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This article analyzes a situation encountered by eParts Services, a web portal provider, when looking to expand into the European market. It focuses on the challenges involved in meeting GDPR regulation and proposes a variety of approaches on how they could meet regulatory needs.

Key Points Ofatumumab with glucocorticoid therapy for cGVHD resulted in 62.5% ORR at 6 months and 53% FFS at 12 months.Safety was observed with ofatumumab plus glucocorticoid for initial therapy., Visual Abstract, Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal response. Safety and feasibility of therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n = 12). We now report the mature results of the phase II expansion of the trial (n = 38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR = complete + partial response [CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial immune suppression agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial was registered at www.clinicaltrials.gov as #NCT01680965.

Purpose:In this first-in-human, phase I, GVHD prevention trial (NCT02891603), we combine pacritinib (PAC), a JAK2 inhibitor, with sirolimus to concurrently reduce T-cell costimulation via mTOR and IL6 activity. We evaluate the safety of pacritinib when administered with sirolimus plus low-dose tacrolimus (PAC/SIR/TAC) after allogeneic hematopoietic cell transplantation.Patients and Methods:The preclinical efficacy and immune modulation of PAC/SIR were investigated in xenogeneic GVHD. Our phase I trial followed a 3+3 dose-escalation design, including dose level 1 (pacritinib 100 mg daily), level 2 (pacritinib 100 mg twice daily), and level 3 (pacritinib 200 mg twice daily). The primary endpoint was to identify the lowest biologically active and safe dose of pacritinib with SIR/TAC (n = 12). Acute GVHD was scored through day +100. Allografts included 8/8 HLA-matched related or unrelated donor peripheral blood stem cells.Results:In mice, we show that dual JAK2/mTOR inhibition significantly reduces xenogeneic GVHD and increases peripheral regulatory T cell (Treg) potency as well as Treg induction from conventional CD4+ T cells. Pacritinib 100 mg twice a day was identified as the minimum biologically active and safe dose for further study. JAK2/mTOR inhibition suppresses pathogenic Th1 and Th17 cells, spares Tregs and antileukemia effector cells, and exhibits preliminary activity in preventing GVHD. PAC/SIR/TAC preserves donor cytomegalovirus (CMV) immunity and permits timely engraftment without cytopenias.Conclusions:We demonstrate that PAC/SIR/TAC is safe and preliminarily limits acute GVHD, preserves donor CMV immunity, and permits timely engraftment. The efficacy of PAC/SIR/TAC will be tested in our ongoing phase II GVHD prevention trial.

The table shows maximum acute GVHD organ stage and overall grade observed through day +100 after transplant on the PAC/SIR/TAC phase I trial.

The table shows the characteristics of patients treated on the PAC/SIR/TAC phase I trial.

Noradrenaline levels in patients with grade 0, grade 1, grade 2 and grade 4 CRS respectively.

Impact of JAK2/mTOR blockade on human NK cell function and proliferation. A) Graph shows the cytolytic activity ({plus minus}SEM) of NK cells after 4 hours of culture with K562 target cells, while exposed to DMSO, ruxolitinib (lμM), pacritinib (1.25μM), sirolimus 10ng/ml, or a combination of pacritinib plus sirolimus. B) Human NK cells (105 ) were stimulated with a cytokine cocktail of recombinant human (rh) IL-2 (200 IU/ml) and rhll-15 (10 ng/ml), in the presence of DMSO, ruxolitinib, pacritinib, sirolimus, or pacritinib plus sirolimus. Drugs were added once on day 0. Cytokines were replenished on day +3. Bar graph shows NK cell proliferation ({plus minus}SEM) on day +5 of the culture using a colorimetric assay.

The table shows the pharmacokinetic analysis of pacritinib concentration over time.

The table shows pacritinib adherence during treatment period according to dose level on the PAC/SIR/TAC phase I trial.

Safety measures monitored on trial including (A) QTcF, (B) cardiac ejection fraction, (C) prothrombin time, (D) partial thromboplastin time, (E) and thrombin time

The table shows adverse events per CTCAE version 5 encountered during the PAC/SIR/TAC phase I trial.

Purpose:One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).Experimental Design:Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.Results:We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.Conclusions:These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.

