Flare Reaction Research Articles

Triphasic Bone Scintigraphy Is Not Useful in Diagnosis and May Delay Surgical Treatment of CRPS of the Hand.

Background: Triphasic bone scintigraphy (TPBS) is often used to diagnose complex regional pain syndrome (CRPS). The primary aim of this study is to determine if the diagnosis of CRPS in patients with a positive TPBS (TPBS +ve) is accurate. A secondary aim is to determine if there was delay in treatment of patients who underwent TPBS compared to those who did not have a TPBS. Methods: Of 225 consecutive patients presenting to the first author's practice with a diagnosis of CRPS, 65 had TPBS performed before referral with 62 having TPBS +ve. The remaining 160 were clinically diagnosed and a TPBS was not done (TPBS-ND). Patients were classified into five categories - wrong diagnosis, dystonic-psychogenic hand, causalgia, flare reaction and irritative carpal tunnel syndrome (ICTS). Patients with flare reaction and ICTS were considered as having true CRPS and the rest were considered as misdiagnosis. The patients' demographics, duration of symptoms, pre- and postoperative pain, functional score and patient satisfaction were compared. Results: Of the 62 TPBS +ve, there were 38 (61%) misdiagnosis. The proportion of misdiagnoses was fewer in the TPBS-ND group (45%; p=0.036). Thirty-two of the 62 TPBS group (52%) and 92/160 (56%) of the TPBS-ND group had surgical treatment. At a mean follow-up of 19 months, pain dropped 6.5 ± 2.5 points in the TPBS +ve group. Disabilities of the arm, shoulder and hand (DASH) score fell by 56 ± 27. The mean single assessment numeric evaluation (SANE) score was 8.6 ± 2.3. These results did not differ substantially from those of the TPBS-ND group. Conclusions: A significant number of patients in this study who had TPBS +ve were misdiagnosed in this study. Outcomes after treatment of CRPS were consistently good despite the results of the TPBS. Patients with TPBS +ve had a significant delay to diagnosis. We conclude that TPBS is not useful in the management of CRPS. Level of Evidence: Level III (Therapeutic).

Pathological landscape of tumor flare reaction to epcoritamab treatment.

Tumor flare reaction (TFR) is characterized by an increase in lesion size during immune-based therapy, often resembling disease progression. It signifies inflammation at the tumor site and is frequently seen in immunotherapy, where it is termed "tumor pseudoprogression." The exact mechanisms behind TFR remain unclear. We report the case of a 62-year-old Japanese man with relapsed and refractory diffuse large B cell lymphoma treated with epcoritamab. On day 10 of the first epcoritamab cycle, after two subcutaneous injections of epcoritamab, the cutaneous lymphoma lesions became swollen. This was identified as TFR, and was managed with a three-day course of intravenous dexamethasone at 12mg/day. The third injection, scheduled for day 15, was delayed by 1week. Four doses of epcoritamab were completed over the initial 35-day period. A skin biopsy was performed on day 30. Histopathological examination showed CD20+ large atypical lymphocytes forming residual nodules, encircled by CD4+ and CD8+ lymphocytes, with a predominance of CD8+ T cells over CD4+ T cells. Although infrequent, TFR may be a significant indicator of tumor response to epcoritamab therapy. The diagnosis of TFR could be underestimated, and proper identification and understanding of its clinicopathological features are crucial for its effective management.

Functional characterization of complete and immunodominant epitopes of a novel pollen allergen from Parthenium hysterophorus.

Background. Parthenium hysterophorus pollen induces chronic clinical conditions such as allergic rhinitis and bronchial asthma. Among the plethora of proteins in the pollens, only few were reported to induce allergy. Currently sensitization to P. hysterophorus pollen allergen is diagnosed by skin prick test (SPT) using the entire pollen extract instead of using the specific allergen. Methods. In P. hysterophorus sensitized patients, SPT was done using the crude pollen extract, 40 kDa allergenic pollen protein and two commercially synthesized allergen epitopes (17 and 24) of P. hysterophorus. Dot-blot of allergen epitopes was done using P. hysterophorus sensitized sera. Crude pollen extract (1, 1.25, 2.5, 5 and 10 µg/mL), 40 kDa allergenic protein (3 µg/mL), and allergen epitopes (3µg/mL) were used to perform Basophil Activation Test (BAT). Results. Crude pollen extract at 2.5, 5, 10 μg/mL and 40 kDa allergenic protein at 3μg/mL concentrations induced wheal and flare reaction by around 15 minutes, whereas commercially synthesized allergen epitopes at 3μg/mL induced wheal and flare reactions in less than 10 minutes. Allergen epitopes (3 µg/mL) revealed strong reactivity with sensitized patient's IgE in dot-blot analysis. Basophil activation Test using crude pollen extract (2.5, 5, 10 µg/mL), 40 kDa allergenic protein (3 µg/mL), and allergenic epitopes (3µg/mL) indicated significant basophil activation (as measured by CD63 expression) in sensitized patients. Conclusions. The 40 kDa allergenic protein and its allergenic epitopes (17 and 24) induced phenotypic and cellular immune responses in P. hysterophorus sensitized individuals. The tested allergenic epitopes (17 and 24) induced faster wheal and flare reactions in comparison with the crude extract and the 40 kDa allergenic protein. The novel 40kDa allergenic protein and its allergen epitopes identified here may be useful for the development of component-resolved diagnosis (CRD) while also serving as a potential therapeutic lead for desensitization treatment for P. hysterophorus pollen induced allergy.

