Objectives
To evaluate clinical and financial impact of pharmacist interventions in an ambulatory adult hematology–oncology department.
Methods
All cancer patients receiving a first injectable ...immuno- and/or chemotherapy regimen were included in this prospective study over a one-year period. The clinical impact of pharmacist interventions made by two clinical pharmacists was rated using the Clinical Economic and Organizational tool. Financial impact was calculated through cost savings and cost avoidance.
Main results: Five hundred and fifty-eight patients were included. A total of 1970 pharmacist interventions were performed corresponding to a mean number of 3.5 pharmacist interventions/patient. The clinical impact of pharmacist interventions was classified as negative, null, minor, moderate, major and lethal in 0, 84 (4%), 1353 (68%), 385 (20%), 148 (8%) and 0 cases, respectively. The overall cost savings were €175,563. One hundred and nine (6%) of all pharmacist interventions concerned immuno- or chemotherapy regimen for cost savings of €148,032 (84% of the total amount of cost savings). The cost avoidance was €390,480. Cost avoidance results were robust to sensitivity analyses with cost of preventable adverse drug event as main driver of the model. When the cost of employing a pharmacist was subtracted from the average yearly cost savings plus cost avoidance per pharmacist, this yielded a net benefit of €223,021. The cost–benefit ratio of the clinical pharmacist was €3.7 for every €1 invested.
Principal conclusions: To have two full-time clinical pharmacists in a 55-bed ambulatory adult hematology–oncology department is both clinically and financially beneficial.
Background: Diabetes negatively impacts cancer prognosis. The objective of this work was to evaluate a tripartite oncologist–pharmacist–diabetologist collaboration in the management of patients with ...diabetes starting chemotherapy. Patients and Methods: The prospective ONCODIAB study (NCT04315857) included 102 adults with diabetes starting chemotherapy by whom a continuous glucose monitoring device was worn for fourteen days from the first day of the first and second chemotherapy cycles. The primary outcome was to assess pharmacist and diabetologist interventions. The secondary outcome was to evaluate the impact of the ONCODIAB follow-up on individualized patient glycemic targets at 6 months. Results: A total of 191 (2 per patient) were made either by clinical pharmacists (n = 95) or diabetologists (n = 96) during the first two chemotherapy cycles. The anatomic therapeutic chemical drug classes most frequently involved in pharmacist interventions were cardiovascular system (23%), alimentary tract and metabolism (22%), and anti-infectives for systemic use (14%). Diabetologists modified the antidiabetic treatment in 58 (62%) of patients: dose reduction (34%), drug discontinuation (28%), drug addition (24%), and dose increase (15%). Glycated hemoglobin decreased from 7.6 ± 1.7% at baseline to 7.1 ± 1.1% at 6 months (p = 0.02). Compared to individualized targets, HbA1c was higher, in the interval, or lower in 29%, 44%, and 27% of patients at baseline vs. in 8%, 70%, and 22% of patients at 6 months, respectively (p < 10−3). Conclusions: In our study, a close collaboration between oncologists, pharmacists, and diabetologists helped by continuous glucose monitoring led to overall medication optimization and better glycemic control in patients with diabetes starting chemotherapy.
Objectives: The UMACOACH Lymphoma is a multidisciplinary monitoring program for patients initiating a first highly haematotoxic treatment for Hodgkin or non-Hodgkin lymphoma. Patient follow-up is ...based on consultation with a pharmacist and planed phone calls by nurses supervised by a clinical haematologist. Our objective was to assess effectiveness and cost of the UMACOACH Lymphoma Program (ULP) and to investigate patient satisfaction and quality of life (QoL). Methods: This French monocentric case-control study included all patients enrolled in the ULP over a one-year period (cases) matched with retrospective patients receiving usual care (controls). Numbers of adverse events (AEs), re-hospitalisations, average relative dose intensity (ARDI), treatment response and survival were compared between the two groups. Among cases, patient satisfaction and QoL using the EORTC-QLQC30 questionnaire before and after treatment were evaluated. Results: Seventy-eight cases were matched to 78 controls. Twenty-six percent grade 3−4 AEs were observed in cases versus 38% in controls (p = 0.001). There were 76 and 88 re-hospitalisations in the case and control groups, respectively (p = 0.217). ARDI > 85% was observed in 92% and 82% of cases and controls, respectively (p = 0.138). No differences were observed in terms of treatment responses and survival. Estimated cost savings were of EUR 81,782 in favour of the case group. An improvement of 5.1 points was observed in the total QoL score before and after treatment in cases. Conclusions: A nurse−pharmacist−haematologist collaboration seems to be promising to reduce grade 3−4 AEs in HL and NHL patients receiving highly haematotoxic chemotherapy regimens. Cost savings from hospitalisation being avoided were also shown.
