Higher Complete Remission Rate Research Articles

Idiopathic Granulomatous mastitis: Clinical characteristics, treatment and outcome in 380 patients

Background: Idiopathic Granulomatous Mastitis (IGM) is a chronic inflammatory disease of the breast. Although most of the studies have reported IGM as a rare disease, recent studies have shown an increase in the prevalence, especially in developing countries. The most important challenge is about the appropriate treatment of this disease that is not established yet. The aim of this cross-sectional study was to review the definite cases of IGM in terms of clinical characteristics and the result of treatment at Motamed Cancer Institute (MCI). Methods and Materials: This retrospective study was conducted on 383 women who were referred to Motamed Cancer Research Institute with a confirmed diagnosis of IGM for a two-year period from March 2015 to February 2018. The demographic and clinical characteristics and the result of treatment options were extracted from the patients’ medical records. The data was statistically analyzed using SPSS version 22. Results: Among 383 pathologically proven cases with IGM, the mean age was 35.6+7.593 years, 97% of them had a history of pregnancy and 95.2% had breastfed. The most common symptoms of the disease were palpable mass, pain, fistula to the skin and inflammation respectively. In response to the prescribed treatments, among 241 patients with available follow-up, the most commonly used treatment was Corticosteroids + Methotrexate (70.1%), the highest complete remission was in the group receiving Corticosteroid (100%) and Methotrexate (97%) respectively and the highest partial remission belonged to Corticosteroid+ Methotrexate with the frequency of 21.3%. The shortest time to complete remission belonged to Methotrexate regimen with a mean duration of 5.83 months and the highest recurrence rate was seen in the group receiving Corticosteroids alone (16.7%). Conclusion: According to the results of this study, among the prescribed treatments, the highest rate of complete remission with the lowest duration and recurrence rate belongs to Methotrexate regimen. Corticosteroids were associated with the high rate of complete remission but high rate of recurrence yet. Given the autoimmune nature of IGM, such results seem expectable and Methotrexate could be recommended especially in moderate to severe forms and as an additional treatment to taper Corticosteroids. Implementation of clinical trials regarding the best treatment options for IGM is recommended.

Comparative efficacy and safety of eleven induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia: a network meta-analysis

The optimal induction chemotherapy regimens for young adult patients with newly diagnosed acute myeloid leukemia (AML) are not well-defined since the lack of direct comparisons between emerging treatments. Network meta-analysis (NMA) is a statistical tool to integrate direct and indirect evidence to evaluate the effect of multiple interventions. Thus, we conducted an NMA to systematically assess the efficacy and safety of different inductions for these patients. PubMed, Embase, Cochrane Library, and Web of Science were searched from establishment to 2020-03-11. Randomized controlled trials (RCTs) using different inductions were included. We deemed 11 trials eligible, including 11 inductions with 5052 participants. Relative risk (RR) and 95% confidence intervals (CIs) were calculated. In terms of complete remission (CR) rate, DAC ranked highest and was significantly higher than IA (RR = 1.27, 95% CI (1.09-1.48)) and DA (RR = 1.28, 95% CI (1.13-1.46)) (p < 0.05). The ranking of DA + Pioglitazone was second only to that of DAC, followed by HAA. For early mortality, HAD, HAA, and DA + GO were significantly higher than DA/IA (p < 0.05). DAC and DA + Pioglitazone showed similar early mortality compared to DA/IA (p > 0.05). Regarding incidence of early grade 3-4 infection, no significant differences between interventions were observed. To conclude, among the included 11 induction regimens, DAC was potentially the top choice for young adult patients with newly diagnosed AML, with highest CR rate, low early mortality, and incidence of early infection. DA + Pioglitazone and HAA also showed a superiority over the others to achieve higher CR rate, while caution should be kept in mind due to the higher early mortality of HAA.

Treatments for Primary Delusional Infestation: Systematic Review.