CD4+ T cell Aurora kinase A activation as a GVHD resistance mechanism. A) Graph shows frequency of CD4+, pHistone 3 serine 10+ (pH3ser10) (downstream of CD28, and parallel to mTOR) T cells (mean{plus minus} SEM) at day +21 among patients treated on dose level 1 or dose level 2 of the phase I trial compared to baseline control values. B) Graph depicts the frequency (mean {plus minus} SEM) of CD4+, pH3ser10+ T cells recovered from NSG spleens at day +14, following transplantation with human PBMCs and then treated with vehicle, pacritinib, 531-201, sirolimus, pacritinib plus sirolimus, or 531-201 plus sirolimus for 2 weeks.

The table shows the maximum chronic GVHD organ involvement and overall score per NIH Diagnosis and Staging Criteria through full extent of study follow up on the PAC/SIR/TAC phase I trial.

Supplementary tables and figure legends

Impact of JAK2 or STAT3 inhibition plus mTOR blockade on DC-allostimulated human T cell production of IFNγ, IL-13, and GM-CSF. 5-day alloMLRs were treated with DMSO vehicle control, pacritinib 1.25μM, S3I-201 5μM, sirolimus 10ng/ml, pacritinib plus sirolimus, or S3I-201 plus sirolimus. The graphs show the concentrations of A) IFNγ, B) IL-13, and C) GM-CSF (mean{plus minus}SEM) as measured in the supernatants of the culture medium by a cytokine multiplex assay.

Extended Methods including information and details regarding flow cytometry, cell lines, allogeneic mixed leukocyte reactions, Treg Suppression Assays, Xenogeneic GVHD modeling, and key reagents.

The table shows donor chimerism in unsorted bone marrow, and peripheral blood CD3 and CD33 populations from patients treated on the PAC/SIR/TAC phase I trial.

Serial measures of absolute neutrophil count (ANC), hemoglobin (Hgb) and platelet counts (PLT) through complete pacritinib treatment period

The table shows donor/recipient CMV serostatus.

Impact of JAK2/mTOR blockade on human T cell responses toward CMV, EBV, Influenza, and tetanus stimulation. A, B) Graphs show the recall proliferation of CD4+ and CD8+ T cell proliferation in response to CEFT peptides. C, D) Graph shows the frequency of IFNy+, CD107a+ CD4+ or cos+ T cells after stimulation with CEFT peptides.

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4+ T cell, CD8+ T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4+ T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19+ B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative therapy for myelodysplastic syndromes (MDS), although it is infrequently offered to older patients. The relative benefits of HCT over non-HCT therapy in older patients with higher-risk MDS have not been defined. METHODS We conducted a multicenter biologic assignment trial comparing reduced-intensity HCT to hypomethylating therapy or best supportive care in subjects 50-75 years of age with intermediate-2 or high-risk de novo MDS. The primary outcome was overall survival probability at 3 years. Between January 2014 and November 2018, we enrolled 384 subjects at 34 centers. Subjects were assigned to the Donor or No-Donor arms according to the availability of a matched donor within 90 days of study registration. RESULTS The median follow-up time for surviving subjects was 34.2 months (range: 2.3-38 months) in the Donor arm and 26.9 months (range: 2.4-37.2 months) in the No-Donor arm. In an intention-to-treat analysis, the adjusted overall survival rate at 3 years in the Donor arm was 47.9% (95% CI, 41.3 to 54.1) compared with 26.6% (95% CI, 18.4 to 35.6) in the No-Donor arm ( P = .0001) with an absolute difference of 21.3% (95% CI, 10.2 to 31.8). Leukemia-free survival at 3 years was greater in the Donor arm (35.8%; 95% CI, 29.8 to 41.8) compared with the No-Donor arm (20.6%; 95% CI, 13.3 to 29.1; P = .003). The survival benefit was seen across all subgroups examined. CONCLUSION We observed a significant survival advantage in older subjects with higher-risk MDS who have a matched donor identified and underwent reduced-intensity HCT, when compared with those without a donor. HCT should be included as an integral part of MDS management plans in fit older adults with higher-risk MDS.

Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day −5 (5 mg orally 3 times a week) with tacrolimus initiated on day −3 plus sirolimus on day −1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8–matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor–stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.

