Gilteritinib with or without venetoclax for relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Patients with FLT3-mutated acute myeloid leukaemia (AML) that relapse or are refractory (R/R) to intensive induction have poor outcomes. Gilteritinib has recently become standard-of-care for patients with R/R FLT3-mutated AML. We investigated whether adding venetoclax to gilteritinib (gilt-ven) improves outcomes as compared with gilteritinib monotherapy. We included patients treated with gilteritinib (n = 19) and gilt-ven (n = 17) for R/R AML after intensive chemotherapy. Gilteritinib and gilt-ven groups did not differ in terms of mCRc rates (53% and 65%, p = 0.51) and realization of allogeneic haematopoietic stem-cell transplantation (HSCT, 47% and 35%, p = 0.5). Overall survival (OS) was comparable between groups, although a trend towards better OS was seen with gilt-ven (12-month OS 58.8% [95% CI 39.5%-87.6%]) versus gilteritinib (42.1% [95% CI 24.9%-71.3%] for gilteritinib). Early salvage with gilt-ven versus any other gilteritinib-based approach was associated with the best outcome (p = 0.031). Combination therapy was associated with increased haematological toxicity. In summary, gilt-ven did not improve remissions or HSCT-realization rates in patients with R/R FLT3-mutated AML as compared with gilteritinib and was associated with increased haematological toxicity. Although OS did not differ, a trend towards better survival was suggested with gilt-ven and a survival benefit was shown for gilt-ven approach when sequenced early for salvage.

Recent Advances in the Biology and CD123-Directed Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive myeloid malignancy of the dendritic cell lineage that affects patients of all ages, though the incidence appears to be highest in patients over the age of 60 years. Diagnosis is based on the presence of plasmacytoid dendritic cell precursors expressing CD123, the interleukin-3 (IL-3) receptor alpha, and a distinct histologic appearance. Timely diagnosis remains a challenge, due to lack of disease awareness and overlapping biologic and clinical features with other hematologic malignancies. Prognosis is poor with a median overall survival of 8 to 14 months, irrespective of disease presentation pattern. Historically, the principal treatment was remission induction therapy followed by a stem cell transplant (SCT) in eligible patients. However, bridging to SCT is often not achieved with induction chemotherapy regimens. The discovery that CD123 is universally expressed in BPDCN and is considered to have a pathogenetic role in its development paved the way for the successful introduction of tagraxofusp, a recombinant human IL-3 fused to a truncated diphtheria toxin payload, as an initial treatment for BPDCN. Tagraxofusp was approved in 2018 by the United States Food and Drug Administration for the treatment of patients aged 2 years and older with newly diagnosed and relapsed/refractory BPDCN, and by the European Medicines Agency in 2021 for first-line treatment of adults. The advent of tagraxofusp has opened a new era of precision oncology in the treatment of BPDCN. Herein, we present an overview of BPDCN biology, its diagnosis, and treatment options, illustrated by clinical cases.

Venetoclax-based salvage therapy for adult patients with relapsed/refractory acute lymphoblastic leukemia.

OBJECTIVES: Dysregulation of BCL-2 family members has been reported in acute lymphocytic leukemia (ALL), with various BH3-dependencies of the leukemic clone. We conducted a multicenter retrospective cohort of patients with relapsed/refractory B or T ALL, with ven-chemotherapy or ven-navitoclax combinations, to assess efficacy and safety. METHODS: Seventeen patients were included in the analysis, median age was 32 years, with 6 B-ALL and 11 T-ALL patients. Nine patients received venetoclax combined with chemotherapy, and 13 patients received venetoclax in combination with navitoclax, vincristine and asparaginase, of which 5 were already exposed to venetoclax in previous lines. RESULTS: ORR was 55% and 46% among the ven-chemotherapy and the ven-navitoclax-chemotherapy, respectively. Most of the responders proceeded to an allogenic bone marrow transplant in both cohorts. The most common adverse effects of the ven-navitoclax combination were infectious complications and hepatotoxicity. CONCLUSIONS: Our data demonstrated the possible efficacy of ven-chemotherapy and ven-navitoclax in r/r ALL with moderate toxicity.

Venetoclax in combination with FLAG-IDA-based protocol for patients with acute myeloid leukemia: a real-world analysis.

