Fractionated vs single-dose gemtuzumab ozogamicin with determinants of benefit in older patients with AML: the UK NCRI AML18 trial.

Addition of gemtuzumab ozogamicin (GO) to induction chemotherapy improves outcomes in older patients with acute myeloid leukemia (AML), but it is uncertain whether a fractionated schedule provides additional benefit to a single dose. We randomized 852 older adults (median age, 68-years) with AML/high-risk myelodysplasia to GO on day 1 (GO1) or on days 1 and 4 (GO2) of course 1 induction. The median follow-up period was 50.2 months. Although complete remission (CR) rates after course 1 did not significantly differ between arms (GO2, 63%; GO1, 57%; odds ratio [OR], 0.78; P = .08), there were significantly more patients who achieved CR with a measurable residual disease (MRD)<0.1% (50% vs 41%; OR, 0.72; P = .027). This differential MRD reduction with GO2 varied across molecular subtypes, being greatest for IDH mutations. The 5-year overall survival (OS) was 29% for patients in the GO2 arm and 24% for those in the GO1 arm (hazard ratio [HR], 0.89; P = .14). In a sensitivity analysis excluding patients found to have adverse cytogenetics or TP53 mutations, the 5-year OS was 33% for GO2 and 26% for GO1 (HR, 0.83; P = .045). In total, 228 (27%) patients received an allogeneic transplantation in first remission. Posttransplant OS was superior in the GO2 arm (HR, 0.67; P = .033); furthermore, the survival advantage from GO2 in the sensitivity analysis was lost when data of patients were censored at transplantation. In conclusion, GO2 was associated with a greater reduction in MRD and improved survival in older adults with nonadverse risk genetics. This benefit from GO2 was dependent on allogeneic transplantation to translate the better leukemia clearance into improved survival. This trial was registered at www.isrctn.com as #ISRCTN 31682779.

Pediatric acute myeloid leukemia - novel approaches.

PURPOSE OF REVIEW: Despite higher remission and survival rates than observed in adults, children with acute myeloid leukemia (AML) still suffer unacceptably high rates of treatment failure and late toxicities. Ongoing work aims to improve these long-term outcomes through improvements in the utilization of current therapies, the incorporation of novel chemotherapy agents, and improved use of current or novel cellular and immunotherapeutic approaches. In this review, we highlight recent advances and contextualize them within this evolving landscape. RECENT FINDINGS: Novel agents such as the B-cell lymphoma 2 inhibitor venetoclax and the menin inhibitors have shown promising results with implications for large portions of the pediatric AML population. Older agents are being used in novel combinations (e.g. gemtuzumab ozogamicin) or are expanding into pediatrics after longer use in adults (e.g. Fms-like tyrosine kinase 3 inhibitors). Finally, immunotherapeutic approaches offer new options for patients with high-risk or relapsed disease. SUMMARY: Recent findings have altered the landscape of pediatric AML therapy with exciting immediate and long-term implications. Ongoing studies may soon define this as standard as well. After many years in which few new therapies have become available for children with AML, recent and upcoming advances may soon dramatically alter the therapeutic landscape.

Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL-MODULE phase I study.

We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3-mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8-21 can be safely combined with IC in newly diagnosed AML.

Preclinical Characterization of Catabolic Pathways and Metabolism of ABBV-011, a Novel Calicheamicin-Based SEZ6-Targeting Antibody-Drug Conjugate.

