Late-onset Neutropenia Research Articles

Recurrent late-onset neutropenia following treatment with different B cell-depleting strategies in multiple sclerosis.

As B cell-depleting therapies in multiple sclerosis (MS) have gained significant importance in the last several years, their long-term safety profile is of considerable clinical interest. Late-onset neutropenia (LON) is a rare, but potentially severe, adverse event that was first described in patients with rheumatic disorders under therapy with rituximab. Ofatumumab was approved in 2021 for the treatment of relapsing-remitting multiple sclerosis (RRMS). Neutropenia occurred in 0.2% of patients in clinical phase 3 trials, and to date, no cases of LON have been reported under ofatumumab treatment. Here, we report a case of repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment. Additionally, we review the literature on rare occurrences of LON in patients with MS, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) undergoing B cell-depleting therapies, including rituximab, ocrelizumab, ofatumumab, inebilizumab, and ublituximab. In our case, the patient presented with repetitive symptomatic LON under ocrelizumab as well as ofatumumab treatment leading to febrile infections, subsequent use of antibiotics, and application of granulocyte-colony-stimulating factor. After repetitive episodes of LON under both B cell-depleting strategies, cladribine was subsequently initiated. A nine-month follow-up showed a normal neutrophil count and no evidence of disease activity. This case highlights the significance of symptomatic late-onset blood count changes under both ocrelizumab and ofatumumab and emphasizes the importance of continuous monitoring of the differential blood count under B cell-depleting treatment. This study was supported by the Deutsche Forschungsgemeinschaft (DFG; SFB CRC-TR-128 to F.Z., V.F., and S.B..; SFB 1080 and SFB CRC-1292 to F.Z..; and SFB/TRR 355 to S.B.) and the Hermann and Lilly Schilling Foundation (to S.B.).

Late-onset Severe Neutropenia in a Patient with Relapsing Remitting Multiple Sclerosis Treated with Ocrelizumab (P10-6.010)

Late-onset Severe Neutropenia in a Patient with Relapsing Remitting Multiple Sclerosis Treated with Ocrelizumab (P10-6.010)

Late-onset Neutropenia after Rituximab Treatment for MPO-ANCA-associated Vasculitis.

An underestimated side effect of rituximab is late-onset neutropenia (R-LON), which often resolves spontaneously and rarely results in a severe infection. We herein report a case of febrile neutropenia due to R-LON in a 91-year-old woman with renal failure who was treated with rituximab to induce remission of MPO-ANCA-associated vasculitis. Fifty-four days after the last rituximab administration, the patient was hospitalized for febrile neutropenia due to R-LON, which improved with granulocyte colony-stimulating factor and antibiotics. Although R-LON may resolve spontaneously and remain unnoticed, it can cause severe infections in the elderly and patients with renal failure.

Rituximab and pregnancy: Late-onset neutropenia in a 2-month infant whose mother received rituximab 2 weeks prior to childbirth.

Late-onset neutropenia (LON) is a rare adverse event that has not been reported from in utero exposure. We describe a case of LON in an infant, whose mother had neuromyelitis optica and received rituximab in the third trimester due to re-emergence of CD19 B cells. The newborn was born without complications but 2 months later was found to have grade IV neutropenia. No etiology was identified. Neutropenia self-resolved within 1 week. This case emphasizes an unmet need for developing guidelines and protocols to manage in utero rituximab exposure.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be >76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.

Neutropenia in Preterm Infants.

The non-specific and antigen-specific components of host defense mechanisms are subject to the adaptation process in the neonate; however, the neutrophil quantitative and qualitative deficiency is one of the most significant causative factors of neonatal-increased vulnerability to infection. To review the incidence and outcome of neutropenia of unknown cause in preterm infants. The incidence of early and late-onset idiopathic neutropenia of prematurity is significant. Conclusion The low neutrophil counts respond quickly to G-CSF treatment; however, due to the low probability of septic complications, particularly in the late-onset neutropenia, a deep diagnostic approach and the potential hematopoietic growth factor treatment should be limited to the severe cases, such as a neutrophil count <500/μL, lasting for more than 2 days.

