1. 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

2. 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

3. 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.

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

5. Thrombopoietin agonists Hypomethylating agents
Lower Risk MDS [IPSS (score ≤1.0) or IPSS-R (score ≤4.0)] Treatment Paradigm
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:

6. 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
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:

7. 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 Jun; 16 Suppl.

8. 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): ; Jädersten M, et al. J Clin Oncol. 2008;26(21): ; Hellström-Lindberg E, et al. Br J Hematol. 2003; 120: ; Bennett CL, et al. Semin Thromb Hemost. 2012;38(8): ; Bennett CL, et al. JAMA. 2008;299(8): ; Bohlius J, et al. Lancet. 2009;373(9674): ; Glaspy J, et al. Br J Cancer. 2010;102(2): ; Tonelli M, et al. CMAJ. 2009;180(11):E62-E71.; Hershman DL, et al. J Oncol Pract. 2014;10(4):

9. 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

10. 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

11. 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 ( )
List A, et al. N Engl J Med. 2006;355: ; Santini V, et al. J Clin Oncol Jun 27.

12. 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:

13. 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.

14. 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:

15. 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):

16. 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): ; Giagounidis A, et al. Ann Hematol. 2008;87(5):

17. 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: 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.

18. 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: ; log-rank P=.0001)
Median OS 24.5 months
Median OS 15 months
Fenaux P, et al. Lancet Oncol. 2009;10(3):

19. 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):

20. 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 (ID 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: ; WijerMans PW, et al. Blood. 2008;112:226.; Deeg HJ. Hematology Am Soc Hematol Educ Program. 2005: ; WijerMans P, et al. J Clin Oncol. 2000;18; ; Silverman LR, et al. J Clin Oncol. 2006;24: ; Steensma DP, et al. Hematol Oncol Clin North Am. 2010;24(2):

21. 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):

22. 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 Abstract 1917.; Caira M, et al. Expert Rev Hematol. 2016;9(6): ; Sullivan LR, et al. Transplant Infect Dis. 2013;15(6): ; Falantes JF, et al. Clin Lymphoma Myeloma Leuk. 2014;14(1):80-86.; Voso MT, et al. Eur J Haematol. 2016;96(4): ; Merkel D, et al. Am J Hematology. 2013;88(2):

23. 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):

24. Renal Impairment
No initial AZA dose adjustment in patients with renal impairment is required
AZA is dose proportional over the 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: ; Laille E, et al. Pharmacotherapy. 2014;34(5):

25. 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): ; Fenaux P, et al. Lancet Oncol. 2009;10(3): ; Cooper MR, et al. Ann Pharmacother ;43:

26. 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): ; Fenaux P, et al. Lancet Oncol. 2009;10(3): ; Cooper MR, et al. Ann Pharmacother ;43:

27. 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):

28. 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): ;
National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Myelodysplastic Syndromes. Version

29. 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: ; Koreth J, et al. J Clin Oncol. 2013;31(21): ; Steensma DP. Leuk Lymphoma. 2016;57(1):17-20.; McClune BL, et al. J Clin Oncol. 2010;28(11):

30. 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