Consolidation Courses Research Articles

Long-term survival can be achieved in a significant fraction of older patients with core binding factor acute myeloid leukemia treated with intensive chemotherapy.

Acute Myeloid Leukemia is mainly a disease of the elderly: however, the knowledge on the outcomes of treatment in core binding factor AML (CBFAML) in older population, is limited. We retrospectively collected data on 229 patients with CBF- AML followed long-term in the last two decades. A 5-year overall survival (OS) of 44.2% (95%CI, 39.9-47.5) and a 5-year event - free survival (EFS) of 32.9% (95%CI, 25.5-40.1) was observed. In a subgroup of >70-year patients who completed intensive therapy (induction + >3 courses of consolidation including autologous stem cell transplant: 10 patients) the median EFS was 11.8 months (95%CI, 9.4 - 15.2) and OS was 40.0% (95%CI, 36.4 - 44.1) at 5yr. In univariate analysis, age >70 (hazard ratio (HR) 1.78, [95%CI, 1.15 - 2.54], p=.008), failure to achieve remission following induction (HR, 8.96 [95%CI, 5.5 - 13.8], p=<.0001), no consolidation therapy (HR, 0.75 [95%CI, 0.47 - 1.84], p=.04) and less than 3 cycles of consolidation (HR, 1.48 [95%CI, 0.75 - 3.2], p=.0004), predicted poorer EFS. Our study shows that intensive therapy, in selected older CBF-AML patients, leads to longer survival. Achieving a CR seems to be the most important first step and at least 3 cycles of consolidation, an important second one. The analysis suggests that these patients should not be excluded from studies with intensive therapies.

Medium-cumulative dose of cytarabine in consolidation therapy shows the greatest benefit in AML patients

BackgroundHigh-dose cytarabine (HDAC) is commonly used for consolidation therapy in young acute myeloid leukemia (AML) patients, but the dosage of cytarabine is still controversial in the clinic due to its obvious post-chemotherapy adverse effects. The aim of this study was to contrast the efficacy in different dose groups of cytarabine after consolidation therapy in Chinese AML patients.MethodsAML patients treated with cytarabine consolidation at Qilu Hospital, Shandong University from January 2010 to September 2022 were retrospectively analyzed, from which 346 AML patients with relatively complete follow-up data were selected for this study. We compared the patients’ overall survival (OS) rate, relapse-free survival (RFS) rate, and hematologic adverse events in terms of their general characteristics, cytarabine consolidation therapy dose, consolidation course, 2022 European Leukemia Net (ELN) risk stratification, and transplantation.ResultsIn AML patients under 60 years of age, the 5-year RFS rate with high-dose cytarabine consolidation therapy was superior to that of small-dose cytarabine (P = 0.024), while the 5-year RFS rate was comparable in the high-dose and intermediate-dose groups, and there was no obvious difference among the three groups in the 5-year OS rate (P > 0.05). OS and RFS of those given more than 3 courses of cytarabine consolidation therapy were better than those in the 1–2 courses group (P = 0.060, P = 0.040). OS and RFS were better in patients with cumulative dose of cytarabine ≥ 36g than in patients with cumulative dose < 36g (P < 0.05), but cumulative dose ≥ 54g was comparable in OS and RFS with ≥ 36–< 54g group (P > 0.05). There was no significant difference in hematologic adverse effects among the three treatment groups.In the latest ELN risk stratification favorable-risk group, the cumulative dose of cytarabine ≥ 36g had a better 5-year RFS rate than the < 36g group (P = 0.038), and in the intermediate-risk group the 5-year OS rate and RFS rate were better in the ≥ 36g group than the < 36g group (P = 0.012, 0.025). In addition, the prognosis of transplanted patients was better than that of non-transplanted patients, whereas in non-transplanted patients, consolidation therapy with ≥ 36g cytarabine can effectively improve outcomes. Multivariate analysis indicated that age, fibrinogen (FIB) and the cumulative dose of cytarabine of ≥ 36–< 54g were predictors of OS, while age, white blood cell (WBC) and HDAC were predictors of RFS.ConclusionThe results of the study showed that consolidation therapy with cytarabine up to a cumulative dose of ≥ 36–< 54g in AML patients who did not undergo transplantation significantly improved patient prognosis. In the latest ELN risk stratification, cumulative doses of cytarabine ≥ 36g had a better prognosis in favorable and intermediate-risk patients.

Effectiveness of the total neo-adjuvant therapy in rectal cancer treatment. Results of the randomized trial

To ASSESS effectiveness of total neoadjuvant therapy (TNT) for patients with rectal carcinoma.Patients and methods: patients with histologically proven rectal carcinoma were randomly assigned in two groups: in the TNT group after the neoadjuvant CRT 50-54 Gy with capecitabine 3 consolidation courses of XELOX were done, in the CTR group - conventional neoadjuvant CRT 50-54 Gy with capecitabine. At the end of the treatment, effect was assessed by MRI using the mrTRG scale. For patients with a full clinical response, who have refused surgery, «watch&amp;wait» approach was used. For other patients effect of neoadjuvant therapy was evaluated by pathomorphological study using the Ryan scale. The primary endpoint of study was the complete response rate (clinical and pathomorphological). Secondary endpoints of study: frequency and structure of intraoperative and postoperative complications, the rate of grade 3–4 toxicity of radiotherapy and chemotherapy, R0-resection rates. The study was registered on the ClinicalTrials.gov (NCT04747951)RESULTS: between October 2020 and October 2023, 183 patients were enrolled in the randomized study: 91 patients in the TNT group and 92 patients in the CRT group. At median (Q1, Q3) follow-up period 24 (14; 28) months, complete clinical response observed in 23% (14/60) of TNT patients and in 7% (5/71) of THL patients (p=0.008). The pCR rate was 20% (9/45) in the TNT group and 8% (5/66) in the CRT group (p=0.05). The frequency of development of toxic reactions of degree 3-4, the frequency and structure of intra- and postoperative complications, as well as the frequency of R0 resection of the group did not differ statistically significantly. The total rate of Grade 3–4 toxicity, rate of intra- and postoperative complications, R0-resections rate did not differ between two groups.CONCLUSION: preliminary results of a randomized study demonstrated the effectiveness and safety of total neo-adjuvant therapy in rectal cancer treatment.

Clinical presentation and outcome of invasive mould disease in paediatric patients with acute lymphoblastic leukaemia

BackgroundChildhood acute lymphoblastic leukaemia (ALL) cure rates have improved, but invasive mould disease (IMD) remains a life-threatening complication. Here, we evaluate the epidemiology, clinical presentation, treatment and outcome of IMD in paediatric patients with ALL. MethodsPatients (1–18 years) treated according to the Dutch Childhood Oncology Group (DCOG) ALL-11 protocol from 2012–2021 were analysed for probable and proven IMD. Data was extracted from the Dutch national registry and the electronic health care system. ResultsAmong 643 patients with ALL, 47 (7.3%) were diagnosed with a probable (n = 29) or proven (n = 18) IMD. Aspergillosis was diagnosed in 42 (89%) patients. Forty-one episodes (87%) occurred during the induction (n = 20) and first consolidation (n = 21) course. The median age at ALL diagnosis was 5 years [IQR 3–10] in the overall group versus 14 years [IQR 7–16] in the IMD group. Two-third of the patients did not receive mould-active prophylaxis. The most prevalent clinical symptoms at presentation were persistent fever and respiratory symptoms. The lungs were the most common site of infection with involvement in 44 (94%) patients, followed by the CNS in 16 (34%) patients. The 6-week and 12-week mortality rate after IMD diagnosis was 10.6% and 14.9%, respectively. Discussion and conclusionIn our paediatric cohort a notable incidence of probable and proven IMD was observed during the early stages of treatment. Remarkable is the high frequency of CNS involvement. These findings highlight the importance of effective prophylactic strategies and warrant early brain imaging.

