In Support of a Patient-Driven Initiative and Petition to Lower the High Price of Cancer Drugs

Comment in Lowering the High Cost of Cancer Drugs--III. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--I. [Mayo Clin Proc. 2016] Lowering the High Cost of Cancer Drugs--IV. [Mayo Clin Proc. 2016] In Reply--Lowering the High Cost of Cancer Drugs. [Mayo Clin Proc. 2016] US oncologists call for government regulation to curb drug price rises. [BMJ. 2015

RadioImmunotherapy for adenoid cystic carcinoma: a single-institution series of combined treatment with cetuximab

<p>Abstract</p> <p>Background</p> <p>Local control in adjuvant/definitive RT of adenoid cystic carcinoma (ACC) is largely dose-dependent. However, some clinical situations do not allow application of tumouricidal doses (i.e. re-irradiation) hence radiation sensitization by exploitation of high endothelial growth factor receptor (EGFR)-expression in ACC seems beneficial. This is a single-institution experience of combined radioimmunotherapy (RIT) with the EGFR-inhibitor cetuximab.</p> <p>Methods</p> <p>Between 2006 and 2010, 9 pts received RIT for advanced/recurrent ACC, 5/9 pts as re-irradiation. Baseline characteristics as well as treatment parameters were retrieved to evaluate efficacy and toxicity of the combination regimen were evaluated. Control rates (local/distant) and overall survival were calculated using Kaplan-Meier estimation.</p> <p>Results</p> <p>Median dose was 65 Gy, pts received a median of 6 cycles cetuximab. RIT was tolerated well with only one °III mucositis/dysphagia. Overall response/remission rates were high (77,8%); 2-year estimate of local control was 80% hence reaching local control levels comparable to high-dose RT. Progression-free survival (PFS) at 2 years and median overall survival were only 62,5% and 22,2 mo respectively.</p> <p>Conclusion</p> <p>While local control and treatment response in RIT seems promising, PFS and overall survival are still hampered by distant failure. The potential benefit of RIT with cetuximab warrants exploration in a prospective controlled clinical trial.</p

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

Background: Despite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90-90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact. Methods: A scoping review was done following Arksey & O'Malley's methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles. Results: Twenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures. Conclusions: This review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied

Efficacy and Toxicity Management of 19-28z CAR T Cell Therapy in B Cell Acute Lymphoblastic Leukemia

This find is registered at Portable Antiquities of the Netherlands with number PAN-0007866

Rabbit Anti-Thymocyte Globulin Exposure (rATG) in CD34+ Selected Hematopoietic Cell Transplantation and Its Impact on Immune Reconstitution and Outcomes in Children and Adults