Delusional infestation, also known as Ekbom syndrome, is a rare delusional disorder characterized by the fixed belief that one is infested with parasites, worms, insects, or other organisms. Although delusional infestation is a psychiatric condition, patients often consult dermatologists with skin findings, and it is currently unclear what treatments are recommended for this disorder. We aimed to systematically review and describe the treatment and management of patients presenting with primary delusional infestation. A systematic search was conducted using Ovid on MEDLINE, Embase, PsycINFO, and the Cochrane Register of Clinical Trials. Relevant data, including treatment, dosage, response, adherence, and side effects, were extracted and analyzed. A total of 15 case series were included, comprising 280 patients (mean age 53.3 years, 65.4% female) with delusional infestation. Overall, aripiprazole had the highest complete remission rate at 79% (11/14), although this was limited to 14 patients. Among drug classes, selective serotonin reuptake inhibitors were the most effective with a 79% (11/14) complete remission rate and 43% (9/21) partial remission rate in patients with comorbid depression, anxiety, or trichotillomania. First-generation antipsychotics and second-generation antipsychotics had similar complete remission rates (56/103, 54.4% vs 56/117, 47.9%, respectively) and partial remission rates (36/103, 35% vs 41/117, 35%, respectively). Due to the rarity of delusional infestation, we only found 15 case series. However, we found that first-generation antipsychotics appear to be similar in effectiveness to second-generation antipsychotics for the treatment of primary delusional infestation. Larger studies and randomized controlled trials are needed to evaluate the efficacy of pharmacological therapy for delusional infestation. PROSPERO CRD42020198161; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=198161.

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies.

Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.

Immunotherapy for microsatellite-instability-high advanced colorectal cancer

Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.

EP406: Germline 16p13.1 microdeletion identified during routine hematologic testing

Inversion 16 or translocation 16;16, resulting in CBFB::MYH11 fusion, accounts for approximately 5–8% of acute myeloid leukemia (AML) and is recognized by the World Health Organization (WHO) as a distinct entity within the category of AML with recurrent genetic abnormalities. It is critical to correctly characterize AML patients with CBFB::MYH11 fusion for appropriate diagnosis and the association with a favorable clinical prognosis (a high rate of complete remission and favorable overall survival). However, germline microdeletions spanning the MYH11 gene region are associated with a rare, but recurrent, 16p13.1microdeletion syndrome. We present this case series to highlight the risk of neoplastic versus germline mutational results involving the MYH11 locus and to initiate a discussion on standardization for reporting incidental germline findings in the setting of hematologic testing. We performed a retrospective review of the Mayo Clinic Cytogenetics Database and identified four cases that were tested using the Mayo homebrew CBFB::MYH11 dual-color, dual-fusion FISH (D-FISH) probe strategy and had a probable MYH11 germline microdeletion (Table 1). In 3 of 4 cases, loss of the MYH11 probe was observed in the absence of CBFB::MYH11 gene fusion. Since the MYH11 deletion was identified in 97-100% of nuclei in each of these cases, this result strongly suggested a germline 16p deletion. In addition, a MYH11 gene deletion is not associated with diagnostic or prognostic significance in the context of myeloid neoplasia. Germline 16p13.1 microdeletion syndrome is characterized by a broad spectrum of clinical phenotypes, with the most severely affected having intellectual disability, epilepsy and additional phenotypic features. However, the 16p13.1 microdeletion has also been identified in individuals with very mild clinical phenotypes and in apparently normal individuals, suggesting either incomplete penetrance and/or variable expressivity of the phenotype. In 3 of 4 patient cases identified in this study through an initial hematologic evaluation, additional studies were recommended to document the constitutional origin of the MYH11 gene deletion. To our knowledge, none of these cases pursued follow-up germline testing. However, in one patient (patient 2) FISH performed at diagnosis showed CBFB::MYH11 fusion in addition to the MYH11 deletion. A follow-up bone marrow specimen demonstrated no evidence of CBFB::MYH11 fusion, but the MYH11 deletion persisted, representing additional evidence for a constitutional deletion of the MYH11 gene region in this patient. These cases illustrate the possibility of discovering incidental constitutional abnormalities when performing testing on hematologic neoplasms. Currently there are no defined guidelines for the detection and reporting of possible germline alterations detected by conventional cytogenetic methods in hematologic disease. Consequently, patients may not be counselled appropriately, and testing consent forms in cancer settings often do not address the possibility of the discovery of germline abnormalities. These cases highlight a need of standardization for reporting incidental germline findings from hematologic testing by clinical laboratories as well as consenting and genetic counselling from the clinical perspective.Tabled 1Age (years)SexReason for referralSpecimennuc ish(MYH11x1,CBFBx2) %Additional clonal abnormalitiesPatient 122FemaleAcute myeloid leukemiaBone marrow100.0NoPatient 259FemaleInversion 16 at diagnosisBone marrow99.6UnknownPatient 339FemaleAcute myeloid leukemia relapseBlood97.4NoPatient 459FemalePancytopeniaBone marrow100.0No Open table in a new tab