Micafungin twice-a-week for prophylaxis of invasive Aspergillus infections in children with acute lymphoblastic leukaemia: A controlled cohort study

ObjectivesInvasive Aspergillus infections during the early phase of childhood acute lymphoblastic leukemia (ALL) treatment come with morbidity and mortality. The interaction with vincristine hampers first-line azole prophylaxis. We describe the efficacy of an alternative twice-a-week micafungin regimen for Aspergillus prophylaxis. MethodsNewly diagnosed paediatric patients with ALL treated according to the ALL-11 protocol received micafungin twice-a-week (9 mg/kg/dose [max. 300 mg]) during the induction course (first 35 days of treatment) as part of routine care. A historical control cohort without Aspergillus prophylaxis was used. During the first consolidation course (day 36-79), standard itraconazole prophylaxis was used in both groups.The percentage of proven/probable Aspergillus infections during the induction/first consolidation course was compared between the cohorts. The cumulative incidence of proven/probable Aspergillus infections was estimated using a competing risk model. For safety evaluation, liver laboratory chemistry values were analysed. ResultsA total of 169 and 643 paediatric patients with ALL were treated in the micafungin cohort (median age: 4 years [range 1-17]) and historical cohort (median age: 5 years [range 1-17]). The percentage of proven/probable Aspergillus infections was 1·2% (2/169) in the micafungin cohort versus 5·8% (37/643) in the historical cohort (p=0.013; Fisher's exact test). The differences in estimated cumulative incidence were assessed (p=0·014; Gray's test). Although significantly higher ALT/AST values were reported in the micafungin cohort, no clinically relevant side effects were observed. ConclusionsTwice-a-week micafungin prophylaxis during the induction course significantly reduced the occurrence of proven/probable Aspergillus infections in the early phase of childhood ALL treatment.

Frontline Aspacytarabine with Venetoclax for Older/Unfit Patients with Acute Myeloid Leukemia: Preliminary Results of a Phase 1 Study

Introduction: Venetoclax (VEN), a selective BCL2 inhibitor, in combination with hypomethylating agents (HMA) or low-dose cytarabine is currently the standard of care for first line treatment of older/unfit patients with acute myeloid leukemia (AML). This, however, requires indefinite cycles of treatment and results in prolonged cytopenias. Aspacytarabine (ASPA, formerly BST-236), a novel pyrimidine antagonist, is a cytarabine prodrug designed to enable high cytarabine dose treatment with reduced systemic toxicity, that was previously proven safe and effective for the treatment of AML in adults unfit for intensive chemotherapy. Given excellent outcomes with intensive chemotherapy with VEN, we hypothesized that higher cytarabine dose using ASPA and VEN followed by a limited consolidation with ASPA may provide superior outcomes than the current standard. Aims: To assess the safety and efficacy of VEN plus ASPA induction treatment regimen in older/unfit AML patients followed by limited consolidation course(s) with ASPA alone. Methods: A phase I/II dose escalation and expansion study using 1 or 2 induction courses with intravenous (IV) ASPA 2.3 or 4.5 g/m 2 daily for 6 consecutive days plus VEN at a dose of 200 mg or 400 mg for 7 days without azole antifungals. Followed by up to 3 consolidation courses with single agent ASPA 2.3/4.5 g/m 2/day for 6 days, in patients with newly diagnosed AML unfit for intensive chemotherapy. Patients with secondary AML are allowed. MRD was evaluated centrally by flow cytometry at Dr. Wood's laboratory, with a sensitivity of 0.1%. Results: Two cohorts are completed with 7 patients enrolled. Table 1 details the cohort treatment. Baseline characteristics and outcome are provided in Table 2. To date, the combination is well-tolerated. As expected, all patients had cytopenia (16% grade 4, and 84% grade 3 and lower), following the induction treatment and non-hematological grade ≥3 reported in more than 1 patient were pneumonia and sepsis both reported in 2 patients). One death occurred in cohort 1: an 80 year-old patient with a cardiac medical history died at home on day 27 of induction, prior to bone marrow analysis, but with full count recovery; death was deemed unrelated to study treatment. One 79-year-old patient from cohort 2 discontinued the study following the 1 st consolidation, while in CR MRD-, due to prolonged laryngitis. In the first, cohort, 1 patient attained a CR MRD- after 1 induction course, and this response is still maintained 6 months from study entry (after 3 consolidation courses of ASPA monotherapy). In the second cohort, all 3 patients' disease entered a CR after 1 course of ASPA and VEN Two achieved CR MRD-, and the 3 rd patient is currently receiving a second induction course, as per protocol. All responding patients had a full count recovery within 35 days and disease continues to be in CR. Conclusions: The combination induction regimen of ASPA and VEN followed by consolidation with ASPA alone, is a promising therapy. The regimen is tolerable, and all patients in cohort 2 have attained a CR with 2/3 MRDneg and the third with treatment ongoing. This treatment may overcome the limitations of prolonged cytopenia and indefinite therapy with HMA/VEN along with a high CR rate. This study is ongoing, and updates will be provided at the conference.

Final Results of the AIEOP (Associazione Italiana Ematologia/Oncologia Pediatrica) AML 2013 Prospective Randomized Trial in Childhood Acute Myeloid Leukemia (AML)

