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F. Monaco et al.
improvements could be a bias. The slow accrual was due to competing protocols at our Centers. Another limitation regards high-risk patients who received dose level-2 TBI (400 cGy). Only five patients were enrolled but, as per protocol design, we met dose escalation rules because of transplant failure. It is possible that, with greater numbers, better results could be achieved.
The incidence of non-relapse mortality remains an issue, being high especially for high-risk patients (cumula- tive incidence of 43% at 2 years). There was no statistical- ly significant difference regarding TBI-dose and GvHD incidence. Different strategies are needed to reduce the toxicity of 450 cGy TBI. Fractionation of the TBI dose was investigated in two preclinical canine experiments, which showed that fractionation of 450cGy TBI was significant- ly less immunosuppressive with a higher rate of graft rejection than when given as a single dose.15,16 Stelljes et al. demonstrated that a conditioning regimen of 8Gy frac- tionated TBI and FLU was feasible with low NRM in patients with AML (8% at 2 years for patients in CR, 37% at 2 years for patients with active disease).17 A novel approach to replace or augment TBI while reducing toxic- ity, consists of using targeted radioimmunotherapy.18 Monoclonal antibodies to CD45 and CD20 coupled to beta (b)-emitting radionuclides (iodine-131 or yttrium-90) have been studied19,20 showing good results but evident disadvantages (e.g. off-target effects and the need to use isolation rooms) in clinical trials. However, the recent sub- stitution with alpha (α)-emitting radionuclides (bismuth- 213 and astatine-211) has given encouraging results,21,22 especially for astatine-211.23 Clinical trials are currently in progress using astatine-211 (clinicaltrials.gov identifier: NCT03128034).
The high incidence of GvHD irrespective of TBI dose remains a problem, especially for grades III-IV acute GvHD and chronic GvHD that reached cumulative inci- dences of 13% at 200 days and 45% at two years. These complications impacted OS and NRM, accounting for one-third of all deaths. Novel approaches are currently being investigated that are aimed at reducing GvHD inci- dence: the triple-drug combination using tacrolimus, mycophenolate mofetil, and sirolimus has been studied with encouraging results,24 and a phase III trial evaluated the addition of sirolimus to cyclosporine and MMF in order to reduce GvHD without impairing graft-versus-tumor effect with significantly less acute GvHD and less NRM with superior overall and progres- sion-free survival (clinicaltrials.gov identifier: NCT01251575).25
Lim et al.26 recently described results from a large retro- spective study by the European Group for Blood and Marrow Transplantation (EBMT) registry which included 1,333 patients with MDS, who were older than 50 years, of whom 833 (62%) underwent reduced intensity condi- tioning (RIC). The RIC regimens included FLU plus inter- mediate doses of one or two alkylating agents including busulfan, melphalan, cyclophosphamide, or thiotepa, or low-dose TBI (200-400 cGy) with or without anti-thymo- cyte globulin or alemtuzumab. OS, NRM and relapse inci- dence (RI) rates at four years were 32%, 32% and 41%, respectively. The median age of patients undergoing RIC was 59 years (range 50-74.7), which was younger than current patients, and no comorbidity data was reported.
27
Similarly, McClune et al. performed another large retro-
spective analysis of data of the Center for International
Blood and Marrow Transplant Research (CIBMTR) involving 1,080 patients of whom 535 had MDS and received an RIC or NMA conditioning regimen before transplantation. Of this cohort, 181 patients were over 60 years of age but, again, no comorbidity scores were reported. At two years after HCT, results for patients 60- 64 years of age or over 65 years old included OS 45% and 38%, RFS 35% and 36%, NRM 35% and 39%, and relapse rate of 29% and 21%, respectively. Recently Scott et al.28 concluded a randomized prospective trial showing that more intensive conditioning might be better than RIC for patients with AML or MDS. A reduction in NRM for RIC (4.4% vs. 15.8% at 18 months) was offset by increased disease progression (37% vs. 3.7% at 18 months), although there were no statistically significant differences in OS and relapse-free survival between the two groups of patients.
Storb and Sandmaier29 analyzed results of eleven differ- ent retrospective studies using RIC or NMA regimens for various hematologic diseases reported by registries or individual transplant centers on nearly 9,000 patients. With a median follow up of three years (range 1.75-5), the incidence of disease progression was 43% (range 22- 65%), NRM 34% (range 6-38%), and OS 38% (22-65%).
Non-myeloablative conditioning has extended the use of allogeneic HCT for patients with myeloid malignancies who were previously not considered candidates for HCT because of advanced age or comorbidities. Initial results with a regi- men based on 200 cGy TBI was associated with a relatively
Figure 4. Incidences of graft-versus-host disease (GvHD) were comparable between different Arms and TBI doses. (A) Acute GvHD, (B) chronic GvHD.
A
B
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haematologica | 2019; 104(6)