New Directions in Aplastic Anemia

Transcription

1 11//15 New Directions in Aplastic Anemia ANDREW C. DI ETZ, MD, MSCR PEDIATRIC BLOOD AND MARROW TRANSPLANTATION CHILDREN S HOSPITAL LOS ANGELES, UNIVERSITY OF SOUTHERN CALIFORNIA Outline Ø Changes in Immunosuppressive Therapy Newer agents Ø Changes in Blood and Marrow Transplantation Unrelated Donors Alternative Donors Minimization of Late Effects Ø Interesting New Biology Telomeres and Outcomes Blood Cell Mutations and Outcomes Bone Marrow Failure Genes ClinicalTrials.gov Search Ø 1 currently open studies Ø currently open in the United States 2 protocols related to BMT for aplastic anemia 22 not really related or specific to aplastic anemia 5 non- therapeutic studies 5 examining Eltrombopag 1 examining horst ATG 1

2 11//15 Changes in Immunosuppressive Therapy Immunosuppressive Therapy Ø Previously Tried WBC growth factors Erythropoietin Danazol and other androgens Sirolimus MMF Cyclophosphamide Ø Under Investigation Tacrolimus Levamisole Alemtuzumab Eltrombopag Romiplostim Alemtuzumab Ø Treatment Naïve 19% response (n=1) Closed early due to lack of efficacy Ø Relapsed 5% response (n=25) 23% relapse and 11% clonal evolution Ø Refractory 3% response (n=2) Trend of improvement over rabbit ATG + CSA Scheinberg et al 2

3 11//15 Eltrombopag Ø % response rate (n=3) Ø Good safety profile Ø 19% clonal evolution Ø Being investigated in combination Desmond et al Changes in Blood and Marrow Transplant Unrelated Donor Transplantation Ø Improvements in: Supportive Care HLA Matching Time to Transplantation Reduced Intensity Strategies Reductions in cyclophosphamide Reductions in or elimination of total body irradiation (TBI) Bacigalupo et al 3

4 11//15 Unrelated Donor Transplantation BMT CTN 31 (United States) Ø 9 patients (1- years old) Ø BMT with fludarabine, low dose TBI, ATG, and cyclophosphamide at different dose levels Graft failure, primary and secondary Cyclophosphamide 5 mg/kg (n=3) 3 (%) (15%) Survival 3 (9%) 39 (95%) Major regimen-related toxicity* (grade 3 or higher) (11%) 9 (22%) Alive and engrafted 35 (92%) 35 (5%) Cyclophosphamide 1 mg/kg (n=1) Data are number (%). *Defined as severity of grade in any organ system or Overall survival (%) er at risk 1 2 Cyclophosphamide 5 mg/kg Cyclophosphamide 1 mg/kg 2 1 Anderlini et al Months after transplant Unrelated Donor Transplantation FCC Regimen (United Kingdom Ø patients (- 19 years old) Ø BMT with fludarabine, cylophosphamide, and alemtuzumab(campath) Samarasinghe et al Related versus Unrelated Donor Transplantation (A) (B) (B) Fig 1. Outcomes following upfront-unrelated donor HSCT are Dufouret al

5 11//15 Unrelated Donor Transplantation versus Immunosuppressive Therapy (A) (B) Dufouret al Unrelated Donor Transplantation with or without Prior Treatment (A) (B) (B) Dufouret al Additional Factors in Unrelated Donor Transplantation 1 BM, matched, 3-yrs Probability, % BM, mismatched, 3-yrs 2 P-value < Months Marrow better than Peripheral Blood Eapen et al Fully matched better than Mismatched 5

6 11//15 Time to examine unrelated donor transplantation up front? North American Pediatric Aplastic Anemia Consortium (NAPAAC) + (PBMTC) TransIT Trial coming in 21!!! Alternative Donor Transplantation Ø Umbilical Cord Blood Collected from the cord attached to the placenta shortly after delivery Naïve cells ogreater mismatch allowed oless GVHD Ø Haploidentical Related family member Half- Match omore GVHD Graft rejection a concern in both! Umbilical Cord Blood Transplantation Peffault de Latouret al Yoshimi et al

