Ehab L. Atallah, MD

This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.¹ The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).  

Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).

The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.

References

1. Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
2. Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
3. Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.

This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.¹ The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).  

Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).

The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.

References

1. Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
2. Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
3. Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.

This month, the phase II randomized study of azacitidine vs. azacitidine + enasidenib was reported by Dinardo et al.¹ The primary endpoint was overall response rate. The study included 101 adult patients with newly diagnosed mutant-IDH2 acute myeloid leukemia (AML) who were ineligible for intensive chemotherapy. They were randomly assigned to enasidenib and azacitidine (Ena-AZA, n = 68) or azacitidine alone (AZA, n = 33). The overall response rate was significantly higher in patients receiving Ena-AZA vs. AZA (74% vs. 36%; odds ratio 4.9; P = .0003). More importantly, the rates of complete remission/complete remission with partial hematologic recovery was higher with Ena-AZA vs. AZA (57% vs. 18% P = .0001). The duration of response was 24.1 months vs 9.9 months for the Ena-AZA vs AZA group. Despite the higher and more durable responses with Ena+AZA, there was no difference in overall survival. The authors attributed that to patients receiving other effective therapies after disease progression. Overall patients tolerated the combination therapy well. The most frequent grade 3 or 4 events in the Ena-AZA vs. AZA groups were thrombocytopenia (37% vs. 19%) and neutropenia (37% vs. 25%).  

Another study from the NCRI AML 16 trial demonstrated that reduced intensity conditioning (RIC) transplant in first remission vs. chemotherapy alone improved survival in older patients with AML who lacked favorable risk cytogenetics and were considered fit for intensive treatment. During a median follow-up of 60 months from remission, patients receiving RIC transplant vs. no transplant had superior survival (37% vs. 20%; hazard ratio [HR] 0.67; P < .001). Survival benefit with transplant in first remission vs. chemotherapy alone was observed across all Wheatley risk groups (adjusted HR 0.68; P < .001). The trial including 932 patients (age 60-70 years) with AML who entered remission and lacked favorable risk. Of these, 144 underwent RIC transplants from either matched sibling donors (n = 52) or matched unrelated donors (n = 92).

The outcome of patients with AML and central nervous system (CNS) involvement at presentation was reported by Ganzel et al. In that study, the investigators evaluated the incidence of CNS involvement in 11 consecutive Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) clinical trials. The incidence of CNS incolvement was 1.111 % (36 of 3240 patients). CNS involvement had no effect on remission rates or survival.

References

1. Dinardo CD et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): a single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. 2021;22(11):P1597-1608 (Nov 1).
2. Russell NH et al. Outcomes of older patients aged 60 to 70 years undergoing reduced intensity transplant for acute myeloblastic leukemia: results of the NCRI acute myeloid leukemia 16 trial. Haematologica. 2021(Oct 14).
3. Ganzel C et al. CNS involvement in AML at diagnosis is rare and does not affect response or survival: data from 11 ECOG-ACRIN trials. Blood Adv. 2021(Nov 12);5(22):4560-4568. doi: 10.1182/bloodadvances.2021004999.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).²This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).²This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

This month, two studies reported on the addition of novel therapies to the backbone of low dose cytarabine. The first study, evaluated the role of adding quizartinib to low-dose cytarabine (LDAC) in older patients with acute myeloid leukemia (AML) not suitable for intensive chemotherapy. The addition of quizartinib to LDAC vs. LDAC alone improved survival and response in older patients with AML with an FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation who were unfit for intensive chemotherapy (IC). Among patients with FLT3-ITD mutation, LDAC+quizartinib improved response in 38% of patients vs. 0% of patients receiving LDAC alone (P = .02). The 2-year overall survival also improved significantly in patients receiving LDAC+quizartinib (hazard ratio [HR] 0.36; P = .024). The study included 202 older patients with AML (de novo AML 63%; secondary AML 25%; high-risk myelodysplastic syndrome 11%) unsuitable for IC with (n = 27) or without FLT3-ITD mutation randomly assigned to receive LDAC+quizartinib or LDAC alone.¹

