Rapid Clinical Response Research Articles

Progressive Multifocal Leukoencephalopathy in a Patient with Multiple Myeloma Receiving Daratumumab and Pomalidomide

Background Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the polyomavirus John Cunningham (JCV) in the setting of immunosuppression. It has been described in patients with hematologic malignancies including multiple myeloma (MM), solid organ malignancies, granulomatous and inflammatory diseases, transplant recipients, lymphopenic patients (including patients with HIV) and with the use of certain drugs (rituximab, natalizumab). We present the first report to our knowledge of a patient with MM developing PML in association with daratumumab and pomalidomide therapy. Case Report A 63yo woman with relapsed/refractory IgA-Lambda MM on daratumumab and pomalidomide, presented to the emergency department after noticing difficulty putting her hair up in a ponytail. Her MM was diagnosed in 2003 and treated with steroids, high-dose melphalan and autologous stem cell transplant, maintenance therapy with thalidomide, switched to lenalidomide; upon relapse in 2010, she was treated with bortezomib, doxorubicin and dexamethasone, followed by bortezomib maintenance. Ten months prior to presentation, she relapsed and was started on daratumumab and pomalidomide, achieving an unconfirmed complete response (uCR), complicated by acquired hypogammaglobulinemia for the prior 8 months without infections. She developed progressive left arm weakness and gait instability; she denied any fevers, dysarthria, vision changes, headaches or seizures. On exam, she was alert and oriented; no cranial nerve abnormality; calculation, concentration and recall were intact; 4/5 strength in left upper extremity and 5/5 strength in all other extremities with preserved sensation and reflexes; coordination intact but a hemiparetic gait; rest of the exam was unremarkable. A brain MRI showed patchy and confluent areas of T2 hyperintense signal in the right greater than left cerebral hemispheres. She underwent a lumbar puncture which was positive for JCV by PCR (98 copies/mL) in her CSF and negative for neoplastic involvement by flow cytometry. The rest of her work-up was unremarkable. A diagnosis of PML was made and daratumumab and pomalidomide were discontinued. On follow-up brain MRIs four and eight weeks later, she had persistent extensive asymmetric patchy T2 hyperintense signal. Repeat LP revealed stable JCV in the CSF (95 copies/mL). Despite the lack of radiologic improvement, she had a remarkable clinical response with near resolution of neurologic symptoms and remains in an uCR. Discussion PML has been reported in association with multiple drugs used in the management of MM including corticosteroids, alkylating agents (cyclophosphamide, melphalan), immunomodulatory drugs (thalidomide, lenalidomide) and proteasome inhibitors (bortezomib, ixazomib), however, an association with pomalidomide or daratumumab has not yet been reported. In a clinical trial of daratumumab and pomalidomide for MM, a case of PML was reported, however, it was not considered to be related to these agents given that the patient received only one dose of daratumumab (Chari A. Blood 2017). PML has been reported in patients with primary hypogammaglobulinemia, however, it is not known whether acquired hypogammaglobulinemia - either due to MM or its therapy - is a risk factor for PML. Furthermore, the role for IVIG in the primary prevention or treatment of PML has not been clearly defined and warrants further study. The current treatment approach of PML remains the restoration of the host's adaptive immune response, including the discontinuation of immunosuppressive agents, unfortunately, evidence is lacking for any specific pharmacologic treatment. Recently, immune checkpoint inhibitors have shown clinical improvement or stabilization in small cohorts of patients with PML (NEJM 2019;380), however, given the safety concerns regarding their use in MM (KEYNOTE-183,-185) and the rapid clinical response seen in this case, no further therapy was instituted. This is the first report of pomalidomide and daratumumab as potential drugs associated with PML. Although it is not possible to ascertain their direct role in the reactivation of JCV, it should help clinicians recognize this potentially fatal complication in patients receiving either immunomodulatory drugs or anti-CD38 monoclonal antibodies, since prompt discontinuation may be life-saving. Disclosures Perry: Celgene: Speakers Bureau. Coleman:Gilead, Bayer, Celgene: Consultancy, Research Funding, Speakers Bureau; Kite Pharmaceuticals: Equity Ownership; Merck: Research Funding; Pharmacyclics: Speakers Bureau. Rossi:Janssen, Celgene, Amgen: Consultancy; BMS: Research Funding. Niesvizky:Takeda, Amgen, BMS, Janssen, Celgene: Consultancy, Research Funding.

