Roy, Vivek

AbstractBackgroundMobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known.MethodsWe evaluated the impact of granulocyte‐colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM).ResultsOverall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 × 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004).ConclusionProducts collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg.

SummaryCD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells.In vitroDara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis.In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report thein vitroandin vivoanti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib.

Key PointsCoexisting psychiatric comorbidities are associated with greater increased health care utilization and cost of care in patients with MM. Clinical complications of MM are seen more frequently in patients with coexisting psychiatric conditions.

AbstractThe prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically‐annotated patients; 5‐year survival rates were 8% for very high risk (VHR), 27% “unfavorable” and 45% “favorable” karyotype. The current study addresses the practice‐relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate‐2 and 21% intermediate‐1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post‐HCT follow‐up of 60 months for living patients (range 34‐170), 28 (42%) deaths were recorded. Five‐year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6‐3.6) for absence of transplant, 3.3 (2.2‐4.8) for VHR karyotype, 1.6 (1.2‐2.1) for unfavorable karyotype, 2.9 (2.0‐4.2) for DIPSS high and 1.7 (1.4‐2.2) for DIPSS intermediate‐2. These observations were further confirmed by analysis of more stringently matched case‐control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.

BACKGROUNDOutcomes have improved significantly in multiple myeloma (MM), but racial disparities in health care access and survival exist. A comprehensive analysis exploring MM care and racial disparities is warranted.METHODSPatients with MM from 1991 to 2010 in the Surveillance, Epidemiology, and End Results‐Medicare database were evaluated for racial trends in clinical myeloma‐defining events (MDEs), the receipt of treatment (drugs and stem cell transplantation; [SCT]), the cost of care, and overall survival (OS).RESULTSAmong 35,842 patients, the frequency of all MDEs at diagnosis increased over time; whereas, in recent years (2006‐2010), all MDEs with the exception of renal dialysis decreased. Blacks had highest rates for all MDEs except bone fractures, which were highest in whites. Over time, the proportion of patients who received any treatment, multiple agents, and SCT increased significantly, and the largest increase was observed in the receipt of immunomodulatory drugs and steroids. There was greater receipt of bortezomib and SCT among whites and blacks and higher receipt of immunomodulatory drugs among Hispanics and Asians (P < .001). Medicare claims were highest during first 6 months after MM diagnosis for blacks and at any time after MM diagnosis for Hispanics. Over time, Medicare claims increased most steadily for Hispanics (P < .001). Hypercalcemia, renal dysfunction, and bone fractures were associated with inferior OS. Blacks and Asians had superior OS compared with whites, but racial differences in OS became less pronounced during 2006 through 2010 (P = .182) compared with prior years (P < .01). Better OS was noted among patients who had higher median incomes.CONCLUSIONSThe current results indicate that there have been significant changes in the management of patients with MM over time and provide an in‐depth understanding of the factors that may help explain racial disparities. Cancer 2018;124:1710‐21. © 2018 American Cancer Society

AbstractOutcomes have improved considerably in multiple myeloma (MM), but disparities among racial‐ethnic groups exist. Differences in utilization of novel therapeutics are likely contributing factors. We explored such differences from the SEER‐Medicare database. A utilization analysis of lenalidomide, thalidomide, bortezomib, and stem cell transplant (SCT) was performed for patients diagnosed with MM between 2007 and 2009, including use over time, use by race, time‐dependent trends for each racial subgroup, and survival analysis. A total of 5338 MM patients were included with median 2.4‐year follow‐up. Within the first year of MM diagnosis, utilization of lenalidomide, bortezomib, SCT, and more than one novel agent increased over time while utilization of thalidomide decreased. There was significantly lower utilization of lenalidomide among African‐Americans (P < 0.01), higher thalidomide use among Hispanics and Asians (P < 0.01), and lower bortezomib use among Asians (P < 0.01). Hispanics had the highest median number of days to first dose of bortezomib (P = 0.02) and the lowest utilization of SCT (P < 0.01). Hispanics and Asians were the only groups without notable increases in lenalidomide and bortezomib use, respectively. SCT utilization increased over time for all except African‐Americans. SCT use within the first year after diagnosis was associated with better overall survival (HR 0.52; 95% CI: 0.4–0.68), while bortezomib use was associated with inferior survival (HR 1.14; 95% CI 1.02–1.28). We noted considerable variability in MM therapeutics utilization with seeming inequity for racial‐ethnic minorities. These trends should be considered to eliminate drug access and utilization disparities and achieve equitable benefit of therapeutic advances across all races.

Key Points PVD is an active combination in relapsed lenalidomide-refractory MM patients. PVD with weekly bortezomib offers a simpler, more convenient, and well-tolerated regimen option.