Showing papers by "Guillermo Garcia-Manero published in 2023"

Frontline combination of ponatinib and hyper‐CVAD in Philadelphia chromosome‐positive acute lymphoblastic leukemia: 80‐months follow‐up results

Abstract: The combination of ponatinib, a third‐generation BCR::ABL1 tyrosine kinase inhibitor, with hyper‐CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)‐positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow‐up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph‐positive ALL were treated with the hyper‐CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase‐chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine‐prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty‐six patients were treated. Their median age was 46 years (range, 21–80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty‐ patients (23%) underwent allogeneic SCT. With a median follow‐up of 80 months (range, 16–129 months), the estimated 6‐year event‐free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3–5 adverse events included infection (n = 80, 93%), increased liver transaminases (n = 26, 31%) and total bilirubin (n = 13, 15%), hypertension (n = 15, 17%), pancreatitis (n = 13, 15%), hemorrhage (n = 12, 13%), and skin rash (n = 9, 10%). Two ponatinib‐related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose‐modifications mentioned earlier, with no further ponatinib‐related deaths observed. The long‐term results of ponatinib and hyper‐CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph‐positive ALL.

Magrolimab in Combination With Azacitidine in Patients With Higher-Risk Myelodysplastic Syndromes: Final Results of a Phase Ib Study

Abstract: PURPOSE Magrolimab is a monoclonal antibody that blocks cluster of differentiation 47, a don't-eat-me signal overexpressed on cancer cells. Cluster of differentiation 47 blockade by magrolimab promotes macrophage-mediated phagocytosis of tumor cells and is synergistic with azacitidine, which increases expression of eat-me signals. We report final phase Ib data in patients with untreated higher-risk myelodysplastic syndromes (MDS) treated with magrolimab and azacitidine (ClinicalTrials.gov identifier: NCT03248479). PATIENTS AND METHODS Patients with previously untreated Revised International Prognostic Scoring System intermediate-/high-/very high-risk MDS received magrolimab intravenously as a priming dose (1 mg/kg) followed by ramp-up to a 30 mg/kg once‐weekly or once‐every-2-week maintenance dose. Azacitidine 75 mg/m2 was administered intravenously/subcutaneously once daily on days 1-7 of each 28-day cycle. Primary end points were safety/tolerability and complete remission (CR) rate. RESULTS Ninety-five patients were treated. Revised International Prognostic Scoring System risk was intermediate/high/very high in 27%, 52%, and 21%, respectively. Fifty-nine (62%) had poor-risk cytogenetics and 25 (26%) had TP53 mutation. The most common treatment-emergent adverse effects included constipation (68%), thrombocytopenia (55%), and anemia (52%). Median hemoglobin change from baseline to first postdose assessment was −0.7 g/dL (range, −3.1 to +2.4). CR rate and overall response rate were 33% and 75%, respectively. Median time to response, duration of CR, duration of overall response, and progression-free survival were 1.9, 11.1, 9.8, and 11.6 months, respectively. Median overall survival (OS) was not reached with 17.1-month follow-up. In TP53-mutant patients, 40% achieved CR with median OS of 16.3 months. Thirty-four patients (36%) had allogeneic stem-cell transplant with 77% 2-year OS. CONCLUSION Magrolimab + azacitidine was well tolerated with promising efficacy in patients with untreated higher-risk MDS, including those with TP53 mutations. A phase III trial of magrolimab/placebo + azacitidine is ongoing (ClinicalTrials.gov identifier: NCT04313881 [ENHANCE]).

The outcomes of patients with chronic myeloid leukemia treated with third‐line BCR::ABL1 tyrosine kinase inhibitors

Abstract: The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second‐generation TKI (2G‐TKI), the optimal third‐line therapy in chronic phase CML (CML‐CP) is not well established. We analyzed 354 patients with CML‐CP treated with a third‐line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G‐TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy‐three (49%) patients received 2G‐TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; p < .001) compared with the 2G‐TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + −log reduction of baseline transcripts (20% 2‐log reduction and 32% 3 + −log reduction). Among the 128 evaluable patients treated with 2G‐TKIs, 44 (34%) achieved 2 + −log reduction of baseline transcripts (13% 2‐log reduction and 21% 3 + −log reduction). With a median follow‐up of 46 months, the 3‐year progression‐free survival was 59% (60% before matching) with 2G‐TKI and 83% (81% before matching) with ponatinib (p < .001). The 3‐year survival was 83% (81% before matching) with 2G‐TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third‐line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML‐CP failing two prior TKIs.

Association between bariatric surgery and outcomes in chronic myeloid leukemia

Abstract: Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown.

Characteristics and clinical outcomes of patients with acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2).

Abstract: Acute myeloid leukemia (AML) with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) has a very poor prognosis. Determinants of clinical outcomes and optimal treatment remain uncertain. We retrospectively reviewed 108 cases of AML with inv(3)/t(3;3) and evaluated clinicopathological characteristics and clinical outcomes: 53 newly diagnosed (ND) AML and 55 relapsed/refractory (R/R) AML. Median age was 55 years. White blood cell (WBC) count ≥ 20 x 109/L and platelet count ≥ 140 x 109/L was observed in 25% and 32% of ND patients, respectively. Anomalies involving chromosome 7 were identified in 56% of patients. The most frequently mutated genes were SF3B1, PTPN11, NRAS, KRAS and ASXL1. In ND patients, the composite complete remission (CRc) rate was 46% overall; 46% with high-intensity treatments and 47% with low-intensity treatments. The 30-day mortality was 14% and 0%, with high- and low-intensity treatment, respectively. In R/R patients, the CRc rate was 14%. Venetoclax based-regimens were associated with a CRc rate of 33%. The 3-year overall survival (OS) was 8.8% and 7.1% in ND and R/R patients, respectively. The 3-year cumulative incidence of relapse was 81.7% overall. Older age, high WBC, high peripheral blast count, secondary AML and KRAS, ASXL1, DNMT3A mutations were associated with worse OS in univariable analyses. The 5-year OS rates were 44% and 6% with or without HSCT in CR1, respectively. AML with inv(3)/t(3;3) is associated with low CR rates, very high risk of relapse and dismal long-term survival. Intensive chemotherapy and HMA provide similar rates of remission and patients achieving CR benefit from HSCT in CR1.

