Successful Rechallenge Research Articles

Pseudoprogression during successful rechallenge of immune checkpoint inhibitor in a NSCLC patient.

Rechallenge of immune checkpoint inhibitors (ICPIs) is one of the attractive but unestablished treatment for recurrent non-small cell lung cancer (NSCLC) patients who have been treated with several-lines of systemic chemotherapy. In some NSCLC patients, effects of ICPI rechallenge therapy have become apparent. In ICPI treatment, although very rare, a phenomenon called pseudoprogression is known. We report the first case of a patient who had pseudoprogression during successful rechallenge of ICPI in a NSCLC patient. Although not fully clarified, factors related to the onset of pseudoprogression and good response to ICPI rechallenge are being investigated. Our case showed that pseudoprogression could be developed even in patients with ICPI rechallenge therapy.

Successful clozapine re-challenge in a case of Atypical Neuroleptic Malignant Syndrome with markedly elevated Creatinine Phosphokinase and no muscle rigidity

Successful clozapine re-challenge in a case of Atypical Neuroleptic Malignant Syndrome with markedly elevated Creatinine Phosphokinase and no muscle rigidity

Abdominal aortitis with immune checkpoint inhibition

Introduction: Aortitis, inflammation of the aorta, is a rare large vessel vasculitis associated with giant cell arteritis, Takayasu arteritis, and other rheumatologic diseases. Aortitis has rarely been reported with cancer immunotherapy. Case Report: We present a case of 43-year-old man treated for a high-grade neuroendocrine tumor who developed aortitis during treatment with the PD-L1 inhibitor atezolizumab. PubMed search revealed no prior cases of this toxicity in associated with PD-L1 inhibition. Conclusion: To our knowledge this is the first case report of aortitis from PD-L1 inhibition. Recognition is important since resolution of symptoms was obtained with corticosteroids. This is also the first report of successful rechallenge with a PD-1 inhibitor without recurrence of aortitis.

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Long-Term Cardiac, Vascular, and Hypertension Safety of Bosutinib (BOS) Versus Imatinib (IMA) for Newly Diagnosed Chronic Myeloid Leukemia (CML): Results from the Bfore Trial

Successful rechallenge with cetuximab after an infusion related reaction to panitumumab in a patient with locally advanced rectal cancer

Incidence of infusion related reaction (IR) is more common with cetuximab (Cmab) than with panitumumab (Pmab). Although little is known about rechallenge IR with monoclonal antibodies, we experienced a successful rechallenge to Cmab after IR to Pmab. A 67-year-old female patient was scheduled for chemotherapy with mFOLFOX6 plus Pmab against unresectable advanced rectal cancer in the hope of tumor shrinkage. On the first administration of Pmab, she complained of dyspnea with shortness of breath and wheezing, even after premedication with steroids and antihistamines. Her reaction was judged as Grade 2 IR to Pmab. For the next course, we tried Cmab. No IRs were observed. Since then, she has undergone seven further courses of treatment, followed by surgical resection. The patient benefited from administration of Cmab after experiencing IR to Pmab, suggesting this treatment to be an option for patients of this type who experience IR to Pmab.

S2288 Nausea and Hepatocellular Injury Associated With Tofacitinib 10 mg Tablets but Not 5 mg: A Case Report