The Meta-Analysis of Bevacizumab Combined with Platinum-Based Treatment of Malignant Pleural Effusions by Thoracic Perfusion

Objective To evaluate the safety of bevacizumab combined with platinum-based thoracic perfusion for treating lung cancer-related malignant pleural effusion (MPE) through meta-analysis. Methods The CNKI, PubMed, Cochrane Library, Embase, Chinese Science and Technology Journal Database (VIP), and Wanfang Databases were searched for randomized controlled trials (RCTs) of bevacizumab combined with platinum-based thoracic perfusion for the treatment of MPE. The references included in the articles were manually searched for additional studies. A meta-analysis of the RCTs was conducted using the RevMan 5.3 application. Results A total of 8 studies involving 540 patients (271 cases in the test group and 269 cases in the control group) were included in the meta-analysis. The test group had a significantly greater risk of elevated blood pressure as well as a higher rate of complete remission (CR) compared to the control group (P < 0.05). In contrast, the incidence of partial remission (PR) was only slightly higher in the test group (P > 0.05), and the risks of leukopenia, vomiting or nausea, rhinorrhea, diarrhea, gastrointestinal bleeding or hemoptysis, proteinuria, abnormal kidney and liver function, arrhythmia, and rashes were not significantly different between the test and control groups (P > 0.05). Conclusion Bevacizumab combined with platinum-based thoracic perfusion can achieve CR of MPE in patients with advanced lung cancer without significantly increasing the risk of adverse effects. The rate of PR was similar for the combination treatment and platinum-based infusion.

Chimeric antigen receptor T‐cell therapy combined with autologous stem cell transplantation improved progression‐free survival of relapsed or refractory diffuse large B‐cell lymphoma patients: A single‐center, retrospective, cohort study

Autologous hematopoietic stem cell transplantation (ASCT) and chimeric antigen receptor T-cell therapy (CART) are salvage therapies that are utilised for treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). However, whether the combination therapy of ASCT and CART (ASCT-CART) can improve the survival of R/R DLBCL remains unknown. Overall, 67R/R DLBCL patients were included, among which 21 patients underwent ASCT-CART therapy and 46 patients underwent ASCT therapy. The median number of mononuclear cells numbers that were infused in the ASCT-CART and ASCT groups was 4.71×108 /kg and 5.36×108 /kg, respectively (p=0.469). The median number of CD34+ cell numbers that were infused in the ASCT-CART and ASCT groups was 2.41×106 /kg and 3.05×106 /kg, respectively (p=0.663). The median number of CART cells that were infused was 2.63×106 /kg with a median transduction rate of 59.83%. The objective response rates to ASCT-CART and ASCT therapy were 90% and 89%, respectively (p=1.000). However, the ASCT-CART group showed higher complete remission (CR) rates than the ASCT group (71% vs. 33%; p=0.003). The ASCT-CART group demonstrated superior 3year progression-free survival (PFS) (80% vs. 44%; p=0.036) and lower 3year relapse/progression rate (15% vs. 56%; p=0.015) compared to the ASCT group. However, the 3year overall survival results indicated that there were no differences between the two groups (80% vs. 69%; p=0.545). For R/R DLBCL patients, ASCT-CART therapy is associated with higher CR rate, better PFS, and lower relapse/progression rate. These data support that ASCT-CART therapy can be used as a salvage therapy for R/R DLBCL patients.

Treatment outcomes with purine nucleoside analog alone or with rituximab for hairy cell leukemia at first relapse.

Frontline treatment of hairy cell leukemia (HCL) with a single course of the purine nucleoside analog (PNA) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, although treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R), practice patterns vary and data supporting each approach are limited. We conducted a multisite outcomes analysis of patients treated for HCL between 1995 and 2018 at six US medical centers. All patients were treated with frontline PNA and subsequently required treatment with a PNA alone (PNA) or with R (+R). Of the 88 patients analyzed, 56 (63.6%) received second-line PNA and 22 (36.4%) received a PNA+R. Baseline characteristics of both groups were similar. There was no difference in median PFS [67months (95% CI 43.8 non-reached (NR)) vs. 65months (95% CI 60-NR)] or 5-year OS [98% (95% CI 0.94-1) vs. 94% (95% CI 0.83-1), p=.104] in the PNA versus PNA+R cohorts, respectively. To our knowledge, this is the largest study evaluating the role of R in treatment of relapsed HCL and suggests that there is no advantage to the addition of R to PNA therapy at the time of first re-treatment.