Early mortality in acute myeloid leukemia with KMT2A rearrangement is associated with high risk of bleeding and disseminated intravascular coagulation

Abstract: Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well‐defined in this entity.

Outcomes of myeloid malignancies in patients previously treated with PARP inhibitors for solid malignancies: A single institution experience.

Abstract: e19000 Background: Treatment with Poly(ADP-ribose) Polymerase proteins (PARP) has improved the survival of patients (pts) with solid malignancies harboring a homologous recombination deficiency (HRD). The association between PARP inhibitors (PARPi) and the development of myeloid neoplasms post cytotoxic therapy (MN-pCT) has been reported. We aim to describe the characteristics and outcomes of pts who develop MN-pCT after treatment with PARPi. Methods: Pts treated with PARPi at a single institution from July 2014 to August 2022, who developed MN-pCT (AML, MDS or CMML), were retrospectively evaluated. Diagnosis of MN-pCT was defined according to the 5th edition of the WHO criteria. Clinical and demographic characteristics along with cytogenetics and molecular features were analyzed. HRD was assessed by NGS on peripheral blood with a 13-gene panel. Results: 1462 pts were treated with PARPi at MDACC. Of these, 15 (1%) developed MN-pCT. These include 9 (60%) with MDS, 5 (34%) with AML, and 1 (7%) with B/Myeloid Mixed-Phenotype Acute Leukemia (MPAL). The median age was 62 (46-74) years and 14 (93%) were female. The most frequently used PARPi was olaparib in 9 (60%) pts. All pts had also previously received platinum-based agents and taxanes. Pts with 19 different solid tumors were included; 11 (85%) had active concomitant solid tumors at the time of MN-pCT. The median time from PARPi treatment to myeloid neoplasm (TTM) was 20.7 months (9.3-39.9). Cytogenetics and molecular features were available in 14 pts (93%). Eight (57%) had complex karyotype. The median number of mutations were 2 (0-4). TP53mut was present in 9 (64%) pts with a median VAF 47.3% (11.9-76.6%) of whom 6 (67%) were biallelic. The ORR to antileukemic therapy was 66% (n = 8): 3 (38%) had CR, 2 (25%) had PR, 2 (25%) had mCR with HI and 1 (13%) had isolated HI. The patient with B/myeloid MPAL was not evaluable for response. Of the responders, 7 (88%) pts relapsed at a median of 2.8 months (1.5-4.2). The median OS and EFS on the whole cohort were 7.8 (3.2-12.4) and 5.3 (3.8-6.7) months respectively. Conclusions: Development of MN-pCT in pts treated with PARPi is rare but most outcomes are very poor. Prospective analysis to evaluate pts at higher risk of developing MN-pCT is warranted in order to select pts who might benefit from novel therapies without increasing the risk of secondary myeloid malignancies. [Table: see text]

Superior outcomes after allogeneic stem cell transplantation (SCT) among patients (Pts) ≥ 60 years (yrs) treated with cladribine (CLAD), low dose cytarabine (LDAC) plus venetoclax (Ven) for newly diagnosed acute myeloid leukemia (AML).

Abstract: 7047 Background: CLAD/LDAC/VEN alternating with AZA-VEN has shown promising outcomes in older pts with AML ( Kadia, JCO Nov 2022). Improved disease control and preserved performance status achieved with CLAD/LDAC/VEN treatment, may translate into superior post-SCT outcomes. Methods: We compared outcomes of pts ≥ 60 yrs of age treated on the phase II study of CLAD-LDAC-VEN who underwent SCT in 1st remission (CR1) to a retrospective cohort of pts ≥ 60 yrs treated with hypomethylating agent (HMA)-VEN based or intensive (INT) therapy who underwent SCT in CR1 between 2013-2022. Relapse free survival (RFS) was from response to relapse/death & overall survival (OS) from start of therapy to death. Results: 35 pts treated with CLAD-LDAC-VEN were compared to 42 pts treated with INT & 40 pts with HMA-VEN therapy for remission induction prior to SCT at our center (Table). The median age of pts in the low-intensity arms were similar (68 yrs), but lower on the INT arm (62 yrs). More pts post INT therapy received a myeloablative conditioning (MAC). At a median follow up of 17+ months (m) for CLAD-LDAC-VEN arm, 59 m for INT arm, and 30 m for HMA arm, the median RFS (NR vs. 50 m vs. 20 m respectively, p <0.01) and OS (NR vs. 58 m vs. 32 m respectively, p < 0.01) was superior for the CLAD-LDAC-VEN arm. 3-yr cumulative incidence of relapse & NRM (as competing events) were both significantly lower with CLAD-LDAC-VEN (4% and 7%) compared to INT (17% and 23%) or HMA-VEN (41% and 27%) therapy. Conclusions: Older pts with AML proceeding to SCT after CLAD-LDAC-VEN therapy had significantly improved survival, characterized by significantly lower rates of NRM and relapse compared to HMA-VEN or INT therapies. Larger studies and longer follow up is needed to confirm its benefit. [Table: see text]

A phase II study of vibecotamab, a CD3-CD123 bispecific T-cell engaging antibody, for MRD-positive AML and MDS after hypomethylating agent failure.