The second study evaluated the combination of LDAC with venetoclax vs. placebo in treatment-naive patients with AML ineligible for IC. LDAC+venetoclax vs. LDAC+placebo improved median overall survival (HR 0.70; P = .04), along with higher rates of complete response (CR) or CR with incomplete hematologic recovery (CRi) (48.3% vs. 13.2%; P < .001) and postbaseline red blood cell and platelet transfusion independence (39.2% vs. 17.6%; P = .002). This was a post hoc analysis performed after an additional 6 months of follow-up of the phase 3 VIALE-C trial, including 211 adult patients with AML who were treatment-naive and unsuitable for IC. Patients were randomly assigned to receive LDAC with venetoclax (n = 143) or placebo (n = 68).²This study was previously reported with a shorter follow up and ddi not demonstrate a survival difference for LDAC+venetoclax vs. LDAC alone. It is very reassuring to see these results with longer follow-up with an improvement of the median overall survival from 4.1 months with LDAC alone to 8.4 months with LDAC+venetoclax. In addition, responses were seen in patients who had prior hypomethylating agents. The CR, CR/CRi and CR/CR with partial hematologic recovery (CRh) rates were 7%, 29%, and 21% respectively.

Finally in a study by Roboz et al. patients who received oral azacytidine as maintenance had no worsening of fatigue or health-related quality of life. Maintenance therapy with oral azacitidine (oral-AZA) did not negatively affect fatigue and health-related quality of life (HrQoL) in patients with acute myeloid leukemia (AML) in complete remission (CR) or CR with incomplete hematologic recovery (CRi) after intensive chemotherapy (IC). Effects of oral-AZA on fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue: difference in overall least square mean change [D] −0.89; 95% CI −2.37- 0.59) and HrQoL (EQ-5D-3L health utility index: D −0.01; 95% CI, −0.03-0.01; EQ-5D visual analog: D −0.95; 95% CI, −4.38-2.47) were comparable to placebo. Findings are from the QUAZAR AML-001 trial, including 444 patients with AML with intermediate- or poor-risk cytogenetics at diagnosis and unsuitable for transplantation. The patients were randomly assigned to receive either oral-AZA (n = 225) or placebo (n = 219) in first CR/CRi after IC. One caveat is that the assessments were performed on Day 1 of each 28 day cycle, which may have allowed for the recovery from side effects of oral azacytidine.³

References

1. Dennis M et al. Randomised evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Blood Adv. 2021 Oct 1.
2. Wei AH et al. 6-month follow-up of VIALE-C demonstrates improved and durable efficacy in patients with untreated AML ineligible for intensive chemotherapy. Blood Cancer J. 2021;11:163.
3. Roboz GJ et al. Oral azacitidine preserves favorable level of fatigue and health-related quality of life for patients with acute myeloid leukemia in remission: results from the phase 3, placebo-controlled QUAZAR AML-001 trial. Haematologica. 2021 Sep 23.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

This month a couple of studies evaluated the role of enasidenib and gemtuzumab in the therapy of patients with AML using clinical and non-clinical trial data. In a propensity score-matching (PSM) analysis, was enasidenib associated with better outcomes compared to standard of care (SoC). The study included adult patients with relapsed/refractory (R/R) AML with an isocitrate dehydrogenase 2 (IDH2) mutation ineligible for hematopoietic stem cell transplantation (HSCT) treated with enasidenib (n = 195) from the AG221 C-001 trial or SoC therapies (n = 78) from the French Chart Review study. The SoC regimens included azacytidine, decitabine, cytarabine containing regimens, and others. Enasidenib was associated with superior overall survival (OS) (hazard ratio [HR] 0.67; 95% CI 0.47-0.97) compared to SoC therapies in patients with R/R AML with IDH2 mutation who were ineligible for HSCT. The median OS was 9.26 months vs. 4.76 months for enasidenib and SoC respectively. The results of this study are not surprising given the data seen in clinical trials. Although not evaluated in this study, the quality of life for patients receiving enasidenib is better when compared to SoC regimens, such as 7 +3 (cytarabine + idarubicin). Other than the limitations of a PSM study, which are well acknowledged by the authors, the main weakness is this study did not include venetoclax in the SoC regimen. It remains unclear whether using venetoclax in the R/R setting in patients with IDH2 mutations would lead to similar outcomes.