Antibody-drug conjugates (ADC) have gained momentum for treatment of cancers, with 14 ADCs currently approved for commercial use worldwide. Calicheamicin is one of the payloads contributing to this trend, being used for both gemtuzumab ozogamicin (GO; trade name: Mylotarg) and inotuzumab ozogamicin (IO; trade name: Besponsa). Here we discuss the catabolic pathway and metabolism of ABBV-011, a novel SEZ6-targeted, calicheamicin-based ADC being investigated for the treatment of small cell lung cancer (SCLC). Specifically, our investigation has found that disulfide bond cleavage in N-acetyl-γ-calicheamicin payload is a key liability that potentially impacts overall stability of the ADC. To our knowledge, there have been no reported observations of disulfide bond cleavage of calicheamicin ADCs. ABBV-011 utilizes a novel linker structure, leading to a distinct metabolic profile when compared with GO and IO. Despite this difference in linker structures, we propose that this liability may also be relevant for other calicheamicin ADCs. Multiple data sets supporting our investigation were acquired as part of the preclinical development of ABBV-011 and demonstrate the utility of in vitro experiments to characterize potential ADC candidates prior to clinical trials. SIGNIFICANCE STATEMENT: Several in vitro and in vivo stability studies of ABBV-011, a calicheamicin-based antibody-drug conjugate (ADC), identified circulating metabolites and catabolites and suggested that disulfide cleavage may be a key liability for the conjugated linker-payload. These observations may be relevant to other disulfide-linked ADCs such as gemtuzumab ozogamicin (Mylotarg) and inotuzumab ozogamicin (Besponsa), both of which have reported similar half-lives that possibly indicate instability.

Extramedullary infiltration in pediatric acute myeloid leukemia: Results from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative.

BACKGROUND: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on patients with EMI. METHODS: We retrieved the clinical data of 713 pediatric patients with AML from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, and analyzed the clinical and prognostic characteristics of patients with EMI at diagnosis and relapse. RESULTS: A total of 123 patients were identified to have EMI at diagnosis and 64 presented with EMI at relapse. The presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in patients with EMI at relapse. Additionally, patients with EMI at diagnosis had a reduced incidence of FLT3 ITD-/NPM1+, whereas those with EMI at relapse displayed a lower frequency of FLT3 ITD+. Patients with EMI at diagnosis exhibited a lower complete remission (CR) rate at the end of Induction Course 1 and higher relapse incidence. Importantly, EMI at diagnosis independently predicted both shorter event-free survival (EFS) and overall survival (OS). Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma (MS)/no central nervous system (CNS) exhibited poorer OS compared to those with CNS/no MS. Furthermore, regarding patients with EMI at diagnosis, SCT failed to improve the survival, whereas GO treatment potentially enhanced OS. CONCLUSION: EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis.

Therapeutic plasma exchange as an intervention for gemtuzumab ozogamicin impaired hemoglobin scavenging: A case and systematic review.

Gemtuzumab ozogamicin (GO) is a CD33 monoclonal antibody-drug conjugate currently in use to treat myeloid malignancies. A unique adverse effect of this medication is destruction of CD33 positive macrophages resulting in reduced clearance of free hemoglobin leading to grossly red plasma. This build-up of free hemoglobin can potentially lead to end organ damage and prevent performance of clinically necessary laboratory evaluation. We present a case of a pediatric patient who developed this adverse effect and was successfully treated with therapeutic plasma exchange (TPE). We also present results from a systematic review of the medical literature and share data from a query of the United States Food and Drug Administration (FDA) Adverse Event Reporting system for GO-related hemoglobin scavenging impairment. Among reported cases, patients undergoing TPE and those receiving steroids had improved outcomes. Practitioners should be aware of this rare drug side-effect and the potential utility of TPE for these patients.

How I diagnose and treat NPM1-mutated AML.

Mutations of the nucleophosmin (NPM1) gene, encoding for a nucleolar multifunctional protein, occur in approximately one-third of adult acute myeloid leukemia (AML). NPM1-mutated AML exhibits unique molecular, pathological, and clinical features, which led to its recognition as distinct entity in the 2017 World Health Organization (WHO) classification of myeloid neoplasms. Although WHO criteria for the diagnosis of NPM1-mutated AML are well established, its distinction from other AML entities may be difficult. Moreover, the percentage of blasts required to diagnose NPM1-mutated AML remains controversial. According to the European LeukemiaNet (ELN), determining the mutational status of NPM1 (together with FLT3) is mandatory for accurate relapse-risk assessment. NPM1 mutations are ideal targets for measurable residual disease (MRD) monitoring, since they are AML specific, frequent, very stable at relapse, and do not drive clonal hematopoiesis of undetermined significance. MRD monitoring by quantitative polymerase chain reaction of NPM1-mutant transcripts, possibly combined with ELN genetic-based risk stratification, can guide therapeutic decisions after remission. Furthermore, immunohistochemistry can be very useful in selected situations, such as diagnosis of NPM1-mutated myeloid sarcoma. Herein, we present 4 illustrative cases of NPM1-mutated AML that address important issues surrounding the biology, diagnosis, and therapy of this common form of leukemia.

