Subsequent Allogeneic Stem Cell Transplantation Research Articles

Blueberry Muffin Baby Syndrome in a Patient with Congenital Leukemia: Clinical Case

Background. Blueberry muffin baby syndrome in newborns is characterized by diffuse nodular skin lesions and it is difficult for diagnosis due to diverse etiology. Etiological factors include congenital infections, intrauterine hemolytic disease, multifocal vascular abnormalities, and neoplastic conditions. Congenital neonatal leukemia is rare disease and it is usually revealed during the first month of life. Clinical case description. This clinical case presents a patient with congenital acute myeloid leukemia and severe skin manifestations. Treatment has included risk-adapted chemotherapy with subsequent allogeneic hematopoietic stem cell transplantation from a haploidentical donor (father). Conclusion. The significance of multidisciplinary approach in management of patients with congenital leukemias consist of timely determination of the disease variant, prognostic risk group, and initiation of programmed treatment.

Cost-effectiveness of blinatumomab for the treatment of B‑precursor acute lymphoblastic leukemia pediatric patients with high‑risk first‑relapse in Mexico

BackgroundBlinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective. MethodsA decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs. ResultsBlinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99 % of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico. LimitationsHealth-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained. ConclusionsBlinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.

Long-term survival outcomes of patients (pts) with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3.

6531 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for pts ≥18 y with R/R B-ALL in the US (≥26 y in the EU). In the 3-y follow-up of ZUMA-3, median overall survival (OS) was 25.6 mo (N=78). Survival benefit was seen regardless of age, prior treatment, or subsequent allogeneic stem cell transplant (sub alloSCT) status (Shah et al. ASCO 2023. #7023). Here we report 4-y survival outcomes for ZUMA-3. Methods: Eligible pts (≥18 y) had R/R B-ALL and received brexu-cel (1×106 CAR T cells/kg) after leukapheresis and lymphodepleting chemotherapy. The primary endpoint was overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate per independent review with OS as a key secondary endpoint. Descriptive statistics are reported for post hoc exploratory subgroup analyses. Results: As of July 23, 2023, median follow-up time in Phase 1 and 2 pts who received the pivotal dose of brexu-cel (N=78) was 53.6 mo (range 44.7-82.3). Median OS (95% CI) was 25.6 mo (16.2-60.4) in all treated pts and 47.0 mo (23.2-not estimable [NE]) in pts with CR/CRi (n=57). In pts <26 y (n=15), median OS (95% CI) was 23.2 mo (9.0-NE) and was 26.0 mo (15.9-NE) in pts ≥26 y (n=63). Median OS (95% CI) in pts with 1 prior therapy (n=15) was 60.4 mo (7.6-NE) and was 25.4 mo (15.9-47.0) in pts with ≥2 prior therapies (n=63). Medians for OS (95% CI) in pts with (n=38) and without (n=40) prior blinatumomab (blina) were 15.9 (8.3-26.0) and 60.4 mo (18.6-NE), respectively. Median OS (95% CI) was 36.3 mo (10.2-NE) in responders who went on to sub alloSCT (n=14) and 60.4 mo (23.2-NE) in those who did not (n=43). The 48-mo OS rate was 40% (95% CI, 28-52) in all pts but appeared lower in pts with prior blina (24%; Table). No new adverse events or deaths occurred since the prior analysis. Grade ≥3 infection rates since the start of study appeared higher in pts <26 y and in pts with prior blina (Table). Rates of non-relapse mortality (NRM) and relapse-related mortality (95% CI) at 48 mo were 25% (15-37) and 34% (24-45; N=78), respectively. Of note, 6/17 NRM events (35%) occurred in pts with sub alloSCT. Conclusions: After >4 y follow-up, pts in ZUMA-3 continued to experience OS benefit regardless of age, prior therapy, or sub alloSCT status, though pts with prior blina had a numerically lower 48-mo OS rate. Small subgroups and unbalanced pt characteristics limit interpretation of these results. No new safety signals were observed. Further studies are needed to fully assess the impact of age, prior therapies, and sub alloSCT on outcomes after brexu-cel. Clinical trial information: NCT02614066 . [Table: see text]

Лечение агрессивного системного мастоцитоза и тучноклеточного лейкоза. Обзор литературы и серия клинических наблюдений

Aim. To provide case reports on the course and treatment of aggressive systemic mastocytosis (ASM) and mast cell leukemia (MCL).
 Materials & Methods. This paper reports the histories of adult patients with ASM (n = 4) and MCL (n = 2) treated with cytoreduction predominantly at the City Clinical Hospital No. 31 (Saint Petersburg). The patients were 36–61 years of age (median 50 years); there were 4 women and 2 men.
 Results. All patients showed stable response to cladribine (n = 3), imatinib (n = 2), and combined lenalidomide, elotuzumab, and dexamethasone treatment with subsequent allogeneic hematopoietic stem cell transplantation (n = 1). With a median follow-up of 124 months (range 55–186 months), 1 out of 2 MCL patients died due to the concomitant hypereosinophilic syndrome progression and secondary infectious complication.
 Conclusion. Cladribine therapy in 2 ASM patients and imatinib therapy in 2 MCL patients yielded stable long-term response with good quality of life being maintained. More comparative studies are required for efficacy assessment and optimum sequencing of chemotherapeutic drugs.

Disparities in Genetic Profiles, Risk Stratification and Outcomes in Adults with Acute Myeloid Leukemia Comparing Patients of Hispanic and Non-Hispanic Ethnicity in Central California

