Sangmin Lee, MD

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Allogeneic stem cell transplantation (SCT) remains the only potential curable option for patients with myelodysplastic syndromes (MDS). While MDS mainly occurs in older patients, MDS does occur in younger patients and prior studies have suggested better overall survival (OS) for younger patients undergoing allogeneic SCT.  Shimomura et al (BMT 2021) analyzed the outcome of 645 patients aged 16-39 years old who received allogeneic SCT in Japan. In this multicenter retrospective analysis, 3 year OS was 71%. In the cohort, 37% of patients had either intermediate-2 or high risk by IPSS, 41% had active disease prior to SCT, and 10% had secondary MDS.  In a multivariate analysis, active disease status, poor cytogenetic risk, and transplant other than from related donor were associated with poor 3 year OS. Cumulative 3 year relapse was 11% and 3 year non-relapse mortality was 19%, which is lower than those of older patients with MDS which ranges from 30-40%. Limitations from this analysis are lack of genetic mutation data, as well as lack of incorporation of prior MDS directed therapy with outcome analysis, however this analysis from a large retrospective cohort provides valuable information regarding outcome in young patients with MDS.

Use of melphalan in multiple myeloma is associated with increased risk of developing MDS and acute myeloid leukemia (AML).  Jonsdottir et al (European Journal of Hematology) reported results of a large population-based study using the Swedish cancer registry to determine relationship of exposure to melphalan treatment for multiple myeloma and development of subsequent MDS and AML. Out of 26,627 patients with multiple myeloma in the Swedish cancer registry, 0.5% (124) patients developed subsequent MDS or AML. The median time from multiple myeloma diagnosis to MDS or AML diagnosis was 3.8 years. There was about threefold higher cumulative exposure to melphalan among those who developed MDS or AML compared to those who did not develop MDS or AML (OR=2.8, 95% CI 1.7-5.2, P < 0.001). There was no difference among the groups in exposure and dosing of radiation therapy, cumulative dose of cyclophosphamide, or doxorubicine. This large population-based study confirms the association between melphalan therapy and development of MDS/AML.

Febrile neutropenia is a common complication for neutropenic patients undergoing therapy. Patients who develop febrile neutropenia are treated with empiric broad-spectrum antibiotics, however there is conflicting recommended duration of antimicrobial treatment in absence of evidence of bacterial infection. The Infectious Disease Society of America recommends antibiotic treatment until marrow recovery, while the European Conference of Infections in Leukemia guidelines suggest consideration of discontinuation after 72 hours if the patient is hemodynamically stable and afebrile for 48 hours. Schauwvlieghe et al (EClinical Medicine 2021) compared the outcome of MDS and AML patients with febrile neutropenia during induction chemotherapy receiving a shortened 3 day empiric antibiotic therapy in absence of documented infection to those receiving antibiotics until neutrophil recovery in a retrospective comparative cohort study in two hospitals in the HOVON network. The shorted antibiotic group received a median of 9 days of antibiotics, compared to 19 days. The primary endpoint was the rate of serious medical complications; there was no statistical difference between the two groups (12.5% for shortened antibiotics vs 8.9% for prolonged antibiotics, P = 0.17).  There was no difference in serious medical complications when adjusting for age, AML risk, non-pulmonary HCT-CI score, and year of admission. There was also no significant difference in infection-related 30-day mortality among the two groups. This study suggests that for patients who develop febrile neutropenia while receiving induction chemotherapy, it may be safe to consider stopping antibiotics after 3 days in absence of infection. A prospective trial should be considered to further evaluate the safety of shortened antibiotic course.

Human leukocyte antigen (HLA)-mismatched hematopoetic stem cell microtransplantation (MST) has previously been evaluated in AML in combination with chemotherapy and suggests potential improvement in outcomes. Li et al evaluated MST combined with decitabine in patients with intermediate or high risk MDS compared to decitabine alone.  Out of 22 patients in the study, the cohort that received MST with decitabine had higher median OS (24 vs 14.2 months, p=0.04), although there was no statistical significant difference in overall response rate. There was no reported graft vs host disease, and adverse events were similar between the two groups. The main limitation of the study was the very small sample size; further prospective studies utilizing MST in MDS are needed to demonstrate benefit.

MDS patients often present with neutropenia and develop worsening neutropenia due to myelosuppression from HMA therapy, resulting in increased risk of infections including invasive fungal infection (IFI). Tey et al reported a retrospective analysis of the rate of IFI in patients with MDS or low blast count AML receiving azacitidine. Out of 117 patients, 61% received antifungal prophylaxis, either with posaconazole (n=70) or voriconazole (n=1). The IFI rate was 7.7% in the cohort with median time of onset of 74 days from start of azacitidine treatment (range 1-226); the IFI rate did not differ statistically between those receiving prophylaxis vs not (5.6% vs 10.9%, p=0.30). However, presence of neutropenia at three months of treatment was associated with increased IFI risk (HR 8.29, p=0.01), and IFI was associated with increased mortality in a multivariate analysis (HR 8.37, p<0.0001). Anti-fungal prophylaxis is currently standard practice for MDS patients who present or develop neutropenia; however, HMA treatment is associated with prolonged neutropenia due to myelosuppression and time to response. A more effective therapy with less myelosuppression is needed for treatment of MDS.

