African Americans with translocation t(11;14) have superior survival after autologous hematopoietic cell transplantation for multiple myeloma in comparison with Whites in the United States.

BACKGROUND: Multiple myeloma (MM) with the translocation t(11;14) may have inferior outcomes in comparison with other standard-risk MM, and it has been suggested to portend a worse prognosis in African Americans in comparison with Whites. This study used the Center for International Blood and Marrow Transplant Research (CIBMTR) database to examine the impact of t(11;14) on the clinical outcomes of patients with MM of African American and White descent. METHODS: This study evaluated 3538 patients who underwent autologous hematopoietic cell transplantation (autoHCT) for MM from 2008 to 2016 and were reported to the CIBMTR. Patients were analyzed in 4 groups: African Americans with t(11;14) (n = 117), African Americans without t(11;14) (n = 968), Whites with t(11;14) (n = 266), and Whites without t(11;14) (n = 2187). RESULTS: African Americans with t(11;14) were younger, had lower Karnofsky scores, and had more advanced stage MM with a higher Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI). Fewer African Americans with t(11;14) (21%) had a coexistent high-risk marker in comparison with Whites with t(11;14) (27%). In a multivariate analysis, race and t(11;14) had no association with progression-free survival. However, overall survival was superior among African Americans with t(11;14) in comparison with Whites with t(11;14) (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P = .03). Survival was also associated with female sex, stage, time from diagnosis to transplant, a low HCT-CI, and receipt of maintenance. CONCLUSIONS: Race may have a differential impact on the survival of patients with t(11;14) MM who undergo autoHCT and needs to be further studied.

Caregivers' Out-of-Pocket Expenses and Time Commitment Following Hematopoietic Stem Cell Transplantation at a Rural Cancer Center.

The emotional and physical toll on caregivers of cancer patients is well documented, but research evaluating the financial burdens and time commitments of caregivers is limited. We suspected that the rural location of our cancer center would intensify these burdens for caregivers. We conducted a prospective trial to assess the out-of-pocket expenses and time commitment of caregivers of hematopoietic stem cell transplantation recipients within the first 4 weeks after discharge from the hospital from a National Cancer Institute (NCI)-designated comprehensive cancer center. These results show that caregivers of autologous recipients paid out-of-pocket expenses of $196 over 4 weeks. If lost wages were included, the expenses increased to $736 during this period. Caregivers of allogeneic recipients had out-of-pocket expenses of $110 in 4 weeks, or a total of $610 when lost wages were included. In the month after discharge from the hospital, caregivers traveled a median distance of 450 miles or 560 miles, depending on whether the patient received an autologous transplant or an allogeneic transplant, respectively. These results demonstrate a compelling need to address caregiver support, given the significant financial out-of-pocket expenses and time commitment.

Age no bar: A CIBMTR analysis of elderly patients undergoing autologous hematopoietic cell transplantation for multiple myeloma.

BACKGROUND: Upfront autologous hematopoietic stem cell transplantation (AHCT) remains an important therapy in the management of patients with multiple myeloma (MM), a disease of older adults. METHODS: The authors investigated the outcomes of AHCT in patients with MM who were aged ≥70 years. The Center for International Blood and Marrow Transplant Research (CIBMTR) database registered 15,999 patients with MM in the United States within 12 months of diagnosis during 2013 through 2017; a total of 2092 patients were aged ≥70 years. Nonrecurrence mortality (NRM), disease recurrence and/or progression (relapse; REL), progression-free survival (PFS), and overall survival (OS) were modeled using Cox proportional hazards models with age at transplantation as the main effect. Because of the large sample size, a P value <.01 was considered to be statistically significant a priori. RESULTS: An increase in AHCT was noted in 2017 (28%) compared with 2013 (15%) among patients aged ≥70 years. Although approximately 82% of patients received melphalan (Mel) at a dose of 200 mg/m2 overall, 58% of the patients aged ≥70 years received Mel at a dose of 140 mg/m2 . On multivariate analysis, patients aged ≥70 years demonstrated no difference with regard to NRM (hazard ratio [HR] 1.3; 99% confidence interval [99% CI], 1-1.7 [P = .06]), REL (HR, 1.03; 99% CI, 0.9-1.1 [P = 0.6]), PFS (HR, 1.06; 99% CI, 1-1.2 [P = 0.2]), and OS (HR, 1.2; 99% CI, 1-1.4 [P = .02]) compared with the reference group (those aged 60-69 years). In patients aged ≥70 years, Mel administered at a dose of 140 mg/m2 was found to be associated with worse outcomes compared with Mel administered at a dose of 200 mg/m2 , including day 100 NRM (1% [95% CI, 1%-2%] vs 0% [95% CI, 0%-1%]; P = .003]), 2-year PFS (64% [95% CI, 60%-67%] vs 69% [95% CI, 66%-73%]; P = .003), and 2-year OS (85% [95% CI, 82%-87%] vs 89% [95% CI, 86%-91%]; P = .01]), likely representing frailty. CONCLUSIONS: The results of the current study demonstrated that AHCT remains an effective consolidation therapy among patients with MM across all age groups.