Abstract: TPS7076 Background: CD123 is a marker of leukemic stem cells that is differentially overexpressed in most patients with acute myeloid leukemia (AML), myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). In contrast, CD123 is expressed at negligibly low levels on normal hematopoietic progenitors, making it a potentially promising therapeutic target. Vibecotamab (formally XmAb14045) is a CD3-CD123 bispecific engaging antibody that has established clinical activity in relapsed/refractory AML. In a phase I study, the overall response rate was 14.8% in patients who received vibecotamab at a dose of ≥ 0.75 µg/kg (Ravandi F et al. ASH 2020 abstract #460). Response rates were notably higher in those with lower disease burden (bone marrow blasts ≤ 25%) where the overall response rate was 25.9%. In light of the activity of vibecotamab in relapsed/refractory low-blast AML, we designed this phase II study to evaluate vibecotamab in other low-blast states, including CD123-positive, MRD-positive AML and in MDS or CMML after failure of hypomethylating agents. Methods: This is a two-arm, open-label, phase II study of vibecotamab in patients with AML in first or second morphological remission with detectable MRD at a level of ≥0.1% by flow cytometry and in patients with MDS (intermediate or higher-risk by IPSS-R) or CMML (CMML-1 or CMML-2) after failure of hypomethylating agents. CD123 expression ≥20% on aberrant myeloid blasts is required for study eligibility. Vibecotamab is given IV in a ramp-up dose schedule on days 1, 3, 5 and 8 of cycle 1, followed by weekly doses of vibecotamab at a dose of 1.7 µg/kg. Patients may receive up to 4 cycles of vibecotamab in 28-day cycles. The primary objective of the AML MRD cohort is to determine the MRD negativity rate after 4 cycles; the primary objective of the MDS/CMML cohort is to determine the response rate (CR + mCR + PR + HI + clinical benefit) after 4 cycles. The target MRD response in the AML MRD cohort is 50%, and the target response rate in the MDS/CMML cohort is 30%. Secondary endpoints include remission duration, duration of MRD response (AML MRD arm), CR rate (MDS/CMML arm), relapse-free survival, overall survival, and safety. Exploratory endpoints include correlation of clinical outcomes with CD123 expression and the dynamics of CD123 expression at treatment initiation and at the time of relapse. Additional immunological correlatives will be performed, including 1.) determination of molecular immune states that predict response or resistance, 2.) functional interrogation of TCR-antigen interactions, and 3.) nomination of leukemic neo-antigens. The planned enrollment is 40 patients (20 in each of the two cohorts). To date, 13 patients have been enrolled (7 in the AML MRD cohort and 6 in the MDS/CMML cohort). The trial is actively accruing at MD Anderson Cancer Center. Clinical trial information: NCT05285813 .

Mini-hyper-CVD with venetoclax (Ven) for patients with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL): A phase II study.

Abstract: e19039 Background: In preclinical studies, Ven has shown promising clinical activity in patients (pts) with R/R ALL. The combination of Ven with low intensity mini-HCVD chemotherapy could improve outcomes in ALL pts. Methods: Pts ≥18 years with R/R Ph-negative B- or T-cell ALL received mini-HCVD alternating with methotrexate and cytarabine for up to 8 cycles. Ven was given at a dose of 400 mg/d on Days (D) 1-14 of Cycle (C) 1 and on D1-7 of C2-8. Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles during maintenance. Maintenance with vincristine, prednisone and Ven was given for up to 2 years. Results: Between 6/2019 and 2/2021, 23 pts were treated, with a median age of 45 years (range, 20-70). 18 (78%) pts had B-ALL and 5 (22%) T-ALL, including 1 pt with ETP ALL. Among the 23 pts, the median number of prior therapies was 2 (range, 1-6) and 13 (57%) had undergone prior allogeneic stem cell transplant (ASCT). Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab. Among 23 pts, 1 was in CR at enrollment. Overall, 12 of 22 (55%) pts responded to therapy (complete response, n=9), of whom 9 achieved best response after C1 and 3 after C2. An additional pt achieved partial response. The overall response rate among the 18 pts who had at least a bone marrow assessment after C1 was 67%. The median duration of follow-up was 26 months (range, 2-35). Among the 13 responders (including the pt in CR at start), 6 (46%) relapsed, 5 (39%) underwent ASCT (4 subsequently relapsed), and 2 (15%) died in remission. The median RFS and OS were 6.4 and 8.1 months, respectively, and the 1-year RFS and OS rates were 15% and 37%, respectively. Survival was worse in pts with adverse cytogenetics versus others (median OS, 6 vs 12 months; 1-yr OS rate, 17% vs 44%; P=0.15). In C1, the median time to platelet recovery was 27 days (range, 0-81) and neutrophil recovery was 21 days (range, 0-36); in C2+, median times to recovery were 25 days (range, 0-76) and 15 days (range, 0-26), respectively. The 30-day and 60-day mortality rates were 0% and 13%, respectively. Conclusions: The combination of low-intensity chemotherapy mini-HCVD with Ven in pts with R/R Ph-negative ALL was well-tolerated and resulted in a response rate of 67%. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts. Clinical trial information: NCT03808610 . [Table: see text]

Phase II trial of mini-hyper-CVD-inotuzumab (InO) followed by blinatumomab (blina) consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).