Dreamm-5: Platform Trial Evaluating Belantamab Mafodotin (a BCMA-directed Immuno-conjugate) in Combination with Novel Agents in Relapsed or Refractory Multiple Myeloma (RRMM)

Background: Patients with RRMM who have relapsed through multiple prior lines of therapy need novel, effective, targeted agents. B-cell maturation antigen (BCMA) is a cell-surface receptor required for plasma cell survival that is ubiquitously expressed on MM cells, but virtually absent on naïve and memory B cells. Belantamab mafodotin (GSK2857916) is a BCMA-directed immuno-conjugate with an afucosylated, humanized anti-BCMA monoclonal antibody (mAb) conjugated by a protease-resistant cysteine linker to a microtubule disrupting agent, monomethyl auristatin F (MMAF). Belantamab mafodotin specifically binds to BCMA, eliminating MM cells by a multimodal mechanism including delivering MMAF to BCMA-expressing malignant cells, enhancing antibody-dependent cellular cytotoxicity, and leveraging immunogenic cell death. In an open-label, phase 1 study (DREAMM-1), belantamab mafodotin monotherapy had a manageable safety profile and demonstrated rapid, deep and durable clinical response (60% overall response rate, 14.3 months duration of response) with significant progression free-survival (PFS; 12 months) in patients with heavily pretreated MM. Belantamab mafodotin is being evaluated in clinical trials in various lines of MM therapy, either as monotherapy or in combination. The DREAMM-5 platform trial is a phase 1/2 study that incorporates an efficient design with 1 master protocol, wherein multiple belantamab mafodotin-containing combinations will be evaluated in separate substudies to identify effective doublet combinations versus a shared belantamab mafodotin monotherapy control arm. Initial substudies will include combinations with the T-cell activating checkpoint mAbs GSK3359609 (an IgG4 inducible T-cell costimulatory [ICOS] agonist antibody that is Fc optimized to selectively enhance T-cell function to enable antitumor responses), GSK3174998 (a humanized wild-type IgG1 anti-OX40 agonistic mAb), and a gamma-secretase inhibitor, Nirogacestat (PF-03084014, SpringWorks Therapeutics). Furthermore, as treatment paradigms evolve, including potential genomic subsets of patients with RRMM and actionable mutations, other control arms may be introduced. The combination agent for evaluation in each substudy will be selected based on scientific rationale and/or results of preclinical experiments with the selected agent in combination with belantamab mafodotin. Methods: Patients with RRMM will be eligible if they have received ≥3 prior lines of therapy (consisting of an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 mAb), have measurable disease (as measured by M-protein and free light chain), and acceptable hematologic and vital organ functions. Participants previously treated with an anti-BCMA targeted therapy are eligible except for prior belantamab mafodotin treatment and chimeric antigen receptor (CAR) T-cell therapy within 3 months of screening. Each substudy will have 2 sequential phases to evaluate safety and efficacy (Figure). The dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N≤10 per cohort), 1 cohort per doublet combination. The primary objective is to identify a recommended phase 2 dose for each doublet combination based on safety and preliminary efficacy. Once a substudy is selected for the cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm. Secondary objectives in CE are to assess AEs, durability of response, PFS, and overall survival. Exploratory objectives include assessment of PK for belantamab mafodotin with each partner agent, bone marrow minimal residual disease status, and plasma soluble BCMA levels as candidate prognostic and predictive biomarkers. DREAMM-5 is designed to efficiently identify novel, highly effective belantamab mafodotin-containing doublet combinations for evaluation in pivotal trials against current standard-of-care MM agents. Acknowledgments: Editorial assistance provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd and funded by GSK. Study funded by GSK (208887); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Biswas:GSK: Employment, Equity Ownership. Holkova:GlaxoSmithKline: Employment, Equity Ownership. Jackson:GlaxoSmithKline: Employment, Equity Ownership. Netherway:GlaxoSmithKline: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Ferron-Brady:GlaxoSmithKline: Employment, Equity Ownership. Yeakey:GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Montes De Oca:GlaxoSmithKline: Employment. Ahlers:GlaxoSmithKline: Employment, Equity Ownership. Franco:GlaxoSmithKline: Employment, Equity Ownership. Ballas:GlaxoSmithKline: Employment, Equity Ownership; Bristol-Myers Squibb: Equity Ownership; AstraZeneca: Patents & Royalties: Uncompensated copyrights. Paul:GlaxoSmithKline: Employment, Equity Ownership. Luptakova:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Dreamm-3: A Phase 3, Open-Label, Randomized Study to Evaluate the Efficacy and Safety of Belantamab Mafodotin (GSK2857916) Monotherapy Compared with Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Participants with Relapsed/Refractory Multiple Myeloma (RRMM)

Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

The efficacy of palliative radiation therapy in the treatment of recurrent and metastatic ovarian cancer.