A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance).

Relapse remains the major cause of death in older patients transplanted for acute myeloid leukemia (AML) in first complete remission or for patients with advanced myelodysplastic syndrome (MDS) at any age. Conventional myeloablative conditioning followed by allogeneic blood or marrow transplantation is associated with significantly less relapse compared with reduced-intensity conditioning when performed in younger patients with AML or MDS, but the toxicity of this approach in older patients is prohibitive. We hypothesized that pharmacokinetic targeting to optimize busulfan (BU) exposure, combined with the administration of azacitidine (AZA) post-transplant would mitigate the risk of relapse while reducing nonrelapse mortality and ultimately improve progression-free survival (PFS). On this phase II multicenter study, 63 patients (40 unrelated donors and 23 matched related donors) received a uniform conditioning regimen consisting of fludarabine i.v. (days -7 to -3), BU targeted to a daily area under the curve (AUC) of 4000 µM/min (days -6 to -3) after the administration of a 25-mg/m2 i.v. test dose on 1 day between days -14 to -9, and antithymocyte globulin (days -6, -5, and -4 (2 doses for matched related donors and 3 for matched unrelated donors only). Beginning on days +42 to +90, all patients were planned to receive up to 6 monthly cycles of AZA at 32 mg/m2 subcutaneously for 5 days. The median age was 62 years (range, 44 to 74); 13 had AML and 50 had MDS; 87% of patients were within 20% of the target AUC based on a validation sample. Forty-one patients (65%) started AZA at a median of 61 days (range, 43 to 91) post-transplant, and 17 patients (41%) completed all 6 cycles of AZA. The cumulative incidence of nonrelapse mortality at 2 years was 33.4% (95% confidence interval [CI], 22%-45%). The cumulative incidence of relapse was 25% (95% CI, 15%-37%) at 2 years. With a median follow-up of 58.9 months, the estimated PFS probability at 2 years and 5 years after transplantation was 41.2% (80% CI, 33.9%-49.9%) and 26.9% (80% CI, 20.4%-35.5%), respectively, for the entire group with a median PFS of 15.8 months (95% CI, 6.7 to 28.3). The probability of overall survival at 2 and 5 years was 45.7% (95% CI, 34.9%-59.9%) and 31.2% (95% CI, 21.3% to 45.8%), respectively, for the entire group with a median overall survival of 19.2 months (95% CI, 8.7 to 37.5). In summary, we demonstrated the feasibility of a novel reduced-intensity conditioning regimen with test dose BU targeted to an AUC of 4000 µM/min. The feasibility of AZA in this setting appears to be limited if applied to an unselected population of older hematopoietic stem cell transplantation recipients. (ClinicalTrials.gov Identifier: NCT01168219.).

Revised International Staging System Is Predictive and Prognostic for Early Relapse (<24 months) after Autologous Transplantation for Newly Diagnosed Multiple Myeloma.

