Managing CMV in the New Era of Antiviral Therapy Practical Considerations in the HCT Setting Disclosures
Roy F. Chemaly, MD, MPH, FIDSA, FACP, Genovefa Papanicolaou, MD, has the has the following financial following financial interests/relationships: interests/relationships: Consultant and/or Advisor for Astellas Pharma Consultant and/or Advisor for Astellas US, Inc.; Chimerix; Clinigen and Merck & Pharma US, Inc.; Chimerix; Clinigen; Merck & Co., Inc. Co., Inc.; Oxford Immunotec; and Shire. Grant/Research Support from Astellas Grant/Research Support from Chimerix; Pharma US, Inc.; Chimerix; Merck & Co., Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals and Shire. Corporation; Oxford Immunotec; and Shire. Other financial interest/relationship with Astellas Pharma US, Inc.; Chimerix; Merck & Co., Inc.; Oxford Immunotec; and Shire as a speaker.
This CME activity is jointly provided by The Medical College of Wisconsin and PVI, PeerView Institute for Medical Education. This activity is supported by independent medical educational grants from Merck & Co., Inc. and Shire. Visit us at www.peerview.com/CMVHCT19
• Watch for the onDemand version in the coming weeks
• Download the slides and Practice Aids
Join the conversation on
Twitter @PeerView Need more information? Send an email to [email protected] A Closer Look at Best Practices to Prevent CMV Infection in Patients Undergoing HCT
Roy F. Chemaly, MD, MPH, FIDSA, FACP Professor of Medicine Director, Infection Control Section Director, Clinical Virology Research Department of Infectious Disease, Infection Control and Employee Health The University of Texas MD Anderson Cancer Center Houston, Texas Case 1
• 55-year-old, CMV R+ man with AML who underwent MUD HCT from a CMV-negative donor after conditioning with busulfan, fludarabine, and ATG • Patient engrafted at day 18; his recent ANC was 1,110 and ALC was 250 • At day 33, on routine surveillance, his CMV PCR was positive for 670 U/mL • Patient is completely asymptomatic with no fever, malaise, or other symptoms CMV in HCT: Background1-3
• CMV infection remains amongst the most significant complications after HCT
• Cumulative incidence of CMV reactivation among allo-HCT is around 36% and in CBT recipients could be as high as 80%
• CMV end-organ disease: The incidence of CMV pneumonia ranges from 1%-6% in autologous HCT recipients and from 10%-30% in allo-HCT recipients
1. Al-Hajjar S et al. Hematol Oncol Stem Cell Ther. 2011;4:67-72. 2. Kotloff RM et al. Am J Respir Crit Care Med. 2004;170:22-48. 3. Ariza-Heredia EJ et al. Cancer Lett. 2014;342:1-8 CMV
Direct effects = Lytic infection Indirect effects • Pneumonia • Graft rejection (SOT) • GI disease • GVHD • Hepatitis • Immunosuppression • Retinitis • Fungal/bacterial infections
Risk Factors for CMV Infection1
HCT Days 0-29 General risk factors for CMV infection and end-organ disease Days 30-100 • CMV-seropositive recipient Risk factors for CMV infection and • Advanced age end-organ disease >100 Days • Type of transplant (MUD, Prior risk factors + Risk factors for CMV infection and haploidentical transplant, CBT) • Presence of GVHD end-organ disease • Conditioning regimen • Delay of T-cell recovery • Steroids use -GVHD (fludarabine antithymocyte globulin, • Delay of T-cell recovery alemtuzumab, TBI) CMV presentation • Non-myeloablative conditioning
• CMV infection is common in • CMV reactivation before day 100 CMV presentation in the high-risk recipients initial period • CMV pneumonia, although rare, is CMV presentation in the • CMV infection the most common end-organ third period • CMV end-organ disease is rare in disease • CMV infection first 30 days • CMV pneumonia • CMV GI disease • CMV CNS disease-retinitis
1. Ariza-Heredia EJ et al. Cancer Lett. 2014;342:1-8. CMV Prevention in HCT Recipients History
1985 1990 1995 2000 When Would You Start Preemptive Therapy?1
CMV CMV Whole Blood DNA Immuno- CMV Plasma DNA Level Doubling Risk Groups Level to Start PET at suppression to Start PET at FHCRCa Time Karolinska Instituteb High Short Cord blood Any level 1,000 copies
Allograft • High-dose steroidsc • T-cell depletion >100 copies/mL 1,000 copies • Anti–T-cell antibodies • CD34 selection Allograft • Low-dose steroids • >500 copies/mL 1,000 copies • No T-cell depletion or • > or 5-fold ↑d anti–T-cell antibodies
• 1,000 copies if GVHD Allograft • >1,000 copies/mL • Other individual • After day 100 • > or 5-fold ↑d assessment based on ↑ Low Long a Assays preformed weekly or twice weekly (highest risk); limit of detection: 25 copies/mL. b Assays performed weekly; limit of detection: 50 copies/mL. c 1 mg/kg of prednisone or higher. d If initial level is less than threshold. 1. Boeckh M, Ljungman P. Blood. 2009;113:5711-5719. When Would You Start Preemptive Therapy?1
CMV CMV Whole Blood DNA CMV Plasma DNA Level Immuno- CMV Plasma DNA Level Doubling Risk Groups Level to Start PET at to Start PET at suppression to Start PET at FHCRCa Time Karolinska Instituteb MD Anderson High Short Any positive Cord blood Any level 1,000 copies but if <500 U/mL then 2 positive in a row Allograft • High-dose steroidsc • T-cell depletion >100 copies/mL 1,000 copies ≥500 U/mL • Anti–T-cell antibodies • CD34 selection Allograft • Low-dose steroids • >500 copies/mL 1,000 copies ≥1,000 U/mL • No T-cell depletion or • > or 5-fold ↑d anti–T-cell antibodies
• 1,000 copies if GVHD Allograft • >1,000 copies/mL • Other individual ≥1,000 U/mL • After day 100 • > or 5-fold ↑d assessment based on ↑ Low Long a Assays preformed weekly or twice weekly (highest risk); limit of detection: 25 copies/mL. b Assays performed weekly; limit of detection: 50 copies/mL. c 1 mg/kg of prednisone or higher. d If initial level is less than threshold. 1. Boeckh M, Ljungman P. Blood. 2009;113:5711-5719. CMV Viral Load and CMV Disease After HCT in the Era of Preemptive Therapy1
MV Cox Proportional Hazards Model Assessing CMV Viral Load as a Time-Dependent Risk Factor for CMV Disease 1 Year After HCT, Stratified by Use of Preemptive Therapy (N = 926)
Adjusted HR (95% CI)
Any positive viremia vs negative viremia, no PET 6.01 (2.4-15.0) Any positive viremia vs negative viremia, with PET 0.24 (0.1-1.3)
>250 U/mL vs ≤250 U/mL, no PET 2.48 (1.3-4.7) >250 U/mL vs ≤250 U/mL, with PET 1.40 (0.6-2.1)
>500 U/mL vs ≤500 U/mL, no PET 2.08 (1.0-4.2) >500 U/mL vs ≤500 U/mL, with PET 1.03 (0.6-1.8)
>750 U/mL vs ≤750 U/mL, no PET 2.95 (1.5-6.0) >750 U/mL vs ≤750 U/mL, with PET 0.93 (0.5-1.7)
>1,000 U/mL vs ≤1,000 U/mL, no PET 3.23 (1.6-6.7) >1,000 U/mL vs ≤1,000 U/mL, with PET 0.87 (0.5-1.7)
0.1 1 10 Risk of CMV Disease
1. Green ML et al. Lancet Haematol. 2016;3:e119-127. CMV Viral Load and Mortality After HCT in the Era of Preemptive Therapy1
Cumulative Incidence of Overall Mortality (A) and Nonrelapse Mortality (B) at 1 Year After HCT in Survivors at Day 100 (n = 832) Stratified by Max CMV VL Before Day 100