Background: Treatment of children with newly diagnosed AML is based on induction therapy, followed by consolidation approaches which differ according to the group of risk patients (pts) are allocated to. In this respect, most treatment protocols stratify pts into 3 risk groups, namely standard (SR), intermediate (IR) and high-risk (HR), mainly based on the molecular/cytogenetic characterization and values of measurable residual disease (MRD) at the end of induction therapy. We report the outcomes of 371 pts with de novo AML other than acute promyelocytic leukemia (aged 0-18) enrolled in the randomized trial AIEOP AML 2013 (EudraCT:2014-000652-28). Patients and methods: pts were diagnosed and enrolled in the trial from 06/2015 to 06/2022 at 33 Centers affiliated to the AIEOP group. Main pt characteristics and criteria used for stratification are shown in Table 1. A marker of recurrent molecular lesions was detected at diagnosis for 247 cases out of the 371 enrolled (67%). Monitoring of flow-cytometry MRD at the end of the 1 st and 2 nd induction course was centrally performed in all pts but 7. The 1 st induction course was common for all pts (ICE scheme), while, then, SR pts were treated with 4 additional chemotherapy courses, all including high-dose cytarabine (HD-Ara-C). IR and HR pts were randomized to receive either a 2 nd ICE or the FLA-Liposomal Doxorubicin (L-Doxo) scheme as 2 nd induction course. IR pts were given 3 additional consolidation courses including HD-Ara-C with other agents or, in the presence of an HLA-compatible sibling, 1 consolidation course followed by allogeneic hematopoietic stem cell transplantation (HSCT). Pts of the HR group were consolidated with 2 courses of HD-Ara-C combined with other cytotoxic agents and, then, had an indication to receive HSCT from either a donor compatible for &amp;gt; 9/10 HLA loci or from an HLA-partially matched relative. Data cut-off for the analysis was March 31, 2023. Results: The proportion of pts allocated to the SR, IR and HR groups were 19% (72 pts), 23% (81 pts) and 58% (218 pts), respectively. Overall, 92% of pts obtained morphological complete remission (CR) at the end of the 2 induction courses [as compared to 87% of the previous AIEOP AML 2002 study (Pession et al. Blood 2012), p&amp;lt;0.05]. Twenty-five pts (7%) experienced a primary induction failure. Only 3 pts died during or after the 2 induction courses, while the subsequent cumulative incidence of 3-yr non-relapse mortality in continuous CR was 6.8%. Leukemia recurrence occurred in 63 pts, this leading to a 3-yr cumulative incidence of relapse of 18.9%. With a median follow-up of 4.5 yrs (range 0.8-8), the 3-yr probabilities of overall (OS) and event-free survival (EFS) were 83.9% and 68.5% (Figure 1), respectively, both values being significantly better (p&amp;lt;0.01) than those of the AIEOP AML 2002 study. The 3-yr OS of SR, IR and HR pts were 99.2%, 84.2% and 79.4%, respectively (p=0.01). The 3-yr estimate of disease-free survival (DFS) was 74.3%, with no difference among the 3 risk groups. The EFS did not differ in IR and HR randomized to receive either a 2 nd ICE or the FLA-L-Doxo scheme as second induction course. Levels of flow-cytometry MRD after the 2 nd induction course strongly influenced the probability of EFS which was 76% and 48% in pts with an MRD value &amp;lt; or &amp;gt;0.1%, respectively (p&amp;lt;0.01). Allogeneic HSCT was performed in 160 pts; in these pts, the 3-yr probabilities of OS and DFS were 87.7% and 85.1%, respectively, with no difference according to the type of donor employed. The DFS of the 10 IR pts given HSCT was 100% as compared to 72.1% of the 71 not transplanted (p=0.07). The outcome of infants treated in this study was particularly good, since their 3-yr probability of EFS was 78.3%. The 3-yr EFS of the 35 pts with FLT3-ITD and of the 75 with KMT2-A rearrangements were 57.1% and 64.7%, respectively. Conclusions: These results indicate that in children enrolled in the trial AIEOP AML 2013 the 3-yr OS and EFS overcomes 80% and approaches 70%, respectively, with a significant improvement as compared to the previous AIEOP protocol. Disease recurrence/primary resistance were the main cause of treatment failure, while the probability of DFS did not differ among the 3 different risk groups, this finding indicating that tailoring of consolidation therapy according to the risk profile was successful in improving the outcome of pts with worse prognostic characteristics. The use of FLA-L-Doxodid not offer any advantage over repeating a 2 nd ICE.

Pediatric Patients with High-Risk B-Cell ALL in First Complete Remission May Benefit from Less Toxic Immunotherapy with Blinatumomab - Results from Randomized Controlled Phase 3 Trial AIEOP-BFM ALL 2017

Background: One of the key questions in trial AIEOP-BFM ALL 2017 focused on the reduction of treatment-related complications by replacing parts of the highly intensive consolidation phase by two courses of Blinatumomab (Blina) in a prospective randomized trial. Herein, we report the toxicity profile of B-cell acute lymphoblastic leukemia (B-ALL) patients (pts) with high-risk (HR) characteristics pending final outcome data. Patients and Methods: 728 pts with HR B-ALL were enrolled from July 15, 2018 to October 31, 2022 in this multicenter trial run in 8 different countries. Patients were included in the HR group in view of the presence of at least one of the following criteria: induction failure; high levels of minimal residual disease (MRD) at day 15 of induction, or at the end of induction (EOI), or at the end of consolidation (EOC); presence of KMT2A::AFF1, of IKZF1+ and positive MRD at EOI (Stanulla et al, JCO 2018), TCF3::HLF, or hypodiploidy. B-ALL pts with one or several of these characteristics represented 20.8% of all pts aged 0-18 years of age with B-ALL. After a 4-drug induction phase, and two weeks of consolidation treatment, patients were randomized to receive Bortezomib in addition to standard consolidation (not part of this report). Before treatment continued with intensive consolidation block HR-1', MRD was analyzed in order to identify patients eligible for subsequent hematopoietic stem cell transplantation (HSCT) based on MRD results. After block HR-1', all B-ALL HR pts were randomized to receive either two courses of consolidation (blocks HR-2', and HR-3'), or two 28-day courses of Blina at 15µg/m 2/d administered by continuous IV infusion (with a 2-week treatment-free interval). Two intrathecal injections of methotrexate (MTX) for CNS prophylaxis were given on days 1 and 29 of each Blina course, respectively. Out of 728 HR B-ALL pts, 619 pts were eligible for randomization [reasons for non-eligibility were: Event (death or relapse) before randomization was due (26), Down syndrome (25; scheduled for a non-randomized intervention with Blina), presence of TCF3::HLF (3; could receive any alternative therapy including Blina), discontinuation/substantial change of preceding therapy (23) or other protocol exclusion criteria (32)]. 572 pts were randomized (92.4% of those eligible). One pt assigned to the experimental arm (EA) and 4 pts assigned to the control arm (CA) received the other arms, respectively. Results: Toxicity was evaluated in randomized pts according to treatment administered during the randomized phase, respectively, until next element started: 268 pts were treated in the control and 281 in the EA (see Table). 16 of them switched in/after the first Blina cycle to the HR blocks due to toxicity or poor response to Blina (due to increasing MRD, &amp;gt;=1x10 -4). Medically relevant adverse reactions of special interest (ARSI) according to MedDRA (specified in the protocol) were evaluated in the randomized treatment phases (CA: HR-2‘/HR-3‘ block, EA: 2 Blina cycles). ARSI were recorded in 61 of 268 pts in the CA (22.8%, 71 ARSI) and in 29 of 281 pts in the EA (10.3% [p&amp;lt;0.001], 33 ARSI); 3 of the 33 ARSI in the EA were related to HR blocks and were observed in 3 of the 16 pts that switched to HR blocks. Life-threatening SAR were seen in 14 pts of the control group (5.2%) and in no patient in the EA (p&amp;lt;0.001). Conclusions: Taken together, these results show for the first time in newly diagnosed pts with HR B ALL, the favorable toxicity profile previously reported with Blinatumomab in pediatric relapsed ALL (Locatelli F et al, JAMA 2021; Brown P et al, JAMA 2021). We have demonstrated that the toxicity profile of Blinatumomab is much more favorable as compared to the intensive chemotherapy approach using HR-blocks. If upcoming analyses of outcome data will show no inferiority of the EA, blinatumomab replacement of some of the intensive chemotherapy blocks will become the new standard of care for treatment if newly diagnosed patients with HR B-ALL.

