MacroGenics : Prophylactic Ruxolitinib for CRS in RR AML Pts Treated w Flotetuzumab (Uy)

Prophylactic Ruxolitinib for Cytokine Release Syndrome (CRS) in Relapse/Refractory (R/R) AML Patients Treated with Flotetuzumab

Geoffrey L. Uy, MD; Michael P. Rettig, Stephanie Christ, MS; PhD; Ibrahim Aldoss, MD; Michael Byrne, DO; Harry Erba, MD, PhD; Martha

L. Arellano, MD; Matthew C Foster, MD; John E. Godwin, MD; Farhad Ravandi, MD; Peter H. Sayre, MD, PhD; Anjali S. Advani, MD; Matthew J. Wieduwilt, MD, PhD; Ashkan Emadi, MD, PhD; Laura Michaelis, MD; Patrick J. Stiff, MD; Martin Wermke, MD; Norbert Vey, MD, PhD; Patrice Chevalier, MD PhD; Emmanuel Gyan, MD, PhD; Christian Recher, MD PhD; Fabio Ciceri, MD; Matteo Giovanni Carrabba, MD; Stefania Paolini, MD; Antonio Curti, MD, PhD; Gerwin A Huls, MD, PhD; Mojca Jongen-Lavrencic, MD, PhD; John Muth, MS; Teia Curtis, BA; Marybeth Collins, BS; Erin Fehr, BS; Kuo Guo, MSc; Jian Zhao, PhD; Kathy Tran, BS; Patrick Kaminker, PhD; Priyanka Patel, Pharm D.; Ouiam Bakkacha, MD; Kenneth Jacobs, MD; Maya Kostova, PhD; Jennifer Seiler, PhD, RAC; Bob Löwenberg, MD, PhD; Sergio Rutella, MD, PhD, FRCPath; Roland B. Walter, MD, PhD, MS; Ezio Bonvini, MD; Jan K Davidson-Moncada, MD, PhD; John F. DiPersio, MD, PhD

Background

• CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies and limits the therapeutic window of novel immunotherapeutic agents.
• Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may blocking CRS by interfering with cytokines including IFNγ and IL6

We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML

patients undergoing treatment with flotetuzumab (FLZ), aCD123 x CD3 bispecific DART® molecule.

Patients and Methods

Characteristic		Non-RUX (n=21)	RUX (n=10)
Age	Median (Range)	58 (28-74)	65 (40-82)
Gender [n(%)]	Female	8 (38.1)	2 (20.0)
	Primary Induction Failure	12 (57.1)	6 (60.0)
AML Status at Study Entry	Early Relapse (CR1 < 6 months)	9 (42.8)	2 (20.0)
	Other	0	2 (20.0)
AML Risk Stratification	Adverse	15 (71.4)	8 (80.0)
Intermediate	6 (28.6)	2 (20.0)
(ELN 2017)
Favorable	0	0
Secondary AML		11 (52.4)	1 (10.0)
Number of Prior Lines of Therapy	Median (Range)	2.0 (1.0, 3.0)	2.0 (1.0, 5.0)
Baseline BM blasts	Mean ± SD	39.1 ± 22.5	24.0 ± 21.8
Median (Range)	40 (10.0, 84.0)	15.0 (5.0, 72.0)

• Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study.
• RUX pts were treated at a single site, Washington University, St. Louis, MO. Randomly selected comparator cohort (non-RUX) pts (n=21) were treated at other clinical sites at same dose during the same timeframe.

• FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-steplead-in dosing in week 1 of cycle 1.
• RUX was dosed at 10 mg (n=6) or 20mg (n=4) BID days -1 through 14.
• CRS was graded per Lee criteria1.

Flotetuzumab dosing:	LID	500ng/kg/day
Days: -11
	14	28
Ruxolitinib (10 or 20 mg bid):

Ruxolitinib modifies cytokine levels

Cytokine analysis showed statistically significant (p<0.05) lower levels of IL4, IL12p70, IL13, IL15, IL17A, IFNα2, but higher levels of GM-CSF were measured in RUX vs non-RUX pts, specifically during co-administration with FLZ.

		IL4		Rux
			Non-RUX
	2000
	1500
pg/mL	1000
	500
	0
	1 2 3 4 5 6 7 8 9	10 11 12 13 14 15 16 17 18 19 20	21 22 23 24	25 26 27 28
		Cycle 1 (day)

			IL12p70	Rux
			Non-RUX
	80
	60
pg/mL	40
	20
	0
	1 2 3 4 5 6 7 8 9	10 11 12	13	14	15 16 17	18 19 20 21 22 23 24 25 26 27 28
			Cycle 1 (day)

			IL13		Rux
				Non-RUX
300
200
pg/mL
100
0
1 2 3 4 5 6 7 8 9	10 11	12 13	14	15 16	17	18 19 20 21 22 23 24 25 26 27 28
		Cycle 1 (day)

pg/mL

50

40

30

20

10

0

1

IL15

Rux

IL17A

Rux

IFNα 2

Rux

Non-RUX

Non-RUX

150

Non-RUX

50

40

	30	100
pg/mL	pg/mL
20
	50

10

																																																						0																																																										0
2 3 4 5 6 7 8 9	10 11 12 13	14	15	16	17	18 19 20 21 22 23 24 25 26 27 28	1 2 3 4 5 6 7 8 9	10	11 12 13	14	15	16	17 18 19 20	21 22 23 24 25 26 27 28	1 2 3 4 5 6 7 8	9	10	11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
																						Cycle 1 (day)																																																Cycle 1 (day)																																											Cycle 1 (day)