(A) (B) 1.0 1.0 Max viral load (U/mL) before day 100 Max viral load (U/mL) before day 100 0.9 Negative 0.9 Negative 0.8 Positive – 150 0.8 Positive – 150
>150 – 1,000 >150 – 1,000
0.7 0.7 >1,000 >1,000 0.6 0.6 0.5 0.5
0.4 0.4
Probability Probability 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 1 2 3 4 5 6 7 8 9 10 11 12 0 1 2 3 4 5 6 7 8 9 10 11 12 Time After Transplant, mo Time After Transplant, mo
Negative 290 287 277 262 246 237 227 217 211 203 Negative 265 257 249 236 216 203 195 189 184 179 Positive – 150 220 215 207 200 189 182 168 162 156 150 Positive – 150 198 192 184 177 165 158 150 145 136 130 >150 – 1,000 218 210 197 191 175 162 152 146 142 132 >150 – 1,000 198 191 176 167 156 148 137 133 130 118 >1,000 93 85 76 73 68 65 63 59 57 55 >1,000 84 76 69 67 63 61 59 57 55 52
1. Green ML et al. Lancet Haematol. 2016;3:e119-127. Cytomegalovirus Infection After Allogeneic-HCT: CMV Reactivation and All-Cause Mortality1
AML BM/PB LR +/+ P Value +/- .18 -/- vs all -/+ .08 + = IR ++ < .0001 < .0001 +/- .21 -/- vs all -/+ .24 + = HR ++ .79 .44 +/- .04 -/- vs all -/+ .14 + = CMV reactivation .65 .01 < .0001 BM/PB +/+ ALL .0001 -/- vs all +/- -/+ .81 + = CMV reactivation .35 .0001 < .0001 CML BM/PB +/+ .06 -/- vs all +\- .80 + = -/+ .56 .28 CMV reactivation .0005 MDS BM/PB +/+ .68 -/- vs all +/- .34 + = -/+ .65 .82 CMV reactivation .003 0.5 1.0 1.5 2.0 Relative Risk of Death 1. Teira P et al. Blood. 2016;127:2427-2438. Case 1 (Cont’d)
• Valganciclovir was started at 450 mg twice daily, adjusted for CrCl of 59 mL/min and VL decreased to <137 U/mL at day 12 of therapy • He subsequently developed N/V and upper endoscopy was consistent with acute GI GVHD, for which he received high-dose corticosteroids • He was switched to IV ganciclovir 2.5 mg/kg every 12 h and he received multiple doses of pegfilgrastim for decreased ANC below 500 • At day 62, he had recurrent N/V and his CMV VL increased to 10,320 U/mL while on oral valganciclovir for secondary prophylaxis and on systemic corticosteroids Case 1 (Cont’d)
A repeat UGI showed CMV disease: CMV gastritis
CMV gastritis with focal CMV infection with gastric ulcerations areas of inflammation IHC for CMV was positive on tissue biopsy Case 1 (Cont’d)
• At that point, foscarnet was started, and CMV genotypic analysis showed the C592G UL97 mutation
• Within 2 weeks of starting foscarnet, the patient’s CMV VL was 1,250 U/mL but patient developed worsening acute kidney injury and foscarnet was held
• At day 110, patient died with worsening/refractory GI GVHD and CMV gastritis, septic shock from E. coli, and multi-organ failure New Antiviral Agents With Activity Against CMV1
1. Foolad F et al. Expert Rev Clin Pharmacol. 2018;11:931-941. Letermovir (MK-8228, AIC246)1-5
• CMV replication involves cleaving of concatemeric genomic DNA and packaging of each genome into preformed virus capsids
• CMV terminase complex (UL51, UL56, UL89) performs these sequential events, a viral process not present in uninfected human cells
• Letermovir inhibits the terminase complex by binding to UL56, UL51
1. Chou S. Antiviral Res. 2017;148:1-4. 2. Chou S. Antimicrob Agents Chemother. 2015;59:6588-6593. 3. Goldner T et al. J Virol. 2011;85:10884-10893. 4. Lischka P et al. Antimicrob Agents Chemother. 2010;54:1290-1297. 5. Buerger I et al. J Virol. 2001;75:9077-9086. Letermovir (MK-8228, AIC246): Phase 2 Dose-Escalation Trial After HCT1 Time to Failure of Prophylaxis Against CMV Infection During the 12-Week Treatment Period (mITT Population)
Letermovir Placebo Variable 60 mg 120 mg 240 mg n = 33 n = 33 n = 31 n = 34
All-cause failure, n (%) 16 (48) 10 (32) 10 (29) 21 (64)
Virologic failure, n (%) 7 (21) 6 (19) 2 (6) 12 (36)
Odds ratio for failure with letermovir vs placebo (95% CI) 0.54 (0.18-1.60) 0.27 (0.08-0.86) 0.24 (0.08-0.74) —
P value (all-cause failure, letermovir vs placebo) .32 .01 .007 —
Time to Prophylaxis Failure, d 1. Chemaly RF et al. N Engl J Med. 2014;370:1781-1789. A Phase 3 Randomized, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of Letermovir for the Prevention of Clinically Significant CMV Infection in Adult, CMV+ Allo-HCT Recipients1
Primary endpoint: Clinically significant CMV infection through post-HCT week 24 (FASa) • Clinically significant CMV infection defined as CMV disease occurrence or treatment with anti-CMV preemptive therapy • Confirmed CMV viremia and CMV disease risk Post-HCT week 14
b Letermovir 480 mg QD PO or IV Patients assessed through CMV-seropositive, adult allogeneic HCT (n = 376) post-HCT week 48; recipients with no CMV viremia or acute preemptive treatment liver injury and GFR ≥10 mL/min given per study (N = 570) Placebo (n = 194) center guidelines
Patients required to begin treatment before post-HCT day 28. a Full analysis set included patients with undetectable CMV DNA at baseline. b 240 mg if concomitantly taking cyclosporine. 1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Patient Disposition1
738 patients provided informed consent and were 168 were excluded assessed for eligibility 117 had detectable CMV before randomization 16 were receiving anti-CMV antiviral agents 5 had exclusionary laboratory results 5 withdrew consent 570 underwent randomization 4 were CMV-seronegative 21 had other reasons
376 were assigned to receive letermovir 194 were assigned to receive placebo 373 received letermovir 192 received placebo 3 did not receive letermovir 2 did not receive placebo
295 completed trial to week 24 136 completed trial to week 24 78 discontinued trial before week 24 56 discontinued trial before week 24 37 died 28 died 23 withdrew consent 16 withdrew consent 9 were withdrawn by a physician 5 were withdrawn by a physician 6 had AEs 3 had AEs 2 were lost to follow-up 4 were lost to follow-up 1 did not adhere to trial regimen 48 had detectable CMV at 22 had detectable CMV at randomization randomization
325 were included in the 170 were included in the efficacy population 373 were included in the safety population 192 were included in the safety population efficacy population
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Definitions1
High risk: Patients meeting ≥1 of the following criteria at the time of randomization 1. Related donor with ≥1 mismatch at 1 of the following 3 HLA-gene loci: HLA-A, -B, or -DR 2. Unrelated donor with ≥1 mismatch at 1 of the following 4 HLA-gene loci: HLA-A, -B, -C, or -DRB1 3. Haploidentical donor 4. Use of umbilical cord blood as stem cell source 5. Use of ex vivo T-cell–depleted grafts 6. Having GVHD of grade ≥2 that led to the use of prednisone (or its equivalent) at a dose of >1 mg/kg/d
Low risk: All patients not meeting the definition of high risk
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Summary of Subject Characteristics