Abstract: e19037 Background: Promising results were seen with low intensity chemotherapy mini-Hyper-CVD (mini-HCVD) in combination with InO in R/R ALL. Adding blina may further improve outcomes. Methods: Pts with R/R Philadelphia-negative B-ALL were treated with mini-HCVD (Cycles 1, 3, 5, 7) and methotrexate/cytarabine (Cycles 2, 4, 6, 8) for 8 cycles. Initially, InO was given on Day (D) 3 of the first 4 cycles at the dose of 1.8-1.3 mg/m2 in Cycle (C) 1, followed by 1.3-1.0 mg/m2 in subsequent cycles. POMP maintenance was for a total of 3 yrs. Protocol was amended after pt #67 to add 4 cycles of blina after 4 cycles of mini-HCVD+InO. InO was given on D2 and 8 at the dose of 0.6 and 0.3 mg/m2 in C1, and then on D2 and 8 at the dose of 0.3 mg/m2 in subsequent cycles; blina was given at standard dose in C5-8. Maintenance was reduced to 12 cycles of POMP with 1 cycle of blina after each 3 cycles of POMP for a total of 4 cycles. Rituximab was given for CD20+ disease. All pts received 8 doses of intrathecal chemotherapy. Results: Between 2/2013 and 7/2021, 110 pts were treated. Patient characteristics are shown in the table. 79 (72%) pts were treated in Salvage (S) 1, and 31 (28%) in S2+. 21 (19%) pts had received prior ASCT. 91 (83%) pts responded (complete remission, 63%). The overall response rate was 93% in S1, 59% in S2, and 57% in S3+. The rates of MRD negativity by flow were higher in S1 vs S2+ (89% vs 67%; P=0.047). 53 (48%) pts underwent ASCT. After a median follow-up of 48 months (mo) (range, 9-115), the median OS and RFS were 17 mo (4-yr, 36%) and 13 mo (4-yr, 37%), respectively. Pts in S1 had better OS compared with S2+ (4-yr OS, 43% vs 18%; P<0.001). The 4-yr RFS was 38% in S1 and 27% in S2+ ( P=0.14). In S1, 41 pts were treated before the amendment and 38 after the amendment; their 4-yr OS was 41% and 48% ( P=0.99), and their 4-yr RFS was 39% and 36%, respectively ( P=0.95). A landmark analysis of pts who achieved remission showed no survival difference between pts who did or did not undergo ASCT, with 4-yr OS of 49% and 48% ( P=0.98), and 4-yr RFS of 46% and 37% ( P=0.68), respectively. Sinusoidal obstruction syndrome (SOS) was noted in 10 (9%) pts, and its incidence decreased from 13% with single dose of InO to 2% with lower and fractionated doses of InO ( P=0.056). Conclusions: The combination of mini-HCVD and reduced-dose InO with sequential blina improved the outcomes of pts with R/R ALL. The new treatment schedule resulted in a lower rate of SOS compared to the original schedule. Clinical trial information: NCT01371630 . [Table: see text]

Clinical outcomes by SF3B1 mutation status in patients (pts) with lower-risk myelodysplastic syndrome (LR-MDS) retreated with erythropoiesis-stimulating agents (ESAs).

Abstract: 7071 Background: Pts with SF3B1-mutated LR-MDS often have a more favorable prognosis versus those with SF3B1 wildtype. A sizeable number of pts with LR-MDS undergo ESA treatment even after experiencing ESA failure in first line. This study evaluated the outcomes of pts with LR-MDS retreated with ESAs in routine clinical practice, stratified by SF3B1 status. Methods: This retrospective cohort study included pts with LR-MDS in the US community setting who initiated ESAs as first-line therapy between January 1, 2016 and June 30, 2019, and were followed through June 30, 2021. Eligible pts discontinued ESAs (treatment gap ≥ 3 wk for epoetin alfa or ≥ 6 wk for darbepoetin alfa) and subsequently reinitiated ESA therapy at least once during follow-up. Ring sideroblasts (RS) ≥ 15% served as a surrogate for pts with unknown SF3B1 mutation status. Outcomes included ESA switches, dose reductions and escalations, ESA failure, and overall survival (OS). Primary ESA failure was defined as no rise in hemoglobin (Hb) ≥ 1.5 g/dL or no decrease in RBC transfusion requirement by 8 wk of treatment. Transfusion-dependent (TD) status was evaluated for pts who were transfusion independent (TI) at baseline. Results: A total of 82 pts with LR-MDS and repeat ESA treatment were included. Median age at start of ESA treatment was 79 y (interquartile range [IQR], 72–85). Diagnosis of MDS-RS, MDS with isolated del(5q), MDS with multilineage dysplasia, and MDS with single lineage dysplasia was reported in 30 (36%), 7 (9%), 9 (11%), and 9 (11%) pts, respectively; 27 (33%) had unknown classification. Median follow-up was 26 mo (IQR, 13–38) with 65% failing ESA therapy by 8 wk. Table shows pts’ SF3B1 mutation status, median OS, pts who had an ESA switch, dose reduction or escalation, experienced ESA failure, and pts who were TI at baseline and became TD during follow-up. Results were similar when RS was not used as a surrogate, and when analyses were limited to pts who were treated with ESAs only throughout follow-up. Conclusions: In this study of pts with LR-MDS retreated with ESAs, primary ESA failure was high with nearly half of TI pts becoming TD during follow-up. OS was poor regardless of SF3B1 status – 2–4 times lower than the remaining life expectancy for a 79-y-old (108 mo for men; 125 mo for women). Although treatment options were limited during the study period, the high primary failure rate suggests that pts with LR-MDS may benefit from alternatives to ESAs. [Table: see text]

