Elderly Patients With Higher-Risk Myelodysplastic Syndromes
Elderly Patients With Higher-Risk Myelodysplastic Syndromes
Increasing the tiny cure rate for elderly MDS patients will require new effective targeted therapies that would be based on better understanding of the genetic landscape and the biologic underpinnings of MDS. Another approach would be to increase the utilization of alloSCT. The low use of alloSCT in elderly MDS patients is related to multiple factors including concerns of excessive TRM, reduced physiologic reserve with advanced age and comorbidities, donor availability, patient preferences and other factors. Age by itself has not been shown to compromise outcomes of RIC-alloSCT in patients with good performance status (PS). Although retrospective data suggest that RIC-alloSCT results in comparable OS with MAC-alloSCT in hematologic malignancies, MDS-specific data are scarce. The reduced TRM with RIC-alloSCT is counterbalanced by increased relapse rates, resulting in long-term survival in 30–50% of patients.
Another potential reason for the low alloSCT utilization in the elderly might be the lack of evidence of a survival advantage with alloSCT over azacitidine. No randomized study directly compared these modalities. A retrospective study of elderly patients aged 60–70 years with HR-MDS and secondary acute myeloid leukemia compared two well-balanced cohorts of transplanted (n = 103) or azacitidine-treated patients (n = 75). The transplanted group had better 2-year OS rate (39%, 95% CI: 30–50% vs 23%, 95% CI: 14–40%) which persisted in multivariate analysis (hazard ratio [HR]: 0.3; p = 0.007).
In the absence of prospective randomized data and high-quality retrospective studies comparing alloSCT with azanucleosides in elderly patients with HR-MDS, DA would be a reasonable approach to assess the question. Koreth et al. showed that for patients with primary MDS aged 60–70 years, non-transplantation strategies are associated with a survival advantage for IPSS LR-MDS, while RIC alloSCT results in survival benefit in patients with HR-MDS when compared with non-transplantation approaches, including azanucleoside therapy.
This study is limited by its retrospective nature and the lack of details regarding comorbidities, PS and other relevant clinical and biological data for many patients including details of prior therapy. Additionally, the various cohorts used in the DA come from wildly different time intervals; patients from the original International MDS Risk Analysis Working group date back to the 1970s. No attempts at matching the patients were made. Although azanucleoside-treated patients with PS >2 and those with renal and liver organ dysfunction (who would not have been candidates for alloSCT) were excluded, patients with other significant comorbidities (e.g., cardiac) that might have otherwise prohibited RIC alloSCT were not excluded. Moreover, HR-MDS patients who received decitabine were included in the assessment although this drug has not been shown to improve survival. Importantly, the IPSS calculation for transplanted patients was made at time of pretransplantation rather than at diagnosis (which is the only time point at which the IPSS has been validated). Thus, the transplanted patients may have been significantly time-censored compared with the non-transplanted patients, selecting for patients with more indolent natural histories. Lastly, only 59 patients (45%) of those who underwent RIC alloSCT had IPSS HR-MDS.
Despite the selection bias and other significant limitations, the robustness of the conclusions were confirmed by testing under multiple plausible assumptions in sensitivity analyses. The LE of the HR-MDS patients who received non-transplantation therapies including azanucleosides was 28 months, which is slightly longer than the median survival of the azacitidine-treated patients in the landmark AZA001 trial (24.5 months), therefore a lower than expected survival in non-transplanted patients probably did not account for the observed results. The benefit of RIC-alloSCT for HR-MDS was mainly due to a long-term survival plateau of 25% despite increased early mortality. The unfortunate news is that only 25% of the transplanted patients appear to be benefitting long-term from therapy, confirming previous studies. In practice, azanucleosides and alloSCT are often used sequentially. Outcomes of patients who fail to respond or lose response to azanucleosides is dismal, including those who undergo subsequent alloSCT, therefore alloSCT should ideally be pursued in eligible patients before azanucleoside failure occurs. The authors did not specifically analyze the patients treated with azanucleosides followed by RIC-alloSCT, a treatment algorithm which many experts recommend.
Although physicians now have stronger evidence to consider RIC-alloSCT in elderly HR-MDS patients, a number of questions remain unanswered. Is pre-alloSCT cytoreduction always needed and if so, should chemotherapy or azanucleosides be used and what BM blast percentage should be targeted? What is the best alloSCT platform in terms of conditioning regimen intensity, drugs and graft-versus-host disease prophylaxis? With the wider use of alternative donors, can the results of this DA be applied to patients undergoing RIC-alloSCT using other graft sources such as umbilical cord blood or HLA-haploidentical donors?
Lastly, the IPSS has been shown to underestimate the risks in a significant minority of patients designated as LR. Though newer prognostic schemes (e.g., MD Anderson low-risk score and the revised IPSS (IPSS-R)) and genetic biomarkers (e.g., EZH2) were reported to identify some of these patients, the optimal therapeutic approach is still not known as the benefits of alloSCT have not been demonstrated in these patients. As the IPSS-R could potentially replace the IPSS, it would be important to study the benefit of RIC-alloSCT in elderly patients in the intermediate-risk group of the IPSS-R. Lastly, effective pharmacologic and immunologic preventive, preemptive and therapeutic approaches for disease relapse will need to be developed as relapse becomes the main reason for treatment failure after RIC alloSCT for MDS.
