Reinduction Therapy Research Articles

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

Lenalidomide Consolidation Added to Rituximab Maintenance Therapy in Patients Remaining PET Positive After Treatment for Relapsed Follicular Lymphoma: A Phase 2 Australasian Leukaemia & Lymphoma Group NHL26 Study.

Outcomes After Salvage Autologous Hematopoietic Cell Transplant for Patients With Relapsed/Refractory Multiple Myeloma: A Single-Institution Experience.

The role of salvage autologous hematopoietic cell transplantation (sAHCT2) for patients with relapsed/refractory multiple myeloma (RRMM) in the era of modern therapeutics is unclear. As prospective data is limited, we conducted a retrospective analysis to determine the outcomes of sAHCT2. We conducted a single-institution, retrospective analysis of patients who received sAHCT2 at The Ohio State University from 2000 to 2018. Patients who received a second transplant as part of a planned tandem or autologous-allogeneic transplant were excluded. Fifty-seven patients were treated with sAHCT2. Patients had a median of 2 lines of therapy after AHCT1 prior to their sAHCT2; 70% had prior immunomodulatory imide drugs, 82% had prior proteasome inhibitor, and 20% had prior anti-CD38 monoclonal antibodies as part of re-induction therapy. Forty-two percent of patients attained ≥VGPR prior to sAHCT2. Seventy-four were treated with melphalan 200 mg/m2 as conditioning regimen before infusion of a median of 3.8×106 CD34+ cells/kg. Fifty-eight percent patients had maintenance therapy and 81% patients attained CR/VGPR as the best response after sAHCT2. The median PFS and OS after sAHCT2 were 1.6 and 3.6 years, respectively. On multivariable analysis, high-risk cytogenetics, not having attained CR/VGPR, and having more than 2 lines of therapy post-AHCT1 were associated with inferior PFS. Melphalan 140 mg/m2 compared to melphalan 200 mg/m2 and no maintenance therapy compared to maintenance therapy were not associated with inferior PFS. There was no transplant-related mortality in this patient cohort. For MM patients deriving durable remission after their AHCT1, sAHCT2 was safe and resulted in deep and durable remissions.

P436 Efficacy and safety of intravenous ustekinumab re-induction therapy in Crohn’s disease patients with secondary loss of response to ustekinumab maintenance therapy: Week 16 results from the POWER trial

Abstract Background After successful induction, a subset of patients with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. The phase 3b randomised, double-blind, multicentre POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD patients with LoR to standard UST every 8 weeks (q8w) maintenance therapy. Methods Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and subsequently experienced LoR were included. LoR for inclusion was defined as CDAI score of ≥220 and ≤450, in addition to elevated CRP (>3mg/L), fCal (>250mg/kg) or endoscopy performed ≤3 months before W0 with evidence of active CD (≥1 ulcerations in the ileum and/or colon). At baseline (W0), randomised patients received either ~6mg/kg IV UST/SC placebo (IV arm), or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing in both groups at W8/16. Clinical and biomarker assessments were made at W0/8/16 and optional ileocolonoscopy at W0/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0/CDAI <150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16. Results The analysis set comprised 215 patients at W0 (IV, n=108; SC, n=107). At W16, 92.6% and 86.0% completed treatment from IV and SC arms, respectively. In both arms (IV, 58.3%; SC, 57.9%) most patients experienced ≥2 biologic failures before initiating UST (Table 1). At W16, 49.1% in the IV arm and 37.4% in the SC arm achieved CRes (p=0.089). Percentages of patients with normalisation of fCal, normalisation of CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in the IV vs SC arm (Table 2). At W16, similar proportions of patients had ≥1 adverse event (AE) (IV, 60.2%; SC, 61.7%) and serious AEs (IV, 5.6%; SC, 5.6%). The proportions of patients with infections were similar between arms (IV, 23.1%; SC, 21.5%), with only 1 serious infection in each arm. Conclusion POWER is the first randomised, controlled, double-blind trial to assess the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. The CDAI-based primary endpoint at W16 was not met. However, patients in this heavily pre-treated population who received IV re-induction showed clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes.

Re-induction therapy in patients with acute myeloid leukemia not in complete remission after the first course of treatment.

A standard salvage regimen for patients with acute myeloid leukemia (AML) who are not in complete remission (CR) after initial induction therapy does not exist. We retrospectively investigated re-induction therapy for 151 patients with AML who did not achieve CR after the initial course between January 2014 and March 2021. The re-induction regimen did not correlate with the CR rate after the second course, whereas patients had similar 5-year overall survival (OS) and event-free survival (EFS) based on different re-induction regimens. Multivariable analysis revealed that International European Leukaemia Net (ELN) risk stratification independently predicted both OS and EFS among patients not in CR after the first course, although the re-induction regimen did not predict prognosis. Urgent salvage alloHSCT may improve the prognosis of patients with refractory AML. In summary, our study showed that the re-induction regimen did not significantly predict the prognosis of patients with AML not in CR after the first course of treatment. The development and selection of an efficient treatment algorithm for the treatment of AML remains a pressing research challenge.