Acute myeloid Leukemia (AML) is the most common type of acute leukemia in adults. Ethnic disparities due to distinct biology and socioeconomic status have been described in AML. Prior studies indicated Hispanic AML patients had a younger age at presentation, more frequent high-risk mutations, and worse survival compared with non-Hispanics. We conducted a retrospective study to investigate the differences in AML risk stratification, mutational profiles and outcomes between Hispanic and non-Hispanic AML patients treated at Community Medical Centers (CMC) in Central California. Methods: We retrospectively analyzed patients ≥ 18 years diagnosed with AML between January 2016-December 2022 and treated at CMC in Fresno, CA. Patients with Acute promyelocytic leukemia and patients without complete cytogenetic and molecular data were excluded. The clinical data including age, sex, ethnicity, race, zip code, WBC on diagnosis, cytogenetics, molecular data and treatment regimens were reviewed. Molecular profiling was performed by next generation sequencing using established myeloid panels by NeoGenomics (NeoTYPE comprising of 63 genes) or Foundation One Heme laboratory (406 genes). Risk groups were identified based on the European Leukemia Network (ELN) 2022 criteria. RedCap data collection tool was used for data collection. A comparison of patient characteristics and rate of genetic alterations between Hispanic and Non-Hispanic patients was done using the Fisher exact test or Chi-square test. Kaplan-Meier Curve with log-rank test was used for evaluation of overall survival (OS) and progression-free survival (PFS). Results: 201 patients met the study criteria, 30 of them did not receive treatment and were included for their diagnostic data only but excluded from the survival analysis. The mean age at diagnosis was 65.6. 58.5% were males and 30% were Hispanic. Hispanic patients were younger than non-Hispanics (57.6 vs 64.6 years, p=0.01). Hispanic patients were also more likely to live in the relatively low Socioeconomic status (SES) neighborhoods (i.e., living in zip codes with the 1st or 2nd quartile of median income level) p=0. 007. More Hispanic patients needed interpreter P<0.001. However, Hispanics were more likely to experience favorable risk AML (8.4 % vs 0.7%, p=0.012), while non-Hispanics had higher rate of poor risk disease (63.8 Vs 55.9%, p=0.012).). There was no significant difference between Hispanics and non-Hispanics in terms of sex, de novo versus secondary AML, WBC at time of diagnosis, Extramedullary or Central nervous system (CNS) involvement, type of induction regimen or rate of consolidative or subsequent allogeneic stem cell transplant. Median OS in Hispanics was 17.3 months compared to 10.28 months for non-Hispanics, p=0.117.and median PFS for Hispanics was 9.17months compared to non-Hispanics at 6.04 months P=0.034 (Figure 1). In univariate analysis PFS and OS were better in patients with normal cytogenetics compared to those with abnormal cytogenetics (15.3 vs 3.52 months and 20.4 vs 7.69 months respectively, p < 0.001) and in patients with favorable compared to intermediate risk and poor risk groups (84.5 vs 11.4 vs 4.1 months for PFS and Non reached vs 18.1 vs 7.8 months for OS, p< 0.001). There was no significant effect of income level in terms of OS or PFS. The most common genetic mutations in our patients were NPM1, FLT3-ITD, DNMT3A, TET2 and TP53. However, there were differences in the rates between Hispanics and non-Hispanics. 5q deletion and STAG2 were more common in non-Hispanics while KMT2C was detected more in Hispanics (table 1). Conclusion: Our study identified biologic differences between Hispanic and non-Hispanic AML patients with heterogeneity in genetic mutations. While Hispanic patients had lower income, they were younger at diagnosis and more likely to have favorable risk AML. Hispanic patients had better PFS and a trend towards improvement in OS. Further studies on larger patient population are warranted to evaluate the effect of ethnicity and SES on outcomes of AML patients.

Venetoclax and Blinatumomab for Adult Patients with Relapsed/Refractory or MRD Positive Ph-Negative B-Precursor ALL: First Results of the GMALL-Bliven Trial

Introduction Prognosis of adult patients with relapsed/refractory (R/R) B-precursor acute lymphoblastic leukemia (BCP-ALL) remains poor. Monotherapy with Blinatumomab in ALL induced a complete remission (CR) in 44% of patients and measurable residual disease (MRD) negative molecular remission (MOL-CR) in 33%. Median overall survival of 7.7 months remains unsatisfactory. In the MRD setting, median survival was 36 months in the context of subsequent allogeneic stem cell transplantation (SCT). The combination of Blinatumomab with Venetoclax may be an effective option in ALL. Objectives In this multicenter phase 1 clinical trial the GMALL study group evaluates the safety of Blinatumomab in combination with Venetoclax in R/R or MRD positive BCP-ALL (NCT05182385). Using RNA sequencing, functional intracellular BH3 profiling, T cell immunomonitoring and effector cell cytotoxicity assays we aim to further elucidate synergy of this combination. Methods The BLIVEN trial includes patients with CD19-positive Ph-negative BCP-ALL aged 18 years and older, with no upper age limit. Eligible patients had either R/R ALL (bone marrow blasts >5%) or molecular failure/relapse (MRD >1xE-04). To assess safety, we determined maximum tolerated dose (MTD) as primary endpoint of the phase I part of the trial as designated recommended phase 2 dose (RP2D). Key secondary endpoint was the MOL-CR rate. Treatment consisted of oral Venetoclax in continuous dosing on day -7 to day 42 of target doses ranging between 200-800 mg once daily, and Blinatumomab as continuous intravenous infusion of 28 µg/d 4 weeks on and 2 weeks off, starting on day 1. For patients with R/R ALL, a cautionary dose step of 9 µg/d Blinatumomab was implemented for one week. MRD was analyzed in the reference laboratory using real-time quantitative PCR (RQ-PCR) of immunoglobulin and T-cell receptor (IG/TR) rearrangements. Results Between February 2022 and May 2023 a total of 7 patients were enrolled in the phase I part at four German centers (Figure 1). Venetoclax target doses were 400 mg (n=3), 600 mg (n=3), and 800 mg (n=1). Median age was 48.5 years (range 22 - 72 years). MRD assessment was available in 7/7 patients. Molecular BCP-ALL subtypes were identified by RNA sequencing in 5/5 analyzed patients, including ZNF384-rearranged ALL (n=2), BCR::ABL1-like (n=2; IGH::CRLF2 rearranged), and KMT2A-rearranged ALL (n=1). Three of seven patients were treated for hematological relapse, while 4/7 patients had molecular failure/relapse at time of enrolment. Among patients with R/R ALL, 2/3 were refractory to front-line therapy with intensive GMALL induction/consolidation therapy, while 1/3 suffered relapse shortly after failure of second allogeneic SCT. CTCAE grade IV neutropenia was identified as adverse reaction related to Venetoclax in one patient. Neutropenia resolved before dose limiting toxicity (DLT) evaluation time (i.e. 42 days after Venetoclax initiation). Overall, no DLT was identified throughout the trial and MTD was not reached. No treatment interruption was noted during cycle 1. Two of seven patients received one treatment cycle of BLIVEN only due to treatment failure, 5/7 patients received two treatment cycles. Response assessment was available for 7/7 patients. Treatment with Blinatumomab/Venetoclax of R/R ALL resulted in CR in 1/3 patients, with the responding patient showing a MOL-CR. The MOL-CR rate in molecular failure/relapse patients was 3/4. Conclusion Salvage therapy with Blinatumomab and Venetoclax exhibited good tolerability without treatment-related mortality. No treatment withdrawals were attributed to safety concerns. Two patients did not respond to BLIVEN combination therapy. Interestingly, both patients exhibited IGH::CRLF2 fusion transcripts.The remaining 5 patients obtained MRD responses, including complete MRD responses, of which 2/2 occurred in ZNF384 rearranged BCP-ALL. Further follow-up and larger patient numbers are needed to establish the potential benefit of this regimen in molecular driver subtypes of BCP-ALL. Enrollment to complete phase I of the BLIVEN trial is currently ongoing. Updated results including RP2D will be presented at the meeting. Acknowledgments This is an independent academic early phase I clinical trial conducted under the sponsor role of the Goethe University, Frankfurt, Germany. It received financial support and supply of Venetoclax by AbbVie Inc..

