Patterns of lower risk myelodysplastic syndrome progression: factors predicting progression to high-risk myelodysplastic syndrome and acute myeloid leukemia.

The patterns of low-risk myelodysplastic syndrome (MDS) progression and the clinical and molecular features of those patterns have not been well described. We divided our low-risk (LR) MDS patients (N=1,914) into 4 cohorts: 1) patients who remained LR-MDS (LR-LR; N=1,300; 68%), 2) patients who progressed from LR to high-risk (HR) MDS (LR-HR) without transformation into acute myeloid leukemia (AML) (N=317; 16.5%), 3) patients who progressed from LR to HR MDS and then AML (LR-HR-AML; N=124; 6.5%), and 4) patients who progressed from LR MDS directly to AML (LR-AML; N=173; 9%). Risk factors for progression included: male gender, low absolute neutrophil count (ANC), low platelet count, high bone marrow (BM) blasts, ferritin >1000 mcg/L, albumin <3.5 g/dL, multi-lineage dysplasia (MLD), and lack of ring sideroblasts. Among patients with marked BM fibrosis (N=49), 18% progressed directly to AML. Somatic mutations (SM) associated with an increased risk of direct or indirect AML progression included SRSF2 and NRAS. SM in IDH1, IDH2 and NPM1 were more common in patients with direct AML transformation. SM associated with progression to higher risk disease only, without AML transformation, were ASXL1, TP53, RUNX1, and CBL. SF3B1 mutation was associated with less progression. About 171 patients (13.1% of all LR-LR patients) died within two years of diagnosis of LR-MDS without disease progression. Among the 61 cases with documented cause of death, 18 patients (29.5%) died from cytopenia and MDS-related complications. Identifying patterns of disease progression of LR MDS patients and their predictive factors will be crucial to be able to tailor therapy accordingly.

Incidence of pleural effusion with dasatinib and the effect of switching therapy to a different TKI in patients with chronic phase CML.

Dasatinib is one of the second generation tyrosine kinase inhibitors (TKI) which is approved for the treatment of patients with chronic phase CML (CP-CML) both in the front line and in the second line setting. Pleural effusion (PE) is a unique toxicity associated with dasatinib use. Our aim was to study the incidence of pleural effusion in our cohort of patients who were treated with dasatinib for CP-CML and the safety upon TKI switch. A total of 390 patients were treated with dasatinib during their course of treatment for CP-CML. A total of 69 patients (17.6%) developed any grade of PE. About 33 (48%) patients developed CTCAE grade 2 PE, 34 (49%) grade 3 and only 1 patient developed grade 4 PE. Recurrence of PE was observed in 34 (49%) patients. While only 12 patients (17.3%) continued using dasatinib after development of PE, dasatinib was discontinued in the other 57 patients. Therapy was switched to bosutinib in 13 patients out of which 6 (46%) patients re-developed PE. While only 12.5% patients developed re-accumulation of pleural fluid in patients switched to imatinib, none of the patients switched to nilotinib re-developed PE. A change in TKI to bosutinib was associated with a 46% risk of recurrence of PE in patients who develop PE on dasatinib for the treatment of CP-CML. The incidence of recurrent PE was markedly lower in patient switched to imatinib or nilotinib.

Outcomes by best response with hypomethylating agent plus venetoclax in adults with previously untreated acute myeloid leukemia.

INTRODUCTION: We aimed to compare outcomes of patients with AML treated with frontline hypomethylating agent and venetoclax (HMA + Ven) who achieved complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), or morphologic leukemia-free state (MLFS) as defined by ELN 2022. METHODS: Patients with AML seen at Moffitt Cancer Center between 2018 and 2022 and treated with HMA + Ven were retrospectively evaluated. RESULTS: About 120 patients achieved blast clearance with best response of CR in 52 (43.3%), CRh in 22 (18.3%), CRi in 31 (25.8%) and MLFS in 15 (12.5%) patients. Greater proportion of patients with MLFS had a prior myeloid malignancy (p = 0.003) and were treated with prior HMA (p < 0.001). Patients that achieved MLFS as their best response had inferior OS compared to the CR/CRh/CRi cohort (8 months vs. 27 months; p < 0.001). RFS was also worse for the MLFS cohort. CONCLUSION: To the best of our knowledge, this is the largest study analyzing differences in outcomes of AML patients treated with HMA + Ven based on best response. We noted that prior myeloid malignancy and use of HMA led to more MLFS as best response compared to CR/CRi. The OS and RFS were inferior for MLFS cohort.

Drivers of deep molecular response and long-term outcomes in patients with core binding factor acute myeloid leukemia.

A swimmer plot on clinical course of patients undergoing allogeneic stem cell transplant for core binding factor acute myeloid leukemia.