Discussion & Five-Year View
Increasing the tiny cure rate for elderly MDS patients will require new effective targeted therapies that would be based on better understanding of the genetic landscape and the biologic underpinnings of MDS. Another approach would be to increase the utilization of alloSCT. The low use of alloSCT in elderly MDS patients is related to multiple factors including concerns of excessive TRM, reduced physiologic reserve with advanced age and comorbidities, donor availability, patient preferences and other factors. Age by itself has not been shown to compromise outcomes of RIC-alloSCT in patients with good performance status (PS). Although retrospective data suggest that RIC-alloSCT results in comparable OS with MAC-alloSCT in hematologic malignancies, MDS-specific data are scarce. The reduced TRM with RIC-alloSCT is counterbalanced by increased relapse rates, resulting in long-term survival in 30–50% of patients.
Another potential reason for the low alloSCT utilization in the elderly might be the lack of evidence of a survival advantage with alloSCT over azacitidine. No randomized study directly compared these modalities. A retrospective study of elderly patients aged 60–70 years with HR-MDS and secondary acute myeloid leukemia compared two well-balanced cohorts of transplanted (n = 103) or azacitidine-treated patients (n = 75). The transplanted group had better 2-year OS rate (39%, 95% CI: 30–50% vs 23%, 95% CI: 14–40%) which persisted in multivariate analysis (hazard ratio [HR]: 0.3; p = 0.007).
In the absence of prospective randomized data and high-quality retrospective studies comparing alloSCT with azanucleosides in elderly patients with HR-MDS, DA would be a reasonable approach to assess the question. Koreth et al. showed that for patients with primary MDS aged 60–70 years, non-transplantation strategies are associated with a survival advantage for IPSS LR-MDS, while RIC alloSCT results in survival benefit in patients with HR-MDS when compared with non-transplantation approaches, including azanucleoside therapy.
This study is limited by its retrospective nature and the lack of details regarding comorbidities, PS and other relevant clinical and biological data for many patients including details of prior therapy. Additionally, the various cohorts used in the DA come from wildly different time intervals; patients from the original International MDS Risk Analysis Working group date back to the 1970s. No attempts at matching the patients were made. Although azanucleoside-treated patients with PS >2 and those with renal and liver organ dysfunction (who would not have been candidates for alloSCT) were excluded, patients with other significant comorbidities (e.g., cardiac) that might have otherwise prohibited RIC alloSCT were not excluded. Moreover, HR-MDS patients who received decitabine were included in the assessment although this drug has not been shown to improve survival. Importantly, the IPSS calculation for transplanted patients was made at time of pretransplantation rather than at diagnosis (which is the only time point at which the IPSS has been validated). Thus, the transplanted patients may have been significantly time-censored compared with the non-transplanted patients, selecting for patients with more indolent natural histories. Lastly, only 59 patients (45%) of those who underwent RIC alloSCT had IPSS HR-MDS.
Despite the selection bias and other significant limitations, the robustness of the conclusions were confirmed by testing under multiple plausible assumptions in sensitivity analyses. The LE of the HR-MDS patients who received non-transplantation therapies including azanucleosides was 28 months, which is slightly longer than the median survival of the azacitidine-treated patients in the landmark AZA001 trial (24.5 months), therefore a lower than expected survival in non-transplanted patients probably did not account for the observed results. The benefit of RIC-alloSCT for HR-MDS was mainly due to a long-term survival plateau of 25% despite increased early mortality. The unfortunate news is that only 25% of the transplanted patients appear to be benefitting long-term from therapy, confirming previous studies. In practice, azanucleosides and alloSCT are often used sequentially. Outcomes of patients who fail to respond or lose response to azanucleosides is dismal, including those who undergo subsequent alloSCT, therefore alloSCT should ideally be pursued in eligible patients before azanucleoside failure occurs. The authors did not specifically analyze the patients treated with azanucleosides followed by RIC-alloSCT, a treatment algorithm which many experts recommend.
Although physicians now have stronger evidence to consider RIC-alloSCT in elderly HR-MDS patients, a number of questions remain unanswered. Is pre-alloSCT cytoreduction always needed and if so, should chemotherapy or azanucleosides be used and what BM blast percentage should be targeted? What is the best alloSCT platform in terms of conditioning regimen intensity, drugs and graft-versus-host disease prophylaxis? With the wider use of alternative donors, can the results of this DA be applied to patients undergoing RIC-alloSCT using other graft sources such as umbilical cord blood or HLA-haploidentical donors?
Lastly, the IPSS has been shown to underestimate the risks in a significant minority of patients designated as LR. Though newer prognostic schemes (e.g., MD Anderson low-risk score and the revised IPSS (IPSS-R)) and genetic biomarkers (e.g., EZH2) were reported to identify some of these patients, the optimal therapeutic approach is still not known as the benefits of alloSCT have not been demonstrated in these patients. As the IPSS-R could potentially replace the IPSS, it would be important to study the benefit of RIC-alloSCT in elderly patients in the intermediate-risk group of the IPSS-R. Lastly, effective pharmacologic and immunologic preventive, preemptive and therapeutic approaches for disease relapse will need to be developed as relapse becomes the main reason for treatment failure after RIC alloSCT for MDS.
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