CME
Physicians: Maximum of 1.25 AMA PRA Category 1 Credits™
Released: May 11, 2022
Expiration: May 10, 2023
Amy E. DeZern, MD, MHS:
Current risk stratification guidelines including the International Prognostic Scoring System (IPSS) and the revised IPSS-R do not account for mutations now recognized to affect risk and prognosis in MDS.25,26
The current report details the efforts by the International Working Group (IWG) for the Prognosis of MDS to integrate key molecular features into IPSS/IPSS-R to create the IPSS-M. IPSS-M was developed using an IWG discovery cohort (N = 2957) and validated in a Japanese cohort (N = 754). Bernard and colleagues27 presented the findings at ASH 2021.27
Amy E. DeZern, MD, MHS:
The median age of patients was 72 years, and 8% had therapy-related MDS.27 Inclusion criteria were blasts <20% and a WBC count <13 x 109/L. Median follow-up was 3.8 years, and 30% of patients were treated with disease-modifying agents according to current guidelines.
Oncogenic mutations from 152 genes with variant allele frequencies >2% were assessed in the cohort. Forty-eight genes were mutated in ≥1% of patients with ≥1 oncogenic mutation in 94% of the patients. The median number of oncogenic lesions per patient was 4 (range 0-20).
Amy E. DeZern, MD, MHS:
Mutations in multiple genes were associated with adverse outcomes after adjusting for age, sex, and MDS type.27 The genes most strongly associated with adverse outcome were TP53 multihit (7% of patients), MLL partial tandem duplication (2.5% of patients), and FLT3 mutations (1.1% of patients).28
SF3B1 mutations were associated with favorable outcomes, modulated by a pattern of comutations that included del(5q), RUNX1, and NRAS mutations among others.27
Amy E. DeZern, MD, MHS:
Leukemia‑free survival was used as the primary endpoint for model development.27 The model was developed using 4 steps: encoding for clinical and molecular variables, determining independent IPSS-M prognostic variables, construction of a continuous risk score, and definition of IPSS-M risk categories for grouping.
Amy E. DeZern, MD, MHS:
In step 1, the researchers incorporated clinical variables that included platelet values, bone marrow blasts, and molecular variables.27
Step 2 involved the identification of independent prognostic variables using Cox multivariable regression. Independent variables were from 16 main effect genes and 15 residual genes.
Amy E. DeZern, MD, MHS:
In step 3, an interpretable risk scoring system was developed to be continuous and patient specific.27 A value of zero on the scale represents a hypothetical average patient, and each 1 unit increase or decrease corresponds to double or one half the risk, respectively.
Step 4 established 6 discrete risk groups: very low, low, moderate low, moderate high, high, and very high. IPSS-M improved risk stratification compared with the current IPSS-R (which has only 5 discrete risk categories) with a 5-point increase in concordance index across all endpoints.
Amy E. DeZern, MD, MHS:
IPSS-M was validated in a Japanese cohort of 754 patients with MDS.27 Similar to the discovery cohort, 42% of patients were restratified from IPSS-R to IPSS-M. IPSS-M was applicable across sexes, low-blast-count AML, and therapy-related MDS.
Amy E. DeZern, MD, MHS:
The IPSS-M web calculator allows healthcare professionals to understand the individual risk score of patients and includes a strategy to account for missing variables by estimating the best, average, and worst scenarios.27
Amy E. DeZern, MD, MHS:
IPSS-M combines conventional parameters with mutations in 31 key genes to improve MDS risk stratification.27 The risk score is personalized as a continuous score and is reproducible and easily interpretable across 6 categories of risk.
Amy E. DeZern, MD, MHS:
Intensive chemotherapy produces a 40% to 50% CR rate in higher‑risk MDS but can cause prolonged myelosuppression leading to early mortality in 10% to 30% of patients.29-36 Since patients with MDS are on the same disease continuum as AML, higher-risk MDS may benefit from the same therapeutics used in AML.
CPX‑351 is a liposomal combination of cytarabine and daunorubicin currently approved by the FDA for patients with AML. Previous studies have found that CPX-351 has superior efficacy vs classical intensive chemotherapy with 7+3 in older adults with newly diagnosed high-risk/secondary AML.37,38 Given the biologic similarities between higher‑risk MDS and AML, it could benefit higher‑risk patients with MDS as well.
The current study, presented by Peterlin and colleagues39 at ASH 2021, is prospectively evaluating CPX-351 in patients with higher-risk MDS, both untreated and after HMA failure.39
Amy E. DeZern, MD, MHS:
The current analysis of the study includes 31 previously untreated patients with IPSS intermediate-2 or high‑risk MDS who are younger than 70 years of age.39 Patients received induction with CPX-351, daunorubicin, and cytarabine. If less than a partial response, patients received a second induction cycle. Patients could then go on to consolidation or optionally receive allogeneic stem cell transplantation (ASCT). Consolidation was ≤4 cycles in responders and could be followed by optional ASCT in suitable patients.
