Correlation of immune fitness with response to teclistamab in relapsed/refractory multiple myeloma in MajesTEC-1.

Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (RRMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with RRMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells, T cells expressing co-inhibitory receptors (CD38, PD-1, PD-1/TIM-3), and soluble BCMA, and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA receptor density were associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive regulatory T cells. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov, NCT03145181/NCT04557098.

Teclistamab in Relapsed or Refractory Multiple Myeloma.

BACKGROUND: Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS: Among 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS: Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Incidence, timing, and management of infections in patients receiving teclistamab for the treatment of relapsed/refractory multiple myeloma in the MajesTEC-1 study.

BACKGROUND: Patients with relapsed/refractory multiple myeloma are at increased risk of infection. Infections during treatment with teclistamab, the first B-cell maturation antigen-directed bispecific antibody approved for triple-class-exposed relapsed/refractory multiple myeloma, was examined in the phase 1/2 MajesTEC-1 study. METHODS: Patients (N = 165) received subcutaneous teclistamab 1.5 mg/kg weekly after a step-up dosing schedule (0.06 mg/kg and 0.3 mg/kg, each separated by 2-4 days). Patients were monitored frequently for infections; prophylaxis and management were per institutional guidelines. RESULTS: At a median follow-up of 22.8 months (range, 0.3-33.6), infections were reported in 132 patients (80.0%). Grade 3/4 infections occurred in 91 patients (55.2%), including COVID-19 (21.2%), respiratory infections (19.4%), Pneumocystis jirovecii pneumonia (4.2%), viral infections (4.2%), and gastrointestinal infections (1.2%). Twenty-one patients died from infections (18 from COVID-19). Median time to first onset of any-grade and grade 3 to 5 infections was 1.7 and 4.2 months, respectively. Overall, 70.9% of patients had ≥1 postbaseline immunoglobulin G (IgG) level <400 mg/dL; median time to IgG <400 mg/dL was 1.2 months (range, 0.2-19.8) and 46.1% received ≥1 dose of IgG replacement. Grade 3/4 neutropenia occurred in 65.5% of patients (median time to grade ≥3 neutropenia/febrile neutropenia was 2.3 months [range, 0-18.1]). CONCLUSION: Based on the infection profile of B-cell maturation antigen-targeted bispecific antibodies such as teclistamab, it is recommended that clinicians and patients remain vigilant for a range of infection types throughout treatment to facilitate prompt intervention. Appropriate screening, prophylaxis, and management of infections, hypogammaglobulinemia, and neutropenia are important. CLINICAL TRIAL REGISTRATION: NCT03145181/NCT04557098 (ClinicalTrials.gov) PLAIN LANGUAGE SUMMARY: Before starting teclistamab, patients should be up to date with vaccinations (including COVID-19) and screened for hepatitis B and C and HIV. Teclistamab should not be given to patients with any active infections. Prophylactic antimicrobials should be administered per institutional guidelines. Prophylaxis for Pneumocystis jirovecii pneumonia and herpes simplex/varicella zoster virus is recommended during teclistamab treatment. Close monitoring of infections and immunoglobulin G (IgG) levels should continue throughout teclistamab treatment. IgG replacement (administered every 3-6 weeks) should be used to maintain IgG ≥400 mg/dL. Growth factors should be considered for grade ≥3 neutropenia with infection/fever and grade 4 neutropenia.

Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE.

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA.

We explored minimal residual disease (MRD) in relapsed/refractory multiple myeloma (RRMM) and transplant-ineligible (TIE) newly diagnosed multiple myeloma (NDMM) using data from 4 phase 3 studies (POLLUX, CASTOR, ALCYONE, and MAIA). Each study previously demonstrated that daratumumab-based therapies improved MRD negativity rates and reduced the risk of disease progression or death by approximately half vs standards of care. We conducted a large-scale pooled analysis for associations between patients achieving complete response or better (≥CR) with MRD-negative status and progression-free survival (PFS). MRD was assessed via next-generation sequencing (10-5 sensitivity threshold). Patient-level data were pooled from all 4 studies and for patients with TIE NDMM and patients with RRMM who received ≤2 prior lines of therapy (≤2 PL). PFS was evaluated by response and MRD status. Median follow-up (months) was 54.8 for POLLUX, 50.2 for CASTOR, 40.1 for ALCYONE, and 36.4 for MAIA. Patients who achieved ≥CR and MRD negativity had improved PFS vs those who failed to reach CR or were MRD positive (TIE NDMM and RRMM hazard ratio [HR] 0.20, P < .0001; TIE NDMM and RRMM ≤2 PL HR 0.20, P < .0001). This benefit occurred irrespective of therapy or disease setting. A time-varying Cox proportional hazard model confirmed that ≥CR with MRD negativity was associated with improved PFS. Daratumumab-based treatment was associated with more patients reaching ≥CR and MRD negativity. These findings represent the first large-scale analysis with robust methodology to support ≥CR with MRD negativity as a prognostic factor for PFS in RRMM and TIE NDMM. These trials were registered at www.clinicaltrials.gov as #NCT02076009, #NCT02136134, #NCT02195479, and #NCT02252172.

Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma.

BACKGROUND: Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, demonstrated an overall response rate of 63.0% in 165 heavily pretreated patients with relapsed or refractory multiple myeloma in the phase 1/2 MajesTEC-1 study. Cytokine release syndrome (CRS), a known manifestation of T-cell redirection, was observed in 119 of 165 patients (72.1%). METHODS: Patients received once-weekly teclistamab 1.5 mg/kg subcutaneously after two step-up doses (0.06 and 0.3 mg/kg). CRS was graded according to American Society for Transplantation and Cellular Therapy criteria and managed according to the study protocol, including use of tocilizumab and/or steroids. RESULTS: Most cases of CRS occurred during the step-up dosing schedule of teclistamab and were grade 1 (50.3% of patients) or grade 2 (21.2% of patients); a single case of grade 3 CRS was reported in a patient with concurrent grade 3 pneumonia. All CRS cases resolved and none led to treatment discontinuation. Overall, 33.3% of patients had >1 CRS event; CRS recurrence was reduced when tocilizumab was administered for the first CRS event compared with when it was not (20.0% vs. 62.2%, respectively). Baseline characteristics such as tumor burden and cytokine levels did not appear to predict CRS incidence or severity. CONCLUSIONS: Findings of this study support the need for preemptive planning and prompt management of CRS in patients treated with T-cell-engaging bispecific antibodies. Intervention with tocilizumab for CRS appears to decrease the likelihood of patients experiencing subsequent CRS events without compromising response to teclistamab. PLAIN LANGUAGE SUMMARY: Cytokine release syndrome (CRS), observed in 72.1% of patients treated with teclistamab in the MajesTEC-1 study, was mostly grade 1 or 2 and manageable, without requiring treatment discontinuation. Most CRS occurred during the step-up schedule, requiring vigilance during treatment initiation. Ensure fever is resolved and patients have no signs of infection before initiating the teclistamab step-up schedule or administering the next teclistamab dose, to avoid exacerbating CRS. Tocilizumab reduced the risk of subsequent CRS in patients receiving it for their first CRS event (20.0% vs. 62.2% in those not receiving it), without affecting response to teclistamab. No baseline characteristics, including tumor burden or cytokine levels, appeared to clearly predict for CRS occurrence or severity.

Plain language summary of the MajesTEC-1 study of teclistamab for the treatment of people with relapsed or refractory multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a phase 1-2 clinical trial called MajesTEC-1. This trial tested the cancer drug teclistamab in people with relapsed or refractory multiple myeloma, a cancer that forms in a certain type of white blood cells known as plasma cells. Most participants who took part in the study had at least 3 prior treatments for multiple myeloma before their cancer came back. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: A total of 165 participants from 9 countries were included in this study. All participants were given teclistamab once per week and monitored for side effects. Once participants started taking teclistamab, they were checked regularly to monitor if their cancer had no change, improved (responded to treatment), or worsened or spread (known as disease progression). WHAT WERE THE RESULTS OF THE STUDY?: After approximately 14.1 months of follow-up (from 2020 to 2021), 63% of participants who were given teclistamab had a decrease in myeloma burden, meaning that they responded to treatment with teclistamab. Participants who responded to teclistamab lived without their myeloma coming back for approximately 18.4 months. The most common side effects were infections, cytokine release syndrome, abnormally low white and red blood cell counts (neutropenia, lymphopenia, and anemia), and low platelet cell counts (thrombocytopenia). Approximately 65% of participants experienced serious side effects. WHAT DO THE RESULTS OF THIS STUDY MEAN?: Overall, more than half of the participants (63%) in the MajesTEC-1 study responded to treatment with teclistamab despite previous myeloma treatment failures. Clinical Trial Registration: NCT03145181, NCT04557098 (ClinicalTrials.gov).

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%). CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial.

BACKGROUND: Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. METHODS: ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. FINDINGS: 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4-43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46-0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2-82·0) in the D-VMP group and 67·9% (62·6-72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34-0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). INTERPRETATION: D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. FUNDING: Janssen Research & Development.

Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL.

Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

A Multicenter Randomized Three-Arm Phase II Study of (1) Everolimus, (2) Estrogen Deprivation Therapy (EDT) with Leuprolide + Letrozole, and (3) Everolimus + EDT in Patients with Unresectable Fibrolamellar Carcinoma.

LESSONS LEARNED: FLC is a complex cancer with many implicated oncogenic pathways. Single or dual targeting does not appear to alter the natural history of the cancer, and novel therapeutics are needed. Estrogen deprivation therapy with letrozole and leuprolide, alone or in combination with the mTOR inhibitor, everolimus, did not demonstrate clinical activity in advanced fibrolamellar carcinoma. The study drugs were well tolerated when administered as single agents or in combination in this patient population. This study demonstrates that, despite the rarity of FLC, multicenter therapeutic clinical trials are feasible and support the value of this consortium. BACKGROUND: Fibrolamellar carcinoma (FLC) is an uncommon malignancy in young people and is sometimes associated with pregnancy and oral contraceptive use. Immunohistochemical staining and genetic profiling of FLC tumor specimens have revealed aromatase overexpression. The overexpression of mTOR and S6 kinase has been noted in 25% of FLC. On the basis of interaction between estrogen and the PI3K/Akt/mTOR pathway, we hypothesized that suppression of estrogen and mTOR signaling could have antineoplastic activity in FLC. METHODS: Patients were randomized to arm A (everolimus), arm B (letrozole/leuprolide; estrogen deprivation therapy [EDT]), or arm C (everolimus/letrozole/leuprolide). Upon disease progression, patients in arm A or B could proceed to part 2 (everolimus/letrozole/leuprolide). The primary endpoint was progression-free survival (PFS) at 6 months (PFS6) assessed using a Simon's minimax two-stage design, hypothesizing an improvement in PFS6 from 40% to 64% with the study regimen. RESULTS: Twenty-eight patients were enrolled. An unplanned analysis was performed because of perceived concern for lack of efficacy. Stable disease was observed in 9 of 26 evaluable patients (35%). PFS6 was 0%. Median overall survival (OS) was 12.4 months (95% confidence interval [CI], 7.4-20.9) for the whole study cohort. Grade 3 adverse events in ≥10% of patients were nausea (11%), vomiting (11%), anemia (11%), elevated aspartate transaminase (AST; 32%), alanine transaminase (ALT; 36%), and alkaline phosphatase (14%). All 28 patients experienced an event for PFS outcome, and four deaths were due to disease progression. CONCLUSION: Neither EDT nor mTOR inhibition improved outcomes in FLC. Other treatment strategies are needed.

Phase II Multicenter, Open-Label Study of Oral ENMD-2076 for the Treatment of Patients with Advanced Fibrolamellar Carcinoma.

LESSONS LEARNED: The fibrolamellar carcinoma-associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and, thus, overexpression of Aurora kinase A. ENMD-2076 showed a favorable toxicity profile. The limited results, one patient (3%) with a partial response and 57% of patients with stable disease, do not support further evaluation of ENMD-2076 as single agent. Future studies will depend on the simultaneous targeting approach of DNAJB1-PRKACA and the critical downstream components. BACKGROUND: Fibrolamellar carcinoma (FLC) represents approximately 0.85% of liver cancers. The associated DNAJB1-PRKACA gene fusion transcript RNA codes for the catalytic domain of protein kinase A and overexpression of Aurora kinase A (AURKA). ENMD-2076 is a selective anti-AURKA inhibitor. METHODS: Patients aged >12 years with pathologically confirmed incurable FLC, with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 or Lansky 70-100, and adequate organ function were eligible. Patients were prescribed ENMD-2076 based on body surface area. The primary endpoint was overall objective response rate by RECIST v1.1, with a null hypothesis of true response rate of 2% versus one-sided alternative of 15%. Secondary endpoints included 6-month progression-free survival (PFS) rate (Fig. 1), median PFS, time to progression (TTP), and overall survival (OS). Safety was evaluated throughout the study. RESULTS: Of 35 patients who enrolled and received treatment, 1 (3%) had a partial response (PR) and 20 (57%) had stable disease (SD). Median TTP, PFS, and OS were 5, 3.9, and 19 months, respectively. The most frequently reported drug-related serious adverse event was hypertension in three patients. Three deaths were reported on-study-two due to disease progression and one due to pulmonary embolism not related to ENMD-2076. CONCLUSION: The study provided no rationale for further studying ENMD-2076 as a single agent in FLC.

Daratumumab-lenalidomide-dexamethasone vs standard-of-care regimens: Efficacy in transplant-ineligible untreated myeloma.

