"Chemotherapy based stem cell mobilization: pro and con"

Transcription

1 "Chemotherapy based stem cell mobilization: pro and con" Mohamad MOHTY Clinical Hematology and Cellular Therapy Dpt. Sorbonne Université Hôpital Saint Antoine Paris, France

2 Disclosures Sponsorship or research funding: Sanofi Fee or other (financial) reimbursement: Sanofi Shareholder: None Other Relations: None

3 EBMT Activity survey on HSCT: main indication AUTOLOGOUS

4 Why the autologous transplant activity in myeloma is increasing?

5 Survival of transplant-eligible myeloma in % 80% 60% 40% 20% 0% Overall Survival MIRT TT, IFM and SWOG Survival Outcomes IFM 2009 IFM 2005 IFM 99 IFM TT3 TT2 TT1 IFM 90 IFM 94 S9321 IFM Deaths / N 226 / / / / / / / / Years from Enrollment Median in Years NR NR IFM 94 IFM 90 FOLLOW-UP OF IFM S9321 TT PROTOCOLS TT3: all risk, age <75 TT2: all risk, age <75 IFM99-02: low risk, age <65 TT1: all risk, age <75 IFM90: all risk, age <65 IFM94: all risk, age <65 IFM99-04: high risk, age <65 S9321: all risk, age <70 Courtesy of M. Attal

6 EMN02/HO95 phase 3 study: second interim analysis Single vs double ASCT by randomization in high risk subgroups ASCT-1 ASCT-2 High risk cytogenetics R-ISS II + III % (77.3% ; 93.2%) % (78.2% ; 92.1%) OS probability % (63.6% ; 83.4%) OS probability % (67.4% ; 84%) ASCT-1 ASCT-2 HR: 0.52 (95% CI, ), P= Months Number at risk Months 0.00 ASCT-1 ASCT-2 HR: 0.48 (95% CI, ), P= Months Number at risk Months Cavo M, et al. Presented at ASH 2017 (Abstract 401), oral presentation.

7 Evolution of the historical 65 year age limit for auto-sct? Registry (Study) EBMT (Auner et al, 2015) Age group (years) Calendar period n (%) TRM (%) (15.0) 1835 (20.1) 4253 (24.3) 6518 (26.6) (2.9) 718 (7.9) 2478 (14.1) 3860 (15.8) 2 (0.1) 100 (1.1) 497 (2.8) 740 (3.0) NA Absolute numbers and % of all reported autologous hematopoietic cell transplants in the calendar period. EBMT, European Group for Blood and Marrow Transplantation; TRM, transplant-related mortality (reported as day-100 all-cause mortality); SCT, stem cell transplantation. Auner HW, et al. Br J Haematol 2015;171:

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9 How do we mobilize autologous stem cells? G-CSF CD-34 Growth factor only CY G-CSF Growth factor + post chemo (Cy+ G-CSF) CD Chemo + Growth factor

10 Stem Cell Mobilization: The Procedure Variables: Different mobilization schemas Different chemotherapy regimens Different instruments Different techniques Inter operator variability Patient tolerance Impact of prior therapies

11 Relationship between transplanted cell dose and platelet recovery (to 20 x 10 9 /L) 1.0 Cox proportional analysis Probability of platelet recovery ( 20 x 10 9 /L) CD34+ cells ( 10 6 /kg) Time post transplant (days) Siena et al. J Clin Oncol 2000;18:

12 Can we improve? Mobilization failures Improve quality of graft Graft size / composition Less toxicity / hospitalizations Avoid chemotherapy Selective mobilization T cells / NK cells Autologous transplants Allogeneic transplants Pharmaco economic benefit

13 «The exact mechanism why lenalidomide inhibits stem cell mobilization is not clear.»

14 Phase III: Bortezomib-Dex vs. VAD IFM study Moreau et al., Leukemia 2010

15 Daratumumab based induction in myeloma: Study Scheme

16 Stem cell mobilization with Plerixafor

17 Plerixafor = Mozobil = AMD3100 First in class hematopoietic stem cell mobilisation agent Unlike G CSF, Mozobil is not a growth factor Reversibly binds the CXCR4 receptor and blocks SDF 1 interaction Mozobil [Summary of Product Characteristics]. Naarden, The Netherlands: Genzyme Europe BV; 2010

18 Mobilization failure: collection of 2x106 CD34+ cells/kg after Plerixafor treatment Previously failed cytokine only mobilisation Previously failed chemo. + cytokine mobilisation Overall success rate of 61.0% with plerixafor remobilisation Overall success rate of 70.5% with plerixafor remobilisation Success rate (%) Remobilization is expensive, and a waste of resources, so can we use Plerixafor to prevent or reduce the risk of mobilization failure? 115 data audited patients Calandra et al. Bone Marrow Transplant 2008