NPM1-Mutated Myeloid Neoplasms: Updated Outcomes with High-Intensive Chemotherapy Regardless of the Blast Percentage

Background: The most recent World Health Organization (WHO) classification has stablished NPM1-mutated myeloid neoplasms (MNs) to be acute myeloid leukemia (AML) regardless of bone marrow (BM) blast percentage. In contrast, the new International Consensus Classification (ICC) considers NPM1-mutant MNs as AML only in the presence of ≥10% BM blasts. Previous studies from our group and others have reported favorable outcomes of NPM1-mutant MNs with <20% blasts when treated with intensive chemotherapy. Here we seek to further evaluate clinical outcomes of this group of pts. Methods: We retrospectively re-evaluated the patient's characteristics, disease features and outcomes in patients with NPM1-mutated oligoblastic AML (<20% blasts) (oligo-AML). In addition, we also evaluated the clinicopathological characteristics in a cohort of patients with secondary NPM1-mutated AML (sAML), the majority of which had received treatment before progressing to AML. The Kaplan-Meier method was used to estimate the overall survival (OS), event-free survival (EFS) and relapse-free survival (RFS). Results: We identified 54 patients with NPM1-mutated oligo-AML. Median age was 62 years (range, 19-87) and most of them were female (59%). Median bone marrow (BM) blasts was 10%. Most patients could have been classified as CMML-2 (7/54, 13%), MDS-EB1 (7/54, 13%) and MDS-EB2 (24/54, 44%), based on the 2016 WHO classification. Median NPM1 variant allele frequency (VAF) was 0.38 (range, 0.05-0.52) and 38 patients (70%) had normal karyotype. These patients harbored a median of 1 co-mutation (range, 0-5), predominantly DNA methylation pathway, such as DNMT3A (31%) or TET2 (23.5%), or RAS pathway, mainly NRAS (25.5%), but rarely exhibited mutations in other functional pathways (Figure 1). Twenty-three patients (43%) progressed to AML with >20% BM blasts within a median of 10.7 months. Of 54 patients, 46 patients (82%) received chemotherapy-based regimens [61% low-intensity chemotherapy (LI-Chemo) based on hypomethylating agents or low-dose cytarabine and 21% high-intensity chemotherapy (HI-Chemo)] and 21 patients (39%) received a stem cell transplant (SCT). With a median follow up of 67.6 months (LI-Chemo of 48.3 months; HI-Chemo of 71.4 months), the median OS, EFS and RFS was 30.4 months, 30.4 months and 14.7 months for the LI-Chemo group, respectively, but median OS, EFS and RFS were not reached (NR) for HI-Chemo group. However, when compared by age, patients with <60 years had trends to have better OS with LI-Chemo or HI-Chemo than patients aged ≥60 years (Figure 2). In addition, 5 patients received chemotherapy-based regimens with venetoclax, however improved OS was only seen when combined with HI-Chemo and SCT (n=2, with a median OS NR without deaths, likely related to younger people). In parallel, we identified 31 patients with NPM1-mutated sAML progressed from oligo-AML. Median age was 67 years (range, 31-83) and female were 58%. Median BM blasts was 40%. Median NPM1 VAF was 0.38 (range, 0.02-0.56). Most patients did not exhibit clonal cytogenetic evolution and remained with a diploid karyotype (65%). Seventy-four percent of patients (17 out of 23 tested) had known prior NPM1-mutated oligo-AML, and in 6 patients NPM1 mutation was acquired at progression. Median number of co-mutations were 3 (range, 0-7). DNTM3A (65%) or TET2 (33.3%) mainly co-occurred with RAS pathway mutations, and in particular FLT3-ITD (26.7%) or FLT3-TKD (13.3%) (Figure 1). Eleven of 31 patients (36%) received LI-Chemo regimens, whereas 15 of 31 patients (48%) had HI-Chemo regimens. Nine patients (29%) underwent SCT. With a median follow up of 39.6 months (LI-Chemo of 55.5 months; HI-Chemo of 39.4 months), the median OS, EFS and RFS was 11.4 months, 12.4 months and NR for LI-Chemo, respectively; and 13.2 months, 6.5 months and NR for HI-Chemo, respectively. No significant differences were seen depending on the number of therapies received for previous oligo-AML. Previously untreated patients who received a venetoclax-based regimen with SCT had prolonged survival (n=4, median OS NR, with median follow up of 41 months). Conclusions: NPM1-mutated acute myeloid leukemia can be treated as such irrespective of blasts burden. For these cases, especially young patients, should be treated with intensive chemotherapy and subsequent allogeneic stem cell transplant as a clear curative approach.