Correlation of previous local vaccination site “flares” during immunotherapy for metastatic melanoma with complete responses to therapy.

e21534 Background: mRNA vaccines have been shown to stimulate T-cells targeting patient-specific tumor neoantigens. When combined with immune checkpoint inhibitors (ICI) in a randomized Phase II trial, mRNA vaccines demonstrated improvement in recurrence free survival and distant metastasis free survival compared to ICI alone. We retrospectively examined patients (pts) with advanced melanoma treated more than 5 years ago on clinical trials with adjuvant NYESO1 or mRNA vaccine therapies (VT) then ICI upon recurrence and analyzed biomarkers correlating with treatment response. Methods: This retrospective study examined 22 pts with advanced melanoma treated between 2004-2017 with adjuvant vaccine therapies (VT). 10 of the 22 pts subsequently developed recurrent disease and were treated with ICI. We evaluated disease free interval following ICI, sex, age, BRAF status, HLA type, site of primary and metastatic disease, initial vaccine treatment, vaccine toxicities, stage and sites of melanoma recurrence, ICI treatment, response and toxicities, vaccine site flares or cutaneous immune related adverse events (irAEs) following ICI. Results: Of the 22 patients (11 male, 11 female) treated with adjuvant VT, median age at first vaccine was 53 years old. HLA type was known for 11 pts. Stage at initial VT was IIB to IIIC. 14 pts recurred following adjuvant VT. Median time from vaccine initiation to melanoma recurrence was 3.2 years (range 6.5 months to 11 years). 10 pts received ICI for recurrent melanoma, 3 pts received ipilimumab, 2 anti-PD1 monotherapy, 4 ipilimumab and nivolumab, and 1 nivolumab/relatlimab. Stage at first ICI was IIIB to IV M1d. 9 pts experienced cutaneous irAEs. 7 pts experienced local vaccine site flare reactions following ICI treatment. Additionally, 2 pts experienced vitiligo, 2 with dermatologic flares (bullous pemphigoid and psoriatic rash), 2 with generalized rash that resolved with steroid cream. 1 pt did not experience rash, vaccine site flare, nor irAE dermatologic flare. Of the pts who recurred, 2 pts had BRAF V600E mutations, and 1 of these pts experienced vaccine flare, the other did not. 1 pt with a BRAF Q16L mutation did not have vaccine flare. 6 out of 7 BRAF wild type pts who recurred and received ICI experienced a localized vaccine site flare. Median disease-free interval following ICI treatment was 1.5 years (range 3 months to 9 years). All 10 pts are disease-free and off ICI being closely monitored. Conclusions: Evidence of prior localized vaccination “flare” may be a biomarker for a complete immunologic response in pts with metastatic disease treated with immunotherapy. ICI targeting CTLA-4 and/or PD-1 both triggered this localized vaccination site response, suggesting that T cell memory and immunologic activation against melanoma antigens translate into clinical responses.

Clinically uninvolved but not healthy-The skin of patients with atopic dermatitis is primed for itch and inflammation.