19 PREDICT EU TRIAL Percentage of patients achieving minimal ( 2 x 10 6 ) cell dose by apheresis day Kaplan Meier Estimate of Persentage of Patients Collecting Minimal ( 2 x 10 6 ) CD34+ cells/kg % 52% 96% 72% 98% 80% MM NHL No. of Apheresis Days Russel et al. Haematologica 2012

20 Are tumor cells mobilized after plerixafor administration? Clonotypic cells/ml peripheral blood* Screening G CSF G CSF + plerixafor * Detection by quantitative allele specific oligonucleotide (ASO) PCR Fruehauf et al. Bone Marrow Transplant 2010;45:

21 Why should we avoid chemobased mobilization?

22 the most common adverse event seen with chemomobilization was febrile neutropenia, which was reported in 43% of studies in which chemotherapy formed part of the mobilization strategy In studies where chemotherapy was used, the percentage of patients requiring hospital admission ranged from 20% to 48%

23 Disadvantages of Chemotherapy Based Mobilization Risk of Infection Time elapsed between chemomobilization and CD34+ cell peak is unpredictable 1,3 Criteria for initiating apheresis varies 2,3,5,6 Need for hospitalization Need for transfusion support Increased costs 1 Hicks ML, et al. Transfusion. 2007;47(4): ; 2 Desikan KR, et al. J Clin Oncol. 1998;16(4): ; 3 Bargetzi MJ, et al. Bone Marrow Transplant. 2003;31(2):99 103; 4 Humpe A, et al. Transfusion. 2000; 40(11): ; 5 Venditti A, et al. Bone Marrow Transplant. 1999;24(9): ; 6 Arora M, et al. Biol Blood Marrow Transplant. 2004;10(6):

24 The QOL is better for patients with steady state mobilization Little data is available but likely to be true. Collection Few studies No comparative trials No studies looking into QOL with chemo mobilization

25 Advantages of Cytokine Only Mobilization Predictable kinetics of mobilization Lower toxicity and resource utilization compared to chemotherapy based Avoid need for hospitalization and transfusions Makes staffing easier

26 Use of Resourses: Plerixafor will use less resources than chemotherapy All Patients Initial peripheral CD34 Pre Plex Era (n = 17) Plex Era (n = 37) Mean (SD) 15.3 (3.9) 8.6 (4.5) Median (Q1 Q3) 16 (13 19) 8 (5 12) Range (min max) (8 20) (1 18) Number of apheresis sessions Mean (SD) 2.4 (0.9) 1.6 (0.7) Median (Q1 Q3) 2 (2 3) 2 (1 2) Range (min max) (1 5) (1 4) Total apheresis blood volume Mean (SD) 21.3 (9.2) 17.4 (7.5) Median (Q1 Q3) 22.3 ( ) 17.4 ( ) Range (min max) ( ) ( ) Total minutes of apheresis Mean (SD) 460 (209) 345 (132) Median (Q1 Q3) 410 ( ) 335 ( ) Range (min max) (170 1,065) ( ) P< Mohty et al. Bone Marrow Transplant 2017

27 How to optimize stem cell mobilization?

28 Factors predictive of poor PBSC collection Factors described to be predictive of poor PBSC collection Age (older patients) 1,2 Disease (more advanced stage) 1 3 Prior chemotherapy Higher no. of prior treatment lines 1 4 Type of chemotherapy (fludarabine, lenalidomide or melphalan) 1 5 Prior irradiation 1,2 Low CD34 + cell count in PB before apheresis 3,4,7 Low platelet count before mobilisation (controversial) 8,9 CD34 + cell count in PB before apheresis is presumably the most robust predictor for poor PBSC collection 1,3,4,7 1. Olivieri et al. Bone Marrow Transplant 2012;47: Perseghin et al. Transfus Apher Sci 2009;41: Sancho et al. Cytotherapy 2012;14: Wuchter et al. Biol Blood Marrow Transplant 2010;16: Kumar et al. Leukemia 2007;21: Sinha et al. Leukemia 2012; 26: Sinha et al. Bone Marrow Transplant 2011;46: Duarte et al. Bone Marrow Transplant 2011;46(Suppl 1):abst. O Nakasone et al. Am J Hematol 2009;84:

29 Approaching an ideal stem cell mobilization regimen Criteria for optimal mobilization regimen Higher probability of collecting optimal number of cells G CSF alone G CSF plus chemo. Plerixafor plus G CSF Manageable tolerability Predictable time to apheresis Fewer apheresis days Prompt and durable engraftment Minimal toxicity and inconvenience for the patient Practical, logistical, and resource benefits

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