Purpose
Daratumumab is the first anti-CD38 monoclonal antibody of the class approved for recurrent and refractory multiple myeloma. Grade 3 and 4 Infusion-Related Reactions (IRRs) are frequent during ...the first and second infusions. Due to the risks associated with severe IRRs, daratumumab is systematically administered over a period of 3.5 hours.
The main objective of this study was to evaluate the safety of a 90-minute daratumumab infusion from the third infusion.
Patients and methods
All patients who had received two or more doses of daratumumab in monotherapy or in combination with standard infusion rates were included. We excluded patients enrolled in clinical trials. For the rapid infusion protocol, 20% of the dose was administered over 30 minutes and the remaining 80% over 60 minutes.
Results
From April 1 to May 31, 2019, 25 patients received 53 90-minute infusions of daratumumab. Premedication included corticosteroids, antipyretics, antihistamines, and if necessary a leukotriene receptor antagonist. No grade 3 or grade 4 IRRs were observed.
Conclusion
From the third infusion, we found that a rapid administration of daratumumab (90 vs 210 minutes) was well tolerated and safe. It would be interesting to test this regimen from the second infusion.
The outcomes of patients with relapsed and refractory multiple myeloma (RRMM) previously treated with the 3 main classes of myeloma therapy-immunomodulatory drugs, proteasome inhibitors, and ...anti-CD38 antibodies-remain poor. Recently, based on the phase II pivotal KarMMa trial showing prolonged overall survival (OS) and progression-free survival (PFS) in heavily treated patients, idecabtagene vicleucel (ide-cel), a B cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy (CAR-T) product, was approved in the United States for the treatment of RRMM. In France, since June 2021, an early access program has authorized the use of ide-cel in the setting of RRMM (defined as progressive myeloma after at least 3 previous regimens, including the 3 main antimyeloma therapies). We report the first French experience through this early access program in a retrospective study of 24 consecutive patients treated with ide-cel at our institution. The patients were evaluated according to International Myeloma Working Group criteria and by positron emission tomography computed tomography (PET-CT) at 1, 3, 6, 9, and 12 months after ide-cel infusion. Most patients had adverse cytogenetic abnormalities, and RRMM with triple-refractory drugs were seen in 79%. Bridging therapy was required for 19 of 24 patients. Before CAR-T cell infusion, lymphodepletion with fludarabine and cyclophosphamide was systematically performed. The median follow-up was 15.2 months. At 3 months after ide-cel infusion, 92% of patients achieved at least a partial response, and 50% achieved a complete response or better (≥CR). At 6 months, 70% of patients had a persistent ≥CR. At 3 and 6 months, bone marrow minimal residual disease (10
level) was undetectable in 79% and 75% of patients, respectively. At 6 months, CR as assessed by PET-CT was achieved in 15 of 20 patients (75%). The median PFS was 14.8 months, and median OS was not reached. Notably, an expansion of circulating CAR-T cells to >180/mm
after infusion was strongly associated with prolonged PFS. Additionally, the level of soluble BCMA measured before infusion was identified as a prognostic factor for PFS, likely correlated to the tumor burden. Grade 1-2 cytokine release syndrome (CRS) occurred in 22 of 24 patients (92%). Only 1 patient (4%) experienced grade ≥3 CRS. The occurrence of neurologic toxicity was infrequent (12.5%) and reversible in all cases. Hematologic toxicity was relatively common, and secondary hypogammaglobulinemia occurred in most patients. Infections (mostly viral) were frequent but most often nonsevere. This study echoes the promising results of the KarMMa trial and identifies possible prognostic indicators in RRMM patients treated with ide-cel, potentially refining treatment strategies and improving outcomes in this challenging context.
Objective
Immunomodulatory drugs (IMIDs: thalidomide, lenalidomide and pomalidomide) are widely used in patients with multiple myeloma (MM). The aim of our study was to validate a questionnaire to ...evaluate the self‐capacity of MM patients to manage IMID treatment including side effects.
Methods
We used a method adapted from the recommendations of the European Organisation for Research and Treatment of Cancer (EORTC) to validate a French questionnaire for patients with MM treated with IMIDs.
Results
The face validity was evaluated in 15 patients and the construct validity in 56 patients. For discriminant validity, two groups were constituted by gender and depending on whether they had a previous IMID treatment. The median questionnaire score was 11.33/16 (IQR 9.75‐12.08) with a minimum of 5.2 and a maximum of 14.75. For discriminant validity, a statistically significant difference was observed for patient capacity to contact healthcare professionals in specific situations and drug intake in case of swallowing disorder. Convergent validity showed an acceptable reliability for the scores of the different questions.