Characteristics and outcomes of patients with blastic plasmacytoid dendritic cell neoplasm treated with frontline HCVAD

AbstractBlastic plasmacytoid dendritic cell neoplasm (BPDCN) is a clinically aggressive blood cancer, often involving the skin, bone marrow, lymph nodes, and central nervous system (CNS) in 20% to 30% of patients. Despite significant progress in CD123- and BCL-2–targeted therapy, most patients are not cured without hematopoietic stem cell transplant (HSCT), and CNS relapses occur quite frequently. Combination approaches with targeted and chemotherapy agents plus incorporation of prophylactic CNS-directed therapy are urgently needed. In this setting, we sought to analyze outcomes using the cytotoxic chemotherapy backbone regimen hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (HCVAD). We conducted a retrospective analysis of patients with BPDCN (n = 100), evaluating complete remission (CR) and median overall survival (OS) among 3 groups: those who received frontline HCVAD-based therapy (n = 35), SL-401 (n = 37), or other regimens (n = 28). HCVAD-based regimens yielded higher CR (80% vs 59% vs 43%; P = .01). There was no significant difference in OS (28.3 vs 13.7 vs 22.8 months; P = .41) or remission duration probability among treatment groups (38.6 vs not reached vs 10.2 months; P = .24). HSCT was performed in 51% vs 49% vs 38%, respectively (P = .455). These results suggest a continued important role for HCVAD-based chemotherapy in BPDCN, even in the modern targeted-therapy era, with high CR rates in the frontline setting. Further studies must establish the clinical activity, feasibility, and safety of doublet/triplet combinations of targeted therapies plus cytotoxic agents and the addition of CNS prophylaxis, with the ultimate goal of durable long-term remission for patients with BPDCN.

Outcomes of relapsed B-cell acute lymphoblastic leukemia after sequential treatment with blinatumomab and inotuzumab

AbstractNovel monoclonal antibody (mAb)-based therapies targeting CD19 and CD22 (blinatumomab and inotuzumab) have shown high rates of complete remission (CR) and been used as a bridging treatment to potentially curative allogeneic hematopoietic stem cell transplantation (alloHSCT) in adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). However, limited data exist on the outcome of patients resistant to both mAbs as well as responses to each agent when progressed after the alternate antigen-targeted mAb. Herein, we report outcomes of 29 patients with R/R B-ALL previously treated with both blinatumomab and inotuzumab. Twenty-five patients (86.2%) received blinatumomab as first mAb (mAb1), and CD19-negative/dim relapses were observed in 44% of the patients. Inotuzumab induced CR in 68% of the patients for post-blinatumomab relapse regardless of CD19 expression status. The median time between mAb1 and mAb2 was 99 days. Twelve (63.2%) of 19 patients who achieved remission after mAb2 underwent alloHSCT. The median time from mAb2 to alloHSCT was 37.5 days. Acute graft-versus-host disease and nonrelapse mortality were observed in 58.3% (grade 3 or higher, 25%) and 41.7%, respectively. With a median follow-up of 16.8 months after mAb2, 19 patients (65.5%) relapsed, and 21 patients (72.4%) have died. Overall survival was not different between alloHSCT and non-alloHSCT patients. In conclusion, patients with B-ALL who relapsed after blinatumomab could be successfully rescued by inotuzumab as a bridge to alloHSCT but represent an ultra-high-risk group with poor overall survival. Further studies, including novel consolidation and treatment sequence, may improve outcomes of these patients.

Efficacy and Safety of Different Immunosuppressive Therapies in Patients With Membranous Nephropathy and High PLA2R Antibody Titer.