The benefit of gemtuzumab ozogamicin (GO) was demonstrated again in a metanalysis that included 15 randomized controlled trials and 15 retrospective studies that compared GO (n = 4,768) with non-GO (n = 6,466) therapies in 11,234 patients with AML (n = 11,105) and high-risk myelodysplastic syndrome (MDS) (n = 129). GO showed superior survival outcomes in patients with AML or high-risk MDS than non-GO therapy, but higher doses increased the risk for early death. GO vs. non-GO arm showed improved overall survival (HR 0.86; P = .003), event-free survival (HR 0.86; P = .015), and relapse-free survival (HR 0.83; P = .001). However, GO vs. non-GO was associated with an increased risk for early death at a dose of ≥6 mg/m² (relative risk [RR] 2.01; P = .005), hepatic-related adverse effects (RR 1.29; P = .02), and bleeding (RR 1.13; P = .018). Finally, a study by the Polish adult leukemia group demonstrated the safety and efficacy of a low dose cytarabine + cladribine regimen. Treatment consisted of 5 mg/m² cladribine intravenously on day 1-5 (in the first cycle) and on days 1 to 3 (in the second cycle) combined with low dose cytarabine (40 mg) subcutaneously once daily on days 1–10. Patients may continue on low dose cytarabine after that if they have achieved at least a partial remission. Rates of overall response and 56-day mortality were 54.0% and 20.5%, respectively. The median overall survival was 6.9 months (95% CI 4.9-9.6) and superior in patients who achieved an objective response (HR 0.04; P < .0001) or partial remission (HR 0.31; P = .0002) compared to nonresponders.

In addition to the better therapies in the last decade, allogeneic hematopoietic stem cell transplantation (allo-HSCT) outcomes have also improved. In a retrospective analysis from the Japanese nationwide transplantation registry the outcomes of patients transplanted with unrelated cord blood (UCB) and Haplo transplant between 2007 to 2014 were worse when compared to patients who had a transplant between 2015 and 2018. For patients who had transplants between 2015 and 2018, the 3-year overall survival of mismatched unrelated donor (MMUD), unrelated cord blood (UCB), and Haplo groups were 60%, 66%, and 63%, respectively (P = .693). The rates of nonrelapse mortality (P = .147), relapse (P = .075), and graft-vs. host disease-free/relapse-free survival (P = .365) were also similar between the 3 groups. For patients with transplant between 2007 to 2014 the 3 year overall survival was 60%, 54%, and 47% for MMUD, UCB, and Haplo transplants respectively. Newer, better drugs, better tolerated regimens, and improved transplant outcomes were the result: many small gains lead to large improvements.

Of the 50 patients enrolled, 90%, 8% and 2% had newly diagnosed AML, myelodysplastic syndrome and mixed phenotype acute leukemia respectively. Overall, 94% (95% confidence interval [CI], 83%-98%) had a composite complete response and 82% (95% CI, 68%-92%) achieved measurable residual disease negativity. At 12 months, the rates of duration of response, overall survival, and event-free survival were 74% (95% CI, 60%-92%), 85% (95% CI, 75%-97%), and 68% (95% CI, 54%-85%), respectively. The most common grade 3 or worse adverse events were febrile neutropenia (84%), infection (12%), and alanine aminotransferase elevations (12%). Only one patient had a p53 mutation and that patient did not respond.  Another study by Alwash et al, demonstrated that 15% of patients acquire a TP53 mutation during AML therapy.

The poor prognosis of patients with a p53 ,mutation was also seen in a retrospective study of patients with newly diagnosed or relapsed/refractory AML treated with 10-day decitabine + venetoclax (DEC10-VEN). Of the 118 patients, 35 had a TP53 mutation. Complete remission/complete remission with incomplete count recovery (57% vs 775), and overall response was better for patients without vs with a TP53 mutation. In addition, overall survival was dismal (5.2 months) for patients with TP53 mutation vs those without (19.4 months).