Emerging treatments for myelodysplastic syndromes: Biological rationales and clinical translation

Abstract: Myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal hematopoietic stem cell disorders characterized by myeloid dysplasia, peripheral blood cytopenias, and increased risk of progression to acute myeloid leukemia (AML). The standard of care for patients with MDS is hypomethylating agent (HMA)-based therapy; however, nearly 50% of patients have no response to the treatment. Patients with MDS in whom HMA therapy has failed have a dismal prognosis and no approved second-line therapy options, so enrollment in clinical trials of experimental agents represents these patients' only chance for improved outcomes. A better understanding of the molecular and biological mechanisms underpinning MDS pathogenesis has enabled the development of new agents that target molecular alterations, cell death regulators, signaling pathways, and immune regulatory proteins in MDS. Here, we review novel therapies for patients with MDS in whom HMA therapy has failed, with an emphasis on the biological rationale for these therapies' development.

A phase 2/3 trial of oral azacitidine (Oral-AZA) in patients (pts) with low- or intermediate-risk myelodysplastic syndromes (MDS).

Abstract: TPS7083 Background: MDS, a heterogeneous group of clonal myeloid malignancies, are characterized by ineffective hematopoiesis and peripheral blood cytopenias, which can often lead to red blood cell (RBC) transfusion dependence and a risk of progression to acute myeloid leukemia (AML). In early clinical trials, 14- and 21-day (d) dosing regimens of the hypomethylating agent Oral-AZA were well tolerated and induced hematologic improvement (HI) in pts with lower-risk (LR) MDS. In a phase 3 trial, Oral-AZA 300 mg QD for 21d per 28d cycle significantly improved the rate of RBC transfusion independence (TI) and induced durable HI versus placebo (PBO) in patients (pts) with LR-MDS with RBC-transfusion-dependent anemia and thrombocytopenia (Garcia-Manero, et al. J Clin Oncol 2021). Grade 3/4 cytopenias were common in the Oral-AZA arm. Given the substantial clinical benefit of Oral-AZA observed in this setting, a new phase 2/3 trial is ongoing to further evaluate the 14d Oral-AZA regimen in pts with International Prognostic Scoring System Revised (IPSS-R)-defined low or intermediate (int)-risk MDS. Methods: This ongoing, multicenter, randomized, phase 2/3 trial (CA055-026; NCT05469737) will evaluate the safety and efficacy of Oral-AZA in pts with IPSS-R low- or int-risk MDS. Key eligibility criteria include ≥ 18 years, ECOG performance status score ≤ 2, and ≥ 1 cytopenia (anemia, thrombocytopenia, or neutropenia). Pts with an absolute neutrophil count < 0.5 × 109/L within a week of randomization will be excluded. Informed consent will be obtained from all participants. The phase 2 portion will enroll and randomize ~42 pts 1:1 to receive open-label Oral-AZA 200 or 300 mg QD for 14d per 28d cycle, plus best supportive care (BSC), to determine the recommended phase 3 dose (RP3D). The primary endpoints are safety and rate of complete remission (CR) within 6 Tx cycles. The secondary endpoints are overall response rate (ORR), and packed (p) RBC-TI and platelet-TI sustained for 84d in ≤ 6 Tx cycles. ORR includes CR, partial remission (PR), marrow CR, and any HI, per IWG 2006 response criteria. In the phase 3 portion, ~188 additional pts will be enrolled and randomized 1:1 to Oral-AZA at the RP3D or PBO for 14d per 28d cycle, plus BSC. Pts in the PBO arm with stable disease at Tx cycle 6 disease assessment or with documented disease progression after ≥ 3 Tx cycles will have the option to cross over into the Oral-AZA arm. The primary endpoint is CR in ≤ 6 Tx cycles. The key secondary endpoint is 84d pRBC-TI. Other secondary endpoints include those described in the phase 2 portion plus overall survival, event-free survival, time to AML progression, iron parameters, health-related quality of life, healthcare resource utilization, and safety parameters. Pts who benefit from Oral-AZA in phase 2 or 3 may continue to receive Tx in an extension phase. Trial recruitment began in December 2022 and is ongoing. Clinical trial information: NCT05469737 .

A phase 1/2 dose escalation study of the BCL-2 inhibitor ZN-d5 and the WEE1 inhibitor azenosertib (ZN-c3) in patients (Pts) with acute myeloid leukemia (AML).