Atopic dermatitis (AD) is a highly prevalent inflammatory skin disorder characterized by episodic exacerbations and remissions. Why the clinically healthy skin of AD patients becomes rapidly inflamed and very pruritic is poorly understood. To investigate cowhage- and histamine-induced itch and skin expression levels of their target receptors in lesional and non-lesional skin of AD, compared to the skin of patients with psoriasis, chronic spontaneous urticaria (CSU) and healthy subjects. Patients with AD, psoriasis and chronic spontaneous urticaria (CSU) as well as healthy control subjects (HC) (n = 20 each) were assessed for differences in itch parameters, neurogenic flare reaction and local blood flow responses to skin provocations with cowhage and histamine. Skin biopsies from 10 AD, 10 psoriasis,11 CSU and 12 HC were obtained to assess expression of protease-activated receptors 2 and 4 (PAR-2, PAR-4), histamine H1 and H4 receptors (H1R, H4R), and mast cells. Provocation of non-lesional skin of AD patients with cowhage resulted in prolonged itch (p = 0.020), which was not observed in psoriasis and CSU. Significantly prolonged and more intense cowhage- and histamine-induced itch (for duration, peak and overall intensity) was also observed in lesional AD skin. Diminished neurogenic flare reaction and blood flow after histamine provocation were shown in AD and psoriasis patients. Non-lesional AD skin along with lesional AD and psoriasis skin showed an increased expression of PAR-2 and PAR-4, H1R and H4R. Mast cell number was higher in lesional AD and psoriasis skin (p = 0.006 and p = 0.006, respectively). The non-lesional skin of AD patients markedly differs from healthy skin in cowhage-induced itch responses and the expression of receptors for proteases and histamine. Proactive therapeutic interventions that downregulate these receptors may prevent episodic exacerbation in AD.

Comparing the Intensity of Pain and Incidence of Flare Reaction Following Trigger Finger Injections Using Betamethasone and Methylprednisolone: A Double-Blinded, Randomized Controlled Trial.

Considerable evidence supports corticosteroid injection as an effective treatment for trigger finger. One common side effect, the flare reaction, is a well-documented phenomenon of increased pain following steroid injections. Its incidence and intensity may be related to steroid composition. The purpose of this study was to determine whether betamethasone and methylprednisolone injections for trigger fingers have differing intensity of pain or incidence flare reaction. Patients with symptomatic trigger finger were recruited during their hand surgery visits. Patients were randomized into 2 treatment groups: betamethasone (40 mg) and methylprednisolone (6 mg) mixed with lidocaine 1%. Treatment group assignment was blinded to the patients and investigators. Visual analog scale pain measurements were taken prior to injection, 5 minutes postinjection, and daily thereafter for 7 days. Sixty-four patients were randomized into the 2 treatment groups. Patients in the betamethasone group reported slightly higher baseline pain compared with the methylprednisolone group, but lower pain on day 1. None of the following days showed a statistically significant difference. The incidence of flare and severe flare reactions of betamethasone injections for trigger finger management was roughly double that of methylprednisolone, but this difference was not statistically significant. Further studies are required to evaluate the relative course of nonflare postinjection pain for different corticosteroid injections for trigger finger injections.

Comparison of triamcinolone and methylprednisolone efficacy and steroid flare reaction rates after shoulder corticosteroid injection: a prospective interrupted time series study.

A corticosteroid flare reaction is a well-described phenomenon that causes significant pain and dysfunction. The paucity of literature impedes decision making regarding which corticosteroid to use for shoulder injection. The purpose of this study was to compare methylprednisolone acetate (MPA) and triamcinolone acetonide (TA) injections in the glenohumeral joint and/or subacromial space in terms of efficacy and the incidence of steroid flare reactions. In this prospective, interrupted time series, parallel study, patients received injections in the glenohumeral joint and/or subacromial space. MPA and TA were used during 2 discrete 3-month periods. The injections consisted of 2 mL of lidocaine, 2 mL of bupivacaine, and 80 mg of either MPA or TA. Visual analog scale (VAS) pain scores were recorded immediately before injection; 1-7 days after injection; and 3, 6, and 12 months after injection. The primary outcome was the incidence of a steroid flare reaction, defined as a post-injection increase in the VAS score by ≥2 points. The secondary outcome was injection failure, defined as a post-injection VAS score greater than the baseline score or the need for another intervention. We used linear mixed models with a patient-level random intercept to identify the mean VAS score change for TA injections in the first week after injection. MPA or TA shoulder injections were administered in 421 patients; of these patients, 15 received bilateral-joint injections whereas 406 received a single-joint injection, for a total of 436 injections (209 MPA and 227 TA injections). Pain scores in the first week after injection were available for 193 MPA and 199 TA injections. Significantly more patients in the MPA cohort reported flare reactions compared with the TA cohort (22.8% vs. 4.0%, P<.001) during the first week after injection. In the first week after injection, the mean VAS score of patients receiving TA injections was 1.05 (95% confidence interval, 0.47-1.63) lower than that of patients receiving MPA injections when adjusted for age, sex, race, pain type, surgeon type, and injection site. At 3 months, surveys for 169 MPA and 172 TA injections were completed, with no significant difference in the rate of injection failure for MPA vs. TA (42.6% vs. 36.1%, P=.224). Treatment failure rates were significantly higher for MPA than for TA at 6 months (78.44% vs. 62.5%, P<.001) but not at 12 months (81.18% vs. 81.42%, P=.531.) CONCLUSION: TA injections resulted in a >5-fold reduction in steroid flare reactions, with statistically superior 6-month efficacy rates, compared with MPA injections. This study supports TA as a more viable corticosteroid option for shoulder injection.