Daratumumab in combination with lenalidomide-dexamethasone (D-Rd) recently received FDA approval for the treatment of transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). The present PEGASUS study compared progression-free survival (PFS) in patients treated with D-Rd in the MAIA trial and patients treated with common standard-of-care regimens from the Flatiron Health electronic health record-derived deidentified database, which has data from patients treated primarily at community-based oncology practices in the United States. Individual-level patient data from both data sources were used to perform an anchored indirect treatment comparison (ITC) of D-Rd to bortezomib-lenalidomide-dexamethasone (VRd) and bortezomib-dexamethasone (Vd); lenalidomide-dexamethasone (Rd) was the common anchor for the ITC. Hazard ratios (HRs) reflecting direct comparisons of PFS within MAIA (D-Rd vs Rd) and Flatiron Health (VRd vs Rd; Vd vs Rd) were used to make ITCs for D-Rd vs VRd and Vd, respectively. After application of MAIA inclusion/exclusion criteria and propensity-score weighting, the Flatiron Health patients resembled the MAIA trial population on measured baseline characteristics. Based on the direct comparison within MAIA, treatment with D-Rd was associated with a significantly lower risk of progression or death compared to Rd (HR 0.54; 95% CI 0.42, 0.71). Based on the ITCs, D-Rd was associated with a significantly lower risk of progression or death compared to VRd (HR 0.68; 95% CI 0.48, 0.98) and Vd (HR 0.48; 95% CI 0.33, 0.69). In the absence of head-to-head trials comparing D-Rd to VRd or Vd, the present ITC may help inform treatment selection in transplant-ineligible patients with NDMM.

Maintenance chemotherapy to reduce the risk of a metachronous Wilms tumor in children with bilateral nephroblastomatosis.

From 2009 to 2018, 10 consecutive patients with Wilms tumors and bilateral nephroblastomatosis, who had completed standard therapy, were provided a maintenance chemotherapy regimen consisting of vincristine and dactinomycin every 3 months for 12 months in order to prevent an early metachronous Wilms tumor. One patient (10%) with Beckwith-Wiedemann syndrome developed a new tumor, without anaplasia. There were no significant toxicities reported during maintenance. All patients are currently alive with no evidence of disease. Further investigations are recommended to determine the utility of this approach.

Acute myeloid leukemia therapy elicits durable complete response in chemoradio-resistant metastatic paraganglioma.

Few effective therapeutic options exist for patients with metastatic paraganglioma (PGL). We report the case of a 16-year-old male who developed acute myeloid leukemia (AML) 30 months following the treatment for metastatic PGL. PGL had been refractory to 131 I-meta-iodobenzylguanidine and temozolomide therapy. However, there was a major reduction in primary tumor allowing its gross total resection, and complete resolution of metastatic disease following AML-directed therapy that included daunorubicin, cytarabine, and etoposide. He remains in remission for both AML and PGL, 48 months post AML chemotherapy. Alternative chemotherapeutic agents should be considered for metastatic PGL resistant to conventional therapy.

Retrospective Evaluation of Palifermin Use in Nonhematopoietic Stem Cell Transplant Pediatric Patients.

BACKGROUND: Palifermin has been proven to decrease the frequency of severe oral mucositis in adult patients with sarcoma and metastatic colorectal cancer receiving chemotherapy. The impact of palifermin on the incidence of mucositis in nonhematopoietic stem cell transplantation (HSCT) pediatric population receiving chemotherapy has never been reported to date. PATIENTS AND METHODS: This is a retrospective analysis of pediatric patients who received palifermin as secondary prophylaxis to prevent chemotherapy-induced mucositis at Memorial Sloan Kettering Cancer Center from January 1, 2008 to 2014. Data from electronic medical records on days to mucositis resolution, use of opioids, use of total parenteral nutrition, duration of hospitalization, and antibiotics are collected and presented here. RESULTS: A total of 18 patients received palifermin for secondary prophylaxis after developing mucositis from the prior chemotherapy cycle. Mucositis did not reoccur in the subsequent cycle for 13 of the 18 patients. The majority of patients who received palifermin prophylaxis had decreased opioids and antibiotics use and decreased duration of hospitalization. Six of the 7 patients previously requiring total parenteral nutrition due to mucositis had decreased supplemental nutritional needs following the use of palifermin. CONCLUSION: Palifermin may provide benefit as secondary prophylaxis in pediatric patients to prevent chemotherapy-induced mucositis.

Second Allogeneic Stem Cell Transplantation for Acute Leukemia Using a Chemotherapy-Only Cytoreduction with Clofarabine, Melphalan, and Thiotepa.