129 Background: Ovarian cancer is the 2nd most common gynecologic malignancy with surgery and platinum-based chemotherapy as the mainstay of initial treatment. However, ovarian cancer has generally high rates of recurrence and metastasis after primary therapy. For patients with progressive or symptomatic disease, radiation therapy (RT) can be utilized as an effective option for palliation. Methods: A retrospective review was conducted of patients treated with palliative RT for symptomatic or recurrent ovarian cancer between 2015-2019 at a single institution. 17 women were identified who received 20 courses of RT. Response was classified as complete response (CR), partial response (PR), and progressive disease (PD). Overall response rate (ORR) was the sum of CR and PR. Results: Median age at RT was 57 (range 36-76). Histologic subtypes were high grade serous (65%), low grade serous (12%), clear cell (12%), and other (12%). The most common indications were pain (65%), bleeding (30%), and asymptomatic progression (20%). 18 of 20 RT courses were delivered to soft tissue or nodal metastases. RT techniques included 2D/3D (60%), IMRT (30%), and SBRT (10%). Dose ranged from 20-60 Gy in 3-28 fractions. 20 Gy in 5 fractions (25%) and 30-31 Gy in 10 fractions (25%) were most common. Of the 16 RT courses for symptomatic disease, clinical ORR was 87.5% within 3 months of RT (50% PR and 37.5% CR). 3 treatments had sustained response beyond 3 months. 2 developed PD. Of 11 RT courses with follow-up imaging, radiographic ORR was 36.1% (27% PR and 9.1% CR) within 3 months of RT. 1 had sustained PR beyond 3 months. Of the 10 RT courses for symptomatic high grade serous histology, PR and CR was seen in 50% and 40% of patients within 3 months (90% ORR). Conclusions: Palliative RT offers high rates of clinical response for symptomatic patients with metastatic ovarian cancer within 3 months of treatment delivery. Rapid clinical response rates were particularly favorable for those with high grade serous histology. RT should be considered as a standard palliative option for patients with symptomatic ovarian cancer metastases. Further prospective studies are warranted to establish the optimal timing, dose, and relation to chemosensitivity in this setting.

P2.14-69 Lorlatinib Rescue Therapy for Life Threatening CNS Disease in Crizotinib-Resistant ROS1-Positive Non–Small Cell Lung Cancer (NSCLC)

C-ros proto-oncogene-1 (ROS1) chromosomal translocations result in constitutively activated receptor tyrosine kinase in 1-2% of NSCLC. Although crizotinib, a first-generation Tyrosine Kinase Inhibitor (TKI) of Anaplastic Lymphoma Kinase (ALK) and ROS1 translocations, has demonstrated efficacy in treatment of ROS1 NSCLC, patients invariably acquire resistance mutations, with a high incidence of brain metastasis at relapse owing to poor CNS drug penetration. Lorlatinib is a novel, third-generation TKI with improved CNS penetration and preclinical activity against crizotinib-resistance mutations, which recently demonstrated efficacy in a phase I/II trial. We report a patient who developed secondary crizotinib-resistance and was successfully treated with lorlatinib. A 73-year-old, female, never-smoker with recently diagnosed stage-IV ROS1-rearranged NSCLC presented with refractory seizures and coma. The patient was on first-line treatment with crizotinib for 6-months, with an excellent systemic response at 2 months. Brain MRI after presentation demonstrated multiple intracranial metastasis with vasogenic edema (Fig.1A). Neurologic status was unchanged despite mannitol, steroids and anti-epileptics. As salvage therapy, the patient received bevacizumab for vasogenic edema and lorlatinib (100mg/daily). After 48-hours, substantial clinical improvement in neurologic function and mental status was observed. A repeat MRI (D+4) demonstrated a slight interval decrease in the largest metastasis and associated edema. At 1-month follow-up, the patient continued to improve clinically with no evidence of lorlatinib toxicity. Brain MRI showed a decrease in the sizes and/or resolution of all previously noted lesions and no new metastases or significant peritumoral edema (Fig.1B). Since clinical trials typically exclude patients with symptomatic, untreated CNS disease, efficacy of newer, targeted agents in mutated-NSCLC is unclear. Here we report on a patient with life threatening, acute neurologic deterioration who derived a meaningful clinical reduction in CNS lesions at 1 month, with favorable CNS response at 2 months. In addition, we observed early evidence of tumor regression on MRI after 4 days of lorlatinib therapy. Of note, her rapid clinical response may have in part been attributable to the addition of bevacizumab. Another important consideration for our patient is that she avoided whole-brain radiation in the acute setting, and its potential adverse sequalae. We note a limitation was the absence of available testing for secondary resistance mutations that developed in this patient, which was highly susceptible to lorlatinib. However, current clinical guidelines (NCCN) do not specifically recommend resistance mutation testing upon progression, and outside of a clinical trial, the current algorithm supports lorlatinib as the agent of choice post-crizotinib failure.

CAR exosomes derived from effector CAR-T cells have potent antitumour effects and low toxicity

Genetically engineered T cells expressing a chimeric antigen receptor (CAR) are rapidly emerging a promising new treatment for haematological and non-haematological malignancies. CAR-T therapy can induce rapid and durable clinical responses but is associated with unique acute toxicities. Moreover, CAR-T cells are vulnerable to immunosuppressive mechanisms. Here, we report that CAR-T cells release extracellular vesicles, mostly in the form of exosomes that carry CAR on their surface. The CAR-containing exosomes express a high level of cytotoxic molecules and inhibit tumour growth. Compared with CAR-T cells, CAR exosomes do not express Programmed cell Death protein 1 (PD1), and their antitumour effect cannot be weakened by recombinant PD-L1 treatment. In a preclinical in vivo model of cytokine release syndrome, the administration of CAR exosomes is relatively safe compared with CAR-T therapy. This study supports the use of exosomes as biomimetic nanovesicles that may be useful in future therapeutic approaches against tumours.