Background: This study aimed to evaluate clinical features and prognosis and therapy option of patients with different risk ranks based on antibody against the M-type phospholipase-A2-receptor (PLA2Rab) level in seropositive M-type phospholipase-A2-receptor (PLA2R)-associated membranous nephropathy (MN) in a large sample size, multi-center study. Method: Based on the unvalidated cut-off value of PLA2Rab above 150 RU/ml as one of the clinical criteria for high risk of progressive kidney function loss in MN according to 2020 Kidney Disease: Improving Global Outcomes (KDIGO) draft guidelines recommendation, a total of 447 patients who received cyclophosphamide (CTX) or tacrolimus (TAC) combined with corticosteroids treatment for 12 months were divided into high titer (>150 RU/ml) group and non-high titer (20–150 RU/ml) group, which were subdivided into CTX subgroup and TAC subgroup. The overall cohort was classified into CTX group and TAC group as well. Clinical parameters levels and remission rates were recorded at 3, 6, and 12 months follow-up. PLA2Rab was tested by enzyme-linked immunosorbent assay. Results: Patients with high titer PLA2Rab were associated with more severe proteinuria and hypoalbuminemia compared to those with non-high titer antibody, accompanied by lower complete remission (CR) and total remission (TR) rates at 3, 6, and 12 months, which even took longer to remission. Similar remission rates differences between the two titer groups were observed in the CTX and TAC groups, respectively. PLA2Rab level at baseline was an independent predictive factor for CR and TR. In the high titer group, CR and TR rates in the CTX subgroup were significantly higher than those in the TAC subgroup at 12 months, although serious adverse events were more frequent in the former. Conclusion: High-risk rank patients with PLA2Rab level above 150 RU/ml have higher disease activity and worse prognosis among patients with seropositive PLA2R-associated MN, even under different immunosuppressive therapeutic models; moreover, CTX combined with corticosteroids was preferred compared to TAC plus corticosteroids, although serious adverse events were more frequent in the former. Additionally, baseline PLA2Rab level was an independent predictive factor for clinical remission.

Blinatumomab in Children and Adolescents with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: A Real-Life Multicenter Retrospective Study in Seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Centers.

Simple SummaryBlinatumomab, a bispecific T-cell engager, binding T-cell CD3 and B-cell CD19 antigens, has remarkably enlarged the treatment options for patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). The aim of our study was to retrospectively assess the safety and efficacy profile of blinatumomab in 39 r/r ALL children treated in seven AIEOP centers in a compassionate or off-label program. This report is among the largest multicentric real-life retrospective analyses on blinatumomab in pediatric r/r BCP ALL. Blinatumomab showed a tolerable safety profile (34.8% of adverse events ≥grade 3, no cytokine release syndrome and no associated toxic deaths) and proved to be very effective (complete remission rate 46% in the 13 patients with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with <5% blasts) in this group of patients affected by r/r BCP-ALL already treated in the frame of very intensive front-line and relapsed protocols.Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity.

From Stem Cell Transplantation to CAR-T Therapy in Relapse-Refractory Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is a highly curable disease when complete remission after immunochemotherapy is achieved. Despite a high complete remission rate, which is a prerequisite for a cure, 20–40% of patients will relapse or fail first-line therapy. Salvage chemotherapy followed by intensification with autologous stem cell transplant (ASCT) has been established as a curative treatment for relapsed chemosensitive patients under 60 years of age. The results have been somewhat disappointing, with less than 50% of patients being eligible for transplant and relapse posttransplant ranging from 60–40%. Improvements have been made with new drugs in development, immunoconjugate bispecific monoclonal antibodies, and chimeric antigen receptor technology (CAR-T). A more precise evaluation of prognostic factors with PET scans and other biological factors during treatment will allow for the design of new treatment strategies. The exceptional response rate in phase 2 achieved with the three available CARTs has now been confirmed with a longer follow-up period. At 2 years, the overall survival (OS) expectancy is 50% with a plateau on the curves. Three randomized studies compared CARTs to the standard of care with ASCT and demonstrated the superiority of CARTs. Despite this superiority, the relapse rate remains 50%, which is significantly better than the standard of care. However, major improvements in OS have not yet been achieved. A clearer definition of eligible patients should also take into account their interim pet-scan, metabolic tumour volume, relation with Ct DNA with follow-up of minimal residual disease.

Efficacy and safety of HpD-PDT for Extramammary Paget's Disease refractory to conventional therapy: A prospective, open-label and single arm pilot study

