Shall young patients with severe aplastic anemia without donors receive BMT from alternative source of HCT? Elias Hallack Atta, MD, PhD

Transcription

1 Shall young patients with severe aplastic anemia without donors receive BMT from alternative source of HCT? Elias Hallack Atta, MD, PhD

2 Declaração de Conflito de Interesse Declaro que possuo conflito de interesse na categoria abaixo: Discussão de uso de drogas off-label: eltrombopag no tratamento de primeira linha da AAS.

3 Shall young patients with severe aplastic anemia without donors receive BMT from alternative source of HCT? YES! NO!

4 1. Yes, clonal hematopoiesis is a commom feature of aplastic anemia 439 patients with AA (NIH, Cleveland Clinic, and Kanazawa University. Whole-exome and targeted sequencing (106 genes) and singlenucleotide polymorphism array karyotyping were performed. 249 somatic mutations were detected among 156 patients (36%); 56 of these 156 patients (36%) had multiple mutations (1-7). The most frequently mutated genes: BCOR/BCORL1 (9.3%), PIGA (7.5%), DNMT3A (8.4%), and ASXL1 (6.2%). Yoshizato T et al. N Engl J Med 2015;373:35-47.

5 1. Yes, clonal hematopoiesis is a commom feature of aplastic anemia PIGA, BCOR, and BCORL1 mutations favored a good response to IST compared to those with ASXL1, DNMT3A, TP53, RUNX1, JAK2, JAK3, and CSMD1) and patients without mutations (P=0.03). Better PFS and OS in the group with favorable mutations (PIGA, BCOR, and BCORL1) compared with unfavorable mutations (ASXL1, DNMT3A, TP53, RUNX1, and CSMD1) and the unmutated group. Yoshizato T et al. N Engl J Med 2015;373:35-47.

6 1. Yes, clonal hematopoiesis is a commom feature of aplastic anemia Some clones are thought to be resistant to the inciting autoimmune insult and/or show faster cycling/less apoptosis, increasing their clone size, giving rise to more selectively dominant clones therein (DNMT3A, ASXL, etc). In other cases, initially dominant clones may regress or remain stable over years (PIGA mutations, BCOR/BCOR mutations). Seishi Ogawa Blood 2016;128:

7 2. Yes, relapse and clonal evolution still occurs after horse ATG + CSA + eltrombopag Relapse occurred in 14% of patients with a response in whom CSA was continued at a low dose beyond 6 months and in 54% in whom cyclosporine was stopped at 6 months. The incidence of cytogenetic clonal evolution at 3 years was 11.7%. Hemolytic PNH developed in 2 pts. HCT was performed in 11.7% at 3 years (6 pts w/o response, 3 relapses, and 3 evolutions). Townsley DM et al. N Engl J Med 2017;376:

8 3. Yes, rabbit ATG is the only ATG preparation available in many countries 6-month response included one RCT and seven cohort trials. Horse ATG was associated with a significant improvement (OR 95% CI = 3.73, p = ). The cohort studies supported the superiority of horse ATG (OR 95% CI = 1.65, p = 0.02). The benefit of horse ATG was mainly driven by a large increase in studies with non-asian (p < ). Yang et al. Annals Hematol 2017 (doi: /s )

9 4. Yes, patients with low ANC have a high risk of early mortality after 1 st line ATG 30.4% For rabbit ATG as first line treatment, one-year OS was significantly lower in patients with an ANC before rabbit ATG 0.1 x 10 9 /L, 51.8% versus 82.2%, P <0.001 (N=185). The odds ratio for early mortality after rabbit ATG is 6.83, P<0.001, for those with an ANC 0.1 x 10 9 /L. Atta et al. Annals Hematol 2017 (doi: /s )

10 5. Yes, response to 2 nd line rabbit ATG is poor for refractory patients to 1 st line rabbit ATG Refractory to first r- ATG/CsA (n=32) 95% CI Relapsed to first r- ATG/CsA (n=5) 95% CI At 3 months 5 (16%) 3-28% 3 (60%) % At 6 months 7 (22%) 8-36% 3 (60%) % Only 1/3 of patients respond to initial rabbit ATG. At least half of patients will remain refractory, even with 2 nd course of rabbit/ horse ATG or alemtuzumab when rabbit ATG is used as first-line therapy. Cle et al. Haematologica Sep; 100(9): e345 e347.