This study reiterates the need for newer therapies for this group of  patients with a TP53 mutation (Kim K et al). The overall outcome of patients treated with DEC10-VEN was  better compared to intensive chemotherapy (IC) in patients with relapsed refractory AML. This was evaluated in a retrospective study assessing the outcomes of adult patients with R/R AML treated with DEC10-VEN (n=65) a vs IC-based regimen (n=130) using propensity score-matched analysis. Patients receiving DEC10-VEN vs IC had superior overall response rate (odds ratio [OR], 3.28; P < .001), minimal residual disease negativity (OR, 2.48; P = .017), event-free survival (hazard ratio [HR], 0.46; P < .001), and overall survival (HR, 0.56; P = .008). Rates of refractory disease (OR, 0.46; P = .011) and 60-day mortality (OR, 0.40; P = .029) were significantly lower in patients receiving DEC10-VEN vs IC.

Of the 50 patients enrolled, 90%, 8% and 2% had newly diagnosed AML, myelodysplastic syndrome and mixed phenotype acute leukemia respectively. Overall, 94% (95% confidence interval [CI], 83%-98%) had a composite complete response and 82% (95% CI, 68%-92%) achieved measurable residual disease negativity. At 12 months, the rates of duration of response, overall survival, and event-free survival were 74% (95% CI, 60%-92%), 85% (95% CI, 75%-97%), and 68% (95% CI, 54%-85%), respectively. The most common grade 3 or worse adverse events were febrile neutropenia (84%), infection (12%), and alanine aminotransferase elevations (12%). Only one patient had a p53 mutation and that patient did not respond.  Another study by Alwash et al, demonstrated that 15% of patients acquire a TP53 mutation during AML therapy.

The poor prognosis of patients with a p53 ,mutation was also seen in a retrospective study of patients with newly diagnosed or relapsed/refractory AML treated with 10-day decitabine + venetoclax (DEC10-VEN). Of the 118 patients, 35 had a TP53 mutation. Complete remission/complete remission with incomplete count recovery (57% vs 775), and overall response was better for patients without vs with a TP53 mutation. In addition, overall survival was dismal (5.2 months) for patients with TP53 mutation vs those without (19.4 months).

This study reiterates the need for newer therapies for this group of  patients with a TP53 mutation (Kim K et al). The overall outcome of patients treated with DEC10-VEN was  better compared to intensive chemotherapy (IC) in patients with relapsed refractory AML. This was evaluated in a retrospective study assessing the outcomes of adult patients with R/R AML treated with DEC10-VEN (n=65) a vs IC-based regimen (n=130) using propensity score-matched analysis. Patients receiving DEC10-VEN vs IC had superior overall response rate (odds ratio [OR], 3.28; P < .001), minimal residual disease negativity (OR, 2.48; P = .017), event-free survival (hazard ratio [HR], 0.46; P < .001), and overall survival (HR, 0.56; P = .008). Rates of refractory disease (OR, 0.46; P = .011) and 60-day mortality (OR, 0.40; P = .029) were significantly lower in patients receiving DEC10-VEN vs IC.

Of the 50 patients enrolled, 90%, 8% and 2% had newly diagnosed AML, myelodysplastic syndrome and mixed phenotype acute leukemia respectively. Overall, 94% (95% confidence interval [CI], 83%-98%) had a composite complete response and 82% (95% CI, 68%-92%) achieved measurable residual disease negativity. At 12 months, the rates of duration of response, overall survival, and event-free survival were 74% (95% CI, 60%-92%), 85% (95% CI, 75%-97%), and 68% (95% CI, 54%-85%), respectively. The most common grade 3 or worse adverse events were febrile neutropenia (84%), infection (12%), and alanine aminotransferase elevations (12%). Only one patient had a p53 mutation and that patient did not respond.  Another study by Alwash et al, demonstrated that 15% of patients acquire a TP53 mutation during AML therapy.

The poor prognosis of patients with a p53 ,mutation was also seen in a retrospective study of patients with newly diagnosed or relapsed/refractory AML treated with 10-day decitabine + venetoclax (DEC10-VEN). Of the 118 patients, 35 had a TP53 mutation. Complete remission/complete remission with incomplete count recovery (57% vs 775), and overall response was better for patients without vs with a TP53 mutation. In addition, overall survival was dismal (5.2 months) for patients with TP53 mutation vs those without (19.4 months).

