Adequate Bone Research Articles

Outcomes of Selective Arthrodesis Based on Joints Affected in 33 Feet With Müller-Weiss Disease

No consensus exists regarding operative treatment of Müller-Weiss disease (MWD). Its only classification is based solely on Méary's angle and serves neither as guide to management nor prognosis. We report on 33 feet that underwent surgery following failed conservative management. Treatment was directed towards joint(s) involved, as determined by clinical examination, plain radiography and SPECT-CT. Thus, surgery consisted of isolated talonavicular in 6 feet, triple in 8, subtalar and talonavicular in 7, talonaviculocuneiform in 4, talonaviculocuneiform with interpositional tricortical iliac crest graft in 6 and pantalar arthrodesis in 2. PROMIS scores for pain interference and depression decreased significantly (p < .001) with significant accompanying increase in physical function (p = .003). Union occurred in 31 of 33 feet (94%) with complete resolution of pain at an average follow-up of 84 months. Of the 2 nonunions, 1 had fracture through the lateral navicular, and the other marked sclerosis and avascularity of the lateral navicular. We describe our pathways for selecting arthrodesis based on the joints affected. Isolated talonavicular arthrodesis was performed in early stages of MWD, which begins at the talonavicular articulation. When disease extended to both sides of the navicular, we performed talonaviculocuneiform arthrodesis. When considering isolated talonavicular, double medial or triple arthrodesis, there should be adequate cancellous bone stock remaining in the lateral part of the navicular, as determined on medial oblique radiographs and CT scan. In case of inadequate bone stock or fracture through the lateral navicular, talonaviculocuneiform arthrodesis with interpositional iliac crest bone graft is recommended.

Nivolumab and Ibrutinib for Treatment of Patients with Refractory or Relapsed Central Nervous System Lymphoma

Background: Central Nervous System (CNS) lymphoma is a distinct entity of large B-cell lymphoma (LBCL) with a unique genomic profile with similarities to the activated B-cell (ABC) subtype, which may offer potential targets for therapy. These aberrancies commonly include MYD88 mutations, which enhances sensitivity to Bruton's tyrosine kinase (BTK) inhibitors, and translocation or copy number alterations of 9p24, which may associate with sensitivity with programmed death (PD)-targeted therapies. Expression of PD-L1 is common in CNS lymphoma and tumor infiltrating lymphocytes, and the majority of CNS lymphomas have a copy gain of 9p24.1. This suggests an attenuated immune response against CNS lymphoma. Ibrutinib in combination with nivolumab has shown safety and clinical activity in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukemia in a phase 1/2 trial, and therefore we hypothesized that this combination may be active in CNS lymphoma. Methods: We conducted an investigator-initiated, open label, single center, phase 2 clinical trial combining ibrutinib with nivolumab to treat patients with relapsed CNS lymphoma (NCT03770416). Adult patients were eligible if they had CNS lymphoma (primary or secondary) refractory to or relapsed after at least 1 prior CNS directed therapy, with adequate organ and bone marrow function, without prior ibrutinib or PD1 inhibitor therapy, and did not require persistent high dose steroids. The trial had two sequentially enrolled cohorts: Cohort A included ibrutinib 560mg oral daily for one cycle (28-days per cycle), followed by ibrutinib combined with nivolumab 240mg IV every 14 days. Cohort B included ibrutinib and nivolumab during the first cycle. Patients with a partial response or greater after 6 cycles of combined ibrutinib and nivolumab could continue therapy for up to 2 years or until progression of disease or unacceptable toxicity occurs. The primary objective was to determine the best overall response rate (ORR) of ibrutinib and nivolumab. Secondary objectives included the ORR of ibrutinib as a lead in prior to the combination, best complete response (CR) rate, landmark survival outcomes, and the safety of the combination. The trial planned to enroll 20 patients in both cohort A and B, but closed early due to slow accrual, due in part to the COVID19 pandemic. Results: The trial accrued 18 patients from February 2019 to June 2022, with all patients evaluable for response. The median age was 63 years (range 43-88), 33% were &amp;gt;70 years, and 78% were female. 89% had primary CNS lymphoma, 50% had non-GCB, 22% had GCB, and 28% were unable to be classified due to missing components of the Hans algorithm. The median number of prior lines of therapy was 2 (range, 1-4), 55% had refractory disease, 17% had prior stem cell transplant, and 11% had prior CAR T-cell therapy. 10 patients were enrolled to Cohort A (ibrutinib lead in), and 8 patients were enrolled to Cohort B (initial combination therapy). Adverse events included 50% with fatigue, 33% with nausea, and 28% with mucositis. For both cohorts, the best ORR was 77.8% (95% CI: 52~94%) and the best CR rate was 50% (95% CI: 26-74%). In cohort A, the ORR of ibrutinib as a lead in after 1 cycle was 90% (95% CI: 55.5-99.7%), and the CR rate was 60%. In GCB patients (n = 4), the ORR and CR rates were 25%. In non-GCB patients (n =9), the ORR and CR rates were 100% and 56%, respectively. With a median follow up time of 34.6 months, the median overall survival (OS) was 25.4 months (95% CI 12.5-NR), and the OS rate at 12 months was 70%. The median progression free survival (PFS) was 6.6 months (95% CI: 2.9 - NR), and the PFS rate at 18 months was 47%. 4 patients withdrew from protocol therapy in CR, including 2 who proceeded to stem cell transplant consolidation, and 2 who stopped due to fatigue. 3 patients withdrew from protocol therapy in PR, 2 due to mucositis and 1 due to arthralgias. 1 patient died of COVID19 infection with a CR after 4 cycles of therapy. Conclusion: Ibrutinib and Nivolumab resulted in significant clinical activity in patients with refractory/relapsed CNS lymphoma. Our trial is limited by small patient numbers but suggests the potential for targeted therapy combinations in future larger clinical studies.

Novel Chemotherapy-Free Initial Treatment of Rituximab Biosimilar Plus Pegylated Interferon α-2b in Pts with Untreated Advanced Indolent B-Cell Non-Hodgkin's Lymphoma: Results of the Ripple 3-Year Follow-up Study