Relapse after allogeneic hematopoietic stem cell transplantation (alloHSCT) remains one of the leading causes of mortality in patients with leukemia. Treatment options in this population remain limited, with concern for both increased toxicity and further relapse. We treated 18 patients with acute leukemia for marrow ± extramedullary relapse after a previous alloHSCT with a myeloablative cytoreductive regimen including clofarabine, melphalan, and thiotepa followed by a second or third transplantation from the same or a different donor. All patients were in remission at the time of the second or third transplantation. All evaluable patients engrafted. The most common toxicity was reversible transaminitis associated with clofarabine. Two patients died from transplantation-related causes. Seven patients relapsed after their second or third transplanation and died of disease. Nine of 18 patients are alive and disease free, with a 3-year 49% probability of overall survival (OS). Patients whose remission duration after initial alloHSCT was >6 months achieved superior outcomes (3-year OS, 74%, 95% confidence interval, 53% to 100%), compared with those relapsing within 6 months (0%) (P < .001). This new cytoreductive regimen has yielded promising results with acceptable toxicity for second or third transplantations in patients with high-risk acute leukemia who relapsed after a prior transplantation, using various graft and donor options. This approach merits further evaluation in collaborative group studies.

Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center.

BACKGROUND: Pediatric oncologists have begun to leverage tumor genetic profiling to match patients with targeted therapies. At the Memorial Sloan Kettering Cancer Center (MSKCC), we developed the Pediatric Molecular Tumor Board (PMTB) to track, integrate, and interpret clinical genomic profiling and potential targeted therapeutic recommendations. PROCEDURE: This retrospective case series includes all patients reviewed by the MSKCC PMTB from July 2014 to June 2015. Cases were submitted by treating oncologists and potential treatment recommendations were based upon the modified guidelines of the Oxford Centre for Evidence-Based Medicine. RESULTS: There were 41 presentations of 39 individual patients during the study period. Gliomas, acute myeloid leukemia, and neuroblastoma were the most commonly reviewed cases. Thirty nine (87%) of the 45 molecular sequencing profiles utilized hybrid-capture targeted genome sequencing. In 30 (73%) of the 41 presentations, the PMTB provided therapeutic recommendations, of which 19 (46%) were implemented. Twenty-one (70%) of the recommendations involved targeted therapies. Three (14%) targeted therapy recommendations had published evidence to support the proposed recommendations (evidence levels 1-2), eight (36%) recommendations had preclinical evidence (level 3), and 11 (50%) recommendations were based upon hypothetical biological rationales (level 4). CONCLUSIONS: The MSKCC PMTB enabled a clinically relevant interpretation of genomic profiling. Effective use of clinical genomics is anticipated to require new and improved tools to ascribe pathogenic significance and therapeutic actionability. The development of specific rule-driven clinical protocols will be needed for the incorporation and evaluation of genomic and molecular profiling in interventional prospective clinical trials.

Allogeneic hematopoietic stem cell transplantation for nonmalignant hematologic disorders using chemotherapy-only cytoreductive regimens and T-cell-depleted grafts from human leukocyte antigen-matched or -mismatched donors.

Nonmalignant hematologic disorders (NMHD) of childhood comprise a variety of disorders, including acquired severe aplastic anemia and inherited marrow failure syndromes. Patients with high-risk NMHD without matched related donors fare poorly with allogeneic hematopoietic alternative donor stem cell transplantation (allo-HSCT) and are at high risk for developing graft-versus-host disease following unmodified grafts. The authors retrospectively analyzed data on 18 patients affected by NMHD, lacking a human leukocyte antigen (HLA)-identical sibling donor, who underwent an alternative donor allo-HSCT at their institution between April 2005 and May 2013. Fifty percent of the patients had received prior immunosuppressive therapy, 72% had a history of infections, and 56% were transfusion dependent at the time of transplant. Cytoreduction included a combination of 3 of 5 agents: fludarabine, melphalan, thiotepa, busulfan, and cyclophosphamide. Grafts were T-cell depleted. All evaluable patients engrafted. Five died of transplant complications. The cumulative incidence of graft-versus-host disease was 6%. No patient had recurrence of disease. Five-year overall survival was 77%. Age at transplant <6 years was strongly associated with better survival. Based on these results, transplant with chemotherapy-only cytoreductive regimens and T-cell-depleted stem cell transplants could be recommended for patients with high-risk NMHD, especially at a younger age.

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study.

BACKGROUND: Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE). METHODS: In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients. FINDINGS: Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4). INTERPRETATION: PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT. FUNDING: Seattle Genetics.