Letermovir, n (%) Placebo, n (%) n = 373 n = 192 Letermovir Placebo Stem cell source n = 373 n = 192 Peripheral blood 279 (75) 134 (70) Male, n (%) 211 (56.6) 116 (60.4) Bone marrow 82 (22) 47 (24) Cord blood 12 (3) 11 (6) Median age, y (range) 53.0 (18-75) 54.0 (19-78) Conditioning regimen and T-cell depletion Race, n (%) Antithymocyte globulin use 138 (37) 58 (30) Alemtuzumab use 12 (3) 11 (6) White 301 (80.7) 162 (84.4) Myeloablative conditioning 186 (50) 97 (51) regimen Asian 40 (10.7) 18 (9.4) Median time to randomization, 9 (0-28) 9 (0-28) Other 32 (8.6) 12 (6.2) days post-transplant (range) Characteristics at randomization Donor CMV-seropositive, n (%) 230 (61.7) 114 (59.4) Engraftment 132 (35) 75 (39) Acute GVHD grade ≥2 2 (0.5) 1 (0.5) CMV DNA detected 48 (13) 22 (11)
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Clinically Significant CMV Infection in the High-Risk and Low-Risk Subgroups1
High-Risk Subgroup Low-Risk Subgroup 100 100 90 90 80 80 70 70 60 Placebo 60 50 50 Placebo 40 40 Letermovir 30 30
20 20 Letermovir Cumulative Rateof Infection, % Cumulative Rateof Infection, % 10 10 0 0 0 2 6 10 14 18 24 0 2 6 10 14 18 24 Time Since Transplantation, wk Time Since Transplantation, wk No. at Risk No. at Risk Placebo 45 44 25 18 15 13 13 Placebo 125 125 110 78 70 64 57 Letermovir 102 100 90 85 82 78 61 Letermovir 223 220 209 194 188 176 151
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. All-Cause Mortality Post-Transplant: Primary Efficacy Population1,2
Through Week 24 Post-Transplant Through Week 48 Post-Transplant
30
Active intervention period Stratified log-rank test, 40 Stratified log-rank test, two-sided P = .03 two-sided P = .1224 25 Letermovir = 20.9% (95% CI, 16.2-25.6) Letermovir = 10.2% (95% CI, 6.8-13.6) 30 Placebo = 25.5% (95%CI, 18.6-32.5) 25.5 % Placebo = 15.9% (95% CI, 10.2-21.6)
20 Placebo Cause Mortality, Cause % Mortality, 15.9 % -
Cause Mortality, Cause % Mortality, 20 - 15 20.9%
10 Letermovir 10 7.1 % Placebo 10.2%
5 0
5.2% All Rate Cumulative of 0 6 14 24 32 40 48
Cumulative Rate All Rate Cumulative of Time Post-Transplant, wk 0 Letermovir No. at Risk Week 0 Week 14 Week 24 Letermovir 325 311 290 262 242 226 138 Time Post-Transplant, wk Placebo 170 161 147 125 117 112 71 1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. 2. MSD data on file. Outcomes of patients with detectable CMV DNA at randomization in the double-blind, placebo-controlled phase 3 trial of letermovir prophylaxis for CMV-seropositive allogeneic hematopoietic-cell transplantation recipients
Marty FM, Ljungman PT, Chemaly RF, Wan H, Teal VL, Butterton J, Yeh WW, Leavitt RY, Badshah C
Oral presentation at ID Week, October 6, 2018 Characteristics of Patients With Detectable CMV DNA at Randomization1
Letermovir, n (%) Placebo, n (%) CMV Infection Risk n = 48 n = 22 Low risk 29 (60.4) 13 (59.1) High risk 19 (39.6) 9 (40.9) Donor Haploidentical 11 (22.9) 4 (18.2) Mismatched unrelated 8 (16.7) 3 (13.6) Cord blood 0 (0.0) 1 (4.5) Ex vivo T-cell depletion 1 (2.1) 0 (0.0) Grade ≥2 GVHD 1 (2.1) 0 (0.0) ATG use 22 (45.8) 9 (40.9) Alemtuzumab use 1 (2.1) 2 (9.1)
1. Marty FM et al. IDWeek 2018. Abstract 1730. Characteristics of Patients With Detectable CMV DNA at Randomization (Cont’d)1
Letermovir Placebo n = 48 n = 22 Median age, y (range) 50 (18-74) 46 (19-78) Male sex, n (%) 35 (72.9) 12 (54.5) White race, n (%) 33 (68.8) 14 (63.6) Hispanic or Latino, n (%) 6 (12.5) 0 (0.0) Median weight, kg (range) 80 (50-141) 62 (41-113) Donor CMV seropositive (D+), n (%) 30 (62.5) 16 (72.7) Cyclosporine use, n (%) 31 (64.6) 10 (45.5) Myeloablative conditioning, n (%) 32 (66.7) 12 (54.5)
1. Marty FM et al. IDWeek 2018. Abstract 1730. Subject Disposition: Reasons for Discontinuing Study Treatment Through Day 100, CMV DNA+ at Randomization1
Letermovir, n (%) Placebo, n (%) Subject Disposition n = 48 n = 22 Lack of efficacy 12 (25.0) 17 (77.3) Adverse event 3 (6.3) 1 (4.5) Withdrawal by subject 4 (8.3) 1 (4.5) Investigator decision 1 (2.1) 0 (0.0) Death on study drug 1 (2.1) 0 (0.0) Other 2 (4.2) 1 (4.5) Completed treatment 25 (52.1) 2 (9.1)
1. Marty FM et al. IDWeek 2018. Abstract 1730. Outcome: Clinically Significant CMV Infection Through Day 1001
Patients With Detectable CMV DNA at Randomization
Letermovir, n (%) Placebo, n (%) n = 48 n = 22 Events 22 (45.8) 20 (90.9) Clinically significant CMV 15 (31.3) 17 (77.3) PET for CMV 15 (31.3) 17 (77.3) CMV disease 1 (2.1) 0 (0.0) Early discontinuation 7 (14.6) 3 (13.6) Missing outcome 0 (0.0) 0 (0.0)
Stratum-adjusted treatment difference: -44.8 (95% CI, -64.7 to -24.8), P < .0001
1. Marty FM et al. IDWeek 2018. Abstract 1730. Time to Clinically Significant CMV Infection1
Patients With Detectable Patients Without Detectable CMV DNA at Randomization CMV DNA at Randomization
100 60
Placebo
% 86.6%
90 % Stratified log-rank test, , , , , two-sided P < .0001 80 50 44.3%
Placebo
Stratified log-rank test, 70 two-sided P = .0289 40 60 51.8% 50 30 40 18.9%
30 20 Letermovir
Cumulative Rate of Cumulative Rate Cumulative Rate of Cumulative Rate 20 Letermovir 10
10
Clinical Significant CMV CMV InfectionSignificant Clinical Clinical Significant CMV CMV InfectionSignificant Clinical 0 0 0 14 24 0 2 6 10 14 18 24 Time Post-Transplant, wk Time Post-Transplant, wk 1. Marty FM et al. IDWeek 2018. Abstract 1730. All-Cause Mortality1
Patients With Detectable Patients With Undetectable CMV DNA at Randomization (N = 70) CMV DNA at Randomization (N = 495)
40 40
Placebo 30 30 Placebo
20 20 Letermovir Letermovir
Cause Mortality Cause 10 10 -
All Stratified log-rank P = .2678 Cumulative Rate Rate Cumulative (%) Stratified log-rank P = .2117 0 0 0 6 14 24 32 40 48 0 6 14 24 32 40 48 Time After Transplantation, wk Time After Transplantation, wk No. at Risk Letermovir 48 45 43 39 38 34 27 325 317 304 282 263 248 165 Placebo 22 22 21 18 17 15 9 170 164 156 139 127 122 81
All-Cause Week 24, % Week 48, % All-Cause Week 24, % Week 48, % Mortality (95% CI) (95% CI) Mortality (95% CI) (95% CI)
Letermovir 15.0 (4.8-25.3) 26.5 (13.6-39.5) Letermovir 12.1 (8.6-15.7) 23.8 (19.1-28.5)
Placebo 18.2 (2.1-34.3) 40.9 (20.4-61.5) Placebo 17.2 (11.5-22.9) 27.3 (20.8-34.4)
1. Marty FM et al. IDWeek 2018. Abstract 1730. A Mortality Analysis of Letermovir Prophylaxis for CMV in CMV-Seropositive Recipients of Allo-HCT1
Letermovir, n/N (%) Placebo, n/N (%) n = 373 n = 192 Death among participants 14/79 (17.7) 26/88 (29.5) with CS-CMVi Death among participants 58/294 (19.7) 19/104 (18.3) without CS-CMVi
Note: Death includes all-cause mortality through week 48 post-HCT. Clinically significany CMV infection is defined through week 24 post-HCT. Denominator in the first row only includes patients with clinically significant CMV infection and does not include participants who discontinued early or had missing data.
Every participant is counted a single time for each applicable row and column.