Background: Indolent B-cell lymphoma (iBCL) are clinically heterogeneous and accounts for 10-15% of all kinds of subtypes in NHL in China. Although iBCL have a relatively good survival, majority of these lymphomas is considered incurable. The favorable activity and safety profile of rituximab monotherapy in the initial treatment of iBCL has been proven. Interferon alpha (IFN-α) was effective in modulating immune responses and may enhance the clinical efficacy of rituximab in vitro and in vivo studies. Clinical combination of rituximab and conventional IFN-α was associated with fewer early treatment failures compared to single agent rituximab. Peginterferon-α-2(peg-IFN-α2) has a longer half-life with less toxicity. It is also recommended as one of the therapeutic options for chronic hepatitis B virus (CHB) infection. The RIPPLE study (ClinicalTrials. gov identifier: NCT04246359) was initiated to evaluate the efficacy and safety of rituximab plus pegylated interferon α-2b for treatment-naive patients with iBCL. This publication provides long-term follow-up data. Methods: This trial enrolled pts aged 18-80 years with newly diagnosed iBCL including follicular lymphoma (FL, grade 1-2,3a), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL), small lymphocytic lymphoma (SLL). Pts were eligible if they had ECOG ≤ 2, adequate organ function and bone marrow function, and at least one measurable or evaluable lesion. Further eligibility criteria were HBsAg positivity with HBV DNA load &amp;lt;3000 IU/mL prior to study; serum ALT level of &amp;lt;5 times the upper limit of normal. During induction phase, pts received rituximab biosimilar (Henliritux ® Shanghai Henlius Biotech) 375 mg/m 2 intravenous infusion on d1. Peg-IFN-α2b (Pegberon ®, Xiamen Amoytop Biotech) was given at a dose of 135ug, subcutaneously, on d1,8. The combination repeated every 21 days for 6 cycles. Responded pts receive rituximab (every 2 months) plus peg-IFN-α2b (every month) maintenance at the dose described above, for up to 2 years until disease progression and intolerance. Simultaneously, CHB pts orally treated with entecavir continuously. The primary endpoint is ORR assessed by investigators per Lugano 2014 criteria. Key secondary endpoints included TTR, DOR, PFS, OS, HBV DNA load clearance, and safety. Adverse events (AEs) were summarized according to NCI CTCAE v5.0. Results: From September 2018 to July 2021, 57 eligible pts with median age of 54 (range, 29-75) years were enrolled from 6 institutions in China. Thirty (56.1%) are female, 21(36.8%) pts were symptomatic and 22(38.6%) pts with FLIPI score≥3, 6(10.5%) pts suffer from hepatitis B with HBV DNA load &amp;lt;3000 IU/mL at study entry. At cutoff date, there were 26(45.6%) FL (grade 1-2), 21(36.8%) MALT, 7(12.3%) FL (grade 3a) , 2(3.5%) SLL, 1(1.8) LPL pts enrolled. Of 57 response evaluable pts, 38(66.7%) pts achieved an objective response including 29(50.9%) pts with CR based on investigators. ORR were 69.2% (18/26), 71.4% (5/7), 61.9% (13/21), 0, 100% (2/2) and the CR rates were 46.2% (12/26), 71.4% (5/7), 52.4% (11/21), 0, 50% (1/2) for FL (grade 1-2), FL (grade3a), MALT, LPL, SLL, respectively (Figure 1-2). Median HBV DNA load clearance time was 1.8 months (1.3-2.1months), no hepatitis B virus reactivation reported. With median follow-up time was 34.2 months (IQR:26.5-42.3 months), median OS, PFS and DoR was not reached; 3-years OS and PFS rate of whole cohort was 92.5%, 70.4%, respectively (Figure 3 C-D). Median TTR was 3.0months (1.5-5.2months). The most common treatment-emergent adverse events (TEAEs) were hematological relevance toxicities. The most common hematological TEAEs (&amp;gt;30%) were neutropenia 63.2% (36/57), anemia 36.5% (19/57), thrombocytopenia 29.8% (17/57). Non-hematological TEAEs (&amp;gt;10%) were fever (28.1%, 16/57), transaminase elevated (26.3%, 15/57), fatigue (26.3%, 15/57), infusion reaction (21.7%, 10/46). No treatment-related death occurred. Conclusion: Rituximab biosimilar plus pegylated interferon α-2b provided favorable response in newly diagnosed advanced iBCL with mild toxicity. No hepatitis B virus reactivation was observed.

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Tafasitamab and Lenalidomide in People with Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 molecule designed to enhance phagocytosis and antitumor activity by preventing CD47-mediated inhibitory signaling. Maplirpacept currently is being evaluated in an ongoing, multi-center, two-part, Phase 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05626322), to evaluate the effects of maplirpacept, in combination with tafasitamab and lenalidomide in participants with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients, and the study will be split into two parts (Figure 1). Phase 1b will determine the maximum tolerated dose or recommended Phase 2 dose (2 dose levels) of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide. In Phase 2, participants will be randomized to high or low doses of maplirpacept, in combination with approved doses of tafasitamab and lenalidomide, as per the Oncology Center of Excellence ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be administered in 28-day cycles. Maplirpacept will be given weekly, by intravenous (IV) infusion, for the first three cycles and subsequently every two weeks. Tafasitamab will be administered, by IV infusion, on Days 1, 4, 8, 15 and 22 in cycle 1, weekly in cycles 2 and 3, then every 2 weeks in cycle 4 and beyond. Lenalidomide will be taken orally, daily for Days 1 to 21 of each 28-day cycle, for the first 12 cycles. In Phase 1b, approximately 20 participants will be allocated to sequential doses of maplirpacept, co-administered with approved doses of tafasitamab and lenalidomide, to select doses for further assessment in Phase 2. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 28 days following the first dose. In Phase 2, approximately 50 participants will be randomized to 1 of 2 different doses of maplirpacept, co-administered with tafasitamab and lenalidomide. The primary endpoint for Phase 2 is objective response as per the Lugano Response Classification Criteria 2014. Secondary endpoints are frequency of adverse events, frequency of clinical laboratory abnormalities, objective response (Phase 1b only), complete response, duration of response, duration of complete response, progression free survival, maplirpacept, tafasitamab and lenalidomide PKs, and immunogenicity of maplirpacept and tafasitamab. Inclusion criteria (Table 1) are adults with histologically confirmed, measurable relapsed and/or refractory DLBCL not otherwise specified, T cell/histiocyte rich large B-cell lymphoma, or Epstein-Barr virus positive DLBCL according to the 5th edition of the WHO classification of lymphoid neoplasms. Additionally, participants with follicular lymphoma grade 3b, or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse are also eligible. Participants with evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible if relapsed or refractory to at least one line of therapy for DLBCL. Further inclusion criteria are participants who are not a candidates for, or are unwilling to receive, high-dose chemotherapy and subsequent stem cell transplant and/or are unable to undergo chimeric antigen receptor T-cell (CAR-T) therapy (e.g. due to logistical limitations), treatment with at ≥1 prior line of systemic therapy (for Phase 2, at least 1, and no more than 2, prior lines of systemic therapy) and prior therapy must include an anti-CD20 antibody. Participants must have adequate bone marrow, renal and hepatic function and an Eastern Cooperative Oncology Group performance status ≤2. Participants must provide a baseline tumor tissue sample (fresh or archival), for biomarker analysis. Exclusion criteria include previous treatment with anti-CD47, anti-CD19 (other than CAR-T) or immunomodulatory agents, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, and participants with active, uncontrolled viral, bacterial or fungal infections.

Narrative Review of Effects of Glucagon-Like Peptide-1 Receptor Agonists on Bone Health in People Living with Obesity.

Glucagon-like peptide-1 Receptor agonists (GLP-1Ras) such as liraglutide and semaglutide have been recently approved as medications for chronic weight management in people living with obesity (PwO); GLP-1 may enhance bone metabolism and improve bone quality. However, the effects of GLP-1Ras on skeletal health remain to be determined and that's the purpose of this narrative review. Nevertheless, bone consequences of intentional weight loss interventions in PwO are well known: (i) significant weight loss induced by caloric restriction and bariatric surgery results in accelerated bone turnover and bone loss, and (ii) unlike caloric restriction interventions, PwO experience a substantial deterioration in bone microarchitecture and strength associated with an increased risk of fracture after bariatric surgery especially malabsorptive procedures. Liraglutide seems to have a positive effect on bone material properties despite significant weight loss in several rodent models. However, most of positive effects on bone mineral density and microarchitecture were observed at concentration much higher than approved for obesity care in humans. No data have been reported in preclinical models with semaglutide. The current evidence of the effects of GLP-1Ra on bone health in PwO is limited. Indeed, studies on the use of GLP-1Ra mostly included patients with diabetes who were administered a dose used in this condition, did not have adequate bone parameters as primary endpoints, and had short follow-up periods. Further studies are needed to investigate the bone impact of GLP-1Ra, dual- and triple-receptor agonists for GLP-1, glucose-dependent insulin releasing polypeptide (GIP), and glucagon in PwO.