Long Lasting and Late Onset neutropenia with and without antibodies against neutrophils. A potential new pathological entity?

Long Lasting and Late Onset neutropenia with and without antibodies against neutrophils. A potential new pathological entity?

Clinical and immunological prophyle of long lasting and late onset neutropenia: beyond primary autoimmune and idiopathic neutropenia

IntroductionPrimary idiopathic (pIN) and autoimmune neutropenia (pAN) of childhood are a benign, self- limiting disorders. pAN patients with atypical features i) early onset but persistence >36 months (named Long Lasting-LL) or ii) Late Onset-LO, rising >3 years and persisting >12 months, were recently shown to display a different immune-hematological profile versus typical pAN. In the present study we analyze a cohort of LL/LO pAN and pIN aiming to identify the immunological pattern and the genetic background. Materials and methodsClinical, immunological and genetic data (NGS panel of 162 immunodeficiency/disimmunity/bone marrow failure genes) of patients with pIN and pAN in the Italian Neutropenia Registry from 2005 to 2022 were retrived.Table 1(abstract: 130) (A) Dynamic of Hematological prophyle; (B) Appearance of autoimmunity overtime (C) Lymphocytes subsets according to age (William T. Shearer, J Allergy Clin Immunol 2003and Leslie R. Bisset, Eur J Haematol 2004)(A)Median Value (IQR)DiagnosisMid- follow-upLast visitWhite Blood cells (×109/L)3.15 (2.8–4.03)3.3 (2.65–3.83)3.23 (2.43 – 4.13) (p= 0.099)Absolute neutrophil Count (×109/L)0.73 (0.3–1.07)0.91 (0.51–1.25)1.03 (0.45–1.46) (p<0.001)Abolute Lymphocyte Count (×109/L)1.71 (1.4–2.54)1.64(1.31–1.93)1.54 (1.14–1.85) (p<0.001)CLow N(%)Normal N(%)High N(%)T-profileCD3+§12 (19)50 (79)1 (2)CD3+CD4+§13 (21)50 (79)0CD3+CD8+§16 (25)47 (75)0CD3CD45RA+ (Naïve)^10 (17)23 (38)27 (45)CD3CD45RO+ (Memory)^20 (33)22 (37)18 (30)CD3CD4CD25brCD45RA+ (T regulatory)^40 (67)15 (25)5 (8)Gamma/delta T cells^3 (5)20 (33)37 (62)HLADR+^10 (17)23 (38)27 (45)B-profileCD19+§16 (25)45 (71)2 (4)CD19+CD27+ (memory)^23 (38)37 (62)0CD27-CD10++CD38++ (Transitional)*11 (32)18 (51)6 (17)CD27-CD10+-CD38+-IgD+ (Naïve)*12 (34)12 (34)11 (32)CD27+IgD+IgM+ (Marginal zone)*7 (20)14 (40)14 (40)CD27+IgD-IgM- (Switched memory)*21 (60)9 (25)5 (15)CD27+IgD-IgM+ (Pre-switched)*030 (85)5 (15)CD27+IgD+IgM- (IgD memory)*033 (94)2 (6)CD27-IgD- (Double negative)*015 (43)20 (57)*B profile (CD19+ excluded) has been performed in 35/63 patients.^60/63 data available. ResultsSixty-three patients (31 females, 32 pAN, 18 LL) with a median age at onset of 9.2 years (IQR 2.0–15.6) and median follow-up of 5.2 years (IQR 4.0–8.2) were eligible. Neither autoimmunity nor other cytopenias were associated to neutropenia at onset. Autoimmune manifestations appeared in 19 (30%) patients, cumulative risk at 6 years was 22.9% (CI 95% 12.9–38.5) (Table 1B). Forty-five patients (71%) suffered of at least one infection, of which severe in 16% of cases. The majority of patients (75%) showed leukopenia and lymphocytes’ decrease overtime (p <0.001) (Table 1A) without immunoglobulin impairment. Twenty-five% of patients had low B and NK cells. T/B profile is reported in Table 1C. Increased CD27+IgD+IgM+ (14/35, 40%) with reduced CD27+IgD-IgM- B cells (21/35, 60%) emerges with a significant increase in CD27-IgD- B cells (20/35, 57%) and T-regulatory and B-memory cells depletion.Genetic analysis performed in 58/63 (92%) of the cohort revealed 6 (10%) pathogenic variants in TNFRSF13B (4), CARD11 (1), FASL (1). ConclusionsLL and LO neutropenias show different clinical and immunological pattern compared to pAN and pIN since their onset. Leukopenia and progressive lymphocytopenia seem to be anticipatory signals that worsen overtime. A peculiar immunological pattern in a subgroup of patients seems to suggest that an underlying immune-dysregulationlead to an exhaustion of B-maturation and a consequent propensity to autoimmunity. These neutropenias would deserve more precise characterization by enlarging the cohort and applying more comprehensive genetic analysis.