1. Maertens J et al. IDWeek 2017. Poster 1029. All-Cause Mortality Through Week 48 Post-Transplant in Participants
With (A) and Without (B) CS-CMVi Through Week 24 Post-Transplant1
(A) 50
Placebo 40 Stratified log-rank test, two-sided P = .03 Letermovir 30
20
Related % Related Mortality, 10
- Cumulative of Rate Cumulative
0 CMV Week 0 Week 24 Week 48 Time Post-Transplant, wk No. at Risk: KM estimates, % (95% CI) Letermovir 57 51: 3.7 (0.0-8.7) 23: 17.2 (6.9-27.4)
Placebo 71 54: 19.1 (9.7-28.4) 25: 31.8 (20.4-43.1)
(B) 50
Placebo 40 Stratified log-rank test, Letermovir two-sided P = .89 30
20
Related % Related Mortality, 10
- Cumulative of Rate Cumulative
0 CMV Week 0 Week 24 Week 48
No. at Risk: KM estimates, % (95% CI) Time Post-Transplant, wk Letermovir 268 211: 11.6 (7.6-15.6) 115: 21.7 (16.5-27.0) Placebo 99 71: 13.1 (6.1-20.0) 46: 20.4 (11.9-28.9) 1. Ljungman P et al. Manuscript submitted. Proportional Hazard Model for All-Cause Mortality Through Week 48 Post-HCT1
Factor Multivariable HR (95% CI) P
Letermovir vs placebo with CS-CMVi 0.45 (0.21-1.00) .05
Letermovir vs placebo without CS-CMVi 1.05 (0.61-1.81) .85
CS-CMVi through week 24 (time-dependent) 2.05 (1.09-3.88) .03
Acute GVHD grades 2-4 (time-dependent) 2.58 (1.69-3.92) < .001
Age (by 10-year increase) 1.29 (1.10-1.52) .002
Baseline CMV risk for CMV reactivation (high vs low) 1.70 (1.13-2.57) .01
1. Ljungman P et al. Manuscript submitted. Most Common Causes of All-Cause Mortality by Preferred Terms (FAS)1
Letermovir, n (%) Placebo, n (%)
n = 325 n = 170 Patients who died 61 (18.8) 40 (23.5) AML 12 (3.7) 10 (5.9) GVHD 7 (2.2) 7 (4.1) Sepsis 6 (1.8) 4 (2.4) Pneumonia 2 (0.6) 3 (1.8) Respiratory failure 7 (2.2) 1 (0.6) Acute lymphocytic leukemia 3 (0.9) 1 (0.6) Multiple organ dysfunction syndrome 2 (0.6) 2 (1.2) Septic shock 2 (0.6) 2 (1.2)
1. Ljungman P et al. Manuscript submitted. Most Common AEs Through Week 16 After Transplantationa
Letermovir, n (%) Placebo, n (%) Difference in % vs placebo P n = 373 n = 192 (95% CI) Any AE 365 (97.9) 192 (100.0) -2.1 (-4.2 to -0.2) .07 GVHD 146 (39.1) 74 (38.5) 0.6 (-8.0 to 8.9) .96 Diarrhea 97 (26.0) 47 (24.5) 1.5 (-6.3 to 8.8) .77 Nausea 99 (26.5) 45 (23.4) 3.1 (-4.6 to 10.3) .49 Fever 77 (20.6) 43 (22.4) -1.8 (-9.2 to 5.2) .70 Rash 76 (20.4) 41 (21.4) -1.0 (-8.4 to 5.9) .87 Vomiting 69 (18.5) 26 (13.5) 5.0 (-1.7 to 11.0) .17 Cough 53 (14.2) 20 (10.4) 3.8 (-2.2 to 9.2) .25 Peripheral edema 54 (14.5) 18 (9.4) 5.1 (-0.8 to 10.4) .11 Fatigue 50 (13.4) 21 (10.9) 2.5 (-3.6 to 7.8) .49 Mucosal inflammation 46 (12.3) 24 (12.5) -0.2 (-6.4 to 5.3) .99 Headache 52 (13.9) 18 (9.4) 4.6 (-1.3 to 9.8) .15 Abdominal pain 44 (11.8) 18 (9.4) 2.4 (-3.3 to 7.5) .47 Acute kidney injury 36 (9.7) 25 (13.0) -3.4 (-9.5 to 1.9) .28 Decreased appetite 38 (10.2) 22 (11.5) -1.3 (-7.2 to 3.9) .74 Hypertension 31 (8.3) 21 (10.9) -2.6 (-8.4 to 2.3) .38 Constipation 27 (7.2) 20 (10.4) -3.2 (-8.8 to 1.5) .26 a Shown here are AEs of any severity that were reported in ≥10% of the patients through week 16 after transplantation. Differences were based on the method of Miettinen and Nurminen. P values were calculated by a 2-sided Fisher’s exact test. 1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Phase 3 Trial of Letermovir Prophylaxis for CMV in HCT: Additional Observations During Safety Review1
• Atrial flutter or atrial fibrillation higher on letermovir − 4.6% letermovir, 1.0% placebo − More patients with cardiac conditions on letermovir arm − Did not lead to study drug discontinuation
• Dyspnea: 8.0% letermovir, 3.1% placebo
• Myalgia: 5.1% letermovir, 1.6% placebo
• Hyperkalemia as AE term: 7.2% letermovir, 2.1% placebo
• Alanine aminotransferase >5x ULN − 3.5% letermovir, 1.6% placebo − Attributed to veno-occlusive disease in some cases
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Phase 3 Trial of Letermovir Prophylaxis for CMV in HCT: Time to Engraftment Through Week 24 Post-HCT1
Patients Who Started Study Drug Before Engraftment, Safety Population
100
80
60
40 Stratified log-rank test, two-sided P = .1047 Engraftment,%
Cumulative Rate of of Rate Cumulative 20 Letermovir Placebo 0 0 2 6 10 14 18 24 Post-Transplant Week No. at Risk Letermovir 235 210 7 1 1 1 1 Placebo 111 97 1 1 0 0 0
1. Marty FM et al. N Engl J Med. 2017;377:2433-2444. Paradigm Shift? Better Overall Survival?
2018
1985 1990 1995 2000 Conclusions
• CMV serostatus and reactivation remains an important variable affecting transplant outcomes, including GVHD incidence, graft failure/rejection, NRM, and survival • Letermovir is a game-changer as a prophylactic agent for CS-CMVi • Letermovir treatment among patients who had detectable CMV DNA at randomization prevented CS-CMVi when compared to placebo • Letermovir may reduce mortality by preventing or delaying CS-CMVi in HCT recipients Focus on Resistant/Refractory CMV: Risk Factors, Clinical Outcomes, and the Role of Novel Antiviral Therapies
Genovefa Papanicolaou, MD Member, Director of Clinical Trials, Infectious Disease Service Memorial Sloan Kettering Cancer Center Professor of Medicine Weill Cornell Medicine Medical College New York, New York Refractory and Resistant (R/R) CMV
Risk Factors
Impact on HCT Outcomes
CMV Resistance Testing
New Therapies Effective CMV Prevention Has Shifted the CMV Continuum No CMV CMV Refractory Resistant viremia Viremia CMV CMV
CMV Worse seropositive outcomes
40%-90% 30%-50% 2%-10% • CMV end-organ • HLA mismatch • HLA mismatch • Refractory viremia disease • T-cell depletion • T-cell depletion • Prolonged • ↑ Organ failure • CMV D- • CMV D- treatment • ↓ Overall survival • GVHD Is R/R CMV of Concern in 2019?