Augmentation of single tooth extraction socket with deficient buccal walls using bovine xenograft with platelet-rich fibrin membrane

BackgroundDifferent techniques and materials such as bone grafts and bioactive agents have been used for alveolar ridge augmentation in extraction sockets with a defective wall, there is not a specific material or technique that has resulted in superior outcomes or prevented total bone loss.ObjectivesThis clinical study aims to evaluate radiographically the effectiveness of using bovine xenograft with platelet-rich fibrin (PRF) membrane on vertical and horizontal alveolar ridge dimensional changes following tooth extraction that are complicated by buccal bone loss.Materials and methodsThis study was conducted in Egypt on fourteen patients with a single posterior tooth indicated for extraction. A preoperative cone-beam computed tomography (CBCT) scan confirmed more than 50% loss in buccal bone in each tooth. Extraction sockets were packed with minced PRF clots mixed with a bovine xenograft. Each extraction socket was sealed by PRF membranes. CBCT scans, performed before tooth extraction and after 6 months, were used to assess alveolar ridge changes both vertically and horizontally.ResultsThere was a significant gain in the buccal and middle of the extraction socket bone height, recording 86.01% (6.33 mm) and 206.45% (9.6 mm), respectively. There was an insignificant bone loss in the lingual bone height and width, recording − 8.49% (-1.06 mm) and − 13.39% (1.05 mm), respectively. The results also showed a non-significant decrease in alveolar bone density (-14.06%) between pre-operative bone present apical to the extraction socket and newly formed bone inside the socket.ConclusionsRidge preservation/augmentation techniques using a bone graft mixed with PRF and covered by PRF membranes in fresh extraction sockets complicated by the loss of buccal bone result in buccal bone augmentation and a reduction in horizontal and vertical ridge collapse after tooth extraction.Clinical relevanceThe bovine xenograft in conjunction with PRF can be used immediately after extraction for ridge preservation, providing adequate bone width and height for implant placement.

Bicortical stability of implants placed in severely atrophic posterior maxilla: A case report

Maxillary sinus lift is a common procedure to achieve adequate alveolar bone height in patients with sinus hyper-pneumatization. Simultaneous implant placement with sinus floor augmentations is possible when appropriate primary stability could be achieved. In severe atrophic posterior maxillary ridge, vertical bone height is sometimes less than 4mm, which may hinder simultaneous implant placements and necessitate two stage procedure. In current study, a novel technique is described to perform a single stage implant placement with bicortical stability in severe atrophic maxilla that can shorten the treatment time of an edentulous patient. During the procedure, to achieve an adequate access a conventional lateral window osteotomy is performed. After elevating the Schneiderian membrane using conventional instruments, an autologous ramus block is harvested from the mandible and then the block will be fixed in correct location in the sinus using screws with appropriate length to build sufficient stability as superior cortex for simultaneous implant insertion.

RTID-08. A RANDOMIZED, MULTICENTER, DOUBLE-BLIND, PHASE 2B STUDY OF IGV-001, AN AUTOLOGOUS CELL IMMUNOTHERAPY WITH ANTISENSE OLIGO IMV-001 TARGETING IGF-1R, VS PLACEBO, IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS

Abstract Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has developed the Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. IGV-001 was well tolerated and multiple efficacy signals were observed in a Phase 1b study in patients with ndGBM, including significant improvements in progression-free survival (PFS), radiographic evidence of tumor response, and changes in immune response biomarkers. A Phase 2b randomized, multicenter, double-blind, placebo-controlled study has been initiated to assess the safety and efficacy of IGV-001 in patients with ndGBM (NCT04485949). After surgical resection, patients will be treated with IGV-001 or placebo followed by SOC. 25 US sites have been selected with a target enrollment of 93 patients (2:1 randomization) and the study is open to enrollment. Key inclusion criteria are 18 to 70 years of age, Karnofsky performance status score ≥ 70, diagnosis of GBM based on the treating neurosurgeon's best clinical judgement, confirmed measurable disease pre-operatively, tumor located in the supratentorial compartment, and adequate bone marrow and organ function. Key exclusion criteria include bihemispheric disease, multicentric disease, or treatment with Tumor Treating Fields prior to documented progression. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety.

Smart Stop: Lenalidomide, Tafasitamab, Rituximab, and Acalabrutinib Alone and with Combination Chemotherapy for the Treatment of Newly Diagnosed Diffuse Large B-Cell Lymphoma

Background: Despite recent advances, first-line (1L) chemoimmunotherapy (CIT) for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is largely unchanged for decades.In the Smart Start trial, we established the feasibility of targeted chemotherapy-free 1L therapy with rituximab (R), lenalidomide (L), and ibrutinib, prior to chemotherapy in patients with newly diagnosed DLBCL with an overall response rate (ORR) and complete response rate (CRR) of 86% and 36%, respectively, prior to chemotherapy, and a 2 year progression free survival rate of 91.3% following 6 cycles of standard CIT (Westin et al, JCO 2023, PMID: 35952327). One patient withdrew from the study after achieving CR and prior to receiving CIT and remains in remission without further therapy at &amp;gt;4 years. BTK inhibitors like acalabrutinib (A) and the immunomodulatory agent L result in synthetic lethality in non-GCB DLBCL models. Both the CD20 antibody R and CD19 antibody tafasitamab (T) demonstrate clinical activity when combined with L in patients with DLBCL. L, T, R, and A are immunomodulatory, driving an anti-tumor immune response. Based upon these data, we are conducting the Smart Stop trial (NCT04978584) to evaluate if the number of CIT cycles can be reduced or omitted after response to targeted therapy, and now report the preplanned interim results from cohort 1. Methods: Eligibility criteria include patients who are 18y+ with previously untreated DLBCL (initially the Hans algorithm was used to select non-GCB DLBCL, but this criteria was removed this criteria) with adequate organ and bone marrow function. Patients with known CNS involvement of lymphoma, recent thrombosis, or inability to tolerate prophylactic anticoagulation are ineligible. Patients receive lenalidomide 25mg on days (d) 1-10, tafasitamab 12mg/kg IV d1, 8, and 15, rituximab 375mg/m2 IV d1, and acalabrutinib 100mg PO twice/d in a 21 day cycle. All patients receive LTRA for 4 cycles, followed by PET/CT scan (CR defined as a 5PS of 1, 2, or 3). In cohort 1, patients receive an additional 6 cycles of LTRA combined with a response adapted number of cycles of CHOP therapy. After 4 cycles of LTRA, patients with CR receive 2 cycles of CHOP, and all other patients receive 6 cycles of CHOP. In the upcoming cohort 2, patients with CR after 4 cycles of LTRA are planned to receive no cycles of CHOP. The primary objectives are to determine the 1A: ORR after 4 cycles of uLTRA and 1B: CRR at of LTRA +/-CHOP at the end of therapy. Results: Cohort 1 enrolled 30 patients from May 2022 - July 2023, with all patients expected to be evaluable for 1A endpoint and 22 patients (73%) evaluable for endpoint 1B by the ASH meeting. The median age was 61 years (range: 32-85), 30% were &amp;gt;= 70 years, and 50% were female. 67% of patients have poor risk R-IPI, 77% had advanced stage, and 83% had an elevated LDH. 83% had the non-GCB subtype and 17% had the GCB subtype of DLBCL. After 4 cycles of LTRA, the ORR is 100% and the CRR is 64% (endpoint 1A, n = 14/22 evaluable at abstract submission, figure 1 schema and swimmer plot). After an additional 2 cycles of LTRA-CHOP, the ORR is 100% and the CRR is 95% (n = 18/19 evaluable at abstract submission). At end of all therapy, the CRR is 100% (endpoint 1B, n = 12 evaluable at abstract submission), including 7 patients who received LTRA for 10 cycles and CHOP for 2 cycles (early CR) and 5 patients who received LTRA for 10 cycles and CHOP for 6 cycles. To date, no patient has progressive lymphoma, including the first 6 patients who have 3 and 6 month follow up scans. 47% of patients experienced rash (13% grade 3), and 40% of patients required a dose reduction of lenalidomide. Conclusions: The Smart Stop trial demonstrates that combination of lenalidomide, tafasitamab, rituximab, and acalabrutinib is highly effective as an initial chemotherapy-free combination in patients with newly diagnosed DLBCL, and may allow for a response adapted reduction in chemotherapy. Response and time to event data will be updated for presentation at the meeting. We will soon open cohort 2 which will enroll an additional 30 patients where those with early CR after 4 cycles of LTRA will receive no cycles of CHOP.