The revised International Staging System (R-ISS) combines ISS with genetic markers and lactate dehydrogenase and can prognosticate newly diagnosed multiple myeloma (MM). Early relapse (<24 months) after upfront autologous hematopoietic cell transplantation (AHCT) strongly predicts inferior overall survival (OS). We examined the ability of R-ISS in predicting early relapse and its independent prognostic effect on postrelapse survival after an early relapse. Using the Center for International Blood and Marrow Transplant Research database we identified MM patients receiving first AHCT within 18 months after diagnosis with available R-ISS stage at diagnosis (n = 628). Relative risks of relapse/progression, progression-free survival (PFS), and OS were calculated with the R-ISS group as a predictor in multivariate analysis. Among early relapsers, postrelapse survival was tested to identify factors affecting postrelapse OS. The cumulative incidence of early relapse was 23%, 39%, and 50% for R-ISS I, R-ISS II, and R-ISS III, respectively (P < .001). Shorter PFS and OS were seen with higher stage R-ISS. R-ISS was independently predictive for inferior postrelapse OS among early relapsers, as was the presence of ≥3 comorbidities and the use of ≥2 induction chemotherapy lines. R-ISS stage at diagnosis predicts early post-AHCT relapse and independently affects postrelapse survival among early relapsers.

Autologous/Allogeneic Hematopoietic Cell Transplantation versus Tandem Autologous Transplantation for Multiple Myeloma: Comparison of Long-Term Postrelapse Survival.

We compared postrelapse overall survival (OS) after autologous/allogeneic (auto/allo) versus tandem autologous (auto/auto) hematopoietic cell transplantation (HCT) in patients with multiple myeloma (MM). Postrelapse survival of patients receiving an auto/auto or auto/allo HCT for MM and prospectively reported to the Center for International Blood and Marrow Transplant Research between 2000 and 2010 were analyzed. Relapse occurred in 404 patients (72.4%) in the auto/auto group and in 178 patients (67.4%) in the auto/allo group after a median follow-up of 8.5 years. Relapse occurred before 6 months after a second HCT in 46% of the auto/allo patients, compared with 26% of the auto/auto patients. The 6-year postrelapse survival was better in the auto/allo group compared with the auto/auto group (44% versus 35%; P = .05). Mortality due to MM was 69% (n = 101) in the auto/allo group and 83% (n = 229) deaths in auto/auto group. In multivariate analysis, both cohorts had a similar risk of death in the first year after relapse (hazard ratio [HR], .72; P = .12); however, for time points beyond 12 months after relapse, overall survival was superior in the auto/allo cohort (HR for death in auto/auto =1.55; P = .005). Other factors associated with superior survival were enrollment in a clinical trial for HCT, male sex, and use of novel agents at induction before HCT. Our findings shown superior survival afterrelapse in auto/allo HCT recipients compared with auto/auto HCT recipients. This likely reflects a better response to salvage therapy, such as immunomodulatory drugs, potentiated by a donor-derived immunologic milieu. Further augmentation of the post-allo-HCT immune system with new immunotherapies, such as monoclonal antibodies, checkpoint inhibitors, and others, merit investigation.

Extracorporeal photopheresis for graft versus host disease: Identifying a clinical pathway and associated resource utilization.

Extracorporeal photopheresis (ECP) is an established therapy for the treatment of graft-versus-host-disease (GVHD) following an allogeneic stem cell transplant. We performed a prospective analysis of patients receiving ECP treatment for GVHD to identify a clinical pathway and resource utilization of this process. The cohort included consecutive allogeneic stem cell recipients with GVHD. ECP was performed using the CELLEX Photopheresis System or the UVAR XTS Photopheresis System (Therakos, Inc, Exton, PA). A clinical pathway was developed and a time and motion study was conducted to define the resource utilization and costs associated with ECP. Patients were treated with either CELLEX (n = 18 procedures) or UVAR (n = 4 procedures). Total time commitment for each procedure for the 2 machines differed. The time for ECP was 117 min (median, range: 91-164 min) using CELLEX and 161 min (median; range: 140-210) using the UVAR-XTS machine. Total costs of each ECP procedure were $3420.50. There is a considerable time commitment of the patient and the clinical staff when employing ECP to treat GVHD. ECP costs are significant considering this is a prolonged therapy continued for several months. With this finalized pathway and costs, we have a standardized clinical pathway for the treatment of GVHD. We are addressing minimizing resource utilization while emphasizing quality care for these patients.