Comparison of Hidac Versus FLAG-IDA in the Treatment of Relapsed Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Retrospective Study

Background Relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are associated with a poor prognosis. It is not known which re-induction therapy provides the highest chance of durable remission. Commonly used re-induction therapies are high dose cytarabine (HiDAC) and triple therapy consisting of fludarabine, cytarabine, idarubicin combined with granulocyte-colony stimulating factor (FLAG-IDA). Re-induction is mostly followed by consolidation therapy consisting of allogeneic stem cell transplantation (SCT) or donor lymphocyte infusion (DLI). In this study, we retrospectively compared the outcomes of HiDAC and FLAG-IDA in patients with relapsed AML or MDS. Patients and methods Two patient cohorts with relapsed AML or MDS treated between October 2015 and December 2021 in two different academic hospitals (Academic Medical Center (A) and VU Medical Center (B)) in Amsterdam, The Netherlands, were compared. Patients at center A were treated with HiDAC, while those at center B were treated with FLAG-IDA as re-induction therapy. Clinical and laboratory data were systematically collected and retrospectively analysed. Outcome measures, including complete remission (CR), overall survival (OS) and event-free survival (EFS; defined as survival until refractory disease, relapse or death), were compared between both cohorts. Results A total of 47 adult patients with a relapsed AML or MDS had been treated with either HiDAC (n=22) or FLAG-IDA (n=25). The two groups did not differ in age, sex or risk classification (see Table 1). In the HiDAC group, 64% of patients had previously undergone an allogeneic SCT compared to 44% in the FLAG-IDA group. HiDAC and FLAG-IDA resulted in comparable rates of CR (71% vs. 74%, P=0.85), 1-year OS (47% vs. 51%, P=0.99, see Figure 1A) and EFS (38% vs. 35%, P=0.71, see Figure 1B). The proportions of patients receiving consolidation treatment (allogeneic SCT or DLI) after re-induction were also comparable between the groups (64% vs. 60%, P=0.42). Patients who received HiDAC had significantly shorter durations of neutropenia and thrombocytopenia compared to patients treated with FLAG-IDA (median 24 days (IQR 20-26) vs. 30 days (22-39), P=0.014, and 22 days (17-26) vs. 36 days (26-53), P<0.001 respectively). The number of transfused pools of thrombocytes was also significantly lower in patients treated with HiDAC compared to those treated with FLAG-IDA (9 (6-14) vs. 12 (9-21), P=0.046). The number of transfused units of red blood cells was significantly higher in the FLAG-IDA group. However, since patients were kept on a higher hemoglobin level at center B than center A, we did not include this comparison in our analysis. The incidence of adverse events was similar in the two treatment groups. Conclusion While remission rates and survival outcomes were similar between both groups, FLAG-IDA was associated with longer periods of myelosuppression and transfusion dependency compared to HIDAC. Although limited by the retrospective design and relative small number of patients, these results favor HiDAC over FLAG-IDA as re-induction therapy for relapsed AML or MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time to Abandon the Day 14 Bone Marrow Biopsy in Acute Myeloid Leukemia Patients Receiving Induction Chemotherapy

Background: Bone marrow biopsy on day 14 of induction therapy for patients with acute myeloid leukemia (AML) is a common practice to determine whether re-induction therapy is warranted. A second bone marrow biopsy on day 28 is performed to assess remission status. We desired to explore what proportion of patients received bone marrow biopsies on day 14 at our institution, how many of these biopsies had disease present, and how these results affected clinical decision-making regarding whether re-induction was pursued. We compared outcomes of patients that received re-induction therapy based on bone marrow biopsies on day 14 versus on day 28 or later. Methods: A single-center retrospective study was performed detailing 252 AML patients that underwent induction therapy between December 1999 and December 2021. Pathology reports were reviewed to document the disease status at day 14 post induction with "7+3” regimen. Response to induction therapy was defined per standard definitions. Statistics are descriptive. Results: Of the 252 patients, 95 had bone marrow biopsies on day 14. Of these patients, 80 had adequate bone marrow sampling to quantify blast cell percentage. Thirty-four of these patients had no detectable blast cells while 46 had some evidence of disease. Of these 46 patients five (11%) had disease but less than 5% blast cells, 19 (41%) had between 5 and 20% blasts, and 22 (48%) had greater than 20% blasts. Of the 46 patients that still showed some evidence of disease, 7 (15.2%) underwent re-induction. This accounted for 2.78% of the total number of patients. One patient was re-induced with less than 5% blasts, 4 with between 5-20% blasts, and 2 with greater than 20% blasts. The rate of complete remission in patients who received re-induction therapy was 50% for day 14 patients and 46.7% for day 28 or later patients (P<0.43). Of the 15 patients with <20% blasts, 14 had a repeat biopsy and 9 (64.3%) went into remission without re-induction therapy. In the 20 patients with >20% blasts, 18 had a repeat biopsy and 5 (27.8%) went into remission without re-induction. Conclusions: Even in patients that had evidence of disease on day 14 bone marrow biopsy only a fraction received re-induction therapy. The rates of complete remission were very similar between patients who underwent re-induction based on day 14 bone marrow biopsy results compared to day 28 or later. Increasing availability of lower intensive regimens might lead to more treatment options and further reduce the need for re-induction based on day 14 disease assessment. Future trials need to reevaluate the need for routine evaluation of disease burden on around day 14 post induction therapy.

Outcomes of Patients Treated with Low-Intensity Re-Induction Therapy for Persistent Disease after a Single Intensive Induction Cycle for Newly Diagnosed Acute Myeloid Leukemia (AML)