A Phase 1 Study Evaluating PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Select Relapsed/Refractory B-Cell Malignancies

Background and Significance: PRT2527 is an investigational, potent, and highly selective cyclin-dependent kinase 9 inhibitor that is being developed for select relapsed or refractory (R/R) hematologic malignancies. CDK9, a key regulator of transcription elongation, has been studied as a potential target for therapy in transcriptionally addicted cancers that are dependent on oncogenic drivers with short half-lives. Although most of these drivers do not respond to direct inhibition, studies suggest that a subset of drivers, eg MYC, MYB, and MCL-1, may be targeted indirectly via CDK9 inhibition. Several nonselective CDK9 inhibitors have shown clinical activity in multiple tumor types, however, tolerability was poor (Mandal, et al. Cancers (Basel). 2021). PRT2527 has demonstrated high specificity and promising antitumor activity in preclinical studies, and a favorable tolerability profile in preliminary data from a Phase 1 study (NCT05159518) in adults with advanced solid tumors. These support further development of PRT2527 in hematologic malignancies as monotherapy and in combination with targeted agents. Combination of CDK9 inhibition and Bruton tyrosine kinase (BTK) inhibition may drive a durable response by enhancing apoptotic priming and shifting dependency toward CDK9 targets MCL1 and BFL1. Zanubrutinib (BGB-3111) is a highly selective, potent, irreversible BTK inhibitor that upregulates the proapoptotic signaling molecule BCL2 modifying factor, an endogenous inhibitor of BCL2, BCLXL, and BCLW (Kong, et al. ChemMedChem. 2018). PRT2527 as monotherapy or in combination with zanubrutinib may be an effective treatment option for select R/R hematologic malignancies. Study Design and Methods: PRT2527-02 is a phase 1, open-label, multicenter, dose-escalation and dose-confirmation study evaluating safety, tolerability, recommended phase 2 dose (R2PD), and preliminary efficacy of PRT2527 as monotherapy and in combination with zanubrutinib in patients (pts) with select R/R hematologic malignancies. Pts eligible to receive PRT2527 monotherapy include those with aggressive B-cell lymphoma subtypes, mantle cell lymphoma (MCL), chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) including Richter syndrome, and T-cell lymphoma subtypes. Pts eligible to receive PRT2527 in combination with zanubrutinib include those with aggressive B-cell lymphoma subtypes, MCL, and CLL/SLL including Richter syndrome. Eligibility criteria include having relapsed or become refractory to standard-of-care therapy, measurable disease or requirement for treatment in accordance with disease-specific criteria for the hematologic malignancies under study, an ECOG PS of 0 to 1, and adequate bone marrow, renal, and liver function. Dose escalation will comprise successive cohorts receiving escalating doses of intravenous (IV) PRT2527 monotherapy once weekly (qw) in a 21-day cycle (cycle ≥2); pts at high risk for tumor lysis syndrome (TLS) and those receiving IV PRT2527 qw in combination with oral zanubrutinib 320 mg may have a 28- or 35-day ramp-up period during cycle 1. Dose escalation and de-escalation decisions will be guided by the prespecified Bayesian optimal interval design method based on dose-limiting toxicities (DLTs) observed in cycle 1. Dose confirmation will consist of indication-specific cohorts receiving the RP2D of PRT2527; pts at high risk for TLS and those receiving combination therapy may have weekly ramp-up dosing to reach RP2D. PRT2527 treatment will continue until disease progression or unacceptable toxicity, whichever comes first. The primary endpoints include safety, tolerability, DLTs, and RP2D of PRT2527 monotherapy and in combination with zanubrutinib. Adverse events will be assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. Secondary endpoints include objective response rate, duration of response, duration of complete response, and pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib. For descriptive analyses, continuous variables will be summarized by mean, standard deviation, median, minimum, and maximum. Response rates will be calculated with the 95% confidence interval. Time-to-event data will be analyzed using the Kaplan-Meier method. The study is open to enrollment and registered at ClinicalTrials.gov (NCT05665530).

Azacitidine Plus Venetoclax Maintenance in Acute Myeloid Leukemia Produces Sustained Remissions with Low Toxicity: Results of a Phase 2 Study

Background: Most patients diagnosed with acute myeloid leukemia (AML) achieve remission following induction therapy. However, disease relapse remains a major clinical concern. The QUAZAR AML-001 study demonstrated improved overall and relapse-free survival with oral azacitidine (CC-486) maintenance. We designed a phase 2 study (NCT04062266) to evaluate low doses of azacitidine plus venetoclax as maintenance therapy following both intensive and low-intensity induction in AML. We present updated results of this study with close to 2 years of median follow-up. Methods: Patients ≥ 18 years of age with non-APL AML in first complete remission (CR) or CR with incomplete count recovery (CRi) not immediately eligible for allogeneic stem cell transplantation (SCT) were eligible. Cohort 1 enrolled patients who had received at least 2 cycles of intensive therapy (defined as containing intermediate to high-dose cytarabine). Cohort 2 enrolled patients who had received at least 3 cycles of low-intensity therapy (defined as hypomethylating agent or low-dose cytarabine-based). Patients with positive measurable residual disease (MRD) by flow cytometry were eligible in CR1 or beyond. Other inclusion requirements were ECOG ≤ 3, adequate hepatic/renal function, and adequate bone marrow reserve (defined as absolute neutrophil count &amp;gt; 0.5 x 10 9/L and platelets &amp;gt; 30 x 10 9/L). Treatment consisted of azacitidine 50 mg/m 2 SQ/IV on D1-5 and venetoclax 400 mg PO (adjusted for concomitant CYP3A inhibitors) on D1-14 in 28-day cycles, up to 24 cycles. Venetoclax duration could be reduced to D1-7 per physician discretion to mitigate myelosuppression and dose modifications during subsequent cycles were allowed. Antibacterial, antifungal, and antiviral prophylaxis were recommended in all patients. The primary objective was relapse-free survival (RFS, defined as time from enrollment to progression or death). Secondary objectives included overall survival (OS), safety/toxicity, and MRD clearance. Patients subsequently becoming eligible for SCT were taken off study and censored for analyses at the time of SCT. Results: 35 patients have been enrolled (25 in cohort 1 and 10 in cohort 2). The median age was 47 years in cohort 1 and 71 years in cohort 2. The baseline characteristics are shown in table 1. The median number of cycles given was 9 (range 1-24). 22/35 (63%) patients had 7 days of venetoclax during cycle 1. Median follow-up is currently 20.9 months (m). For the full cohort, the median RFS was not reached (NR; 2-year 60%) and the median OS was NR (2-year 75%). In cohort 1, the median RFS and OS were NR (2-year 71%) and NR (2-year 77%), respectively. In cohort 2, the median RFS and OS were 23.5 m (2-year 34%) and NR (2-year 67%), respectively. When stratified by ELN 2017, patients who were favorable (n=16), intermediate (n=11), and adverse (n=8) had a median RFS of NR (2-year 85%), NR (2-year 64%), and 4.0 m (2-year 0%), respectively. Corresponding median OS were NR (2-year 91%), NR (2-year 76%), and 14.9 m (2-year 27%), respectively. 4/8 (50%) of the ELN adverse patients had complex cytogenetics and/or TP53 mutations. Patients who were MRD-positive at enrollment (n=7, 3 with prior venetoclax exposure) had significantly shorter RFS compared to those who were MRD-negative (median 4.0 m versus NR, p&amp;lt;0.01). Only 2/7 (29%) MRD-positive patients converted to MRD-negative while on maintenance. As mutations in NPM1, IDH1, or IDH2 may sensitize AML to venetoclax, we analyzed RFS based on the presence or absence of these mutations (figure 1). Patients with sensitizing mutations had a trend towards longer RFS (median RFS NR versus 23.5 m, 2-year RFS 79% vs 36%, p=0.08). The most common grade 3/4 adverse events were infections (26%), neutropenia (17%), thrombocytopenia (17%), hypotension (6%), and neutropenic fever (6%). 4 (11%) patients required cycle 2 venetoclax dose reductions. 8 (23%) of patients went off protocol to receive SCT. All observed deaths (n=8) occurred following AML relapse (n=7) or SCT-related complications (n=1). Conclusions: Lower dose azacitidine plus venetoclax is a feasible and safe maintenance strategy in AML. This approach yields encouraging results in MRD-negative patients with non-adverse ELN risk (favorable or intermediate risk). A genetic-guided strategy may help select patients who benefit the most from this combination (i.e. those with NPM1, IDH1, or IDH2 mutations).

