Remission Reinduction Research Articles

A Real-World Evidence on Effectiveness and Safety of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia

Introduction Blinatumomab, a bispecific T-cell antibody, has emerged as a novel therapy with a promising efficacy and tolerable safety in patients with B-cell acute lymphoblastic leukemia (B-ALL). However, there is a paucity of data on blinatumomab for patients with newly diagnosed and relapsed/refractory (R/R) B-ALL in frontline and relapsed settings outside the clinical trials. This study aimed to describe the treatment patterns, effectiveness and safety of blinatumomab in Chinese patients with B-ALL. Methods In this retrospective observational study, data of patients with B-ALL who received at least one dose of blinatumomab in frontline or relapsed settings between August 2021 and June 2023 were collected from electronic medical data of the Department of Haematology of the First Affiliated Hospital of Soochow, China. The primary endpoint of the study was the treatment pattern of blinatumomab therapy, including median treatment cycles. Secondary endpoints included complete remission (CR)/CR with incomplete blood cell recovery (CRi) rate, minimal residual disease (MRD) negativity (i.e., complete MRD remission, defined as MRD <0.01%), median event-free survival (EFS) and 1-year EFS rate, median overall survival (OS) and 1-year OS rate, duration of response (DOR) and adverse events (AEs). Results In total, 96 patients with B-ALL (53 males and 43 females) were included. Of these, 53 received frontline treatment (blinatumomab used for first line remission induction: n=6; first line consolidation: n=39; first line induction or consolidation unknown: n=8), and 43 were R/R patients (blinatumomab for remission re-induction: n=28; R/R consolidation: n=14; R/R re-induction or consolidation unknown: n=1). The median age was 34 years (range: 11-67). Among R/R patients, 18 (18.8%), 12 (12.5%) and 13 (13.5%) had received 2, 3, and ≥3 previous lines of treatments, respectively. Sixteen patients were refractory to the last treatment. Among patients using blinatumomab for consolidation, MRD status at the start of therapy was positive in 29 (30.2%), and negative in 23 (24.0%) patients. Most of the patients (66.7%) received 1 cycle of blinatumomab followed by 2 (20.8%), 3 (7.3%), 4 (4.2%), and 5 (1.0%) cycles of the drug. The median treatment cycle was 1 (range: 1-5) with a median follow-up of 205 days (range: 15-652). In frontline treatment, all those using blinatumomab for remission induction and first line unknown status achieved CR with the CR/CRi rate of 100% (14/14) after blinatumomab. In patients with evaluable MRD (n=47) in the frontline setting, 87.2% (n=41) achieved MRD negativity within the 2 cycles of blinatumomab. In the following cycles, 3 more patients achieved MRD remission with overall complete MRD remission rate of 93.6% (44/47). In R/R re-induction patients, the CR/CRi rate was 50% (14/28) after blinatumomab treatment. Complete MRD remission rate in R/R patients who achieved CR within 2 cycles of blinatumomab was 73% (19/26). Median EFS was not reached (NR) in both frontline and R/R patients and the 1-year EFS rate was 90.8% (95% CI: 67% - 97%) and 55.1% (95% CI: 30% - 74%), respectively (Figure 1). Stratification of EFS by CR status at blinatumomab initiation showed 1-year EFS rate of 93.8% and 100% in first line consolidation and remission induction patients, respectively, whereas, R/R consolidation and re-induction patients showed 1-year EFS rate of 66.8% and 59.3%, respectively. None of the frontline treated patients died until the last follow-up time. In R/R patients the median OS was not reached and the 1-year OS rate was 70.9% (95% CI: 50% - 84%). OS stratified by CR status in R/R patients showed 1-year OS of 87.5% in consolidation and 69.9% in re-induction patients. Median DOR was NR in both frontline and relapsed settings. Seven (7.3%), and 3 (3.1%) patients reported any grade, and grade ≥3 cytokine release syndrome, respectively. Immune effector cell-associated neurotoxicity syndrome was reported by 1 patient (grade ≥3). Infection of any grade and grade ≥3 was reported by 6 (6.2%) and 4 (4.2%) patients, respectively. Increase in liver enzymes and neutropenia were observed in 1 patient (grade ≥3) each. Conclusion This study showed that using blinatumomab for remission induction and consolidation with one to five cycles was effective in the treatment of patients with B-ALL in the frontline as well as relapsed settings and had a tolerable safety profile.

Specific KIR-HLA genotypes predict outcomes in refractory or relapsed primary central nervous system lymphoma

ABSTRACTIntroductionAn effective salvage regimen for the reinduction of remission is lacking for refractory or relapsed primary central nervous system lymphoma (r/r PCNSL). This study aimed to evaluate the efficacy and safety of cytarabine plus temozolomide in treating r/r PCNSL and to explore the associated prognostic factors.MethodsA single-center retrospective cohort study was conducted to assess the efficacy and safety of cytarabine and temozolomide (AT) in r/r PCNSL patients. KIR and HLA genotyping was performed on peripheral blood samples.ResultsThirty PCNSL patients receiving an AT regimen (cytarabine 3 g/m2 for 2 days combined with temozolomide 150 mg/m2 for 5 days) in our institution were analyzed. The median age was 65 years (range 25–79 years). A total of 43.4% of patients (13/30) achieved an overall response within a median follow-up of 16 months (95% confidence interval [CI]: 11–23 months). The median PFS and OS of the cohort were 1.5 months (95% CI: 1–4 months) and 19.5 months (95% CI: 11 months to not calculable), respectively. Patients harboring KIR3DL1/HLA-B genotypes predicting low affinity had a higher response rate (p = 0.042) and longer median PFS (3 months) than those with KIR3DL1/HLA-B genotypes predicting high affinity (1 month) (p = 0.0047). Cox regression analysis indicated that KIR/HLA-B genotypes were independently associated with PFS (p = 0.043). However, KIR/HLA-B genotypes had no impact on the OS of the cohort. The toxicity of AT treatment was mild and manageable.ConclusionThe AT regimen was well tolerated, and patients with specific KIR-HLA genotypes may benefit from this regimen.