Final Analysis for the Primary End-Point of Gimema AML1718, a Safety Run-in and Phase 2 Open-Label Study of Venetoclax, Fludarabine, Idarubicin and Cytarabine (V-FLAI) in the Induction Therapy of Non Low-Risk Acute Myeloid Leukemia

Background: Acute myeloid leukemia (AML) poses significant challenges, especially in intermediate and high-risk cases due to modest rates of complete remission (CR) of 50-60% yelding a 2-year survival probability of about 30-40%. Preliminary results from the AML1718 part 1 trial have demonstrated remarkable improvements, with a composite complete remission (CCR) rate reaching an impressive 82%, and a 1-year survival probability of 72%. These findings represent a substantial advancement compared to historical data. Hereby, we present the comprehensive results of the AML1718 study, with a primary focus on the CCR as the primary endpoint. Methods: The safety and efficacy of venetoclax (VEN) in combination with FLAI (fludarabine, cytarabine, and idarubicin as a first-line treatment for newly diagnosed adult patients with ELN 2017 intermediate- or high-risk AML) was investigated in the GIMEMA AML1718 phase 1/2 multicenter trial (NCT03455504). The study followed a modified two-stage Simon's design, including safety run-in cohorts (SRI-C1 and SRI-C2), an extension phase (Part 1 with P1-C1 and P1-C2 cohorts), and a confirmatory cohort (P2). VEN was administered at a daily dose of 400 mg in combination with FLAI (V-FLAI 400) in SRI-C1 and P1-C1, while in SRI-C2 and P1-C2, the VEN dose was escalated to 600 mg/day (V-FLAI 600). In P2 we used the lower effective dosage of V-FLAI 400, with centralized measurable residual disease (MRD) assessment with flow cytometry following ELN guidelines. After V-FLAI induction, consolidation therapy with cytarabine-based regimens and consideration for allogeneic stem cell transplant (HSCT) were conducted. Adjustments to the VEN dose were made for patients concurrently receiving posaconazole. VEN administration was discontinued until recovery for patients achieving remission by day 21 and during consolidation courses. Results: Since February 2019, a total of 124 patients were treated in this study, 6 in SRI-C1, 6 in SRI-C2, 22 in P1-C1, 23 in P1-C2, and 67 in P2. Among them, 95 patients received V-FLAI 400 and 29 patients received V-FLAI 600. Posaconazole was administered to 115 patients (93%) as antifungal prophylaxis during the first course. The patient population had a median age of 55 years (ranging from 18 to 66), with 70 patients (56%) being male. According to ELN 2017 risk, 67 patients (54%) were classified as intermediate- and 57 patients (46%) as high-risk. Sixteen (13%) patients had a seconday AML. Genetic mutation analysis showed that 4/56 tested patients (7.1%) had IDH1, 11/55 (20%) IDH2, 16/108 (14.7%) FLT3 ITD, 3/112 ( 2.8%) NPM1 mutation; TP53 data are not yet available. The primary endpoint, the CCR, was achieved in 93 out of 124 patients (75%) after the 1 st course (table 1). One patient initially in partial remission (PR) achieved CR after the second V-FLAI induction. In P2, 47/67 patients achieved CCR (70.0%, with 9 patients not yet tested). Central MRD analysis showed that that 31 out of 48 tested patients obtained MRD negativity at day 28 of course 1 (64.5%, treshold 0.1% by flow). With a median follow-up of 10 months, 60 patients (49%) underwent hematopoietic stem cell transplant (HSCT) in CR, and 1 patient underwent HSCT in partial remission. The median overall survival (OS) was 22.4 months (95% confidence interval [C.I.] 13.4 months - not reached, Figure 1), with a 12-month OS probability of 64% (95% C.I. 54% - 76%). The median disease-free survival (DFS) was 20.7 months (95% C.I. 12.1 months - not reached), and the 12-month DFS probability was 64% (95% C.I. 50% - 76%). The treatment was found to be safe, with only 4 deaths recorded during induction (3.2%), and a 60-day mortality rate of 6% including disease progression-related deaths. Infections were the most commonly reported grade 3+ adverse events. Overall, the safety profile of the treatment regimen was consistent with any intensified AML induction regimen. Among transplanted patients, no instances of graft failure or higher-than-expected incidence of graft-versus-host disease (GVHD) were observed. No significant differences were observed between the 400 mg and 600 mg arms. Conclusions: V-FLAI demonstrated remarkable efficacy without any safety concerns. Impressive CCR rate and MRD-negativity qualify the combination for randomized comparisons . A virtual-randomized phase 3 trial is currently being prepared.

No Place like Home: Home-Based Intravenous Arsenic Trioxide for the Treatment of Acute Promyelocytic Leukemia (APL)

Introduction: APL has transitioned from a highly fatal malignancy to a disease that is curable with a combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO). Intravenous (IV) administration of ATO remains the standard of care for consolidation, however, its use is associated with long infusion times, electrolyte disturbances, and QTc prolongation that has historically required frequent outpatient infusion center administration and monitoring. Following induction, patients receive a cumbersome schedule of ATO through daily infusions 5 days each week (typically Monday-Friday) 4 weeks on 4 weeks off for 4 cycles. Oral formulations of ATO are poorly water soluble, have not demonstrated adequate absorption in the gastrointestinal (GI) tract leading to significant GI upset and are not approved for use in the United States. Beginning in 2020, patients treated at our institution were given the option of receiving ATO at home through a partnership via Qualitas Specialty Pharmacy of RWJBarnabas Health. This retrospective review evaluates the feasibility, safety, and efficacy of administration of ATO in the home infusion setting for patients with APL receiving ATO consolidation. Methods: Through retrospective chart review, we evaluated patients who received consolidation therapy of ATO through home infusion from 2020-2023. Eligible patients included those with an ECOG of &amp;lt;2, absence of baseline QTc prolongation (defined as &amp;gt;500ms), and patients without significant kidney dysfunction or hepatotoxicity at baseline. We evaluated each patient for adverse effects such as QTc prolongation, electrolyte disturbances, liver function test (LFT) abnormalities, neutropenic fever, bacteremia, unplanned Emergency Room (ER) or urgent care visits, and unexpected hospitalizations (via Common Terminology Criteria for Adverse Events version 5). Results: Fifteen patients aged 19-79 (median = 43) were reviewed with 60% being male and 40% female. Sixty percent had a baseline ECOG 1 and 40% had an ECOG 0. Twenty percent of patients had a prior malignancy (n=3). Eighty percent of the patients experienced grade (gd) 1-3 electrolyte abnormalities (47% gd 1 hyperphosphatemia, 13% gd 1 hyperkalemia, 7% gd 2 hyperkalemia, 7% gd 3 hyperkalemia, 13% gd 1 hypokalemia, 13% gd 1 hypermagnesemia, 7% gd 3 hypermagnesemia, 7% gd 1 hypomagnesemia, 33% gd 1 hypernatremia, 33% gd 1 hyponatremia, &amp; 7% gd 2 hyponatremia). Of the 15 patients receiving treatment, 27% experienced gd 1 alanine aminotransferase (ALT) increase, 13% of patients experienced gd 1 aspartate aminotransferase (AST) increase, and 7% of patients experienced gd 2 hyperbilirubinemia. For QTc prolongation, 53% of patients experienced gd 1 prolongation, 7% of patients experienced gd 2 prolongation, and 13% of patients experienced gd 3 prolongation. One out of the 15 patients experienced treatment delays due to QTc prolongation. While forty percent of patients visited either the ER and/or urgent care during consolidation therapy, no visits were deemed therapy related. Reasons for urgent evaluation included infections (n=3), vertigo (n=1), low back pain (n=1), facial numbness (n=1), fall (n=1), abdominal pain (n=1), and hemorrhoidal bleeding (n=1). Two patients were hospitalized, due to a renal infarct (n=1) and a subdural hematoma after a fall (n=1). None of the 15 patients experienced febrile neutropenia/bacteremia while receiving consolidation therapy. Of the 11 patients who completed consolidation at the time of this abstraction, all (100%) had complete remission demonstrated on post-consolidation bone marrow. One of the 11 patients relapsed within 6 months of consolidation; however, is now in remission following two additional consolidation courses and a bone marrow transplant. Four patients have not yet completed four cycles of ATO consolidation. One patient was transitioned from home infusion to clinic treatment due to out-of-pocket cost. Conclusions: Our study demonstrates that home infusion of ATO is both safe and highly effective for patients. Therapy was well tolerated with predictable and manageable toxicity. Prospective studies are needed to evaluate the efficacy and safety in comparison to patients receiving ATO in the infusion center as well as to assess patient-reported and cost outcomes. Given the safety profile of home-based ATO, we have implemented at home ATO consolidation as standard therapy for all eligible patients.