INTRODUCTION: Tofacitinib (tofa) is a non-selective Janus kinase inhibitor, approved for treatment of moderately to severely active ulcerative colitis (UC), and is available in 5mg and 10mg tablets (tabs). We present a case of a patient with UC who transitioned from tofa 5mg tabs to 10mg tabs with subsequent nausea and liver transaminase elevation and propose it is due to distinct ingredients in the 10mg tab formulation. CASE DESCRIPTION/METHODS: Our patient is a 42-year-old woman with a 12-year history of left-sided UC. She was previously treated with oral and rectal 5-ASA, infliximab, certolizumab, and vedolizumab. While on vedolizumab she developed a new synovitis of her fingers. In 2017, she was transitioned to tofa 5mg tab twice daily (BID) and achieved remission from her arthropathy and colitis. Two years later, she relapsed and subsequently dose escalated to tofacitinib 10mg BID, taken as two 5mg tabs BID. She was well with this formulation and dose for a year. A recent refill was transitioned to the 10mg tab formulation. After 3 doses of this formulation, she developed nausea. She continued the therapy for 5 additional doses. At this point, we advised stopping the therapy; the nausea resolved within 24 hours. On re-challenge with the 10mg formulation, nausea recurred after 2 doses, so liver enzymes were obtained. Her transaminases were double from baseline (AST = 45, ALT = 55, GGT = 25). Bilirubin, alkaline phosphatase and synthetic function remained normal. She denied any new drugs, herbal supplements or alcohol use. Her therapy was discontinued for two days; repeat labs were normal. After re-challenge with two 5 mg tabs BID and one week of follow-up, the patient’s transaminases remain normal and she is asymptomatic. DISCUSSION: We describe a UC patient who developed drug induced liver injury from the 10 mg formulation of tofa. We believe the drug-induced liver injury occurred from the excipient dyes (Brilliant Blue FCF Aluminum Lake and Indigo Carmine Aluminum Lake) found in the 10 mg formulation (and in the 22 mg XR formulation) but are not in the 5 mg formulation (or in the 11 mg XR formulation) (Table). Both dyes are triarylmethanes, which have been previously implicated in hepatocellular injury. Our suspicion was further confirmed by a positive de-challenge (discontinuation of the 10mg tabs) and successful re-challenge with the 5 mg tabs without recurrence of symptoms or chemistry abnormalities. Clinicians should be aware of this reaction and when it is suspected, consider the alternate formulation.Table.: Ingredients in tofacitinib (Xeljanz) tablets.

Successful Rechallenge With Cytarabine After Isolated Hyperbilirubinemia: A Rarely Reported Adverse Effect.

Successful Rechallenge With Cytarabine After Isolated Hyperbilirubinemia: A Rarely Reported Adverse Effect.

Successful clozapine rechallenge following recurrent clozapine-associated pancreatitis: a case report

BackgroundAcute pancreatitis is a rare but recognised complication of clozapine leading to termination of treatment.Case presentationWe present the case of a 39-year-old man with treatment-resistant schizoaffective disorder and a history of recurrent acute pancreatitis attributed to clozapine. After 15 years of unremitting symptoms with disruptive and aggressive behaviour, he was admitted for a clozapine rechallenge. Despite experiencing two further episodes of acute pancreatitis during clozapine treatment that led to its temporary withdrawal, clozapine was successfully re-established under gastroenterology consultation with close monitoring which resulted in progressively marked improvement of his mental state.ConclusionsThis case demonstrates that patients who develop pancreatitis during clozapine treatment may be cautiously rechallenged with specialist gastroenterology support.

Rechallenge of clozapine in a patient with a history of clozapine-induced myocarditis

Clozapine is the only antipsychotic with proven efficacy in treatment-resistant schizophrenia, but some life-threatening side effects limit its use. Here we report a patient with clozapine-induced myocarditis and successful rechallenge. The patient still uses clozapine and has not developed myocarditis over 36 months of observation. It may be possible to use clozapine even after myocarditis and thus improve symptoms and functionality of schizophrenia patients.

Re-Challenge with Clozapine after Neuroleptic Malignant Syndrome and Seizure in a Patient with Di-George Syndrome: Case Report and Review of Literature

Background: Individuals with 22q11.2DS, a genetic subtype of Schizophrenia, respond as well to clozapine as those with other forms of Schizophrenia. It has been reported that serious and rare adverse events like seizures, and myocarditis have been associated with clozapine treatment in this population. To the best of our knowledge, the incidence of neuroleptic malignant syndrome (NMS) as an adverse effect of antipsychotic use in patients with this disorder has not yet been reported. Aim: In this article, we discuss a case of clozapine-induced NMS and subsequent re-challenge in a patient with 22q11.2DS-associated schizophrenia. The aim of this study is to accumulate scientific data about rare presentations, and serve as a major educational tool, and highlight the unique challenges faced when using clozapine in a patient with DiGeorge Syndrome. Methods: This is a descriptive case report of a patient encountered in the inpatient unit which includes retrospective review of the patient’s electronic medical record and a literature review of antipsychotic medications-induced NMS. Conclusion: This study demonstrates a successful re-challenge with clozapine after the patient developed NMS and seizures during the initial treatment and also highlights how, in addition to drug level monitoring, considering pharmacogenetic testing early in treatment might help minimize adverse drug reactions in individuals with known genetic disorders such as 22q11.2DS.

