Page 103 - 2021_06-Haematologica-web

Improved outcomes for non-myeloablative allo-HCT
AB
C
Figure 2. Adjusted cumulative incidence rates of acute and chronic graft-versus-host disease by era of transplant. (A) Grades 2–4 acute graft-versus-host disease (GVHD), (B) grades 3–4 acute GvHD, and (C) chronic GvHD. Era of transplant: 1997–2003 (black line), 2004–2009 (blue line), and 2010–2017 (red line).
starting on the day before HCT, significantly reduced the incidences of stages 2–4 liver and intestinal acute GvHD and grades 3–4 acute GvHD, and improved both 1-year OS and NRM.4
The overall incidence of relapse was significantly lower during 2010–2017 compared to earlier time periods. This corresponded both with an increasing use of higher TBI doses (3–4.5 Gy) for patients who did not receive preced- ing myelosuppressive chemotherapy, and with an increas- ing proportion of patients who underwent HCT with dis- eases at a lower risk of relapse. The majority of our patients who received increased TBI dosing carried a diag- nosis of AML, MDS, or a myeloproliferative neoplasm based on a prospective TBI dose escalation study showing a reduction in relapse with higher TBI dosing in MDS/MPN patients who had not had previous myelosup- pressive (induction-type) chemotherapy.34 The lower grade MDS/MPN patients benefitted by increasing the TBI dose to 3 Gy whereas the patients with excess blasts or a history of CMML benefitted by increasing the TBI dose to 4.5 Gy. Based on the findings in the low grade MDS patients, the TBI dose was increased to 3 Gy in AML patients who had not received induction chemotherapy in the preceding 3–6 months or had a previous allogeneic transplant from a different donor. In a sub-analysis, we found no significant change in the rate of relapse in the subset of AML patients who underwent HCT in CR1/CR2, a finding that has also been noted in AML patients who predominantly received high-intensity con- ditioning prior to HCT.35 While we also noted an increase in the number of AML patients in CR1/CR2 with MRD at the time of non-myeloablative HCT, we recognize that
the detection of MRD and its association with disease risk-stratification relative to HCT evolved over our time period of analysis and may have affected the selection of patients in our cohort who underwent HCT after non- myeloablative conditioning versus receiving other thera- pies.
The overall incidence of relapse-related mortality trend- ed toward improvement for our 2004–2009 and 2010– 2017 patient cohorts. Hypomethylating agents, in particu- lar, gained increasing use for the treatment of relapsed myeloid malignancies during our later time periods,36,37 and are likely a contributor to the observed modest attenua- tion of relapse-related mortality. More recently, there has been an expansion in the treatment armamentarium for relapsed disease including ibrutinib, venetoclax, and ena- sidinib,38-40 checkpoint inhibitors,41,42 tyrosine kinase inhibitors,43 and monoclonal antibodies.44,45 Many of these agents were used too infrequently to have influenced the outcomes reported here, but we anticipate that their use will increase and may lead to further reduction in mortal- ity after relapse.
Interestingly, we found that the significant improve- ments in OS, PFS, rate of grades 2–4 acute GvHD, and in the incidence of infectious complications continued to occur over our total period of analysis. However, the sta- tistically significant improvements in other clinical out- comes were limited to particular eras. For example, NRM, relapse-related mortality, rate of grades 3–4 acute GvHD, rate of chronic GvHD, and the incidences of liver and kid- ney injury improved significantly only when 2004– 2009 was compared to 1997–2003; the rate of relapse or pro- gression improved significantly only in the most recent
haematologica | 2021; 106(6)
1605