Chip-AML22 Master Protocol: An Open-Label Clinical Trial in Newly Diagnosed Pediatric De Novo Acute Myeloid Leukemia (AML) Patients Including a Linked Phase II Trial with Quizartinib in FLT3-ITD/ NPM1wt Patients - a Study By the NOPHO-DB-SHIP Consortium

Background and Significance Pediatric AML is a heterogeneous disease with current rates for event-free survival (EFS) of 50-60% and for overall survival (OS) of 70-80%, for newly diagnosed patients. In patients with refractory and relapsed disease, and in subsets as defined by AML biology and treatment response, prognosis is dismal. To further improve EFS, the NOPHO-DB-SHIP consortium has initiated trial CHIP-AML22. Building on the successes achieved by the recent trial from this consortium (NOPHO-DBH AML-2012, preliminary data as per June 2023, n=878: 5-years pEFS 63%, 5-years pOS 78%), CHIP-AML22 will incorporate innovative elements, mainly the FLT3-inhibitor quizartinib (Vanflyta®) that was recently approved by the FDA and PMDA in combination with chemotherapy for the treatment of newly diagnosed adult AML patients with FLT3-ITD mutations, and gemtuzumab ozogamicin (GO, Mylotarg ®) that improved outcome in adult and pediatric AML when added to chemotherapy. CHIP-AML22 will maintain the approach of treatment-response driven risk-adapted treatment, intensified induction treatment for patients with ≥5% AML cells in the bone marrow (BM) after course 1, and consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk patients after the first consolidation course HAM. Study Design and Methods This clinical trial will enroll newly diagnosed de novo patients aged ≥1 day to ≤18 years to 2 randomized studies in the Master protocol, to the linked quizartinib trial, or the standard arm of the Master (Figure 1). Innovations include: (1) a phase II, single arm, open-label study on the safety, efficacy, pharmaco-kinetics and -dynamics of quizartinib in combination with chemotherapy, and as single-agent after allo-SCT, in FLT3-ITD/ NPM1wt AML; All patients will receive quizartinib monotherapy for 6 months post-SCT, except those that were negative for measurable residual disease determined with multiparameter flow cytometry (MFC-MRD) in BM1 and remained negative (study CHIP-AML22/Quizartinib); (2) a phase III, open-label randomization with gemtuzumab ozogamicin (GO; Mylotarg®) added to induction therapy MEC for pediatric CD33-positive newly diagnosed AML patients aimed at improved outcome (study Ri), (3) a phase III, open-label randomization with three (standard of care) versus two (investigational) courses of consolidation chemotherapy for standard-risk patients as non-inferiority trial (study Rc), and (4) refining risk-group adapted treatment, aimed at improved outcome. Novel high-risk categories are patients with RAM-phenotype and/or CBFA2T3::GLIS2, and patients with KMT2A-rearranged AML (excluding KMT2A::MLLT3) with ≥0.1% AML cells after course 1 in BM1. Patients with ≥15% AML cells on day 22 BM after course 1, or ≥0.1-5% AML cells by MFC-MRD after course 2 in BM2 (end-of-induction), or those with FLT3-ITD/NPM1wt remain to be high-risk, similar to AML-2012. Further, dexrazoxane is recommended to all patients before receiving daunorubicin or mitoxantrone, aiming to prevent late-onset cardiotoxicity. The quizartinib trial includes a safety run-in with a modified rolling-6 design and two dose levels with 6 evaluable patients per dose level. In study Ri, patients assigned to the experimental GO-arm will receive GO twice during induction with MEC at a dose of 3 mg/m 2 (max 5 mg) with an interim-analysis for superiority of any of these two arms. The investigational arm of the Rc randomization will omit HA 3E. Both the quizartinib trial and each randomization will also be compared to historical controls from the AML-2012 trial. CHIP-AML22 expects to enroll 130-140 patients per year and it will take 7-8 years to reach the total number of 905 patients needed to answer all study questions. Patients will be followed-up for at least 5 years from diagnosis and thus, the total study duration is expected to be 12-13 years. The Master protocol (EU CT: 2023-504999-25) and linked quizartinib trial (EU CT: 2023-505000-27-00) were approved by the Dutch Ethical Review Authority and as of July 2023, enrollment in the Master protocol including study Rc has started in The Netherlands. Study Ri and the linked quizartinib trial are expected to open in Q4 2023. At least 15 other countries with nearly 60 sites will participate in CHIP-AML22: Belgium, Denmark, Estonia, Finland, Hong Kong, Iceland, Israel, Latvia, Lithuania, Norway, Portugal, Spain, Sweden, Switzerland and Uruguay.