2016 Patient A 2018 Patient B 66-year-old female patient with MDS, 55-year-old male patient with DLBCL, T-cell depleted HCT haploidentical HCT • Day 33: CMV viremia • Day 7: CMV viremia • Day 131: CMV colitis – Pancytopenia/stem cell boost • Day 170: Resistance to GCV/CDV – Letermovir, foscarnet, maribavir, • Day 210: CMV pneumonitis CMV-IGIV, CMV CTL • Day 220: Death • Month 9: CMV retinitis right eye, weekly
7 GCV FOS GCV FOS intravitreal injections BCV BCV 6 • Month 11: Retinal detachment, no CMV • Month 13: Alive, loss of vision in right eye 5 Death due to CMV disease: 4 Colitis, pneumonitis 3
2 Mutation tests: UL54 mutation found:
1 Negative GCV; CDV CMV VL in Plasma, U/mL logPlasma, in VL CMV 0 0 20 40 60 80 100 120 140 160 180 200 220 Time After HCT, d Consensus Definitions for Refractory and Resistant CMV1 • Suboptimal decline in viral load in response to antiviral therapy Refractory CMV Infection
Persistent viral load (<1 log10 decrease) from viral load level at start of CMV therapy after ≥2 weeks of appropriately dosed antiviral therapy
Refractory CMV End-Organ Disease Lack of improvement (or worsening) in signs and symptoms after ≥2 weeks of appropriately dosed antiviral drugs
Resistant CMV Virus with mutations that decrease susceptibility to one or more antiviral drugs
1. Chemaly RF et al; Resistant Definitions Working Group of the Cytomegalovirus Drug Development Forum. Clin Infect Dis. 2018 Aug 22 [Epub ahead of print]. HLA Mismatch, GVHD, and T-Cell Depletion Are Risk Factors For Refractory CMV Infection
Cumulative Incidence of Refractory 50% of TCD Had Viral Load >1,000 U/mL CMV Infection1 After 2 Weeks of Therapy2
GVHD HLA-Mismatched Donor ≥1,000 U/mL <1,000 U/mL Negative
1001
1.01 P < .001 1.01 P < .001 0.990 HLA- 0.880 0.8 Acute 0.8 mismatched GVHD donor 0.770
, , % 0.6 0.6 0.6 60 0.550 0.4 No acute 0.4 0.440 GVHD Matched sibling Patients 0.330
0.2 0.2 0.220
Cumulative Incidence of of Incidence Cumulative
Cumulative Incidence of of Incidence Cumulative Refractory CMV Infection CMV Refractory Refractory CMV Infection CMV Refractory 0.110 0 0 0 20 40 60 80 100 0 20 40 60 80 100 00 Baseline 1 2 3 4 5 6 Time After Allo-HCT, d Time After Allo-HCT, d Time on Antiviral Treatment for CMV, wk
1. Liu J et al. Clin Microbiol Infect. 2015;21:1121.e9-15. 2. Kim SJ et al. Transpl Infect Dis. 2018;e12881. Refractory CMV Is Associated With Worse Outcomes1
CMV Disease Non-relapse Mortality
1.0 1.0
P < .001 P = .012
0.8 0.8
0.6 0.6
0.4 0.4 With refractory CMV infection
0.2 With refractory CMV infection Nonrelapse Mortality
Cumulative Incidence of of CumulativeIncidence 0.2 No refractory CMV infection No refractory CMV infection 0.00 0.00 Cumulative Incidence of CMV CMV of CumulativeDiseaseIncidence 0 200 400 600 800 1,0001000 0 200 400 600 800 1,0001000 Time After Allo-HCT, d Time After Allo-HCT, d
1. Liu J et al. Clin Microbiol Infect. 2015;21:1121.e9-15. Faster Clearance of CMV Viremia Is Associated With Better Survival1
1.0 • CMV clearance by 0.8 treatment day 35 was associated with a 0.6 74% reduction in NRM
Log-rank P = .01 (adjusted HR = 0.26; 0.4 Cleared viremia by treatment day 35 95% CI, 0.1-0.8; P = .02) Unresolved viremia by treatment day 35 0.2
Survival Probability Survival • Initiation of preemptive 0 31 24 21 20 0 34 33 32 29 0 therapy at lower viral load 0 100 200 300 400 was associated with Time Post-Transplant, d faster clearance
1. Camargo J et al. Biol Blood Marrow Transplant. 2018;24:806-814. Case 1
140,000140000 27-year-old male patient with Valganciclovir 120,000120000
T-cell ALL, CMV R+/D-
• History of fungal infection pre-HCT 100,000100000 • Matched PBMC • Thiotepa, cyclophosphamide, 80,00080000 TBI, ATG 60,00060000 • GVHD prophylaxis: T-cell depletion
40,00040000 Viral Load, U/mL Load, Viral Post-HCT 20000 • Letermovir, acyclovir, 20,000 2,000 posaconazole, SMZ-TMP 0 • Visit week 14: + thrush, 14 15 16 17 18 19 20 21 22 23 24 25 anorexia, vomiting Time Post-HCT, wk • + daily marijuana use • CMV <137 U/mL
Case 1 (Cont’d)
140,000140000 Valganciclovir
Week 16 visit 120,000120000
• CMV VL 20,000 100,000100000
• GCV induction started 80,00080000
60,00060000 3 weeks later… 40,00040000 • CMV VL 120,000 U/mL Load, Viral 20,00020000
2,000 0 14 15 16 17 18 19 20 21 22 23 24 25 Time Post-HCT, wk Case 1 (Cont’d)
140,000140000 Valganciclovir 27-year-old male patient with 120,000120000
T-cell ALL, CMV R+/D- 100,000 100000 80,00080000 CMV resistance testing: 60,00060000 No mutations in UL97, U54
40,00040000 Viral Load, U/mL Load, Viral
20,00020000
2,000 Patient admits he was 0 14 15 16 17 18 19 20 21 22 23 24 25 not compliant Time Post-HCT, wk
Case 2
Day • 30-year-old male, refractory acute lymphoblastic lymphoma • Patient and donor are CMV seropositive 1 • GVHD prophylaxis: T-cell depletion
Day • CMV viremia 400 U/mL 12 • Started induction foscarnet
Day • CMV <137 U/mL 28 • Switched to valganciclovir maintenance
Day • CMV viral load 20,000 U/mL 70 • Diarrhea
Day • Resistance testing: UL97 L596S mutation 87 Resistance Develops After Persistent Viral Replication on Antiviral Treatment
Resistant CMV 10%1 Worse Survival With CMV Disease2 100
Mutation n (%) 90 78.3% (170/217) UL97 only 12 (63) 80
70 GCV only 12 (63) 60 Days of CMV treatment, 114 (72-140) 50 median (IQR) 38.5% (5/13) 40 Weeks with CMV VL
6 (3.5-9.5) Survival Overall ≥5,000 U/mL, median (IQR) 30 20 CMV end-organ disease 11 (58) CMV disease 10 No Yes 0 Log-rank P = .0007
0 100 200 300 400 1. Kim SJ et al. Transpl Infect Dis. 2018;e12881. Time After HCT, d 2. Huang YT et al. Biol Blood Marrow Transplant. 2018 Nov 15 [Epub ahead of print]. Suspect Antiviral Drug Resistance When …
CMV viremia (DNAemia or antigenemia) fails to improve
(ie, <1 log10 decrease in CMV DNA levels in blood or serum) after 2 weeks of appropriately dosed and delivered antiviral therapy CMV end-organ disease or recurrent viremia occurs during prolonged antiviral therapy (>6 weeks of antiviral drug exposure, including 2 weeks of full-dose therapy) in the presence of risk factors Prolonged Viral Replication While on Antivirals May Select for CMV Resistance Mutations1
Prolonged drug administration (before and/or after transplant) + Low antiviral drug levels Resistance + Subclinical CMV load + Low immune status + • Drug induced • T-cell depletion (eg, haploidentical donor transplants) • Cord blood transplantation
Resistance is uncommon in HCT recipients from matched donors (0%-5%) and up to 14.5% in high-risk patients
1. Boeckh M et al. Blood. 2009;113:5711-5179. Resistance Mutations Arise in Genes Essential for Viral Replication or Drug Anabolism1
UL97
UL54
1. Lurain NS, Chou S. Clin Microbiol Rev. 2010;23:689-712. Genotypic Assays for CMV Resistance
• Performed directly on clinical specimens
• Rapid turnaround time
• Objective identification of mutations
• Correlation with phenotypic resistance
Analysis reliable if CMV viral load ≥1,000 U/mL
Correlation of Genotypic With Phenotypic Resistance1
UL54 (pol) Resistance Mutations Characterized By Marker Transfer/Recombinant Phenotyping • Phenotypic resistance Amino Acid(s)/Mutation Ratioa (fold-increase in IC50) Region Codon # Wild- Mutant GCV FOS CDV Type • Low-level resistance ExoI 301 D N 2.6 0.5 3.0 may be managed ExoII 408 N D 4.9 1.3 5.6 with higher doses 408 N K 4.2 0.7 21.0 of antivirals 410 N K 2.9 0.8 3.0 412 F C 4.2 1.2 18.0