Efficacy and Safety Analysis of Combination Therapy Based on Liposomal Mitoxantrone (Lipo-MIT) in Relapsed/Refractory NK/T-Cell Lymphoma

Background: Currently, there is no standard treatment for relapsed/refractory NK/T-cell lymphoma (NKTCL), which is characterized by highly aggressive and poor prognosis. New drugs are urgently needed to improve the therapeutic effect. Liposomal mitoxantrone (Lipo-MIT) is approved in China for the treatment of relapsed or refractory peripheral T-cell lymphoma patients who have received at least one line standard therapy previously. Phase II study data showed that the objective response rate (ORR) of patients after monotherapy was 41.7% and the complete response rate (CR) was 23.1%. Progression-free survival (PFS) was 8.5 months. Lipo-MIT showed excellent anti-tumor effect in patients with NKTCL subtype, with an ORR of 42.9%, which broke the limitation of natural resistance of NKTCL to anthracyclines. To further improve the efficacy, we tried a combination therapy based on Lipo-MIT in patients with relapsed/refractory NKTCL. Herein we will report its efficacy and safety. Methods: Nine patients with relapsed/refractory NKTCL were enrolled in this study, all of whom had previously received pegaspargase-based combination chemotherapy. The salvage treatment was a combination regimen based on Lipo-MIT. The efficacy was evaluated after every 2 cycles using PET-CT or MRI scan, and hematological and non-hematological adverse events were collected after treatment. Progression-free survival (PFS) was defined as the time from initiation of Lipo-MIT to disease progression, recurrence, death, or last follow-up. Overall survival time (OS) was defined as the time from initiation of Lipo-MIT to death from all causes or the last follow-up. Results: The median age of the nine patients was 53 years old (17-67 years old), and the male-female ratio was 7:2. Eight patients had stage IV NKTCL, one was stage II NKTCL, and all patients had an NRI score of ≥3. The median number of previous treatment lines was 2 (1-4). Three patients had recurrent NKTCL, and six patients had refractory disease to previous treatments, among whom two patients had concurrent hemophagocytic syndrome. The salvage treatment regimens were as follows: Lipo-MIT + pegaspargase + dexamethasone (N=3); Lipo-MIT + pegaspargase + dexamethasone +PD1 monoclonal antibody (N=2); Lipo-MIT +PD1 monoclonal antibody + dexamethasone (N=2); Lipo-MIT + etoposide + pegaspargase + dexamethasone (N=2). Efficacy was evaluable in all patients and the median number of treatment cycles was 3 (2-6). The best response rates were as follows: complete response in 3 (33.3%) patients, partial response in 4 (44.4%) patients, stable disease in 1 (11.1%) patient, and progressive disease in 1 (11.1%) patient. At a median follow-up of 4 months (2-13 months), 6 patients died, including 5 from disease progression and 1 from pegaspargase -associated acute pancreatitis, with a median PFS of 5 months and a median OS of 7 months. One patient underwent allogeneic hematopoietic stem cell transplantation after achieving a complete response and has been disease-free for more than 13 months now. The main adverse reactions of Lipo-MIT combination regimen were grade 3 or more bone marrow suppression (N=7), skin cyanosis (N=4), liver insufficiency (N=4), coagulation dysfunction (N=4), acute pancreatitis (N=1). The median recovery time from myelosuppression was 17 days (6-35 days). There was no correlation between skin cyanosis and efficacy. Conclusion: Combination therapy based on Lipo-MIT has a high remission rate for relapsed/refractory NKTCL, but the duration of remission needs to be further extended, and subsequent allogeneic hematopoietic stem cell transplantation may prolong survival. Lipo-MIT has obvious myelosuppression toxicity, and active supportive therapy should be given when combined with other cytotoxic drugs. In the future, it is worthwhile to conduct prospective clinical trials to explore the optimal combination therapy based on Lipo-MIT in relapsed/refractory NKTCL.

Impact of prior therapies and subsequent transplantation on outcomes in adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with brexucabtagene autoleucel in ZUMA-3

BackgroundBrexucabtagene autoleucel (brexu-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the USA for adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) and...

Impact of age, prior therapies, and subsequent transplant on long-term outcomes of adults with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) treated with brexucabtagene autoleucel (brexu-cel) in ZUMA-3.

7023 Background: Brexu-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved in the US for adults with R/R B-ALL and in the EU for adults ≥26 y with R/R B-ALL based on positive results of ZUMA-3. After 3-y follow-up in ZUMA-3, brexu-cel demonstrated an overall complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate of 71% and a median overall survival (OS) of 26.0 mo in all treated pts (N = 55) and 38.9 mo in pts with CR (n = 31; Shah et al. EU CAR T 2023. Abstract 34). Here we report 3-y outcomes by age, prior therapies, and subsequent allogeneic stem cell transplant (alloSCT). Methods: Pts (≥18 y) had R/R B-ALL and received 1 brexu-cel infusion (1×10⁶ CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was overall CR/CRi rate per independent review. Post hoc subgroup analyses were exploratory, with descriptive statistics reported. Results: As of July 23, 2022, the median follow-up in Phase 2 (N = 55) was 38.8 mo (range, 32.7-44.6). The CR/CRi rate (95% CI) was 67% (35-90) for pts < 26 y (n = 12) and 72% (56-85) for pts ≥26 y (n = 43). The median (95% CI) OS was 28.6 mo (0.6-not estimable [NE]) for pts < 26 y and 34.1 mo (15.9-NE) for pts ≥26 y. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 92% of pts < 26 y and in 88% of pts ≥26 y. For pts with 1 prior therapy (n = 10), the CR/CRi rate was 90% (95% CI, 55-100) and for pts with ≥2 prior therapies (n = 45), the CR/CRi rate was 67% (95% CI, 51-80); medians (95% CI) for OS were not reached (NR; 2.1-NE) and 25.6 mo (14.2-38.9), respectively. The incidence of Grade ≥3 TRAEs was 90% for pts with 1 prior therapy and 89% for pts with ≥2 prior therapies. The CR/CRi rates (95% CI) for pts with (n = 25) and without (n = 30) prior blinatumomab (blina) were 60% (39-79) and 80% (61-92). The median (95% CI) OS was 14.2 mo (3.2-26.0) for pts with prior blina and NR (18.6-NE) for pts without prior blina; Grade ≥3 TRAEs occurred in 80% and 97% of pts, respectively. For responders (CR/CRi) who did (n = 10) or did not (n = 29) proceed to subsequent alloSCT, the median (95% CI) OS was NR (7.6-NE) and 38.9 mo (18.6-NE), respectively. Similar efficacy results were observed in a pooled subgroup analysis of Phase 1 and 2 pts treated at the pivotal dose (N = 78), with a median follow-up of 41.6 mo (range, 32.7-70.3). Conclusions: Adults with R/R B-ALL benefitted from brexu-cel, regardless of age, number of prior therapies, prior blina exposure, or subsequent alloSCT status. Survival appeared longer in pts with fewer prior therapies and in blina-naïve pts; however, small pt numbers and unmatched baseline characteristics limit interpretation of these results. Additional studies are needed to determine the impact of prior therapies and/or subsequent alloSCT on outcomes of pts who receive brexu-cel. Clinical trial information: NCT02614066 .