IMWG /ECOG Frailty Score Was a Good Indicator for ASCT Candidate Selection for NDMM in China from a Hcmmd Retrospective Study

Background Autologous hematopoietic stem cell transplantation (ASCT) has always been considered as the standard choice for newly diagnosed multiple myeloma (NDMM) patients less than 65 years old, or even older. At present, how to define the patients who is suitable for transplantation is still controversial in clinic in China. Rate of utility of ASCT in front line was as low as 10%. The screening of transplant patients mainly depends on the evaluation of the general condition of patients, the wishes of patients and their families, and the evaluation of organ function by physical examination. In this way, it is particularly difficult for doctors in non-transplant medical units to recommend stem cell transplantation for patients. Based on “HemaTank” Chinese multiple myeloma database(HCMMD), a retrospective study of construction of special disease cohort and prognostic model for multiple myeloma were conducted to explore the posibilities of utility of IMWG/ECOG frailty score to select transplantation candidate, and the prognostic significance of frailty score in all MM patients. Methods In this study, 322 NDMM in the first affiliated Hospital of Soochow University from August 2018 to October 2022 were analyzed retrospectively. All patients were valuated with IMWG/ECOG frailty score before each cycle of treatment, which included age, the ECOG score, and the Charlson Comorbidity Index. Patients with IMWG frailty score≥2 were defined as frail, with score &amp;lt;2 were unfrail. Transplant patients received 4 courses of induction of VRd regimen followed by ASCT, and 2 courses of VRD consolidation after transplantation. Non-transplant patients received 8 courses of induction with VRD regimen. Standard risk patients received lenalidomide as maintenance therapy until PD. High risk patients received V+R as maintenance treatment until PD. Results The median age of 322 patients was 58(29-79). 178(55.3%) patients were male. 170 (52.8%) patients were unfrail at diagnosis, with a mean age of 56.72±7.11. 77.8% of the unfrail patients were less than 65 years old. 152 patients were frail at diagnosis, with a mean age of 59.47±8.28. 68% of the patients were less than 65 years old. There were statistical differences in age, DS stage, ISS stage and R-ISS stage between the two groups. (P &amp;lt; 0.05). After induction therapy, 246 patients (76%) rescored IMWG/ECOG frailty score before ASCT. 46 patients changed from frail state at first diagnosis to nonfrail before transplantation, mainly because of the improvement of ECOG score and renal function. There is no change from a nonfrail state at the first diagnosis to a frail state when entering the ASCT program. After logistics regression analysis of IMWG/ECOG score, age, renal function and CCI, unfrailty is the best indicator of selection patients as ASCT candidate, OR=0.37, 95%CI 0.21-0.63 (P &amp;lt; 0.001). At the time of ASCT, there was no significant difference in the ORR of induction therapy between frail and unfrail patients. But the granulocyte and platelet reconstruction during ASCT in the frail group was slower than that in the unfrail group, P&amp;lt;0.0001. The transplantation-related mortality was 0. In this cohort, the PFS and OS of the NDMM patients accepted VRD+transplantation was all better than those received VRD only. Most importantly, the OS of the frail patients scored at the time of ASCT was much poorer (P&amp;lt;0.05) than that of the unfrail group with no significant difference in PFS between two groups. But there were no significant differences in PFS and OS of the patients who changed from frail to unfrail after induction therapy compared with those remained unfrail at diagnosis and after induction therapy. Conclusion IMWG/ECOG frailty score can be used to select ASCT candidate for NDMM patients. In the study 144 patients (84.7%) remained unfrail at diagnosis and before transplantation accepted ASCT. and 46 frail patients (30.2%) at diagnosis transferred from frail to unfrail after induction and accepted transplantation. It was suggested that the IMWG/ECOG frailty score evaluated before transplantation is more instructive for long-term overall survival. The OS of unfrail patients was better than that of frail patients even with no significant difference in PFS.

Association of Minimal Residual Disease by a Single-Tube 8-Color Flow Cytometric Analysis With Clinical Outcome in Adult B-Cell Acute Lymphoblastic Leukemia: A Real-World Study Based on 486 Patients.

Minimal/measurable residual disease (MRD) measured by molecular and multiparametric flow cytometry (MFC) has been proven to be predictive of relapse and survival in patients with B-cell acute lymphoblastic leukemia (B-ALL). A universally applicable antibody panel at a low cost but without compromising sensitivity and power of prognosis prediction in adult B-ALL remains unestablished. To report our experience of using a single-tube 8-color MFC panel to measure the MRD status as a prognostic indicator in adult B-ALL patients. We retrospectively analyzed the characteristics, MRD status, and prognosis of adult B-ALL based on a large real-world cohort of 486 patients during a 10-year period. MRD assessed by MFC and polymerase chain reaction (PCR) assays for BCR-ABL+ patients showed concordant results in 74.2% of cases. MRD- status by our MFC panel could clearly predict a favorable relapse-free survival (RFS) and overall survival (OS) both at the end of induction and at the end of 1 consolidation course. Patients with continuous MRD- and with at least 1 MRD- result showed a favorable RFS and OS compared with those with at least 1 MRD+ result and continuous MRD+, respectively. The single-tube 8-color MFC panel demonstrated a low cost, decent sensitivity, and comparability with polymerase chain reaction-MRD but an excellent performance in predicting RFS and OS, and thus could potentially be taken as a routine indicator in the evaluation of the treatment response for adult patients with B-ALL.

Prognostic Impact of Persistent Measurable Residual Disease in Patients with Acute Myeloid Leukemia FLT3+ Treated with Intensive Chemotherapy Plus Midostaurin - a Retrospective Study of the Polish Adult Leukemia Group (PALG)

Background: Measurable residual disease (MRD) is detected during morphological remission after standard chemotherapy in acute myeloid leukemia (AML) patients (pts). It is a strong prognostic factor for relapse and shorter overall survival (OS). Immunophenotyping by multiparameter flow cytometry (MFC) is currently the most commonly used method in AML pts. There is still a lack of studies evaluating MRD in specific AML populations in the era of targeted therapies, including thyrosine kinase inhibitors. A retrospective study in adult pts with a newly diagnosed AML FLT3+ treated with intensive chemotherapy plus midostaurin has been performed to evaluate the prognostic impact of positive MRD (MRD+) on RFS and OS. Objectives: To assess the prognostic impact of MRD status during the clinical course of AML FLT3+ on RFS and OS. Patients and methods: Seventy three pts with AML FLT3 were treated in Polish hematological centers between 2018 and 2021. Bone marrow aspiration was performed after induction and consolidation treatment to assess response and MRD by MFC. MRD+ was defined as ≥ 0.1% abnormal cells within mononucleated cells by MFC with diagnostic leukemia-associated immunophenotype (LAIP) and different from normal (DfN) aberrant immunophenotype approaches. Results: The median age of the pts was 55 (range: 18-74). Induction regimen was DA "3+7" in 50 (70%), DA-90 in 8 (11%), DAC in 11 (15%), other in 2 (4%) pts. Fifty seven (78%) pts achieved first composite complete remission (CRc=CR+CRi) after 1 or 2 courses of induction, 12 (17%) had primary refractory disease (PRD) and 2 (3%) pts died in aplasia. Median number of consolidation courses was 2 (range: 1-4). Fifty one (89%) pts with CR1 fulfill the criteria for MRD analysis after 1 or 2 courses of induction and 34 (48%) pts after consolidations. Thirty four pts had 2 timepoints evaluation: after induction and at the end of consolidation courses. MRD+ was reported in 35 (68%) of pts after induction (median 0.5; IQR 0.25-0.85) and in 19 (52%) of pts at the end of consolidations (median 0.64; IQR 0.22-1.99). Analysis of 4 pts groups was performed: Group 1.: MRD+ after induction and at the end of consolidations (persistent MRD+)(n=16; 47%); Group 2.: MRD+ after induction with conversion to MRD- at the end of consolidations (n=6; 18%); Group 3.: MRD- after induction with conversion to MRD+ at the end of consolidations (n=2; 6%); Group 4.: MRD- after induction and at the end of consolidations (persistent MRD-)(n=10; 29%); Baseline clinical characteristics were similar between 4 groups regarding age, FLT3-ITD and FLT3-TKD frequency, FLT3-ITD allelic ratio (AR), WBC, PLT, peripheral blood and bone marrow blast percentage, AML type: de novovs sAML vs tAML (p-values > 0.05). The probability of 1- year RFS was significantly lower in pts with persistent MRD+ (group 1.) vs group 2. vs 3. vs 4. (27% vs 83% vs 50% vs 78%; p=0.034, respectively). Relapse rate after 1 year was in group 1. vs 2. vs 3. vs 4.: 73% vs 16% vs 50% vs 20% (p=0.015), respectively. The shorter OS, but insignificant, was noted in group 1. vs 2. vs 3. vs 4. (p=0.49). A univariate analysis revealed that allo-HSCT (hazard ratio [HR] 0.345; 95% confidence interval (CI), 0.152-0.784; p=0.011) and male sex (HR, 0.433; 95% CI, 0.217-0.861; p=0.017) are predictors for longer OS. MRD- at the end of consolidations (HR, 0.211; 95% CI, 0.066-0.669; p=0.008), persistent MRD- (HR, 0.252; 95% CI, 0.070-0.909; p=0.035), allo-HSCT (HR, 0.416; 95% CI, 0.183-0.947; p=0.0368) are predictors for longer RFS. However, older age (HR, 1.049; 95% CI, 1.018-1.081; p=0.0017) and higher WBC (HR, 1.005; 95% CI, 1.002-1.008; p=0.0022) are predictors for shorter RFS. Conclusions: We observed high rate of CR1 MRD+ AML FLT3 pts after induction (68%) and at the end of consolidations (52%). Significantly lower RFS and higher relapse rate, but not OS, were noted in pts with persistent MRD+ in comparison to pts in other MRD groups. Longer follow-up period and larger studies are necessary to confirm our preliminary findings.