Clinical Images: Optic perineuritis in relapsing granulomatosis with polyangiitis.

The patient, a 76-year-old man who was previously diagnosed as having granulomatosis with polyangiitis (GPA) and was receiving rituximab maintenance therapy every 6 months, presented with malaise, night sweat, transient lockjaw, and right-sided facial pain and swelling following dental extraction 2 weeks earlier. He subsequently developed retrobulbar pain, conjunctival injection, chemosis, and fluctuating visual impairment. T1-weighted contrast magnetic resonance imaging (MRI) of the orbit revealed contrast enhancement of the right optic nerve sheath sparing the optic nerve itself (“doughnut sign”) consistent with optic perineuritis (coronal image in A; axial image in B). Laboratory evaluation showed elevated C-reactive protein (276 mg/liter) and leukocytosis (13,430/μl) (Supplementary Table 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Blood cultures and cerebrospinal fluid analysis including mycobacterial and fungal polymerase chain reaction showed no evidence of infection. Moreover, empirical antibiotic therapy did not result in clinical improvement. In GPA, optic neuropathy accompanied by retrobulbar pain and/or oculomotor nerve palsy usually occurs as a result of compression by inflammatory orbital masses (1, 2). However, it may rarely be encountered due to posterior ischemic neuropathy, optic neuritis, and/or perineuritis without inflammatory pseudotumor (1). Imaging may reveal signs of pachymeningitis, often subtle, and additional orbital apex infiltration (1-3). In some patients, high levels of inflammation markers can be detected (1, 2). Optic perineuritis has a poor prognosis with frequent recurrence of symptoms following reduction of glucocorticoid dose, thus requiring aggressive immunosuppressive treatment with cyclophosphamide and/or rituximab (1, 2). In our patient, immunosuppressive therapy was switched to combined rituximab and pulse cyclophosphamide treatment with the addition of a glucocorticoid for the re-induction of remission, resulting in protracted resolution of clinical symptoms and MRI findings (Supplementary Figure 1, http://onlinelibrary.wiley.com/doi/10.1002/art.42426). Disclosure Form Supplementary Figure 1: MRI follow-up showing resolution of contrast enhancement of the right optic nerve sheath following re-induction of remission with combined rituximab and pulse cyclophosphamide treatment and addition of glucocorticoid (A coronal image, B axial image). Supplementary Table 1: Laboratory values Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Treatment Options for Recurrent Primary CNS Lymphoma.

Primary CNS lymphoma (PCNSL) constitutes a rare extranodal variant of non-Hodgkin lymphoma (NHL) with an annual incidence of 0.45/100,000. Given the paucity of large prospective clinical trials, there is no consensus treatment for refractory or relapsed (r/r) PCNSL, and available strategies are largely based on retrospective analyses. Patient age, performance status, previously administered treatment, duration of response, and molecular characteristics guide selection of salvage therapy. Patients with a good performance status (KPS >70), particularly ≤65 years, and adequate organ function should be considered for salvage polychemotherapy. Based on its high overall response rate even in the relapsed setting, we choose high-dose (≥ 3.5g/m2) methotrexate (HD-MTX) based regimens, e.g., R-MPV (rituximab, HD-MTX, procarbazine, and vincristine), for remission re-induction as long as patients were sensitive to first line HD-MTX-based regimens, especially when duration of previous response was ≥ 1 year. Following successful remission induction, we choose myeloablative chemotherapy (e.g., thiotepa, busulfan, cyclophosphamide) and subsequent autologous stem cell transplant in curative intent whenever feasible. Alternatively, conventional chemotherapy regimens (for example, monthly HD-MTX) or low-dose whole-brain radiation therapy (WBRT) are selected for consolidation in non-transplant candidates in complete remission. In cases of HD-MTX refractory disease or contraindications, we use pemetrexed; temozolomide/rituximab; high-dose cytarabine; or whole brain radiation for remission induction. Clinical trial participation is considered as well. Emerging therapies for upfront or salvage therapy under ongoing investigation include bruton tyrosine kinase inhibition (e.g., ibrutinib), immunomodulatory drugs (e.g., lenalidomide), immune checkpoint inhibitors (ICI, e.g., nivolumab), and chimeric antigen receptor T (CAR-T) cell therapy.

Rituximab-associated hypogammaglobulinemia in ANCA-associated vasculitis: Incidence and time course.