Introduction: Intensive chemotherapy with 7+3 or CPX-351 remains standard of care for fit adults with newly diagnosed AML. Nearly 50% achieve a remission after one induction cycle, and up to an extra 20% can achieve remission after a second intensive cycle. However, intensive re-induction increases morbidity through significant prolongation of cytopenias. Furthermore, certain patients (pts) may be less likely to respond to intensive re-induction, namely those with adverse risk disease. Recently, with effective non-intensive options, such as venetoclax (Ven) combinations, or IDH inhibitors, we offered low intensity re-induction to select pts with persistent disease after initial intensive therapy as a potential means of reducing morbidity, and potentially improving chance for response. This study describes the characteristics and clinical outcomes of pts with residual disease after intensive induction, treated with either Ven or IDH inhibitor re-induction. Methods: A chart review of ND-AML pts treated between 1/2017 and 2/2022 was performed. We identified pts who either received 7+3 or CPX-351 for initial induction. We then selected pts who had a nadir BM biopsy demonstrating persistent AML (>5% blasts), who then received either a Ven combination or an IDH inhibitor as next treatment. To characterize pt burden, we collected hospitalization duration, PRBC and platelet transfusion burden over 30 days after re-induction, neutropenic fever rates, ICU admission rates, and death within 30 days. We also collected clinical outcomes including CRc after 1 cycle of therapy, best response, proportion of pts proceeding to allogeneic HCT (alloHCT), and leukemia free survival (LFS). Results: A total of 15 pts were identified. Median age of pts was 61 years (22-67), 5 (33%) pts had ELN intermediate risk disease, 10 (67%) pts had ELN adverse risk disease; 5 (33%) pts had mutations in IDH1/2, and 4 (27%) pts had mutations in TP53. Most pts, 11 (73%), received initial induction with 7+3 chemotherapy; on post induction nadir marrow, a median 34% (10-90%) blasts were observed. For re-induction, 11 (73%) pts received a Ven combination (either with decitabine or azacitidine), and 4 (27%) received an IDH1 inhibitor (with azacitidine in 2 pts). Most common reason documented for re-induction choice was adverse risk disease, followed by presence of IDH mutation, followed by loss of fitness for additional intensive therapy. Median hospitalization duration from induction day 1 was 27 days (20-41); median time in hospital after re-induction was initiated was 6 days (0-27). After initiation of re-induction therapy, over the next 30 days, median number of PRBC transfusions administered to these pts was 1 (0-8), median number of platelet transfusions was 2 (0-17). Overall, 2 (13%) pts were re-hospitalized for neutropenic fever, including 1 (8%) pt who was admitted to the ICU and subsequently died (Table 1). In terms of response, 9 (60%) pts achieved a CRc after one cycle of low-intensity therapy. This includes 6 pts who received a Ven combination, and 3 patients who received ivosidenib (with or without azacitidine). Subsequently, 8 (73%) pts on a Ven combination achieved a CRc as best response, and 4 (100%) pts achieved CRc utilizing ivosidenib (Table 1). Ten (67%) pts proceeded to alloHCT. Overall, median leukemia free survival was 377 days (95% CI 235-518), and 7 (47%) pts remain alive at last follow-up (Figure 1). Conclusion: Among pts with residual disease after initial intensive induction, switching to a Ven combination or IDH inhibitor potentially reduces pt burden through shorter hospital stays, and lower burden of neutropenic fevers and transfusions. Furthermore, this strategy has promising efficacy, and serves as a successful bridge to alloHCT. A control cohort of pts receiving intensive re-induction is being composed from pts treated at our institution and will add further context. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed or Refractory Acute Leukemia

Introduction: Current guidelines support allogeneic hematopoietic cell transplantation (allo-HCT) in patients with acute leukemia who achieve complete remission (CR) and are at high risk for relapse. Patients with primary refractory disease or those refractory to re-induction therapy after relapse have a poor prognosis in the absence of allo-HCT. While several studies have addressed the role of allo-HCT in those settings, the measurable benefit of allo-HCT has not been defined in such patients. Most previous studies have included patients who received myeloablative conditioning and did not address the possible impact of molecular genetic risk factors. Objective: The present study assessed outcomes of allo-HCT in patients with refractory or relapsed (R/R) acute leukemia receiving myeloablative (MAC) or reduced intensity conditioning (RIC) regimens. Our goal was to identify novel risk factors associated with improved outcomes to aid patient selection in the setting of R/R acute leukemia. Methods: Patients with R/R acute leukemia undergoing allo-HCT at Memorial Sloan Kettering Cancer Center (MSK) between 2009 and 2020 were included. Patients had a marrow blast count of 5% or more at the time of allo-HCT and were classified into one of the following categories: primary induction failure (PIF), at least 2 lines of induction therapy; not in CR (NCR), no more than one line of induction therapy; untreated relapse (UR); and refractory relapse (RR), no remission after at least one line of re-induction therapy for relapse. Results: We identified 101 patients with acute myeloid leukemia (AML; n=94), acute lymphoblastic leukemia (ALL; n=3), biphenotypic acute leukemia (n=2), and plasmacytoid dendritic cell leukemia (n=2). Table 1 depicts patient and transplant characteristics. Median blast count at the time of allo-HCT was 8% (IQR, 5%,15%). 37 patients had at least one genomic alteration, and 30 patients had circulating blasts at the time of transplant. Grafts were from HLA-identical siblings in 30 patients, from HLA-matched unrelated donors in 51 patients and from HLA-mismatched or HLA-haploidentical donors in 20 patients. 61 and 40 patients received MAC and RIC, respectively. Graft source was unmodified bone marrow (n=8), unmodified peripheral blood stem cells (PBSC; n=80), or CD34+ cellselected peripheral blood stem cells (n=7). Overall survival (OS) at 4 years was 25% (95% CI: 18%, 35%). In univariate analysis, RIC (HR 1.71, p=0.035), presence of circulating blasts (HR 2.21, p=0.002), and high pre-transplant ferritin levels (HR 1.43, p=0.049) were associated with inferior OS. In multivariate analysis, RIC was associated with reduced OS. The 4-year cumulative incidence of relapse/disease progression and non-relapse mortality (NRM) was 54% (95% CI: 43%, 63%) and 24% (CI, 16%, 33%) respectively. In univariate analysis, RIC, presence of circulating blasts, and elevated pre-transplant ferritin levels were associated with increased NRM. In multivariate analysis, RIC and elevated pre-transplant ferritin levels were associated with high NRM. The cumulative incidence of acute graft-vs-host disease (aGVHD) was 45% (95% CI: 35%, 54%) at day 100. There was no statistically significant effect of genomic and molecular parameters on NRM and OS. However, high risk molecular mutations (TP53, RUNX1, ASXL1 or FLT3-ITD) had borderline association with relapse/disease progression (HR 1.7, p=0.073). Conclusion: Allo-HCT provides durable remission in a select group of patients with relapsed or refractory acute leukemia with an OS of 25% at 4 years. The presence of circulating blasts and elevated ferritin levels at the time of allo-HCT was associated with increased NRM and inferior OS in this retrospective analysis. Known high-risk gene mutations did not affect outcomes in this population. The impact of these parameters should be evaluated in a larger cohort of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Inotuzumab Ozogamicin Induction Followed By Standard Chemotherapy Yields High Remission Rates and Promising Survival in Older (>55 Years) Patients with De Novo B-Lymphoblastic Leukemia (GMALL-Initial1 Trial)