Background Fatigue is a prominent quality of life concern among recipients of hematopoietic cell transplantation (HCT). Purpose The present study investigated whether objectively measured sleep efficiency and sedentary behavior are related to greater reports of fatigue. Methods Eighty-two allogeneic HCT recipients who were 1–5 years post-transplant and returning for a follow-up visit participated (age M = 56, 52% female, 56% leukemia). They wore an actigraph assessing sleep efficiency and sedentary behavior for one week and completed an electronic log assessing fatigue each evening during the same period. Results Twenty-six percent of patients reported clinically meaningful fatigue. On average, fatigue was mild (M = 2.5 on 0–10 scale, SD = 2.0), sleep was disturbed (sleep efficiency M = 78.9%, SD = 8.9), and patients spent the majority of time in sedentary (M = 55.4%, SD = 10.2) or light (M = 35.9%, SD = 8.6) activity. Multilevel model analysis of between-person differences indicated that patients who experienced less efficient sleep the previous evening provided greater evening reports of average fatigue, b = –0.06, 95% CI (–0.11, –0.01). Similarly, within-person analyses indicated that when patients experienced less efficient sleep the previous evening or were more sedentary as compared to their average, they provided greater evening reports of average fatigue, b = –0.02, 95% CI (–0.05, –0.004); b = 4.46, 95% CI (1.95, 6.97), respectively. Conclusions Findings demonstrate that poor sleep and daily sedentary behavior are related to evening reports of fatigue and should be considered modifiable targets for intervention.

Purpose:One of the challenges of adoptive T-cell therapy is the development of immune-mediated toxicities including cytokine release syndrome (CRS) and neurotoxicity (NT). We aimed to identify factors that place patients at high risk of severe toxicity or treatment-related death in a cohort of 75 patients with large B-cell lymphoma treated with a standard of care CD19 targeted CAR T-cell product (axicabtagene ciloleucel).Experimental Design:Serum cytokine and catecholamine levels were measured prior to lymphodepleting chemotherapy, on the day of CAR T infusion and daily thereafter while patients remained hospitalized. Tumor biopsies were taken within 1 month prior to CAR T infusion for evaluation of gene expression.Results:We identified an association between pretreatment levels of IL6 and life-threatening CRS and NT. Because the risk of toxicity was related to pretreatment factors, we hypothesized that the tumor microenvironment (TME) may influence CAR T-cell toxicity. In pretreatment patient tumor biopsies, gene expression of myeloid markers was associated with higher toxicity.Conclusions:These results suggest that a proinflammatory state and an unfavorable TME preemptively put patients at risk for toxicity after CAR T-cell therapy. Tailoring toxicity management strategies to patient risk may reduce morbidity and mortality.

BACKGROUND Quantification of skeletal muscle using computed tomography (CT) is accessible using cancer patients' standard oncologic images. Reduced muscle mass may be related to reduced respiratory muscle strength; however, the impact of this on lung functional parameters is not characterized in adult allogeneic haematopoietic stem cell transplant (alloHCT) recipients. METHODS A consecutive retrospective series (n = 296) of patients who had alloHCT at a comprehensive cancer centre between March 2005 and April 2015 were included. Pre-transplant CT scans were used to quantify skeletal muscle and adipose tissue at the fourth thoracic (T4) and/or third lumbar (L3) level. Tumour and patient characteristics were recorded, including forced expiratory volume in 1 second (FEV1 ) by spirometry. Regression models were created to characterize predictive relationships. RESULTS A total of 296 patients (♂n = 161; ♀n = 135) were included, all of whom had chest CT as part of standard care; a subset of these (n = 215, 72.6%) also had abdominal CT. Diagnoses were non-Hodgkins lymphoma (n = 165), acute myeloid leukaemia (n = 66), Hodgkin's disease (n = 14), acute lymphocytic leukaemia (n = 14), myelodysplastic syndromes (n = 18), and other (n = 19). In multivariable linear regression adjusted for sex (P

There is a lack of large comparative study on the outcomes of reduced intensity conditioning (RIC) in acute myeloid leukemia (AML) transplantation using fludarabine/busulfan (FB) and fludarabine/melphalan (FM) regimens. Adult AML patients from Center for International Blood and Marrow Transplant Research who received first RIC allo-transplant between 2001 and 2015 were studied. Patients were excluded if they received cord blood or identical twin transplant, total body irradiation in conditioning, or graft-versus-host disease (GVHD) prophylaxis with in vitro T-cell depletion. Primary outcome was overall survival (OS), secondary end points were leukemia-free survival (LFS), nonrelapse mortality (NRM), relapse, and GVHD. Multivariate survival model was used with adjustment for patient, leukemia, and transplant-related factors. A total of 622 patients received FM and 791 received FB RIC. Compared with FB, the FM group had fewer transplant in complete remission (CR), fewer matched sibling donors, and less usage of anti-thymocyte globulin or alemtuzumab. More patients in the FM group received marrow grafts and had transplantation before 2005. OS was significantly lower within the first 3 months posttransplant in the FM group (hazard ratio [HR] = 1.82, P < .001), but was marginally superior beyond 3 months (HR = 0.87, P = .05). LFS was better with FM compared with FB (HR = 0.89, P = .05). NRM was significantly increased in the FM group during the first 3 months of posttransplant (HR = 3.85, P < .001). Long-term relapse was lower with FM (HR = 0.65, P < .001). Analysis restricted to patients with CR showed comparable results. In conclusion, compared with FB, the FM RIC showed a marginally superior long-term OS and LFS and a lower relapse rate. A lower OS early posttransplant within 3 months was largely the result of a higher early NRM.

