Retrospective cohort (cohort 1)
Erythropoiesis stimulating agents
Patients receiving ESA according to the ELN guidelines versus patients receiving ESA without guideline endorsement
When we looked at erythropoiesis stimulating factors, we found that 57 patients in cohort 1 received erythropoiesis stimulating agents (ESA) in-label and guideline-adherent, while six patients were treated off-label. Patients treated according to the guidelines lived for a median of 65 months (95%CI: 37.2; 97.8), while patients treated outside the guidelines lived for a median of 173 months (95%CI: 0.0; 379.4). However, the difference was statistically not significant (p = 0.099).
Patients receiving ESA according to the ELN guidelines versus patients eligible for ESA treatment but not receiving it
We identified 15 patients who did not receive ESA despite being eligible according to the guidelines. Their survival (median 29 months, 95%CI: 0.0; 70.8) was statistically not different from that of the 57 patients receiving ESA according to the guidelines (median 65 months, 95%CI: 37.2; 97.8) (p = 0.509).
Iron chelation therapy
Patients receiving ICT according to the ELN guidelines versus patients receiving ICT without guideline endorsement
Fifty-three patients received ICT in-label and guideline-adherent and lived for a median of 70 months (95%CI: 48; 92). In addition, 19 patients received ICT off-label and lived for a median of 90 months (95%CI: 40.1; 139.9). The difference was statistically not significant (p = 0.652).
Patients receiving ICT according to the ELN guidelines versus patients eligible for ICT but not receiving it
The group of 53 patients who were treated in-label and guideline-adherent with an iron chelator achieved a survival benefit compared with 24 patients who were eligible according to the ELN guidelines but never received ICT (median overall survival 70 months (95%CI: 48; 92) versus 32 months (95%CI: 2.4; 61.6)). The difference was statistically significant (p = 0.012, Fig. 1).
Patients receiving lenalidomide according to the ELN guidelines versus patients receiving lenalidomide without guideline endorsement
Sixteen patients received lenalidomide in accordance with the ELN guidelines, with a median overall survival of 69 months (95%CI: 47.86; 90.14). Their survival was not significantly different from 34 patients who did not meet the ELN criteria but were still treated with lenalidomide (median 77 months, 95%CI: 34; 120) (p = 0.639). According to our review of documents, these patients did not meet the ELN criteria because they received lenalidomide despite not being RBC transfusion dependent.
Patients receiving lenalidomide according to the ELN guidelines versus patients eligible for lenalidomide treatment but not receiving it
For the 16 patients receiving lenalidomide according to the guidelines, survival was not significantly different when compared to 13 patients who received only BSC despite being eligible for lenalidomide treatment (median overall survival 65 months (95%CI: 47.9; 90.1) versus 93 months (95%CI: 0.0; 210.4)) (p = 0.677).
Patients receiving HMAs according to the ELN guidelines versus patients receiving HMAs without guideline endorsement
Among 66 patients treated with azacitidine, only one patient received it outside the guideline recommendations. We were thus not able to formally compare guideline-adherent and non-adherent treatment.
Patients receiving HMAs according to the ELN guidelines versus patients eligible for HMA treatment but not receiving it
Sixty-five patients were treated with azacitidine, whereas 100 patients were not treated even though they were eligible according to the guidelines. The median overall survival of treated patients was 29 months (95%CI: 25.9; 32.1) while patients who received best supportive care only lived for a median of 17 months (95%CI: 4.9; 29.1) (p = 0.399, Fig. 2).
Allogeneic stem cell transplantation
Patients undergoing alloSCT according to the ELN guidelines versus patients receiving alloSCT without guideline endorsement
The aforementioned therapies are all non-intensive. In contrast, alloSCT represents the most intensive and potentially toxic but also potentially curative treatment applicable to MDS patients. Cohort 1 included 118 patients undergoing alloSCT in accordance with the ELN guidelines, whereas 40 patients did not meet the ELN guideline criteria but were still transplanted. In the latter group, 25 patients (62.5%) had only mild cytopenias and a blast percentage below the required threshold, or a favorable karyotype. Further, thirteen patients (32.5%) with a low-risk IPSS underwent alloSCT, and two patients (5.0%) were transplanted while being older than 70 years. The median survival of patients who were transplanted despite not being formally eligible was 77 months (95%CI: 44.7; 109.4), compared to 65 months in guideline-adherent patients (95%CI: 29.9; 100.1, p = 0.482, Fig. 3).
Patients undergoing alloSCT according to the ELN guidelines versus patients eligible for alloSCT but not receiving it
While 118 patients underwent alloSCT in accordance with the guidelines, 348 patients were not transplanted even though they were eligible. Patients undergoing alloSCT lived significantly longer than patients who were eligible but were not transplanted (p < 0.0005, Fig. 4). Median survival of patients undergoing alloSCT was 65 months (95%CI: 29.9; 100.1) compared to 16 months (95%CI: 13.6; 18.5) in patients who received BSC only.