Rituximab (RTX) is approved for remission induction and maintenance of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Observational studies demonstrate decline in immunoglobulin (IgG) in AAV post-RTX. The time course for the onset of hypogammaglobulinemia (Hypo-IgG) post-RTX is unknown. This is a key determinant in deciding whether to continue RTX for reinduction or maintenance of remission for AAV. We evaluated the trends of Hypo-IgG among AAV patients post-RTX therapies. An observational single-tertiary-center study of AAV patients treated with RTX for remission induction or maintenance (induction therapy, maintenance therapy, and combined induction and maintenance therapy) between 1998 and 2018. Poisson regression was used to compare the inciden- ces of Hypo-IgG: mild (450-700 mg dL-1), moderate (200-450 mg dL-1), and severe (􏰃200 mg dL-1). Ig levels were measured every 3-6 months after RTX use. Mean (SD) age at last visit was 59 (16) years, 93% were Caucasians, 64% were females, and 71 (63%) had granulomatosis with polyangiitis (GPA). Hypo-IgG occurred in 47 patients: one (2%) severe, 13 (28%) moderate, and 33 (70%) mild. Lower incidences of mild Hypo-IgG post-RTX were seen during induction compared to maintenance (IR 5.04 per 100 000 days vs 5.45 per 100 000 days, incidence rate ratio (IRR) 1.08, 95% CI 0.34, 3.19). Moderate Hypo-IgG occurred at 2.29 per 100 000 days during induc- tion and 1.82 per 100 000 days during maintenance (IRR 0.79, 95% CI 0.08, 4.84). Hypo-IgG is common among AAV treated with RTX, occurring in 42% of patients in this single-center cohort. The nadir IgG levels occur during remission induction, and the IgG levels remain relatively stable or increase over time in those receiving RTX for remission maintenance.

Engineering CD5-Targeted Chimeric Antigen Receptors and Edited T Cells for the Treatment of T-Cell Leukemia

Remission reinduction poses a great challenge in treating relapsed T-cell malignancies. These patients have poor outcomes when treated with chemotherapy alone. Treatment of relapsed B-cell malignancies using chimeric antigen receptor (CAR) T-cell therapy has had great success. However, the same approach will be difficult to apply to the treatment of T-cell malignancies due to the lack of T-lymphoblast specific antigens. Therefore, T cells modified with anti-T cell CARs target themselves, potentially resulting in fratricide of CAR T cells and killing of normal T cells. We have been investigating mechanistic approaches to evade fratricide-based limitations of CAR therapy for T-cell leukemias. Since the majority of T-cell leukemias express CD5, we hypothesized that if CD5 expression was knocked down/out in effector T cells, the issue of fratricide would be eliminated. We used CRISPR/Cas9 genome editing to knock out CD5 expression in CD5-positive T cells, resulting in CD5-negative T cells that were used as CAR-expressing effector cells. In order to target CD5, CARs were generated using two structurally different antigen recognition sequences - a traditional immunoglobulin-based single chain variable fragment (scFv) and a lamprey-derived variable lymphocyte receptor (VLR). We have previously shown this VLR can be used as an alternative for CAR-based antigen recognition. Here, we compare non-CRISPR T cells to CD5-edited T cells when modified with either a CD5-VLR-CAR or CD5-scFv-CAR. Our in vitro studies show both CARs yield comparable T-cell activation in non-CRISPR T cells and that CD5-edited CAR-modified T cells have a substantial reduction in self-activation. Furthermore, CD5-edited CAR-modified cells become activated in the presence of CD5-positive target cells to a greater degree than do non-CRISPR CAR-modified T cells (p<0.05 at all effector:target ratios of 2:1, 1:1 and 1:5). We, and others, have shown a decrease in cell surface CD5 protein expression following lentiviral gene transfer of a CD5-CAR transgene cassette in non-CD5 edited T cells using both VLR and scFv-based vectors. This downregulation has been speculated to be due to the interaction of the cell surface CAR with the target antigen. We also show that CD5-CAR expression in CD5-edited CAR-modified T cells is increased compared to CD5-CAR expression in non-CRISPR CAR-modified T cells (see Figure). Therefore, the interaction of the CAR with the cell surface antigen not only decreases antigen levels, but CAR levels as well. The decreased fratricide, increased CAR expression and activation of CD5-edited CAR-modified T cells in the presence of target cells should lead to more potent and durable anti-leukemia effects. Overall, our preclinical data show an advantage to using CD5-edited effector T cells when utilizing CAR-T cell therapy to target difficult to treat relapsed T-cell malignancies. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rituximab as therapy to induce remission after relapse in ANCA-associated vasculitis

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the...

P365 Identification of predictive factors of AZA/6-MP treatment outcome in paediatric luminal Crohn’s disease: a multicentre study of the paediatric IBD Porto group of ESPGHAN

Abstract Background According to current guidelines, most paediatric patients in Europe diagnosed with Crohn′s disease (CD) are prescribed long-term immunosuppressive therapy with azathioprine (AZA). This study aimed to develop a predictive model allowing to stratify patients who will not benefit from AZA maintenance treatment and who require a more intensive therapeutic approach early after diagnosis. Methods The study was designed to develop a clinical prediction rule using retrospective data analysis from patients included to prospective inception cohort, the EUROKIDS-IBD until 2017. In total, 1190 CD patients using AZA were selected from the registry in 13 European centres. Of these, 441 patients who responded to induction treatment, started AZA treatment within 6 weeks from the time of diagnosis and maintained remission at week 12 were entered into this multicentre study. The primary outcome was time to clinical relapse defined as a necessity of re-induction of remission. A sequence of Cox models was fitted to predict the risk of relapse. Variables appearing to be significant in univariate risk analyses were added to the model one by one and non-significant terms were dropped. Results More than 50 % of patients did not experience a clinical relapse within 2 years of AZA treatment (Figure 1). The median time to relapse was 2.11 (CI 1.59–2.46) years. Out of all tested parameters available at the time of diagnosis,8 were predictive in the context of early relapse. Only 4 of these variables, namely centre (p = 0.0009), age (HR = 1.389 95% CI (1.004–1.921), p = 0.047), CRP (HR = 1.504 95% CI (1.116–2.027), p = 0.008) and BMI Z-score (HR = 0.830 95% CI (0.742–0.928), p = 0.001), remained significant in multivariate analyses. Conclusion In paediatric CD patients achieving clinical remission after induction treatment at week 12, AZA was effective as maintenance treatment in over 50% of patients for 2 years. Due to low values of HR, the possibility to predict relapse on AZA treatment appears to be limited. Acknowledgement: This work was supported by the Grant Agency of Charles University in Prague [grant number 364617] and by Ministry of Health, Czech Republic-conceptual development of research organisation, Motol University Hospital, Prague, Czech Republic [00064203].