Successful rechallenge of rituximab following severe rituximab-induced acute thrombocytopenia in a patient with splenic marginal zone lymphoma

Rituximab-induced acute thrombocytopenia (RIAT) is a relatively rare complication of rituximab treatment that has been infrequently reported in a number of patients with malignant lymphoma. Most commonly encountered in mantle cell lymphoma, the extent to which RIAT occurs in splenic marginal zone lymphoma is unknown. In this report, we describe a case of RIAT in a patient with splenic marginal zone lymphoma. Rituximab was safely rechallenged with increased premedications and slowed infusion rate. While the exact mechanism of this phenomenon has yet to be elucidated, diligent monitoring of platelet counts following rituximab infusion can be considered in high-risk patients to avoid potential adverse events. Split dose rituximab for high-risk patients may provide an alternative approach to improve patient safety.

Evaluation of Biomarkers As Predictors of Blinatumomab Toxicity and Real-World Management of Blinatumomab Toxicity in B-Acute Lymphoblastic Leukemia Patients

The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) is active in pts w/ relapsed/refractory B-ALL or persistent minimal residual disease. Notable toxicities include cytokine release syndrome (CRS), a constellation of symptoms related to brisk systemic inflammatory response, and a spectrum of neurologic toxicities (NTX). BLIN prescribing information provides basic CRS/NTX management guidance, but limited reports describe "real-world" toxicity management strategies (TMS) and outcomes. We further previously reported association between higher baseline and peak levels of acute phase reactants (APR; C-reactive protein [CRP]/ferritin), time to APR peak, and incidence of CRS/NTX post-BLIN (King et al. ASH Annual Meeting, 2017). While CRS is also mediated in part by IL-6, routine monitoring of IL-6 levels during BLIN is not currently standard. As such, we sought to determine rates/severity of CRS/NTX at our institution, efficacy of TMS, and utility of APR/IL-6 in predicting CRS/NTX post-BLIN. We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated B-ALL receiving BLIN between 1/1/2011 and 3/31/19 at Memorial Sloan Kettering Cancer Center (MSK). NTX was classified/graded w/ CTCAEv5.0 (Common Terminology Criteria for Adverse Events). CRS was graded per CTCAEv5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) criteria. The primary objective was to characterize rates/clinical features of CRS/NTX. Secondary objectives included assessing the nature/efficacy of TMS, and association of APR/IL-6 levels w/ CRS. Maximal (max) fold increase in APR/IL-6 was measured from pre-BLIN baseline to peak value during BLIN cycle 1 (C1). APR/IL-6 levels/fold changes were compared between groups using the Wilcoxon-Mann-Whitney test w/o adjustment for multiple comparisons. 59 pts were identified, including 31 male pts (52%). Median age at start of BLIN was 57 yrs (range, 20-76). Median number of prior therapies was 1, including 8 pts w/ previous allogeneic hematopoietic cell transplant (alloHCT) and 5 w/ prior chimeric antigen receptor T-cell therapy (CAR-T). No pt had baseline organ dysfunction or central nervous system (CNS) disease. All pts were admitted for initiation of BLIN C1. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for R/R ALL) in 52 pts and at 28 mcg/day IVCI in 7 pts for MRD (per Gökbuget et al., Blood, 2018). During BLIN C1, 34/59 pts experienced CRS (57%), w/ max grade (G) 1 (n=24), G2 (n=9) or G3 (n=1). CTCAEv5.0/ASTCT grading was concordant in all cases. Eight of 34 (23%) were managed w/ brief interruption of blinatumomab (BIB) for G1 (n=3) and G2 (n=5) CRS. Median duration of BIB was 39 hours (h) (range, 21-91h). Three pts had concomitant NTX and received brief courses of dexamethasone (DEX, daily dose of 24 mg). One pt w/ grade 2 CRS received tocilizumab for hypotension suboptimally responsive to fluid boluses (FB) w/ IL-6 level = 25754 pg/mL. Remaining pts w/ BIB (5/8) received FBs for hypotension. One pt permanently discontinued BLIN during C1 due to rapidly progressive B-ALL. All pts managed w/ BIB were successfully re-challenged w/ BLIN and finished C1 w/o recurrence of CRS. Of the 25/34 (74%) pts w/ CRS not managed w/ BIB, 5 received FBs, w/ 1 pt receiving a FB and a single dose of DEX. Five pts developed recurrent CRS (≥24 hours after resolution); 4/5 recurrences occurred in pts not managed w/ BIB. NTX, excluding isolated headache, was observed in 8/59 pts (14%) during BLIN C1 (Table 1) w/ max G1 (n=4), G2 (n=3), or G3 (n=1). Four pts w/ NTX were managed w/ BIB and a brief course DEX; 3/4 had concomitant CRS. Median time to onset of CRS and NTX were 1 day (d) (range 0-15) and 2 d (range 0-10), respectively. Non-significant trend toward higher peak IL-6 was noted in pts w/ G1 vs. G0 CRS (p=0.07; Fig 1A, note log scale); median peak levels of CRP were higher in pts w/ G1 vs G0 CRS (p=0.01, Fig 1B); median peak ferritin levels were higher in pts w/ G2 vs. G0 CRS (p=0.01, Fig 1C). While CRS was common during C1 of BLIN, supportive management was sufficient in most pts; BIB was an effective strategy and allowed successful BLIN re-challenge. The incidence of ≥G2 NTX was low and all cases of NTX were reversible w/ supportive care or BIB ± DEX. Peak APR levels correlated w/ CRS severity. Authors noted concordance of CRS grading between CTCAE and ASTCT, suggesting the feasibility of a single, BITE-specific grading system. Disclosures King: Astrazeneca: Other: Advisory board; Genentech: Other: Advisory Board ; Incyte: Other: Advisory Board. Park:Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy; Allogene: Consultancy. Geyer:Amgen: Research Funding; Dava Oncology: Honoraria.