BackgroundExtramammary Paget's Disease (EMPD) is an intraepithelial cancer that is prone to recurrence and sometimes refractory to therapy. A few EMPD cases have been treated with Photodynamic therapy (PDT), which reported high complete remission (CR) rates and low recurrence with hematoporphyrin derivatives (HpD) The aim of this study was to further explore the efficacy and safety of HpD-PDT for EMPD patients. MethodsOpen-label, single arm, pilot study was designed to investigate the role of HpD-PDT in EMPD. The HpD sensitizer was given intravenously at a dose of 3 or 5 mg/kg 48 h before light irradiation with a laser 630 nm red light at a dose level of 150–200 J/cm2. Clinical parameters involving gender, age, disease course, previous treatment, tumor thickness, long diameter of lesion, TNM staging, EMPD staging, HpD dosage, Visual Analogue Scale (VAS) score, 1st month visit result, subsequent treatment, follow up period and endpoint outcomes were collected to evaluate efficacy and safety of the intervention. ResultsEleven patients with pathologic confirmed EMPD were treated with HpD-PDT. The thickness of skin lesions which were located in vulva, penis, scrotum, and perianal area is 0.8∼6.7 mm (mean thickness 2.9 mm). All patients were followed up for an average of 17.4 months (12∼27 months). Complete remission (CR) rate and partial remission (PR) rate at the 1st month were 90.1% (10/11) and 9.1% (1/11) respectively. At the end of follow-up, 72.7% of the subjects (8/11) showed CR. Pain, infection, photosensitivity and uroschesis are recorded as adverse events (AEs) in this population, and no event of hepatic impairment was reported. After treatment, all the eleven patients showed different degrees of scar in the treatment site, but none of them had any structural or functional abnormalities. ConclusionsAccording to our study, HpD-PDT in EMPD is able to offer acceptable disease outcomes including relatively high CR rate, with good cosmetic and functional outcomes, and could be considered a potential recommended therapy for patients with EMPD. Trial RegistrationChinese Clinical Trial Register (ChiCTR-1900024965).

Prognostic Significance of Cytokine Release Syndrome in B Cell Hematological Malignancies Patients After Chimeric Antigen Receptor T Cell Therapy.

Cytokine release syndrome (CRS) is the most common on-target toxicity of chimeric antigen receptor (CAR) T cell therapy. However, the prognostic significance of CRS has not been well elucidated. The aim of our study was to evaluate the association between CRS and efficacy after anti-CD19 CAR-T therapy in a retrospective cohort of 22 patients with relapsed/refractory B cell hematological malignancies. The complete remission (CR) rates after CAR-T therapy were 68%, and median value for progression-free survival (PFS) was 6.8 months. Eight of 22 (36.4%) patients showed ≥ grade 2 CRS. Statistical analysis found that patients with ≥ grade 2 CRS had higher CR rates and longer PFS than those with < grade 2 CRS. Moreover, bridging hematopoietic stem cell transplantation was another independent predictor for PFS. These data suggested that appropriate CRS may be beneficial to the efficacy of CAR-T therapy. The Clinical Trial Registration number is NCT03110640, NCT03302403.

Decitabine in Combination with Fludarabine and Cyclophosphamide As Lymphodepletion Regimen Followed By CD19/CD22 Bispecific Targeted CAR-T Therapy Significantly Improves Survival in Relapsed/Refractory B-ALL Patients: A Pilot Study

Background: CD19/CD22 bispecific targeted chimeric antigen receptor T cell (CAR-T) therapy has achieved impressive progress in patients with relapsed/refractory B cell acute lymphoblastic leukemia (R/R B-ALL), with high rates of complete remission (CR). However, T cell exhaustion caused by de novo DNA methylation restricts the capacity of CAR-T. Decitabine (DAC), a DNA methyltransferase inhibitor, has been demonstrated to reverse exhaustion-associated DNA-methylation programs, promote the rejuvenation of CAR-T cells and enhance anti-leukemic effect of CAR-T cells in vitro. To date, there are limited reports about the use of DAC as a part of lymphodepletion therapy before CAR-T cell therapy. Here, we report efficacy and safety of DAC in combination with fludarabine and cyclophosphamide (FC) regimen followed by CD19/CD22 CAR-T cell therapy for patients with R/R B-ALL.Method:We conducted a phase 1/2 clinical trial to investigate the efficacy and safety of CD19/CD22 CAR-T in the treatment of R/R B-ALL (NCT03614858). Fourteen patients were treated with DAC (total dose 100mg/m 2 in 3 days) followed by FC regimen (fludarabine 30mg/m 2 × 3d and cyclophosphamide 300mg/m 2 × 3d) (DAC group), while twelve patients received FC regimen prior to CAR-T cell infusion (CON group). A total of 1 or 2 × 10 7 CAR-T cells/kg were infused at dose escalation.Results: Baseline characteristics of patients in both groups had no significant differences except previous hematopoietic stem cell transplantation (HSCT). There were more patients with relapse after HSCT in DAC group (42.9% versus 0%, P=0.017). All patients did not achieve remission before lymphodepletion. The day 28 CR rates were 100% in DAC group and 91.7% in CON group. Furthermore, minimal residual disease (MRD) negative CR rates were 71.4% and 58.3%, respectively (P = 0.683). There was no significant difference in the proportion of nontransplant patients after CAR-T treatment between two groups. Among the nontransplant patients after CAR-T infusion in DAC group, 16.7% (1/6) of patients relapsed at 4 months. However, among 4 nontransplant patients in CON group, 1 patient achieved NR after CAR-T therapy and 3 patients relapsed at 1.5, 5, and 10 months. There were significant differences in overall survival (OS) and leukemia-free survival (LFS) between two groups: 3-year OS, 88.9% (DAC) versus 33.3% (CON), P = 0.01 and 3-year LFS, 92.3% (DAC) versus 21.8% (CON), P = 0.002. Multivariable analysis showed that addition of DAC to the lymphodepletion regimen was associated with better OS (hazard ratio [HR] 0.107, [95% CI, 0.013-0.875], P = 0.037) and LFS (HR 0.081, [95% CI, 0.01-0.65], P = 0.018). Cytokine release syndrome was observed in all patients.Conclusion: In summary, DAC in combination with FC regimen followed by CD19CD22 CAR-T cells was feasible and well tolerated. Our study demonstrated DAC combined with FC was an independent prognostic factor correlated with better survival in relapsed/refractory B-ALL patients. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic-Hematopoietic Stem Cell Transplantation Is Effective and Safe for Relapsed/ Refractory B-ALL Patients Who Cannot Get Remission or MRD Negative after CART Treatment