The primary endpoint of the study is the response to induction therapy, for which patients were evaluated Days 28-42. Responses were evaluated using European LeukemiaNet (ELN) 2017 criteria for AML and IWG 2006 criteria for MDS. The secondary endpoints include overall survival (OS), event‑free survival, measurable residual disease (MRD), and ORR.
Amy E. DeZern, MD, MHS:
The median age of all patients was 62 years, and the predominant WHO classification was MDS-excess blasts 2 in 26 patients (84%).39 Of interest, 26 patients (84%) had intermediate‑2 risk disease and not high‑risk disease categorized by the original IPSS. When assessed using IPSS-R, 9 patients (29%) had intermediate risk, 17 patients (55%) had high risk, and 5 patients (16%) had very high risk. Only 4 patients (13%) had poor-risk or very poor–risk karyotypes.
Amy E. DeZern, MD, MHS:
The ORR by IWG 2006 criteria was 87% with a 23% CR rate. Another 45% of patients achieved marrow CR, and 16% achieved marrow CR with hematologic improvement.39 The ORR was 87% by ELN 2017 criteria, with 52% of patients achieving CR. The benefit in response was seen across all studied MDS subtypes.
Amy E. DeZern, MD, MHS:
The rate of MRD positivity decreased from 58% at screening to 30% postinduction. MRD negativity increased from 11% to 22% following induction.39
Amy E. DeZern, MD, MHS:
Hematologic recovery of platelets to >20 x 109 g/L was a median of 16 days, with recovery to >50 x 109 g/L taking a median of 28 days.39
AEs during induction included 1 case of grade 3 mucositis and 4 cases of grade 1/2 alopecia. Remarkably, there were no deaths or ICU management required during induction.
Amy E. DeZern, MD, MHS:
Ultimately, 12 of the 31 patients went on to receive consolidation, and 29 patients received ASCT.39
At a follow-up of 270 days, 4 patients had relapsed after 3-6 months of response and 5 patients had died. Four of the deaths were transplant-related, and the remaining death was from disease relapse.
Amy E. DeZern, MD, MHS:
CPX‑351 is an effective first‑line treatment for higher‑risk MDS that can bridge patients to ASCT.39 The safety profile compares favorably with intensive chemotherapy and other event and response metrics similar to what has been observed in patients with AML. Most patients had a normal karyotype, but CPX-351 still may be a reasonable option for patients with poor and very poor karyotype.
Amy E. DeZern, MD, MHS:
Chronic cytopenias are a challenging clinical conundrum in patients with low‑risk/intermediate-risk MDS causing complications and reduced quality of life. Lenalidomide is approved for MDS with del(5q) based on its ability to induce disease remission and confer transfusion independence; its use in patients without del(5q) is limited because of significant thrombocytopenia.40,41 Eltrombopag is an oral thrombopoietin receptor agonist that increases platelets and may reverse lenalidomide’s antimegakaryopoietic effects.42,43
The present study, presented at ASH 2021 by Gonzalez-Lugo and colleagues,44 evaluated the safety and efficacy of lenalidomide plus eltrombopag in patients with lower‑risk/intermediate‑risk MDS.44
Amy E. DeZern, MD, MHS:
This was a multicenter, open‑label phase II trial of 52 adult patients with symptomatic anemia untransfused with hemoglobin ≤10 g/dL, RBC transfusion dependence, or platelets <50,000 with hemoglobin >10 g/dL.44 All patients had IPSS low-risk or intermediate-risk disease and did not have prior exposure to lenalidomide or eltrombopag. Twenty-one patients were treated with eltrombopag alone, 16 with lenalidomide alone, and 15 with the combination.
The primary endpoints were hematologic improvement per 2006 IWG criteria, safety, and tolerability. Secondary endpoints included the duration of hematologic improvement and the time to hematologic improvement and bone marrow response.
This was a complex trial design because there were 2 arms and several hold parameters to avoid the hematologic toxicity of lenalidomide, which can cause significant thrombocytopenia in patients.
Amy E. DeZern, MD, MHS:
Each cohort was analyzed separately and in aggregate; in the total population, the mean age was 71 years and 32 patients (71%) were male.44 Mean hemoglobin among all patients was 8.35 g/dL and similar across all cohorts. The mean platelet count in the total population was 126.3 cells/mm3 but was substantially lower among patients in the eltrombopag arm (21.8 cells/mm3) and higher among patients receiving lenalidomide alone (256.7 cells/mm3).