As-Required Filgrastim for Late-Onset Neutropenia Complicating Long-Term Clozapine Treatment: a Case Report.

Clozapine is considered the most effective antipsychotic for schizophrenia, but it can cause neutropenia and even agranulocytosis. We describe the first case in Hong Kong involving the use of filgrastim, a recombinant form of human granulocyte colony-stimulating factor, to enable clozapine continuation therapy for a severely ill patient with treatment-resistant schizoaffective disorder who developed recurrent neutropenia after almost 20 years of continuous clozapine therapy. Therefore, clinical vigilance is important, regardless of clozapine treatment duration. Filgrastim can facilitate long-term clozapine therapy in patients with clozapine-induced neutropenia.

Neutropenia complicating anti-CD20 treatment in patients with multiple sclerosis: A retrospective case series and a systematic review of reported cases

BackgroundNeutropenia is an infrequent complication of treatment with CD20 depleting agents and may require the administration of granulocyte-colony stimulating factors (G-CSF), which have been associated with an increased relapse risk in patients with multiple sclerosis (PwMS). The management of this side effect is still matter of debate. MethodsAim of this study is to evaluate the clinical features and the management of neutropenia occurring in anti-CD20 treated PwMS through a single-center case series and a systematic review of the literature, performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. ResultsA total of 19 patients were included (3 from our clinical experience, 16 from the systematic review). Median age was 38 years-old (25-69) and nearly 70% were female, most of these patients had already received a median of 3 (0-4) previous treatments. Neutropenia occurred in 11 patients treated with ocrelizumab and 8 with rituximab, after a median of 2 (1-7) infusions and 9.5 (1-42) months from the first infusion. Most of these patients had late-onset neutropenia, that occurred after a median time of 90 days (2-156). About 70% of patients were symptomatic and most were treated with G-CSF or antibiotics. No relapses after G-CSF were reported. In those who did not suspend anti-CD20 (68.8%), neutropenia reoccurred in 18.2% of cases. Finally, switching between rituximab and ocrelizumab seem not to affect the occurrence of neutropenia. ConclusionOur data provides practical evidence regarding the occurrence and the management of neutropenia during treatment with anti-CD20 in PwMS.