3. Statin induced immune mediated necrotising myopathy: a case report

IntroductionStatins are a commonly used group of drugs which lowers low density lipoprotein (LDL) levels by competitively inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Though they are effective and safe, about 0.1% patients on statins can develop severe myonecrosis or immune mediated necrotising myopathy (IMNM).Here we present a case of IMNM secondary to atorvastatin exposure, resulting in severe muscle weakness and prolonged hospitalisation, and positive treatment response to intravenous immunoglobulin (IVIG).Case descriptionA 59-year-old Caucasian lady with a history of hypothyroidism and hyperlipidaemia, presented with 5 weeks’ history of progressive weakness in both upper and lower limbs which was preceded by flu like symptoms. She was also having swallowing difficulty and had neck-flexor weakness. There was MRC grade 2 power around hips, knees and shoulders, with normal power distally. She had been started on atorvastatin 10 mg 6 months ago, which was stopped due to myalgia.She was admitted to the hospital, and soon developed respiratory muscle weakness. She had serial SVC assessment and required nasogastric feeding. Electromyography suggested myositis. MRI of the thighs showed extensive myositis, muscle biopsy confirmed necrotising myopathy. Autoantibodies were negative, but she had high titre HMGcoA reductase antibodies (anti-HMGCR).Creatine kinase levels on presentation was 24230 U/L, which increased to 31000 U/L. Initial SVC was 33% of predicted. CT scan of chest abdomen and pelvis did not reveal any malignancy. Cardiac MRI did not reveal myocarditis, though her troponin-T levels were raised 1096 ng/L.She was non responsive to 3 pulses of 1 gm methyl-prednisolone. She was treated with IVIG, cyclophosphamide infusions and oral prednisolone. She made steady progress and was discharged with SVC of 70%, CK of 664 U/I, proximal muscle strength of 3/5 and feeding orally. She received 9 cycles of 900 mg cyclophosphamide followed by mycophenolate mofetil 2gm/day.However, her CK levels plateaued to between 650 and 700; proximal lower limb power was fluctuating between 4 and 3. She received another course of IVIG- 6 months after the onset of myositis which significantly improved her power, which sustained for around 4 months. The plan is to manage her with serial IVIG infusions.DiscussionStatins can cause adverse muscle related events, ranging from mild myalgia to severe myopathy and rhabdomyolysis. Rarely, patients can develop immune mediated necrotising myositis, as in our patient. IMNM can cause persisting myositis with predominantly proximal muscle weakness, and runs a protracted course. Statin-induced IMNM is associated with presence of anti HMGCR antibodies.There are no clinical trials to guide therapeutic decisions in IMNM, however some case series and observational studies have shown improvement with immunosuppression. IVIG have been shown to be effective in anti HMGCR associated IMNM, as in our case.Even after stopping statins, IMNM can progress and patients can have prolonged weakness requiring immunosuppression. Around 50% patients continue to have significant weakness even after 2 years of treatment, indicating an unfavourable prognosis.Our patient continues to have waxing waning weakness with persistently raised CK, and IVIG infusions seems to give a rapid clinical response , though sustaining for 3 to 4 months, indicating a need for repeated infusions. The other treatment option remains rituximab, which has shown to have some efficacy in anti-SRP positive IMNM.Our patient had hypothyroidism, which is known to potentiate statin induced myopathy, however, strong association with IMNM is not established.Around 80% patients with anti HMGCR associated myositis have prior statin exposure, however, a subgroup of patients, especially among Asians, can have anti-HMGCR antibody and myositis even without statin exposure. This indicates a possible a genetic susceptibility to statins. Also, exposure to oyster mushroom and red yeast rice have been reported to be associated with anti-HMGCR antibodies in this subgroup of patients.Key learning pointsStatins can cause muscle related adverse events. 2-11% patients can have mild myalgia and myopathy, however necrotising myopathy is extremely rare (0.1%). Anti-HMCGCR antibodies are associated with statin induced IMNM. IMNM has a protracted course and can continue for years after stopping statins. Long term Immunosuppression is required in IMNM. IVIG is effective in refractory cases. Anti-HMCGCR antibodies can be found in statin naïve patients. Hypothyroidism can potentiate statin induced myopathy. The risk of muscle injury is higher when taking a statin which is extensively metabolised by cytochrome P450 3A4 (CYP3A4) - like simvastatin and atorvastatin, with CYP3A4 inhibitors. Pravastatin, rosuvastatin are preferred in these cases.Conflict of interestThe authors declare no conflicts of interest.

17. Tick-borne relapsing fever: a fever syndrome mimic

17. Tick-borne relapsing fever: a fever syndrome mimic

Rapid clinical response predicts consistent long-term response in patients with moderate-to-severe psoriasis: Ixekizumab vs. ustekinumab

Rapid clinical response predicts consistent long-term response in patients with moderate-to-severe psoriasis: Ixekizumab vs. ustekinumab

Combination of Immunotherapy With Targeted Therapy: Theory and Practice in Metastatic Melanoma.