GM-CSF				Rux
			Non-RUX

150
100
pg/mL
50
0
1 2 3 4 5 6 7 8 9	10 11 12	13	14	15	16	17 18	19	20 21 22 23 24 25 26 27 28
		Cycle 1 (day)

		IL6				Rux				IFNg			Rux
					Non-RUX						Non-RUX
3000								300
2000								200
pg/mL								pg/mL
1000								100
0								0
1 2 3 4 5 6 7 8 9	10 11 12 13	14	15 16	17 18	19 20 21	22 23	24 25 26 27 28	1 2 3 4 5 6 7 8 9	10 11	12 13	14 15 16	17 18	19 20	21 22 23 24 25 26 27 28
	Cycle 1 (day)						Cycle 1 (day)

Cytokine levels for pts treated with FLZ at 500 ng/kg/day continuously in 28-day cycles following multi-steplead-in dosing in week 1 of cycle 1. RUX pts (blue) received ruxolitinib 10 mg or 20mg BID days -1 through 14 (yellow block).

Ruxolitinib did not impact Incidence, Severity or Duration of Cytokine Release Syndrome

• Most CRS events occurred in the first 2 weeks of FLZ administration in both groups.
• In the RUX and non-RUX groups median severity of CRS events were 1 and 2 per patient, respectively.
• Median CRS duration was equal for both groups.

	100
events)				Non-RUX
			Non-RUX
	75			Rux
of total	50													p= 0.96
(%	25
event			RUX
CRS
	0			0	1	2	3	4	5	6	7	8	9	10
	1	2	3	4	Duration of CRS Events (days; median ± 95% CI)

Cycle 1 (week)

Events per Pt (median, range)

5
4		C1 D1-14
Non-RUX	p= 0.84
3		C1 D1-28

2

C1 D1-14

1								RUX										p= 0.87
							C1 D1-28
0
	-14		-28		-14		-28	0	1	2	3	4	5	6	7	8	9	10
C1	D1	C1	D1	C1	D1	C1	D1	Time Spent in CRS Cycle 1 (days; median ± 95% CI)
	RUX			non-RUX

More CRS-directed treatments were used during cycle 1 for CRS management in the ruxolitinib group

Doses administered

	Tocilizumab	Steroids	Vasopressors
Non-RUX (n=21)	12	4	2
RUX (n=10)	13	1	1
Pts treated % (n)
	Tocilizumab	Steroids	Vasopressors
Non-RUX (n=21)	33.3% (7)	14.3% (3)	4.8% (1)
RUX (n=10)	60% (6)	10% (1)	10% (1)

Ruxolitinib did not Impact Dose Intensity or Anti-leukemic Activity

• Dose intensity (DI) at FLZ dose of 500 ng/kg/day was comparable, with median DI of 95.6% and 98.3% in RUX and non- RUX cohorts, respectively.
• Complete response rate (BM < 5% blasts) was similar: 4 (40%) in RUX pts, and 6 (28.6%) in non-RUX pts
• Two RUX (50%) and 4 non-RUX (66.7%) responders transitioned to stem cell transplant

Flotetuzumab (ng/kg/day)

500

400

300

200

100

0

						350	Survival	100				non-RUX	Survival	100			non-RUX
						300					RUX					RUX
						100	of							of
					(%)	Probability	50						Probability	50
					75
					Change	50		0							0
						0	5	10	15	20	25		0	10	20	30
						25			Duration of Response (months)				Overall Survival (months)
		Planned Dose
			BM	0
		non-RUX
		RUX			Best	-25
					-50
1	8	15	22	29		-75	RUX
	non-RUX
		Days in Cycle 1				-100

Conclusions

• Prophylactic RUX produced a clear difference in cytokine profiles but no discernable improvement in clinical CRS or response rates in FLZ treated patients.
• A larger study may be required to determine the prophylactic role of RUX in CRS.

Acknowledgements

We are grateful to the patients who participated in this study and their families

Clinical trial teams at the study centers:

Max S. Topp , MD, Universitätsklinikum Würzburg; Martin Wermke, MD,Universitätsklinikum Carl Gustav Carus an der Technischen

Universität Dresden; Norbert Vey, MD, Institut Paoli-Calmettes; Fabio Ciceri, MD, Matteo Carraba, MD, University Vita-Salute San Raffaele; Stefania Paolini, MD, Antonio Curti, M.D, PhD, Policlinico Sant'Orsola-Malpighi; Gerwin A. Huls, MD, University Medical Center Groningen; Bob Lowenberg, MD, Mojca Jongen-Lavrenic, MD, Erasmus University Medical Center; Geoffrey L. Uy, MD, Washington University School of Medicine; Harry Erba, MD PhD, Duke University Medical Center; Martha Arellano, MD, Emory University School of Medicine; Matthew C.

Foster, MD, UNC Lineberger Comprehensive Cancer Center; John Godwin, MD, Providence Cancer Center; Farhard Ravandi-Kashani, MD, The University of Texas M D Anderson Cancer Center Department of Leukemia; Kendra Sweet, MD, Moffitt Cancer Center; Peter Sayre, MD, University of California, San Francisco; Anjali Advani, MD, Cleveland Clinic; Matthew Wieduwilt, MD, UCSD Moores Cancer Center; Ibrahim Aldoss, MD, City of Hope National Medical Center; Michael T. Byrne, DO, Vanderbilt-Ingram Cancer Center; Ashkan Emadi, MD, University of Maryland; Laura Michaelis, MD, Medical College of Wisconsin; Kristen Petit, MD, University of Michigan; Roland Walter, MD, PhD, Fred Hutchinson Cancer Research Center; Jessica Altman, MD, Northwestern Medicine

CP-MGD006-01 Team

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