Emerging therapies for inv(16) AML.

The core binding factor composed of CBFß and RUNX subunits plays a critical role in most hematopoietic lineages and is deregulated in acute myeloid leukemia (AML). The fusion oncogene CBFß-SMMHC expressed in AML with the chromosome inversion inv(16)(p13q22) acts as a driver oncogene in hematopoietic stem cells and induces AML. This review focuses on novel insights regarding the molecular mechanisms involved in CBFß-SMMHC-driven leukemogenesis and recent advances in therapeutic approaches to target CBFß-SMMHC in inv(16) AML.

The clinical impact of the molecular landscape of acute myeloid leukemia.

Research into the underlying pathogenic mechanisms of acute myeloid leukemia (AML) has led to remarkable advances in our understanding of the disease. Mutations now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, particularly the large subset of cytogenetically normal AML. Despite the progress in unraveling the tumor genome, only a small number of recurrent mutations have been incorporated into risk-stratification schemes and have been proven to be clinically relevant, targetable lesions. The current World Health Organization Classification of myeloid neoplasms and leukemia includes eight AML categories defined by recurrent genetic abnormalities as well as three categories defined by gene mutations. We here discuss the utility of molecular markers in AML in prognostication and treatment decision-making. New therapies based on targetable markers include IDH inhibitors (ivosidenib, enasidenib), venetoclax-based therapy, FLT3 inhibitors (midostaurin, gilteritinib, and quizartinib), gemtuzumab ozogamicin, magrolimab and menin inhibitors.

Impact of gemtuzumab ozogamicin consolidation on hematopoietic stem cells (HSCs) mobilization in AML: analysis of 20 patients.

Gemtuzumab ozogamicin (GO), is an anti-CD33 monoclonal antibody, approved for AML CD33 + , those patients with low and intermediate-risk who obtain a complete response may also be candidated for consolidation with autologous stem cell transplantation (ASCT). However, there are scant data on the mobilization of hemopoietic stem cells (HSC) after fractionated GO. We retrospectively studied data from five Italian centers and identified 20 patients (median age 54 years, range 29-69, 15 female, 15 NPM1mutated) that attempted HSC mobilization after fractionated doses of GO + "7 + 3" regimen and 1-2 cycles of consolidation (GO + HDAC + daunorubicin). After chemotherapy and standard G-CSF, 11/20 patients (55%) reached the threshold of 20 CD34 + /µL, and HSC were successfully harvested, while 9 patients (45%) failed. The median day of apheresis was Day + 26 from the start of chemotherapy (range 22-39 days). In good mobilizer patients, the median circulating CD34 + cells were 35.9 cells/µL and the median CD34 + harvested were 4.65 × 106/kg of patients' body weight. With a median follow-up of 12.7 months, at 24 months from the first diagnosis, 93.3% of all 20 patients were alive and the median overall survival was 25 months. The 2-year RFS rate from the timepoint of the first CR was 72.6%, while the median RFS was not reached. However, only five patients underwent ASCT and achieved full engraftment.In conclusion, in our cohort of patients, the addition of GO reduced HSC mobilization and harvesting, which was reached in about 55% of patients. Nevertheless, further studies are warranted to evaluate the effects of fractionated doses of GO on HSC mobilization and ASCT outcomes.

Children's Oncology Group's 2023 blueprint for research: Myeloid neoplasms.

During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.

Gemtuzumab Ozogamicin Monotherapy Is a Well-tolerated Palliative Chemotherapy Option in Pediatric Multiply Relapsed Acute Myeloid Leukemia: A Multicenter Case Series and Review of the Literature.

Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody that is Food and Drug Administration approved in upfront acute myeloid leukemia (AML) for patients over 1-month old, and for relapsed or refractory AML in patients over 2 years old. GO is now integrated in upfront pediatric AML treatment, and often in CD33+ relapse treatment combined with intensive conventional chemotherapy. Although GO was initially tested as a monotherapeutic agent in relapsed or refractory AML, there are few data in pediatric patients supporting this indication. In this review, we report 4 cases of multiply relapsed pediatric AML patients who were treated with GO monotherapy with palliative intent. Three of 4 patients obtained a complete response with GO reinduction, either as monotherapy or paired with conventional chemotherapy. Three patients remained in remission respectively for 5, 17, and 9 months with GO continuation monotherapy. The literature was reviewed regarding the use of GO in pediatric AML relapse settings.

Evaluation of the efficacy of ursodiol for prevention of hepatotoxicity in patients receiving gemtuzumab ozogamicin and inotuzumab ozogamicin.

Gemtuzumab ozogamicin (GO) and inotuzumab ozogamicin (InO) are indicated for newly diagnosed or relapsed/refractory CD33-positive acute myeloid leukemia and relapsed/refractory B-cell precursor acute lymphoblastic leukemia respectively. Patients undergoing therapy with these agents are at increased risk for hepatotoxicity. Forty-nine patients received either GO or InO with concomitant ursodiol (n=14) or no ursodiol (n=35) for hepatotoxicity prophylaxis. Hepatotoxicity occurred in 2 (14%) patients in the ursodiol group compared to 15 (43%) patients in the no ursodiol group (p=0.10). Median days (17 versus 11; p=0.66) and doses (4 versus 2; p=0.28) to development of hepatotoxicity were higher in the ursodiol versus no ursodiol group. After adjusting for concomitant hepatotoxic medications and prior chemotherapy, ursodiol did not significantly reduce the incidence of hepatotoxicity. Ursodiol prophylaxis was associated with a similar incidence of hepatotoxicity compared to no ursodiol, but may delay the time to occurrence.

Cost-effectiveness analysis of gemtuzumab ozogamicin for the treatment of de novo CD33-positive Acute Myeloid Leukaemia (AML) in Italy.

BACKGROUND: Based on the results from the ALFA-0701 study, gemtuzumab ozogamicin (GO) has been approved by the European Medicine Agency and by the Italian Drug Agency for the first line treatment of de novo acute-myeloid leukemia (AML). In this analysis, we assessed the cost-effectiveness of GO in combination with daunorubicin and cytarabine (DA), vs DA alone, adopting the perspective of the Italian National Health Service. METHODS: For this analysis, a cohort state transition model was developed. The model was designed to capture health states and events that occur throughout the entire disease course and that impact costs and outcomes. The ALFA-0701 study was the main source of clinical data for this analysis. In the model, patients had the same baseline characteristics and experienced the same clinical improvements as in the ALFA-0701 study. Economic data (resource consumption and unit costs) were adapted to reflect expenditure for the Italian National Health Service. Utilities per health state and disutilities due to adverse events were based on the literature and on the general population for those functionally cured. A lifetime horizon was adopted, with both costs and outcome being discounted of 3.0%, annually. Deterministic and probabilistic sensitivity analyses were conducted to assess the robustness of results. RESULTS: In the base case (lifetime horizon; primary source of data: study ALFA-0701; perspective: Italian National Health Service; discount rate on costs and outcomes: 3.0%), GO + DA was more effective DA both in terms of life-year (LY) survival (6.42 LY vs 5.75 LY, respectively) and quality-of-life adjusted survival (4.69 QALY vs 4.19 QALY, respectively). The overall costs were almost similar in the two groups (slightly lower with GO + DA than with DA; €162,424 and €162,708, respectively). The use of GO increased the costs of drug therapy but saved costs of relapse and costs associated with transplantation (HSCT). CONCLUSIONS: If results of the ALFA-0701 study are applied to the Italian healthcare environment, then gemtuzumab ozogamicin, in combination with daunorubicin and cytarabine, would clinical outcomes and reduce lifetime costs, compared with daunorubicin and cytarabine alone for the first line treatment of de novo AML. TRIAL REGISTRATION: Not applicable.