Late-onset neutropenia induced by anti-B cell therapy with rituximab in patients with ANCA-associated systemic vasculitis

In the last decade, anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (SV) has been treated with the anti-B-cell drug, rituximab (RTM) both for induction and maintenance therapy. One of the problems of the treatment with RTM in patients with ANCA-SV is the risk of late-onset neutropenia (LON), mechanisms of development of which have not been studied enough yet.Objective: to evaluate the incidence and outcomes of LON in patients with ANCA-SV treated with RTM. Patients and methods. A retrospective analysis of the register of 140 patients with ANCA-SV who received RTM treatment at the V.A. Nasonova Research Institute of Rheumatology from 2009 to 2021 years. The median duration of RTM treatment was 49 (6–121) months, the median of the total RTM dose was 3.5 (0.5–9.5) grams. The duration of follow-up exceeded 6 months after the first administration of RTM.Results and discussion. LON was detected in 16 (11.4%) patients, of which 6 suffered from Wegener's granulomatosis with polyangiitis (GPA), 4 – microscopic polyangiitis (MPA), 4 – Churg-Strauss eosinophilic granulomatosis with polyangiitis (EGPA) and 2 – undifferentiated ANCA-SV. In 8 (50%) out of 16 patients, LON developed within 2 months after the 1st course of RTM, in the remaining 8 patients, on average, after 10 (4– 15.5) months. A lethal outcome was documented in 5 (31.2%) of 16 cases of LON (1 with MPA, 3 with GPA, and 1 with EGPA) on average 2 (1.5–9) months after the 1st course of RTM, at the same time, in 4 patients LON was complicated by pneumonia, including 2 with septic shock, in another 1 case LON was combined with the development of acute myocardial infarction and progression of chronic renal failure. Overall mortality among 140 patients with ANCA-SV treated with RTM was 11.4%, while in cases with a fatal outcome, the frequency of LON reached 31.2%.Conclusion. Thus, LON induced by RTM is a common (11%) and clinically significant consequence of B-cell depletion in patients with ANCA-SV, in every 5th case it is complicated by serious infections (including sepsis in 13%) and accounts for a significant proportion in the structure of lethal outcomes (31.2%).Patients treated with RTM require careful monitoring of absolute neutrophil count both during the first months after initiation of anti-B-cell therapy and thereafter. In the combined administration of RTM with cytotoxic drugs (primarily cyclophosphamide) in patients with ANCA-SV, it is necessary to consider the risk of LON developing, secondary immunodeficiency, and infectious complications. During the coronavirus pandemic, one should remember that treatment with interleukin 6 inhibitors used in severe COVID-19 can also be accompanied by neutropenia and requires careful dynamic monitoring of the absolute number of neutrophils in patients with ANCA-SV treated with RTM. It is necessary to inform both patients and physicians of the risk of LON development during the treatment of RTM in ANCA-SV and other rheumatic diseases.

Double edge sword

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAVs) are characterized blood vessel inflammation and necrosis which may lead to diffuse alveolar hemorrhage (DAH) resulting in life threatening respiratory failure. We present a case of microscopic polyangiitis presented in respiratory failure secondary to DAH that developed a rare treatment related complication. A 50 year old lady presented in respiratory failure with hemoptysis &amp; falling hemoglobin. Chest X-ray showed bilateral inhomogeneous opacities and urine showed granular casts and red blood cells. Red colored bronchoalveolar lavage was obtained and serology came positive for pANCA. She was treated with corticosteroid and rituximab. The patient improved initially, but later developed rituximab induced late onset neutropenia. She unfortunately developed pulmonary mucormycosis and could not be revived. Thus, rituximab behaved as a “double edge sword”, helping the patient initially but later making her susceptible for opportunistic infection.

Ocrelizumab associated late-onset neutropenia in the patient with multiple sclerosis: Case report and literature review

Introduction. Ocrelizumab is a recombinant humanized monoclonal antibody that selectively depletes CD20-expressing B cells, which is approved for the treatment of the relapsing and primary progressive multiple sclerosis (MS). It is extremely rarely associated with late-onset neutropenia (LON), as an adverse event. Case outline. We describe a case, from the Treatment Registry of the Clinic of Neurology, University Clinical Center of Serbia, Belgrade, of a transient, asymptomatic LON detected in a naive relapsing?remitting MS patient, six-months after treatment with ocrelizumab. Conclusion. Having in mind all the presently available data, which indicate that rarely occurring LON on ocrelizumab is asymptomatic and transient in the majority of cases, we assume that it may be suggested that only in patients with complaints suggesting the presence of possible infection, additional complete blood count monitoring should be mandatory, exclusively at that moment, apart from the precisely defined regular follow-up.