Phase 1 study of ziftomenib (KO-539) in combination with venetoclax or venetoclax/azacitidine or standard induction cytarabine/daunorubicin (7+3) chemotherapy for the treatment of patients with acute myeloid leukemia.

TPS7079 Background: Relapsed or refractory (R/R) acute myeloid leukemia (AML) with nucleophosmin 1-mutations ( NPM1-m) or KMT2A-rearrangment ( KMT2A-r) represent a high unmet need. Ziftomenib is a potent and selective inhibitor that targets the menin-mixed-lineage leukemia (MLL) lysine[K]-specific methyltransferase 2A ( KMT2A) interaction driving leukemogenesis in these subtypes. An ongoing Phase 1/2 study (KO-MEN 001) has demonstrated meaningful clinical activity and tolerability with ziftomenib monotherapy in R/R AML. In preclinical testing, ziftomenib combined with venetoclax induced synergistic lethality in KMT2A-r and NPM1-m human AML cell lines and patient-derived cells. Moreover, treatment with ziftomenib plus venetoclax/azacitidine has induced prolonged durable remissions in mice with KMT2A-r AML xenografts. Therefore, administration of ziftomenib in combination with standard-of-care (SOC) therapies may provide additional clinical benefit for patients with newly diagnosed or R/R NPM1-m and KMT2A-r menin-dependent AML. Methods: KOMET-007 (KO-MEN-007, NCT# ) is a 2-part dose escalation (Phase 1a) and expansion (Phase 1b) study to evaluate the safety, tolerability, and preliminary antileukemic activity of ziftomenib in combination with non-intensive chemotherapy (NIC) and intensive chemotherapy (IC) in patients with NPM1-m and KMT2A-r AML. During Phase 1a, the ziftomenib dose will be escalated with standard doses of either venetoclax and azacitidine (zifto/ven/aza) or cytarabine and daunorubicin (zifto/7+3) in defined genetic cohorts ( NPM1-m and KMT2A-r) using a rule-based approach (n = 6 per cohort/dose level) to select ziftomenib doses for expansion/validation in Phase 1b. The Phase 1b portion will also evaluate zifto/ven/aza in newly diagnosed AML ( KMT2A-r and NPM1-m) and zifto/ven in R/R AML ( NPM1-m only). The overall primary objectives are to establish the minimum biologically effective, dose limiting toxicities, and recommended Phase 2 dose of ziftomenib combined with NIC and IC backbones in each genetically defined cohort. Additional secondary endpoints include preliminary antileukemic efficacy (including MRD-negative responses and number of patients able to transition to subsequent allogeneic stem cell transplant), pharmacokinetic, and pharmacodynamic data. Exploratory end points include biomarkers for efficacy and resistance, pharmacodynamic biomarkers and activity in isolated myeloid sarcoma. Clinical trial information: NCT04067336 .

Combining the HCT-CI, G8, and AML-Score for Fitness Evaluation of Elderly Patients with Acute Myeloid Leukemia: A Single Center Analysis.

Accurate assessment of elderly acute myeloid leukemia (AML) patients is essential before intensive induction chemotherapy and subsequent allogeneic hematopoietic stem cell transplantation. In this context, we investigated the capacity of three scores for frailty prediction. At diagnosis, 197 patients were clinically evaluated for appropriate treatment intensity. In parallel and independently, the G8-score, the Hematopoietic Stem Cell Index (HCT-CI) and the AML-score for CR were determined for each patient and analyzed with respect to overall survival (OS). The G8-score and the HCT-CI were able to significantly separate "fit" from "unfit" patients, <0.001 and p = 0.008. In univariate Cox models, the predictive role for OS was confirmed: for the G8-score (HR: 2.35, 95% CI 1.53-3.60, p < 0.001), the HCT-CI (HR: 1.91, 95% CI 1.17-3.11, p = 0.009) and the AML-score (HR: 5.59, 95% CI 2.04-15.31, p = 0.001), the latter was subsequently used to verify the cohort. In the multivariate Cox model, the results were confirmed for the G8- (HR: 2.03, p < 0.001) and AML-score (HR: 3.27, p = 0.001). Of interest, when combining the scores, their prediction capacity was significantly enhanced, p < 0.001. The G8-, the HCTCI and the AML-score represent valid tools in the frailty assessment of elderly AML patients at diagnosis.

Clinical Study of Blinatumomab in the Treatment of Adult Relapsed/Refractory Ph-Negative Acute B-Lymphoblastic Leukemia

To investigate the efficacy and safety of CD19/CD3 bisecific monoclonalantibody (Blinatumomab) in the treatment of adult patients with relapsed / refractory Ph-negative acute B-lymphoblastic leukemia (R/R-B-ALL). Ten adult R/R B-ALL patients were all treated with Blinatumomab. Each treatment cycle was administered for 28 days and stopped for 14 days. The dose was 9 μg/day for the first 7 days of cycle 1, and 28 μg/day for days 8-28 if there were no adverse reactions. From the second cycle onwards, the daily dose was 28 μg. The remission, survival time (EFS and OS) and adverse reactions were observed after treatment. Nine patients with curative effect could be evaluated. Four patients achieved CR after one course, and one patient achieved CR after two courses, the overall remission rate was 55.6%(5/9). The median EFS was 4 months (1-12 months), and the median OS was 6 months (2-44 months). Nine of the 10 patients had fever of different degrees. Serum levels of cytokines such as IL-6, IL-10, IL-17 and IFN-γ increased. Two patients resumed medication after 1 week of treatment interruption due to neurotoxicity and CRS, respectively. One patient was discontinued due to grade 3 CRS and died of tropical candidiaemia. Blinatumomab has a good response rate in the treatment of relapsed/refractory B-ALL patients, but the duration of remission is shorter. Drug-related adverse reactions are mainly CRS and neurotoxicity. Inflammatory factors IL-6, IL-10, IL-17 and IFN-γ can be used as indicators to monitor CRS. The bisspecificity MAbs provide an opportunity for subsequent allogeneic hematopoietic stem cell transplantation in R/R-B-ALL patients.