Hematologic Immune-Related Adverse Events from Immune Checkpoint Inhibitors: A Systematic Review of Case-Reports and Case-Series

Introduction: Immune checkpoint inhibitors (ICI) have proven to be a significant breakthrough in modern cancer therapy. However, this has come at a cost of immune-related adverse events (irAE) affecting various organ systems. Hematological irAEs including autoimmune hemolytic anemia (AIHA), pure red cell aplasia (PRCA), immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), hemophagocytic lymphohistiocytosis (HLH), aplastic anemia and pancytopenia, are well recognized side effects of ICI. Due to their rarity, existing literature is confined to case reports and series. We conducted a systematic review of all published case reports and series till date to summarize clinical presentation, risk factors, management, and outcomes of patients who develop hematologic irAEs during ICI treatment. Methods: Using free text and controlled vocabulary (MESH and EMTREE terms), we performed a systematic search of the literature using Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection. Eligibility criteria included any case report or case series describing at least one hematologic irAEs developing during and likely related to ICI therapy for solid/hematologic malignancy. Two authors independently screened the titles, abstracts, and the full text of the selected papers. Patients who had received at least one FDA approved ICI (PD-1, PDL-1 or CTLA-4 inhibitors), and subsequently developed a decline in one or more of cell lines were included. Data regarding clinical presentation, concomitant other irAEs, treatment and clinical outcomes was extracted using a standardized data extraction form and summarized using descriptive statistics. Results: Of the 19856 articles screened, a total of 59 articles were selected for full-text review, and a total of 54 reports describing 57 cases met our eligibility criteria. The median age at the time of presentation was 63 y(interquartile range (IQR) 51-74) yrs, and 29 (50.9%) were males. PD-1 inhibitors were implicated in 35 (61%), CTLA-4 inhibitors in 14 (25%) and PD1/CTLA4 combination therapy in 7 (12%). The most common malignancies included metastatic melanoma (n=32, 56%) and non-small cell lung cancer (n=16, 28%). Only 8 patients (14%) reported a pre-existing history of autoimmune disease and only 11 (19%) had additional irAES involving other organ systems. AIHA (n=16, 28%), ITP (n=12, 21%) and pancytopenia (n=13, 23%) were the three most common subtypes of hematologic irAEs. Two or more cell lines were affected in 13 patients (23%). Twenty-six (46%) of the irAEs were detected on regular laboratory tests. The median number of cycles prior to the onset of hematologic irAEs was 3 (IQR 2-4). Among treatment strategies, corticosteroids were used in most patients (n=50, 88%). Other treatment modalities employed included Intravenous Immunoglobulin (IVIg) (n=14; 25%), hematopoietic growth factors and other supportive treatment were Treatment strategies were based on the actual irAE and the patient's condition. Corticosteroids, transfusion of blood products, hematopoietic growth factors, and other supportive treatment were primarily employed in most patients. Steroids were used in 50 (88%) patients and intravenous immunoglobulins in 14 (25%). Other immunosuppressants, anti-thymocyte globulins, and plasma exchange were used in select patients. Most of the patients (n=44, 77%) were described as having improved or recovered blood counts with treatment. Only 5 (9%) of these patients were rechallenged with the same or other ICI therapy. Among these, the same hematologic irAE recurred in 2 patients (40%). Cytopenia, as an irAE, was directly responsible for the death of 8 patients (14%). Conclusion: Hematologic irAEs are rare but potentially fatal adverse effect of ICI therapy. Although it can have diverse manifestations, AIHA and ITP are the most common subtypes. Almost half of these patients are clinically silent and detected in routine laboratory evaluation. Most hematologic irAEs appear early during the course of therapy and without pre-existing/concomitant irAEs. Most cases report successful resolution with treatment that commonly include high dose corticosteroids, and successful re-challenge has been reported in a few cases. Disclosures No relevant conflicts of interest to declare.

