Discontinuation of Eculizumab treatment after hematological remission in patients with atypical and drug-induced hemolytic uremic syndrome

Introduction: To evaluate the effect of therapeutic plasma exchange(TPE) and eculizumab on hematological and renal survival in atypical hemolytic uremic syndrome(aHUS). Additionally, to examine the reliability of discontinuation of eculizumab treatment. Methods: This was an observational and retrospective study of 18 patients diagnosed with aHUS. Results: The median age of the study population was 30(22-66) years. Four of 18 patients achieved hematological remission with the TPE alone. However, one patient in the died after three sessions of TPE. Eculizumab was used in 13 patients and no death was observed. One year after treatment, improved kidney function was observed in 2 of 3(66%) patients for TPE and 5 of 9(56%) patients for Eculizumab. We discontinued eculizumab treatment in 9 patients. One of the patients who had a C3 gene mutation experienced disease relapse after Eculizumab discontinuation. None of the patients who had drug associated aHUS, developed disease relapse after Eculizumab discontinuation. Conclusion: Eculizumab treatment is a life-saving therapy in aHUS. Treatment discontinuation may be considered at least six months after hematologic remission in patients who had stable renal function or no expectancy for renal survival. Moreover, drug-associated cases seem to tend not to develop disease relapse in the long term.

Glucocorticoid and Antibiotic Treatment-induced Recapitulated Hematological Remissions in Acute Myeloid Leukemia: Implications for Ligand-dependent Growth and Survival Advantage

Leukemia-transformed multipotential hematopoietic cells have acquired the increased self-renewal capacity and impaired myeloid differentiation to mature blood cells. The emergence of symptomatic leukemia also critically requires the acquisition of growth and survival advantage in leukemic cells. Untreated leukemia patients usually demonstrated a progressive process. However, spontaneous remission occasionally occurred in a very small number of leukemia patients, which frequently followed a febrile episode and antibiotic treatment and was generally attributed to the activation of anti-neoplastic activities. Here we report a 63-year-old Chinese man who presented with the main complaints of abdominal pain, febrile episode and urticaria-like skin lesions. He was diagnosed with acute myeloid leukemia (AML-M4) with t(8;21)(q22;q22)/RUNX1-RUNX1T1 on the basis of morphological, immunological, cytogenetic and molecular analysis. He also had a mutated FLT3-TKD gene. He was treated with antibiotics and glucocorticoid for the gastrointestinal infection and the urticaria-like skin lesions. The infection and skin lesions were quickly resolved. Unexpectedly, along with the relief of the febrile episode, abdominal symptoms and skin lesions, he achieved a hematological remission. After relapse, repeating this treatment resulted in the second hematological remission. These recapitulated treatment responses strongly suggested that inflammatory stresses arising from the gut inflammatory lesions, which could be largely mitigated by antibiotic and glucocorticoid treatment, sustained the growth and survival advantage of the leukemic cells.

Interferon-Alpha (IFN) Therapy Discontinuation Is Feasible in Myeloproliferative Neoplasm (MPN) Patients with Complete Hematological Remission