Effectiveness and safety outcomes in patients with EBV+ PTLD treated with allogeneic EBV-specific T-cell immunotherapy (tabelecleucel) under an expanded access program (EAP) in Europe.

7521 Background: Pts with relapsed or refractory (r/r) EBV+ post-transplant lymphoproliferative disease (PTLD) in Europe have had historically poor overall response rates and median overall survival (OS) with no approved treatment options. Tabelecleucel, an off-the-shelf, allogeneic EBV-specific T-cell immunotherapy has shown clinical benefit and favorable safety profile in the treatment of EBV+ PTLD failing rituximab ± chemotherapy (Prockop EBMT 2021, ATC 2021, ASH 2022). Its recent European marketing authorization (EMA) represents the first approval of an allogenic T-cell immunotherapy globally. Methods: Atara Bio supported expanded access requests for tabelecleucel in Europe. Here we report updated effectiveness and safety data for r/r EBV+ PTLD pts who provided consent for research between Sep 2020 and Dec 2022. Results: 74 EAP requests were received from 10 countries for pts with r/r EBV+ diseases. 27 EBV+ PTLD pts consented to secondary use of data and 24 pts had received ≥1 dose of tabelecleucel, including 4 pts with primary central nervous system (PCNS) PTLD. 16 of 24 (66.7%) PTLD pts achieved a partial (PR) (33.3%) or complete (CR) (33.3%) response, with median time to response (TTR) of 1.0 mo (0.8–2.2). Response rate for PCNS PTLD pts was 75% (1 CR, 2 PR). 1-yr OS Kaplan–Meier (KM) estimate rates were 73.7% (95% CI: 47.3, 88.3) overall, 87.5% in allogeneic hematopoietic stem cell transplant (HCT) and 66.5% in solid organ transplant (SOT), with a median follow-up time of 9.9 (2.4–13.9) and 6.0 (0.7–18.0) mo, respectively. Serious treatment-emergent adverse events (TESAEs) were reported in 7 (29.2%) pts, including 1 fatal event of disease progression. Predefined risks for tabelecleucel were reported in 3 pts; 1 (4.2%) SOT pt had a TESAE of liver transplant rejection (grade 2) and 2 (8.3%) HCT pts had non-serious TEAEs of chronic graft-versus-host disease (grade 1 and 2). No cases of cytokine release syndrome or tumor flare reaction were reported. No AEs were reported as related to tabelecleucel by the treating physician. Conclusions: These updated real-world results for pts with r/r EBV+ PTLD post-HCT or post-SOT treated in the European EAP continue to reinforce the favorable risk:benefit profile of tabelecleucel and are in line with clinical study data supporting its recent EMA approval. [Table: see text]

DIAGNOSIS AND OUTCOMES OF 225 CONSECUTIVE CASES OF CRPS OF THE HAND.

The lack of specific tests and potential diagnostic inaccuracy may be behind the stunning figures of complex regional pain syndrome (CRPS) cases. The author tested the hypothesis that patients "diagnosed with" CRPS at referral could be assigned to recognized conditions and treated accordingly. From January 2018 to April 2021, 225 consecutive patients attended the author's office having been diagnosed with and treated for CRPS for an average of 16±26 months. There were 180 females and 45 males - no patient was excluded. All patients could be allocated in named conditions: 79 had a wrong diagnosis; 7 had a true causalgia; 16 were dystonic-psychogenic hands; 20 presented a flare reaction; and 90 had an "irritative" carpal tunnel syndrome. The remaining 13 patients had a miscellany of symptoms within a substandard management setting. Surgery was offered to 175 with a correctable cause; 50 (20 of whom had a tangible cause responsible for their pain) declined and their outcome is unknown. The remaining 125 were operated and tracked for an average of 20±9 months. In the operated group, pain dropped 7.5±2.2 points (p<0.0001) on a numerical rating scale of 0 to 10. Disabilities of the Arm, Shoulder and Hand (DASH) scoring fell from 80 to 16 (p<0.0001). Operated patients rated their satisfaction on a scale of 0 to 10 as 8.9±1.9. . Unlike CRPS, all patients in this series had a true, diagnosable condition explaining their clinical picture. Most patients who accepted to be operated had a favorable outcome.