Introduction: Acute lymphoblastic leukemia (ALL) represents approx. 5% of all newly diagnosed leukemias in patients (pts) between 55 and 70 years of age. Incorporation of novel antibody-based therapies in the first line induction therapy bears the potential of a significantly increased response rates and survival together with a reduction of treatment toxicity. Methods: This open label phase II study (ClinicalTrials.gov, identifier: NCT03460522) of the German Multicenter Study Group on Adult Acute Lymphoblastic Leukemia was conducted at 13 centers. Pts aged >55 years with newly diagnosed Ph/BCR-ABL negative B-precursor ALL (at least CD20 positivity of leukemic blasts) were eligible. The 1st induction cycle consisted of InO 0.8mg/m2 on day1 and 0.5mg/m2 on d8 and d15 together with dexamethasone 10 mg/m2 (day7-8, day14-17) and one intrathecal injection (i.th.) of methotrexate (MTX), cytarabine (AraC) and dexamethasone (Dex). The 2nd and 3rd induction cycle consisted of InO 0.5mg/m2 on day 1, 8 and 15 plus i.th. MTX/AraC/Dex. Pts achieving a complete remission (CR) were offered to receive 5 conventional consolidation therapies (3 x ID-MTX/asparaginase; 2 x ID-AraC) and one reinduction therapy (idarubicine/ AraC/ cyclophosphamide / Dex.) in combination with rituximab (for CD20+ ALL), followed by a maintenance therapy with 6-MP/MTX. The primary endpoint was event free survival (EFS) at 12-months follow-up. An event was defined as any of the following: persisting bone marrow blasts after 2 cycles of InO, relapse or death. An event rate of ≤40% at 12 months follow-up was considered to qualify the experimental treatment as very promising for additional testing. Results: 43 out of the 45 pts included were analyzed regarding the primary end point. Two pts were excluded per protocol from further analysis, as they received only one cycle of induction or withdraw consent. At diagnosis, median age was 64 years (range 56-80 years, 20 pts ≥65 years and 12 pts ≥70 years), median bone marrow blast count was 80% and median CD22 expression on leukemic blasts was 69% (range 21-99). 38 pts were diagnosed with a common- and 5 with a pro-B ALL. 42/43 pts completed all 3 cycles of induction therapy. All 43 pts achieved a complete remission (CR/CRi), mainly after the 1st induction. Median time between start of 1st induction to start 2nd induction, from 2nd to 3rd induction and from 3rd induction to 1st consolidation therapy was 21 days, 28 days and 30 days, respectively. Results of minimal residual disease (MRD), measured by real-time quantitative PCR, are available for all 43 pts, with 23/43 (53%) and 31/42 (74%) pts being MRD negative after 2nd and 3rd induction therapy, respectively. With a median follow-up of 697 days, the probability of OS at 1 and 2 years is 91% (95% C.I. 82-99%) and 81% (95% C.I. 69-94%), respectively. No patient died within the first 6 months after start of induction therapy. 5 events occurred within the first year after study inclusion, 3 deaths in CR and 2 relapsed ALL, resulting in event rate of 12% and a probability of EFS at 1 year (primary endpoint of the study) of 88% (95% CI 79-98). EFS at 2 years was 73% (95% CI 59-88). So far, 7 pts with persisting/reappearance of MRD (2 pts) or relapse (5 pts) were treated with blinatumomab. 9 pts received an aSCT (4 pts in CR1 and 5 pts >CR1), 6 of these pts are alive in CR. Regarding adverse events (AEs) during induction cycles 1, 2 and 3, most common AEs ≥CTC grade 3 reported were leukocytopenia (in 74%, 19% and 2% of all cases, respectively), anemia (37%, 5%, 0%), thrombocytopenia (49%, 7%, 2%) and elevation of liver enzymes (14%, 5%, 0%). One patient was reported with suspected veno occlusive disease (after 2nd induction therapy). Classical factors which may be associated with inferior survival outcomes like age, diagnosis of pro-B ALL, disease burden at diagnosis, co-morbidity or no MRD negative CR after induction had no significant impact on OS or EFS. Conclusion: Three cycles of InO as induction therapy for the treatment of older pts with de novo acute B-lymphoblastic leukemia resulted in a very high remission rate. Given that our study met the primary end point (predefined event rate at 1 year ≤40%, observed event rate 12%), these promising study results could be a rationale for integrating InO induction therapy in future treatment recommendations. Ideally, this novel induction therapy should be evaluated in prospective randomized trials. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Delineation of Predictive Features of AML Patients with Recurrent Relapse Who Achieved Repeated Complete Remission after Multiple Re-Induction and Consolidation Therapies

Delineation of Predictive Features of AML Patients with Recurrent Relapse Who Achieved Repeated Complete Remission after Multiple Re-Induction and Consolidation Therapies

Reduced Intensity Reinduction Followed By Blinatumomab Achieves Excellent MRD Clearance with Reduced Toxicity and Facilitates Timely Transplant in Children and Young People with Relapsed B-Precursor Acute Lymphoblastic Leukemia