Molecular Advances in Sinusoidal Obstruction Syndrome/Veno-Occlusive Disease.

Sinusoidal obstruction syndrome/veno-occlusive disease (SOS/VOD) detected in the liver has been considered a severe complication of hematopoietic stem cell transplantation (HSCT). SOS/VOD is characterized by hepatomegaly, right upper quadrant pain, jaundice, and ascites. The severe forms of the disease may result in multi-organ dysfunction (MOD) with a high mortality rate (>80%). The development of SOS/VOD can be rapid and unpredictable. Therefore, early identification and severity assessment is crucial in facilitating prompt diagnosis and timely treatment. Effective treatment and potential prophylaxis with defibrotide highlight the need for characterizing a sub-group of patients at high risk for SOS/VOD. Moreover, antibodies that are conjugated with calicheamicin, gemtuzumab, and inotuzumab ozogamicin, have led to renewed interest in this syndrome. Evaluation and management of serious adverse events associated with gemtuzumab and inotuzumab ozogamicin are recommended. We review hepatic-, transplant- and patient-related risk factors, criteria for diagnosis and grading classification, and SOS/VOD potential biomarkers. Furthermore, we examine pathogenesis, clinical presentation, diagnostic criteria, risk factors, prophylaxis, and treatment of SOS/VOD occurring post HSCT. Moreover, we aim to provide an up-to-date summary of molecular advances in the diagnosis and management of SOS/VOD. We performed a comprehensive review of the literature and examined the recently available data, mostly using the PubMed and Medline search engines for original articles published over the last decade. In the era of precision medicine, our review provides up-to-date knowledge of genetic or sera markers for SOS/VOD with the goal of identifying a subset of high-risk patients.

The Use of Gemtuzumab Ozogamicin as Salvage Therapy in Patients with Acute Myeloid Leukemia: A Monocentric Real-World Experience.

Background and Objectives: Relapsed or refractory acute myeloid leukemia (r/r AML) is a disease with a poor prognosis. Limited treatment options are available in r/r AML. Here, we administered gemtuzumab ozogamicin (GO) as salvage therapy in twenty-four patients with r/r AML. The aim of the study was to determine the role of GO in r/r AML in real life. Material and Methods: This retrospective observational study recruited 24 adult patients with diagnosed r/r AML from 2018 to 2022. Twenty-four patients with r/r AML were treated with GO. GO treatment was used as monotherapy in 23 patients and in combination with cytarabine in 1 patient. At the time of diagnosis, the risk status of all patients was determined as favorable, intermediate, or adverse according to the 2017 ELN AML guidelines. Results: The median follow-up was 44.3 (13-144) months. Fifteen (62.5%) of the twenty-four patients were in the intermediate-risk cytogenetics group and nine (37.5%) were in the favorable cytogenetics group. The most common adverse events included nausea/vomiting in 79.17% (n = 19) of patients, headache in 62.50% (n = 15), elevated LFTs in 37.50% (n = 9), febrile neutropenia in 25% (n = 6), and bleeding in 25% (n = 6). The most common cause of death was infection. The most common causes of mortality were septic shock, accounting for 33.3% (n = 8) of deaths, and opportunistic lung infection, accounting for 12.5% (n = 3) of deaths. Acute infusion-related toxicities associated with GO were usually transient and, in most cases, responded to the standard of care treatment. After treatment with GO, 16.6% (n = 4) of patients achieved MLFS and 37.5% (n = 9) achieved CR. The overall response rate was 54.1%. The median overall survival time of the patients was 44 months (37.8-50.2 months). Disease-free survival was 22 months (0-48.6 months). The 5-year survival rate was 33%. Conclusions: A low dose of GO improved the overall survival and disease-free survival in r/r AML patients. GO treatment had a positive safety profile in terms of toxicity.

CD33-directed immunotherapy with third-generation chimeric antigen receptor T cells and gemtuzumab ozogamicin in intact and CD33-edited acute myeloid leukemia and hematopoietic stem and progenitor cells.