Metastatic melanoma is the most aggressive and obstinate skin cancer with poor prognosis. Variant novel applicable regimens have emerged during the past decades intensively, while the most profound approaches are oncogene-targeted therapy and T-lymphocyte mediated immunotherapy. Although targeted therapies generated remarkable and rapid clinical responses in the majority of patients, acquired resistance was developed promptly within months leading to tumor relapse. By contrast, immunotherapies elicited long-term tumor regression. However, the overall response rate was limited. In view of the above, either targeted therapy or immunotherapy cannot elicit durable clinical responses in large range of patients. Interestingly, the advantages and limitations of these regimens happened to be complementary. An increasing number of preclinical studies and clinical trials proved a synergistic antitumor effect with the combination of targeted therapy and immunotherapy, implying a promising prospect for the treatment of metastatic melanoma. In order to achieve a better therapeutic effectiveness and reduce toxicity in patients, great efforts need to be made to illuminate multifaceted interplay between targeted therapy and immunotherapy.

PET/CT Imaging of Human TNFα Using [89Zr]Certolizumab Pegol in a Transgenic Preclinical Model of Rheumatoid Arthritis.

Tumor necrosis factor alpha (TNFα) drives inflammation and bone degradation in patients with rheumatoid arthritis (RA). Some RA patients experience a rapid clinical response to TNFα inhibitors such as certolizumab pegol (CZP) while other patients show limited to no response. Current methods for imaging RA have limited sensitivity and do not assist in the selection of patients most likely to respond to immune-mediated therapy. Herein, we developed a novel positron emission tomography (PET) radiotracer for immuno-PET imaging of TNFα in transgenic human TNFα-expressing mice. CZP was modified with p-isothiocyanatobenzyl-deferoxamine (DFO) and radiolabeled with Zr-89. The biological activity of [89Zr]DFO-CZP was evaluated by HPLC and binding assay using human recombinant TNFα (hTNFα). The feasibility of specific immuno-PET imaging of human TNFα was assessed in a transgenic mouse model of RA that expresses human TNFα. This model resembles the progression of RA in humans by maintaining lower levels of circulating hTNFα and exhibits chronic arthritis in the forepaw and hind paw joints. The dosimetry of [89Zr]DFO-CZP in humans was estimated using microPET/CT imaging in Sprague Dawley rats. [89Zr]DFO-CZP was isolated with radiolabeling yields of 85 ± 6% (n = 5) and specific activities ranging from 74 to 185MBq/mg (n = 5). Following size exclusion purification, the radiochemical purity of [89Zr]DFO-CZP was greater than 97%. [89Zr]DFO-CZP retained high immunoreactivity with more than 95% of the radioactivity shifted into higher molecular weight complexes. Images showed increasing uptake of the tracer in forepaw and hind paw joints with disease progression. No uptake was observed in the model previously administered with an excess amount of unmodified CZP and in normal control mice, demonstrating in vivo specific uptake of [89Zr]DFO-CZP. The feasibility of immuno-PET imaging of human TNFα with [89Zr]DFO-CZP has been demonstrated in a preclinical model of RA.

Abstract P1-15-10: A prospective multicenter real-world study on neoadjuvant treatment and clinical outcome in TNBC patients

Abstract Introduction Controversy exists with regards to the optimal regimen for neoadjuvant chemotherapy (NAC) of TNBC. Platinum-based regimens seem to be more active in TNBC improving pCR rates significantly. But adding platinum to an anthracycline/taxane chemotherapy regime comes at the expense of greater toxicity. Its impact on survival and long-term-outcomes remains undetermined. Practical guidelines vary across leading international professional societies. In this real-world multicenter study neoadjuvant regimens, pCR rates and survival were evaluated. Material and methods This study was conducted from 2012-2017 in six certified breast cancer centers in the region of Hanover, Germany, including rural and urban populations by using a personal questionnaire and data from the medical records. All patients with primary TNBC (ER<1%, PR<1%, Her2/neu 0, 1+ or 2+ FISH/CISH negative) and no evidence of distant disease were eligible. Results 143/217 patients (66%) received NAC and 74/217patients (34%) adjuvant chemotherapy. 63/143 (44%) patients achieved pCR. 23/63 (35%) received platinum-based NAC and 40/63 (65%) received chemotherapy without platinum. In 80 patients pCR was not achieved. 12/80 patients received platinum and 68/80 non platinum-based NAC. pCR was significantly higher among patients with platinum-based chemotherapy (chi-square, p < 0.003). 20/23 patients who achieved pCR received NAC containing anthracycline/taxane/carboplatin, 3/23 patients received a taxane/carboplatin-based regime. Treatment discontinuation was seen in 12/35 (34%) patients receiving platinum-based NAC vs 15/108 (14%) in non-platinum-based NAC. Mean follow up was 17 months (1-70months). A significant difference in OS (p=0.007) and DFS (p=0.001) was seen for patients with a pCR. Conclusion Our trial confirms that platinum based NAC achieves significantly higher rates of pCR in patients with TNBC. pCR was associated with significantly longer DFS and OS. The CALBG protocol (CALBG 40603) was the preferred choice of treatment regimen followed by the GeparSixto protocol. In our study the pCR rate was comparable to that of both trials in which pCR rates of 60% (CALBG 40603) and 53% (GeparSixto) were achieved. However, in our trial 34% of the patients discontinued treatment due to toxicity. Therefore these protocols should be used in carefully selected patients. In a real world setting less toxic chemotherapy regimens achieved a pCR rate of 37%. In terms of toxicity and adherence to chemotherapy, these regimens are reasonable alternative options. In daily care close monitoring of treatment response is essential during NAC. In patients who have a rapid clinical response to platinum-free NAC the benefit of adding platinum is questionable. In contrast, the addition of platinum seems to be appropriate in those patients who show only limited response under NAC. Citation Format: Kuehnle E, Kaur P, Siggelkow W, Luebbe K, Schrader I, Uleer C, Noeding S, Noeding K-H, Noesselt T, Arfsten M, Busch C, Krentel N, Hillemanns P, Dörk T, Park-Simon T-W. A prospective multicenter real-world study on neoadjuvant treatment and clinical outcome in TNBC patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-15-10.