Probiotic Supplementation Decreases Chemotherapy-induced Gastrointestinal Side Effects in Patients With Acute Leukemia.

In children with acute leukemia, gut microbiota is modified secondary to chemotherapy administration, leading to gastrointestinal side effects. Probiotics are microorganisms that can restore gut microbiota and may help alleviate gastrointestinal symptoms. The aim of this pilot study was to assess the effects of probiotic supplementation on chemotherapy-induced gastrointestinal side effects in children with acute leukemia (AL). In this randomized pilot study, patients under 17 years of age diagnosed with AL who were on remission induction or remission reinduction chemotherapy were randomly assigned to receive probiotic supplementation (a concentration of 5×109 CFU per sachet was administered at a standard dose twice daily, by mouth) or no probiotic supplementation. The primary endpoint was the prevalence of gastrointestinal side effects. Vomiting, nausea, flatulence, dyspepsia, diarrhea, constipation, abdominal pain, and abdominal distention were assessed in both groups. Gastrointestinal side effects were less prevalent in the probiotic group, and 3 of the 8 gastrointestinal side effects (nausea, vomiting, and abdominal distension) significantly decreased in the probiotic group (P<0.05). We found for diarrhea a relative risk of 0.5 (95% confidence interval [CI], 0.2-1.2; P=0.04); for nausea an RR of 0.5 (95% CI, 0.4-0.8; P=0.04) and for vomiting an RR of 0.4 (95% CI, 0.2-0.9; P=0.04). Daily supplementation with Lactobacillus rhamnosus reduced chemotherapy-induced gastrointestinal side effects in children with AL.

Achados anatomopatológico post mortem do linfoma de células grandes em canino: Relato de caso

Lymphoma is a hematopoietic neoplasm commonly diagnosed in dogs. Its etiology is still unknown and is probably multifactorial. It happens mainly in middle-aged animals or elderly people with no racial predilection. In Veterinary Medicine the most common classification of lymphoma is based on the anatomical location of the tumor masses, such as, multicenter, mediastinal, alimentary and extranodal. The latter is characterized as the appearance of an isolated lymphoid tumor in any organ not belonging to the primary or secondary lymphoid tissue. Other common locations include the nervous system, heart, eyes, nasopharynx, bones, testicles, urinary bladder, and penis. The clinical signs of this neoplasm are varied and depend on its anatomical location. For the definitive diagnosis it is necessary to perform the histopathological or cytological evaluation of the affected tissues, however, the accomplishment of complementary tests is necessary for clinical staging. Polychemotherapy is the most widely used and effective treatment in dogs with lymphoma and dozens of protocols are available. The steps of chemotherapy are induction of remission, maintenance of remission, and re-induction of remission or rescue therapy. The objective of this work was to describe the postmortem anatomopathological findings of large cell lymphoma in a 3-year-old Chow Chow canine, in order to contribute to further studies about this neoplasm.

Survival after Post-Hematopoietic Stem Cell Transplantation AML Relapse: A Single Center Experience

Introduction Post-allogeneic hematopoietic stem cell transplantation (HSCT) acute myeloid leukemia (AML) relapse has a dismal prognosis and no standard of care treatment. Current common treatment options for (re)inducing a graft versus leukemia effect (GvL) are cessation of immunosuppressive therapy, administering hypomethylating agents or high dose chemotherapy. After reinduction of remission is achieved, the effect can be consolidated with a donor lymphocyte infusion (DLI) or a second allogeneic HSCT. In this study we analyzed outcomes of patients with post-allogeneic HSCT AML relapse in our institute. Objectives To evaluate outcome of patients with post-allogeneic HSCT AML relapse, who received different types of reinduction therapy regimens and of whom a subgroup underwent immunological consolidation therapy. Methods Data was collected from the medical history of all 83 adult patients that had received an allogeneic stem cell transplantation for AML or high-risk myelodysplastic syndrome (MDS) at the Amsterdam University Medical Centers between January 1st 2010 and 31st December 2016 and who relapsed before December 31st 2017. In this retrospective analysis, patients were divided into a curative intent treatment group and a palliative care group. Statistical analysis was done with IBM SPSS version 24.0.0.1 using Mann-Whitney U, Chi-square testing, Pearson's R for ordinal variables and Kaplan Meier survival analysis with log rank testing. Results 50 (60%) of the 83 patients were treated with the intent to cure and the other 33 (40%) received palliative care. Of the patients treated with curative intent, 13 (26%) survived. The patients in the palliative care group were older than the patients in the curative intent group (median age 58 vs 53 year, P=0.043). They also had a higher bone marrow blasts count (median 37.5% vs 20.5%, P=0.025), and shorter time between allo HSCT and relapse (median 21 weeks with IQR of 6-28 vs median of 21 weeks with IQR 14-47.25, P=0.047). Within the curative intent group these variables did not differ significantly between survivors and deceased. Of the patients in the curative intent group 44% reached CR and of these patients 50% survived. The majority of the survivors received high dose cytarabine treatment (69%) and immunologic consolidation therapy (69%). A relapse ≤ 12 weeks after allogeneic HSCT but not relapse Conclusion This retrospective analysis of a real-life, non-preselected patient group with post-allogeneic HSCT AML or MDS relapse demonstrated that patients who were fit enough to receive high-dose reinduction therapy, followed by a immunologic consolidation with DLI or a second allogeneic HSCT had the best chance to obtain durable remissions, in particular when immunologic consolidation was performed when the patient had obtained complete remission.