Effect of glycerin on immediate cutaneous reactions of histamine (positive) and phosphate-buffered saline (negative) controls in intradermal skin testing of healthy dogs: A randomised, blinded study.

Glycerinated allergen extracts contain 50% glycerin, an excellent preservative. While glycerin is a recognised irritant in humans, the utility of glycerinated extracts for intradermal testing has not been validated in dogs. To determine and compare the effects of glycerin on immediate cutaneous reactions to intradermal injections of histamine and saline in healthy dogs. Eight healthy laboratory beagles. The study was designed as a randomised, blinded study. Intradermal injections of histamine (positive control) and saline (negative control) in aqueous and glycerinated (50%) forms were performed on the right thorax. Global wheal scores (GWS) at 20 min were evaluated by two independent investigators blinded to the interventions. There were no wheal and flare reactions observed after the intradermal injections of phenolated saline. By contrast, 50% glycerosaline injections induced erythema and induration in all dogs. Global wheal scores were significantly higher in aqueous histamine (Friedman test, p< 0.0001) and 50% glycerinated histamine (Friedman test, p= 0.0084) compared to phenolated saline controls. Interestingly, only aqueous histamine (Friedman test, p= 0.01) had significantly higher GWS than 50% glycerosaline injections, while no significant difference in GWS between 50% glycerinated histamine and 50% glycerosaline groups was observed (Friedman test, p= 0.59). This study demonstrates that intradermal injection of 50% glycerosaline induces erythema and induration skin reactions in healthy dogs that can mimic positive reactions to allergenic extracts. Further dilutions of glycerinated positive and negative control solutions need to be optimised for intradermal testing in dogs.

Myricetin alleviated immunologic contact urticaria and mast cell degranulation via the PI3K/Akt/NF-κB pathway.

Immunologic contact urticaria (ICU) is characterized by the wheal and flare reaction from direct contact with a chemical or protein agent, which involves a type I hypersensitivity mediated by allergen-specific immunoglobulin E (sIgE). Myricetin (Myr), a bioactive flavonoid, exhibits antiinflammatory activities. Our results showed that treatment with Myr could alleviate ICU symptoms, including a decrease in the number of wheals and scratching, and inhibit ear swelling in the IgE/DNFB-induced mice. The serum level of IgE, histamine, interleukin (IL)-4, TNF-α, and MCP-1 were reduced in Myr-treated mice. Myr also attenuated mast cells (MCs) degranulation and H-PGDS, TSLP, IL-33, PI3K, Akt, and NF-κB mRNA levels in ICU model. The IgE-mediated anaphylaxis mouse models demonstrated anti-allergic effects of Myr. In vitro analysis showed that Myr reduced IgE-induced calcium (Ca2+ ) influx, suppressed degranulation, and chemokine release in LAD2 cells (human primary mast cells). Myr can significantly inhibited PLCγ1, Akt, NF-κB, and p38 phosphorylation. In conclusion, the study demonstrated that Myr alleviate ICU symptoms and inhibit mast cell activation via PI3K/Akt/NF-κB signal pathway.

Ethical Considerations Surrounding Employment Mandated Coronavirus Disease 2019 Vaccination and Allergy Skin Testing for the Coronavirus Disease 2019 Vaccine.

Ethical Considerations Surrounding Employment Mandated Coronavirus Disease 2019 Vaccination and Allergy Skin Testing for the Coronavirus Disease 2019 Vaccine.

Opioid toxicity: histamine, hypersensitivity, and MRGPRX2.

Insights into the pathophysiology of many non-immune-mediated drug reactions referred to as toxicities, sensitivities, intolerances, or pseudoallergies have resulted from research identifying the mastocyte-related G-protein-coupled receptor (GPCR) member X2 (MRGPRX2), a human mast cell receptor mediating adverse reactions without the involvement of antibody priming. Opioid-induced degranulation of mast cells, particularly morphine, provoking release of histamine and other preformed mediators and causing hemodynamic and cutaneous changes seen as flushing, headache and wheal and flare reactions in the skin, is an example of results of MRGPRX2 activation. Opioids including morphine, codeine, dextromethorphan and metazocine as well as endogenous prodynorphin opioid peptides activate MRGPRX2 at concentrations causing mast cell degranulation. Unlike the canonical opioid receptors, MRGPRX2 shows stereochemical recognition preference for dextro rather than levo opioid enantiomers. Opioid analgesic drugs (OADs) display a range of histamine-releasing potencies from the strong releaser morphine to doubtful releasers like hydromorphone and the non-releaser fentanyl. Whether there is a correlation between histamine release by individual OADs, MRGPRX2 activation, and presence or absence of adverse cutaneous effects is not known. To investigate the question, ongoing research with recently pursued methodologies and strategies employing basophil and mast cell tests resulting from MRGPRX2 insights should help to elucidate whether or not an opioid's histamine-releasing potency, and its property of provoking an adverse reaction, are each a reflection of its activation of MRGPRX2.