Venetoclax in combination with intensive therapies is explored in both the upfront and relapse/refractory (R/R) setting, and available data suggest that such regimens are effective albeit with added hematological and infectious toxicity. We conducted a multicenter retrospective cohort study of patients with acute myeloid leukemia (AML) treated with venetoclax in combination with FLAG-IDA protocol. Twenty-five patients were included in this analysis (median age 53.4 years). Most patients were treated for R/R AML (n = 24, 96%) with a median of one (range 0-3) previous lines of therapy and 44% of patients (n = 11) having prior allogeneic hematopoietic cell transplantation (HCT). Median follow-up was 10 (range, 4-26) months. Platelet and neutrophil recovery were observed at a median of 31 (95% CI 17.6-38.3) and 23 (95% CI 20-28) days, respectively. The most common adverse events were infectious (blood stream infections, 48% and invasive fungal infections, 32%). Thirty-day mortality was 12%. Composite complete remission (CRc) was 72% for the entire cohort and 91% in patients treated for post-HCT relapse. Incidences of relapse-free and overall survival at 12 months were 67% (95% CI 58-76%) and 50% (95% CI 31-69%), respectively. Real-world data show that the addition of venetoclax to FLAG-IDA protocol is effective in patients with high-risk AML, most notably in the post-HCT relapse setting. Prophylaxis and surveillance for infections are crucial.

Gilteritinib monotherapy for relapsed/refractory FLT3 mutated acute myeloid leukemia: a real-world, multi-center, matched analysis.

Patients with FLT3-mutated relapsed or refractory (R/R) acute myeloid leukemia (AML) have a dismal prognosis. Gilteritinib is a FLT3 tyrosine kinase inhibitor (TKI) recently approved for patients with R/R AML. We aimed to characterize real-world data regarding gilteritinib treatment in FLT3-mutated R/R AML and to compare outcomes with matched FLT3-mutated R/R AML patients treated with chemotherapy-based salvage regimens. Twenty-five patients from six academic centers were treated with gilteritinib for FLT3-mutated R/R AML. Eighty percent were treated with a prior intensive induction regimen and 40% of them received prior TKI therapy. Twelve patients (48%) achieved complete response (CR) with gilteritinib. The estimated median overall survival (OS) of the entire cohort was eight (CI 95% 0-16.2) months and was significantly higher in patients who achieved CR compared to those who did not (16.3 months, CI 95% 0-36.2 vs. 2.6 months, CI 95% 1.47-3.7; p value = 0.046). In a multivariate cox regression analysis, achievement of CR was the only predictor for longer OS (HR 0.33 95% CI 0.11-0.97, p = 0.044). Prior TKI exposure did not affect OS but was associated with better event-free survival (HR 0.15 95% CI 0.03-0.71, p = 0.016). An age and ELN-risk matched comparison between patients treated with gilteritinib and intensive salvage revealed similar response rates (50% in both groups); median OS was 9.6 months (CI 95% 2.3-16.8) vs. 7 months (CI 95% 5.1-8.9) in gilteritinib and matched controls, respectively (p = 0.869). In conclusion, in the real-world setting, gilteritinib is effective, including in heavily pre-treated, TKI exposed patients.

Cardiac Disorders Associated with Cellular Therapy and Novel Agents for Acute Leukemia.

BACKGROUND: Several novel strategies have emerged in the last decade as potential therapies for patients with chemorefractory lymphoproliferative diseases and acute leukemia. While these treatments include exciting drugs that dramatically change the landscape of treatment, the organ-toxicity profile associated with these therapies may be significant. This article focuses on cardiac disorders associated with chimeric antigen receptor T-cell (CAR-T) therapy, as well as with novel regimens for acute leukemia.

Evaluating outcomes of adult patients with acute lymphoblastic leukemia and lymphoblastic lymphoma treated on the GMALL 07/2003 protocol.

Chemotherapy-based approaches still constitute an essential feature in the treatment paradigm of adult acute lymphoblastic leukemia (ALL). The German Multicenter Study Group (GMALL) is a well-established protocol for ALL. In this study, we assessed our recent experience with the GMALL 07/2003 protocol reviewing all adult ALL patients who were treated with GMALL in three major centers in Israel during 2007-2020. The analysis comprised 127 patients with a median age of 41 years (range 17-83). Sixty-two were B-ALL (49%), 20 (16%) patients were Philadelphia chromosome positive ALL, and 45 (35%) were T-ALL. The 2-year and 5-year overall survival rates were 71% and 57%, respectively. The 2-year relapse rate was 30% with 2-year and 5-year leukemia-free survival rates of 59% and 50%, respectively. Adolescents and young adults experienced significantly longer overall survival (84 months versus 51 months; p=0.047) as well as leukemia-free survival compared with older patients (66 months versus 54 months, p=0.003; hazard ratio=0.39, 95% confidence interval, 0.19-0.79; p=0.009). T-ALL patients had longer survival compared to B-ALL patients while survival was comparable among Philadelphia chromosome positive patients and Philadelphia chromosome negative patients. An increased number of cytogenetic clones at diagnosis were tightly associated with adverse prognosis (15-month survival for ≥2 clones versus 81 months for normal karyotype; p=0.003). Positive measurable residual disease studies following consolidation were predictive for increased risk of relapse (64% versus 22%; p=0.003) and shorter leukemia-free survival (11 months versus 42 months; p=0.0003). While GMALL is an effective adult regimen, a substantial patient segment still experiences relapse.