Abstract: TPS7077 Background: B-cell lymphoma 2 (BCL-2) is an anti-apoptotic protein and pathway inhibition combined with chemotherapy and/or targeted therapeutics has led to significant clinical benefit in pts with AML. Disruption of cell cycle regulation may complement BCL-2 inhibition as many malignant cells are dependent on proteins that regulate cell cycle progression. The cell cycle checkpoint protein, WEE1, is highly expressed in genomically unstable malignancies and inhibition of WEE1 induces tumor cell apoptosis. It has been previously reported that the combination of ZN-d5 (an oral, selective BCL-2 inhibitor) and azenosertib (an oral, highly potent WEE1 inhibitor) synergistically enhance killing of AML cells both in vitro and in vivo, as well as in TP53-mutated models (Izadi, AACR 2022). Based on this strong pre-clinical rationale, a Phase 1/2 study was designed to evaluate the novel combination of ZN-d5 and azenosertib in pts with relapsed/refractory (R/R) AML. Methods: This phase 1/2 open-label study (ZN-d5-004C, NCT05682170) is determining the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and clinical activity of ZN-d5 + azenosertib in pts with AML. The phase 1 dose-escalation stage is based on a Bayesian Optimal Interval design. Phase 2 is an open-label expansion to be conducted if supported by safety and efficacy data from the dose-escalation stage. Prior to initiating dose-escalation for the ZN-d5 + azenosertib combination, an azenosertib monotherapy cohort is being enrolled, as it has not been previously administered to pts with hematologic malignancies. For the dose-escalation azenosertib monotherapy (n≈15) and ZN-d5 combination (n≈40) cohorts, pts must have relapsed/refractory (R/R) disease after ≥1 line of AML therapy that may include the BCL-2 inhibitor, venetoclax. In phase 1, an azenosertib monotherapy cohort will be opened prior to investigation of ZN-d5 + azenosertib in combination. In phase 2, ZN-d5 + azenosertib will be given at the RP2D. Alternative dosing schedules may also be investigated based on emerging clinical data. The primary endpoints are adverse events and dose-limiting toxicities. Secondary endpoints include the rate and duration of remission according to the European LeukemiaNet 2017 criteria, including complete remission (CR), CR with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), partial remission (PR), stable disease, progressive disease, relapse after remission (including molecular relapse), remission rate (CR + CRi), overall response rate (CR + CRi + MLFS + PR), and rate of and time to relapse. Pts will remain on study until disease progression, failure to respond, remission if additional therapy is clinically indicated, withdrawal of consent, loss to follow-up, or death. Clinical trial information: NCT05682170 .

Outcomes of patients with therapy‐related myeloid neoplasms after treatment with poly(ADP‐ribose) polymerase proteins inhibitors for solid tumours

Abstract: mechanisms. 4,9,10 Of interest, we did not find clinical benefit in patients who received venetoclax. In a subgroup analysis, we found no difference in response for patients with wild- type TP53 ( TP53wt ) compared to TP53 mutated (80% vs. 57% [ p = 0.41]). This was also true for patients with HRD compared to patients without HRD (71% vs. 60% [ p = 0.68]). Also, we did not find a statistically significant difference in OS and EFS according to TP53 status, or the presence of HRD (Figure 1C– F). On the other hand, favourable risk phenotypes could also occur. For instance, one patient developed secondary APL and had good outcome. This has never been reported in patients treated with PARPi but is known to occur in a small subset of MN- pCT. 11– 13 Treatment with PARPi has been reported to increase the likelihood of developing secondary myeloid malignancies. 6 However, this study was not designed to analyse the role of PARPi in the development of MN- pCT. In conclusion, the data presented here helps us under-stand the natural history of patients that develop MN- pCT after being treated with PARPi for solid malignancies. These data have clinical implications for patients treated with these agents and potentially in the future in the development of clinical trials for this specific patient population. In addition, as PARPi are also being studied as anti- leukaemia agents, these data could serve as a clinical control for some of these trials.

Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)-naive transfusion-dependent (TD) patients (pts) with lower-risk myelodysplastic syndromes (LR-MDS).

Abstract: 7003 Background: Most pts with LR-MDS have limited responses to ESAs, thus there is an unmet need to treat anemia and reduce TD. Here we report interim results from the open-label, randomized phase 3 COMMANDS trial (NCT03682536) comparing the efficacy and safety of luspatercept vs epoetin alfa in ESA-naive pts with LR-MDS. Methods: Eligible pts were ≥ 18 years old with IPSS-R-defined LR-MDS with or without RS, < 5% bone marrow blasts, sEPO levels < 500 U/L, required RBC transfusions (defined as 2–6 RBC units/8 weeks [wk] for ≥ 8 wk immediately prior to randomization), and were ESA naive. Pts were randomized 1:1 to receive subcutaneous luspatercept (starting dose 1.0 mg/kg, titration up to 1.75 mg/kg) once every 3 wk or epoetin alfa (starting dose 450 IU/kg, titration up to 1050 IU/kg) weekly for ≥ 24 wk. Primary endpoint was achievement of RBC transfusion independence (TI) ≥ 12 wk within the first 24 wk, with a mean hemoglobin increase ≥ 1.5 g/dL. Secondary endpoints included achievement of hematologic improvement-erythroid (HI-E) response ≥ 8 wk per IWG 2006 criteria, RBC-TI 24 wk and ≥ 12 wk, and safety. Results: As of Aug 31, 2022, 178 pts received luspatercept and 176 epoetin alfa, with median treatment durations of 41.6 and 27.0 wk, respectively. Baseline pt characteristics were balanced across treatment arms. Of 301 pts included in the efficacy analysis, 86 (58.5%) pts receiving luspatercept vs 48 (31.2%) epoetin alfa achieved the primary endpoint of RBC-TI ≥ 12 wk with concurrent mean Hb increase ≥ 1.5 g/dL within the first 24 wk ( P < 0.0001). HI-E ≥ 8 wk was achieved by 109 (74.1%) luspatercept and 79 (51.3%) epoetin alfa pts ( P < 0.0001 ). Within the first 24 wk of treatment, RBC-TI 24 wk and ≥ 12 wk was achieved by 70 (47.6%) and 98 (66.7%) luspatercept pts, respectively, vs 45 (29.2%) and 71 (46.1%) epoetin alfa pts ( P = 0.0006 and 0.0002). Treatment-emergent adverse events (TEAEs; any grade) were reported by 164 (92.1%) luspatercept and 150 (85.2%) epoetin alfa pts; 8 (4.5%) and 4 (2.3%) pts discontinued due to TEAEs. Treatment-related AEs were reported by 54 (30.3%) luspatercept and 31 (17.6%) epoetin alfa pts. AML progression was reported in 4 (2.2%) luspatercept and 5 (2.8%) epoetin alfa pts. Overall rates of death were comparable between arms during treatment and post-treatment (32 [18.0%] luspatercept, 32 [18.2%] epoetin alfa pts). Conclusions: Compared with epoetin alfa, luspatercept led to clinically meaningful and statistically significant improvements in RBC-TI and erythroid response, as well as duration of response. Luspatercept safety results were consistent with previous findings. These data show, for the first time, superiority of an innovative therapy over ESAs in ESA-naive pts with TD LR-MDS. Luspatercept could represent a new standard of care for pts with TD LR-MDS. Clinical trial information: NCT03682536 .