▪Background: Chimeric antigen receptor T-cell (CART) Therapy has induced high rates of complete remission (CR) in the patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), but a small portion of them still cannot obtain CR or minimal residual disease (MRD) negative. Salvaged allogeneic hematopoietic stem cell transplantation (allo-HSCT) could be the only curative treatment for this setting. According to previous reports, around 20% to 30% overall survival (OS) has been seen in the patients with r/r B-ALL treated with salvaged allo-HSCT.Aim: In current study, the efficacy and safety of allo-HSCT for the patients with r/r B-ALL who cannot achieve CR or MRD negative after CART therapy were evaluated.Methods: Between January 2018 and June 2021, 23 consecutive patients with r/r B-ALL who did not achieve CR or MRD negative after CART treatment and received allo-HSCT in our hospital were included. The median age was 10 (1-47) years old. The median disease course was 24 (8-89) months. Eight patients were in non-remission (NR) and 15 cases were MRD positive (10 detected by flow cytometry, and 5 detected by RT-PCR). The median blast in bone marrow (BM) in NR series was 39 (0.5-94)% in which two patients were only extramedullary leukemia, and the median flow cytometric MRD level in BM in MRD positive series was 0.11 (0-3)%. One patient had TP53 mutation, one had MLL-AF4 fusion gene and one had both TP53 mutation and MLL-AF4 fusion gene. Nineteen patients (82.6%) received at least two kinds of CART therapies (murinized CD19, humanized CD22, humanized CD19) and 4 patients (17.4%) received one kind of CART therapy (murinized CD19, humanized CD22 or humanized CD19). Three patents underwent second transplantation. Eighteen patients (78.3%) received allo-HSCT from haploidentical donors and 5 patients (21.7%) from unrelated donors (HLA 10/10 matched in 3 and 9/10 matched in 2). Myeloablative conditioning regimens with total body irradiation (fractionated, total 10 Gy) /etoposide (200mg/m 2 x 3) /fludarabine (30mg/m 2 x 5) or cyclophosphamide (1.8g/m 2 x 2) /rabbit anti-T-cell globulin were used. Cyclosporine, mycophenolate mofetil and short-term methotrexate were employed for graft-versus-host disease (GVHD) prophylaxis. Some patients received maintenance regimens with targeted medicine based on their fusion genes or gene mutations up to 2 years post-transplant.Results:All patients achieved durable engraftment. For the patients in NR (n=8) before transplantation, the median follow-up time was 336 (22-803) days. Four of them had been alive free of leukemia and MRD negative, and 4 patients died of relapse. One-year OS and leukemia-free survival (LFS) were 85.7% and 35.7%, respectively. No patient died of transplant-related events. Two patients developed grade III acute GVHD (aGVHD) and 1 patient had extensive chronic GVHD (cGVHD). All of them were resolved with immune-suppressants. CMV and EBV reactivation was detected in 6 and 1 patients, respectively. One patient had severe lung fungal infection and 1 case developed mild hemorrhagic cystitis. For the patients with MRD positive (n=15) before transplantation, the median follow-up time was 359 (42-872) days and one-year OS and LFS were 68.1% and 40.9%, respectively. Seven patients relapsed, three of them achieved MRD negative CR with donor-derived CART therapies, and 3 patients died of relapse. Six patients developed grade III~IV aGVHD and one patient had extensive cGVHD. All of them were resolved except one patient died from grade IV aGVHD. CMV and EBV reactivation was found in 6 and 1 patients, respectively. Three patients had mild hemorrhagic cystitis. No other severe infection occurred.Conclusion: Our results indicate that salvaged allo-HSCT has improved survival remarkably in r/r B-ALL patients who failed not only chemotherapy but also CART therapy.One-year OS and LFS can reach 85.7% and 35.7%, 68.1% and 40.9% in NR and MRD positive cohorts, respectively. Transplant-related mortality is quite low (1/23). The leading cause of death is disease recurrence (7/23). Under our protocol, allo-HSCT is a safe and effective salvaged modality for r/r B-ALL who cannot obtain CR or MRD negative with CART therapy. DisclosuresNo relevant conflicts of interest to declare.