Conclusion
The questionnaire has shown to be a valid tool for the assessment of the adherence and side‐effect management skills for MM patients with IMID treatment.
Objectives
To investigate the efficacy, safety, and cost of a pomalidomide‐dexamethasone regimen in patients with relapsed and refractory multiple myeloma (RRMM).
Methods
All patients (n = 63) ...treated with pomalidomide‐dexamethasone for RRMM in our university hospital between August 2013 and October 2015 were included.
Results
Pomalidomide was discontinued early due to progression (before the 4th cycle) in 17 (27%) patients. No case was discontinued for intolerance. The only independent factor that predicted early pomalidomide discontinuation was time from diagnosis to pomalidomide initiation <3 years. Overall response rate was 51% including complete response in 8%, very good partial response in 25%, and partial response in 19% patients. Thirteen (33%) patients showed stable disease. Median overall survival was 6.4 months in the 17 patients who discontinued pomalidomide early vs 26.8 months in the 14 patients with stable disease vs not achieved in the 32 responders (log‐rank; P < 10−3). The most common grade ≥3 adverse events were neutropenia (14%) and infections (25%). The incremental cost‐effectiveness ratio of pomalidomide‐dexamethasone compared with dexamethasone alone was estimated at €39 911 per life‐year gained.
Conclusions
The study demonstrated that pomalidomide‐dexamethasone regimen has a long‐term favorable safety‐efficacy profile in RRMM patients. The survival benefit is substantial even in patients with stable disease.
Background. Pomalidomide in association with dexamethasone is approved for RRMM in 3rd line and beyond based on the MM-003 multicenter international phase 3 study that demonstrated greater efficacy ...for Pomalidomide plus dexamethasone over high dose dexamethasone. However, MM-003 mainly recruited advanced RRMM with a median of 5 prior lines. Few data is available regarding real life Pomalidomide-based treatment in 3rd and 4th line RRMM.
The aim of this study was to study efficacy and safety of Pomalidomide-based treatment in 3rd and 4th line RRMM.
Methods. We studied 108 consecutive RRMM treated with Pomalidomide-based treatment in 3rd and 4th line in a multicenter-based study. All assessment made according to IMWG.
Results. The median age was 62.5 (range, 30-86), with 36% older than 65 years, sex ratio M/F 1.25 and ISS disease stage 2 or 3 in 58%. 100% were exposed to bortezomib and refractory to Lenalidomide. 52 patients (48%) had pomalidomide-based therapy as 3rd, and 56 (52%) as 4th line. 73% of patients received a double-based therapy (Pomalidomide plus Dexamethasone) and 27% received a triple based therapy (Pomalidomide, Cyclophosphamide and Dexamethasone).
Overall ORR was 55%, with 20% ≥VGPR including 5% CR, and was not statistically different in 3rd versus 4th line, and with PCd versus Pd, although the former was always better.
With a median f-up of 45 months, overall 77% and 49% had relapsed and died, respectively, with significantly less in benefit to combination and 3rd line compared to Pd and 4th line (p=0.020). The median PFS was 6 (CI95% 2.3;9.6) and 9 (5.5;12.5) months in 3rd and 4th line (p=0.04), and 6 (CI95% 2.8;9.2) and 12 (8.5;15.5) months in Pd and PCd (p=0.04), respectively. Interestingly, the estimated 3 years PFS for 3rd line and PCd was 34% and 32% respectively, greatly superior to 4th line and Pd, 13% and 18%, respectively. Similarly, the median OS from start of Pomalidomide was not reached in 3rd and in PCd lines versus 23months (5;49), (p=0.04), and 32 months (5;-) for 4th line and Pd use, respectively.
Pomalidomide was never permanently discontinued for safety issues, but 30 (28% of patients had to reduced pomalidomide dose, 25% to N-1 that is 3mg/d and 3% at N-2 that is 2mg/d. Expectedly, more patients (increased by 10%) had to reduce pomalidomide dose in 4th line compared to 3rd line, although it was not statistically significant, but not with PCd versus Pd. Indeed Cyclophosphamide but not pomalidomide is reduced in modified in dose or scheme when facing safety issues. No patient died related to adverse events. AEs leading to pomalidomide-based modification in schema included hematological in 40% and non hematological AEs in 12% of patients. Overall, the most common adverse events grade 3 or 4 were neutropenia (22%), anemia (11%), thrombocytopenia (7%) and infectious disease (5%).
Conclusion. Pomalidomide-based therapy demonstrates efficacy in the real life with a manageable safety profile. We demonstrate herein that early use and combination improves MM on pomalidomide in the real life. Further prospective studies are warranted to confirm this data on a larger MM population.