7 11//15 BMT CTN 152 CHAMP Umbilical Cord Blood Transplantation Percent survival Months Flu Flu Flu Flu Flu GVHD Prophylaxis: Cy Cy Tacro/CSA + MMF ATG ATG ATG ATG TBI Flu = Fludarabine 3 mg/m 2 IV daily Cy = Cyclophosphamide 5 mg/kg IV daily TBI = 2 cgy ATG = Thymoglobulin dosed on weight & baseline lymphocyte count Chan et al + Yoshimi et al + Unpublished Haploidentical Transplantation Wang et al Gao et al BMT CTN 152 CHAMP Haploidentical Transplantation Percent survival Months Flu Flu Flu Flu Flu GVHD Prophylaxis: Tacrolimus, MMF, & Cy Cy Post-HSCT Cy ATG ATG ATG TBI Cy Cy Flu = Fludarabine mg/m IV daily 3 2 Cy TBI = Cyclophosphamide 1.5 mg/kg IV daily = 2 cgy Cy = Cyclophosphamide 5 mg/kg IV daily ATG = Thymoglobulin.5 mg/kg (day-9) & 2 mg/kg (day -,-) Esteveset al + Unpublished

8 11//15 Transplantation Late Effects Ø Very minimal in today s era of reduced intensity transplantation Most patients, however, will go on to live healthy lives without impact on educational attainment or fertility and only very minimal risk of late complications. Ø Primarily driven by chronic by: Chronic graft- versus- host disease Moderate to high doses of TBI (> cgy) Dietz et al Transplantation Late Effects Related Donor N (Percent) Unrelated Donor N (Percent) 11 Survivors 1-year survivors No late effects 9 (93) 25 (5) One late effect 1 () (13) Multiple late effects 5 (1) (2) 2-year survivors No late effects 22 (9) 25 () One late effect 1 (9) 5 (1) Multiple late effects 11 (1) 9 (3) 5-year survivors No late effects 5 () 11 (1) One late effect (11) (25) Multiple late effects (2) 2 (1) BMT from Buchbinder et al Transplantation Late Effects Ø Most common: Endocrine Issues (<1%) Bone health (1-25%) Ø Secondary cancer: Original reports >1% More recently <2% 15-2% after immunosuppression

9 11//15 Growth in Children after Transplantation Sanders et al Pregnancies after Transplantation No increased rate of congenital malformations! Sanders et al Quality of Life Ø 9 adult survivors assessed with Short Form- 3 physical function Survivors vs. controls (n=19) no difference! Educational, work or school status, financial situation, and marital status of the of patients vs. controls no difference! Insurance issues different! 1% denied health insurance after transplant vs. 2% of controls 2% denied life insurance after transplant vs. 1% of controls Sanders et al 9

10 11//15 Self Assessment of Long- Term Health Deeg et al Interesting New Biology Telomere Length and Evolution Calado et al 1

11 11//15 Telomere Length and Evolution Scheinberg et al Telomere Length and Relapse Scheinberg et al Telomere Length and Survival Scheinberg et al 11