Late-onset neutropenia after anti-CD20 therapy for multiple sclerosis, neuromyelitis optica spectrum disorders and MOG antibody-associated disease: A prospective study

Late-onset neutropenia (LON) after anti-CD20 therapy is a poorly described side effect in inflammatory disorders of the CNS. In this prospective study, patients treated with Rituximab or Ocrelizumab for MS, neuromyelitis optica spectrum disorders or MOG antibody-associated disease (MOGAD) were asked to perform complete blood count (CBC) every two weeks for six months, with the aim of identifying LON. Out of 152 patients, two (1,32%) had an absolute neutrophil count <1,000/mm3: one patient with MOGAD had agranulocytosis and one patient with MS had grade 3 neutropenia. Both were asymptomatic. These results confirm that LON after anti-CD20 therapy in inflammatory disorders of the CNS is not exceptional. Nevertheless, this biological complication remains too infrequent to justify close systematic CBC follow-up.

Late onset neutropenia after rituximab and obinutuzumab treatment – characteristics of a class-effect toxicity

Late onset neutropenia (LON) after rituximab is a previously described complication. We aimed to assess and characterize LON after obinutuzumab, a novel anti-CD20 antibody, in the real-world setting and compare it to LON after rituximab therapy. We retrospectively analyzed 330 consecutive patients with lymphoproliferative neoplasms (rituximab-treated n = 283; obinutuzumab-treated n = 47). LON occurred in 23% patients with similar incidence in rituximab (n = 66, 23%) or obinutuzumab (n = 10, 21%) groups (p = 0.853). Patients treated for CLL and post-transplantation lymphoproliferative disease (PTLD) were at higher risk to develop LON (multivariate analysis: HR for CLL − 6.62 CI 95% 1.33–32.92; HR for PTLD 15.82 CI 95% 2.04–122.4). Febrile neutropenia was uncommon during LON and occurred in 15 patients (4.5%; rituximab (n = 14) and obinutuzumab (n = 1). These data suggest that LON after obinutuzumab treatment is as common as with rituximab. The similarities in LON after rituximab and obinutuzumab argue for a possible class effect for anti-CD20 monoclonal antibodies.

Late-onset complications with bendamustine versus CHOP or CVP based chemoimmunotherapy in indolent Non-Hodgkin’s lymphoma

Bendamustine is a preferred first-line chemoimmunotherapy regimen for indolent non-Hodgkin’s lymphoma (iNHL). Emerging evidence suggests an increased incidence of late-onset complications with bendamustine-based regimens compared with CHOP/CVP; however, this evidence is limited. We retrospectively compared late-onset complications from January 2005 to May 2020 in adults with previously untreated iNHL who received rituximab or obinutuzumab with CHOP, CVP, or bendamustine. Forty-six patients received CHOP/CVP; 119 received bendamustine. No difference in incidence of late-onset infections was observed. Bendamustine led to a higher rate of prolonged and unresolved lymphocytopenia and a greater incidence of late-onset neutropenia. Many patients receiving bendamustine did not have lymphocyte recovery even three years following administration. Ongoing infection prophylaxis with bendamustine-based regimens may offset translation of these laboratory findings to late-onset infectious risk.