Chronic Inhibition of Complement C1s By TNT009 Produces Sustained, Complete Remission in Patients with Severe, Transfusion-Dependent Cold Agglutinin Disease (CAD)

Background: We recently presented that the humanized anti-complement C1s monoclonal antibody, TNT009, rapidly stoppedhemolysisand correctedanemiain patients with severe CAD in an ongoing Phase 1b clinical trial. After completion of washout from protocol treatment, these patients suffered relapse of CAD with a drop inhemoglobinto pre-dose levels. We now report on the clinical experience of their extended re-treatment under the Named Patient provision of the Austrian Drug Act, which provided the occasion: 1) to explore lower dose regimens and alternative dosing schedules; 2) to try to recapitulate the initial success of complete remission under protocol treatment; 3) to test the durability of response with a longer term maintenance treatment with TNT009.Methods: In order to test a lower dose regimen of TNT009, the Phase 1b trial dosing of 60 mg/kg IV once weekly for both loading and maintenance was reduced to 45 mg/kg IV once weekly (4x) followed by maintenance with 45 mg/kg every other week. A simplified dosing regimen was then tried, using a single priming dose of 60 mg/kg on Day 0 followed by 60 mg/kg every other week (biweekly) thereafter beginning on Day 7. This TNT009 biweekly maintenance with 60 mg/kg was continued indefinitely to test the durability of the effect, to monitor for safety, and to serially assess their hematologic response to TNT009.Results:All infusions were well tolerated without premedication and without relevant adverse effects. TNT009 re-exposure immediately decreased CH50 activity and increased complement C4 levels, confirming the rapid onset ofpharmacodynamiceffect. The concordant and sustained effect of TNT009 on hematologic parameters related tohemolysisandanemiasis illustrated in the composite Figure 1 for the first patient treated, C1001. This patient has undergone three treatment episodes with TNT009: weekly dosing at 60 mg/kg under the Phase 1b protocol (left); weekly → biweekly 45 mg/kg (center); 60 mg/kg on Day 0 and biweekly thereafter starting on Day 7 (right). Note that the CH50 serves as apharmacodynamicmarker for the effective inhibition of the classical complement pathway by TNT009. Each new episode of treatment with TNT009 induced remission ofhemolyticanemia, and relapse occurred following washout (60 mg/kg weekly x 4) orpharmacodynamicbreakthrough (45 mg/kg maintenance regimen). Although it appears that the reduced dose maintenance regimen of 45 mg/kg biweekly does not suffice to maintain full C1s inhibition, there is no evidence oftachyphylaxisas restoration of full dose treatment at 60 mg/kg biweekly was able to restore remission again.A similar pattern of results was observed in the other patients offered Named Patient treatment with TNT009, but with two instructive exceptions. Patient C1004 had unsuspected erythropoietin deficiency and did not achieve complete normalization ofhemoglobinuntil concomitant treatment with erythropoietin was begun. Patient C1003 did not have CAD but Cold Agglutinin Syndrome (CAS) secondary to an extensivelymphoplasmacyticlymphoma (LPL). Initially she was treated with TNT009 monotherapy and did not respond. TNT009 was then stopped and her LPL was treated withibrutinib, resulting in a gradual amelioration of heranemiauntil anintercurrentinfection triggered relapse of herhemolyticanemia. At that time re-treatment with TNT009 (whileibrutinibwas continued) quickly normalized her hematologic parameters. Eventually TNT009 was able to increasehemoglobinlevels to >12 g/dLin all 5 of 5 treated patients.Conclusion:TNT009 was previously shown to induce rapid correction ofhemolyticanemiain severe CAD patients in a Phase 1b trial. It has now been shown that subsequent washout of TNT009 leads to relapse in all patients, and that re-induction of remission by TNT009 is possible in all. Long-term maintenance of remission can be achieved by dosing TNT009 at 60 mg/kg biweekly, the dose regimen to be tested in larger-scale clinical trials of CAD. [Display omitted] DisclosuresGilbert:Truenorth Therapeutics, Inc.: Employment, Equity Ownership. Panicker:Truenorth Therapeutics, Inc.: Employment. Parry:Truenorth Therapeutics, Inc.: Employment, Equity Ownership. Jaeger:Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses.