Successful therapeutic rechallenge after a severe episode of high dose methotrexate-induced choreoathetosis: A case report.

Methotrexate (MTX) is an essential chemotherapy drug used in the treatment of malignancies, but it is known to cause complications to the central nervous system. We report a case of severe MTX neurotoxicity in an adult presenting with choreoathetosis despite a normal clearance of MTX. High dose-MTX has been successfully rechallenged without any neurological sequelae. We reviewed the relevant literature of similar manifestations and summarized their clinical data, magnetic resonance imaging features and treatment given. None of them has recurrence of neurotoxicity. We concluded that it is safe to persist with MTX even after a previous episode of toxic leukoencephalopathy.

Management Strategies for Early-Onset Pulmonary Events Associated with Brigatinib

IntroductionRare cases of early-onset pulmonary events (EOPEs) occurring within days of the start of administration of brigatinib have been reported (incidence 3%–6% with use of the recommended dose of 90 mg for 7 days and then a 180-mg step-up dosing regimen). Current prescribing information suggests dose interruption and then dose reduction for grade 1 or 2 events and discontinuation for recurrent or higher grade events. However, clinical experience suggests that alternative strategies exist to safely maintain dosing. MethodsCase vignettes illustrating different EOPE clinical scenarios were assembled; they included (1) successful treatment through the initial EOPE, (2) successful rechallenge after the EOPE, (3) successful rechallenge after the EOPE with utilization of a shallower step-up regimen, and (4) unsuccessful rechallenge. ResultsRapid tolerization to EOPEs within 5 to 8 days may occur with continued dosing, suggesting that dose interruption could be avoided with close observation and temporary supportive care (including supplemental oxygen). If dose interruption occurs, restarting administration of brigatinib at 30 mg, followed by dose increases in 30-mg increments every 3 days to the full dose as tolerated (“shallow step-up dosing”) may maximize safety during rechallenge. As compromised baseline respiratory function may increase the rate of clinically apparent EOPEs, proactive use of shallow step-up dosing could be considered in select cases. ConclusionsClinically apparent EOPEs are a rare complication of brigatinib. They occur within days of starting administration of the drug, with rapid tolerization possible during continued dosing. Adapting the EOPE nomenclature to include the word transient (TEOPE) may further clinician and patient understanding in distinguishing these events from the pneumonitis seen with other tyrosine kinase inhibitors. Improved education and appropriate supportive care and dosing should allow more patients to maximally and safely benefit from brigatinib.

Leveraging Transcriptional Dynamics to Improve BRAF Inhibitor Responses in Melanoma