Amy E. DeZern, MD, MHS:
The rate of most grade 3/4 AEs was higher among patients receiving lenalidomide alone vs eltrombopag alone.44
There were 3 deaths—1 each due to pneumonia, sepsis, and gallbladder cancer. Two patients suffered major bleeding events in the eltrombopag-only arm. One patient in the eltrombopag-only arm had a reversible increase in blasts, which was seen in other trials of thrombopoietin mimetics in lower‑risk MDS. Five patients discontinued treatment due to AEs.
Amy E. DeZern, MD, MHS:
The ORR was modest at 35% in the total population.44 Some patients treated with eltrombopag alone had hematologic improvement (35%), 29% had bilineage response, and 6% achieved CR. No patients receiving lenalidomide alone achieved these responses. Patients who received lenalidomide alone had a 46% rate of RBC transfusion‑independence vs 24% with eltrombopag alone.
Patients who received lenalidomide plus eltrombopag had a 21% rate of RBC transfusion-independence and a 21% rate of hematologic improvement. The bilineage response rate in patients who received the combination was 14%, but the CR rate was improved at 14%.
At the time of data cutoff, there were 2 patients receiving eltrombopag alone, 1 patient receiving lenalidomide, and 2 patients receiving the combination with ongoing responses.
Amy E. DeZern, MD, MHS:
Lenalidomide and eltrombopag showed modest efficacy and were safe in this low‑risk/intermediate-risk patient population.44 The median duration of response was 1.5 years, consistent with previous studies.
Monotherapy yielded response, but it is unclear if it was durable. Blast increase and increase in bone marrow fibrosis each affected 1 patient in the cohort receiving eltrombopag alone. These complications need to be considered when weighing the risk‑benefit profile for these drugs. We need to be realistic and consider them both as they are both oral and available to our patients.
Amy E. DeZern, MD, MHS:
HMAs remain the standard of care for higher‑risk MDS but are associated with <20% CR rate and median OS of 12-18 months.45 Early studies suggest a role for the addition of venetoclax to an HMA in higher‑risk MDS.46,47
The current retrospective analysis, presented by Komrokji and colleagues48 at ASH 2021, compared clinical outcomes in patients with higher‑risk MDS treated with first‑line HMA, first‑line HMA in combination with venetoclax, or venetoclax plus HMA after HMA failure.48
Amy E. DeZern, MD, MHS:
This retrospective analysis included 1193 patients receiving first-line treatment with HMA at Moffitt Cancer Center.48 Among patients who received single-agent HMA, the majority received azacitidine (n = 1027) vs decitabine (n = 131). An additional 35 patients were treated off‑label with a combination of HMA and venetoclax, with the majority receiving azacitidine (n = 26) and the remaining 9 receiving decitabine. Among the patients who received single-agent HMA, 31 subsequently received venetoclax plus HMA for R/R MDS without transformation to AML.
Response rate and median OS (from diagnosis) were assessed with a median follow-up of 96 months for first-line single agent HMA, 15 months for combination therapy, and 36 months for combination therapy in R/R MDS.
Amy E. DeZern, MD, MHS:
The median age was 68 years in patients receiving HMA alone or HMA plus venetoclax, and most patients were male (66%-71%).48 Patients who received HMA alone were fairly evenly split between intermediate-risk, high-risk, and very high‑risk disease by IPSS-R, but 46% of the combination‑treated patients were classified as very high risk.
The median myeloblast percentage was 8% in patients receiving HMA alone vs 13% in patients receiving the combination therapy (P <.005). The mean WBC count and absolute neutrophil count among patients receiving HMA alone also were substantially lower than in patients who received combination therapy (WBC: P <.005; absolute neutrophil count: P <.005). Somatic mutations were common among both cohorts, with ASXL1 and TP53 mutations affecting >20% of the patients in each cohort.
Amy E. DeZern, MD, MHS:
The ORR for the combination was 77% with a 34% CR rate; ORR was 40%, and CR rate was 13% in patients who received HMA alone (P <.005).48 ORR also was significantly higher with combination therapy in patients with ASXL1 mutations (87% vs 32%; P <.005) and in TP53‑mutated patients (75% vs 44%; P = .038). However, there was no difference in median OS with combination therapy vs HMA monotherapy from diagnosis (21 vs 20 months) or start of treatment (19.4 vs 17.2 months).
The rate of AML transformation was higher, though not statistically significant, with HMA monotherapy (37% vs 23%; P = .08). A higher frequency of patients in the combination cohort went on to receive stem cell transplantation, and their outcomes compared favorably with a 2-year OS of 91% vs 51% with HMA monotherapy.