Venetoclax Added to Cladribine (CLAD) + Low Dose AraC (LDAC) Alternating with Azacitidine (AZA) Is Highly Active As Frontline Therapy in Older Patients with Newly Diagnosed Acute Myeloid Leukemia in a Phase 2 Study

Background The combination of venetoclax with AZA for patients with newly diagnosed AML who are older or unfit for intensive chemotherapy significantly improves remission rates and survival compared to AZA alone. A low-intensity backbone combining venetoclax with cladribine (CLAD) plus low-dose araC (LDAC) alternating with HMA has demonstrated encouraging results in older patients with newly diagnosed AML (Kadia TM, et al. J Clin Oncol. 2022). Here we report an updated cohort of patients with longer-term follow up treated on the phase 2 clinical trial of venetoclax added to CLAD/LDAC alternating with AZA. Methods This is a phase 2 study (NCT03586609) investigating the combination of venetoclax with CLAD/LDAC alternating with AZA in older (age ≥ 60 years) or patients <60 years that are unfit for intensive chemotherapy with newly diagnosed AML (excluding APL, CBF). The primary objective was composite complete response rate (CRc; CR+CRi); secondary endpoints were overall survival (OS), disease-free survival (DFS), overall response rate (ORR), and toxicity. Induction was with cladribine 5 mg/m2 IV on D1-5 and araC 20mg SQ BID on D1-10. Consolidation/maintenance consisted of 2 courses of cladribine 5 mg/m2 IV on D1-3 and araC 20 mg SQ BID on D1-10 alternating with 2 cycles of AZA 75 mg/m2 on D1-7, for up to 18 courses. Venetoclax 400 mg was added for each course with dose adjustments for concomitant CYP3A inhibitors. Venetoclax was given for 21 days during induction and for 7-14 days for consolidation depending on measurable residual disease (MRD) and tolerability. One cycle was 4 weeks and up to 2 cycles of induction were allowed. Results A total of 93 patients were treated on study with a median age was 68 years (range: 57 - 84); 28 (30%) patients were ≥ 70 yrs and 1 patient <60, unfit for intensive chemotherapy was enrolled. 29 (31%) patients had secondary or therapy related AML. 52 (56%) had diploid cytogenetics with 11 (12%) having adverse cytogenetics at enrollment. By European Leukemia Network (ELN) risk, 24%, 24%, and 53% were favorable, intermediate, and adverse risk, respectively. The most commonly mutated genes were DNMT3A in 28 (30%), NPM1 in 26 (28%), RAS in 23 (25%), TET2 in 22 (24%), and IDH2 in 20 (22%). TP53 was mutated in 8 (9%) patients. Among 93 evaluable patients the CRc rate was 92%. Best response was CR in 72 (78%), CRi in 13 (14%), no response in 5 (5%), and death in 2 (2%) patients. In responding patients with a bone marrow sample evaluable for assessment of MRD by flow cytometry, 71/85 (84%) achieved MRD negativity while on study. Responses were preserved across ELN risk groups with the CRc (CR/CRi) rate of 95% (86%/9%), 95% (82%/14%), and 90% (73%/17%) for patients with ELN favorable, intermediate, and adverse risk, respectively. CRc rate for TP53 mutated disease was 88% (7/8, 86% MRD negative) and for NPM1 mutated disease was 96% (25/26, 100% MRD negative). 35 (41%) responders received a subsequent allogeneic stem cell transplantation (alloSCT). Early mortality was low with two patients (2%) dying within 4 weeks and five patients (5%) dying with in 8 weeks. The most frequent grade 3/4 non-heme adverse events were febrile neutropenia (n=12), infection (n=7), atrial fibrillation (n=2), and allergic reaction (n=2). One patient developed grade 4 tumor lysis syndrome. With a median follow up of 22.8 months, the median duration of response (DOR) is not reached (95% CI: NE - NE months). Estimated 12- and 24-month DOR are 88.4% (95% CI: 81.0 - 96.4%) and 81.0% (95% CI: 71.0 - 92.4%), respectively. Median disease-free survival (DFS) is not yet reached (95% CI: 24.5 - NE months). Estimated 12- and 24-month DFS are 76.0% (95% CI: 66.8 - 86.4%) and 63.4% (95% CI: 52.1 - 77.1%), respectively. Median overall survival (OS) is not yet reached (95% CI: 25.4 - NE months). Estimated 12- and 24-month OS are 75.7% (95% CI: 66.9 - 85.7%) and 68.3% (95% CI: 58.1 - 80.1%), respectively (Figure). Conclusion Venetoclax added to CLAD/LDAC alternating with AZA is a highly effective, lower-intensity regimen which is well tolerated among older patients with newly diagnosed AML, producing high CRc and MRD negative remission rates and is effective in transitioning older adults to alloSCT. The rates of DFS and OS are encouraging. Further study of this non-anthracycline containing regimen is warranted in older patients both fit and unfit for intensive chemotherapy as a safe and effective induction treatment strategy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Outcomes with Low-Dose Inotuzumab and Mini-Hyper-CVD Followed By Blinatumomab Consolidation in Relapsed-Refractory Acute Lymphoblastic Leukemia: Results of a Phase II Study