412 F V 4.3 1.1 15.5
413 D A 6.5 0.8 11.0
413 D E 4.8 0.8 4.3
IV 495 N K 1.1 3.4 1.1 a IC50 of mutant/IC50 of wild type. 1. Lurain NS, Chou S. Clin Microbiol Rev. 2010;23:689-712. Management of Refractory/Resistant CMV1
Refractory CMV or CMV drug resistance suspected CMV viremia (DNAemia or antigenemia) not improving or increasing after • Prior antiviral exposure 2 weeks of adequate therapy in drug-naïve patients OR New or worsening CMV end-organ disease with >6 weeks of therapy • Phenotypic resistance
(fold-increase in IC50) Was the patient receiving GCV or VCV? YES • Tolerability/toxicities Switch to FOS AND Check for genotypic analysis for drug resistance AND Reduce immunosuppression if possible
(+) UL97 mutation(s) (+) UL54 mutation(s)
≥5-fold GCV EC50 (ie, M460V, H530Q, A594V, L595S, C603W, L595F) ≤5-fold GCV EC50 Refer to (+) UL54 mutation(s) (M460I, C592G, L595W) management algorithm
Continue FOS monotherapy AND YES Suspected or confirmed CMV NO Increase GCV dose AND Consider adding leflunomide as adjunct therapy, particularly end-organ disease? Consider half-dose of FOS for maintenance therapy; if no response or serious toxicities, consider one or a combination of investigational agents
1. El Chaer F et al. Blood. 2016;128:2624-2636. Case 3
46-year-old female patient with AML CMV R+/D+ Letermovir 16,00016000 • Mismatched PBMC 14,00014000
• Thiotepa, cyclophosphamide, 12,00012000 TBI, ATG 10,00010000 • GVHD prophylaxis: 8,0008000 T-cell depletion • Day 11: CMV viral load 6,0006000
<137 U/mL U/mL Load, Viral 4,0004000 • Started on letermovir 2,0002000 137 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time Post-HCT, wk Case 3 (Cont’d)
CMV viral load rising after 12 weeks of letermovir Letermovir prophylaxis 16,00016000 14,00014000
Requires G-CSF intermittently 12,00012000 10,00010000
8,0008000 6,0006000
Viral Load, U/mL Load, Viral 4,0004000 2,0002000 137 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time Post-HCT, wk Letermovir Resistance Is Due to Mutations in the CMV Terminase Complex1,2
1. Bogner E et al. J Virol. 1998;72:2259-2264. 2. Ligat G et al. FEMS Microbiol Rev. 2018;42:137-145. Letermovir Resistance in Clinical Isolates1,2
1. Knoll BM et al. Bone Marrow Transplant. 2018 Nov 6 [Epub ahead of print]. 2. Turner N et al. Antimicrob. Agents Chemother. 2019 Jan 14 [Epub ahead of print]. Case 3 (Cont’d)
After 2 weeks of Valganciclovir valganciclovir, CMV viral load Letermovir 16,00016000 <1 log10 decline 2 weeks 14,00014000
The patient requires 12,00012000 intermittent G-CSF 10,00010000 UL56 C325F <1 log10 8,0008000 Letermovir resistance 6,0006000
Viral Load, U/mL Load, Viral 4,0004000 2,0002000 137 0 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time Post-HCT, wk CMV Modalities
Antivirals Biologics
GCV • Vaccines Brincidofovir Letermovir Maribavir Foscarnet • Antibodies
DNA Terminase UL97 • Adoptive cell therapy POL
Nucleus Cytoplasm Maribavir: Overview of Efficacy and Safety in Phase 2 Trials
HCT + SOT HCT + SOT
Refractory/resistant Preemptive treatment CMV infection
Comparable rates of patients achieving Within 6 weeks, 67% of patients had 1 undetectable CMV DNA within 6 weeks undetectable plasma CMV DNA with maribavir and valganciclovir2
Side effects: Dysgeusia and nausea, vomiting
1. Papanicolaou G et al. 2017 BMT Tandem Meetings (BMT 2017). Abstract 45. 2. Maertens JA et al. BMT 2017. Abstract 229. Maribavir Versus Valganciclovir for Preemptive Treatment of CMV Viremia1,2
• Randomized, multicenter, dose-ranging, active-controlled phase 2 trial – Primary endpoint: Undetectable plasma CMV DNA (<200 copies/mL) within 3 or 6 weeks of treatment Week 12
Maribavira 400 mg twice daily PO (n = 40) Stem cell or SOT a recipients aged ≥18 y; Maribavir 800 mg Follow-up CMV DNA twice daily PO (n = 40) 12 weeks 1,000-100,000 copies/mL; a Maribavir 1,200 mg post-treatment no CMV organ disease twice daily PO (n = 39) (N = 159) Valganciclovirb 900 mg twice daily PO (n = 40) • 52% of patients received stem cell transplant a Patients receiving maribavir knew they were receiving this drug, but we blinded to dose; valganciclovir treatment open label. b Twice weekly weeks 1-3, then once daily; adjusted for renal function. 1. Maertens J et al. IDWeek 2016. Abstract 2287. 2. Maertens JA et al. BMT 2017. Abstract 229. Maribavir or Valganciclovir for CMV Viremia: Phase 2 Trial1
MBV 400 mg BID MBV 800 mg BID MBV 1,200 mg BID VGC 900 mg BID/QD 100.0 89.5 84.2 80.0 80.0 76.2 75.0 73.7 70.0
60.0 47.6 40.0
Within 6 Weeks, % 6Weeks, Within 20.0
Undetectable Plasma CMV DNA CMVDNA Plasma Undetectable 0.0 HCT SOT
1. Maertens JA et al. BMT 2017. Abstract 229. Maribavir or Valganciclovir for CMV Viremia: Phase 2 Trial (Cont’d)1
MBV MBV MBV VCG Treatment Week 6 400 mg BID 800 mg BID 1,200 mg BID 900 mg BID
N 40 40 39 40
Patients with 31 33 28 26 undetectable plasma (77.5%) (82.5%) (71.8%) (65.0%) CMV DNA ~50% HCT, 50% SOT European Centers Treatment effect rate 0.79 0.83 0.74 0.67 (95% CI) (0.64-0.91) (0.67-0.93) (0.57-0.87) (0.50-0.81)
Treatment comparison 2.13 2.97 1.48 1 OR (95% CI) (0.72-6.30) (0.94-9.35) (0.53-4.16) (reference)
Patients with missing 1 (2.5%) 0 1 (2.6%) 1 (2.5%) data
1. Maertens JA et al. BMT 2017. Abstract 229. Maribavir Versus Valganciclovir for Preemptive Treatment of CMV Viremia1 Time to Confirmed Undetectable Plasma CMV DNA Within 6 Weeks (ITT Population)
MBV 400 mg BID (n = 39) MBV 800 mg BID (n = 40) MBV 1,200 mg BID (n = 38) MBV all doses (n = 117) VGC 900 mg (n = 39)
1. Maertens JA et al. BMT 2017. Abstract 229. Maribavir Versus Valganciclovir for Preemptive Treatment of CMV Viremia (Cont’d)1,2
MBV 400 mg MBV 800 mg MBV 1,200 mg MBV All Doses VCG Outcome (n = 40) (n = 40) (n = 39) (n = 119) (n = 40) Undetectable CMV DNA 65.0 57.5 59.0 60.5 55.0 within 3 wk, % P vs VCG .28 .72 .64 .41 — Undetectable CMV DNA 77.5 82.5 71.8 77.3 65.0 within 6 wk, % P vs VCG .17 .06 .45 .08 — CMV recurrence, % (n/N)a Within 6 wk 0 5.9 (2 / 34) 0 2.0 (2 / 98) 0 During study period 30.3 (10 / 33) 23.5 (8 / 34) 12.9 (4 / 31) 22.4 (22 / 98) 17.9 (5 / 28) Discontinuation for AEs, %b 30.0 / 12.5 12.5 / 10.0 25.6 / 17.9 22.7 / 13.4 12.5 / 10.0 TEAEs, %b 97.5 / 62.5 95.0 / 62.5 100.0 / 76.9 97.5 / 67.2 85.0 / 22.5 Serious TEAEs, %b 40.0 / 7.5 42.5 / 2.5 48.7 / 20.5 43.7 / 10.1 32.5 / 2.5 Death, %b 5.0 / 0.0 2.5 / 0.0 7.7 / 0.0 5.0 / 0.0 7.5 / 0.0 a In patients with ≥2 undetectable CMV DNA results, only 1 of which had to precede post-treatment follow-up. b Overall/drug related. 1. Maertens J et al. IDWeek 2016. Abstract 2287. 2. Maertens JA et al. BMT 2017. Abstract 229. Maribavir Versus Valganciclovir for Preemptive Treatment of CMV Viremia (Cont’d)1,2
MBV 400 mg MBV 800 mg MBV 1,200 mg MBV All Doses VCG Outcome (n = 40) (n = 40) (n = 39) (n = 119) (n = 40) Clearance of viremia Undetectable CMV DNA 65.0 57.5 59.0 60.5 55.0 at 6 weeks: within 3 wk, % 77% maribavir P vs VCG .28 .72 .64 .41 — vs 65% valganciclovir Undetectable CMV DNA 77.5 82.5 71.8 77.3 65.0 within 6 wk, %
P vs VCG .17 .06 .45 .08 — No new safety concerns CMV recurrence, % (n/N)a