Melanoma is known to be a heterogeneous tumor, but the impact of this heterogeneity upon therapeutic response is not well understood. In the current study, we used single cell mRNA analysis and our Single Cell HETerogeneity (SinCHET) platform to define the transcriptional diversity of melanoma and its dynamic response to both BRAF inhibitor therapy and treatment holidays. Our analyses showed melanoma cell lines and patient specimens to be composed of >3 co-existent, transcriptionally distinct states. Among these, State #1 had increased expression of cyclin D1, ERBB3, STAT3/5, MITF and I²-catenin and lower expression of c-JUN and RTKs such as Axl and EGFR. State #2 was characterized by higher expression of ERBB3, Axl and the transcription factor c-JUN. State #3 was characterized by high Axl, c-JUN, E2F1, WEE1, c-MET and EGFR expression and lower expression of MITF, ERBB3 and SMAD9. The cell state composition was dynamically regulated in response to BRAF inhibitor therapy, with State #1 declining and States #2 and #3 increasing in response to drug. The percentage of cells in State #1 recovered following a drug holiday, allowing for a successful therapy rechallenge. Other melanomas that lacked State #1 had varying degrees of intrinsic drug resistance and were not amenable to rechallenge. We next leveraged the differences in fitness between the different transcriptional states in the absence and presence of drug to develop a mathematical model that optimized therapy schedules to retain the drug sensitive population. In vivo validation of the mathematical model demonstrated that the personalized adaptive dosing schedules were better at suppressing tumor growth than either continuous or fixed intermittent BRAF inhibitor schedules. Together our studies provide the first preclinical evidence that transcriptional heterogeneity at the single cell level predicts for the initial sensitivity to BRAF inhibitor therapy. We further demonstrate that manipulating transcriptional heterogeneity through personalized adaptive therapy schedules that can delay the time to resistance. Funding Statement: Supported by SPORE grant P50 CA168536, R21 CA198550, R21 CA216756 (to KSMS) K99 CA226679 (to IS), Moffitt Cancer Center PSOC, U54 CA193489 (EK & AA) and the Cancer Center Support Grant P30 CA076292 from the NIH (NCI/NIH). We also acknowledge the support Miami Center for AIDS Research (CFAR) at the University of Miami Miller School of Medicine funded by P30AI073961. Declaration of Interests: We have no competing interest to declare. Ethics Approval Statement: All animal experiments were carried out in compliance with ethical regulations and protocols approved by the University of South Florida Institutional Animal Care and Use Committee.

Safety and Efficacy of Ibrutinib in Combination with Rituximab and Lenalidomide in Previously Untreated Subjects with Follicular and Marginal Zone Lymphoma: An Open Label, Phase II Study

IntroductionGiven the relapsing nature of indolent non-Hodgkin lymphomas (iNHL), the prolonged natural history suggests many patients will undergo multiple lines of therapy over the course of their disease. Combination approaches with rational selection of synergistic mechanisms of action are desirable to improve outcomes and minimize overlapping toxicity. Rituximab and lenalidomide (R2) has resulted in favorable efficacy and manageable toxicity in phase II and III studies (Fowler et al, Lanc Oncol 2014; Fowler et al, ASCO abstract 2018) in untreated iNHL. Ibrutinib, a BTK inhibitor and active B-cell receptor signaling pathway inhibitor, is an attractive agent to build upon R2 given the therapeutic activity in the microenvironment via enhanced T cell activation and function, reduction in inflammatory cytokines, and diminished interaction with macrophages (Niemann et al, Clin Can Res 2015). We hypothesized that the addition of ibrutinib to R2 (IR2) would result in enhanced efficacy; the concern from the Phase I study was the potential for excess grade 3 rash (Ujjani et al, Blood 2016). In an attempt to reduce the incidence of grade 3 rash observed in the phase 1 study, an alteration in the cycle 1 dose of lenalidomide was done to assess the efficacy and safety of IR2 in untreated follicular (FL) and marginal zone lymphoma (MZL) in an open-label phase II, single center study.MethodsIn this phase II study, adults with untreated stage II, III, or IV FL (grade 1, 2, or 3a) or MZL, who were in need of therapy, received an initial cycle of lenalidomide 15mg/day (days 1-21 of a 28 day cycle), ibrutinib 560mg/day, and 4 weekly doses of rituximab (375mg/m2). For cycles 2-12, patients received 20mg of lenalidomide on days 1-21, 560mg of ibrutinib daily, and rituximab (375mg/m2) on day 1 of each cycle. The primary endpoint was progression-free survival (PFS) at 2 years. Secondary endpoints include: complete response (CR), partial response (PR), overall response (ORR), duration of response (DOR) and overall survival (OS).ResultsForty-eight patients with FL (N=38) and MZL (N=10; nodal MZL N=4; splenic ZML N=3; MALT N=3) were enrolled. Median age was 60 years (range 37-81), 67% were male (N=32), 3 (6%) had stage II disease, 12 (25%) stage III, and the remainder had stage IV disease (69%). With a median follow up of 19 months, the estimated 2 year PFS rate was 76% (95% CI: 60-96%). Among FL patients, the ORR according to Lugano criteria was 97%, with a CR rate of 78%. Among MZL patients, the ORR was 80% with a CR rate of 60%.No deaths have been observed to date. Seven (15%) subjects discontinued therapy due to treatment related adverse events (AEs), 3 due to recurrent grade 3 rash, 2 due to pneumonitis (1 grade 2, 1 grade 3), 1 due to pneumonia (grade 3), and 1 due to ventricular arrhythmia (grade 4). The most common grade ≥3 AEs were rash (46%), neutropenia (15%), and diarrhea (13%). The majority of patients with grade 3 rash were managed with interruption in study drugs and antihistamines with successful re-challenge. The most common grade 2 AEs included fatigue (23%), diarrhea (15%), myalgias (17%), rash and edema (each 10%). One patient experienced atrial fibrillation (grade 2) and 1 had an upper GI bleed (grade 3); both successfully resumed treatment without dose reduction. Correlative and minimal residual disease studies are currently underway and will be presented at the meeting.ConclusionsIbrutinib in combination with rituximab and lenalidomide for untreated FL and MZL was associated with promising efficacy. The toxicity profile was manageable. Modification of lenalidomide dose did not significantly impact the incidence of grade 3 or higher rash. Biomarkers are underway to identify patients most likely to benefit from triplet therapy. DisclosuresNastoupil:Merck: Honoraria, Research Funding; Janssen: Research Funding; TG Therappeutics: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Spectrum: Honoraria; Genentech: Honoraria, Research Funding; Karus: Research Funding; Juno: Honoraria. Westin:Celgen: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Samaniego:ADC Therapeutics: Research Funding. Neelapu:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Karus: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Unum Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding.