Background: Patients (pts) with relapsed-refractory (R-R) acute lymphoblastic leukemia (ALL) have a poor prognosis. The combination of low-intensity chemotherapy with mini-hyper-CVD (mini-HCVD) and inotuzumab has shown encouraging results. The aim of this study is to evaluate whether the sequential addition of blinatumomab to mini-HCVD-inotuzumab with lower doses of weekly inotuzumab might further improve outcomes. Methods: Pts with Philadelphia chromosome-negative B-cell ALL were included. Odd cycles of mini-HCVD consisted of cyclophosphamide (150 mg/m2 every 12 h on days 1-3), vincristine (2 mg flat dose on days 1 and 8), and dexamethasone (20 mg on days 1-4 and days 11-14) without anthracyclines. Even cycles consisted of cytarabine (0.5 g/m2 given every 12 h on days 2 and 3) and methotrexate (250 mg/m2 on day 1). During the first 4 courses, pts received rituximab when CD20 expression was ≥20%, and intrathecal chemotherapy. Initially, inotuzumab was administered on day 3 of the first 4 cycles at the dose of 1.3-1.8 mg/m2 in course 1, followed by 1.0-1.3 mg/m2 in subsequent courses. Pts received maintenance therapy with POMP, consisting of 1 year of monthly prednisone 50 mg/d for 5 days and vincristine at 2 mg every month, along with 3 years of 6-mercaptopurine 50 mg twice daily and weekly oral methotrexate 10 mg/m2. An amendment to the protocol was made after the inclusion of 67 pts to add 4 cycles of blinatumomab after 4 cycles of the combination mini-HCVD + inotuzumab. Inotuzumab was given on days 2 and 8 at the dose of 0.6 and 0.3 mg/m2 in course 1, respectively, followed by days 2 and 8 at the dose of 0.3 and 0.3 mg/m2 in subsequent courses; blinatumomab was continuously infused over 28 days every 42-day cycle for 4 cycles. Maintenance therapy was reduced to 12 courses of POMP with 1 course of blinatumomab after each 3 courses of POMP for a total of 4 courses. The decision to undergo allogeneic stem cell transplantation (ASCT) was based on the discretion of the treating physician after discussion with the patient. Results: Between February 2013 and July 2021, 112 pts were treated on study, including 45 pts with mini-HCVD + inotuzumab + blinatumomab. Baseline characteristics and outcomes are summarized in Table 1. The median follow-up is 41 months (range, 3-112). Before the study amendment, 67 pts were treated: 38 (57%) in salvage(S)1, and 29 (43%) in S2+. Nineteen pts (28%) had received prior ASCT. After the amendment, additional 45 pts were treated: 42 (93%) in S1, and 3 (7%) in S2+; 3 (7%) pts had prior ASCT. The overall response rate (ORR) was 83% (CR, 63%) in the entire cohort, 76% (CR, 60%) pre-amendment, and 93% (CR, 67%) post-amendment. Among 91 responders evaluable for measurable residual disease (MRD), 76 pts (82%) achieved MRD negativity by multicolor flow cytometry, with higher rates of MRD negativity in S1 (89%). The rates of MRD negativity before and after the amendment were 82% and 85%, respectively. Overall, 53 (47%) pts underwent ASCT: 29 (43%) pts pre-amendment and 24 (53%) post-amendment. The median overall survival (OS) for the entire cohort was 17 months, with a 3-year OS rate of 41%. After the amendment, the addition of blinatumomab resulted in superior median OS (37 months vs 14 months) and 3-year OS rates (55% versus 34%) (Figure 1). Pts in S1 had better survival compared with those in S2+, with 3-year OS of 51% and 17%, respectively (P=0.001). In a 2-month landmark analysis among pts in S1, the median OS was 57 months in those who received blinatumomab compared with 31 months in those who did not. Overall, pts who achieved MRD negativity had higher 3-year OS rate of 55% compared to 10% in pts who were MRD-positive at best response (P=0.0001). Survival with mini-HCVD + inotuzumab +/- blinatumomab compared favorably to that of inotuzumab monotherapy: 17 months vs 6 months; P<0.0001. A 3-month landmark analysis among responders showed similar 3-year OS rates between pts who underwent subsequent ASCT and those who did not (55% vs 48%, respectively). Veno-occlusive disease (VOD) was observed in 10 of the 112 pts (9%), and its incidence was reduced from 13% with single dose of inotuzumab to 2% with fractionated dose schedule (P=0.056). Conclusion: The addition of blinatumomab to mini-HCVD-inotuzumab, along with a lower weekly dose of inotuzumab, further improves the outcomes of pts with R-R ALL. These adjustments reduced the rate of VOD and improved survival. Long-term survival was similar regardless of subsequent ASCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cost-Effectiveness of KTE-X19 for Adults with Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia in the United States.

IntroductionDespite currently available treatments for adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL), survival outcomes remain poor, highlighting the need for new therapeutic strategies. This study estimates the cost-effectiveness of KTE-X19 to treat adults with R/R ALL from a US payer perspective.MethodsThe model had two components: a decision-tree, where pre-infusion costs for patients who ultimately did not receive KTE-X19 are accounted for, followed by a partitioned survival analysis, where all KTE-X19 infused patients would enter the three-state (pre-progression, progressed disease, death) model. Comparators included current standard of care treatments, i.e., blinatumomab (BLIN), inotuzumab ozogamicin (INO), and salvage chemotherapy (CHEMO). Both standard parametric and mixture cure models were used to model survival. Efficacy, safety, healthcare resource utilization, and health state utility inputs were derived from the ZUMA-3 trial (NCT02614066) and literature. Cost inputs were derived from literature or publicly available sources. Outcomes and costs were discounted 3% annually. Results of KTE-X19 versus comparators are reported as total and incremental life-years (LYs), quality-adjusted life-years (QALYs), costs, and resulting incremental cost-effectiveness ratio (ICER). Deterministic and probabilistic sensitivity analyses (PSA) and key scenario analyses were also performed.ResultsIn the base case, incremental QALYs for KTE-X19 were 2.44, 3.26, and 4.61 versus BLIN, INO, and CHEMO, respectively. Incremental costs were $50,913, $251,532, and $432,027, respectively, resulting in ICERs of $20,843/QALY (versus BLIN), $77,271/QALY (versus INO), and $93,768/QALY (versus CHEMO). Deterministic sensitivity analysis results were most sensitive to subsequent allogeneic stem cell transplant rates and post-progression utilities. PSA found that KTE-X19 is 78.4%, 74.0%, and 75.4% likely to be cost-effective versus BLIN, INO, and CHEMO, respectively. Across most scenarios, at a willingness-to-pay (WTP) threshold of $150,000/QALY, KTE-X19 was cost-effective versus all treatments.ConclusionsCompared to current options for adults with R/R ALL, KTE-X19 is cost-effective, driven primarily by improved survival.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02201-6.

Two-year follow-up of KTE-X19, an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult patients (Pts) with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) in ZUMA-3.