S256: TABELECLEUCEL FOR EBV-DRIVEN POST-TRANSPLANT LYMPHOPROLIFERATIVE DISEASE FOLLOWING ALLOGENEIC HEMATOPOIETIC CELL OR SOLID ORGAN TRANSPLANT AFTER FAILURE OF RITUXIMAB ± CHEMOTHERAPY (ALLELE)

Background: Tabelecleucel is an investigational, off-the-shelf, allogeneic Epstein–Barr Virus (EBV)-specific T-cell immunotherapy being explored in patients (pts) with EBV-driven post-transplant lymphoproliferative disease (EBV+ PTLD). Median overall survival (OS) after rituximab (R) ± chemotherapy (C) failure is 0.7 months in EBV+ PTLD post allogeneic hematopoietic cell transplant (HCT) (Sanz ASH 2021) and 4.1 months post solid organ transplant (SOT) after R+C failure (Dharnidharka ASH 2021), demonstrating an urgent need for therapies in this ultra-rare disease. Tabelecleucel has shown promising outcomes (Prockop JCI 2020). Additionally, an investigator-assessed objective response rate (ORR) of >60% with >80% 2-year OS (Prockop EBMT 2021, Prockop ATC 2021, Prockop ASH 2021) was seen in pts with relapsed/refractory (R/R) EBV+ PTLD, with either complete or partial response to tabelecleucel. Safety data in >180 pts with tabelecleucel treated EBV+ PTLD demonstrate tumor flare reaction (TFR) as the only identified risk (Atara Biotherapeutics, Data on file). Aims: Report data from the ongoing Phase 3 ALLELE study (NCT03394365). Methods: ALLELE is a multicenter, open-label study investigating tabelecleucel in pts with EBV+ PTLD post HCT after R failure (n=33) and post SOT after R±C failure (n=33). Pts receive tabelecleucel at 2 x 106 cells/kg on Days 1, 8 and 15 in 35-day cycles. Response is evaluated by investigator and by independent oncologic response adjudication (IORA; primary assessment) using Lugano Classification with LYRIC modification. Efficacy endpoints include ORR, duration of response (DOR), time to response (TTR), and OS. Pts are assessed post treatment for up to 5 years for survival. Results: As of May 2021, 38 pts (14 HCT, 24 SOT) were evaluable by IORA and had the opportunity for 6 months follow-up. Median age was 52.9 (range, 3.2–81.5) years, 44.4%/47.2% of pts were high/intermediate risk per PTLD-adapted prognostic index, and median number of lines of prior systemic treatment was 1 (range, 1–5). R/R HCT and SOT pts received a median (range) of 3 (1–5) and 2 (1–6) cycles of tabelecleucel, respectively. ORR was 50.0% (19/38, 95% CI: 33.4, 66.6) overall, 50.0% (7/14, 95% CI: 23.0, 77.0) in HCT, and 50.0% (12/24, 95% CI: 29.1, 70.9) in SOT (Table). Overall, median TTR was 1.1 (0.7–4.7) months, 11 of 19 responders had DOR > 6 months, and median DOR was not reached (Table). Median OS was 18.4 (95% CI: 6.9, NR) months overall, not yet reached for HCT, and 16.4 (95% CI: 3.5, NR) months for SOT. 1-year survival rates were 61.1% (95% CI: 42.9, 75.0) overall, 66.8% (95% CI: 32.4, 86.6) for HCT, and 57.4% (95% CI: 35.2, 74.5) for SOT. Median OS was NR (95% CI: 16.4, NR) for responders and 5.7 (95% CI: 1.8, 12.1) months for non-responders. Responders had a higher 1-year survival rate vs non-responders: 89.2% (95% CI: 63.1, 97.2) vs 32.4% (95% CI: 12.1, 54.9) (Table). Serious treatment emergent AEs (TEAEs) and fatal TEAEs were reported in 57.1% and 7.1% of HCT and 62.5% and 16.7% of SOT pts respectively. No fatal TEAE was treatment related. There were no reports of TFR, infusion reactions, cytokine release syndrome, marrow rejection, or transmission of infectious diseases, and no events of graft vs host disease or organ rejection reported as related to tabelecleucel. Image:Summary/Conclusion: Tabelecleucel Phase 3 data show clinically meaningful outcomes and promising ORR and OS in a pt population with poor survival and no approved therapies. Tabelecleucel was well tolerated without evidence of safety concerns typically observed with other adoptive T-cell therapies.