Hulin:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Perrot:Janssen: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Macro:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Financial support for congress. Laribi:Hospira: Other: Grant; Amgen: Other: Personal fees; Novartis: Other: Grant and personal fees; Gilead: Other: Personal fees; Roche: Other: Grant; Takeda: Other: Grant and personal fees; Sandoz: Other: Grant; Teva: Other: Grant. Leleu:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.
In contrast to natural antibodies that rely mainly on the heavy chain to establish contacts with their cognate antigen, we have developed a bispecific antibody format in which the light chain (LC) ...drives antigen binding and specificity. To better understand epitope-paratope interactions in this context, we determined the X-ray crystallographic structures of an antigen binding fragment (Fab) in complex with human CD47 and another Fab in complex with human PD-L1. These Fabs contain a κ-LC and a λ-LC, respectively, which are paired with an identical heavy chain (HC). The structural analysis of these complexes revealed the dominant contribution of the LCs to antigen binding, but also that the common HC provides some contacts in both CD47 and PD-L1 Fab complexes. The anti-CD47 Fab was affinity optimized by diversifying complementary-determining regions of the LC followed by phage display selections. Using homology modeling, the contributions of the amino acid modification to the affinity increase were analyzed. Our results demonstrate that, despite a less prominent role in natural antibodies, the LC can mediate high affinity binding to different antigens and neutralize their biological function. Importantly, Fabs containing a common variable heavy (VH) domain enable the generation of bispecific antibodies retaining a truly native structure, maximizing their therapeutic potential.In contrast to natural antibodies that rely mainly on the heavy chain to establish contacts with their cognate antigen, we have developed a bispecific antibody format in which the light chain (LC) drives antigen binding and specificity. To better understand epitope-paratope interactions in this context, we determined the X-ray crystallographic structures of an antigen binding fragment (Fab) in complex with human CD47 and another Fab in complex with human PD-L1. These Fabs contain a κ-LC and a λ-LC, respectively, which are paired with an identical heavy chain (HC). The structural analysis of these complexes revealed the dominant contribution of the LCs to antigen binding, but also that the common HC provides some contacts in both CD47 and PD-L1 Fab complexes. The anti-CD47 Fab was affinity optimized by diversifying complementary-determining regions of the LC followed by phage display selections. Using homology modeling, the contributions of the amino acid modification to the affinity increase were analyzed. Our results demonstrate that, despite a less prominent role in natural antibodies, the LC can mediate high affinity binding to different antigens and neutralize their biological function. Importantly, Fabs containing a common variable heavy (VH) domain enable the generation of bispecific antibodies retaining a truly native structure, maximizing their therapeutic potential.
Mixed oxides of uranium and plutonium U1-yPuyO2-x are currently studied as reference fuel for Sodium-cooled Fast Reactors (SFRs). To predict the margin to fuel melting, an accurate description of ...both solidus and liquidus temperatures of these materials is crucial. In this work, after a critical review of the literature data, the parameters of the liquid phase of the CALPHAD models of the Pu–O and U–Pu–O systems are reassessed based on the model of Guéneau et al.. A good agreement between the calculated and selected experimental data is obtained. Using this model, the melting behaviour of U1-yPuyO2±x oxides is then studied as a function of plutonium content and oxygen stoichiometry. The congruent melting for the mixed oxides is found to be shifted towards low O/M ratios compared to the end-members (UO1.97 and PuO1.95). The temperature of this congruent melting is nearly constant (3130–3140 K) along a ternary phase boundary from UO1.98 to U0.55Pu0.45O1.82 and then decreases with Pu content to a maximum of approximately 3040 K for PuO1.95. This observation is explained by the stabilisation of the hypo-stoichiometric mixed oxides due to the increase of the configurational entropy at high temperatures by the formation of oxygen vacancies and related cation mixing. The influence of the atmosphere used in the laser heating melting experiments on the oxygen stoichiometry of the sample and its solidus and liquidus temperatures is investigated. The determination of this O/M ratio after laser melting tests using XANES is also reported. The simultaneous presence of U6+, U5+, U4+, Pu3+ and Pu4+ is observed, highlighting the occurrence of charge compensation mechanisms. The samples are highly oxidised in air whereas close to stoichiometry (O/M = 2.00) in argon. These results are in agreement with the computed solidification paths. This work illustrates the complex melting behaviour of the U1-yPuyO2±x fuels and highlights the need for the CALPHAD method to accurately describe and predict the high-temperature transitions of the U–Pu–O system.
•New CALPHAD models of the liquid phase of the Pu–O and U–Pu–O systems are developed.•Cationic distributions and O/M ratios of molten samples were determined by XANES.•A congruent-melting line is predicted for O/M < 2.00 with the stabilisation of the oxide.•The formation of oxygen vacancies and the reduction of plutonium stabilises the oxide.•The O/M ratio evolution is described during cooling from the melt to room temperature.
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