A Phase II Study of Isatuximab in Combination with Pomalidomide and Dexamethasone in Patients with Multiple Myeloma Progressing on or after One Line of Lenalidomide-Containing Therapy

Introduction Relapse in patients (pts) with multiple myeloma (MM) is a common occurrence, resulting in a continued need for novel treatment approaches. Isatuximab (Isa), a monoclonal antibody (mAb), combined with pomalidomide (Pom) and dexamethasone (Dex), is indicated for the treatment of pts with relapsed/refractory multiple myeloma who have received ≥2 prior therapies including lenalidomide and a proteasome inhibitor and have demonstrated disease progression on the last therapy. The current study aims to evaluate the efficacy and safety of IsaPomDex in pts with MM relapsing for the first time after one line of treatment containing lenalidomide (Len). Methods EAE115 (NCT05298683) is an ongoing, investigator-initiated, phase II, prospective, open-label, multicenter study aiming to enroll 108 pts. Eligible pts are adults with documented MM who have evidence of progressive disease, by the International Myeloma Working Group criteria, on or after treatment with only one prior line of anti-myeloma therapy with lenalidomide (≥2 cycles, alone or in combination) and a proteasome inhibitor. Pts must also have adequate bone marrow and hepatic function and an Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with previous anti-myeloma therapy with any anti-CD38 mAb, pomalidomide, or stem cell transplant within 12 weeks before treatment initiation. Pts receive six 28-day cycles of Isa 10 mg/kg (once weekly [QW] by intravenous [IV] infusion on days 1, 8, 15, and 22 in cycle 1 and days 1 and 15 in subsequent cycles), Pom 4 mg (per Os on days 1-21, each cycle), and Dex 40 mg or 20 mg for pts ≥75 years old (per Os or IV on days 1, 8, 15 and 22, each cycle). Fifteen to 60 minutes before Isa infusions, patients receive pre-medications to mitigate potential infusion-related adverse reactions. Following initial 6 cycles, pts achieving at least very good partial response (VGPR) are randomized 1:1 to receive Isa (Q2W or Q4W) plus PomDex, and pts achieving &amp;lt;VGPR continue treatment with Isa (Q2W) plus PomDex. Treatment is given until progressive disease, death, unacceptable adverse events (AEs), lost to follow-up, or consent withdrawal. The study primarily evaluates the overall response rate (ORR; defined as partial response [PR] or better) to IsaPomDex therapy at six months. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty pts had received at least one dose by the cut-off date, of whom 16 (80.0%) were continuing with IsaPomDex treatment; four (20.0%) pts had discontinued due to physician or pt decision or progressive disease or death. At baseline (cycle 1, day 1), pts had a median age of 72.0 years (range: 60.0-85.0), 10 (50.0%) were male, and 13 (65.0%) had ECOG PS 0. Eleven (55.0%) pts were at stage II by the revised International Staging System, 9 (45.0%) pts had lytic bone lesions, 5 (25.0%) pts had high-risk cytogenetics, and 1 (5.0%) pt had soft-tissue plasmacytomas (Table 1). Regarding previous treatment outcomes, 14 (70.0%) pts had achieved ≥VGPR (stringent complete response, 2 [10.0%] pts; complete response, 2 [10.0%] pts; VGPR, 10 [50%] pts). Five (25%) and 1 (5.0%) pts achieved partial and minimal response, respectively. Six (30.0%) pts had received ASCT in the prior line. At a median follow-up of 3.4 (range: 0.6-6.1) months, the median number of IsaPomDex cycles received was 3.0 (range: 1.0-7.0); one (5.0%) pt received six treatment cycles. Of the 18 (90.0%) response evaluable pts (2 pts were ongoing without 2 efficacy assessments) VGPR and PR were achieved by 4/18 (22.2%) and 9/18 (50.0%) pts, respectively. ORR was achieved by 13/18 (72.2%) pts, and the median (range) time from IsaPomDex study dose to first response (≥PR) was 1.0 (range: 0.9-1.3) months. Thirteen (65.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these pts, 10 (50.0%) had a ≥1 grade (gr)≥3 TEAE and 4 (15.0%) had ≥1 gr ≥3 serious TEAE. The most common TEAEs were neutropenia in 9 pts (45.0%), anaemia in 3 pts (15.0%) and fatigue in 3 pts (15.0%). The most common gr ≥3 TEAE was neutropenia in 7 pts (35.0%) (Table 2). Conclusions Second-line treatment with IsaPomDex in pts with MM who have progressed on or after one Len-containing line of treatment appears to be effective, although longer follow-up is needed to assess its efficacy. No new safety signals were observed with the combination.

A Phase 2 Study of Isatuximab in Combination with Bortezomib, Cyclophosphamide, and Dexamethasone, Followed By Isatuximab and Lenalidomide Maintenance in Newly Diagnosed Patients with Multiple Myeloma and Severe Renal Impairment