Background: Although patients with MPN may achieve complete hematological remission (CHR) with cytoreductive therapy (CRT), lifelong treatment represents a major burden for these chronically ill patients. IFN has emerged as a major MPN therapy thought to positively alter the natural history of MPN and appears to be the only drug that can provide long-term CHR after discontinuation in some patients (Hasselbalch HC et al., Seminars in Immunopathology, 2019). In this study, we aimed to identify clinical and molecular factors associated with long-term CHR after IFN treatment discontinuation and to compare clinical outcome of patients who discontinued therapy, to patients who continued IFN treatment despite achieving a CHR. Methods: All MPN patients followed between January 2000 and May 2020 in our institution who received at least 3 months of IFN were included. Logistic regression analysis was performed to identify variables associated with long-term CHR after discontinuation. Cumulative incidence of relapse was calculated from time of IFN discontinuation, considering death without relapse as a competitive event. Overall survival (OS) and thrombotic/hemorrhagic events free survival (EFS) curves were estimated using the Kaplan-Meier method and compared by cause-specific hazard Cox models. Results: 381 patients treated with IFN were included in the study. Median age at MPN diagnosis was 44 years [interquartile range: 33-54]. 171 had polycythemia vera (PV), 169 essential thrombocythemia (ET) and 34 primary myelofibrosis (PMF). JAK2V617F was the most frequent driver mutation (78.8% of patients), while CALR and MPL were mutated in 15.5%, and 2.9% of patients respectively. Median driver variant allele frequency (VAF) at time of IFN therapy initiation was 34% [12; 51]. Reasons to start IFN included age younger than 50 years in 44.9%, intolerance/resistance to previous therapies in 17.8% or pregnancy in 1.8% patients. CHR was achieved with IFN in 77.2% of patients. After a median follow-up of 72.4 months [28.4; 119.7] from IFN initiation, 131 patients were still on IFN treatment, while 250 patients had discontinued therapy. No significant difference was observed between continued and discontinued IFN patients in terms of MPN subtype, initial clinical, biological or molecular characteristics. Reasons for discontinuation were toxicity in 128 (50.4%), prolonged hematological CHR in 76 (29.9%), failure in 16 (6.3%) and other in 30 (11.8%) patients. At time of IFN discontinuation, 170 (66.9%) patients were in CHR and the median driver mutation VAF was 12% [3; 35]. Of note, IFN was re-introduced in 61 patients who lost CHR with a second CHR rate of 83.6%, arguing for the absence of development of IFN resistance in post-discontinuation relapses. In multivariate logistic regression analysis, stopping for prolonged CHR (OR 3.52, 95%CI [1.18; 10.56], p=0.024) was associated with a higher CHR without CRT rate, while VAF ≥ 10% at time of IFN discontinuation (OR 0.26, 95%CI [0.1; 0.65], p=0.004) was associated with lower long-term CHR without CRT. Accordingly, VAF ≥ 10% at time of IFN discontinuation (HR 3.06 [1.59; 5.90], p=0.001) was independently associated with a higher cumulative incidence of relapse after IFN discontinuation (Figure A). Driver VAF at IFN discontinuation time was available for 117 patients. 53 patients (45.3%) had a driver VAF < 10% at IFN discontinuation. Finally, we compared discontinued IFN patients who stopped IFN for CHR (n=76) to patients who obtained CHR and are still on IFN therapy (n=116). Hematological transformation could not be evaluated due to very low incidence of events: 2 patients from each group progressed to myelofibrosis while leukemic progression was only observed in 1 patient. Importantly, OS (HR 0.23, 95%CI [0.5; 1.14], p=0.07) and EFS (HR 0.53, 95%CI [0.19; 1.45], p=0.217) were not significantly different between patients who discontinued and those who continued IFN. Conclusion: Overall, our study demonstrates that IFN discontinuation represents a safe strategy in MPN patients who achieved CHR, and particularly in patients with a driver VAF lower than 10% at time of discontinuation. Importantly, relapsed patients did not develop IFN resistance. Our data contributes to set the frame for future clinical trials evaluating the possibility of IFN treatment holidays in good responding MPN patients. Disclosures Benajiba: Gilead Foundation: Research Funding. Kiladjian:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees.

The Presence of Minimal Residual Disease, As Determined By Highly Sensitive Quantitation of NPM1-Mutatation, Provided Powerful Prognostic Information in Acute Myeloid Leukemia