Introduction Despite the emergence of effective novel immunotherapies, the outcome of relapsed pediatric B-cell acute lymphoblastic leukemia (B-ALL) remains poor due to treatment-related mortality (TRM) and resistant disease. In response to accumulating evidence on the efficacy and low toxicity of blinatumomab in relapsed B-ALL and the availability of highly active CD19-targeted chimeric antigen receptor T-cell therapy (CART), we redesigned the United Kingdom (UK) relapse treatment pathway, based on two key guiding principles: 1) to reduce chemotherapy burden and associated toxicity through a move away from the highly intensive ALL R3 backbone towards increased reliance on blinatumomab to clear disease, and 2) to identify treatment failures early and direct them to CART, given the poor responses reported with hematopoietic stem cell transplant (HSCT) in this context. Methods Patients were treated with UKALL induction chemotherapy (<16yr: 3-drugs; >16yr: 4-drugs) until adequate blast clearance. Patients with blasts <5% at Day 15 progressed directly to blinatumomab; remaining patients continued to Day 28. Following reinduction, patients received up to 2 cycles of blinatumomab as a single agent. HR patients (early/very early relapses and/or HR cytogenetics) proceeded to HSCT once minimal residual disease (MRD) <0.01%. Those with high-risk (HR) isolated central nervous system (CNS) disease had the option to proceed directly to HSCT following CSF blast clearance without blinatumomab. All Standard risk (SR) patients continued on chemotherapy alone. Patients who were refractory after re-induction (>25% disease), blinatumomab (MRD >0.01%), or for whom there was no available donor were considered for CART. All patients were required to be discussed at a national tumour board, and data were subsequently collected every 3 months for analysis. Events were defined as death, relapse, and secondary cancer. Results Between September 2018 and July 2022, 111 patients were treated on the pathway; 63 (56.8%) were HR and 48 (43.2%) were SR. There were 26 patients >15yr, 3 Infant ALL, 2 Ph+ ALL and 4 with Down Syndrome. Induction therapy achieved disease reduction to <5% and CNS clearance in 98 patients (88%). Of the 90 patients with BM involvement, 52.2% required only 15 days of induction therapy. Induction failure (>25% blasts) occurred in 6.3%, comparable to the 7.1% using the R3 induction in the COG AALL1331 trial (p=1.00); 6/7 patients with induction failure successfully underwent CART infusion. The rate of end of induction MRD <0.01% in the HR group was also similar to COG AALL1331 (30% vs. 27.4%, p=0.669). Importantly, there were no cases of TRM with the reduced intensity induction, compared to 2.4-4% reported with the ALL R3 induction (p=0.06). Ninety patients received blinatumomab, of whom 87% achieved a complete MRD response, with grade 3 or 4 treatment-related toxicity in 11 patients (12.2%). Amongst HR patients, 86.8% underwent HSCT, significantly more than in the blinatumomab-treated IR/HR arm of COG AALL1331 (66%, p=0.02). With a median follow-up of 12 months (range 2-49), 19% of HR patients and 8.3% of SR patients have relapsed, comparable to results achieved in the blinatumomab-treated arm of the COG AALL1331 trial. There were no deaths in the SR group, and 12 deaths in the HR group (6 due to relapse/refractory disease, 6 due to post-HSCT TRM). Conclusions Our findings demonstrate that a reduced intensity reinduction can achieve equivalent disease control to the more intensive ALL R3 induction, with a substantial reduction in TRM. Although follow-up is short, consolidative blinatumomab achieved very high rates of MRD clearance, allowing a greater number of HR patients to reach potentially curative therapy with HSCT, the key predictor of outcome in the COG AALL1331 trial. We propose that our strategy represents a new standard of care for reinduction therapy in relapsed childhood B-ALL. DO and AV are joint senior authors Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Maintenance Therapy with Combination of Azacitidine, Danazol and Thalidomide after Intensive Chemotherapy in Acute Myeloid Leukemia Patients