Background: Rabbit anti-thymocyte globulin (rATG) is used in allogeneic hematopoietic cell transplantation (alloHCT) to prevent graft versus host-disease (GVHD) and graft rejection. In the T-cell replete setting, post-HCT rATG exposure is variable with high exposures resulting in delayed CD4+immune reconstitution (CD4+IR) and higher mortality. The goal of this study was to estimate the rATG exposure in pediatric and adult recipients of ex vivo T-cell depleted CD34+ selected alloHCT and correlate it with outcomes to determine the optimal exposure. Methods: We performed a retrospective analysis of patients who underwent their first myeloablative-conditioned ex vivo CD34+ selected alloHCT between 2008 and 2018. Post-HCT rATG exposure was estimated as area under the curve (AUC) (mg*d/L) using a validated population pharmacokinetic (PK) model (Admiraal et al.,Lancet Hematology 2017). Outcomes of interest were CD4+IR, defined as CD4+&amp;gt;50/uL at two consecutive measures within 100 days of HCT, non-relapse mortality (NRM), overall survival (OS), GVHD, and relapse. We evaluated the association between post-HCT rATG exposures and CD4+IR using a smoothed effect to define the optimal post-HCT rATG exposure. We subsequently analyzed outcomes in 3 post-HCT rATG exposure groups, &amp;lt;30 mg*d/L, 30-55 mg*d/L, and &amp;gt;=55 mg*d/L. Cox proportional hazard models and multi-state competing risk models were used for analyses. Results: Of 554 patients included, 239 (43%) were female, median age at HCT was 49 (range 0.2 to 73) years and 425 (76.7%) received matched donor transplant, while 129 (23.3%) patients received mismatched donor HCT. In this cohort of patients, 515 (93%) underwent alloHCT for hematologic malignancies - leukemia: 356 (64.3%), myelodysplastic syndrome: 122 (22%), and other hematological malignancies: 37 (6.7%) while 39 (7%) underwent alloHCT for non-malignant indications. Total Body Irradiation based conditioning regimen was administered in 177 (32%) patients. Among all 554 patients, 540 (97%) attained engraftment. Median post-HCT rATG exposure was 47mg*d/L (range 0 - 101 mg*d/L). A decreasing post-HCT AUC (optimum &amp;lt;30 mg*d/L) was associated with higher probability of CD4+IR (p&amp;lt; 0.0001, Figure 1a); lower NRM (p=0.03, Figure 1b) and improved OS (p=0.05, Figure 1c). Patients who attained CD4+IR earlier had lower rates of NRM (p&amp;lt;0.0001, Figure 1d). On further assessing rATG exposure post allo-HCT by three cut -off levels (&amp;lt;30mg*d/L, 30-55 mg*d/L and &amp;gt;=55 mg*d/L), time to CD4+IR varied depending on the ATG exposure (Figure 1e). In multivariable cox models, post-HCT rATG exposure &amp;gt;=55 mg*d/L was associated with an increased risk of NRM as compared to the lower exposure of &amp;lt;30 mg*d/L (HR: 4.11, CI: 1.52, 11.2, Figure 1f), and inferior OS (HR: 2.03, CI: 1.03,4.00, Figure 1g). In addition, post-HCT rATG exposure &amp;gt;=55 mg*d/L was associated with a higher risk of acute GVHD (HR: 2.28, CI: 1.01, 5.16, Figure 1h). In patients with hematologic malignancies, post-HCT rATG exposure was not associated with relapse (HR: 0.73, CI: 0.31,1.7). In the entire cohort of 554 patients, 9 (1.6%) patients had graft rejection: 1 primary rejection in the post-HCT ATG exposure &amp;lt;30mg*d/L group, 6 secondary rejections in the post-HCT ATG exposure of 30-55 mg*d/L group and 2 secondary rejections in the post-HCT ATG exposure &amp;gt;=55mg*d/L group. Among all patients, 204 (37%) died secondary to reasons such as relapse of disease: 73 (36%), infection: 51 (25%), GVHD: 40 (20%), toxicity/organ failure: 29 (14%) and other causes: 11 (5%). Conclusions: In a large cohort of patients who underwent ex vivo CD34+ selected alloHCT, higher post-HCT rATG exposure led to higher NRM, a paradoxical increase in GVHD, and lower OS driven by poorer CD4+ IR. The increased rates of GVHD with higher post-HCT exposure may be related to increased infections in these cohorts, though this needs to be explored further. Individualizing rATG dosing by PK targeting to a low post-HCT rATG exposure may improve outcomes. We intend to validate these results in a forthcoming prospective clinical trial. Figure 1 Disclosures Scordo: McKinsey &amp; Company: Consultancy; Angiocrine Bioscience, Inc.: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Other: Ad-hoc advisory board. Curran:Celgene: Research Funding; Novartis: Consultancy, Research Funding; Mesoblast: Consultancy. Kernan:Amgen: Current equity holder in publicly-traded company; Merck: Current equity holder in publicly-traded company; Johnson and Johnson: Current equity holder in publicly-traded company; Pfizer: Current equity holder in publicly-traded company. O'Reilly:Atara Biotherapeutics: Consultancy, Patents &amp; Royalties: EBV-specific T-cell bank, Research Funding. Prockop:Mesoblast, Inc,: Consultancy, Honoraria, Research Funding; Atara: Research Funding; Jasper: Research Funding. Scaradavou:Excellthera: Membership on an entity's Board of Directors or advisory committees. Shah:Amgen Inc.: Research Funding; Janssen: Research Funding. Giralt:OMEROS: Consultancy, Honoraria; NOVARTIS: Consultancy, Honoraria, Research Funding; KITE: Consultancy; MILTENYI: Consultancy, Research Funding; ACTINUUM: Consultancy, Research Funding; TAKEDA: Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Research Funding. Perales:Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; MolMed: Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Boelens:Bluebird Bio: Consultancy; Advanced Clinical: Consultancy; Race Oncology: Consultancy; Bluerock: Consultancy; Omeros: Consultancy; Avrobio: Consultancy; Takeda: Consultancy. </jats:sec

Antithymocyte globulin exposure in CD34+ T-cell–depleted allogeneic hematopoietic cell transplantation