Subcutaneous Rituximab Given to Patients for Other Indications Than CD20+ B-Cell Lymphoma: A Monocentric Study of 20 Cases

Background: Rituximab (R) is the first anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various B-cell lymphoid malignancies. Administered intravenously (IV), it has been shown to be also efficient to treat other hematologic situations such as Epstein-Barr virus (EBV) reactivation, especially after hematopoietic stem cell transplantation (HSCT), or immune thrombocytopenic purpura (ITP). Finally, survivals of younger patients with CD20-positive Philadelphia-negative acute lymphoblastic leukemia (ALL) are significantly increased when combining IV-R with chemotherapy. Recently, a subcutaneous (SC) formulation of R (SC-R) has been approved for B-cell lymphoma that provides a highly-concentrated fixed dose of rituximab with the advantages of reducing treatment times and nursing workload and potentially providing greater comfort and convenience for patients and lesser dosing errors, shorter preparation time or reduced drug wastage for pharmacy dispensers. At our knowledge, there is no published data addressing the tolerance and the efficacy of SC-R given to patients with other indications than CD20+ B cell lymphoma.Patients and Methods: We have retrospectively analyzed all cases who received at our center at least one dose of SC-R but with no lymphoma indication. Three situations were considered: EBV reactivation (post transplantation or not), ITP or ALL treatment. All patients received their first(s) dose(s) of R IV (375mg/m2/injection) and a switch to SC-R (1400mg/injection) was realized only if they didn't experience grade 3 or 4 adverse event (AE) with IV formulation. Our rules is to provide R (IV+SC) weekly, up to 4 doses for ITP (in case of platelets counts <30000/mm3 with no response to corticosteroids or immunoglobulin) and EBV reactivation (in case of 2 positive PCR > 4 log10 number of viral DNA copies), while GRAALL schedule is followed for R administration in CD20+ ALL patients. Tolerance of SC-R (mainly infusion related or late-onset neutropenia (LON)) was appreciated using National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 and any grade 3 or 4 AE related to SC-R was sufficient to stop treatment. Success of SC-R was defined by either a documentation of a negative EBV PCR or absence of ALL relapse or platelets counts reaching at least 100000/mm3.Results: Between February 2016 and June 2017, 20 patients (male n=17) with a median age of 60 years old (range: 33-76) received SC-R in our institution. Overall, 102 R including 58 SC-R were administered with a median of 3 R (range: 2-26) and 2 SC-R (range: 1-16) injection per patient, respectively. The median follow-up from the last SC-R administration was 4.4 months (range: 0.2-11.2 months).No grade 3/4 infusion related reaction were documented in this series while 4 out of 16 assessable cases presented with LON at a median of 45 days (range: 44-70) after the last SC-R injection. Neutropenia lasted a median of 6 days (range: 4-9) with the help of GCSF and was not responsible for complication.Eleven cases received SC-R for EBV reactivation (including 8 after allogeneic transplant and 3 in a context of aplastic anemia) with a median of 3 R (IV+SC, range: 1-4) and 2 SC-R (range: 1-3) injections. One patient died of concomitant invasive fungal infection and was not evaluable for efficacy. All of the ten other patients were documented with negative EBV PCR after treatment.Four patients received SC-R during ALL first line treatment with a median of 11 R (IV+SC, range: 3-26) and 6 SC-R (range: 1-16) injections. Two patients have received more than the number of R infusion scheduled (17 and 26) because of high toxicity related to the chemotherapy and it was chosen to deliver a maintenance therapy with vincristine/SC-R and prednisone. None of the four ALL patients had relapsed so far at 2, 8, 18 and 20 months from diagnosis with a median follow up of 13 months (2-20).Five patients received SC-R for ITP with a median of 3 R (IV+SC, range: 3-4) including 2 SC-R (range: 1-3) injections. Three patients obtained platelets count improvement within a median of 28 days (19-48) and none relapsed so far.Conclusion: SC-R seems to demonstrate a comparable efficacy/safety profile as IV-R when given to patients for other indications than CD20+ B-cell lymphoma. There should be no restriction to use SC-R for these patients in the future as it may improve quality of care for both patient and health providers. DisclosuresTouzeau:AbbVie: Research Funding. Le Gouill:Roche: Consultancy, Honoraria, Research Funding; janssen: Consultancy, Honoraria; servier: Consultancy, Honoraria, Research Funding; bayer: Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Research Funding. Moreau:Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria.

