care: Essential to All Patients to Improve QoL Transfusional support PRBC transfusions when <7-8g/dL or SX Platelet transfusions when <10,000/mm3 Irradiated products suggested for transplant candidates Cytomegalovirus (CMV)-negative or leuko-reduced blood products Aminocaproic acid if bleeding refractory to platelet transfusions or profound thrombocytopenia Iron overload If >20 to 30 RBC transfusions have been received, consider daily chelation with deferoxamine subcutaneously or deferasirox orally For patients with serum ferritin levels >2500 ng/mL, aim to decrease ferritin levels to <1000 Patients with low creatinine clearance (<40 mL/min) should not be treated with deferasirox or deferoxamine Constipation Change from ondansetron to granisetron Garcia-Manero G. Am J Hematol. 2015;90(9):831-841.; National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version 1.2016.

Transplant? Older patients + medically fit + advanced disease  ?? decision to proceed with RIC HCT Worry of SAEs, M&M Patients older than 60 years with high-risk MDS were shown to have a modest survival advantage with early use of HCT compared with the use of HMAs (Markov decision analysis) Better pre-HCT performance status predicts improved 2-year OS QoL does not seem to factor in to the decision making Relatively low percentage of all patients with MDS (~2-5%) undergo HCT in world for their disease El-Jawahri A, et al. Bone Marrow Transplant. 2016;51:1121-1126.; Koreth J, et al. J Clin Oncol. 2013;31(21):2662-2670.; Steensma DP. Leuk Lymphoma. 2016;57(1):17-20.; McClune BL, et al. J Clin Oncol. 2010;28(11):1878-1887.

Summary MDS can be a chronic disease Management of therapy in the older patient has challenges, but can be overcome Awareness of the onset duration and management of AEs can facilitation treatment Goal to permit patients to continue therapy for maximum benefit