11 6. Yes, donor availability has increased to almost 95% with alternative donors 20-30% of patients will have an HLA-id donor 70-80% of patients won t have an HLA-id donor Alternative donors - Cord blood - HLA-id unrelated donor - Haploidentical related donor

12 6. Yes, donor availability has increased to almost 95% with alternative donors A dose of at least TNC/kg of recipient body weight is adequate for CBT. Almost all patients in all racial and ethnic groups aged less than 20 years will have a 4/6 or better HLA-matched cord-blood unit with an adequate cell dose (most units have adequate cell dose for patients with less than 50 kg). Gragert et al. NEJM 2014; 371:

13 6. Yes, donor availability has increased to almost 95% with alternative donors 1 st million donors 10,759,087 donors (more minorities) 9% per year 75% 52% 49% 19% 19% 18% 16% Gragert et al. NEJM 2014; 371:

14 6. Yes, donor availability has increased to almost 95% with alternative donors Haplotype 1 Haplotype 3 Haplotype 2 Haplotype 4 Ovum Sperm Child A (patient) Child B Child C Child D Child E)

15 7. Yes, progressive decrease in transplant-related mortality for unrelated HCT Transplant-Related Mortality after Adult Bone Marrow or PBSC Primary HCT for Leukemia, MDS, MPN, or Lymphoma ( ). SOURCE: CIBMTR, the research program of NMDP/Be The Match

16 8. Yes, similar outcomes between related and unrelated HLA identical HCT for SAA Risk score: peripheral blood, interval diagnosis to transplant >180 days, lack of use of ATG, donor/recipient cytomegalovirus sero-status other than negative/negative, and age 20 years. 3 groups: low (score 0 3; n=391), intermediate (score 3 6; n=709), and high-risk group (score >6; n=348). Bacigalupo et al. Haematologica 2015, 100:

17 8. Yes, similar outcomes between related and unrelated HLA identical HCT for SAA Similar 2-year OS between upfront unrelated HCT and MSD (96% vs. 91%, P = 0.30) and EFS ( 92% vs. 87%, P = 0.37). Similar 2-year OS between upfront unrelated HCT and IST (96% vs. 94%, P = 0.68). Better EFS with upfront unrelated HCT vs. IST (92% vs. 40%, P = 0,0001). Dufour et al. Br J Haematol 2015, 171:

18 9. Yes, post-transplant cyclophosphamide has made haploidentical HCT feasible +4 Luznik L, et al. Blood. 2001;98: Mayumi H, et al. Immunobiology. 1996;195: Eto M, et al. J Immunol. 1991;146:

19 9. Yes, post-transplant cyclophosphamide has made haploidentical HCT feasible - 16 patients who underwent haplo transplantation using a RIC regimen with post-cy. Stem cell sources: BM (N=13) or PBSCs (N=3). - Neutrophil engraftment =94% and platelet engraftment =75%. Two patients had secondary graft failure and were salvaged with another transplant. - Three patients developed acute GVHD being grades 2-4 in two. Five patients have died and the 1-year OS was 67.1%. Esteves et al. Bone Marrow Transplant May;50(5):685-9.

20 9. Yes, post-transplant cyclophosphamide has made haploidentical HCT feasible - 16 patients with refractory SAA: 13 haploidentical donors and 3 unrelated donors. - The nonmyeloablative conditioning regimen consisted of rabbit antithymocyte globulin (0.5 mg/kg days -9 e 2 mg/kg -8/-7), fludarabine (30 mg/m 2 days -6-2), low-dose cyclophosphamide (14.5 mg/kg days -6/-5), and TBI (200 cgy day -1). Post-transplant cyclophosphamide (50 mg/kg days +3 and +4) was administered for GVHD prophylaxis, mycophenolate mofetil (D+5 35), and tacrolimus (day +5 1 year). - Graft failure, primary or secondary, was not seen in any of the patients. All 16 patients are alive, transfusion independent, and without evidence of clonality. The median follow-up is 21 months. - Two patients had grade 1-2 skin-only acute GVHD. These same two also had mild chronic GVHD of the skin/mouth requiring systemic steroids (immunosuppression interrupted by 15 and 17 months. All other patients stopped immunosuppression at 1 year. DeZern, et al. Biol Blood Marrow Transp 23 (2017):

21 10. Yes, the costs for salvage HCT are high patients: 63% IST alone, 22.3% HCT without IST, and 14.7% received both admissions were evaluated with a total LOS of 24,369 days. US$ - ICU utilization was significantly higher in the transplant group that failed IST (P=0.0058). US$ - Costs were significantly different across the groups: a median of $244,513 for patients treated with IST, $793,009 for those who underwent SCT alone and $1,365,051 for those that had both forms of therapy (p<0.0001). Joshi et al. Blood :2333.

22 Take-home points: Shall young patients with severe aplastic anemia without donors receive BMT from alternative source of HCT? 1. Yes, clonal hematopoiesis is a commom feature of aplastic anemia. 2. Yes, relapse and clonal evolution still occurs after horse ATG + CSA + eltrombopag. 3. Yes, rabbit ATG is the only ATG preparation available in many countries. 4. Yes, patients with low ANC have a high risk of early mortality after 1 st line ATG. 5. Yes, response to 2 nd line rabbit ATG is poor for refractory patients to 1 st line rabbit ATG. 6. Yes, donor availability has increased to almost 95% with alternative donors. 7. Yes, progressive decrease in transplant-related mortality for unrelated HCT. 8. Yes, similar outcomes between related and unrelated HLA identical HCT for SAA. 9. Yes, post-transplant cyclophosphamide has made haploidentical HCT feasible. 10. Yes, the costs for salvage HCT are high.

23 Obrigado!