12 11//15 Mutations in Aplastic Anemia The A n e w e ng l a n d j o u r na l Multiple mutations Missense mutation Nonsense mutation m e dic i n e of Frameshift mutation Splice-site mutation U.S. Cohorts Other mutation Japanese Cohort Ø Next G eneration S equencing ( n=39) BCOR or BCORL1 PIGA DNMT3A ASXL1 JAKs RUNX1 TP53 Splicing Cohesin CSMD1 TET2 RIT1 SETBP1 GNAS PRC2 LAMB WT1 IDH2 CUX1 RBBP CBL PRPF BRCC3 PEG3 ATRX PHF ATM KRAS MPL NF1 POT1 RAP1A STAT3 DIS3 SH2B3 TERT Ø Clonal hematopoiesis detected in % Ø More m utations with age Frequency of Mutation (%) B C No. of Mutations P<.1 All mutations; P<.1 PIGA and BCOR or BCORL1; P=. Not PIGA, BCOR, or BCORL1 mutations; P<.1.5 Variant Allele Frequency Frequency of Mutation Yoshizato et al All mutations; P<.1 PIGA and BCOR or BCORL1; P=.9 Not PIGA, BCOR, or BCORL1 mutations; P< Mo after IST At diagnosis Age (yr) 3 Time of Sampling n engl j med 33;1 nejm.org July 2, 215 The New England Journal of Medicine Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on August 2, 215. For personal use only. No other uses without permission. Copyright 215 Massachusetts Medical Society. All rights reserved. Mutations in Aplastic Anemia The n e w e ng l a n d j o u r na l A Response to Immunosuppressive Therapy m e dic i n e of B Overall Survival 1 Overall Survival (%) CR.5 Frequency PIGA, BCOR or BCORL1 P=.3 1. PR.5 DNMT3A, ASXL1, TP53, RUNX1, CSMD P= Months NR Mutation Set 15, 15, 1, 5, DNMT3A, ASXL1, RUNX1 JAK2, JAK Reticulocytes 1 P=.3 OR51A , 2 2, Variant Allele Frequency 15, 1, 2 DNMT3A, ASXL1, TP53, RUNX1, CSMD1 5, P=.5 UBR Months of Reticulocyte Count (per mm3) Mutations in Aplastic Anemia n e w e ng l a nd j o u r na l Platelet Count (per mm3) PIGA, BCOR or BCORL1 3, The Hemoglobin (g/dl) MEPCE PDED EPHA5 Months KCNH2 RPE5 No. at Risk DNMT3A EBF2No. at Risk GARS CYP2A PIGA, BCOR or BCORL1 PIGA, BCOR or BCORL NRK COBL ZCH ASXL * * DNMT3A, ASXL1, DNMT3A, ASXL1, FAHD2B TSC22D1 RUNX1, JAK2, JAK3 TP53, RUNX1, SETBP1 EHD2 MLL2 CSMD1 YTHDF2.1 IKZF1 LARGE EYA TET2. COG1 CULB PDE3A Figure 2. Clinical Correlations with Somatic Mutations. BCOR Base FZD Gene-set enrichment analysis line with the use of algorithms for a penalized likelihood approach to variable selection was used to identify Years sets of genes that were associated with a good or poor response to immunosuppressive therapy (Panel A), overall survival (Panel B), Years PR C) in the NIH cohort. Panel A shows an inferior response to immunosuppressive therapy in a group hatg (Panel and progression-free survival NR Gradually achieved independence CsA mutations (DNMT3A, ASXL1, TP53, RUNX1, JAK2, JAK3, or CSMD1) and a superior response in patients of patients with unfavorable G Alemtuzumab from transfusions with favorable mutations (PIGA or BCOR and BCORL1) as compared with patients in an unmutated group (P =.3 by the chi-square test). The width of each column represents the number of patients in each group. CR denotes complete response, NR nonresponse, and Progression of Disease, Patient curves NIH5 PR partialdresponse. In Panel B, Kaplan Meier for overall survival are shown for three groups: patients with favorable mutations Old Woman in PIGA or BCOR and BCORL1, patients in the unmutated group, and patients with unfavorable mutations in DNMT3A, ASXL1, TP53, 3, 2, 2 White RUNX1, or CSMD1. In Panel C, Kaplan Meier curves for progression-free survival among patients with favorable mutations in PIGA, cells BCOR or BCORL1, patients in the unmutated group, and patients with unfavorable DNMT3A, ASXL1, RUNX1, JAK2, or JAK3 mutations 15, 1 are shown. In Panel D, Kaplan Meier curves for overall survival among patients younger than years of age are shown for three groups: patients with favorable mutations in PIGA or BCOR and BCORL1, patients in the unmutated group, and patients with unfavorable muta15, 1, Immune-mediated Recoverytests were used for statistical comparisons among the groups. The untions in DNMT3A, ASXL1, TP53, RUNX1, or CSMD1. Log-rank emoglobin destruction of HSCs mutated group included patients with other candidate-gene mutations that did not cluster in gene-set enrichment analysis with either 5, favorable or unfavorable groups. Results were similar when patients in the unmutated group (no candidate-gene mutations detected) s Reticulocytes were used as the reference group. Thirteen patients with mixed mutations were excluded from the gene-set enrichment analysis. ASXL1 CACNA1E VEGFC TSC22D1 YTHDF2 SXL1 ANKS1B LUM FZD OR51A TET2 RANBP PEX2 GA1 BCOR COG1 ZNF33 MUC1 ADCY SETBP1 EHD2 C15orf2 PGBD2 DNMT3A n engl j med 33;1 nejm.org July 2, 215 ARMCX DUSP The New England Journal of Medicine APOB Downloaded from nejm.org at UNIV OF SOUTHERN CALIF on August 2, 215. For personal use only. No other uses without permission. Copyright 215 Massachusetts Medical Society. All rights reserved. 1 2 Onset of Base CDK HYAL CDON DMD SNX1 ADAMTS5 C2orf19 CACNA1D ATXN D Overall Survival in Patients < Yr of Age Yoshizato et al Platelets BCOR or BCORL1 White cells PIGA,Hemoglobin 1 23 Reticulocyte Count (per mm3) 2, White-Cell Count 1 Reticulocytes 3, Platelet Count (per mm3) 2 3) Progression-free Survival (%) (per mm B Patient NIH5, -Yr-Old Man C Progression-free Survival Platelets Hemoglobin (g/dl) Hemoglobin Reticulocyte Count (per mm3) Old Woman No. at Risk PIGA, BCOR or BCORL DNMT3A, ASXL1, TP53, RUNX1, CSMD1 Favorable (N=3) Platelet Count (per mm3) (N=13) Overall Survival (%) Unfavorable (N=33) Hemoglobin (g/dl). m e dic i n e Years CR Aplastic Anemia line Years Yoshizato et al