Abstract Traditional weight-based dosing results in variable rabbit antithymocyte globulin (rATG) clearance that can delay CD4+ T-cell immune reconstitution (CD4+ IR) leading to higher mortality. In a retrospective pharmacokinetic/pharmacodynamic (PK/PD) analysis of patients undergoing their first CD34+ T-cell–depleted (TCD) allogeneic hematopoietic cell transplantation (HCT) after myeloablative conditioning with rATG, we estimated post-HCT rATG exposure as area under the curve (arbitrary unit per day/milliliter [AU × day/mL]) using a validated population PK model. We related rATG exposure to nonrelapse mortality (NRM), CD4+ IR (CD4+ ≥50 cells per µL at 2 consecutive measures within 100 days after HCT), overall survival, relapse, and acute graft-versus-host disease (aGVHD) to define an optimal rATG exposure. We used Cox proportional hazard models and multistate competing risk models for analysis. In all, 554 patients were included (age range, 0.1-73 years). Median post-HCT rATG exposure was 47 AU × day/mL (range, 0-101 AU × day/mL). Low post-HCT area under the curve (&amp;lt;30 AU × day/mL) was associated with lower risk of NRM (P &amp;lt; .01) and higher probability of achieving CD4+ IR (P &amp;lt; .001). Patients who attained CD4+ IR had a sevenfold lower 5-year NRM (P &amp;lt; .0001). The probability of achieving CD4+ IR was 2.5-fold higher in the &amp;lt;30 AU × day/mL group compared with 30-55 AU × day/mL and threefold higher in the &amp;lt;30 AU × day/mL group compared with the ≥55 AU × day/mL group. In multivariable analyses, post-HCT rATG exposure ≥55 AU × day/mL was associated with an increased risk of NRM (hazard ratio, 3.42; 95% confidence interval, 1.26-9.30). In the malignancy subgroup (n = 515), a tenfold increased NRM was observed in the ≥55 AU × day/mL group, and a sevenfold increased NRM was observed in the 30-55 AU × day/mL group compared with the &amp;lt;30 AU × day/mL group. Post-HCT rATG exposure ≥55 AU × day/mL was associated with higher risk of a GVHD (hazard ratio, 2.28; 95% confidence interval, 1.01-5.16). High post-HCT rATG exposure is associated with higher NRM secondary to poor CD4+ IR after TCD HCT. Using personalized PK-directed rATG dosing to achieve optimal exposure may improve survival after HCT.</jats:p

Two Chemotherapy-Based Conditioning Regimens Compared To TBI-Based Conditioning Secure Consistent Engraftment Of T-Cell Depleted Allogeneic HSCT, Similarly Low Incidences Of Gvhd and Favorable Rates Of Disease-Free Survival (DFS)

Abstract To ascertain the therapeutic potential of non-TBI-based conditioning for CD34+ HPC-selected , T cell-depleted allografts, we conducted a trial comparing our standard regimen, arm (A) 1375cGy HFTBI+ thiotepa,5 mg/kg/day x 2 days + cyclophosphamide 60 mg/kg/day x 2 days vs. arm (B) Busulfex 0.8 mg/kg/6h x12 (dose adjusted) + melphalan 70 mg/kg/day x 2 + fludarabine 25 mg/m2/day x5 and arm (C) Clofarabine 20 mg/m2/day x 5 + melphalan 70 mg/m2/day x 2 + thiotepa 5 mg/kg/day x2, as preparation for T-cell depleted CD34+ PBSC transplants from GCSF-mobilized leukocytes fractionated with the CliniMACS device. Primary endpoints were engraftment, GVHD, transplant-related mortality (TRM) and 2 yr OS and DFS (Confer Table). Stratification of pts to arms A (standard), B or C was based on the patient’s disease, disease stage and clinical factors such as age, prior therapy or comorbidities enhancing risks of TBI. Arm B was the non-TBI arm predominantly used for myeloid and Arm C for lymphoid malignancies. Prior to transplant, recipients of HLA-matched or non-identical transplants received rabbit thymoglobulin at 2.5 mg/kg/day x2 or 3 days respectively, to prevent graft failure. No GVHD drug prophylaxis was given post transplant. A total of 181 consecutive patients, accrued between 5/13/2010 and 6/12/2013, were analyzed (81 in arm A, 78 in arm B, 22 in arm C). These pts have been followed for a median of 12.1 months. Donors were related or unrelated and HLA-matched for 74% of the patients and 1-2 HLA allele disparate for 26%. Median age for the entire group was 50.5 years, with older pts predominating in the non-TBI groups (medians arm A ,31.9 yrs; arm B , 61.9 yrs; arm C, 44.6 yrs). The CD34+ PBSC transplants provided a mean dose of 9.7x106 CD34+ progenitors/Kg (range 1.4-89.7) and 4.5x103 CD3+ T-cells/Kg (range 0.6-25.3). All pts engrafted; but 2 pts (2.5%) in arm B experienced late graft failure, one of whom was reconstituted after a secondary graft. Overall the incidence of grade II-IV acute GVHD was 18%, and 14% for recipients of HLA-matched grafts. TRM at 1 year was 10% in Arm A, and 15% in Arms B and C. Two year OS and DFS for each arm are: arm A, 66.7% and 58.4%; arm B 62.3% and 59.5%; arm C 52% and 53%. For the 101 pts who received standard risk transplants (i.e., pts with high risk forms of AML, ALL or NHL in 1o CR, AML in 2o CR, MDS RA/RCMD, CML in 1o CP or MM in CR1, VGPR or first PR ), 2 year OS and DFS are: arm A 68% and 62%; arm B 67% and 66%; arm C 86% and 86%, with relapse rates at 2 yrs of: arm A 23%, arm B 15%, and arm C 14%. These results thus identify two non-TBI-based conditioning regimens that secure consistent engraftment of rigorously T-cell depleted allogeneic HSCT and can yield favorable long-term DFS and OS with low incidences of GVHD and relapse. Table 1 Overall Results Graft 1 Year Acute GVHD II – IV 2 Year PTs ENG Failure TRM ALL HLA-Matched O.S. DFS ARM A 81 81 0 10% 23% 17% 66.7% 58.4% ARM B 78 78 2 15% 12.3% 13% 62.3% 59.5% ARM C 22 22 0 15% 27% 20% 52% 53% Disclosures: No relevant conflicts of interest to declare. </jats:sec