TCR Diversity Is a Predictive Marker for Donor Lymphocyte Infusion Response

Background: Relapse of disease remains a frequent cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). For patients with imminent relapse, therapeutic donor lymphocyte infusions (DLI) offer a treatment option for re-induction of complete remission of the underlying disease by employing the graft-versus-leukemia (GvL) effect. Moreover, DLI is used pre-emptively to prevent relapse in patients with high risk disease. DLI is given in increasing doses, adapted to clinical signs of graft-versus-host disease (GvHD) or molecular markers of disease, i.e. donor chimerism or minimal residual disease. There is a need for reliable monitoring of the immunologic response preceding the clinical outcome, enabling a precise administration of DLI dose escalation and thus possibly preventing overshooting immune reactions. With the advent of deep sequencing technology direct measure of high resolution T cell receptor (TCR) diversity can be used as a read-out of the immunologic response in the patient at the molecular level.Aims: In this study we aim to elucidate whether TCR-diversity can serve as a biomarker for clinical outcome of DLI treatment.Patients and Methods: We assessed 19 patients, who received DLI after HSCT. Therapeutic DLI was given in 14 patients and prophylactic DLI in 5 patients. The majority of patients (n=14) was treated for AML or MDS, 2 for ALL, and 3 for MPN. Peripheral blood samples for TCR-sequencing were obtained from the patient pre-DLI, at 2 and 4 weeks post DLI, and subsequently when available. Also, donor samples were collected. Donor's and patient's lymphocytes were FACS-sorted into CD8+ and CD4+ conventional (Tconv) and CD4+CD127-CD25+ regulatory T cells (Treg). Sorted subpopulations were subject to cDNA-based CDR3-region amplification by RACE-PCR allowing assessment of the entire TCR-β repertoire. Reliable generation of CDR3 amplicons was possible from as few as 4000 cells. These were then sequenced using the Illumina MiSeq platform. Reads were annotated by the IMGT.org database; further bioinformatics analyses included VDJtools and the tcR R-package.Results: GvL response (remission or stable disease) could be achieved in 14/19 patients; 8 of these patients developed acute GvHD ≥III°. Flow cytometric analysis showed that the ratio between CD8+ and CD4+ Tconv in the DLI is predictive of response to DLI: DLIs containing a majority of CD4+ Tconv were associated with development of GvHD (n=8, CD8:CD4 = 35.3%:54.9%) , whereas patients responding to DLI with GvL only had received a higher proportion of CD8+ T cells (n=6, CD8:CD4 = 59.1%:29.5%); comparison of ratios met statistical significance (Mann Whitney test, p=0.0027).TCR sequencing revealed that the diversity of the TCR-repertoire seems to be predictive of the clinical course of the patient after DLI. GvHD development within 2 weeks of blood sampling time (n=4) was preceded by an increase of Treg repertoire diversity (assessed with inverse Simpson's diversity index, 1/Ds). Compared to the pre-DLI repertoire 1/Ds, mean increase was 143.67% vs. a 36.04% decrease in patients not developing GvHD (n=7; Mann Whitney test, p=0.02). Steroid treatment of GvHD (n=2) led to a mean decrease of 49.71% of Treg TCR 1/Ds compared to the previous time point. Analysis of GvL response revealed an association of remission induction with a trend towards decreased 1/Ds of the CD8+ TCR-repertoire (mean decrease of 27.66% at d28 after DLI compared to pre-DLI vs. 0.31% decrease in patients showing no GvL effect). Assessment of TCR CDR3 region clonotype expansion over time is shown for a patient responding with GvHD (Fig. 1A) and GvL (Fig. 1C) to DLI and a patient progressing without response to DLI (no GvHD Fig. 1B, no GvL Fig. 1D).Conclusion: Our data indicate that TCR sequencing allows the assessment of TCR-diversity change as a surrogate parameter of DLI response. While an increase of Treg diversity seems to indicate the development of GvHD, repertoire compression of the CD8 compartment may be predictive of GvL response. Taken together, monitoring TCR repertoires may become a valuable predictive tool to improve DLI therapy and furthermore, analysis of expanding clonotypes after DLI enables identification of individual CDR3 sequences associated with DLI response. [Display omitted] DisclosuresHeuser:Pfizer: Research Funding; Novartis: Consultancy, Research Funding; BerGenBio: Research Funding; Karyopharm Therapeutics Inc: Research Funding; Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding.

De-intensifying treatment in established rheumatoid arthritis (RA): Why, how, when and in whom can DMARDs be tapered?

As more patients with established rheumatoid arthritis (RA) achieve remission or low disease activity, strategies such as tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) are being investigated. In several trials, DMARD discontinuation was associated with a higher risk of relapse, ranging from 56% to 87% at 1 year. Tapering, either by dose reduction or by injection spacing, may limit the risk of relapse. Half-dose etanercept (ETN) versus full-dose continuation was not associated with an increased relapse risk at 1 year in two trials. Progressive antitumor necrosis factor injection spacing was shown to be equivalent to full regimen continuation in terms of persistent flare and disease activity at 18 months in one trial, but not in another one. Reintroduction of a DMARD at previous dose/regimen was usually associated with remission re-induction. The risk of relevant structural damage progression was not increased. Safety improvement has not yet been demonstrated. The annual cost reduction when tapering biologic DMARDs (bDMARDs) was 3500-6000 €/patient. Research questions to be addressed include defining flare that requires reinitiation of treatment, such that patients facilitate the maintenance of remission during tapering by timely communication with their rheumatology team.