Sustained Response to Imatinib in a Pediatric Patient with Concurrent Myeloproliferative Disease and Lymphoblastic Lymphoma Associated with a CCDC88C-PDGFRB Fusion Gene

Background: The WHO defined myeloid and lymphoid neoplasms (MLN) with eosinophilia associated with PDGFRB, PDGFRA, FGFR1 rearrangements as a new entity in 2016. PDGFRB-rearranged MLN sensitive to imatinib were described in adult patients. We report the first pediatric patient with PDGFRB-rearranged myeloproliferative disorder associated with T-lymphoblastic lymphoma bearing the t(5; 14)(q33;q32) translocation who was successfully treated with imatinib only. Methods/Aims: Analysis of bone marrow and peripheral blood cells by fluorescent in situ hybridization identified the PDGFRB partner as CCDC88C. Whole genome sequencing of the patient’s DNA identified the exact junction site, confirmed by PCR amplification and Sanger sequencing. A real-time quantitative PCR assay was designed to quantify the fused CCDC88C-PDGFRB product. Results: A 2.5-year-old boy was diagnosed with myeloproliferative disorder and eosinophilia associated with lymphoblastic lymphoma both bearing the CCDC88C-PDGFRB fusion. Imatinib therapy resulted in rapid clinical, hematological, and cytogenetic response. Molecular response to treatment was monitored by a real-time PCR assay specific for the CCDC88C- PDGFRB fusion. Conclusion: This is the first description of MLN with eosinophilia in the pediatric age group. Response to treatment with imatinib only was monitored by specific quantitative PCR assay with sustained remission lasting 5.5 years from diagnosis.

Molecularly targeted therapies in non-small cell lung cancer: The evolving role of tyrosine kinase inhibitors.

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer. Patients with NSCLC are diagnosed at a locally advanced or metastatic stage where prognosis with palliative chemotherapy is poor. The discovery of epidermal growth factor receptor (EGFR) mutations has revolutionized cancer treatment for NSCLC by promoting the development of molecularly targeted therapies like tyrosine kinase inhibitors (TKIs). This review summarizes the clinical efficacy and tolerability of EGFR-TKIs, including osimertinib, in EGFR-mutated advanced NSCLC. EGFR-TKIs have demonstrated superior response and overall survival rates compared with chemotherapy in EGFR-mutated NSCLC. However, despite the initial rapid and durable clinical responses, acquired resistance to first- and second-generation TKIs eventually develops in most cases, with disease progression observed mostly within 12 months of treatment initiation. Osimertinib, a potent third-generation TKI, irreversibly inhibits mutated EGFR alleles, including T790M. In addition to longer survival and higher response rate, osimertinib has a favorable safety profile with a lower incidence of grade ≥3 treatment-related adverse events compared with other TKIs. Based on the efficacy and safety results, recently the National Comprehensive Cancer Network (NCCN) has included osimertinib as the "preferred first-line of treatment" in patients with metastatic EGFR mutationpositive NSCLC. Thus, osimertinib as first-line therapy for EGFRpositive patients irrespective of the T790M mutation status could be an ideal choice in the Indian setting where only 50% of patients opt for any second-line therapy after first-line failure.

ET190L1-ArtemisTM T Cell Therapy Results in Durable Disease Remissions with No Cytokine Release Syndrome or Neurotoxicity in Patients with Relapsed and Refractory B-Cell Lymphoma