Disease-related thrombocytopenia in myelofibrosis is defined by distinct genetic etiologies and is associated with unique prognostic correlates.

BACKGROUND: Thrombocytopenia in patients with myelofibrosis (MF) is prognostically detrimental and poses a therapeutic challenge. MF patients with thrombocytopenia are considered high-risk by most prognostic models and their distinct phenotype has given rise to the emerging concept of cytopenic MF. Yet, the mechanisms underlying thrombocytopenia in MF are poorly understood. METHODS: This study aimed to highlight the genetic mechanisms driving low platelet counts in treatment-naive MF patients, establish their phenotypic correlates, and assess prognostic factors specific to this group of patients. RESULTS: The authors found that most patients presenting with low platelets had a clear thrombocytopenia-specific genetic abnormality involving a U2AF1 Q157 mutation, deletion 20q, molecular complexity (three or more mutations), or high-risk karyotype. Etiologic clustering did not correlate with prognosis; however, thrombocytopenic patients were found to have unique prognostic variables including low serum albumin and mutations of SRSF2 and TP53. This led to the proposal of a prognostic model (SRSF2, albumin, TP53 score) that stratifies thrombocytopenic patients as low, intermediate, or high-risk with corresponding median survivals of 93.5, 29.5, and 7.2 months, respectively. CONCLUSIONS: This study demonstrates that thrombocytopenia in MF is driven by different genetic mechanisms and is not uniformly high-risk. As novel agents with improved hematologic safety profiles enter the treatment landscape, thoughtful, risk-adapted therapeutic decisions will be required for MF patients with thrombocytopenia. LAY SUMMARY: A significant minority of patients with myelofibrosis (MF) present with low platelets. Historically, these patients have been viewed as having "high-risk" disease, but this may not be uniformly true. Our study shows that there are various different causes for low platelets in MF, some of which represent high-risk disease whereas others do not. Additionally, our study shows that genetic mutations affecting the genes SRSF2 and TP53 are uniquely problematic in this group, as is a low serum albumin level. This study helps to risk-stratify MF patients with thrombocytopenia, thereby providing more information to guide informed and individualized treatment decisions.

Molecular annotation of extramedullary acute myeloid leukemia identifies high prevalence of targetable mutations.

BACKGROUND: Genomic landscape of extramedullary acute myeloid leukemia (EM-AML), including myeloid sarcoma (MS) and leukemia cutis (LC), is not well characterized. The potential utility of next-generation sequencing (NGS) using EM tissue is not established. METHODS: In this multicenter retrospective study, clinical and NGS data were collected on patients with EM-AML. All statistical analyses were performed in SPSS Statistics (v 26). RESULTS: Our study included 58 patients with EM-AML. The median age at diagnosis was 62 years; 59% of patients had MS and 33% had LC. EM-AML was isolated (i.e., without blood or marrow involvement) in 31% and was first noted at relapse in 60% of patients. Median overall survival in our cohort was 18.2 months overall, with 19.1 months and 11.6 months in the newly diagnosed and the relapsed/refractory patients, respectively. At least one targetable or potentially targetable alteration was present in 52% of patients with EM-site NGS, with 26% IDH1, 21% NPM1, 11% IDH2, 6% FLT3, and 13% KMT2A-PTD. Mutations in IDH1 were significantly more prevalent on NGS from EM tissue than non-EM (blood or marrow) samples (26% vs. 3%; p = .030). Three of four patients treated with IDH inhibitors based on EM-site NGS experienced a complete response. CONCLUSIONS: Targetable mutations are frequent in EM-AML and EM-site NGS is warranted for selecting potential targeted therapies for patients with EM-AML.

Splicing factor 3B subunit 1 (SF3B1) mutation in the context of therapy-related myelodysplastic syndromes.

Splicing factor 3B subunit 1 (SF3B1) somatic mutation in the context of therapy-related myelodysplastic syndromes (t-MDS) has not been well defined. In a large cohort of patients with MDS, those with known SF3B1 somatic mutation were compared as de novo MDS (n = 289) and t-MDS with mutant SF3B1 (SF3B1mut ; n = 31). Baseline characteristics, concomitant mutations, and acute myeloid leukaemia (AML) transformation were similar between the two groups. The median overall survival (OS) of de novo MDS SF3B1mut was significantly longer compared to t-MDS SF3B1mut but not significantly different when adjusted for comorbidities. Comparing t-MDS wild-type SF3B1 (SF3B1WT ; n = 241) to t-MDS SF3B1mut (n = 31), complex cytogenetics were seen in 37.4% versus 10.3% (p = 0.009), tumour protein p53 (TP53) mutation was 36.1% versus 10% (p = 0.004), and AML transformation was 34.4% compared to 12.9% (p = 0.016) respectively. OS was significantly shorter in SF3B1WT versus SF3B1mut . When applying the International Working Group for Prognosis of MDS (IWG-PM) proposed SF3B1 criteria, OS was significantly shorter in SF3B1mut t-MDS compared to de novo MDS SF3B1mut with no significance in AML transformation. Survival was compared between t-MDS SF3B1mut who met the new proposed IWG-PM criteria to t-MDS SF3B1mut who did not meet criteria to survival of SF3B1WT t-MDS. OS was 53 versus 22 and 18 months respectively (p = 0.006). AML transformation was 0%, 26.7% and 32.3% (p = 0.021). Leukaemia-free survival was not reached among the three.

Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm.

BACKGROUND: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin. METHODS: In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 µg or 12 µg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response. RESULTS: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 µg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups. CONCLUSIONS: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.).

TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype.

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.

A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33-positive AML.

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 µg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia.

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia.

In older patients with acute myeloid leukemia, the more frequent presence of biologically inherent therapy-resistant disease and increased comorbidities translate to poor overall survival and therapeutic challenges. Optimal front-line therapies for older patients with acute myeloid leukemia remain controversial. We retrospectively evaluated survival outcomes in 980 elderly (≥70 years) acute myeloid leukemia patients from a single institution between 1995 and 2016. Four treatment categories were compared: high-intensity (daunorubicin/cytarabine or equivalent), hypomethylating agent, low-intensity (low-dose cytarabine or similar without hypomethylating agents), and supportive care therapy (including hydroxyurea). At a median follow up of 20.5 months, the median overall survival for the entire cohort was 7.1 months. Multivariate analysis identified secondary acute myeloid leukemia, poor-risk cytogenetics, performance status, front-line therapy, age, white blood cell count, platelet count, and hemoglobin level at diagnosis as having an impact on survival. High-intensity therapy was used in 360 patients (36.7%), hypomethylating agent in 255 (26.0%), low-intensity therapy in 91 (9.3%), and supportive care in 274 (28.0%). Pairwise comparisons between hypomethylating agent therapy and the three other treatment groups demonstrated statistically significant superior median overall survival with hypomethylating agent [14.4 months) vs high-intensity therapy 10.8 months, hazard ratio 1.35, 95% confidence interval (CI): 1.10-1.65; P =0.004], low-intensity therapy (5.9 months, hazard ratio 2.01, 95%CI: 1.53-2.62; P<0.0001), and supportive care (2.1 months, hazard ratio 2.94, 95%CI: 2.39-3.61; P<0.0001). Our results indicate a significant survival benefit with hypomethylating agents compared to high-intensity, low-intensity, or supportive care. Additionally, high-intensity chemotherapy resulted in superior overall outcomes compared to low-intensity therapy and supportive care. Results from this study highlight the need for novel therapeutic approaches besides utilization of intensive chemotherapy in this specific aged population.

Genetically inspired prognostic scoring system (GIPSS) outperforms dynamic international prognostic scoring system (DIPSS) in myelofibrosis patients.

A genetically inspired prognostic scoring system (GIPSS) that stratifies primary myelofibrosis (PMF) patients by genetic variants alone was recently proposed. While non-inferior to the dynamic international prognostic scoring system (DIPSS), the lack of overlapping prognostic variables between the models leads to increased risk for disagreement between two valid prognostic models and presents a challenging clinical situation. In an external cohort of 266 molecularly annotated myelofibrosis (MF) patients, we demonstrated that the GIPSS model significantly differentiated between four risk groups (low, int-1, int-2, high) with median OS that was not reached, not reached, 60.5 and 28.9 months, respectively. High-risk patients had significantly inferior leukemia-free survival (LFS) (P < 0.0001). We identified a cohort of prognostically ambiguous patients (n = 39) in which GIPSS and DIPSS models differed by ≥2 risk groups. Among these patients, a similar proportion were up-staged by DIPSS (n = 19) and GIPSS (n = 20). Patients upstaged by GIPSS (genetically high-risk) had a trend toward inferior OS compared with patients upstaged by DIPSS (clinically high-risk) (P = .08) and significantly worse LFS (P = .04). Patients deemed intermediate-2 and high-risk by GIPSS who underwent allogeneic transplant had improved OS compared with those that did not (P = .04). GIPSS is a valid disease-specific prognostic system and outperforms DIPSS in patients where the two models disagree. Additionally, while GIPSS was developed for PMF; the current study shows, however, that the contemporary genetic model performs equally well for both primary and secondary myelofibrosis.

Between a rux and a hard place: evaluating salvage treatment and outcomes in myelofibrosis after ruxolitinib discontinuation.