INTRODUCTION Despite the efficacy and outcome of AML patients increases in recent decades, the rate of relapse is still high, especially in the patients who are ineligible for allo-HSCT. How to prevent relapse is still a major therapeutic challenge. Recently, several drugs including Azacitidine (AZA), CC-486, Lenalidomide, androgen, Midostaurin, etc, used as maintenance therapy have shown a better EFS or OS, indicating that maintenance therapy is an important aspect of AML treatment. Herein, we reported the data of 11 AML patients who were administered AZA combined with Danazol (DNZ) and Thalidomide (THD) as maintenance therapy after intensive chemotherapy (IC). The purpose of this study was to observe the efficacy and safety of this maintenance therapy. METHODS Between Feb 2017 and Mar 2021, 11 patients diagnosed with AML were treated at the Baiyun Hospital. The induction therapy involved daunorubicin (DNR) 60 mg/m2/day on days 1-3, cytarabine (Ara-c) 100 mg/m2/day on days 1-7. If the patient did not achieve CR, salvage therapy was administered. Post-remission, three cycles of consolidation chemotherapy with high-dose Ara-c (3g/m2/q12h d1-3) and two cycles of reduced dose of chemotherapy (DA/HA/EA) were administered. Patient remained in CR after IC and was treated with 6-8 cycles of AZA combined with DNZ and THD maintenance therapy. AZA subcutaneous injection at 100 mg/day (approximate 50-75 mg/m2/day) d1-7, DNZ 200 mg Bid and THD 100 mg/day po followed by AZA, every four weeks. After completing the 6-8 cycles, patients continued the maintenance therapy with DNZ and THD for at least three years unless relapse or intolerance occurred. Disease evaluation included bone marrow and blood test until the duration of CR over five years. RESULTS Between Feb 2017 and Mar 2021, 11 patients who were enrolled in this study. Baseline patient and disease characteristics are summarized in Table 1. All 11 patients were treated with DA induction therapy, 10 patients achieved CR, 1 patient achieved remission after salvage therapy. 10 of 11 patients completed all consolidation therapies. 1 patient diagnosed AML with t (8;21) refused to continue chemotherapy because of renal failure after CR, and was directly switched to maintenance therapy. 9 0f 10 patients completed all IC and started on maintenance therapy. 1 AML with t (8;21) patient relapsed after stopping chemotherapy for two months and achieved CR2 by FLAG re-induction therapy refused continued chemotherapy and transplantation, and was directly switched to maintenance therapy. All patients received a median of 7 (6-12) courses of AZA combined with DNZ and THD maintenance therapy. Treatment was well tolerated and accepted by the patients. Common adverse events included mild neutropenia, thrombocytopenia, and elevated aminotransferase. No patient discontinued the maintenance therapy due to adverse events. Until June 2022, the median follow-up time was 37 (14-63) months. The RFS at 1-year and 3-years was 100% and 71.1%; the OS at 3-years was 100%, respectively (Figure 1a, 1b). All 11 patients, 3 died and 8 patients were alive with RFS. Of the 3 patients who died, 1 relapsed at 36 months and died due to disease progression at 46 months. The remaining 2 patients, one was diagnosed and died with secondary mixed phenotypic acute leukemia (NOS, T/My), the other died in a road accident. Notably, 2 cases of AML with t (8; 21) (one patient relapsed after IC, another patient developed renal failure) remained in CR by the end of follow-up. The CR duration was 24 and 13 months, respectively. The clinical outcomes of maintenance therapy after IC treatment for 11 patients are summarized in Figure 1c. Conclusion: AZA combined with DNZ and THD maintenance therapy is safe and effective in AML patients who are ineligible for allo-HSCT. Keywords: Azacitidine; Danazol; thalidomide; maintenance therapy; AML Figure 1 Response and long-term outcomes of the entire cohort Figure 1 legend, a. Relapse-free survival of the 11 patients. b. Overall survival of the 11 patients. c. Swimmer plot of the 11 patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Inotuzumb Ozogamicin on Outcome in Relapsed or Refractory Acute B-Lymphoblastic Leukemia Patients Prior to Allogeneic Hematopoietic Stem Cell Transplantation

Background: The outcome of patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) is poor. At present, allogeneic hematopoietic stem cell transplantation (allo-HCT) is considered the only curative option for patients with r/r B-ALL with best outcomes achieved after effective salvage re-induction therapy and transplantation in complete remission (CR). Veno-occlusive disease, also known as sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of allo-HCT. Inotuzumab ozogamicin (INO) is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, developed as a targeted therapy for B-cell malignancies. Rate of VOD/SOS is increased after therapy with INO. Aims: To characterize a series of relapsed/refractory (r/r) ALL patients (pts) and evaluate outcome after treatment with INO prior to allo-HCT, particularly with respect to risk of VOD/SOS. Methods: We studied 25 r/r pts (median age, 34 years; range, 16-64 years), who were treated with INO between 2016 and 2022 within a compassionate use program (n=7) or in-label after EMA approval (n=18) One of the 25 pts were previously treated with tyrosine kinase inhibitors for chronic myeloid leukemia and progressed to blast crisis of B-lymphoid lineage. All 25 pts were CD22 positive at relapse/progressive disease. Up to 4 INO cycles (≤2 cycles, n=22; 3-4 cycles, n=3) were administered according to the previously approved regimen. Results: At the time of r/r B-ALL median white blood cell and platelet counts were 47.1/nl (range, 1.3-300/nl) and 33.5/nl (range, 5-313/nl), respectively. Five pts (20%) were female; ECOG was ≤ 2 in all pts. Cytogenetic analysis at the time of r/r EM-ALL was available in 14 pts. Six pts displayed a t(9;22), 6 had a normal karyotype, 1 was complex and 1 had a deletion 6q as well as trisomy 13. Seventeen (68%) patients achieved CR after the first INO cycle. Prior to allo-HCT, 17 (68%) pts achieved CR, 3 (12%) a partial remission, 4 (16%) were refractory and one (4%) relapsed after CR achievement. Median follow-up was 41.6 months (95%-CI, 31.1-NR) and median overall survival (OS) was 9.0 months (95%-CI, 5.78-RD months; Figure 1). One- and two-years OS rates were 45.2% (95%-CI, 28.8-70.8%) and 40.7% (95%-CI, 24.8-66.7%), respectively. VOD/SOS after allo-HCT occurred in 7 (28%) pts. Of those, 5 pts died due to VOD and multi-organ failure, all had received ≤2 INO cycles. Risk factor for VOD/SOS was allo-HCT during first-line therapy (p=0.05), whereas age, gender, donor, dose intensity of conditioning or remission status before allo-HCT had no impact. Relapse/progressive disease occurred in eight (32%) pts and all pts succumbed of their disease. Cumulative incidences of relapse/progression or death after 12 months were 20.7% (standard error,E 8.5%) and 32.7% (standard error, 9.8%). Eight (32%) pts died in remission and nine (36%) pts are in ongoing CR. Conclusions: This outcome analysis demonstrates that treatment with INO is an effective approach with successful bridge-to-transplant. However, risk of VOD/SOS is high, necessitating continuous monitoring and recognition of VOD/SOS risk factors.