Background: As recurrence of acute myeloid leukemia (AML) is difficult to predict, it is important to detect it by measuring minimal residual disease (MRD). PML-RARA, RUNX-RUNX1T1, CBFB-MYH11 are regarded as the reliable MRD markers. However, in AML with normal karyotype and many other forms, no MRD markers have been established. NPM1 mutations, occurring in approximately 30% of adult AML cases, and 50-60% of AML cases with normal karyotype, represent one of the most frequent mutations in AML. Recently, NPM1 mutation is reported to be useful in assessing MRD. We undertook a retrospective and prospective investigation of the usefulness of NPM1 mutation as an MRD marker in Japanese patients with AML. Methods: The subjects were 38 NPM1-mutated AML patients with first hematological remission at several hospitals related to our institution between 2001 and 2018. This study was approved by the ethics committee of Nippon Medical School and the informed consents were obtained from all patients, according to the Declaration of Helsinki. We analyzed peripheral blood cells or bone marrow cells at diagnoses, and evaluated only bone marrow cells after diagnoses. Detection of NPM1 mutation was carried out using allele-specific real time PCR following creation of a complementary primer. After dilution of the samples, sensitivity to TCTG, CATG, and CCTG was found to be 0.001%. The NPM1 mutant copies were qualified only at successful amplification of internal control. Results: The median age of the patients was 58 years (18-79 years). There were 32 cases with intermediate cytogenetic prognosis and 6 cases with unclear chromosomal profile. Of the 38 cases, 14 cases (37%) were FLT3-ITD-positive and allogeneic hematopoietic stem cell transplantation was carried out in 14 cases (37%). The base sequence was TCTG in 36 cases and CCTG in 2 cases. Persistence of NPM1-mutatation was present in 25 patients with first hematological remission (66%). Compared with patients with MRD negative, patients with MRD positive were associated with DNMT3A mutation (MRD positive 12/25 vs MRD negative 0/13, p=0.003). The rate of relapse in patients with MRD positive was significantly higher than those of in patients with MRD negative (MRD positive 76% vs MRD negative 23%, p=0.004). The rates of relapse free survival (RFS) and overall survival (OS) in patients with MRD positive were significantly lower than those in patients with MRD negative (RFS at 2 years: MRD positive 14% vs MRD negative 86% p=0.003; Figure 1, OS at 2 years: MRD positive 25% vs MRD negative 93%, p<0.001). In FLT3-ITD negative group, the rates of RFS in patients with MRD positive were significantly lower than those in patients with MRD negative. (RFS at 2 years: MRD positive 21% vs MRD negative 92% p=0.001; Figure 1). Conclusion: The presence of MRD with NPM1 mutation is significantly associated with relapse and it is useful to decide their treatment strategy. Especially, there is the usefulness of NPM1 mutation as an MRD marker in NPM1 positive Flt3-ITD negative AML patients who are generally classified as favorable risk. According to previous reports, it is known that NPM1-mutated AML sometimes relapse with losing NPM1 mutations. However, in this study, all NPM1-mutated AML relapse without losing NPM1 mutations. We need to collect more patients and are going to confirm whether there are patients who relapse with losing NPM1 mutations or not. We plan to analyze the genetic background of MRD positive and negative patients with next-generation sequencing. We are going to announce the genetic characteristics in addition to this result at ASH. Disclosures Usuki: Astellas Pharma Inc: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau. Kako:Bristol-Myers Squibb: Honoraria; Pfizer Japan Inc.: Honoraria. Inokuchi:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria; Pfizer: Honoraria.

Upfront Ixazomib Plus Dexamethasone Induce Promptly Hematological Response in Patients with Light-Chain Amyloidosis