Outcomes of individuals with clonal hematopoiesis evaluated at a cancer center.

Abstract: 7072 Background: Clonal hematopoiesis (CH) refers to the presence of somatic mutations in individuals without overt hematological disorders. CH, including CH of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), is associated with hematologic malignancies and other systemic comorbidities. There are currently no established guidelines regarding the optimal monitoring and management of patients with CH, and the impact of CH in patients with concomitant underlying malignancies remains unknown. Methods: Patients seen at a tertiary cancer center with at least 1 somatic mutation detected by next generation sequencing on bone marrow aspirate or peripheral blood between January 2015 and March 2021 were included. Patients with donor-derived CH or any morphologic evidence of a myeloid neoplasm were excluded. Results: We evaluated 78 patients – 76% had a history of malignancy and 73% had other comorbidities. The mutations most frequently observed were DNMT3A (40%), TET2 (31%), TP53 (26%), and ASXL1 (18%). The median overall survival for all patients was not reached (2-year survival rate of 79%). Most deaths were related to primary malignancies (35%), comorbidities (20%), or myeloid neoplasms (20%). Due to concomitant use of antineoplastic therapy and other causes of cytopenia in 19 patients, we further categorized patients into 4 groups: CHIP on treatment (CHIP-T), other CHIP (CHIP-O), CCUS on treatment or with a non-myeloid hematologic malignancy (CCUS-T), and other CCUS (CCUS-O). Transformation to a myeloid neoplasm occurred in 12 patients (15%). The 3-year cumulative incidence of transformation was higher in CCUS-O (24%) and CCUS-T (21%) compared to the CHIP group (6%, p = 0.48). On univariate analysis, increasing age, variant allele frequency (VAF) ≥ 0.2, hemoglobin < 10 g/dL, and any chromosomal abnormalities were associated with higher risk for transformation. By multivariate analysis, transformation was only significantly associated with VAF ≥ 0.2 (hazard ratio (HR) 18.25; 95% confidence interval (CI): 3.59, 92.73; p = 0.0005) and hemoglobin < 10 g/dL (HR 15.62; 95% CI: 3.29, 74.05; p = 0.0005). Conclusions: CH in predominantly cancer patients is associated with cardiovascular disease and transformation to myeloid neoplasms, especially in those with higher mutational burdens and anemia. However, patients die more frequently from their primary malignancy or comorbidities than from a myeloid neoplasm. Close monitoring of hematologic progression and extra-hematologic manifestations of CH is crucial. Further investigation into the identification of individuals at high risk of myeloid transformation and potential early therapeutic interventions for this population is warranted.

Evolving trends and outcomes in older patients with acute myeloid leukemia including allogeneic stem cell transplantation.

Abstract: Outcomes in older patients with acute myeloid leukemia (AML) have historically been poor. Given advances in low-intensity therapy (LIT) and stem cell transplantation (SCT), we performed a retrospective single-center study to evaluate the contemporary outcomes of this population. We reviewed all patients ≥60 years with newly diagnosed AML between 2012 and 2021 and analyzed treatment and SCT-related trends and outcomes. We identified 1073 patients with a median age of 71 years. Adverse clinical and cytomolecular findings were frequent within this cohort. In total, 16% of patients were treated with intensive chemotherapy, 51% with LIT alone, and 32% with LIT plus venetoclax. The composite complete remission rate with LIT plus venetoclax was 72%, which was higher than with LIT alone (48%, p < .0001) and comparable to intensive chemotherapy (74%, p = .6). The median overall survival (OS) with intensive chemotherapy, LIT, and LIT plus venetoclax was 20.1, 8.9, and 12.1 months, respectively. 18% of patients received SCT. SCT rates were 37%, 10%, and 22% in patients treated with intensive chemotherapy, LIT, and LIT plus venetoclax, respectively. The 2-year OS, relapse-free survival (RFS), cumulative incidence (CI) of relapse, and CI of treatment-related mortality with frontline SCT (n = 139) were 59%, 52%, 27%, and 22%, respectively. By landmark analysis, patients undergoing frontline SCT had superior OS (median 39.6 vs. 21.4 months, p < .0001) and RFS (30.9 vs. 12.1 months, p < .0001) compared with responding patients who did not. Outcomes in older patients with AML are improving with more effective LIT. Measures should be pursued to increase access to SCT in older patients.

Phase 1b clinical study of IRAK 1/4 inhibition for low-risk myelodysplastic syndromes refractory/resistant to prior therapies.