Towards Possible Cure of Cancer by Immunotherapy of Minimal Residual Disease

Based on predictive, preventive and personalized medicine (PPPM) strategy for treatment of cancer, immunotherapy and additional targeted anti-cancer modalities should be considered for cure of cancer at an early stage of the disease following successful conventional treatment. Alternatively, PPPM strategy should be applied at the stage of minimal residual disease (MRD) induced following successful re-induction of second or subsequent remission. Fortunately, a stage of minimal residual disease can be accomplished in most patients with cancer following conventional treatment but in the absence of visible disease or lack of symptoms, additional treatment is usually denied. Considering PPPM using innovative and safe treatment focusing on immunotherapy should be considered for patients at risk because eradication of MRD can be accomplished whereas treatment of overt disease may no longer be possible. Similarly to the treatment of infectious diseases, the goal should be to recognize the high-risk cases upfront and treat MRD because residual malignant cells cannot be detected by available imaging technologies. The take home message is that at the stage of minimal residual disease focusing on immunotherapy and other targeted anti-cancer modalities may be safe, successful and possibly the only way to cure cancer, or at least to better control tumor progression.

Lifting the mantle: Unveiling new treatment approaches in relapsed or refractory mantle cell lymphoma

The management of relapsed/refractory mantle cell lymphoma (MCL) remains a clinical challenge. A standard second-line treatment for relapsed/refractory MCL does not exist. Management of relapsed/refractory MCL requires an individualized treatment approach, incorporating factors such as: functional status, prior treatments, response to prior therapies, and disease biology. Generally, there are two categories of salvage therapy; the first, non-cross-resistant cytotoxic chemotherapeutic agents and, the second, pathway-targeted agents. For transplant eligible patients, the optimal therapy usually consists of salvage, remission re-induction phase followed, whenever possible, by a consolidation phase. Bendamustine and/or high dose cytarabine plus rituximab based chemotherapy represent the most common salvage therapy with an overall response rate of 70–80%. Consolidation with a reduced intensity conditioning allogeneic stem cell transplantation represents the only potentially curative treatment. Overall survival ranges from 30% to 50% at 5years with this approach. For transplant ineligible patients, ibrutinib is the most effective treatment with an overall response rate of almost 70% and median response duration of 17.5months. Lacking an effective consolidation, this approach is not considered curative. In this review we characterize the main therapeutic approaches available in this setting and summarize our preferred clinical treatment approach.

Use of Clofarabine in the Treatment of Relapsed or Refractory Acute Myeloid Leukemia in Adults: The French Experience

Abstract 2623 Introduction.Relapsed or refractory acute myeloid leukemia (AML) patients (pts) have a dismal outcome and conventional chemotherapy offers almost no chance of cure. Consequently, allogeneic transplantation (alloSCT) has been widely used for these patients, but outcome is limited by a high relapse rate. There is no generally established standard for reinduction of remission. Clofarabine is a second-generation purine nucleoside analogue mainly evaluated in older adults with untreated AML, but there are limited data in relapsed/refractory AML. The aim of the present study was to establish the role of clofarabine in a large series of adults with relapsed/refractory AML. Methods.Eighteen French centers participated in this retrospective study. Eligibility criteria were as follows: confirmed diagnosis of AML, pts >18 years (yrs) old at clofarabine treatment, and clofarabine used outside of a clinical trial. Relapses after alloSCT were included, but use of clofarabine as part of the conditioning regimen of alloSCT was not included. Data were collected regarding patient demographics, leukemia characteristics, previous treatments and the use of clofarabine including the regimen used and the outcome following treatment. Results.Between January 2007 and June 2011, 100 pts were treated with clofarabine for relapsed/refractory AML. At first diagnosis of AML, median age was 58 yrs, male:female ratio was 60:40, 86% of pts had performance status 0–1, 57% had white blood cells < 10000/mm3, 37% had secondary AML (prior myelodysplastic syndrome 54%), 39% had unfavorable cytogenetics, 58% had intermediate cytogenetics and 3% had favorable cytogenetics, 14/55 had NPM1 mutation, 19/69 had FLT3 internal tandem duplication. At clofarabine treatment, median age was 59 yrs (range 18–77), 42 pts were in first relapse, 35 in relapse >1, and 23 had primary refractory AML. Anthracycline was previously used in 92 pts. Twenty three relapses occurred after alloSCT. Clofarabine was used as single agent (n=22) or in combination with low-dose cytarabine (LDAC, 20–40 mg/m2/d for 4–14 days, n=18) or intermediate-dose cytarabine (IDAC, 1000–2000 mg/m2/d for 3–5 days, n=56) or other drugs (n=4). The dose of clofarabine at cycle 1 was 20 mg/m2/d (n=26), 30 mg/m2/d (n=32), 40 mg/m2/d (n=40) or other (n=2) for a median number of 5 days (mean 4.9, range 3–5). Among all pts, 30 achieved complete remission (CR), and 9 achieved CR with incomplete recovery (CRi), for an overall response rate of 39%. Six pts died during cycle 1, all of infection. Responding pts received a median number of 2 cycles (mean 2.1, range 1–6). Thirteen pts underwent subsequent alloSCT and four pts proceeded to donor lymphocyte infusion. No predictive factor of response was found in univariate analysis among age (cut-off at 60 yrs), sex, de novo vs secondary AML, cytogenetics (unfavorable vs intermediate), molecular genetics, line of treatment (first relapse vs relapse>1 vs refractory AML), relapse after alloSCT vs other relapse (for patients < 65 yrs with equally distributed cytogenetics), regimen (monotherapy vs LDAC vs IDAC) or dose of clofarabine (20 vs 30 vs 40 mg/m2/d). The median disease-free survival (DFS) was 17 months (mo). No factor significantly influenced DFS in univariate analysis, even though DFS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with 1-yr DFS being 100% vs 60% (p=0.1). Median overall survival (OS) was 19 mo for responding pts (CR+CRi) vs 3 mo in treatment failure (p<0.0001). In univariate analysis, median OS was better in male than in female (6.8 mo vs 4.1 mo, p=0.03), and in intermediate vs unfavorable cytogenetics (5.4 mo vs 4.1 mo, p=0.04); median OS tended to be better in relapse after alloSCT than in other relapse (for patients < 65 yrs with equally distributed cytogenetics) with median OS being 21 mo vs 4 mo (p=0.09). In multivariate analysis, cytogenetics was the only prognostic factor for OS (p=0.02). Conclusion.This study suggests that clofarabine-based salvage regimen is safe and can be effective in the treatment of relapsed/refractory AML. Durable remissions were achieved, especially in AML relapsed after alloSCT, allowing pts the option of (second) transplantation with the potential of long term cure. Disclosures:Off Label Use: clofarabine is approved for relapsed ALL in children.