This study reiterates the need for newer therapies for this group of  patients with a TP53 mutation (Kim K et al). The overall outcome of patients treated with DEC10-VEN was  better compared to intensive chemotherapy (IC) in patients with relapsed refractory AML. This was evaluated in a retrospective study assessing the outcomes of adult patients with R/R AML treated with DEC10-VEN (n=65) a vs IC-based regimen (n=130) using propensity score-matched analysis. Patients receiving DEC10-VEN vs IC had superior overall response rate (odds ratio [OR], 3.28; P < .001), minimal residual disease negativity (OR, 2.48; P = .017), event-free survival (hazard ratio [HR], 0.46; P < .001), and overall survival (HR, 0.56; P = .008). Rates of refractory disease (OR, 0.46; P = .011) and 60-day mortality (OR, 0.40; P = .029) were significantly lower in patients receiving DEC10-VEN vs IC.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

CPX-351 is a liposomal cytarabine and daunorubicin. It was FDA approved in 2017 for the treatment of patients with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The approval was based on the results from a randomized trial comparing CPX-351 vs standard 7 +3 chemotherapy in patients older that 65 with t-AML or AML-MRC. The 5-year results from that study were recently published by Lancet et al. At 5 years of follow-up, CPX-351 continued to show benefit in older patients with t-AML or AML-MRC vs standard chemotherapy with cytarabine for 7 days and daunorubicin for 3 days (7+3) . The median OS in favor of CPX-351 vs 7+3 group was maintained (hazard ratio, 0.70; 95% confidence interval [CI], 0.55-0.91). At 5 years, survival estimates were higher for CPX-351 vs 7+3 (18% [95% CI, 12%-25%] vs 8% [95% CI, 4%-13%]). Overall, 5% of deaths in both groups were considered related to the study treatment. Overall, more patients treated with CPX-351 were able to proceed to stem cell transplantation (SCT) compared to those treated with 7 + 3 (35% vs 25%).

The 3-year overall survival from SCT was 56% vs 23% for patients treated with CPX-351 vs 7 +3. Of the responding patients who did not proceed to SCT, only 3 patients were alive at 5 years. Although this data is encouraging, it demonstrates that we have a long way to go to improve the outcome of these patients. In addition, more patients who achieve remission should proceed to SCT in order to improve the survival of this patient population (Lancet JE et al). In terms of supportive care during induction chemotherapy, two published studies this month evaluated two approaches to aiming to decrease the morbidity from infections: prospective monitoring for fungal infections and the use of romyelocel with G-CSF. Prospectively monitoring for fungal infections was performed as an observation study imbedded within a phase 3 Children’s Oncology Group trial (ACCL0933). The study included 471 patients with AML (age, 3 months-30 years) receiving fluconazole (n=235) or caspofungin (n=236).

Twice-weekly surveillance with galactomannan enzyme immunoassay (GM-EIA) and b-D-glucan (BDG) assay were performed in all patients. The negative predictive value was greater than 99% for an individual or combination of GM-EIA and BDG assays. However, true positive results were not observed in any sample collected within 7 days of an invasive aspergillosis/candidiasis diagnosis, resulting in sensitivity and positive predictive value for each test of 0%. This approach was ineffective at detecting invasive fungal diseases (IFDs) in children, adolescents, and young adults with acute myeloid leukemia (AML) receiving antifungal prophylaxis (Fisher BT et al).

A different approach to reduce infection morbidity and mortality during induction chemotherapy is the administration of romyelocel. Myeloid progenitor cells are cells that can produce granulocytes but have no long-term reconstitution capability.  Romyelocel is a cryopreserved product, of MPC manufactured by ex vivo expansion of CD34⁺ hematopoietic stem cells. Romyelocel is capable of producing granulocytes, and thereby may reduce the severity or duration of neutropenic fevers. This phase 2 study included 163 patients with de novo AML receiving induction chemotherapy. Evaluable patients (n=120) were randomly assigned to receive either romyelocel-L plus G-CSF (n=59) or G-CSF monotherapy (n=61). From days 15 to 28, romyelocel-L plus G-CSF vs G-CSF monotherapy significantly reduced the mean duration of febrile episodes (2.36 days vs 3.90 days; P = .02) and incidence of infections (6.8% vs 27.9%; P = .0013). Length of hospitalization was significantly shorter in the romyelocel-L plus G-CSF vs G-CSF monotherapy group (25.5 days vs 28.7 days; P = .002). These results are encouraging, and a phase III trial is suggested by the authors. (Desai PM et al).