Abstract: TPS7085 Background: Chronic stimulation of both interleukin-1 receptor (IL-1R) and toll-like receptors (TLRs) in myeloid progenitors is thought to cause a bone marrow proinflammatory environment responsible for persistent cytopenia in patients with low-risk (LR)-MDS. IRAK1 and IRAK4 are serine/threonine kinases that are critical for the downstream signaling of IL-1R and most TLRs resulting in the production of proinflammatory cytokines and NLRP3 inflammasome-driven pyroptosis leading to bone marrow inflammation and cell death. Thus, IRAK1/4 inhibition is a potential target for the treatment of LR-MDS by decreasing inflammation and cell death within the bone marrow allowing the restoration of hematopoiesis. R289 is a prodrug that is converted to the active drug R835 in the gastrointestinal (GI) tract. R835 is a potent and selective inhibitor of IRAK1 and IRAK4 kinases and inhibits TLR and IL-1R-dependent proinflammatory cytokine production in multiple cell types. In vivo, R835 blocks TLR4 and IL-1R-dependent systemic cytokine release in mice. The safety and pharmacokinetic properties of R289/R835 were evaluated in a phase 1 healthy volunteer study (Study C-906289-001). R289 was well tolerated with no serious or severe adverse events (AEs) reported. Most AEs were mild and transient; the most common AEs (mild/moderate) were headache and GI disturbance. Overall, the trial supported the advancement of R289 into further studies. An open-label Phase 1b study to determine the tolerability and preliminary efficacy of R289 for patients with LR-MDS refractory to prior therapies is currently enrolling patients. Methods: The current study (NCT05308264) includes a dose escalation phase (up to 12 patients) and a dose expansion phase (up to 10 patients). Inclusion criteria for both phases will include patients ≥18 years with a definitive diagnosis of LR-MDS. Exclusion criteria will include prior treatment for MDS that concluded <4 weeks prior to study treatment. Dose Escalation Phase: Dose escalation will utilize a 3+3 design to determine the maximum tolerated dose (MTD). R289 tablets can be taken orally with or without food. Dose limiting toxicity (DLT) will be assessed at each dose level. The DLT evaluation period will be 28 days. After completion of the DLT evaluation period, patients who do not experience DLTs may remain on treatment at their respective dose level if they continue to demonstrate clinical benefit without toxicity. Dose Expansion Phase: Up to 10 additional patients with LR-MDS will be enrolled; the primary endpoint of the study will be the safety and tolerability of R289. The secondary endpoints will include an assessment of preliminary efficacy and characterization of the pharmacokinetics of R289. R289 will be administered to all patients at a dose not to exceed the MTD determined in the Dose Escalation Phase. The trial is currently recruiting at 8 US sites. Clinical trial information: NCT05308264 .

Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia

Abstract: Abstract Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab ( P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

Venetoclax for Acute Myeloid Leukemia in Pediatric Patients: A Texas Medical Center Experience

Abstract: Simple Summary Pediatric patients with relapsed or refractory acute myeloid leukemia (AML) have poor survival with current therapy. Venetoclax is a small molecule inhibitor that has shown promise in both adult and pediatric leukemias. Here we describe the joint experience of the Texas Medical Center (The University of Texas MD Anderson Cancer Center and Baylor College of Medicine/Texas Children’s Hospital) use of venetoclax in combination with various therapies for the treatment of pediatric relapsed AML. We report the safety and efficacy of this regimen in this population. Abstract The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6–21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.

Optical genome mapping for cytogenomic analysis of hematological neoplasms.

Abstract: e19016 Background: Optical genome mapping (OGM) provides a genome-wide analysis for structural variants and copy number changes in one-assay. Compared with conventional G-banded karyotyping (GBK), OGM provides significantly higher resolution and does not require metaphase cells. In this study, we assessed the added value of OGM for cytogenomic analysis of hematological neoplasms. Methods: OGM was performed on blood or bone marrow using Saphyr from Bionano Genomics on 63 patients diagnosed with various types of hematological malignancy (see Table). Variant calling was made by the Rare Variant Analysis pipeline on Bionano Access after applying recommended filters. Each patient had karyotype and/or fluorescence in situ hybridization (FISH) results available for comparison and confirmation. Only Tier 1 (pathogenic) and Tier 2 (likely pathologic) abnormalities were included for comparison purposes in this study. Results: The results were completely concordant between GBK/FISH and OGM in 30 (47.6%) patients, including 10 patients who showed no cytogenetic abnormality (normal). Fully discordant results were found in 8 (12.7%) patients: 2 had an abnormal karyotype but normal OGM, the discrepancy was mainly due to the clonal size (<20%) below the limitation of detection of OGM; 6 had a normal karyotype but cytogenetic abnormalities were detected by OGM, the discrepancy was mainly due to failure of tumor cells growth (n=5) or subtle cytogenetic abnormality undetectable by GBK (n=1). Partially concordant results between karyotype/FISH and OGM were observed in 25 (40%) patients, some abnormalities were detected by both, some were detected by GBK alone (n=4) or by OGM alone (n=25), the latter group included 10 cases with chromothripsis which only be detected by OGM. Overall, OGM provided clinically significant information in 14 (22%) patients regarding diagnosis, risk stratification, and/or identifying therapeutic targets. The added value was more common in lymphoid neoplasms (9 of 27 patients, 33%). Conclusions: OGM provides additional clinically relevant cytogenetic information in the workup of hematological neoplasms. This added value is more apparent in lymphoid neoplasms. These improvements are largely contributable to the higher resolution provided by OGM and analysis independent of metaphase cells. A major limitation of OGM usage is the need for a clonal size of at least 20%. [Table: see text]