101P - Effect on oxaliplatin-free interval for successful rechallenge of oxaliplatin in colorectal cancer patients who had experienced an oxaliplatin: Related hypersensitivity reaction

101P - Effect on oxaliplatin-free interval for successful rechallenge of oxaliplatin in colorectal cancer patients who had experienced an oxaliplatin: Related hypersensitivity reaction

Effective long-term temozolomide rechallenge in a macroprolactinoma

SummaryWe describe the 20-year course of a 63-year-old male with a macroprolactinoma that acquired resistance to treatment and aggressive behavior after a 4-year successful treatment with cabergoline. He was submitted to multiple surgical resections by a skilled surgeon, fractionated radiotherapy and was eventually treated with temozolomide. After a first 6-month standard cycle, a relapse occurred and he was treated again successfully.Learning points:Prolactinomas are the most frequent type of pituitary adenoma.They usually have a benign course.In most cases dopamine-agonist drugs, mainly cabergoline, are first-line (and usually only) treatment.Occasionally prolactinomas can have or acquire resistance to treatment and/or aggressive behavior.Temozolomide (TMZ), an oral alkylating drug, can be effective in such aggressive tumors.Multimodal treatment (surgery, radiation, cabergoline and TMZ) is warranted in aggressive pituitary tumors.We describe here successful rechallenge with TMZ after relapse occurring 18 months after a first TMZ cycle.

Re-titration rates after clozapine-induced neutropenia or agranulocytosis: A case report and literature review.

Clozapine-induced neutropenia occurs in 3-5% of individuals treated with clozapine. Current US guidelines require interruption of clozapine when the absolute neutrophil count (ANC) drops below 1000 cells/mm3. There is minimal available guidance for what dosing schedule to use when restarting clozapine after an episode of neutropenia. Here, we present a case of a 50-year-old Caucasian female with a history of schizoaffective disorder who was successfully rechallenged on clozapine one month after developing clozapine-induced neutropenia (ANC 600 cells/mm3). To understand published re-titration rates of clozapine after neutropenia, we conducted a literature review using a using the PubMed database and found only seven case reports that unambiguously reported a clozapine dosing schedule during re-challenge. All were successful except one, a case of clozapine rechallenge after agranulocytosis. Including this case presentation, six out of eight cases restarted clozapine more cautiously than recommended by the US guidelines for a new clozapine initiation. We cannot comment what role a slower or more rapid titration plays in a successful rechallenge after neutropenia with the available evidence. We encourage researchers to publish their dosing schedule in detail after an episode of neutropenia or agranulocytosis.