Prospective cohort (cohort 2)
In cohort 2, 85 patients received the advice to watch and wait. Since they were in no need for any treatment at their first visit, they were simply asked to return for follow-up visits. Forty-nine of them adhered to this recommendation, while 31 patients decided to try a more active approach. Fourteen patients (45.2%) received BSC, and six (19.4%) were treated with HMAs. Three patients (9.7%) received lenalidomide, and another three underwent chemotherapy. Two non-adherent patients (6.5%) decided to undergo alloSCT. The alternative therapeutic approach of three patients was unknown.
The non-adherent patients appeared to live longer (median 265 months (95%CI: 194.9; 335.6)) than the adherent patients (91 months (95%CI: 67.8; 114.4)), but the difference was statistically not significant (p = 0.799).
Best supportive care
Among 100 patients recommended to restrict treatment to best supportive care, including RBC and platelet transfusions, HGFs, and ICT, 84 were adherent, whereas 13 chose to try more intensive treatment. Due to small numbers of patients in the subgroups, a separate analysis for ICT as performed in the retrospective cohort was not feasible. In this group, five patients (38.5%) decided to be treated with BSC. Four patients (30.8%) underwent alloSCT and two (15.4%) received azacitidine. Two patients (7.7%) were treated using lenalidomide. The two groups did not differ significantly in terms of overall survival (median 188 months (95%CI: 81.2; 294.8) versus 106 months (95%CI: 50.9; 161.1)) (p = 0.664). Matched-pair analysis was not necessary for the comparison between BSC and more intensive treatment, since all patients in this group received BSC anyway.
Thirteen patients were recommended to start treatment with lenalidomide, 9 of whom actually received this immunomodulatory drug while four did not. These four patients chose to receive BSC only. All patients were classified as lower-risk MDS. Since all patients were alive at the end of the study, no conclusions could be drawn as to a possible survival advantage. However, a matched-pair analysis provided valuable clues. When matching the nine adherent patients with 30 patients receiving BSC only, the adherent patients showed a significant survival benefit (median OS 182 months (95%CI: 148.7; 216.5) versus 73 months (95%CI: 40.2; 107.0)) (p = 0.004). Patients in both of the groups had MDS del5q as defined by the WHO.
Fifty-three patients were advised to be treated with azacitidine. Comparing 33 adherent with 15 non-adherent patients, no significant difference in survival was found (median OS 33 months (95%CI: 17.1; 58.8) versus 54 months (95%CI: 11.1; 96.6)) (p = 0.197). Nine patients (60%) decided to follow a best supportive care concept; three (20%) underwent chemotherapy while another two (13.3%) were transplanted. One patient (6.6%) did not receive any therapy at all. In five cases, a comprehensive follow-up was not possible. Again, the matching procedure yielded useful information and verified the trend we showed in patients receiving HMAs in the retrospective group. Thirty-three adhering patients showed a highly significant survival advantage over 128 matched patients who received BSC but would have been eligible for treatment with azacitidine as well (median OS 46 months (95%CI: 31.3; 60.7) versus 9 months (95%CI: 7.2; 10.8)) (p < 0.005, Fig. 5). The 128 matching partners were part of a historical control cohort. Since azacitidine was not yet approved at the time of their first diagnosis, these patients did not receive a recommendation for treatment with azacitidine.
Intensive and non-intensive chemotherapy
Of 16 patients who were advised to undergo chemotherapy, nine received this treatment, while the other seven patients opted for another therapeutic approach. Three patients (42.9%) received azacitidine, while two (28.6%) decided for BSC. Two other patients (28.6%) underwent alloSCT instead. Overall survival was not significantly different (median 35 months (95%CI: 23.6; 46.6) versus 32 months (95%CI: 20.6; 43.6)) (p = 0.954). We were not able to identify matching partners who only received BSC.
Allogeneic stem cell transplantation
Among 95 patients who were advised to undergo alloSCT, 63 patients were transplanted within six months, whereas 26 patients were treated differently. Nine patients (27.4%) decided for BSC, another nine (27.4%) received HMAs. Four patients (15.4%) decided for watchful waiting. Four patients (15.4%) underwent chemotherapy. Due to comorbidities, eleven non-adherent patients (42%) could not be transplanted. Seven patients (26%) declined the option of alloSCT due to various personal reasons. For five other patients (19%), we were not able to find a suitable donor within a period of six months.
Without applying our matching criteria, a survival benefit of alloSCT was noted (median OS 74 months (95%CI: 25.05;122.95) versus 28 months (95%CI:7.52; 48.48)) (p = 0.015).
In our matched-pair analysis, 47 patients who underwent alloSCT were compared with 73 matched patients who were treated with BSC only. Transplanted patients achieved a highly significant survival benefit compared with eligible patients who did not undergo alloSCT (median OS 74 months (95%CI: 24.4; 123.6) versus 15 months (95%CI: 7.8; 22.2)) (p < 0.0005, Fig. 6). As we were looking at a historical matching cohort, it was not possible to ascertain why alloSCT was not carried out in the latter patients who were formally eligible according to guideline criteria.