Home Administration of Subcutaneous Rituximab Is Safe and Associated with Significant Cost Saving: A Single Center Experience

IntroductionRituximab is as a cornerstone of treatment of B-cell malignancies, given as monotherapy (including maintenance after induction) or in combination with chemotherapy. While developed as IV infusion, subcutaneous formulation is now available. It has been demonstrated that, compared to IV infusion, subcutaneous injection is quicker (5 minutes injection), easier to manage and non-inferior with respect to efficacy, in follicular lymphoma, chronic lymphocytic leukemia, and diffuse large B-cell lymphoma. Home administration of chemotherapies for patients treated for hematological malignancies is widely used, as it has demonstrated safety, cost saving and improvement of quality of life. However, few datas have been reported for monoclonal antibodies.ObjectivesThe aim of our study was to describe our experience of home administration of SC rituximab to evaluate feasibility, safety and back to in-hospital administration. We also compared costs to in-hospital administration.MethodsWe included consecutive patients treated with at least one SC rituximab injection at home, from January 2016 to July 2017. All patients received approved dosage, ie.1400 mg. Patients received before injection paracetamol, prednisone and dexchlorpheniramine. Patients were eligible if 1°) they have previously received at least one IV infusion and one SC injection in ambulatory unit of our institution; 2°) they did not experienced adverse reaction to both administrations; 3°) they did not present comorbidity that require medical evaluation before each injection; 4°) their home was considered adequate for safe administration; 5°) they consented to home administration.ResultsWe included 39 patients; median age was 71y (range: 40 to 88), 25 females and 14 males. Median CIRS was 3 (range: 0 to 10). Majority of patients had hematological malignancies (follicular lymphoma: n=25, mantle cell lymphomas: n=7, marginal zone lymphoma: n=3, hairy cell leukemia: n=1) and 3 had autoimmune hemolytic anemias. Rituximab was administered as a part of the first line therapy for 26 patients and as maintenance therapy for 37. The median and mean number of previous in-hospital SC injections was 1 (range 1 to 10) and 3.1, respectively. A total of 174 injections were performed at home (median per patient: 4, range: 1 to 10). Few side effects were notified; late-onset neutropenia (n=3), upper and lower respiratory tract infections (n=4), P. jirovecii pneumonia (n=1), grade 3 diarrhea of unknown etiology (n=1), incidental cancers (n=2) and one non-related death. Finally, 4 patients required hospitalization due to complication. One patient went back to in-hospital administration because of bone pain and local skin reaction related to injection. In France, the cost of care is a flat fee determined by the Health authorities which is 1049 euros for standard one-day hospitalization in ambulatory unit of public hospital, 233 euros for private and 201 euros for public one-day home hospitalization. In our cohort, home administration is associated with a cost saving of 146 592 euros (842 euros per injection, 3758 euros per patient), to which we must add patients' transport cost.ConclusionOur study showed that home administration of subcutaneous rituximab is feasible, safe, and well tolerated, leading to an alternative to standard hospitalization. Moreover, amount of cost saving should justify promotion of home administration by Health authorities. If quality of life is improved by home administration it must be confirmed by prospective studies. Currently, home administration of SC rituximab but also brentuximab vedotin, eculizumab and more recently daratumumab is part of our standard of care. DisclosuresWolfromm:Janssen: Consultancy. Delarue:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Differential Impact of Signaling Inhibitor Treatment Versus Standard Chemoimmunotherapy on Chronic Lymphocytic Leukemia T Cells: Clinical Implications