Outcomes of Acute Myeloid Leukemia (AML) in Adolescents and Young Adults (AYAs) Compared to Adults in a Referral Center from Lower Myanmar

Introduction Acute myeloid leukemia (AML) is the second most common form of haematological malignancies with high prevalence among all age groups in Myanmar. However, there are very limited data particularly related to AML in adolescents and young adults (AYAs). To fill the gap in AML data from resource-constraint countries and to compare the treatment outcomes of AYAs (15-39 years) with adults (40 years and above), a hospital-based, prospective study was conducted between January 2019 to October 2021, on the cases of AML treated at the North Okkalapa General and Teaching Hospital, one of three referral centers of Myanmar. Methods All cases of AML other than acute promyelocytic leukemia (APL) received two courses of induction containing daunorubicin and cytarabine followed by three courses of consolidation with high dose cytarabine. Treatment of APL included differentiation agents (all-trans-retinoeic acid and arsenic trioxide) based induction with addition of daunorubicin and cytarabine in high-risk cases until remission followed by chemotherapy free consolidation and maintenance up to two years. Patients were followed up for a minimum of one year and overall survival (OS) was calculated using the Kaplan-Meier method. Results A total of 140 including 81 (57.9%) AYAs and 59 (42.1%) adults with newly diagnosed de-novo AML were treated during 34-months period. Median age of AYA AML was 22 years (range-13-39 years) whereas that of adult AML was 54 years (range-40-76 years). There was no gender difference (49.2% versus 50.7%, for male and female). Among AML subtypes, M4 was the commonest subtype (28.5%) and APL, M3 (22.8%) was the second most prevalent AML followed by M2 (18.5%) and M5 (10.7%) subtypes. Cytogenetic data was available in 37 of 108 (34.2 %) non-APL cases with 16.2 %, 67.6% and 16.2 % respectively had good, intermediate, and high-risk cytogenetics. Of 108 non-APL including 61 (56.5%) AYAs and 47 (43.5%) adults, 46 (42.6%) died within one week or during induction and remaining 62 (57.4%) achieved remission at the end of induction. Among 32 APL (20 AYAs and 12 adults), mortality rate was 21.9% due to early death (12.5%) and induction death (9.4%) with only 78% achieved remission after induction. There was no statistically significant difference between the remission rates of AYAs and adults, in both APL (75.0% versus 83.3%, respectively, p=0.68) and non-APL groups (60.65% versus 53.2% respectively, p=0.43). During follow-up, 29 (20.7 %) were lost to follow-up while 6 non-APL AML (5 AYAs and 1 adult, 5.6%) relapsed within one year with 18 of 32 APL (56.3%) and 32 of 108 non-APL AML (29.6%) remained alive at one year. Two-year cumulative survival for AYAs compared to adults was 47% vs 42% respectively for non-APL AML (p=0.42) and 74% vs 83% for APL (p=0.608) with no statistically significant difference between two age groups. Conclusion In this resource limited setting, although having higher proportion of younger population and better prognostic types like APL, remission rate and survival was still low due to higher number of early and induction deaths which could be improved by early diagnosis and better supportive care.

Optimizing the Development of Prototype Learning Mode of Professional Ability Consolidation (PKP) Courses of the PGSD-UT Study Program in the Archipelago Region

Every semester, Professional Capability Consolidation (PKP) courses are always a scourge for Elementary School Teacher Education (PGSD) students of the Universitas Terbuka (UT). It is due to the lack of student knowledge of the procedures for implementing PKP courses and the limited skills of students in making practical reports. It affects their scores because they do not meet the minimum criteria, and students fail to pass the course. Especially during the pandemic, the implementation of practical courses that are usually held face-to-face is now all based on webinar tutorials. The learning process becomes more difficult for students living on islands with various limitations. This study aims to develop a prototype learning mode to overcome these problems with three main activities, including (1) making procedural video for implementing PKP courses of S1-PGSD, (2) training in writing PKP S1-PGSD UT reports, (3) assisting the undergraduate-PGSD students in the islands face-to-face. The study results show that it was necessary to develop advanced videos as a complement and elaborately detailed procedures for implementing the PKP courses for the students of S1-PGSD UT, the need for writing training with a greater number of meetings and writing practices, and the suitability of holding face-to-face mentoring of PKP courses for the students of S1-PGSD.

Profile Analysis of Student Involvement of the Faculty of Teacher Training and Education at the Universitas Terbuka in Professional Capability Consolidation Courses

This study aimed to provide an overview of the responses of Universitas Terbuka students regarding involvement in the lecture process for students who take practical courses, namely Professional Ability Consolidation (PKP). The research method used in this research was descriptive quantitative ex post facto, which describes the conditions that were happening at that time and not the result of a certain manipulation treatment. Respondents in this study amounted to 201 people (165 women and 36 men). The research instrument was conducted through a questionnaire distributed online containing four indicators, namely Level of Academic Challenge, Active/collaborative learning, Student-faculty interaction, and Enriching educational experience. The results of this study indicate that in general, they have given a good response to the statements in each indicator except for the negative statements, this indicates that the majority of students in their PKP courses have been involved in the lecture process and the results of the two different tests carried out are based on 11 (eleven) the only characteristics that exist are types of work (teacher and non-teacher) which show significant differences.