Amy E. DeZern, MD, MHS:
The addition of venetoclax to an HMA after unsuccessful single‑agent HMA is common in the clinic. Among the 31 patients with R/R MDS who had venetoclax added, the ORR was favorable at 61%, with 48% marrow CR.48
The median OS from diagnosis for the R/R arm was 33 months vs only 20 months in the first-line setting with HMA alone and 21 months with combination therapy (P = .02). Nine of the patients who received HMA plus venetoclax for R/R MDS underwent ASCT, but there was no difference in median OS vs patients who did not go on to transplant (31 vs 33 months; P = .70).
Amy E. DeZern, MD, MHS:
This retrospective analysis showed first‑line HMA plus venetoclax has higher ORR and CR rates than HMA alone.48 HMA plus venetoclax also may salvage the effect of a poor‑risk molecular phenotype like an ASXL1 mutation. The addition of venetoclax to HMA after relapse also may prolong OS.
Since this was a small population with a short follow-up for some cohorts, I think we really need phase III data to see if these data remain consistent. I look forward to the prospective trial data.
Amy E. DeZern, MD, MHS:
We are always looking for novel approaches to the treatment of AML and higher‑risk MDS that will provide durable responses and are well tolerated. An emerging therapeutic target is TIM-3, a coinhibitory immune-myeloid receptor involved in regulation of adaptive and innate immune responses.49,50 In recent years, TIM-3 inhibitors have shown promising activity in both AML and MDS.
Sabatolimab is an investigational high-affinity, IgG4 antibody that targets TIM-3 with promising durable responses in the initial reports of this phase Ib study.50-53 The current abstract, presented by Brunner and colleagues53 at ASH 2021, is the final analysis of safety and efficacy of sabatolimab plus HMA from the trial.53
Amy E. DeZern, MD, MHS:
This multiarm and open‑label trial enrolled 101 patients with very high‑risk or high‑risk MDS by IPSS‑R or AML.53 Patients were unfit and ineligible for standard chemotherapy and could not have received prior HMA therapy. Patients received either decitabine or azacitidine in combination with sabatolimab during 28-day cycles.
The primary endpoints were maximum tolerated dose, recommended dose, safety, and tolerability. Secondary endpoints were ORR and duration of response.
Amy E. DeZern, MD, MHS:
The average age of patients with MDS was 70 years vs 75 years in patients with AML; 54% of patients in both cohorts were male.53 Ninety percent of patients in both cohorts had an Eastern Cooperative Oncology Group performance status of zero or 1. All 53 patients with MDS had high risk or greater by IPSS-R, and 30 patients (62.5%) with AML had adverse risk by 2017 ELN criteria.
In both cohorts, more patients received azacitidine vs decitabine in combination with sabatolimab. The investigators also looked at TP53 status in MDS and AML, as well as ≥1 ELN adverse risk mutation.
Amy E. DeZern, MD, MHS:
Sabatolimab was well tolerated with common AEs similar in profile to HMA alone.53 Dose modifications and interruptions for sabatolimab were required in 39% of patients, and 3 patients with AML discontinued due to AEs. There was 1 suspected treatment‑related death from septic shock.
Amy E. DeZern, MD, MHS:
One concern with immunotherapies is imAEs, but these were uncommon in this trial, affecting 13% of the patients with MDS and 21% of the patients with AML.53 The most common imAE was peripheral neuropathy, which affected 2 patients (3.8%) with MDS and 2 patients (4.2%) with AML.
There were no grade ≥3 imAEs among patients with MDS and no grade ≥4 imAEs in patients with AML. There were no late‑onset serious imAEs observed. Of the 7 patients with an imAE, all achieved remission, so it may correlate with response.
Amy E. DeZern, MD, MHS:
Among patients with MDS, the ORR was 56.9% with a CR rate of 19.6%, a marrow CR of 23.5%, and a marrow CR with hematologic improvement of 11.8%.53 Patients with AML had an ORR of 42.5% with a CR rate of 25.0%, and no patients achieved a marrow CR.
The estimated 12‑month progression-free survival for patients with MDS was 54.0% and 26.8% in patients with AML. The median duration of response was 17.1 months for patients with MDS and 12.6 months among patients with AML.
Amy E. DeZern, MD, MHS:
Among patients with MDS, ORR was 71.4% in the 14 patients with TP53‑mutated disease and 65.6% among the 32 patients with ≥1 ELN-adverse risk factor.53 In patients with AML, ORR was 40% among 5 patients with TP53-mutated disease and 53.8% among the 13 patients with ≥1 ELN-adverse risk factor.
Amy E. DeZern, MD, MHS:
The combination of sabatolimab plus HMA was well tolerated in patients with high-risk/very high-risk MDS and newly diagnosed AML without excess concern for imAEs.53 Treatment resulted in durable clinical benefit, even in patients with adverse clinical features.
Evaluation of sabatolimab-based therapy in patients with MDS and AML is ongoing in the phase II/III STIMULUS clinical trial program, and I am really looking forward to additional data to determine if we can add sabatolimab to our therapeutic arsenal.
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