Venetoclax combinations induce high response rates in newly diagnosed acute myeloid leukemia patients ineligible for intensive chemotherapy in routine practice.

Combinations of the BCL-2 inhibitor, venetoclax, with either hypomethylating agents (HMA) or low dose cytarabine (LDAC), have shown promising results in clinical trials of AML patients unfit for intensive therapy. We report on the efficacy and safety of venetoclax combinations in AML patients treated outside of clinical trials. Complete remission (CR) + CR with incomplete count recovery (CRi) were achieved in 61% of patients, with similar CR+CRi rates in with secondary AML, and in patients who were previously treated with HMA (61% and 43%, respectively). Relapse occurred in 25% of patients, with a median event-free survival (EFS) of 11.7 months (95% CI, 10.09-13.35) in responding patients. At a median follow up of 8.7 months, the median overall survival (OS) was 9.8 months (95% CI 6.42-13.3) in the entire cohort. In multivariate analysis adverse karyotype was the only negative predictor of CR/CRi (p = .03), while both ECOG performance status (PS) and adverse karyotype were significantly associated with shorter OS (p = .023 and .038, respectively). Median OS was higher in patients achieving CR/CRi and in patients proceeding to allogeneic stem cell transplantation (allo-SCT). Treatment was well tolerated, with side effects similar to those described in the randomized clinical trials. Tumor lysis syndrome (TLS) occurred in 12% of patients. Our data support the efficacy and safety of venetoclax combinations in newly diagnosed AML patients not eligible for intensive therapy. According to our data, secondary AML patients could benefit from venetoclax combinations similarly to de-novo AML patients, and allo-SCT could be offered to selected patients achieving CR/CRi.

Midostaurin in combination with chemotherapy is most effective in patients with acute myeloid leukemia presenting with high FLT3-ITD allelic ratio who proceed to allogeneic stem cell transplantation while in first complete remission.

OBJECTIVES: Midostaurin, a multikinase and FLT3 inhibitor, is the first non-chemotherapy agent approved and widely adopted for the treatment of FLT3-ITD acute myeloid leukemia (AML). Yet, its role in improving survival of patients referred to allogeneic stem cell transplantation (allo-SCT) in first complete remission (CR1) needs to be defined. METHODS: This multicenter study retrospectively evaluated the outcome of 119 FLT3-ITD AML patients [59 (49.6%) males and 60 females] intensively treated between 2015 and 2019 at five Israeli centers. In our cohort, allo-SCT in CR1 was widely implemented (47%) and patient stratification was based on the current allelic ratio (AR) cutoff of 0.5. RESULTS: Ninety-eight patients (82.3%) achieved CR1/CR with incomplete count recovery (CRi). Death during induction was reported in 7 (5.9%) patients. In multivariate analysis, midostaurin use and allo-SCT in CR1 were the most significant factors affecting overall survival (OS). Midostaurin incorporation in chemotherapy regimens significantly improved CR + CRi rates (P = .002), reduced relapse rates (P = .02), and was remarkably advantageous for high-AR patients (2-year OS 82%). In low-AR patients, the midostaurin effect was much less prominent. CONCLUSIONS: Our results demonstrate benefits of midostaurin incorporation in intensive chemotherapy regimens, particularly for high-AR AML patients to whom it should be offered along with allo-SCT in CR1.

Venetoclax is safe and efficacious in relapsed/refractory AML.

Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.

Midostaurin in combination with intensive chemotherapy is safe and associated with improved remission rates and higher transplantation rates in first remission-a multi-center historical control study.