Studies by us and others have documented the clonal architecture of the T cell repertoire in chronic lymphocytic leukemia (CLL), with T cell clones which persist and expand over time in untreated patients, appear disease-specific and may be shared among different patients, thereby indicating selection by restricted antigens. Here, we investigated T cell repertoire dynamics in CLL after different types of treatment by employing high-throughput next-generation sequencing in order to comprehensively assess changes in relation to the type of treatment as well as the clinical response. We analyzed 42 pre- and 3-month post-treatment blood samples from 16 CLL patients who received (i) standard chemoimmunotherapy (FCR regimen, n=5), (ii) ibrutinib (IB, n=9), and/or (iii) rituximab-idelalisib (R-ID, n=7). At the post-treatment sampling, all patients who received FCR had achieved complete remission (CR), and all patients on IB or R-ID had achieved partial remission (PR). Two patients, one on IB and one on R-ID, who later achieved CR were analyzed at that timepoint, as well. We excluded patients who developed rituximab-related late-onset neutropenia after FCR, since it is known to be mediated by cytotoxic T-cell clones. Starting material was PB mononuclear cells. TRBV-TRBD-TRBJ gene rearrangements were RT-PCR amplified and subjected to paired-end NGS. Raw NGS reads were processed through a previously published, purpose-built bioinformatics pipeline designed for paired-read stitching, sequence curation, clonotype computation and repertoire analysis. Only productive TRBV-TRBD-TRBJ rearrangements were included in the analysis (n= 7,494,236, 85.3% of filtered-in sequences, median 178,063/sample). For repertoire analysis, clonotypes (i.e. TRB rearrangements with identical TRBV gene usage and amino acid complementarity-determining region 3 sequence) were considered (median 11,290 distinct clonotypes/sample). The TRBV gene repertoire remained relatively stable after treatment across all treatment groups. All cases displayed significant clonal T cell expansions both pre- and post-treatment (median cumulative frequency of the 10 most expanded T cell clonotypes/sample 30.3% versus 38.6%, respectively). However, differences were noted between the three treatment subgroups. More specifically, clonality (measured as the median cumulative frequency of the 10 most expanded clonotypes/sample) significantly increased after FCR (20.8% to 39.0%, p=0.03) and R-ID (33.0% to 41.1%, p=0.001), whereas it tended to decrease after IB (36.1% to 31.0%, p=0.34). Notably, achieving deeper clinical response (from PR to CR) correlated with a significant increase of clonality in the R-ID case (41.0% to 56.2%), but had no impact in this respect for the IB case (48.3% to 48.1%). The increased clonality in the R-ID case culminated from further expansion of 5 major clonotypes which also dominated the pre-treatment repertoire, suggesting that they may correspond to T-cell clones with anti-tumor properties activated by treatment. Overall, FCR resulted in reconstitution of the T-cell repertoire (median of 2/10 most frequent T-cell clones pre-treatment remained significantly expanded post-treatment), whereas pre-treatment major clones persisted after both IB and R-ID (8/10 and 7/10, respectively). In conclusion, NGS immunoprofiling in CLL documents the differential impact of various treatments on T cells. Particularly, chemoimmunotherapy increases T cell clonality likely through an ablative mechanism, in contrast to signaling inhibitors which retain T cell clones that may have developed in response to tumor antigens and possibly activate them, at least as indicated for the R-ID case, with obvious clinical implications. DisclosuresAgathangelidis:Gilead Sciences: Research Funding. Stavroyianni:Gilead Sciences: Honoraria; Takeda: Honoraria; Janssen Pharmaceuticals: Honoraria. Stamatopoulos:Janssen Pharmaceuticals: Honoraria, Research Funding; Novartis SA: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria, Research Funding.

Rituximab- and ocrelizumab-induced early- and late-onset neutropenia in a multiple sclerosis patient

Rituximab- and ocrelizumab-induced early- and late-onset neutropenia in a multiple sclerosis patient