Introduction Renal impairment (RI), a common complication of multiple myeloma (MM), is associated with increased risk of early death. Reversal of MM-associated RI is a key predictor of improved survival. Regimens containing bortezomib and dexamethasone are the treatment backbone for newly diagnosed (ND) patients (pts) with MM and severe RI, even those requiring dialysis. In the ICARIA-MM study, the addition of isatuximab (Isa) to pomalidomide and dexamethasone improved the renal response rate (RRR) in pts with relapsed/refractory MM and RI. We investigated the effect of induction treatment with Isa plus bortezomib, cyclophosphamide, and dexamethasone (VCd) on the renal function of pts with NDMM and severe RI. Additionally, we evaluate the efficacy and safety of IsaVCd induction, followed by Isa and lenalidomide (Len) maintenance. Methods EAE116 (NCT05147493) is an ongoing, investigator-initiated, phase II, prospective, open-label study aiming to enroll ~51 pts in six Greek hospitals. Eligible pts are adults with documented NDMM by International Myeloma Working Group (IMWG) criteria and severe RI (estimated glomerular filtration rate [eGFR] &amp;lt;30 ml/min/1.73m 2) or in need of dialysis. Pts must also have adequate bone marrow and hepatic function and Eastern Cooperative Oncology Group performance status (ECOG PS) ≤2. Excluded are pts with prior/current systemic therapy or stem cell transplantation for any plasma cell dyscrasia, history of malignancy other than MM, meningeal involvement of MM, cardiac disease, hepatitis, ongoing grade (gr) ≥2 peripheral neuropathy, or those with major surgery within two weeks before cycle (Cyc)1, day (D)1. In induction (six 28-day cycles), pts receive: Isa 10 mg/kg IV (Cyc 1: D1, 8, 15, 22; Cyc 2-6: D1, 15); bortezomib 1.3 mg/m 2 SC (Cyc 1: D1, 4, 8, 11; Cyc 2-6: D1, 8, 15, 22); cyclophosphamide 300 mg/m 2 IV (Cyc 1: D1, 8, 15; Cyc 2-6: D1, 8, 15, 22); and dexamethasone 40 mg PO or IV (Cyc 1: D1, 2, 3, 4, 9, 10, 11, 12; Cyc 2-6: D1, 8, 15, 22). In maintenance (Cyc 7 onwards), pts receive Isa 10 mg/kg IV (D1 of each Cyc) and Len 10 mg PO (or adjusted according to renal function) daily (D1-28 of each Cyc). Fifteen to 60 minutes before Isa infusions, pts receive pre-medications to mitigate potential infusion-related reactions. Treatment continues until disease progression, unacceptable toxicity, or consent withdrawal. The study primarily assesses the RRR (proportion of pts with partial renal response or better, using the eGFR cutoff values of the IMWG response criteria) at six months of treatment with IsaVCd. Other study objectives assess the pts' overall response rate (ORR; defined as partial response [PR] or better) and the safety of IsaVCd. Adverse events are classified using the Medical Dictionary for Regulatory Activities. Herein, we present safety and efficacy data for all treated patients (cut-off date 15/05/23. Results Twenty-five pts have been enrolled and have received ≥1 study treatment dose; of these, 20 (80.0%) are continuing with treatment and five (20.0%) have died. At baseline, pts had a median age of 70.0 years (range 46.0-87.0), 18 (72.0%) were male, and 22 (88.0%) had ECOG PS ≤1. Thirteen (52.0%) pts were at stage II and 12 (48.0%) pts at stage III by the revised International Staging System, 6 (24.0%) pts had lytic bone lesions, 5 (20.0%) pts had high-risk cytogenetics, and 5 (20.0%) pts had soft-tissue plasmacytomas. Seven (28.0%) pts were in need of dialysis (Table 1). At a median follow-up of 3.9 months (range 0.1-8.3), pts have received a median of 4.0 treatment cycles (range 1.0-9.0). Eight (32.0%) pts have completed ≥ 6 treatment cycles. RRR was achieved by 5/11 (45.5%) pts who had initiated treatment 6 months before the cutoff date. The median time to RR was 2.8 months (range 0.9-7.0). Of the 19 (76.0%) response evaluable pts, 11 (57.9%) achieved ORR (very good partial response: 6 [31.6%]; PR: 5 [26.3%]). The median time to first response was 1.0 months (range 0.9-1.9). Twenty (80.0%) pts had ≥1 treatment-emergent adverse events (TEAE). Of these, 10 (50.0%) pts had ≥1 gr ≥3 TEAE and 7 (43.8%) pts had ≥1 gr ≥3 serious TEAE. The most common gr ≥3 TEAE was peripheral neuropathy in 5 pts (20.0%) (Table 2). Conclusions Pts with NDMM and severe RI treated with upfront IsaVCd achieve RR consistent with those reported in the literature for pts receiving bortezomib-based therapy, although longer follow-up is needed to assess the regimen's impact on RI. No new safety signals were observed with IsaVCd.

Trial in Progress: A Phase 1 Study of KTX-1001, an Oral, First-in-Class, Selective MMSET Inhibitor in Patients with Relapsed and Refractory Multiple Myeloma

Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Subcutaneous (SC) Mosunetuzumab (mosun) As First-Line Therapy for Patients (pts) with High Tumor-Burden Follicular Lymphoma (FL): First Results of a Multicenter Phase 2 Study

Introduction: Cytotoxic chemotherapy plus anti-CD20 antibodies is the current standard of care for pts with newly diagnosed high-burden FL. While effective, this approach is burdened by toxicities, including infections and second cancers, and up to 20% of pts progress within 2 years and have poor outcomes. Intravenous (IV) mosun is a CD20xCD3 bispecific antibody recently approved for the treatment of pts with relapsed or refractory FL based on remarkable efficacy data, and its activity may be even greater in chemotherapy-naïve patients. Furthermore, SC mosun proved as effective as, and possibly better tolerated than, the IV formulation while increasing administration efficiency and convenience. Here, we present the first results of a phase 2 multicenter trial of SC mosun in patients with untreated high-burden FL. Methods: Key eligibility criteria included: Age ≥18 years, stage 2-4 FL in need of therapy per GELF criteria, being fit for chemoimmunotherapy, adequate bone marrow and organ function. SC mosun was administered at the dose of 5 mg on D1 and 45 mg on D8 and D15 of C1, and 45 mg on D1 of each subsequent 21-day cycle. Premedication consisted of dexamethasone, diphenhydramine, and acetaminophen before each mosun dose during C1 and on C2D1 if cytokine release syndrome (CRS) occurred in C1. Subjects with ≥3 CRS risk factors (stage 3-4, bulky disease, bone marrow (BM) involvement, elevated LDH) received dexamethasone 10 mg for 3 days with each mosun dose in C1 and C2. Prophylactic hospitalization was not required. Treatment lasted 8 cycles in pts who achieved complete response (CR), and up to 17 in those with partial response. Response was assessed per the Lugano 2014 and LYRIC 2016 criteria. BM evaluation was mandated in pts with baseline BM involvement who achieved radiographic CR. CRS and neurotoxicity were graded per the 2019 ASTCT criteria. Results: Between July 2022 and July 2023, 43 pts were enrolled. Median age was 55 years (range 26-77), 40% of pts had bulky disease (≥7 cm), 25% had grade 3A FL, and 27% had a FLIPI score ≥3. The median SUV max was 11.5 (range 3.7-41.1)(Table). At the cutoff date of 07/21/2023, 4 pts were in screening, 22 were on treatment, and 13 completed treatment. Four pts discontinued therapy early due to progressive disease (1), or adverse events (AE) (3, one related to study drug). Out of 230 patient-cycles administered, 9 (4%) were delayed due to AEs, by a median of 13 days (range 7-17). Among 39 safety-evaluable pts, the most common treatment-emergent AE were injection site reaction (72%, all G1), CRS (51%), fatigue (33%), dry skin (33%), skin rash (26%), ALT elevation (23%), and AST elevation (21%). G≥3 neutropenia occurred in 4 pts (10%), while infections occurred in 10 pts (26%), and were G1-2 in 8 cases and G3 in 2 cases. One pt died of cardiac arrhythmia in the setting of COVID19-associated pneumonia. CRS occurred most commonly after C1D1 and was G1 in 18 pts (90%) and G2 in 2 (10%). Median time to onset of the first CRS episode was 31h (2-91). Hospitalization and tocilizumab were only required in the two pts who experienced G2 CRS. Twenty-six pts were evaluable for response (1 had concurrent neoplasm at first response assessment, 1 had indeterminate response (IR)3 per LYRIC criteria, and 15 are yet to be evaluated). The best overall response rate was 96% and the CR rate was 81%. All 22 CR were seen at the first response assessment (Figure). Similar response rates were observed among higher-risk subgroups, including pts with high-risk FLIPI (figure), grade 3A FL (ORR 100%, CR 75%), bulky disease (ORR 100%, CR 82%), or SUVmax ≥13 (ORR 83%, CR 83%)). At a median follow-up for response-evaluable pts of 6.0 months, 2 pts have experienced progression, one with CD20-negative FL at the end of therapy, the other with DLBCL diagnosed 6 weeks after treatment initiation on a left axillary lymph node with baseline SUV 41 and not previously biopsied. Conclusion: SC mosun demonstrated a manageable safety profile and highly encouraging efficacy in pts with newly diagnosed high-burden FL, including those with higher-risk disease. Assessment of durability of responses will require additional follow-up. Enrollment continues and updated data will be presented.