Phase II Study of Cladribine, Idarubicin, Cytarabine (CLIA) Plus Gilteritinib in Patients with FLT3 Mutated Acute Myeloid Leukemia (AML)

Phase II Study of Cladribine, Idarubicin, Cytarabine (CLIA) Plus Gilteritinib in Patients with FLT3 Mutated Acute Myeloid Leukemia (AML)

Impact of Choice of Induction Regimen on Overall Survival and Post-Remission Survival Among Older Adults with Acute Myeloid Leukemia

Older patients make up the majority of those diagnosed with acute myeloid leukemia (AML), however, many of these patients are not able to tolerate intense induction chemotherapy regimens. The use of lower intensity induction such as hypomethylating agents (HMA) with or without venetoclax or other targeted therapies has widened the scope of patients who are able to receive induction chemotherapy and move towards a hematopoietic stem cell transplant. Recent data from the Center of International Blood and Marrow Transplant research showed that patients aging >64 years accounted for 26% of all allogeneic transplantations in 2019 compared to only 9% in 2009. We have previously published a report showing that induction with FLAG +/- Idarubicin (FLAG+ IDA) results in better post remission survival than '7+3'induction (Solh et al, Leuk res 2020). In order to determine how induction chemotherapy affects post-remission outcomes among older patients with AML, 289 patients over the age of 55 year who received either FLAG±IDA, 7+3, or HMA based induction at a single institution were analyzed. Median follow up was 48 months. Patient and disease characteristics were as follows: Median age 64 (55,83) years, secondary AML (10%), abnormal cytogenetics (49%), and NCCN non-favorable risk (76%). Induction regimens included FLAG+/- Ida (n=208, 72%), 7+3 (n=60, 21%) and HMA based (n=21, 7%). A total of 248 patients (86%) achieved CR/Cri after induction with a median time from induction to CR of 28 days. Patients who received induction with FLAG±IDA reached a higher rate of CR after one cycle (92% vs 75% vs 62%) and had a shorter time to CR (27 vs 33vs 55 days) compared to '7+3' or HMA based therapy (p<0.001 for both). FLAG±IDA had better overall survival and DFS 3 years post-remission compared to '7+3' and HMA OS (50%, 45%, 22%, p=0.021) and DFS (45%, 37%, 8% p=0.01) respectively. A total of 133 patients received allogeneic transplantation. Transplant rate was similar between FLAG+/- IDA (n=100) and 7+3 (n=29) at 48% and was significantly better than HMA-based induction 19% (n=4) (p=0.03). Post-transplant survival and DFS was not significantly different between FLAG+/-Ida and 7+3, however both were better compared to HMA based induction with OS (54%, 44%, 25%) and DFS (51%, 44%, 25%) . On multivariate analysis on post remission survival and disease free survival, NCCN risk and age were both associated with OS ( high risk NCCN vs others HR 3.63, P<0.001; Age per 5 year increment HR 1.16, p=0.049) and NCCN risk was the only factor associated with worse DFS ( high vs others HR 2.4, p<0.0001). The choice of induction regimen did not significantly impact post-remission survival outcomes.In conclusion, Older patients with AML achieve higher rates of complete remission, shorter time to remission and better post-remission survival with FLAG+/-IDA than 7+3 or HMA-based induction. DisclosuresSolh: BMS: Consultancy; Partner Therapeutics: Research Funding; Jazz Pharmaceuticals: Consultancy; ADCT Therapeutics: Consultancy, Research Funding.