Phase I dose escalation of LAVA-051, a novel bispecific gamma-delta T-cell engager (Gammabody), in relapsed/refractory hematological malignancies.

2577 Background: LAVA-051 is a 27kD humanized bispecific single domain antibody (VHH) that directly engages CD1d and the Vδ2-TCR chain of Vγ9Vδ2-T cells and additionally stabilizes the interaction between CD1d and type 1 NKT cells (Nature Cancer 2020;1:1054-1065) to mediate potent killing of CD1d-expressing tumor cells. By engaging innate-like T cell subsets with inherent antitumor activity, namely Vγ9Vδ2-T and type 1 NKT cells, LAVA-051 has the potential to combine high therapeutic efficacy with limited off-tumor toxicity. CD1d is expressed by tumor cells in the majority of patients with CLL (chronic lymphocytic leukemia) and MM (multiple myeloma), while expression in AML (acute myeloid leukemia) is most pronounced on (myelo)monocytic subtypes. Tolerability studies in non-human primates with cross-reactive surrogate bispecific γδ-T cell engagers showed a good safety profile without signs of CRS (cytokine release syndrome). Methods: This is an open label, accelerated titration design, phase 1/2a study in patients with relapsed/ refractory CLL, MM, and AML (NCT04887259). The phase 1 study starts with single-patient cohorts for the first 3 dose levels followed by a 3+3 design. The primary objectives of the study are to investigate the safety and tolerability of LAVA-051 and to determine its recommended Phase 2a dose (RP2D). Secondary objectives of the study include evaluation of PK, PD, immunogenicity, and preliminary antitumor activity. The (flat) starting dose was determined to be 0.45 µg. LAVA-051 is administered by IV infusion over 2 hours twice a week. Results: As of Feb 14, 2022, a dose level of 45 µg has been reached with no reports of CRS (ASTCT grading) or dose limiting toxicities (DLTs). Six patients in total have been treated with LAVA-051; 4 patients (2 MM, 2 CLL) were evaluable for DLTs during cycle 1 at dose levels 0.45 µg, 3 µg, 15 µg and 45 µg. Treatment emergent AEs (TEAEs) (CTCAEv5.0) were predominantly of grade 1 and 2 severity (e.g. fever, chills, and headache). One patient (45 µg) reported a grade 2 infusion related reaction (IRR) that lasted less than 12 hours following the first administration only. Frequency and severity of TEAEs did not increase with escalating doses and all TEAEs were reversible. One patient with CLL developed symptoms consistent with a tumor flare reaction during cycle 1, and continues on cycle 5 of treatment with stable disease at 15 µg. PK data indicate increasing drug exposure in correlation with increasing doses of LAVA-051, and PD data indicate a dose-dependent increase in LAVA-051 receptor occupancy of the Vγ9Vδ2-T cell receptor. Importantly, no consistent or significant changes in measured cytokines have been observed. Updated results will be presented at the congress. Conclusions: LAVA-051 has been well tolerated early in dose escalation with on-mechanism pharmacodynamics consistent with Vγ9Vδ2-T cell engagement. Clinical trial information: NCT04887259.

Severity of Flare Reactions in Diethylenetriamine Pentaacetate Chelations: Report on Different Immune Dampening Strategies in Clinical Practice.