7010 Background: Brexucabtagene autoleucel (KTE-X19) is an autologous anti-CD19 CAR T-cell therapy approved in the US to treat adult R/R B-ALL based on the ZUMA-3 study. The overall complete remission (CR) rate (CR + CR with incomplete hematologic recovery [CRi]) was 71% (95% CI, 57-82) after 16.4 mo median follow-up (N = 55; Shah et al. Lancet 2021). Here, we report updated outcomes with longer follow-up in these pts and in a larger pooled analysis of Phase (Ph) 1 and 2 pts who received the pivotal dose of KTE-X19. Methods: Eligible adults (≥18 years) had R/R B-ALL and received a single infusion of KTE-X19 at the pivotal dose (1×106 CAR T cells/kg) following leukapheresis and conditioning chemotherapy. The primary endpoint was CR/CRi rate by central review. Results: As of 23 July 2021, median follow-up was 26.8 mo (range, 20.7-32.6) for treated Ph 2 pts (N = 55). The CR/CRi rate per central review was 71% (95% CI, 57-82; 56% CR; 15% CRi). Eleven pts (20%; 8 CR and 2 CRi) proceeded to subsequent allogeneic stem cell transplant (alloSCT). Median duration of remission (DOR) censored at subsequent alloSCT was 14.6 mo (9.4-not estimable [NE]); not censored: 18.6 mo (9.6-NE); 6/39 responders (15%) had ongoing responses at data cutoff. Median (95% CI) relapse-free survival (RFS) was 11.6 mo (2.7-20.5) censored at subsequent alloSCT and 11.7 mo (2.8-20.5) not censored at subsequent alloSCT; 18-mo RFS rates (95% CI) were 35% (20.5-50.6) and 42% (28.0-55.0), respectively. Median (95% CI) overall survival (OS) was 25.4 mo (16.2-NE) among all KTE-X19-treated pts and not reached (25.4-NE) in pts with CR (n = 31). For Ph 1/2 pts (N = 78) who received the pivotal KTE-X19 dose (median follow-up: 29.7 mo; range 20.7-58.3), the CR/CRi rate by independent review was 73% (95% CI, 62-82). Medians (95% CI) for DOR, RFS, and OS were 18.6 mo (9.6-NE), 11.7 mo (6.1-20.5), and 25.4 mo (16.2-NE), respectively. A subgroup analysis revealed that in pts aged 18-39 (n = 36), 40-59 (n = 27), and ≥60 (n = 15) years, the CR/CRi rates (95% CI) were 69% (52-84), 70% (50-86), and 87% (60-98); 24-mo OS rates (95% CI) were 48% (30-64), 54% (33-71), and 57% (28-78), respectively. In pts with pre-KTE-X19 infusion marrow blast percentages &gt; 25 to ≤50 (n = 12), &gt; 50 to ≤75 (n = 14), and &gt; 75 to 100 (n = 30), CR/CRi rates (95% CI) were 83% (52-98), 86% (57-98), and 57% (37-75); 24-mo OS rates (95% CI) were 58% (27-80), 55% (26-77) and 37% (19-55), respectively. There were no new safety signals; the proportion of treated Ph 2 pts with Gr ≥3 treatment emergent adverse events was unchanged since prior data cutoff. One pt had an ongoing neurologic event of Gr 1 finger numbness. Conclusions: With longer follow-up and an expanded data set by independent review, outcomes remain durable in adults with R/R B-ALL, most of whom were heavily pretreated, with median OS not yet reached in pts with CR. Long-term safety was favorable. Clinical trial information: NCT02614066.

Phase II Study of Venetoclax Added to Cladribine (CLAD) and Low Dose AraC (LDAC) Alternating with 5-Azacytidine (AZA) in Older and Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Phase II Study of Venetoclax Added to Cladribine (CLAD) and Low Dose AraC (LDAC) Alternating with 5-Azacytidine (AZA) in Older and Unfit Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Efficacy of HMA +/- Venetoclax or Intensive Chemotherapy in Blast-Phase Myeloproliferative Neoplasms

▪IntroductionBlast-phase (BP), or leukemic transformation is a rare and devastating complication of myeloproliferative neoplasms (MPNs) (primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET), and post-PV/ET myelofibrosis). Patients with BP-MPNs have a poor prognosis with a median overall survival of less than 6 months, and there is no standard treatment regimen for these aggressive diseases (Dunbar et al, Blood. 2020). The development of hypomethylating agent (HMA)/venetoclax (Ven) combination offers new hope for some with AML, but has been relatively disappointing in BP-MPN, though data are limited and retrospective (Masarova et al, Blood Adv. 2021; Gangat et al, Am J Hematol. 2021). Here, we add our experience with several common treatment regimens for BP-MPN.MethodsWe retrospectively analyzed data from 39 consecutive patients with BP-MPNs diagnosed from December 2008 to February 2021 who received treatment at the University of Michigan. We included all patients with a previous diagnosis of MPNs who had ≥ 20% blasts in the peripheral blood or bone marrow, and subsequently received systemic therapy. One patient with a myeloid sarcoma was included as well. Disease characteristics at time of BP-transformation were noted. Patients were divided into the following groups based on 1 st-line induction therapy: 7+3 (daunorubicin and cytarabine), FLAG (fludarabine, high-dose cytarabine and G-CSF), hypomethylating agent only (decitabine or azacitidine), and HMA/Ven. Patients were followed for 2 years post-diagnosis. Differences in induction response were assessed using the Chi-square test. Differences in overall survival were calculated using the Kaplan-Meier regression with the log-rank test. Two patients who received alternate induction therapy outside of the four groups were not included in these analyses.ResultsThe composite BP-MPN population had a median advanced age of 69 years old and a median ECOG performance status (PS) of 1. Most (97.4%) had received systemic treatment prior to their transformation for their MPN, with 71.8% receiving hydroxyurea and 41.0% receiving ruxolitinib. The rate of response (CR, CRi, MLFS) was highest in the HMA/Ven group at 42.9%, followed by FLAG (29.4%), HMA only (11.1%), and 7+3 (0%), p = 0.033 (Table 3). Despite the higher response rate, differences in 2-year OS were not significantly different among the 4 groups: 7+3 (25.0%), FLAG (7.7%), HMA (0%), HMA/Ven (20.0%) (p=0.92, Figure 1). Median time to relapse after achieving remission ranged from 2-10 months, and did not vary significantly based on induction regimen. Patients in the HMA and HMA/Ven groups had higher incidences of death with induction at 77.8% and 28.6%, respectively (Table 3).ConclusionsThe highest rates of response, including complete remission, were achieved with the combination of HMA and venetoclax compared to intensive induction chemotherapy or HMA alone. However, this did not translate into significant differences in OS, which is consistent with other retrospective reports. No responses were seen with 7+3 induction, though several patients were able to go on salvaged with other therapies and subsequent allogeneic stem cell transplantation thereafter. Finally, the baseline poor ECOG PS of the HMA group and borderline ECOG PS of the HMA/Ven group also contribute to their low survival rates.Larger, prospective studies comparing currently available treatment regimens in BP-MPN would be helpful, but ultimately new therapies are desperately needed for this high-risk disease. [Display omitted] DisclosuresBixby: Takeda: Consultancy. Talpaz: Constellation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Grant/research support ; Celgene: Consultancy; Imago: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

A Phase II Study of Inotuzumab Ozogamicin for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia

A Phase II Study of Inotuzumab Ozogamicin for the Treatment of Measurable Residual Disease-Positive B-Cell Acute Lymphoblastic Leukemia