What to do with bad PBSC mobilizers?

What to do with bad PBSC mobilizers? Rafael F. Duarte Director Programa de Trasplante Jefe Sección de Onco-Hematología

Are poor mobilizers a real problem? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor for Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies in poor mobilizers

Are poor mobilizers a real problem? Is there a need for improvement? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor for Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies in poor mobilizers

What s a poor mobilizer? Poor or failed mobilization is often defined as a collection of <2 x 10 6 cells/kg 1,2 Factors associated with poor PBSC mobilization Patient age >60 years 3 Underlying disease 2,3 Previous RT and chemotherapy 1-3 Novel induction strategies may adversely affect mobilization Lenalidomide results in a significantly lower yield of CD34+ cells (P<0.001) and increased number of apheresis collections required (P<0.004) 4,5 Rituximab 6 Fludarabine 7 1. Goterris R, et al. Bone Marrow Transplant. 2005;36(10):847-853. 2. Micallef IN, et al. Hematol J. 2000;1(6):367-373. 3. Stiff PJ. Bone Marrow Transplant. 1999;23(suppl 2):S29-S33. 4. Kumar S, et al. Leukemia. 2007;21(9):2035-2042. 5. Mazumder A, et al. Leukemia. 2008;22;1280-1281. 6. Benekli M et al. Bone Marrow Transplant. 2003;32(2):139-143. 7. Herbert KE, et al. Leukemia 2009;23(2):305-312.

What are the consequences of suboptimal mobilization? Failure to mobilize a sufficient number of CD34+ cells may result in: Increased number of days of apheresis Need for bone marrow harvest Ineligibility for transplantation Additional burden on patients Use of sub-optimal apheresis product may lead to Delayed, partial, or failed stem cell engraftment 1 Increased need for transfusions 2 1. Haas R, et al. Blood 1994; 2. Schiller G, et al. Blood 1995

No major innovations in this area for a long time A small number of stem cells are found in peripheral blood during homeostasis 1 Chemomobilized PBSCs are first used in auto-hsct; PBSCs then become a widely used alternative to bone marrow 3 Mobilization with growth factor alone or growth factor plus chemotherapy becomes standard in clinical practice 7,8 1960 1970 1980 1990 2000 and beyond An increased number of stem cells are observed in the peripheral blood following chemotherapy 2 GM-CSF 4 and G-CSF 5 mobilize high numbers of PBSCs (1988) and begin to be used in auto-hsct 6 Novel strategies 1. Goodman JW and Hodgson GS. Blood. 1962;19:702-714. 2. Richman CM, et al. Blood. 1976;74(6):1031-1039.3. Kessinger A, et al. Blood. 1988;71(3):723-727. 4. Socinski MA, et al. Lancet. 1988;1(8596):1194-1198. 5. Duhrsen U, et al. Blood. 1988;72(6):2074-2081. 6. Gianni AM, et al. Lancet. 1989;2(8663):580-585. 7. Bensinger W, et al. J Clin Oncol. 1995;13(10):2547-2555. 8. Tricot G, et al. Blood. 1995;85(2):588-596.

Are poor mobilizers a real problem? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor for Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies in poor mobilizers

Mozobil (plerixafor injection) A bicyclam molecule 1 Reversibly binds to CXCR4 receptor and blocks SDF-1 interaction 2 Very water-soluble 1 Highly charged 3 Low molecular weight (MW = 502) 1 Rapidly increases mobilization of CD34+ hematopoietic stem cells 1

Are poor mobilizers a real problem? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor for Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies in poor mobilizers

Plerixafor Phase III Registration Trials in MM and NHL NHL patients 1 (Study 1) n = 298 R G-CSF (10 micrograms/kg/day) + plerixafor (0.24 mg/kg) G-CSF (10 micrograms/kg/day) + placebo MM patients 2 (Study 2) n = 302 R G-CSF (10 micrograms/kg/day) + plerixafor (0.24 mg/kg) G-CSF (10 micrograms/kg/day) + placebo 1) DiPersio et al. J Clin Oncol. 2009;27(28):4767-4773; 2) DiPersio et al. Blood 2009;113:5720-5726.

Median PB CD34+ cell count (cells/µl) WHAT TO DO WITH POOR PERIPHERAL BLOOD STEM CELL MOBILIZERS? Plerixafor Phase III Registration Trials in MM and NHL PB CD34+ Cell Levels with G-CSF + Plerixafor Placebo + G-CSF Plerixafor + G-CSF (p < 0.001) 4.8-fold (p < 0.001) 5.0-fold 1.7-fold 1.4-fold Day 4 Day 5 Day 4 Day 5 Study 1 (NHL) 1 Study 2 (MM) 2

Plerixafor Phase III Registration Trials in MM and NHL Efficacy and Safety in Optimal Conditions Evidence of Limited Utility in our Clinical Context FDA Approval EMA Approval

Are poor mobilizers a real problem? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor for Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies in poor mobilizers