A Multicenter, Open-Label, Phase 1b/2 Study to Evaluate the Effects of Maplirpacept in Combination with Glofitamab in People with Relapsed or Refractory Diffuse Large B Cell Lymphoma

Background Maplirpacept (PF-07901801) is an anti-CD47 fusion protein constructed to enhance phagocytosis and antitumor activity via inhibition of CD47-mediated signaling. Maplirpacept is currently being investigated in an ongoing Phase 1, multi-center, 1a/1b study in participants with advanced hematologic malignancies (NCT03530683). Early safety and efficacy results for maplirpacept monotherapy have previously been reported in patients with refractory or relapsed lymphomas (Patel et al. Blood 2021;138:3560). Study Design This trial is a multicenter, open-label, Phase 1b/2 study (NCT05896163), to evaluate the effects of maplirpacept in combination with fixed doses of glofitamab, after a single dose of obinutuzumab, in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The estimated enrollment is 70 patients; the study will be split into 2 parts (Figure 1). Phase 1b will determine the maximum tolerated dose of maplirpacept, with fixed doses of glofitamab and obinutuzumab. In Phase 2, participants will be randomized to low or high doses of maplirpacept, with fixed doses of glofitamab and obinutuzumab, consistent with the FDA ‘Project Optimus’ initiative for dose optimization and selection in oncology drug development. Study interventions will be given intravenously in 21-day cycles. At Cycle 0, participants will receive a single pre-treatment dose of obinutuzumab followed by 2 step-up doses of glofitamab. The combination of maplirpacept with full dose glofitamab will be given at Cycle 1 Day 1. Maplirpacept will be given weekly for the first 3 cycles, then every 3 weeks. Glofitamab will be given every 3 weeks for up to 11 cycles. Subsequently, participants will continue to receive maplirpacept alone. In Phase 1b, participants will be allocated to sequential doses of maplirpacept, given with fixed doses of glofitamab, after 1 dose of obinutuzumab, to select doses of maplirpacept for further evaluation. The primary endpoint for Phase 1b is to assess dose limiting toxicities up to 21 days following the first dose. In Phase 2, participants will be randomized to 2 different doses of maplirpacept, administered with fixed doses of glofitamab, after 1 dose of obinutuzumab. The primary endpoint for Phase 2 is objective response as per the Lugano 2014 response criteria. Secondary endpoints include frequency of adverse events and clinical laboratory abnormalities, objective response (Phase 1b only), duration of response, complete response, duration of complete response, progression free survival, serum concentration vs time for maplirpacept and glofitamab, and immunogenicity of maplirpacept and glofitamab. Adult patients with histologically confirmed relapsed or refractory DLBCL (including DLBCL NOS, primary mediastinal large B cell lymphoma and transformed follicular lymphoma, T cell/histiocyte-rich large B-cell lymphoma, Grade 3b follicular lymphoma or composite lymphoma with a DLBCL component with a subsequent DLBCL relapse), will be eligible (Table 1). Participants with histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma are eligible, except for participants with history of Waldenström macroglobulinemia. Treatment with at least 1 prior line of anti-CD20 antibody-based therapy will be included. For Phase 2, no more than 2 prior lines of systemic therapy will be permitted. Patients who are not candidates for, or who are unwilling to undergo high dose chemotherapy and subsequent stem cell transplant and/or are unable or unwilling to receive chimeric antigen receptor T-cell therapy (e.g. for logistical reasons) will be eligible. All patients should have adequate bone marrow, hepatic, and renal function (eGFR ≥45 mL/min) and ECOG performance status ≤2. Exclusion criteria include prior treatment with an anti-CD47 agent, prior anti-CD20xCD3 containing regimen, refractoriness to an obinutuzumab monotherapy containing regimen, prior allogeneic stem cell transplantation or autologous stem cell transplantation within 12 weeks prior to enrolment, high grade B-cell lymphoma with BCL2 and Myc rearrangement, active bacterial, viral, fungal, mycobacterial, parasitic, or other infection.

Trial in Progress: Phase 1 Trial Evaluating the Safety and Tolerability of Odronextamab in Combination with Cemiplimab in Relapsed/Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Background and Significance CD20×CD3 bispecific antibodies (bsAbs) have emerged as an important immunotherapeutic approach for relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). These agents have shown compelling efficacy in indolent B-NHL, with the CD20×CD3 bsAb odronextamab demonstrating 75% complete response (CR) rates and encouraging durability of responses (median duration of response [DoR], 20.5 months) in heavily pretreated patients with R/R follicular lymphoma in the ELM-2 study (Kim TM, et al. ASH. 2022). In comparison, patients with R/R diffuse large B-cell lymphoma who were treated with odronextamab in the same study demonstrated a CR rate of 31%, and median DoR was 10.2 months (Kim WS, et al. ASH. 2022). These data indicate an unmet need for treatment strategies that can improve the depth and durability of responses in patients with aggressive R/R B-NHL. Combination therapy with drugs that complement the mechanism of action of CD20×CD3 bsAbs may provide an opportunity to address this unmet need. Cemiplimab is a human immunoglobulin G4 (IgG4) monoclonal antibody directed against programmed cell death protein 1 (PD-1), blocking PD-1- and programmed cell death ligand 1 (PD-L1)-driven inhibitory T-cell signaling. Combining odronextamab and cemiplimab provides an attractive therapeutic opportunity to improve anti-tumor efficacy while restricting T-cell exhaustion, and preliminary results for this combination provided proof of concept, with evidence of clinical activity and manageable tolerability in patients with B-lymphoid malignancies (n=12; Topp MS, et al. ASH. 2017). Here, we investigate whether the addition of cemiplimab to odronextamab can improve the depth and durability of response in patients with previously treated aggressive B-NHL. Study Design and Methods This is a Phase 1, open-label, multicenter, dose-escalation and -expansion study that will take place at up to 28 sites globally (NCT02651662). Intravenous (IV) odronextamab is administered in 21-day cycles, initially as monotherapy and with step-up dosing during Cycle (C) 1 to mitigate the risk of cytokine release syndrome (Figure). Full-dose odronextamab is administered on Day (D) 1, D8 and D15 of C2-C4, and then on D15 of each cycle during maintenance (C5 onwards) until disease progression or treatment discontinuation. IV cemiplimab starts on C2D15 at the specified dose level (DL1-DL7) and is administered on D15 of subsequent cycles. The dose-limiting toxicity (DLT) period is 28 days from the start of cemiplimab administration. At the end of dose escalation, a regimen will be selected for further investigation in dose expansion. Approximately 60 patients will be enrolled. Patients will be aged ≥18 years with aggressive CD20+ B-NHL that is R/R after ≥2 lines of systemic therapy containing an anti-CD20 antibody and an alkylating agent. Patients must have measurable disease, Eastern Cooperative Oncology Group performance score (ECOG PS) ≤1, and adequate bone marrow and organ function. Exclusion criteria include primary central nervous system lymphoma, prior allogeneic stem cell transplantation, autoimmune disease, prior adverse events from anti-PD-1/PD-L1 therapy, and uncontrolled infections. Primary endpoints are safety, tolerability, DLTs, and to determine the recommended Phase 2 dose of the combination regimen of odronextamab and cemiplimab. Secondary endpoints include pharmacokinetics, immunogenicity, and preliminary anti-tumor activity (overall response rate, CR rate, and DoR, according to the Lugano classification). There are no formal hypotheses for this study and analyses will be descriptive in nature.