Background:Chimeric antigen receptor (CAR) T-cell is rapidly emerging as a promising new therapy for cancer. Although it can induce rapid clinical responses, it is also associated with cytokine release syndrome (CRS), the most commonly observed toxicity, which in some cases can lead to life-threatening multi-organ failure. To ameliorate these problems we developed a novel chimeric T-cell therapy platform, the ARTEMIS™ platform, which functionally matches the potency of CAR T-cells, but dramatically reduces the release of cytokines upon killing of target-positive tumor cells. Herein, we describe the first-in-human clinical study of anti-CD19-ARTEMIS, ET190L1-ARTEMISTM, in relapsed and refractory (r/r) B-cell lymphoma.Methods:This dose escalating study is a single-center clinical study to evaluate the safety and efficacy of ET190L1-ARTEMIS T cells in patients with r/r CD19+ non-Hodgkin lymphoma, including diffused large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma/chronic lymphocytic lymphoma, and splenic marginal zone lymphoma. All patients received conditioning chemotherapy of cyclophosphamide and fludarabine followed by a single infusion of ET190L1-ARTEMISTM T cells at the dose of 1x106, 3x106, and 6x106 ARTEMIS+ T cells per kilogram respectively. The primary endpoint is safety and estimation of the maximum tolerated dose of ET190L1-ARTEMISTM T cells. Secondary objectives include ARTEMIS T-cell engraftment and response assessment by Lugano criteria.Results:Manufacturing was successful for all patients. As of July 18, 2018, 21 patients received autologous ET190L1-ARTEMIS T cells, 3 were infused with 1 × 106 (low dose), 13 received 3 × 106 (medium dose) and 5 received 6 × 106 (high dose) ARTEMIS+ T cells/kg. Expansion of ARTEMIS T cells after infusion was observed in all patients by qPCR and flow cytometry using anti-idiotype antibody. No dose-limiting toxicities and no greater than Grade 2 drug-related adverse events (AEs) were observed. Inflammatory-related cytokines in blood including IL-2, IL-4, IL-6, IL-8, IL-10, IFNgamma, TNFalpha, and GM-CSF were below detection level in most time points post infusion. AEs consisted of transient fever (38 ~ 39.2°C) from 1 to 4 days post infusion in 9 patients, transient grade 1 skin rash (1 × 106/kgcohort) in one patient. All of these AEs were limited and spontaneously resolved, except in 3 patients where symptomatic treatment for fever was given. No hypotension or any other clinical signs of CRS or neurotoxicity were observed. No anti-IL6 drug was given nor any hospitalization for AEs were needed. One patient with a large lymphoma mass on the right side of the neck experienced transient hand-tremor and unilateral tongue numbness on the right side, possibly due to the rapid shrinkage of tumor nodules around the neck (Table 1). Efficacy assessment was planned at 1, 2, 3, 6, 9, 12 18 and 24 months post infusion.All subjects (n=21) completed 1st month efficacy assessment: 11/21 (52%) responders, with 6/11 (55%) complete remission (CR) and 5/11 (45%) partial remission (PR). Of the 11 responders at 1 month, 8 completed 3rd month efficacy assessment, with 6/6 CRs maintained CR and 2/2 PRs had disease progression. Of the 11 responders at 1 month, 6 completed 6th month efficacy assessment, with 5/6 CRs maintained CR and 1/6 CRs releapsed. Of the 2 SDs at 1 month, 1 progressed at 4.5 month (Table 2). The median follow up time is 3 months and the range of follow up time is 1-8 months.Conclusions:The interim results show that ET190L1-ARTEMISTM T cell therapy is safe and demonstrated promising efficacy in r/r B-cell lymphoma patients at the current dose and schedule, including 11/21 responders and excellent safety profile, with no CRS and neurotoxicity observed. The durability of these efficacy and safety results will be assessed in longer follow up. Clinical trial information: NCT02658929 [Display omitted] DisclosuresLong:Eureka Therapeutics, Inc.: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Rizzieri:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Nejadnik:Eureka Therapeutics, Inc.: Employment. Zhu:Beijing Cancer Hospital: Employment. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership.

RET rearrangements are actionable alterations in breast cancer

Fusions involving the oncogenic gene RET have been observed in thyroid and lung cancers. Here we report RET gene alterations, including amplification, missense mutations, known fusions, novel fusions, and rearrangements in breast cancer. Their frequency, oncogenic potential, and actionability in breast cancer are described. Two out of eight RET fusions (NCOA4-RET and a novel RASGEF1A-RET fusion) and RET amplification were functionally characterized and shown to activate RET kinase and drive signaling through MAPK and PI3K pathways. These fusions and RET amplification can induce transformation of non-tumorigenic cells, support xenograft tumor formation, and render sensitivity to RET inhibition. An index case of metastatic breast cancer progressing on HER2-targeted therapy was found to have the NCOA4-RET fusion. Subsequent treatment with the RET inhibitor cabozantinib led to a rapid clinical and radiographic response. RET alterations, identified by genomic profiling, are promising therapeutic targets and are present in a subset of breast cancers.

Calcipotriol/betamethasone dipropionate aerosol foam for the treatment of psoriasis vulgaris: case series and review of the literature.