The addition of midostaurin, a FLT3-inhibitor, to intensive chemotherapy (IC) was previously shown to improve outcome of younger patients with FLT3-mutated AML. The toxicity and efficacy of adding midostaurin to IC in patients not originally included in the RATIFY study or with intensified daunorubicin dosing are unknown. We conducted a retrospective, multi-center, historical-control study to characterize the safety and efficacy of adding midostaurin to IC in a "real-world" setting. Sixty-nine adult patients were included in the analysis (midostaurin n = 34, historical controls n = 35) with a mean follow-up of 18.4 (± 15) months. Median age of patients was 60 (range 26-82) years; 32% and 20% of patients were > 65 and 70 years, respectively. No differences in baseline characteristics were noted between the groups. Midostaurin was administered with 90 mg/m2 daunorubicin in 29% of patients; One-third of patients experienced dose reductions/interruptions during midostaurin therapy. Overall toxicity was comparable between the midostaurin and control groups.CR/CRi rates were higher in patients treated with midostaurin compared with controls (80% vs. 57%, p = 0.047) and significantly more patients in the midostaurin group were transplanted in first remission (95% vs. 68%, p = 0.04).Median OS and DFS were higher in the midostaurin vs. control group (not reached vs. 11 months (p = 0.085) and 13 vs. 6 months (p = 0.09), respectively). In our analysis, midostaurin was not associated with increased toxicity including in older patients, in those with secondary AML or when administered with intensified daunorubicin dosage. Higher remission rates in the midostaurin group and increased transplantation rates in first CR were associated with a trend towards better outcomes.

Sequential therapy for patients with primary refractory acute myeloid leukemia: a historical prospective analysis of the German and Israeli experience.

Primary refractory acute myeloid leukemia (AML) is associated with a dismal prognosis. The FLAMSA-reduced intensity conditioning protocol (total body irradiation or treosulfan-based) has been described as an effective approach in patients with refractory leukemia undergoing allogeneic hematopoietic cell transplantation. A modified protocol (without amsacrine) has also recently been used. We retrospectively analyzed the transplantation characteristics and outcomes of all consecutive patients between the years 2003 and 2017 (n=51) diagnosed with primary refractory AML who underwent transplantation at the University of Cologne and the Tel Aviv Medical Center. Median age was 54 years and median follow up was 37 months. Median time to neutrophil and platelet engraftment was 13 (range, 8-19) and 13 (range, 7-30) days, respectively. None of the patients had primary graft failure. Incidences of grade 2-4 and grade 3-4 acute graft-versus-host disease (GvHD), overall and moderate-severe chronic GvHD were 50% (95%CI: 41-67%), 12% (95%CI: 3-25%), 61% (95%CI: 47-72%), and 42% (95%CI: 34-51%), respectively. Anti-thymocyte globulin administration was associated with lower incidence of acute GvHD (HR: 0.327; P=0.02). Non-relapse mortality at three months and three years were 6% and 16%, respectively. Relapse incidences were 6% and 29%, respectively. Overall survival rates at three months, three and five years were 90%, 61%, and 53%, respectively. Chronic GvHD disease was associated with a decreased mortality rate (HR: 0.397; P=0.045). We conclude that sequential therapy in patients with primary refractory acute myeloid leukemia is safe and provides a remarkable anti-leukemic effect with durable survival and should be considered for every patient with primary refractory disease.

The management of hodgkin lymphomas in pregnancies.

Hodgkin lymphoma is the most common hematological malignancy in pregnancy. Its management presents several unique challenges, as decisions have to take both maternal and fetal risks into consideration. Using three hypothetical cases, we review current evidence and guidelines and suggest our recommendations for managing pregnant Hodgkin lymphoma patients. The opportunity for a prompt and accurate diagnosis should not be missed; this may be achieved by vigilance to suggestive symptoms, performance of biopsy which is not contraindicated during pregnancy and use of MRI for staging. Most patients should receive treatment with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) after completion of the first trimester. Bridging therapy with corticosteroids or vinblastine should be considered during the first trimester. In most cases of early disease, the addition of chemotherapy cycles to the treatment plan seems preferable to radiation therapy. Diagnosis at relapse raises unique dilemmas regarding second-line chemotherapeutic regimens and timing of consolidation with high-dose therapy and autologous stem cell transplantation, an approach which is contraindicated during pregnancy. Considering the excellent outcomes of Hodgkin lymphoma outside pregnancy, every effort should be made to strive toward a curative treatment plan while balancing the multiple issues and dilemmas which arise when treating this malignancy in a pregnant patient.

Regulation of the action of early mitotic inhibitor 1 on the anaphase-promoting complex/cyclosome by cyclin-dependent kinases.