Finally, a study by MDACC reported disappointing results with the use of venetoclax in patients with tp53 mutation. Findings are from a retrospective analysis of 238 patients with newly diagnosed TP53-mutated AML treated with either VEN-based (n=58) or non-VEN-based (n=180) therapies. The addition of venetoclax to standard treatment regimens (VEN-based) did not improve clinical outcomes in patients with TP53-mutated acute myeloid leukemia (AML), highlighting the need for novel therapies in this patient population. Overall, there was no significant differences in overall survival (median, 5.7 months vs 6.6 months; P = .4), relapse-free survival (median, 3.5 months vs 4.7 months; P = .43), 4-week mortality (7% vs 10%; P = .5), and 8-week mortality (22% vs 17%; P = .4) in patients receiving VEN-based vs non-VEN-based therapies (Venugopal S et al). Clearly, better therapies are needed for this patient population.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Measurable residual disease (MRD) in acute myeloid leukemia (AML) is both predictive and prognostic. However, the best time and method to define its prognostic role remains unclear. This month, 2 papers evaluate the role of MRD testing at different time points during therapy.

The first paper by Tsai et al studied MRD by next-generation sequencing (NGS) after induction and consolidation. The second paper by Kim et al evaluated the role of NGS MRD before and after allogeneic hematopoietic cell transplantation (allo-HCT).

The study by Tsai et al was a retrospective study that analyzed 1005 bone marrow samples serially collected at diagnosis, the first CR after induction chemotherapy (MRD^1st), and after the first consolidation (MRD^2nd) chemotherapy from 335 patients with de novo AML. Patients with antecedent cytopenia, hematologic diseases, and therapy-related AML (t-AML) were excluded. Patients who achieved complete remission with incomplete hematologic recovery (CRi) or had DNMT3A, TET2, and ASXL1 (DTA) only mutations were not included in the analysis. Multiple previous studies have demonstrated that persistence of DTA only mutations have no prognostic impact. Patients with positive MRD^1st (MRD^1st-)but negative MRD^2nd (MRD^2nd-)had good prognosis similar to those with negative MRD at both time points (cumulative incidence of relapse (CIR), P = .140; relapse-free survival (RFS), P = .231; overall survival (OS), P = .188). The median OS for patients with MRD^1st-MRD2^nd- (n = 147), and MRD^1st+MRD^2nd- (n = 60) was not reached compared to 3.1 years for patients with MRD^1st+MRD^2nd+ (n = 75). Only 9 patients progressed from MRD^1st- to MRD^2nd+ and their median survival was 3.6 years.

In the study by Kim et al utilizing NGS pre- and postHCT, the detection of MRD using NGS had a prognostic value before and 1 month after allo-HCT. This study included 146 patients with AML who underwent allo-HCT in complete remission between 2013 and 2018. The OS was 82%, 64%, and 44% for patients who were MRD negative both pre and post HCT, MRD+ then MRD- after alloHCT and MRD+ both pre- and postHCT respectively. In this study, myeloablative conditioning (MAC) pre allo-HCT did not overcome the negative prognostic value of MRD+ disease prior to allo-HCT. This is in contradiction to the BMT CTN0901 where MAC did overcome the negative prognostic impact of MRD+ disease prior to alloHCT. The authors suggest that this difference could be due to the limited number of genes assessed in the BMT CTN0901 study. Both of those studies demonstrate that achieving NGS MRD negativity either with chemotherapy consolidation or alloHCT leads to better outcome and can be used as a meaningful endpoint in AML studies.