Human leukocyte antigen (HLA)-mismatched hematopoetic stem cell microtransplantation (MST) has previously been evaluated in AML in combination with chemotherapy and suggests potential improvement in outcomes. Li et al evaluated MST combined with decitabine in patients with intermediate or high risk MDS compared to decitabine alone.  Out of 22 patients in the study, the cohort that received MST with decitabine had higher median OS (24 vs 14.2 months, p=0.04), although there was no statistical significant difference in overall response rate. There was no reported graft vs host disease, and adverse events were similar between the two groups. The main limitation of the study was the very small sample size; further prospective studies utilizing MST in MDS are needed to demonstrate benefit.

MDS patients often present with neutropenia and develop worsening neutropenia due to myelosuppression from HMA therapy, resulting in increased risk of infections including invasive fungal infection (IFI). Tey et al reported a retrospective analysis of the rate of IFI in patients with MDS or low blast count AML receiving azacitidine. Out of 117 patients, 61% received antifungal prophylaxis, either with posaconazole (n=70) or voriconazole (n=1). The IFI rate was 7.7% in the cohort with median time of onset of 74 days from start of azacitidine treatment (range 1-226); the IFI rate did not differ statistically between those receiving prophylaxis vs not (5.6% vs 10.9%, p=0.30). However, presence of neutropenia at three months of treatment was associated with increased IFI risk (HR 8.29, p=0.01), and IFI was associated with increased mortality in a multivariate analysis (HR 8.37, p<0.0001). Anti-fungal prophylaxis is currently standard practice for MDS patients who present or develop neutropenia; however, HMA treatment is associated with prolonged neutropenia due to myelosuppression and time to response. A more effective therapy with less myelosuppression is needed for treatment of MDS.

Human leukocyte antigen (HLA)-mismatched hematopoetic stem cell microtransplantation (MST) has previously been evaluated in AML in combination with chemotherapy and suggests potential improvement in outcomes. Li et al evaluated MST combined with decitabine in patients with intermediate or high risk MDS compared to decitabine alone.  Out of 22 patients in the study, the cohort that received MST with decitabine had higher median OS (24 vs 14.2 months, p=0.04), although there was no statistical significant difference in overall response rate. There was no reported graft vs host disease, and adverse events were similar between the two groups. The main limitation of the study was the very small sample size; further prospective studies utilizing MST in MDS are needed to demonstrate benefit.

MDS patients often present with neutropenia and develop worsening neutropenia due to myelosuppression from HMA therapy, resulting in increased risk of infections including invasive fungal infection (IFI). Tey et al reported a retrospective analysis of the rate of IFI in patients with MDS or low blast count AML receiving azacitidine. Out of 117 patients, 61% received antifungal prophylaxis, either with posaconazole (n=70) or voriconazole (n=1). The IFI rate was 7.7% in the cohort with median time of onset of 74 days from start of azacitidine treatment (range 1-226); the IFI rate did not differ statistically between those receiving prophylaxis vs not (5.6% vs 10.9%, p=0.30). However, presence of neutropenia at three months of treatment was associated with increased IFI risk (HR 8.29, p=0.01), and IFI was associated with increased mortality in a multivariate analysis (HR 8.37, p<0.0001). Anti-fungal prophylaxis is currently standard practice for MDS patients who present or develop neutropenia; however, HMA treatment is associated with prolonged neutropenia due to myelosuppression and time to response. A more effective therapy with less myelosuppression is needed for treatment of MDS.

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

For patients with myelodysplastic syndromes (MDS), allogeneic stem cell transplantation (SCT) is currently the only curative treatment, however, is associated with risk of transplant-related mortality, as well as relapse. Reduced intensity conditioning (RIC) regimens may decrease toxicity yet there may be increased risk of relapse compared to myeloablative conditioning (MAC) regimens. In an analysis of MDS patients enrolled on the BMT CTN 0901 study, which was a phase III randomized clinical trial comparing outcomes by conditioning intensity prior to allogeneic stem cell transplantation in adult patients with myeloid malignancy, 42% of patients had detectable mutations in a set of 10 genes prior to conditioning with RIC or MAC. Presence of mutations prior to conditioning was associated with increased risk of relapse (3 year relapse, 40% vs 11%, p=0.022) and decreased overall survival (3 year OS 55% vs 79%, p=0.045). Among those with detectable mutations, receiving RIC had higher relapse rates (3 year relapse 75% vs 17%, p=0.003) and lower relapse-free survival (3 year RFS 13% vs 49%, p=0.003) compared to receiving MAC, although there was no difference in overall survival. Further investigation is warranted given small sample size of MDS patients, however, there may be benefit of considering MAC conditioning in MDS patients with detectable mutations prior to conditioning for allogeneic SCT.