NUP98-HOXA9 Bearing Acute Myeloid Leukemia

Acute myeloid leukemia (AML) with NUP98-HOXA9 fusion gene is rare, which is caused by t(7;11)(p15;p15). Not only the prognosis is poor, the efficacy of conventional induction regimen is also barely satisfactory. Here we report two cases of NUP98-HOXA9 bearing AML. Patient 1 was a 54-year-old female. In September of 2019, she felt fatigue with complete blood count (CBC) result of leukocytes 246.78× 109/L, hemoglobin 81g/L, and platelet 119 × 109/L. Peripheral blood smear showed 5% blast cells, and bone marrow (BM) smear demonstrated AML-M5. Chromosome 46, XX, t (7; 11) (p15; p15) [20], NuP98/HOXA9 fusion gene, EVI1 expression, FLT3-ITD and KRAS mutation was also found in her BM. One course of standard induced chemotherapy regimen IA reached CR, with MRD＜10-4, low expression of EVI1, and FLT3-ITD(-)，normal chromosome, but NuP98/HOXA9（+）. After the second course of IA, relapse occurred partly due to delayed admission under the influence of COVID-19. Reinduction with IA, azacytidine +HE, FLAG regimen failed to reach remission, and the patient died of bone marrow suppression and gastrointestinal bleeding. Patient 2 was a 65-years-old male. In September of 2019, he suffered from fatigue and CBC showed leukocytes 2.52× 109/L, hemoglobin 36g/L and platelet 139 × 109/L. Peripheral blood smear showed immature cells of 7%, and his BM smear demonstrated AML-M4. Chromosome 46, XY, t (7; 11) (p15; p15) [18]/46, XY[1], NuP98/HOXA9 fusion gene and IDH2 R140Q mutation were found in the patient. He had a history of chemotherapy for small cell lung cancer. After induced by regimen of DIAG, DHEG and DCAG successively, he did not reach remission. Repeated fever and lung infection occurred during the course of the disease. He was discharged automatically due to the progression of lung cancer. NuP98/HOXA9 bearing AML is more common in young Asian women, and the majority is type M2. The two patients in this report were older with M4 or M5 type, which was rare in this kind of leukemia. NuP98/HOXA9 is a poor prognostic factor for AML. Patient 1 could reach cytogenetic CR after IA induction, relapsed before transplantation, and the effect of reinduction therapy was poor; Patient 2 did not achieve remission. It is suggested from the these patients that patients with NuP98/HOXA9 bearing AML should undergo hematopoietic stem cell transplantation as soon as possible after CR with intensive therapy if their physical conditions permit.

Acute lymphoblastic leukemia with the t(17;19) translocation: hope has appeared! Multimodal immunotherapy in a 3-year-old child with refractory disease: a case report

Acute lymphoblastic leukemia (ALL) with translocation t(17;19)(q21-q22;p13) TCF3::HLF (E2A::HLF) accounts for less than 1% of childhood B-lineage ALL. Since the first description, patients with this type of ALL are stratified into high-risk group. The disease often has a unique clinical presentation with disseminated intravascular coagulation and hypercalcemia, that are uncommon in other types of B-lineage ALL. This type of ALL is characterized by an extremely poor prognosis despite intensive treatment and hematopoietic stem cell transplantation (HSCT) in the first remission. In the last decade, some new data on the mechanisms of leukemogenesis in this type of ALL made it possible to come closer to understanding the reasons for the high refractoriness to chemotherapeutic agents. Along with the reports on the possible effectiveness of the BCL-2 (venetoclax) and Aurora kinase A (alisertib) inhibitors in this type of ALL, cellular immunotherapy (various chimeric antigen receptor (CAR)-T cell constructs), anti-CD19 (blinatumomab) and anti-CD22 (inotuzumab ozogamicin) monoclonal antibodies appear promising in the treatment of this disease. To date, there are neither published data on direct comparisons of the effectiveness of these methods nor specific recommended therapy protocols for these patients. It is also unclear if the new therapeutic approaches can completely replace HSCT or they only increase relapse-free survival after it. Here, we review the data on this translocation published in the medical literature and present a case report of a 3-year-old boy with this type of leukemia, who did not respond to four-component induction therapy according to the ALL-MB 2015 Protocol and received anti-CD19 CAR-T therapy with the achievement of the first MRD (minimal residual disease)-negative remission, which lasted 11 months. After MRD-relapse and unsuccessful attempt at therapy with autologous CD19/CD22 CAR-T cells, the patient developed an extended isolated bone marrow relapse. He achieved the second MRD-negative remission after reinduction therapy with inotuzumab ozogomycin and received allogeneic HSCT from a related donor. At the time of writing, the patient is in complete molecular remission for 16 months after transplantation. The patient's parents have consented to the use of de-identified clinical information and photos of the patient in scientific research and publications.

Effect of cumulative daunorubicin dose on cardiotoxicity after allogeneic stem cell transplantation

Cardiotoxicity after allogeneic stem cell transplantation (SCT) is associated with a high rate of mortality and worsening quality of life. The relation between daunorubicin dose and post- allogeneic stem cell transplantation (SCT) cardiotoxicity remains unclear. We retrospectively evaluated 171 patients with acute myeloid leukemia (AML) who underwent their first allogeneic SCT at our institution between 2005 and 2021. High-dose daunorubicin (50 mg/m2/day for 5 days) and cytarabine were usually used as induction therapy for AML. The median cumulative daunorubicin dose was 310 mg/m2 (range, 0–950 mg/m2), and 43 patients received two courses of induction therapy with high-dose daunorubicin (daunorubicin doses of ≥500 mg/m2). Cardiotoxicity developed in 12 patients, and the cumulative incidence at 2 years after SCT was 7.1%. Univariable analysis revealed that female sex, left ventricular ejection fraction (LVEF) of < 60% before SCT, and daunorubicin doses of ≥ 500 mg/m2 were associated with cardiotoxicity. Multivariable analysis showed that a daunorubicin dose of ≥ 500 mg/m2 was an independent risk factor for cardiotoxicity. LVEF decline during the study was observed with an increase in the daunorubicin dose, and only a daunorubicin dose of ≥ 500 mg/m2 was associated with a pre-SCT decreased LVEF. Second induction therapy with high-dose daunorubicin is a risk factor for cardiotoxicity after SCT. This should be taken into consideration when determining reinduction therapies for SCT-eligible patients with relapsed or refractory AML.