Effects of Switching from Stavudine to Raltegravir on Subcutaneous Adipose Tissue in HIV-Infected Patients with HIV/HAART-Associated Lipodystrophy Syndrome (HALS). A Clinical and Molecular Study

HIV-1/HAART-associated lipodystrophy syndrome (HALS) has been associated with exposure to stavudine (d4T) through mitochondrial dysfunction. We performed a 48-week study to assess the effects of switching from d4T to raltegravir (RAL) on metabolic and fat molecular parameters of patients with HALS. Forty-two patients with HALS and a median exposure to d4T > 7 years were switched to RAL and followed for 48 weeks. Fasting metabolic tests, HIV RNA, CD4 cell count, and fat measured by DEXA were obtained at baseline and week 48. mtDNA and gene transcripts for PPAR gamma, adiponectin, cytochrome b, Cox IV, TNF alpha, MCP-1 and CD68 were assessed in paired subcutaneous fat tissue biopsies. Lipid parameters, fasting glucose, insulin, and HOMA-IR did not change significantly. Whole body fat (P = 0.0027) and limb fat mass (P<0.0001) increased from baseline. Trunk/limb fat ratio (P = 0.0022), fat mass ratio (P = 0.0020), fat mass index (P = 0.0011) and percent leg fat normalized to BMI (P<0.0001) improved after 48 weeks. Relative abundance of mtDNA, expression of PPAR gamma, adiponectin, Cyt b, and MCP-1 genes increased, whereas Cox IV, TNF alpha, and CD68 did not change significantly from baseline. Switching from d4T to RAL in patients with HALS is associated with an increase in limb fat mass and an improvement in markers of adipocyte differentiation and mitochondrial function in SAT

Strategies to reengage patients lost to follow up in HIV care in high income countries, a scoping review

AbstractBackgroundDespite remarkable achievements in antiretroviral therapy (ART), losses to follow-up (LTFU) might prevent the long-term success of HIV treatment and might delay the achievement of the 90–90-90 objectives. This scoping review is aimed at the description and analysis of the strategies used in high-income countries to reengage LTFU in HIV care, their implementation and impact.MethodsA scoping review was done following Arksey &amp; O′Malley’s methodological framework and recommendations from Joanna Briggs Institute. Peer reviewed articles were searched for in Pubmed, Scopus and Web of Science; and grey literature was searched for in Google and other sources of information. Documents were charted according to the information presented on LTFU, the reengagement procedures used in HIV units in high-income countries, published during the last 15 years. In addition, bibliographies of chosen articles were reviewed for additional articles.ResultsTwenty-eight documents were finally included, over 80% of them published in the United States later than 2015. Database searches, phone calls and/or mail contacts were the most common strategies used to locate and track LTFU, while motivational interviews and strengths-based techniques were used most often during reengagement visits. Outcomes like tracing activities efficacy, rates of reengagement and viral load reduction were reported as outcome measures.ConclusionsThis review shows a recent and growing trend in developing and implementing patient reengagement strategies in HIV care. However, most of these strategies have been implemented in the United States and little information is available for other high-income countries. The procedures used to trace and contact LTFU are similar across reviewed studies, but their impact and sustainability are widely different depending on the country studied.</jats:sec