Safety of the total neo-adjuvant therapy in rectal cancer treatment. Preliminary results of the randomized trial

AIM: assess tolerability and safety of total neoadjuvant therapy (TNT) with three consolidation courses of XELOX for patients with rectal carcinoma.PATIENTS AND METHODS: patients with histologically proven rectal carcinoma were randomly assigned in two groups: in the TNT group after the neoadjuvant CRT 50–54 Gy with capecitabine 3 consolidation courses of XELOX were done, in the CTR group — conventional neoadjuvant CRT 50–54 Gy with capecitabine. The RTOG scale was used to assessed radial reactions, and the NCI-CTC v5.0 scale was used to evaluate toxicity. For selected patients with a complete clinical response «watch and wait» approach was used. Postoperative complications were graded according with the Clavien-Dindo scale. The primary endpoint of study was the complete response rate (clinical and pathomorphological). Secondary endpoints of study: frequency and structure of intraoperative and postoperative complications, the rate of grade 3–4 toxicity of radiotherapy and chemotherapy, R0-resection rates. The study was registered on the ClinicalTrials.gov (NCT04747951).RESULTS: between October 2020 and March 2022, 145 patients were enrolled in the randomized study: 72 patients in the TNT group and 73 patients in the CRT group. The full course of neoadjuvant treatment was completed in 90% patients in the TNT group, comparing with 96% in the CRT group (p = 0.65). The total rate of severe adverse effects of radiation therapy was 59% in the TNT group, comparing with 67% in the CRT group (p = 0.48), with 3–4 grade by RTOG scale were observed only in two cases in the CRT group. During chemotherapy severe adverse effects were observed in 54% in the TNT group comparing with 19% in the CRT group (p &lt; 0.001). Grade 3–4 toxicity was 3% in the TNT group comparing with 2% in the CRT group. The rate of intra- and postoperative complications did not differ between two groups.CONCLUSION: TNT is a safe alternative to conventional CRT.

Management and outcome of gestational trophoblastic neoplasia patients with brain metastasis: Ten years’ experience in a trophoblastic referral center (460)

<b>Objectives:</b> To determine the clinical outcome of gestational trophoblastic neoplasia patients with brain metastasis. <b>Methods:</b> A review of records of all women with brain metastasis from gestational trophoblastic neoplasia from January 1, 2010, to December 31, 2019, was done. Patients' sociodemographic and clinical-pathologic profiles were described. Using the Kaplan-Meier survival curve, the survival time was determined. <b>Results:</b> A total of 19 patients were included; 13(68.42%) patients had neurological symptoms upon diagnosis and one (5.26%) patient had these symptoms during treatment. The most common neurological symptom was headache. Sixteen patients had the World Health Organization (WHO) prognostic score of >12, two had >7, and one had 3 (A case of tumor recurrence ten years after remission from her low-risk GTN). Nine patients (47.36%) had single brain metastasis, three (15.78%) had two, three (15.78%) had three, one (5.26%) had five, and two (10.52%) were reported to have multiple lesions. The location for brain metastasis was known in eighteen patients and was not identifiable in one due to massive hemorrhage. The location of the brain metastases were as follows: parietal (<i>n</i> = 3), frontal (<i>n</i> = 2), occiput (<i>n</i> = 2), temporal (<i>n</i> = 1), frontotemporal (<i>n</i> = 1), frontoparietal (<i>n</i> = 1), frontal and parietal (<i>n</i> = 2), cerebral and cerebellar (<i>n</i> = 1), parietal and occipital (<i>n</i> = 1), parietal, posterior, and occiput (<i>n</i> = 1), frontal and medial (<i>n</i> = 1), frontoparietal, frontal and thalamus (<i>n</i> = 1), and parietal and superior sagittal sinus (<i>n</i> = 1). The size of brain metastasis ranged from 0.2 to 4.0 cm. All received EMACO with an increase in the Methotrexate infusion to 1 g/m² as first-line treatment. Three (15.78%) patients were given induction chemotherapy with Etoposide 100 mg/m² and Cisplatin 20 mg/m². Fifteen (78.94%) patients underwent concomitant whole brain radiation at a dose of 2,000-3,000 cGy (in 10 fractions of 200-300 cGy), and two were given intrathecal Methotrexate 12.5 mg. The most common tox- icities from EMACO chemotherapy were infections in 84.21% (16/19), hypokalemia in 73.68% (14/19), and anemia grade 2-4 in 69.42% (13/19). Nine out of thirteen (69.23%) patients diagnosed with neurological symptoms achieved biochemical remission. One patient who had neurological symptom during the course of treatment was given palliative care. Four out of four (100%) patients who had no neurological symptoms achieved biochemical remission. Three (15.78%) patients had resistance to EMACO and were given EP-EMA. Four (21.05%) patients underwent an adjunctive hysterectomy. Two patients had a histopathologic result of choriocarcinoma, and one had an invasive mole. Two (10.52%) patients died of cerebral hemorrhage during treatment. One patient (5.26%) could not continue her chemotherapy because she got pregnant before her first consolidation course. The median follow-up was 25.35 months. Six patients were contacted, and five (83.33%) had resumed a normal life. There were fourteen early deaths. Causes of death were cerebral hemorrhage in nine (64.28%) patients, gastrointestinal hemorrhage in two (14.28%) patients, pulmonary embolism in two (14.28%) patients and pulmonary hemorrhage in one (7.14%) patient. After excluding early deaths, the proportion of patients surviving between 1 to 3 years was at 84% and those surviving past 3 years was 76%. The median survival was approximately 2.5 years. <b>Conclusions:</b> Brain metastasis continues to bear a poor prognosis despite the early institution of chemotherapy.

Early mortality continues to be a barrier to excellent survival in childhood acute promyelocytic leukemia: a retrospective study of 62 patients spanning 17 years

Data on childhood acute promyelocytic leukemia (APL) from low-and middle-income countries is limited. Early mortality is a concern and often not highlighted in clinical trials. The retrospective study was conducted on patients (≤12 years) with APL from 2003 to 2021 at a single center in India. Patients were treated with all-trans-retinoic acid (ATRA) and chemotherapy. Induction and three courses of consolidation were followed by maintenance for 2 years. In 2015, the protocol was updated with following modifications: (a) obtaining diagnostic cerebrospinal fluid at end-of-induction rather than at diagnosis, (b) administering intrathecal cytarabine regardless of risk-category, (c) risk-stratified administration of chemotherapy, and (d) inclusion of ATRA in all the cycles of consolidation. Sixty-two patients were diagnosed over the 17 years. The median age was 8 years (range: 0.9–12). Half had high-risk disease. Differentiation syndrome was observed in 32%, none being fatal. Eighteen (29%) patients died due to hemorrhage (83%) or septicemia (17%). Thirteen (21%) had early mortality (≤15 days), all due to hemorrhage. A platelet count <20 × 109/L predicted early mortality (odds ratio: 4.5; 95% CI: 0.9–22, p = 0.06). Treatment abandonment reduced from 23.5% during 2003–2015 to nil during 2015–2021 (p = 0.006). Three (8%) patients relapsed. The 4-year OS of all patients and the patients who survived >15 days was 70.1% and 89.6%, respectively. The 4-year EFS, including abandonment and early mortality, before and following updated protocol, was 61.4% and 65.5%, respectively (p = 0.77). Early mortality continues to be a barrier to an otherwise excellent survival in childhood APL. A significant reduction in treatment abandonment in recent years is gratifying.