TP53 mutations are found in 10-20% of patients with MDS and confer worse outcomes. Eprenetapopt (APR-246) is a small molecule inhibitor that stabilizes mutant p53 and induces apoptosis in TP53-mutant cells. In a phase Ib/II study of eprenatapopt combined with azacitidine in patients with TP53-mutatnt MDS or acute myeloid leukemia (AML), overall response in MDS patients (n=40) was 73%, with 50% achieving complete remission and 58% achieving a cytogenetic response. Median overall survival was 10.8 months, and no dose limiting toxicities were observed. Despite the promising early trial results, the phase 3 clinical trial evaluating eprenetapopt with azacitidine compared to azacitidine in MDS patients with TP53 mutation did not meet the primary endpoint of complete remission rate (33.3% vs 22.4%, p=0.13) (Aprea Press Release, 12/28/2020). Further results including secondary endpoints from the phase 3 trial will be reported in the future. 

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Currently there are limited therapeutic options for myelodysplastic syndromes (MDS) after failure of standard therapy. Options for patients with lower risk MDS patients without presence of deletion 5q (del5q) or SF3B1 mutation are limited after growth factor support. Lenalidomide has been used as a single agent in patients with low risk non-del5q MDS refractory to erythropoietin stimulating agents (ESA) with limited erythroid response. A phase III US intergroup trial  compared erythroid response in low risk MDS non-del5q MDS patients after ESA to either combination of lenalidomide and epoetin alfa (EPO) versus lenalidomide alone. After four cycles of treatment, major erythroid response was higher in the combination group compared to lenalidomide alone (28.3% vs 11.5%, p=0.004). The response was durable, with median major erythroid response duration of 23.8 months compared to 13 months for lenalidomide alone. In patients with low risk MDS with del5q where lenalidomide is considered, lenalidomide should be considered in combination with epoetin alfa.

For higher risk MDS patients, standard upfront treatment is hypomethylating agents (HMA), either azacitidine or decitabine. Given increased PD-1 and PD-L1 expression in high risk MDS, pembrolizumab, a monoclonal antibody targeting PD-1, is currently being evaluated in MDS. Updated results of a phase II study evaluating combination of pembrolizumab and azacitidine in untreated higher risk MDS patients was reported in ASH 2020. Untreated MDS patients with intermediate-1 and high risk by IPSS were enrolled and treated with standard azacitidine in combination with pembrolizumab 200mg IV on day 1 every 21 days. Out of 17 patients, overall response rate was 80%, with 3 patients achieving complete remission (CR), 4 patients achieving marrow CR, 4 patients achieving marrow CR with hematologic improvement, and one patient demonstrating hematologic improvement of erythrocytes. Median overall survival was not reached with median follow up of 13.8 months. Pembrolizumab with azacitidine should be further investigated in MDS.

Poly(ADP-ribose) polymerase (PARP) inhibitors are utilized in a range of solid tumor cancers. There are emerging concerns of PARP inhibitors with increased risk of developing MDS and acute myeloid leukemia (AML). A meta-analysis of 28 randomized control trials (RCT) with PARP inhibitors was done to evaluate risk of developing MDS and AML. Based on 18 RCTs with placebo control, PARP inhibitors increased risk of MDS and AML compared to placebo (Peto OR 2.63, p=0.026).  There was increased incidence of MDS and AML in the PARP inhibitor group compared to placebo (0.73% vs 0.47%). The median treatment duration was 9.8 months and median latency period since first exposure to a PARP inhibitor was 17.8 months. Use of PARP inhibitors is associated with increased risk of development of MDS and AML, and patients should be monitored accordingly.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.

Higher expression of Wilms’ tumor 1 (WT-1) has been associated with poor survival in MDS. To further characterize the prognostic value of WT-1 expression level, peripheral WT-1 mRNA expression level at baseline was measured in MDS patients undergoing treatment with azacitidine. Lower WT-1 mRNA level was associated with higher overall response, as defined by CR, marrow CR, partial response, or HI (p=0.03), although WT-1 mRNA level did not show difference in overall survival. This was a small retrospective, single center study; role of WT-1 mRNA level as a biomarker for response to azacitidine should be further investigated.

Results of a multi-center trial comparing reduced intensity allogeneic stem cell transplant (SCT) to hypomethylating agents or best supportive care in higher risk MDS patients aged 50-75 was reported in the annual meeting of the American Society of Hematology in 2020. Patients with intermediate-2 or higher risk by IPSS were assigned based on SCT or no SCT arm based on donor status, and patients who had donor proceeded to reduced intensity SCT within 6 months of enrolment. In an intent-to-treat analysis, the study showed different in 3-year overall survival, which was the primary endpoint between SCT vs non-SCT arms (47.9% vs 26.6%, p=0.0001). Leukemia-free survival at 3 years was also greater for the SCT arm (35.8% vs 20.6%, p=0.003). Allogenic stem cell transplant is currently offered to patients with higher risk MDS given this is the only potential curable approach for MDS patients. This study further supports allogeneic stem cell transplant for older patients with higher risk MDS.