The novel coronavirus, SARS-CoV-2, was first detected as a respiratory illness in December 2019 in Wuhan City, China. Since then, coronavirus disease 2019 (COVID-19) has impacted every aspect of our lives worldwide. In a time when terms such as social distancing and flattening the curve have become a part of our vernacular, it is essential that we understand what measures can be implemented to protect our patients and healthcare workers. Undoubtedly, healthcare providers have had to rapidly alter care delivery models while simultaneously acknowledging the crucial unknowns of how these changes may affect clinical outcomes. This special feature reviews strategies on how to mitigate transmission of COVID-19 in an effort to reduce morbidity and mortality associated with the disease for patients with cancer without infection, for patients with cancer with COVID-19 infection, and for the healthcare workers caring for them, while continuing to provide the best possible cancer care. [Editor’s Note: This article includes the most current information available at time of publication; however, recommendations regarding public safety and practice may change rapidly in this situation. Individuals should get the most up to date information from the CDC website.]

Central nervous system (CNS) manifestation of chronic graft versus host disease (cGVHD) is a rare, difficult to diagnose phenomenon that can follow allogeneic hematopoietic stem cell transplantation (HSCT). CNS-cGVHD typically onsets 2-31 months post-transplant, involves diffuse infiltration of inflammatory cells, demyelination, and cerebral vasculitis, and is associated with an extremely poor prognosis. We present a case of a 37-year-old man who developed seizures, myopathy, bilateral upper and lower extremity weakness, confusion, and irritability almost 2 years after HSCT for acute myeloid leukemia (AML). CNS-cGVHD diagnosis was confidently determined via magnetic resonance imaging (MRI) demonstrating enhanced focal white matter lesions, cerebrospinal fluid (CSF) studies demonstrating elevated globulin (12.7 mg/dL; normal range: 0-6 mg/dL) and elevated immunoglobulin G (IgG) synthesis rate (13.9 mg/d; normal range: ≤ 8 mg/d), and a right brain biopsy demonstrating encephalitis, perivascular inflammation, microglial activation, and gliosis with predominately intramural and perivascular CD3+ T-cells, CD4+ and CD8+ cells. Complete resolution of neurological symptoms, including seizures, was achieved with a combination of steroids, ibrutinib, intravenous immunoglobulin (IVIG), and anti-seizure medications. Improvements to CNS-cGVHD was further indicated by normalized MRI studies without abnormal enhancements and improved CSF studies with reduction in globulin levels (11.3 mg/dL) and complete normalization of IgG synthesis rate (≤ 0 mg/d). It is imperative that CNS-cGVHD be considered in patients that present with neurological signs post-transplant. An early, confident diagnosis generates prompt intervention and as demonstrated, can lead to complete resolution of neurological symptoms.

We conducted a prospective study of adult allogeneic hematopoietic cell transplantation (HCT) recipients to assess pre- and post-HCT physical function. Baseline measurements included a wrist actigraphy, a 6 min walk test (6MWT), an international physical activity questionnaire (IPAQ), and a Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) as well as serial post-HCT assessments of 6MWT, IPAQ, and FACT-BMT. Forty-seven patients were evaluable for functionality assessments, with a median follow-up of 54.5 months for surviving recipients. No patients demonstrated vigorous or very vigorous activity at any time during monitoring by wrist actigraphy; patients spent a median of 6 h daily sedentary. Self-reported activity via the IPAQ showed 36%, 43%, and 21% of subjects reporting light, moderate, and vigorous activity prior to HCT, respectively. Post-HCT 6MWTs on day +30 demonstrated the greatest association with subsequent survival and non-relapse mortality. A decline in 6MWT distance over time also demonstrated worsened overall survival. This study shows the feasibility of fitness assessments and the ability to risk stratify for subsequent mortality, particularly using the 6MWT on the day +30 single time point assessment and change scores from baseline to day +30 post HCT. These pilot findings suggest important targets for future study.