Within 6 wk 0 5.9 (2 / 34) 0 2.0 (2 / 98) 0 During study period 30.3 (10 / 33) 23.5 (8 / 34) 12.9 (4 / 31) 22.4 (22 / 98) 17.9 (5 / 28) Discontinuation for AEs, %b 30.0 / 12.5 12.5 / 10.0 25.6 / 17.9 22.7 / 13.4 12.5 / 10.0 TEAEs, %b 97.5 / 62.5 95.0 / 62.5 100.0 / 76.9 97.5 / 67.2 85.0 / 22.5 Serious TEAEs, %b 40.0 / 7.5 42.5 / 2.5 48.7 / 20.5 43.7 / 10.1 32.5 / 2.5 Death, %b 5.0 / 0.0 2.5 / 0.0 7.7 / 0.0 5.0 / 0.0 7.5 / 0.0
a In patients with ≥2 undetectable CMV DNA results, only 1 of which had to precede post-treatment follow-up. b Overall/drug related. 1. Maertens J et al. IDWeek 2016. Abstract 2287. 2. Maertens JA et al. BMT 2017. Abstract 229. Maribavir for Refractory or Resistant CMV Infection: Phase 2 Trial1
• Multicenter, randomized, dose-ranging, parallel-group study • HCT/SOT recipients older than 12 years with CMV infection that is – Refractory: <1 log reduction in CMV viral load after ≥14 days of treatment with (val)ganciclovir or foscarnet, and ≥1,000 DNA copies/mL at screening – Resistant: Refractory plus resistant mutations in UL97 and/or UL54 • Patients (stratified by SCT vs SOT) randomized 1:1:1, blinded to dose, to receive oral maribavir 400, 800, or 1,200 mg BID for up to 24 weeksa
a Halving a dose was allowed per protocol for tolerability issues. 1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print].. Maribavir for Refractory or Resistant CMV Infection: Phase 2 Trial (Cont’d)1
CMV Viremia <200 Copies/mL by Week 6
CMV DNA Within 6 Weeks, % Within Weeks, 6 DNA CMV Confirmed Undetectable Plasma Undetectable Confirmed MBV MBV MBV MBV 400 mg BID 800 mg BID 1,200 mg BID all doses (n = 40) (n = 40) (n = 40) (N = 120)
1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Median Time to Undetectable Plasma CMV DNA at Any Time During the Study1
Time to Undetectable CMV Viremia
MBV 400 mg BID MBV 800 mg BID MBV 1,200 mg BID MBV all doses
Treatment, Day
1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Efficacy Outcomes for Maribavir (ITT Population): Primary Efficacy Endpoint1
Patients With Confirmed Undetectable Plasma CMV DNA Within 6 Weeks, n (%) Maribavir Maribavir Maribavir All Doses Outcome 400 mg BID 800 mg BID 1,200 mg BID (N = 120) (n = 40) (n = 40) (n = 40) Yes, n (%) 28 (70.0) 25 (62.5) 27 (67.5) 80 (66.7) No, n (%) 12 (30.0) 15 (37.5) 11 (27.5) 38 (31.7) Patients with missing data (no post-baseline CMV measurement 0 0 2 (5.0) 2 (1.7) within 6 weeks), n (%) Treatment effect estimate by group Estimated ratea 0.70 0.63 0.68 0.67
95% CI 0.53-0.83 0.46-0.77 0.51-0.81 0.57-0.75
1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Maribavir for Refractory or Resistant CMV Infection: Phase 2 Trial1 Recurrence of CMV Viremia On study drug Post study druga 30.0% 25.0% 25.0% 25.0% 22.2% 20.0% 16.7% 15.0% 10.0% 8.3% 8.3% 5.6% 5.0% 0.0%
0.0% CMV CMV Recurrence, % Maribavir Maribavir Maribavir Maribavir 400 mg BID 800 mg BID 1,200 mg BID all doses (n = 40) (n = 40) (n = 40) (N = 120)
a Follow-up assessments through 2 weeks post-treatment. 1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Efficacy Outcomes for Maribavir (ITT Population): Secondary Efficacy Endpoint1 CMV Recurrence in Patients Achieving Undetectable CMV DNA
MBV MBV MBV All Doses Outcome 400 mg BID 800 mg BID 1,200 mg BID (N = 120) (n = 40) (n = 40) (n = 40)
Patients achieving confirmed undetectable CMV DNA during the study, as defined in the 29 27 30 86 recurrence analysis, n
Patients with CMV recurrence at any time during the study, n (%)c
Yes 7 (24.1) 11 (40.7) 12 (40.0) 30 (34.9)
No 22 (75.9) 14 (51.9) 17 (56.7) 53 (61.6) Treatment effect estimate by group Estimated rate 0.24 0.41 0.40 0.35
1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Kaplan-Meier Plot for Time From Confirmed Undetectable Plasma CMV DNA to CMV Recurrence1
1.01 0.9
0.8
Free - 0.7 0.6 0.5 0.4 Maribavir 400 mg (n = 29) 0.3 Maribavir 800 mg (n = 27) 0.2 Maribavir 1,200 mg (n = 30)
0.1 Maribavir all doses (N = 86) Remaining EventRemaining
Cumulative Probability Cumulative of Probability 0 0 7 14 21 28 35 42 49 56 63 70 77 84 91 98 105 112 119 126 133 140 147 154 161 168 175 182 189 196 203 Time, d No. of Patients With Event/At Risk 0/ 0/ 0/ 1/ 0/ 2/ 4/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ Maribavir 400 mg 29 29 29 27 27 23 19 18 17 17 16 16 16 16 16 15 13 13 12 10 10 10 9 9 8 8 8 8 8 8
Maribavir 800 mg 0/ 0/ 0/ 3/ 2/ 0/ 2/ 1/ 1/ 0/ 0/ 0/ 0/ 0/ 1/ 0/ 0/ 1/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 0/ 27 27 25 22 20 18 14 13 12 12 12 11 10 10 9 9 9 8 7 7 6 5 5 5 5 5 5 4 4 3
Maribavir 1,200 mg 0/ 0/ 0/ 0/ 2/ 1/ 1/ 0/ 1/ 0/ 0/ 1/ 0/ 0/ 2/ 0/ 1/ 0/ 1/ 0/ 0/ 1/ 0/ 1/ 0/ 0/ 0/ 0/ 0/ 0/ 30 30 30 28 26 25 22 21 20 19 19 17 17 17 14 14 13 13 11 10 10 10 9 8 7 5 5 5 4 4
Maribavir all doses 0/ 0/ 0/ 4/ 4/ 3/ 7/ 1/ 2/ 0/ 0/ 1/ 0/ 0/ 3/ 0/ 1/ 1/ 1/ 0/ 0/ 1/ 0/ 1/ 0/ 0/ 0/ 0/ 0/ 0/ 86 86 84 77 73 66 55 52 49 48 47 44 43 43 39 38 35 34 30 27 26 25 23 22 20 18 18 17 16 15
1. Papanicolaou GA et al. Clin Infect Dis. 2018 Oct 16 [Epub ahead of print]. Maribavir: Ongoing Phase 3 Studies
A Phase 3, Multicenter, Randomized, Open-label, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Treatment Compared to Investigator-assigned Treatment in Transplant Recipients With Cytomegalovirus (CMV) Infections That Are Refractory or Resistant to Treatment With Ganciclovir, Valganciclovir, Foscarnet, or Cidofovir • ClinicalTrials.gov Identifier: NCT02931539 • Status: Recruiting
A Phase 3, Multicenter, Randomized, Double-blind, Double-dummy, Active-controlled Study to Assess the Efficacy and Safety of Maribavir Compared to Valganciclovir for the Treatment of Cytomegalovirus (CMV) Infection in Hematopoietic Stem Cell Transplant Recipients • ClinicalTrials.gov Identifier: NCT02927067 • Status: Recruiting Preemptive Therapy Is Associated With Toxicities1
Acute Kidney Injury Decrease ANC or PLT
12.5% 31.4% FOS 26.4%
VCG 73.6%
FOS (n = 32) VCG (n = 89)
1. Zavras P et al. 2019 Transplantation and Cellular Therapy Meetings of ASBMT and CIBMTR. GCV Treatment Is Associated With Neutropenia1
278 BM Recipients, GCV Prophylaxis From Engraftment Through Day 100
Rate in Pts Treated With Invasive Fungal Rate in Pts Treated With Neutropenia Bacteremias Ratea Ratea G-CSF or GM-CSFa Infections G-CSF or GM-CSFa None (n = 119) 19 1.48 — 17 1.33 — <1,500/mcL (n = 47) 11 2.03 — 5 0.92 — <1,000/mcL (n = 25) 4 1.30 — 2 0.65 — <750/mcL (n = 31) 11 3.28 2.77 (n = 6) 4 1.19 — <500/mcL (n = 37) 14 3.36 4.69 (n = 12) 6 1.44 2.00 (n = 12) <200/mcL (n = 19) 11 5.98 6.80 (n = 6) 7 3.81 3.44 (n = 6)
ANC <750 Was Associated With Worse Outcomes Outcome RR (95% CI) P Overall survival 2.03 (1.41-2.93) .0001 Event-free survival 2.09 (1.47-2.97) .0001 Nonrelapse mortality 2.05 (1.28-3.28) 0.028 a Number of episodes per 1,000 patient-days. 1. Salzberger B et al. Blood. 1997;90:2502-2508. Foscarnet Therapy Is Associated With Nephrotoxicity in HCT1
Renal Renal Deaths by Study Year/Center Patients Total Dysfunction Dysfunction Year 1 End of FOS Long-Term FOS-treated R/R 7/25 (24%) Current study 2015 Johns Hopkins 39 (all FOS) 12/39 (31%) 20/39 (51%) SOT + HCT at 6 mo Pierce et al 2015 Northwestern FOS-treated R/R SOT 31 (all FOS) 10/31 (32%) 5/21 (24%) 3/21 (14%) 2014 University 38 cases, 15/37 (41%) Fisher et al GCV-R SOT 8/38 (21%) NR of Washington 110 controls at 3 mo 2014 University Minces et al GCV-R lung transplant 16 (14 FOS) 5/16 (31%) 10/14 (71%) NR of Pittsburgh GCV-R kidney Myhre et al 2011 Oslo University 27 (10 FOS) 2/10 (20%) NR NR transplant