Background: CyBorD (bortezomib, cyclophosphamide, and dexamethasone) is considered as an effective induction regimen in newly diagnosed light chain amyloidosis (AL) patients. Although a full dose of dexamethasone (Dex) leads to a higher response rate, the dose is strictly limited, usually because of fluid retention. Additionally, supervised administration of bortezomib weekly, if applied, increases the cost and inconvenience of treatment for service providers and patients.Ixazomib(IXA), an oral proteasome inhibitor, was reported highly effective as a single agent in relapsed or refractory AL amyloidosis. The objective of this observation is to evaluate the feasibility and efficiency of adding a lower dose of Dex to IXA (Id) as an upfront regimen in AL pts. Patients and Methods: Between 9/29/2018-4/1/2019, twenty-five newly diagnosed (ND) AL pts were sequentially enrolled. All AL pts had positive Congo Red staining in biopsy specimens confirmed by immunoelectron microscopy(IEM). Ixazomib 4mg D1,8,15 and Dexamethasone 10mg D1,8,15,22 were given for a 28-day schedule until disease progression or intolerance. Efficiency and safety profiles were assessed at the beginning of each cycle. Patients who had not achieved PR after 3 cycles received additional oral cyclophosphamide (50mg daily). The patients not achieving PR after 3 more cycles would switch to salvage therapies such as lenalidomide-base regimens or melphalan-based regimens. Upfront Id regimen can be prolonged for 2 cycles after a best hematological response (CR) has been achieved. The primary objective was to determine the response rate of this regimen and to evaluate the safety and tolerability of Upfront Id. Secondary objectives included PFS and OS. Results: Patients(n=25) received a median of 4 cycles (1-8) of Id regimen. Most patients were at late stage (20 pts in MAYO stage III, 4 pts in stage I and 1 pts in stage II). The interphase FISH analysis in BM plasma cells finds translocation t(11,14) in 8 pts.(Table 1) All patients were evaluable for toxicity and twenty-four for the response. The ORR was 66.7%(16/24) post cycle 1 and 70.8%(17/24) post cycle 4. Best hematological response achieved to date of this study is CR in 10pts, VGPR in 5 pts. 5 of the 7 pts did not reach their hematological remission have a t(11,14) translocation. With a median of 197 days (34-281) follow-up, 68%(17/25) of the patients were still alive, and 41.7%(10/24) with their best hematological response. 4 of the patients died of sudden and the rest due to the progression of heart failure. (Figure 1) According to CTC AE 5.0, Grade III/IV AEs (no. of pts) included: diarrhea 16%(4), thrombocytopenia 12%(3), general edema 8%(2), hypokalemia 8%(2), AST increased 4%(1), hyperuricemia 4%(1), and pneumonitis 4%(1). All the 4 patients with serious diarrhea quit therapy because of intolerance. (Table 2) Conclusions: Adding low dose dexamethasone to Ixazomib can induce rapid and profound hematological remission in newly diagnosed AL pts, especially in patients without t(11,14). This entirely oral, chemotherapy-free combination regimen ensures patients' compliance. The relatively low incidence of Grade III/IV AEs also makes the regimen seemingly a broad usage in MAYO stage III pts. However, diarrhea and thrombocytopenia in these patients still need awareness. OffLabel Disclosure: Ixazomib (Ixa) is the first oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM) in > 60 countries including US and China. In this single-center real-world study, we present the efficacy and safety profile of Ixazomib-based therapy as frontline therapy in patients with AL amyloidosis.

The Expression of Human Telomerase Reverse Transcriptase in Adult Acute Myeloid Leukemia and Its Correlation With Various Clinico-Pathological Parameters

BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by clonal expansion of myeloid progenitors (blasts) in the bone marrow and peripheral blood, AML accounts for 80% of acute leukemia in adults, its incidence increase with age. AML can be a fatal disease so research to predict prognosis is important. Telomerase (TA) is an enzyme that stabilizes the telomere length and makes the cell immortal. It is present in some of the normal cells, fetal cells, adult germ cells, and presents in 85% of tumors in humans, it has been shown that TA can be used as a prognostic marker in some solid and hematological neoplasms. Telomere length is a factor that predicts telomere function. AIM: We test the quantitative amount of human telomerase reverse transcriptase (hTERT) gene expression in AML (diagnosed according to FAB) adult and its correlation with various clinic-pathological parameters. PATIENTS &amp; METHODS: We used the TRAP assay to assess the hTERT gene expression in mononuclear blood cells from 40 newly diagnosed AML patients, 25 AML patients after completing their course of treatment, and 15 control health subjects. RESULTS: The mean value of hTERT in AML and control groups were [1.59 &plusmn; 1.27 anm and 0.035 &plusmn; 0.046 anm respectively], and this difference was significantly higher in patients than in control group (p = 0.0001). The telomerase activity was positive in 27 (67.5%) AML patients, while 13 (32.5%) AML patients were negative for telomerase activity. Twenty-five patients after induction chemotherapy were followed up by bone marrow and peripheral blood examination to determine the patient&rsquo;s response to therapy. Complete hematological remission was achieved in 12 (48.0%) patients and incomplete hematological remission in 13 (52.0%) patients (14%). The hTERT level was significantly higher in patients before induction chemotherapy than after completion of the induction course (p = 0.0001). The hTERT level at diagnosis in patients who did not achieve complete hematological remission was significantly higher than that in patients who achieved complete hematological remission (p = = 0.026). The hTERT level after induction therapy was significantly higher in patients who did not achieve complete hematological remission than in patients who achieved complete hematological remission (p = 0.003). CONCLUSION: Our research suggests that the hTERT expression could serve as a prognostic marker for AML patients.&nbsp;