The Clinical Characteristics and Prognosis of AYA and Older Adult ETP-ALL/LBL: A Real-World Multicenter Study in China.

Early T-cell precursor (ETP) lymphoblastic leukemia/lymphoma is a high-risk T lymphoblastic leukemia/lymphoma (T-ALL/LBL) subgroup. We performed a real-world multicenter study to explore the clinical characteristics and prognosis of adolescent and young adults (AYA) and older adult ETP leukemia/lymphoma. A total of 103 patients with ETP-ALL/LBL in five centers in China between January 2016 and February 2021 were included in this study. The median age was 29 years (range, 15–70 years). Next-generation sequencing was performed in 94 patients and revealed that NOTCH1 (35.1%, 33 cases) was the most frequently mutated gene, followed by JAK3 (16.0%, 15 cases), PHF6 (13.80%, 13 cases) and EZH2 (11.70%, 11 cases). Complete remission (CR) was obtained in 74.2% (72/97) of patients, and 6 relapsed/refractory patients received a decitabine combined with AAG priming regimen as reinduction therapy with a CR rate of 50%. With a median follow-up of 18 months (0.5–60 months), the 2-year overall survival (OS) and relapse-free survival (RFS) rates for the entire cohort were 54% and 57.7%, respectively. Allogeneic stem cell transplantation (allo-SCT) was performed in 59.8% (58/97) of patients. After landmark analysis at 6 months, the 2-year OS rates was 77% of patients with allo-SCT at CR1 and 25% of patients with chemotherapy alone (p < 0.001). A multivariate analysis suggested that allo-SCT and CR after the first course induction were independent prognostic factors for OS. Collectively, we reported the largest cohort study with AYA and older adult ETP-ALL/LBL, and we found that ETP-ALL/LBL was highly invasive and had a poor long-term prognosis. Allo-SCT could significantly improve ETP-ALL/LBL patient survival.

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 4.5mg/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.

Reinduction of an Anti-EGFR-based First-line Regimen in Patients with RAS Wild-type Metastatic Colorectal Cancer Enrolled in the Valentino Study.

BackgroundIn patients with RAS/BRAF wild-type metastatic colorectal cancer (mCRC), growing evidence supports anti-epidermal growth factor receptor (EGFR) retreatment, whereas little is known on the outcomes of anti-EGFR-based reinduction therapy during the upfront strategy.MethodsWe included patients enrolled in the Valentino study who had disease progression and received at least one dose of post-progression therapy. The Kaplan–Meier method and Cox proportional hazards regression were used for the survival analysis. When comparing the outcomes of anti-EGFR-based reinduction versus any second line, a propensity score–based matching was used.ResultsLiver-limited/single site of disease (P < .001 and P = .002), left-sidedness (P = .029), surgery of metastases (P = .003), early tumor shrinkage, and deeper responses (P = .018 and P = .036) were associated with the use of anti-EGFR-based reinduction versus any other second line. All patients treated with reinduction had an anti-EGFR-free interval of at least 3 months. In the propensity score–matched population, progression-free survival (PFS) was similar in the 2 treatment groups, the overall survival (OS) was significantly longer for patients treated with reinduction (P = .029), and the response rate was higher in patients treated with reinduction (P = .033). An oxaliplatin-free interval ≥12 months, left-sidedness, and molecular hyperselection beyond RAS/BRAF were associated with significantly better outcomes after anti-EGFR-based reinduction.ConclusionsReinduction strategies with anti-EGFR-based regimens are commonly used in clinical practice. Our data highlight the importance of clinical–molecular selection for re-treatments and the need for prospective strategy trials in selected populations.

Treatment of AML Relapse After Allo-HCT

With advances in allogeneic hematopoietic stem cell transplant (allo-HCT), disease relapse has replaced transplant-related mortality as the primary cause of treatment failure for patients with acute myeloid leukemia (AML). The efficacy of allo-HCT in AML is a consequence of a graft-versus-leukemia (GVL) effect that is mediated by T lymphocytes, and unique mechanisms of immune evasion underlying post-allo-HCT AML relapses have recently been characterized. Relapsed AML following allo-HCT presents a particularly vexing clinical challenge because transplant-related toxicities, such as graft-versus-host (GVHD) and infections, increase the risk of treatment-related morbidity and mortality. In general, the prognosis of relapsed AML following allo-HCT is poor with most patients failing to achieve a subsequent remission and 2-year survival consistently <15%. The two factors that have been found to predict a better prognosis are a longer duration of post-transplant remission prior to relapse and a lower disease burden at the time of relapse. When considered in combination with a patient’s age; co-morbidities; and performance status, these factors can help to inform the appropriate therapy for the treatment of post-transplant relapse. This review discusses the options for the treatment of post-transplant AML relapse with a focus on the options to achieve a subsequent remission and consolidation with cellular immunotherapy, such as a second transplant or donor lymphocyte infusion (DLI). While intensive reinduction therapy and less intensive approaches with hypomethylating agents have long represented the two primary options for the initial treatment of post-transplant relapse, molecularly targeted therapies and immunotherapy are emerging as potential alternative options to achieve remission. Herein, we highlight response and survival outcomes achieved specifically in the post-transplant setting using each of these approaches and discuss how some therapies may overcome the immunologic mechanisms that have been implicated in post-transplant relapse. As long-term survival in post-transplant relapse necessarily involves consolidation with cellular immunotherapy, we present data on the efficacy and toxicity of both DLI and second allo-HCT including when such therapies are integrated with reinduction. Finally, we provide our general approach to the treatment of post-transplant relapse, integrating both novel therapies and our improved understanding of the mechanisms underlying post-transplant relapse.