Another completely different direction to improve patient outcomes is the evaluation of the gut microbiota. Several studies have demonstrated the negative impact of disturbed gut microbiota on several outcomes in patients with AML receiving intensive chemotherapy. A study by Malard et al demonstrated that autologous fecal microbiota transfer (AFMT) was safe and effective for gut microbiota restoration in patients with AML receiving intensive chemotherapy and antibiotics. After AFMT treatment, α-diversity indices returned to their initial median levels (Shannon index, P = .70; Inverse Simpson index, P = .90) and the b-diversity index showed the restoration of microbial communities, particularly for Lachnospiraceae and Ruminococcaceae families. Gut microbiota composition was preserved even after consolidation chemotherapy with high-dose cytarabine. No serious adverse events were reported, and only 3 patients experienced transient gastrointestinal symptoms. This approach may be considered in the future to improve the outcome of patients or allogeneic stool transfer is another option currently being studied. Clearly gut microbiota have an effect on outcome, and future studies will demonstrate the best and safest way to reconstitute gut microbiota in patients with hematological malignancies.

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).

Several studies published this month have shed some more light on the treatment and prognosis of certain molecular subgroups such as FLT3, spliceasome mutations and IDH mutation. A study from MD Anderson Cancer Center (MDACC) demonstrated the efficacy of FLT33 inhibitors in the treatment of patients with very low allelic burden. Patients who recived both a FMS-like tyrosine kinase inhibitor (FLT3i) during induction and an allogeneic HCT at time of first remission had better 5 year overall survival (OS) (100%) than those who received neither (27%). The 5-year OS rate among patients who did not receive FLT3i-based induction but underwent allo-SCT in CR1 was 71%. None of the patients who received a FLT3i had detectable FLT3 at time of relapse, compared to 67% for those who did not. The main weakness of the study is the small number of patients (total of 50 patients). This study however does provide some provocative data regarding the validity of the FLT3 allelic ratio in decisions regarding treatment and prognosis. The results of this study need to be validated in a larger cohort of patients.

A study by Lachowiez et al, further refined the prognostic significance of spliceosome mutations in patients treated with ven + HMA. Of the 119 patients, 39 had spliceosome mutations. The overall response and prognosis was not different between patients with and without spliceosome mutations. However, SRSF2 was associated with IDH2 mutation and the median OS was not reached vs, patient with U2AF1 who had a higher association with RAS mutations (OS 8 months). The prognostic role of standard cytotoxic chemotherapy in improving the outcome of patients with an IDH mutation was studied by the group. In a re-evaluation of the randomized trial comparing the addition of fludarabine or cladrbaine to standard 7 +3, 50 patients with an IDH mutation were evaluated. Patients with an IDH mutation who received cladribine. IDH2 mutation had a positive impact on OS in patients treated with DAC regimen (54% vs. 33%; P = .0087) but not in those treated with daunorubicin+cytarabine (DA; 21% vs. 23%; P = .22) regimen. Moreover, DAC induction was independently associated with a reduced risk for death when the observations were censored at allogeneic hematopoietic stem cell transplant (hazard ratio, 0.21; P = .02).

Although hypomethylating agents + venetoclax (HMA +ven) have shown efficacy in multiple patient subgroups, the outcome of patients with post-MPN acute myeloid leukemia (AML) remains poor even with HMA + ven. In a retrospective study, 31 patients with post MPN AML were treated with HMA + ven. The overall survival for patients with relapsed post MPN AML was 3 months with none of the 9 patients achieving a CR/CRi. As for the patients with previously untreated post MPN-AML, the median survival was still poor at 8 months with 43% achieving CR/CRi. This study highlights the large unmet need in this patient population. In comparison, in a retrospective study by Piccini et al, of the 47 patients with relapsed/refractory (R/R) AML treated with venetoclax based regimens the composite CR rate was 55%. These outcomes are similar to other studies of venetoclax based regimens in patients with R/R AML. 

In a retrospective study from the European Society for Blood and Marrow Transplantation (EBMT) registry, the outcomes of patients receiving mismatched unrelated donor (MMUD) with post transplant cyclophosphamide (PTCy) had better outcomes compared to patients receiving cord blood transplantation (CBT). The 2 year leukemia free survival (LFS) for CBT vs MMUD was 42.8% vs 60.5% and OS was 46.85 vs 62.8%. This retrospective study demonstrated that PTCy can improve the outcomes of patients receiving of MMUD (Dholaria B et al. J Hematol Oncol. 2021 May).