Immunotherapies, such as chimeric antigen receptor (CAR) modified T cells and antibody-drug conjugates (ADCs), have revolutionized the treatment of cancer, especially of lymphoid malignancies. The application of targeted immunotherapy to patients with acute myeloid leukemia (AML) has been limited in particular by the lack of a tumor-specific target antigen. Gemtuzumab ozogamicin (GO), an ADC targeting CD33, is the only approved immunotherapeutic agent in AML. In our study, we introduce a CD33-directed third-generation CAR T-cell product (3G.CAR33-T) for the treatment of patients with AML. 3G.CAR33-T cells could be expanded up to the end-of-culture, that is, 17 days after transduction, and displayed significant cytokine secretion and robust cytotoxic activity when incubated with CD33-positive cells including cell lines, drug-resistant cells, primary blasts as well as normal hematopoietic stem and progenitor cells (HSPCs). When compared to second-generation CAR33-T cells, 3G.CAR33-T cells exhibited higher viability, increased proliferation and stronger cytotoxicity. Also, GO exerted strong antileukemia activity against CD33-positive AML cells. Upon genomic deletion of CD33 in HSPCs, 3G.CAR33-T cells and GO preferentially killed wildtype leukemia cells, while sparing CD33-deficient HSPCs. Our data provide evidence for the applicability of CD33-targeted immunotherapies in AML and its potential implementation in CD33 genome-edited stem cell transplantation approaches.

The cure of leukemia through the optimist's prism.

Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate for core-binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5-year survival rate for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third-generation BCR-ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.

Single-dose (4.5 mg/m2 ) gemtuzumab ozogamicin in combination with fludarabine, cytarabine and anthracycline as reinduction therapy in relapsed or refractory paediatric acute myeloid leukaemia.

Despite major therapeutic improvements, children with relapsed/refractory Acute Myeloid Leukaemia still have poor outcomes and overall survival does not exceed 40%. New treatments are required to improve their outcome; Gemtuzumab ozogamicin (GO), an anti-CD33 immunoconjugate antibody, is a potent cytotoxic agent whose efficacy has been demonstrated mainly in adults. The main objective of this retrospective multicentre study was to assess the outcome of children treated, between February 2008 and August 2019, with GO at a single 4.5 mg/m2 dose, in combination with Fludarabine, Cytarabine and antssshracyclines, in context of a first relapse (n = 26) or refractory disease (n = 3). The remission rate was 83% (24/29 children) and 20 children (69%) were allografted. With a median follow-up of 1.2 years (range: 0.1-8), the overall survival was 49% (CI95% = 33; 72). Most common adverse event was febrile neutropenia with microbiological identification in 55% of cases. Veno-occlusive disease occurred in 6 patients (21%), of which 5 subvened after bone marrow transplantation, and resolved within 2-32 days (median 10.5 days). Administration of GO in combination with FLA-anthracyclines chemotherapy appears to be a good reinduction regimen for relapsed or refractory AML with a good safety profile. These results warrant larger prospective study.

De Novo design of a humanized antiCD33 antibody-oridonin conjugate for acute myeloid leukemia therapy.

Acute myeloid leukemia (AML) is the most common blood cancer in adults. Patients' 5-year overall survival is less than 30% thus having a poor prognosis. To date, the development of novel target therapies is still necessary to ameliorate patients' survival. Antibody-drug conjugates (ADCs) represent a promising class of drugs for the treatment of AML. CD33 is highly expressed on AML cells, and the FDA-approved CD33-targeted ADC drug-gemtuzumab ozogamicin (GO) has proved the feasibility of CD33-targeted ADC drug design. In this study, we constructed a novel CD33-targeted ADC drug composed of a humanized anti-CD33 antibody and oridonin as a payload with a cleaved chemical linker. Oridonin is a natural product that has great cancer therapy potential while its poor bioavailability and targeting ability limited its clinical use. Herein, we demonstrated that antiCD33-oridonin specifically delivered oridonin in AML cells improved AML cells killing ability of oridonin. Meanwhile, it did not show any non-specific toxicity on CD33 negative cells. In summary, we developed a novel AML targeting ADC with clinical application potential, and therefore provided a new solution for the druggability improvement of oridonin.