Plerixafor Failed Placebo Cases in the Registration Trials Multiple Myeloma Non-Hodgkin s Lymphoma Placebo + G-CSF n = 154 Placebo + G-CSF n = 148 7 entered rescue 100% achieved 2 10 6 cells/kg 100% underwent transplant 57% underwent tandem transplant 52 entered rescue 63.5% achieved 2 10 6 cells/kg 13.5% achieved 5 10 6 cells/kg 88% underwent transplant

Success Rate (%) WHAT TO DO WITH POOR PERIPHERAL BLOOD STEM CELL MOBILIZERS? Plerixafor American Compassionate Use Program 66% of cases collected 2 10 6 CD34+ Cells/kg Comparison by Disease Type G. Calandra, et al. BMT 2008 60% 76% 71% N=63 N=17 N=35

Plerixafor European Compassionate Use Program R. Duarte, et al. European Consortium on Stem Cell Mobilization

Plerixafor European Compassionate Use Program MOBILIZATION SUCCESS ECOSM Communications on Plerixafor at EBMT 2011 Abstract Yield of Presenting CD34/kg Authors Focus 3.1 x10^6/kg on Primary Endpoint P 1073 I.H. Gabriel, et al. 528 (75%) >2 x10^6/kg Elderly patients 100 90 80 70 60 50 40 30 20 10 0 P 1075 K. Hübel, et al. Lymphoma subtypes (Hodgkin ) P 1077 G. Basak, et al. Overweight/Obesity P 1083 O. Jaksic, et al. Apheresis volume P 1100 Z. Koristek, et al. Paediatric patients P 1202 N. Worel, et al. Non-haematological indications O 377 R.F. Duarte, et al. Multivariate analysis of the series chemo-based vs steady-state, previous AutoHCT, new chemo agents (e.g. lenalidomide, fludarabine, etc), 1

Plerixafor European Compassionate Use Program Disease Subtypes 100 90 80 70 60 50 40 30 20 10 0 p= 0.001 81 65 81 79 MM NHL HL Other

Plerixafor European Compassionate Use Program Baseline Platelet Count 100 90 80 70 60 50 40 30 20 10 0 p= 0.001 54 PLAT<100 77 PLAT>100

Plerixafor European Compassionate Use Program Prior Chemotherapy Lines 100 90 80 70 60 50 40 30 20 10 0 p= 0.001 77 62 <4 Lines 4 Lines

Plerixafor European Compassionate Use Program Prior Agents 100 90 80 70 60 50 40 30 20 10 0 p= 0.410 p= 0.016 p= 0.867 68 75 Lena No Lena Fluda No Fluda 58 74 74 70 RadioTh No RadioTh

Plerixafor European Compassionate Use Program Steady-state vs Chemo-based 100 90 80 70 60 50 40 30 20 10 0 p= 0.221 77 73 Steady-State Chemo-based

Plerixafor European Compassionate Use Program MULTIVARIATE ANALYSIS OF FACTORS INFLUENCING MOBILIZATION SUCCESS Underlying Disease (NHL vs others) <0.001; OR: 2.54 (1.72-3.74) Prior lines of Tx (>3 lines) <0.001; OR: 2.24 (1.45 3.47) Trombocytopenia (<100) 0.008; OR: 2.54 (1.27 5.09)

Plerixafor European Compassionate Use Program Age Sex UNIVARIATE ANALYSIS OF FACTORS INFLUENCING MOBILIZATION SUCCESS n.s. n.s. Underlying Disease <0.001 Prior lines of Treatment 0.001 Prior Fludarabine 0.016 Prior Lenalidomide Prior Melphalan Prior Radiotherapy n.s. n.s. n.s. Prior Mobilization Attempts 0.04 Prior chemo vs GCSF n.s. Platelets <100 0.001 Other cytopenias n.s.

Current Mobilization Strategies: Is there a need for improvement? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor in Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies and Algorithms

Efficient Algorithms and Strategies using Plerixafor

Efficient Algorithms and Strategies using Plerixafor I.N.M. Micallef; Rochester, MN Based on CD34 targets Does not base decisions on clinical risk factors They monitor CD34 levels in PB on days 4 and 5 of steady state GCSF mobilization (chemo excluded), and patients get plerixafor on day 5 if low CD34 (<10) or 1 st day collection <0.5 x10 6 /kg S.H. Abhyankar; Kansas, KS Based on CD34 targets and some risk factors CD34 levels on day 5: <10 if target 2.5 x10 6 /kg; <20 if target 5 x10 6 /kg CD34 collected on 1 st day < half the desired target (2.5 or 5 x10 6 /kg) Lenalidomide (>4), delayed count recovery, other reasons, treated upfront on day 4 J. Shapiro; Tampa, FL Based on Risk Factors and/or CD34 targets High risk patients, based on the following criteria, are treated upfront with plerixafor on day 4: Received 3 lines of chemotherapy Received 2 lines of chemotherapy plus a radioimmunoconjugate (Zevalin or Bexxar ) Received 2 lines of chemotherapy plus radiation to extensive fields (mantle, craniospinal, pelvis) Received 4 or more courses of HyperCVAD or more than 4 cycles of lenalidomide Hypocellular marrow (defined as 25% cellularity) Platelet count < 1 x 10 5 /µl in the absence of chemotherapy within the last 3 week Previous failure to collect after G-CSF or chemotherapy priming Standard Risk patients (others), get plerixafor on day 5 if low CD34 (<10) or 1 st day collection