Safety Results of a Phase I Study of Zandelisib + R-CHOP in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL)

Introduction: Emerging data have identified distinct genetic subtypes of DLBCL based on the diverse oncogenic molecular drivers with varying clinical outcomes when treated with standard R-CHOP. Relapse post frontline treatment could be curbed by integrating novel agents upfront. The phosphatidylinositol 3 kinase (PI3K) signalling pathway contributes to the oncogenesesis of both germinal center derived and activated B-cell (ABC) DLBCL subtypes (Wright, et al Cancer Cell, 2020). Zandelisib, a highly selective oral PI3Kδ inhibitor has proven efficacy in B cell lymphoma with a favorable toxicity profile when administered in intermittent dosing schedule (Pagel, et al Lancet Oncol 2022). We conducted a phase I/2 trial to evaluate the safety and efficacy of zandelisib in combination with R-CHOP chemotherapy in newly diagnosed DLBCL. The study enrollment was closed in 12/2022 after the development of zandelisib was discontinued. We present the results of the phase I (P1) trial. Methods: In this investigator-initiated trial, patients (pts) with untreated DLBCL with ECOG performance status (PS) ≤ 2, adequate bone marrow (BM) and organ function were enrolled from 08/2021-12/2022 at Cleveland Clinic (NCT04517435). ECOG PS 3 was allowed if it was attributed to the lymphoma diagnosis. The study was supported by the MEI Pharma. The P1 study had 2 dose escalation cohorts in combination with standard doses of R-CHOP every 21 days for 6 cycles; zandelisib was dosed 60 mg daily on days 1-4 in cohort 1 and daily on days 1-7 in cohort 2. If the 3 subjects in dose level 1 (D1) did not experience any dose limiting toxicity (DLT) during cycle 1 (C1), pts were enrolled into D2. In phase 2 (P2), a cycle of R-CHOP prior to the study treatment was allowed, if clinically deemed. All pts received pneumocystis jirovecii (PJP) and viral prophylaxis. Disease response was assessed after C3 and C6. Primary end point for P1 was to assess safety and tolerability of the combination and to determine recommended P2 dose (RP2D) of zandelisib. Pts who received at least 1 cycle of study treatment were included in the safety analysis. Primary objective of P2 is progression free survival (PFS) at 1 year. Pt and disease characteristics were analyzed using descriptive statistics. Results: We enrolled a total of 13 pts (P1: 9 and P2: 4) in the study prior to termination. The median age was 67 (range 46-79) years, with majority being female (53.8%), with an ECOG PS of 0-2 (100%). Most pts had stage III-IV disease 10/13 (77%), IPI ≥3 in 8/15 (62%), elevated LDH 9/13 pts (69%), and extranodal involvement 7/13 (54%). 3 pts had BM involvement. DLBCL was germinal center (GC) subtype in 77% of the pts. FISH studies revealed translocations in BCL2 (46%), BCL6 (8%) and c-myc (0%). There was no DLT observed in cohort 1 and zandelisib 60 mg daily on D1-7 was the RP2D. 12 of 13 enrolled pts completed 6 cycles of the study regimen prior to study closure. Of the 12 evaluable pts, the ORR was 100% with 9 pts (75%) achieving CR and 3 PR (25%). No pt experienced disease progression prior to study closing. Median time from treatment start to response was 165 (range 48-189) days. The most common adverse events were diarrhea (38%), neutropenia and anemia (31% each), fatigue, constipation, leukopenia and thrombocytopenia (23% each). Other AEs include colitis, nausea, hypoalbuminemia and hypokalemia (15% each). Of the 2 pts who developed colitis, 1 pt had G1 colitis which resolved, while the other pt discontinued the study after 2 cycles due to G3 colitis and bowel obstruction. Another pt experienced G3 jejunal perforation after completing cycle 6. Other G≥3 AE observed were neutropenia and leukopenia each (23% each), lung infection and lymphopenia (8% each). All pts were alive at the time of study closure. Conclusion: In this phase 1/II study, encouraging efficacy was observed with zandelisib + R-CHOP, but this should be interpreted with caution as the study was incomplete. There is a potential signal for increased gastrointestinal toxicity (one G3 colitis, one G3 bowel perforation) in this small sample size and larger prospective trials are needed to further assess the toxicity profile of the combination of oral PI3K inhibitors with R-CHOP.

Fragility spinal fractures among cirrhotic liver transplant candidates in Croatia

IntroductionExisting data on fragility spinal fractures prevalence in liver transplant candidates are scarce and inconsistent. This may be due to other comorbidities, besides hepatic osteodystrophy (HO), that contribute to bone loss and fragility fracture prevalence in chronic liver disease (CLD). ObjectivesThe aim of this study was to investigate the prevalence of spinal thoracic and lumbar fragility fractures among cirrhotic, non-chronic kidney disease (CKD), non-diabetic liver transplant candidates and to explore their relationship with clinical characteristics, laboratory markers and dual-energy x-ray absorptiometry (DXA) results. Material and methodsThis cross-sectional observational study was conducted at Merkur University Hospital, Croatia, between February 2019 and May 2023. Adult patients with liver cirrhosis referred for liver transplantation were included. Patients with acute infection, CKD, diabetes mellitus, malignancies, inflammatory bone diseases and those on corticosteroid or antiresorptive therapy were excluded. Clinical, laboratory and radiological assessment was carried out and patients were accordingly allocated into non-fractured and fractured group for the purpose of statistical analysis. ResultsA total of 90 patients were included in the study. There was 123 fractures, 87 (70.7 %) in the thoracic and 36 (29.3 %) in the lumbar region. Eighty-nine (72.4 %) fractures were grade 1, 31 (25.2 %) were grade 2 and 3 (2.4 %) were grade 3. Patients in the fractured group were significantly older (p < 0.001). No significant differences between fractured and non-fractured group according to laboratory and DXA parameters were noted. Subgroup with lumbar fractures had significantly lower bone mineral density values at L1-L4 region. Statistically significant negative correlation between bone specific alkaline phosphatase (BALP) and hip total BMD (rho = -0.414, p < 0.001) and spine total BMD (rho = -0.258, p = 0.014) values was found. ConclusionPresent study confirmed detrimental impact of CLD and HO on bone strength. DXA measurement correlated with the presence of lumbar fragility fractures. A combination of standard X-ray imaging and DXA is needed for adequate bone evaluation in pretransplant period and BALP could be useful for detecting HO in CLD. Searching for other risk factors and implementing bone turnover markers and additional imaging techniques for bone loss evaluation in liver transplant candidates is needed.

Trends in Maxillary Sinus Filling Using a Lateral Surgical Approach

Dental rehabilitation using osseointegrated implants is a routine for dentists. Maxillary sinus lift surgery is essential in expanding the indications for dental implants, as it re-establishes adequate bone volume for the installation of implants in the ideal areas in the middle posterior portion of maxillae that have undergone the physiological process of pneumatization. This article describes the chronology of this technique and its increase over time.