Ruxolitinib is a JAK1/2 inhibitor that is effective in managing symptoms and splenomegaly related to myelofibrosis (MF). Unfortunately, many patients must discontinue ruxolitinib, at which time treatment options are not well defined. In this study, we investigated salvage treatment options and clinical outcomes among MF patients who received and discontinued ruxolitinib outside the context of a clinical trial. Among 145 patients who received ruxolitinib, 23 died while on treatment, 58 remained on treatment at time of analysis, leaving 64 people available for analysis. Development of cytopenias was the most common reason for discontinuation (38%) after median treatment time of 3.8 months (mo). The majority of patients received some form of salvage therapy after ruxolitinib discontinuation (n = 42; 66%), with allogeneic hematopoietic stem cell transplant (alloHSCT) (n = 17), being most commonly employed. Lenalidomide, thalidomide, hydroxyurea, interferon, and danazol were used with similar frequency. The response rate to salvage treatment was 26% (8 responses) and responses were most often seen with lenalidomide or thalidomide. Improved outcomes were observed in patients who underwent alloHSCT or received salvage therapy compared to those who did not receive additional therapy. Median overall survival (OS) after ruxolitinib discontinuation was 13 months. These findings show that salvage therapy can provide clinical responses after ruxolitinib discontinuation; however, these responses are rare and outcomes in this patient population are poor. This represents an area of unmet clinical need in MF.

The prognostic value of circulating myeloblasts in patients with myelodysplastic syndromes.

The prognostic value of peripheral blasts (PB) is not well-studied in patients with myelodysplastic syndromes (MDS). We evaluated the impact of PB on overall survival (OS) and transformation to acute myeloid leukemia (AML) in a large cohort. The MDS database at the Moffitt Cancer Center was retrospectively reviewed to identify patients with ≥ 1% PB (PB-MDS) and those without PB (BM-MDS). We also assessed the correlation between PB and gene mutations. One thousand seven hundred fifty-eight patients were identified, among whom 13% had PB near the time of diagnosis. PB-MDS patients were more likely to be younger with trilineage cytopenia, complex karyotype, higher-risk disease, transfusion dependence, and therapy-related MDS. The rate of AML transformation was 49 vs. 26% (p < 0.005) and median OS was 16.5 vs. 45.8 months (p < 0.005) in the PB-MDS and BM-MDS groups, respectively. In Cox regression analysis, the presence of PB was an independent prognostic covariate for OS, HR 1.57 (95% CI 1.2-2). Among 51 patients with an available gene panel, the rate of ≥ 1 gene mutation in the PB-MDS group (n = 4) was 100% compared to 81% in the BM-MDS group (n = 47). The presence of PB in MDS is an adverse independent prognostic variable that refines prognostic discrimination.

CPX-351: changing the landscape of treatment for patients with secondary acute myeloid leukemia.

Multiple novel therapeutic agents against acute myeloid leukemia (AML) have been evaluated in the past several decades without meaningful clinical improvement in outcomes, especially for AML patients age ≥60, where the overall incidence of AML is highest. Therapeutic options mainly consist of hypomethylating agents, ongoing clinical trials and, less commonly, intensive cytotoxic chemotherapy. CPX-351, a novel liposomal formulation which encapsulates cytarabine and daunorubicin in 5:1 molar ratio, has shown promising efficacy, leading to recent US FDA approval for front-line therapy for patients with therapy-related AML and AML with myelodysplasia-related changes based on a large multicenter Phase III clinical trial. This review summarizes the clinical development of CPX-351 as induction therapy.

What are the most promising new agents in acute myeloid leukemia?

PURPOSE OF REVIEW: Although the treatment paradigm for acute myeloid leukemia (AML) had been largely unchanged for many years, in-depth molecular characterization has revolutionized our understanding of mutations that drive the disease, subsequently serving to guide current clinical investigation. Furthermore, recent advances in the field have highlighted the importance of optimizing known efficacious agents by improving drug delivery or bypassing resistance mechanisms. The current status of novel agents which are shaping the clinical management of AML patients are summarized in this review. RECENT FINDINGS: Practice changing findings over the past year include improved overall survival (OS) in a molecularly defined AML subgroup as well as in elderly patients with secondary AML (sAML). Specifically, synergistic combination of daunorubicin and cytarabine (i.e., CPX-351) was found to improve OS in sAML patients. Furthermore, although multiple mutation specific inhibitors have been developed, optimal combination with additional agents appears critical, as monotherapies have not resulted in durable remissions or improved outcomes. Improved OS via the addition of midostaurin to intensive chemotherapy in FLT3 mutant AML supports this concept. SUMMARY: For the first time in AML, personalized therapy has become possible through improved understanding of the molecular architecture and survival pathways of an individual's disease. The landscape of AML treatment is encouraging, with multiple novel agents likely to gain approval over the next 5 years.

Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study.

BACKGROUND: Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. METHODS: We did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP. FINDINGS: We identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone. INTERPRETATION: Patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk. FUNDING: Moffitt Cancer Center.