Efficient Algorithms and Strategies using Plerixafor I.N.M. Micallef; Rochester, MN Based on CD34 targets Change from Plerixafor-1 (day 5) to Plerixafor-2 (day 4)

Efficient Algorithms and Strategies using Plerixafor L.J. Costa; Charleston, SC Based on CD34 levels on day 4 Establishes correlation between day 4 PB CD34 levels and GCSF-mobilized CD34 target collected Pros: 1) Predictability, regardless of risk factors, 2) Better utilization apheresis resources, 3) apheresis performed on the right day Cons: 1) Underestimates impact of plerixafor if very low CD34 levels on day 4, 2) algorithm could vary from center to center multicenter validation (???)

Plerixafor: Experience at ICO & BST CD34+ <10/µL in PB on day 4: 105 consecutive Myeloma and Lymphoma patients with of G- CSF mobilization for Auto-HCT. I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST P <0.001 I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST P <0.001 I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST P <0.001 I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST P <0.001 for all comparisons I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST 1! 2! 3! 4! 5! 6! 7! Table 4. Plerixafor use as a remobilization versus preemptive strategy.! PB CD34+ count on Day 4, cells/µl Mean (s.d.) Min-Max PB CD34+ count on Day 5, cells/µl Mean (s.d.) Min-Max Fold-expansion Day 4 to Day 5 Mean (s.d.) Min-Max Collection 2 CD34+ cells x10 6 /kg, n (%) Overall First apheresis only CD34+ yield, cell count x10 6 /kg Overall Mean (s.d.) Min-Max First apheresis only Mean (s.d.) Min-Max Doses of plerixafor* Mean (s.d.) Min-Max Remobilization (n=25) 3.7 (2.3) 0.9-9.8 16.2 (13.4) 1.9-58 4.7 (3.14) 1.5-13 16/25 (64%) 11/25 (44%) 2.44 (1.46) 0-6.74 2.0 (1.55) 0-6.74 1.48 (0.59) 1-3 Preemptive (n=13) 4.9 (2.3) 1.6-8.6 22.4 (9.8) 4-36.6 4.9 (2.39) 2.1-10 12/13 (92%) 11/13 (85%) 3.73 (1.63) 0-7.21 3.28 (1.79) 0-7.21 1.08 (0.28) 1-2 P 0.124 0.120 0.888 0.118 0.016 0.025 0.040 0.025 * Doses of plerixafor (i.e. days of plerixafor treatment) administered with an intention to reach the primary endpoint to collect 2/kg CD34+ cells, including 33 doses in 28 patients who met the target and 17 doses administered to 10 patients who did not. 8!! I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Plerixafor: Experience at ICO & BST 1! 2! 3! 4! 5! 6! 7! Table 4. Plerixafor use as a remobilization versus preemptive strategy.! PB CD34+ count on Day 4, cells/µl Mean (s.d.) Min-Max PB CD34+ count on Day 5, cells/µl Mean (s.d.) Min-Max Fold-expansion Day 4 to Day 5 Mean (s.d.) Min-Max Collection 2 CD34+ cells x10 6 /kg, n (%) Overall First apheresis only CD34+ yield, cell count x10 6 /kg Overall Mean (s.d.) Min-Max First apheresis only Mean (s.d.) Min-Max Doses of plerixafor* Mean (s.d.) Min-Max Remobilization (n=25) 3.7 (2.3) 0.9-9.8 16.2 (13.4) 1.9-58 4.7 (3.14) 1.5-13 16/25 (64%) 11/25 (44%) 2.44 (1.46) 0-6.74 2.0 (1.55) 0-6.74 1.48 (0.59) 1-3 Preemptive (n=13) 4.9 (2.3) 1.6-8.6 22.4 (9.8) 4-36.6 4.9 (2.39) 2.1-10 12/13 (92%) 11/13 (85%) 3.73 (1.63) 0-7.21 3.28 (1.79) 0-7.21 1.08 (0.28) 1-2 P 0.124 0.120 0.888 0.118 0.016 0.025 0.040 0.025 * Doses of plerixafor (i.e. days of plerixafor treatment) administered with an intention to reach the primary endpoint to collect 2/kg CD34+ cells, including 33 doses in 28 patients who met the target and 17 doses administered to 10 patients who did not. 8!! I Sánchez-Ortega, et al. Bone Marrow Transplant 2015 Jan; 50(1): 34-39.

Current Mobilization Strategies: Is there a need for improvement? Plerixafor, Mozobil Product characteristics Efficacy data in the Phase III Registration Clinical Trials Plerixafor in Poor Mobilizers Efficiency requires additional evidence From the available evidence to Efficient Mobilization Strategies and Algorithms

What to do with bad PBSC mobilizers? Rafael F. Duarte Director Programa de Trasplante Jefe Sección de Onco-Hematología