Reindução da remissão clínica com adalimumabe após interrupção do tratamento: uma alternativa no manejo da doença de Crohn

Introdução: o Adalimumabe (ADA) é um anticorpo monoclonal totalmente humano, utilizado no tratamento da doença de Crohn (DC). Nos casos com necessidade de interrupção desta terapia, o resgate da resposta é controverso, e o papel da reindução da remissão com dose total de ataque pode ser uma alternativa nos casos graves da DC. Não há relatos desta forma de tratamento na literatura. O objetivo deste estudo foi relatar a experiência de dois pacientes tratados com reindução da remissão com ADA, após sua interrupção. Método: análise retrospectiva de dois casos submetidos a reindução em meio a uma coorte de 24 pacientes em uso de ADA para DC. Resultados: são descritos dois casos de pacientes jovens, em tratamento com ADA subcutâneo, que tiveram necessidade de interrupção da terapia (um por abscesso perineal extenso e outro por dificuldade de acesso ao fornecimento da medicação). Ambos foram tratados pela reindução com dose total de ataque do ADA, com bons resultados, sem efeitos adversos. Conclusão: não há na literatura estudos controlados que comparem a reindução com outras formas de resgate da terapia após a parada de qualquer agente anti-TNF. Experiências isoladas mostram bons resultados com esta alternativa terapêutica em casos graves e selecionados.

Allogeneic hematopoietic cell transplantation for acute leukemia in first relapse or second remission

BackgroundThe role of pre-transplant salvage chemotherapy has been controversial in relapsed acute leukemia.MethodsWe investigated post-transplant outcomes in 65 patients with acute leukemia treated with allogeneic hematopoietic cell transplantation (HCT) during first relapse or second remission.ResultsThe 5-year cumulative incidence of relapse (CIR) was 52.3%. Multivariate analysis for CIR revealed that patients with unfavorable cytogenetics and those not in remission at the time of HCT had a significantly high CIR (P = 0.031 and P = 0.031, respectively). Allogeneic HCT was performed in 14 patients after first relapse without salvage chemotherapy ("untreated relapse" group), 15 patients failed chemotherapy for reinduction of remission before HCT ("refractory relapse" group), and 36 patients attained second remission with salvage chemotherapy before HCT ("second remission" group). The 5-year CIR for patients in the untreated relapse group (57.1%) was higher than that for those in the second remission group (42.3%), but it was lower than that for patients in the refractory relapse group (66.7%). Among patients who underwent allogeneic HCT in relapse, those with bone marrow (BM) blasts ≤30% had a lower 5-year CIR than those in florid relapse (BM blasts >30%) (57.7% vs. 70.6%).ConclusionOur results do not support the role of salvage chemotherapy aimed at re-induction of remission before allogeneic HCT in patients with acute leukemia after first relapse. Patients with early relapse do not appear to benefit from salvage chemotherapy before HCT.

Pre-Emptive Treatment With Rituximab of Molecular Relapse After Autologous Stem Cell Transplantation in Mantle Cell Lymphoma

Minimal residual disease (MRD) is predictive of clinical progression in mantle-cell lymphoma (MCL). According to the Nordic MCL-2 protocol we prospectively analyzed the efficacy of pre-emptive treatment using rituximab to MCL patients in molecular relapse after autologous stem cell transplantation (ASCT). MCL patients enrolled onto the study, who had polymerase chain reaction (PCR) detectable molecular markers and underwent ASCT, were followed with serial PCR assessments of MRD in consecutive bone marrow and peripheral blood samples after ASCT. In case of molecular relapse with increasing MRD levels, patients were offered pre-emptive treatment with rituximab 375 mg/m(2) weekly for 4 weeks. Of 160 MCL patients enrolled, 145 underwent ASCT, of whom 78 had a molecular marker. Of these, 74 were in complete remission (CR) and four had progressive disease after ASCT. Of the CR patients, 36 underwent a molecular relapse up to 6 years (mean, 18.5 months) after ASCT. Ten patients did not receive pre-emptive treatment mainly due to a simultaneous molecular and clinical relapse, while 26 patients underwent pre-emptive treatment leading to reinduction of molecular remission in 92%. Median molecular and clinical relapse-free survival after pre-emptive treatment were 1.5 and 3.7 years, respectively. Of the 38 patients who remain in molecular remission for now for a median of 3.3 years (range, 0.4 to 6.6 years), 33 are still in clinical CR. Molecular relapse may occur many years after ASCT in MCL, and PCR based pre-emptive treatment using rituximab is feasible, reinduce molecular remission, and may prevent clinical relapse.