The aim of this study was to report early clinical experience with various forms of immune dampening to mitigate the expected flare reaction in patients suffering from gadolinium deposition disease (GDD) receiving DTPA chelation. All patients were clinical subjects, and no prospective research was performed on them. The study included 31 consecutive patients (21 women; age, 46.2 ± 12.5 years). The diagnosis of GDD was clinically made. The severity of the flare over the week after each chelation session was rated on a scale from 1 to 10 (where 1 is negligible, 10 is intolerably severe). Patients were followed for up to 5 chelation sessions. Four immune dampening strategies were used: (1) no concurrent treatment; (2) antihistamine plus montelukast (AH); (3) steroid/antihistamine taper postchelation (SAHT); and (4) steroid/antihistamine extending from prechelation to 5 days postchelation (extended hypersensitivity medication regimen; EHMR). The data were analyzed with generalized linear mixed models and with linear regression. A total of 102 flare scores were obtained at different time points. Ten patients underwent 5 chelations. The severity of the flare after the first chelation was significantly higher in cases of no concurrent therapy (8.4 ± 2.6) and AH (7 ± 1.4) compared with SAHT (6 ± 1.3) and EHMR (5 ± 1.1). Patients who underwent SAHT and EHMR experienced less severity of flare after the first chelation (P = 0.0049 and P = 0.0005, respectively). Considering all time points, the results were also significantly better with SAHT and EHMR. Based on early clinical experience, EHMR seems to manage flare reactions in DTPA chelation well. This strategy may represent the first standard therapy in patients with GDD.

Disease Flare and Reactogenicity in Patients With Rheumatic and Musculoskeletal Diseases Following Two-Dose SARS-CoV-2 Messenger RNA Vaccination.

To evaluate disease flare and postvaccination reactions (reactogenicity) in patients with rheumatic and musculoskeletal diseases (RMDs) following 2-dose SARS-CoV-2 messenger RNA (mRNA) vaccination. RMD patients (n=1,377) who received 2-dose SARS-CoV-2 mRNA vaccination between December 16, 2020 and April 15, 2021 completed questionnaires detailing local and systemic reactions experienced within 7 days of each vaccine dose (dose 1 and dose 2), and 1 month after dose 2, detailing any flares of RMD. Associations between demographic/clinical characteristics and flares requiring treatment were evaluated using modified Poisson regression. Among the patients, 11% reported flares requiring treatment; there were no reports of severe flares. Flares were associated with prior SARS-CoV-2 infection (incidence rate ratio [IRR] 2.09, P=0.02), flares in the 6 months preceding vaccination (IRR 2.36, P < 0.001), and the use of combination immunomodulatory therapy (IRR 1.95, P < 0.001). The most frequently reported local and systemic reactions included injection site pain (87% after dose 1, 86% after dose 2) and fatigue (60% after dose 1, 80% after dose 2). Reactogenicity increased after dose 2, particularly for systemic reactions. No allergic reactions or SARS-CoV-2 diagnoses were reported. Flares of underlying RMD following SARS-CoV-2 vaccination were uncommon. There were no reports of severe flares. Local and systemic reactions typically did not interfere with daily activity. These early safety data can help address vaccine hesitancy in RMD patients.

Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein-Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Multicenter, Open-Label, Phase 3 Study of Tabelecleucel for Solid Organ or Allogeneic Hematopoietic Cell Transplant Recipients with Epstein-Barr Virus-Driven Post Transplant Lymphoproliferative Disease after Failure of Rituximab or Rituximab and Chemotherapy (ALLELE)

Microinjection of pruritogens in NGF-sensitized human skin

Single intradermal injections of nerve growth factor (NGF) evoke prolonged but temporally distinct sensitization patterns to somatosensory stimuli. Focal administration of the non-histaminergic pruritogen cowhage but not histamine resulted in elevated itch at day 21 after NGF administration. Here, we injected bovine adrenal medulla peptide 8–22 (BAM8–22), β-alanine (β-ALA) and endothelin-1 (ET-1) into NGF-treated skin of 11 healthy volunteers and investigated the corresponding itch/pain and flare reactions. β-ALA was the weakest pruritogen, while BAM8–22 and ET-1 were equally potent as histamine. NGF did not sensitize itch or flare reactions induced by any compound, but injection and evoked pain were increased at day 21 and 49. The involvement of histamine H1 receptors in itch was explored in eight subjects after oral cetirizine. ET-1-induced itch and flare were significantly reduced. BAM8–22 and β-ALA itch were not affected, but flare responses after BAM8–22 reduced by 50%. The results indicate that a single NGF injection does not sensitize for experimentally induced itch but increases pain upon pruritogen injection. In healthy humans, pruritic and algetic processing appear differentially regulated by NGF. However, in patients suffering chronic itch, prolonged elevation of NGF-levels under inflammatory conditions may contribute to elevated itch.

Recurrence of Tumor Flare Reaction in a Chronic Lymphocytic Leukemia Patient During ChlorambucilRituximab Treatment 6 Years After Lenalidomide

Recurrence of Tumor Flare Reaction in a Chronic Lymphocytic Leukemia Patient During ChlorambucilRituximab Treatment 6 Years After Lenalidomide