2010 Nagoya 65 CMV disease a Asakura et al FOS-treated HCT 45/65 (69%) 3% NR University (all FOS)
Reddy et al 2007 Duke University GCV-R lung transplant 6 (all FOS) 1/6 (17%) 2/6 (33%) 0/6 (0%)
b Isada et al 2002 Cleveland Clinic GCV-R SOT 13 (10 FOS) 9/10 (90%) NR NR a Asakura et al included 320 allogeneic HCT recipients, 65 of whom received FOS for treatment of CMV disease, whereas others were treated with FOS for preemptive therapy or prophylaxis. Mortality data estimated. Renal dysfunction data refers to the entire group which included those receiving FOS for preemptive therapy. b Although overall nephrotoxicity was not reported in Isada et al, 4 of 5 (80%) of kidney transplant recipients developed graft loss. 1. Avery RK et al. Transplantation. 2016;100:e74-e80. Brincidofovir: Phase 3 CMV Prevention Study (SUPPRESS)1
By week 14, end of treatment • Fewer clinically significant CMV infections in brincidofovir arm than in placebo group (24% vs 38%, P = .002) By week 24, end of follow-up • Similar rates of clinically significant CMV infections in brincidofovir (51%) and placebo (52%) arms • Brincidofovir arm had more diarrhea and more empiric treatment of GVHD (corticosteroids and other immunosuppressive therapies) • An intravenous formulation of brincidofovir is in development
1. Marty FM et al. Biol Blood Marrow Transplant. 2016;22:s23. Abstract 5. Third-Party CMV-Specific T-Cells1,2
• Small single-center studies have shown feasibility, safety, and effectiveness
• CMV or multivirus specificities
• No major safety concerns
• Randomized trials are needed
1. Prockop S et al. 58th American Society of Hematology Annual Meeting (ASH 2016). Abstract 61. 2. Tzannou I et al. J Clin Oncol. 2017;35:3547-3557. CMV Responses With Off-the-Shelf Multivirus-Specific T-Cells1 Third-Party CMV-Specific T-Cells Patients Outcome, % (n/N) Multivirus T-Cells, CMV Responses2 (N = 15) 1.01 Response • CRa + PRb 73 (11/15) 0.8 • CR 40 (6/15) • SD + PD 27 (4/15) 0.6
6-month overall survival 0.4 Probability • Responder (CR + PR) 73 (8/11) • Nonresponder (SD + PD) 25 (1/4) 0.2 0 • In vivo expansion of CMV CTLs evident in 0 7 14 21 28 35 42 responders, absent in nonresponders Time Post-Infusion, d
• In all patients receiving CMV CTLs at investigative site (N = 66), no serious AEs Cells specific for CMV, EBV, ADV, BKV probably/definitely related to treatment; CMV responses in 17 patients n = 1 GVHD possibly related to treatment a CR = No CMV viremia, biopsy-proven resolution of disease. b PR = 2 log10 decline in CMV viremia, resolution of symptoms. 1. Tzannou I et al. J Clin Oncol. 2017;35:3547-3557. Third-Party CMV-Specific T-Cells for Resistant CMV: Key Results1
Patients Outcome, % (n/N) Overall Survival by T-Cell Response (N = 15) Response 100 • CRa + PRb 73 (11/15) • CR 40 (6/15) 80 Responder
• SD + PD 27 (4/15) (CR + PR; n = 11) 6-month overall survival 60 • Responder (CR + PR) 73 (8/11) • Nonresponder (SD + PD) 25 (1/4) 40
• In vivo expansion of CMV CTLs evident in % Survival, Nonresponder responders, absent in nonresponders 20 (SD + PD; n = 4) P = .04 • In all patients receiving CMV CTLs at 0 investigative site (N = 66), no serious AEs 0 2 4 6 probably/definitely related to treatment; Time, mo n = 1 GVHD possibly related to treatment a CR = No CMV viremia, biopsy-proven resolution of disease. b PR = 2 log10 decline in CMV viremia, resolution of symptoms. 1. Prockop S et al. ASH 2016. Abstract 61. CMV Vaccines1
Multi-peptide CMV modified vaccinia Ankara (MVA) vaccine • Phase 2 randomized trial ongoing • ClinicalTrials.gov Identifier: NCT02506933
Phase Ib pilot trial two injections of CMVPepVax (at days 28 and 56 post-HCT) • Targeting HLA0201 demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and use of antivirals1 • ClinicalTrials.gov Identifier: NCT01588015
Phase 3 randomized trial of ASP00113 the Astellas DNA-based vaccine for prevention of CMV in CMV seropositive HCT did not show difference in mortality or CMV viremia compared to placebo
1. Nakamura R et al. Lancet Haematol. 2016;3:e87-e98. CMV Monoclonal Antibodies: Early Development1-3
Efficacy and Safety Study of CSJ148 in HCT • ClinicalTrials.gov Identifier: NCT02268526 • Completed
1. https://clinicaltrials.gov/ct2/show/NCT02268526. Accessed January 28, 2019. 2. Martins JP et al. Science. 2019;363:288-293. 3. Krauvar LM et al. Antimicrob Agents Chemother. 2015;59:1558-1568. Conclusions
Maribavir has shown efficacy and safety for preemptive therapy and R/R CMV; phase 3 studies are ongoing for these indications
The availability of multiple modalities will enhance our ability to select the optimal strategy for each patient
Laboratory assays (resistance genotype, CMV immunity) are used to inform the type and duration of CMV therapy
Adoptive cell therapy trials with off-the-shelf CTLs are ongoing Bridging the Gap From “Alive” to “Well”
CMV Spectrum • Prevent death (1980s) • Prevent end-organ disease (1990s) • Prevent viremia (2017) • Reduce treatment-related toxicities • Individualized approach • Patient-centered outcomes Abbreviations
• ADV: adenovirus • CMV: cytomegalovirus • FOS: foscarnet • ALC: absolute lymphocyte count • CR: complete response • G-CSF: granulocyte-colony • ALL: acute lymphoblastic leukemia • CS-CMVi: clinically significant stimulating factor • allo-HCT: allogeneic hematopoietic cytomegalovirus infection • GCV: ganciclovir cell transplantation • CTL: cytotoxic T lymphocyte • GCV-R: ganciclovir-resistant • AML: acute myeloid leukemia • D+: seropositive donor cytomegalovirus • ANC: absolute neutrophil count • D-: seronegative donor • GFR: glomerular filtration rate • ATG: antithymocyte globulin • DLBCL: diffuse large B-cell • GM-CSF: granulocyte-macrophage colony-stimulating factor • BID: twice per day lymphoma • GVHD: graft-versus-host disease • BKV: BK virus • EBV: Epstein-Barr Virus • EC : 50% effective concentration • HCMV: human cytomegalovirus • BM: bone marrow 50 • exo: exonuclease • HCT: hematopoietic cell • CBT: cord blood transplant transplantation • FAS: full analysis set • CDV: cidofovir • HLA: human leukocyte antigen • CML: chronic myeloid leukemia • FHCRC: Fred Hutchinson Cancer Research Center • HR: high risk Abbreviations
• IC50: half maximal inhibitory • PB: peripheral blood • SD: stable disease concentration • PBMC: peripheral blood • SOT: solid-organ transplant • IHC: immunohistochemistry mononuclear cell • TBI: total body irradiation • IQR: interquartile range • PCR: protein chain reaction • TCD: T-cell depleted • IR: intermediate risk • PD: progressive disease • TEAE: treatment-emergent adverse • LTV: letermovir • PET: positron emission tomography event • MBV: maribavir • PLT: platelet • UGI: upper gastrointestinal • MDS: myelodysplastic syndrome • POL: polymerase endoscopy • mITT: modified intent-to-treat • PR: partial response • VCG: valganciclovir • MSKCC: Memorial Sloan Kettering • QD: daily • VL: viral load Cancer Center • R+: seropositive recipient • MUD: matched unrelated donor • R/R: relapsed/refractory • N/V: nausea/vomiting • RR: risk ratio • NRM: non-relapse mortality • sCr: serum creatinine