Cell cycle regulation is characterized by alternating activities of cyclin-dependent kinases (CDKs) and of the ubiquitin ligase anaphase promoting complex/cyclosome (APC/C). During S-phase APC/C is inhibited by early mitotic inhibitor 1 (Emi1) to allow the accumulation of cyclins A and B and to prevent re-replication. Emi1 is degraded at prophase by a Plk1-dependent pathway. Recent studies in which the degradation pathway of Emi1 was disrupted have shown that APC/C is activated at mitotic entry despite stabilization of Emi1. These results suggested the possibility of additional mechanisms other than degradation of Emi1, which release APC/C from inhibition by Emi1 upon entry into mitosis. In this study we report one such mechanism, by which the ability of Emi1 to inhibit APC/C is negatively regulated by CDKs. We show that in Plk1-inhibited cells Emi1 is stabilized and phosphorylated, that Emi1 is phosphorylated by CDKs in mitotic but not S-phase cell extracts, and that Emi1 phosphorylation by mitotic cell extracts or purified CDKs markedly reduces the ability of Emi1 to bind and to inhibit APC/C. Finally, we show that the addition of extracts from S-phase cells to extracts from mitotic cells protects Emi1 from CDK-mediated inactivation.

Inhibitory factors associated with anaphase-promoting complex/cylosome in mitotic checkpoint.

The mitotic (or spindle assembly) checkpoint system ensures accurate chromosome segregation by preventing anaphase initiation until all chromosomes are correctly attached to the mitotic spindle. It affects the activity of the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets inhibitors of anaphase initiation for degradation. The mechanisms by which this system regulates APC/C remain obscure. Some models propose that the system promotes sequestration of the APC/C activator Cdc20 by binding to the checkpoint proteins Mad2 and BubR1. A different model suggests that a mitotic checkpoint complex (MCC) composed of BubR1, Bub3, Cdc20, and Mad2 inhibits APC/C in mitotic checkpoint [Sudakin V, Chan GKT, Yen TJ (2001) J Cell Biol 154:925-936]. We examined this problem by using extracts from nocodazole-arrested cells that reproduce some downstream events of the mitotic checkpoint system, such as lag kinetics of the degradation of APC/C substrate. Incubation of extracts with adenosine-5'-(gamma-thio)triphosphate (ATP[gammaS]) stabilized the checkpoint-arrested state, apparently by stable thiophosphorylation of some proteins. By immunoprecipitation of APC/C from stably checkpoint-arrested extracts, followed by elution with increased salt concentration, we isolated inhibitory factors associated with APC/C. A part of the inhibitory material consists of Cdc20 associated with BubR1 and Mad2, and is thus similar to MCC. Contrary to the original MCC hypothesis, we find that MCC disassembles upon exit from the mitotic checkpoint. Thus, the requirement of the mitotic checkpoint system for the binding of Mad2 and BubR1 to Cdc20 may be for the assembly of the inhibitory complex rather than for Cdc20 sequestration.

Role of Polo-like kinase in the degradation of early mitotic inhibitor 1, a regulator of the anaphase promoting complex/cyclosome.

Early mitotic inhibitor 1 (Emi1) inhibits the activity of the anaphase promoting complex/cyclosome (APC/C), which is a multisubunit ubiquitin ligase that targets mitotic regulators for degradation in exit from mitosis. Levels of Emi1 oscillate in the cell cycle: it accumulates in the S phase and is rapidly degraded in prometaphase. The degradation of Emi1 in early mitosis is necessary for the activation of APC/C in late mitosis. Previous studies have shown that Emi1 is targeted for degradation in mitosis by a Skp1-Cullin1 F-box protein (SCF) ubiquitin ligase complex that contains the F-box protein beta-TrCP. As with other substrates of SCF(beta-TrCP), the phosphorylation of Emi1 on a DSGxxS sequence is required for this process. However, the protein kinase(s) involved has not been identified. We find that Polo-like kinase 1 (Plk1), a protein kinase that accumulates in mitosis, markedly stimulates the ligation of Emi1 to ubiquitin by purified SCF(beta-TrCP). Cdk1-cyclin B, another major mitotic protein kinase, has no influence on this process by itself but stimulates the action of Plk1 at low, physiological concentrations. Plk1 phosphorylates serine residues in the DSGxxS sequence of Emi1, as suggested by the reduced phosphorylation of a derivative in which the two serines were mutated to nonphosphorylatable amino acids. Transfection with an small interfering RNA duplex directed against Plk1 caused the accumulation of Emi1 in mitotically arrested HeLa cells. It is suggested that phosphorylation of Emi1 by Plk1 is involved in its degradation in mitosis.