An aerosol foam formulation of a once-daily, fixed-dose combination of a synthetic vitamin D3 analog/synthetic corticosteroid (calcipotriol [Cal] 50 µg/g and betamethasone dipropionate [BD] 0.5 mg/g) has recently been introduced for the topical treatment of plaque psoriasis in adults. Data from several sources – randomized controlled trials, case reports (as highlighted in this review), and real-world evidence (RWE) – underscore the considerable and rapid clinical response, effectiveness, and favorable safety and tolerability of Cal/BD aerosol foam in mild-to-moderate psoriatic patients previously treated with class 3 or 4 topical corticosteroids, in patients unsatisfied with ongoing phototherapy in combination with topical therapy and in patients with moderate-to-severe psoriasis. In addition, our case series, considered together with other RWE, highlights that Cal/BD aerosol foam is more effective and with greater levels of patient preference and acceptability than comparator preparations. Thus, Cal/BD aerosol foam offers several treatment advantages, including relief of itch, and is an appropriate first-line topical therapy for consideration in patients with psoriasis of any severity.

Enhanced effect of checkpoint inhibitors when given after or together with IMM-101: significant responses in four advanced melanoma patients with no additional major toxicity

BackgroundThe use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) has revolutionised the treatment of metastatic melanoma. However still more than the half the patients do not respond to single-agent immunotherapy. This has led to the development of combining these agents in an attempt to enhance the anti-cancer activity. More than 300 different studies with 15 different drug doses are currently ongoing. Combining different checkpoint inhibitors (CPIs) does indeed lead to an increase in response rate, but this is associated with significant toxicity. IMM-101 is a heat killed Mycobacterium preparation which induces marked immune modulation and little systemic toxicity. It has been reported as having activity in melanoma as single agent and in pancreatic cancer in combination with gemcitabine, the latter in a randomised study.MethodsHere we report the effect of adding CPIs to 3 patients who had previously been on IMM-101, either as a trial or a named patient programme and a patient who received the IMM-101 together with nivolumab.ResultsAll 4 patients had rapid and very good responses, three of them maintained over 18 months with no significant additional toxicity.ConclusionsThe rapid and complete clinical responses seen in these patients may suggest that IMM-101 is activating a complementary pathway which is synergistic with CPI treatment.

ULTRASOUND TUMOR ABLATION: IMMUNE EFFECTS AND PERSPECTIVES OF INTEGRATION IN THE MODERN TREATMENT OF ADVANCED CANCER

Despite significant progress in molecular oncology and immuno-oncology, only 20-30 % of patients with advanced cancer can be cured with modern treatments indicating that new approaches are needed. Further improvements in immunotherapy of cancer are associated with enhanced tumor immunogenicity, induction of inflammatory phenotype and inhibition of immune suppression at the tumor microenvironment level. In this context, high-intensity focused ultrasound (HIFU) ablation have several advantages, particularly it is able to elicits a rapid clinical and immune response, is non-invasive, have low local morbidity, allows repeated sonications, have relative low cost and does not require long hospitalization. In addition to cytoreduction and decreasing of systemic immune suppression, HIFU generates a tumor debris depot acting as vaccine in situ. Immunogenic cell death elicits a CD4+ and CD8+ cytotoxic T-cell response, but several regulatory mechanisms, particularly PD-1L expression, are promoted in response to enhanced immune cells infiltration of heated and distal tumors. This results in low rate of durable and clinically relevant abscopal effects. For these reasons HIFU is currently viewed as a part of strategies targeting multiple steps of cancer immune cycle (TLR agonists, GM-CSF, cytokines, CTLA-4, PD-1 / PD-1L inhibitors, T-cell co-stimulation agonists, adoptive cell therapy etc). Higher rate of abscopal effects and improved survival have been shown in some preclinical studies using thermal ablations in combination with immunotherapy. In this setting, there is an opportunity to use check-point inhibitors in reduced doses. In addition, tumor ablation after non-effective immunotherapy could induce a new cancer antigens spreading, T-cell repertoire changes and enhance tumor responsiveness to treatment. Based on encouraging preclinical data, this exiting approach is currently explored in some ongoing trials aiming to evaluate the optimal treatment sequences and its clinical efficacy.

Predictive factors for structural remission using abatacept: Results from the ABROAD study

Objective: To investigate the effect of abatacept (ABA) on preventing joint destruction in biological disease-modifying anti-rheumatic drug (bDMARD)-naïve rheumatoid arthritis (RA) patients in real-world clinical practice.Patients and methods: RA patients were collected from the ABROAD (ABatacept Research Outcomes as a First-line Biological Agent in the Real WorlD) study cohort. They had moderate or high disease activity and were treated with ABA as a first-line bDMARD. Radiographic change between baseline and 1 year after ABA treatment was assessed with the van der Heijde’s modified Total Sharp Score (mTSS). Predictive factors for structural remission (St-REM), defined as ΔmTSS ≤0.5/year, were determined.Results: Among 118 patients, 81 (67.5%) achieved St-REM. Disease duration <3 years (odds ratio (OR) = 3.152, p = .007) and slower radiographic progression (shown as ‘baseline mTSS/year <3’, OR = 3.727, p = .004) were independently significant baseline predictive factors for St-REM irrespective of age and sex. St-REM prevalence increased significantly if clinical remission based on the Simplified Disease Activity Index was achieved at least once until 24 weeks after ABA treatment.Conclusion: Shorter disease duration, smaller radiographic progression at baseline, and rapid clinical response were predictive factors for sustained St-REM after ABA therapy in bDMARD-naïve RA patients.