13 11//15 Bone Marrow Failure Genetics Ø MarrowSeq Ø of 1 patients with bone marrow failure or MDS had clinically significant mutations identified Table 1. Inherited bone marrow failure and myelodysplastic syndrome genes. Dyskeratosis Fanconi Diamond-Blackfan Congenital Other Familial AML and MDS congenita anemia neutropenia inherited MDS/leukemia BMF/MDS CTC1 FANCA GATA1 ELANE ABCB CBL ABL1 NPM1 DKC1 FANCB RPS GPC3 AK2 CEBPA ASXL1 NRAS NHP2 FANCC RPS1 GFI1 ANKRD2 GATA2 BCL2L11 PML NOP1 BRCA2 (FANCD1) RPS1 HAX1 ATR PAX5 BCOR PRPFB a RTEL1 FANCD2 RPS19 WAS LIG RUNX1 BCR RARA TERC FANCE RPS2 MPL BRAF RPS1 TERT FANCF RPS2 NBN DNMT3A SF1 TINF2 FANCG RPL5 RMRP ETV SF3A1 WRAP53 FANCI RPL11 SBDS FLT3 SF3B1 BRIP1 (FANCJ) RPL35A SRP2 IDH1 SRSF2 FANCL IDH2 TET2 FANCM JAK2 TP53 PALB2 (FANCN) KIT U2AF1 RAD51C (FANCO) KRAS U2AF2 SLX (FANCP) MET WT1 a ERCC (FANCQ) MLL ZRSR2 Zhang et al Acknowledgements Patients and Families Colleagues and Mentors 13