Maintenance versus Induction Therapy Choice on Outcomes after Autologous Transplantation for Multiple Myeloma.

Bortezomib (V), lenalidomide (R), cyclophosphamide (C), and dexamethasone (D) are components of the most commonly used modern doublet (RD, VD) or triplet (VRD, CVD) initial induction regimens before autologous hematopoietic cell transplantation (AHCT) for multiple myeloma (MM) in the United States. In this study we evaluated 693 patients receiving "upfront" AHCT after initial induction therapy with modern doublet or triplet regimens using data reported to the Center for International Blood and Marrow Transplant Research from 2008 to 2013. Analysis was limited to those receiving a single AHCT after 1 line of induction therapy within 12 months from treatment initiation for MM. In multivariate analysis, progression-free survival (PFS) and overall survival were similar irrespective of induction regimen. However, high-risk cytogenetics and nonreceipt of post-transplant maintenance/consolidation therapy were associated with higher risk of relapse. Patients receiving post-transplant therapy had significantly improved 3-year PFS versus no post-transplant therapy (55% versus 39%, P = .0001). This benefit was most evident in patients not achieving at least a complete response post-AHCT (P = .005). In patients receiving upfront AHCT, the choice of induction regimen (doublet or triplet therapies) appears to be of lower impact than use of post-transplant therapy.

Impact of pre-transplant depression on outcomes of allogeneic and autologous hematopoietic stem cell transplantation.

BACKGROUND: To evaluate the impact of depression before autologous and allogeneic hematopoietic cell transplantation (HCT) on clinical outcomes post-transplantation. METHODS: We analyzed data from the Center for International Blood and Marrow Transplant Research to compare outcomes after autologous (n = 3786) or allogeneic (n = 7433) HCT for adult patients with hematologic malignancies with an existing diagnosis of pre-HCT depression requiring treatment versus those without pre-HCT depression. Using Cox regression models, we compared overall survival (OS) between patients with or without depression. We compared the number of days alive and out of the hospital in the first 100 days post-HCT using Poisson models. We also compared the incidence of grade 2-4 acute and chronic graft-versus-host disease (GVHD) in allogeneic HCT. RESULTS: The study included 1116 (15%) patients with pre-transplant depression and 6317 (85%) without depression who underwent allogeneic HCT between 2008 and 2012. Pre-transplant depression was associated with lower OS (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.04-1.23; P = 0.004) and a higher incidence of grade 2-4 acute GVHD (HR, 1.25; 95% CI, 1.14-1.37; P < 0.0001), but similar incidence of chronic GVHD. Pre-transplant depression was associated with fewer days-alive-and-out-of-the hospital (means ratio [MR] = 0.97; 95% CI, 0.95-0.99; P = 0.004). There were 512 (13.5%) patients with Pre-transplant depression and 3274 (86.5%) without depression who underwent autologous HCT. Pre-transplant depression in autologous HCT was not associated with OS (HR, 1.15; 95% CI, 0.98-1.34; P = 0.096) but was associated with fewer days alive and out of the hospital (MR, 0.98; 95% CI, 0.97-0.99; P = 0.002). CONCLUSION: Pre-transplant depression was associated with lower OS and higher risk of acute GVHD among allogeneic HCT recipients and fewer days alive and out of the hospital during the first 100 days after autologous and allogeneic HCT. Patients with pre-transplant depression represent a population that is at risk for post-transplant complications. Cancer 2017;123:1828-1838. © 2017 American Cancer Society.

Post-Transplant Outcomes in High-Risk Compared with Non-High-Risk Multiple Myeloma: A CIBMTR Analysis.

Conventional cytogenetics and interphase fluorescence in situ hybridization (FISH) identify high-risk multiple myeloma (HRM) populations characterized by poor outcomes. We analyzed these differences among HRM versus non-HRM populations after upfront autologous hematopoietic cell transplantation (autoHCT). Between 2008 and 2012, 715 patients with multiple myeloma identified by FISH and/or cytogenetic data with upfront autoHCT were identified in the Center for International Blood and Marrow Transplant Research database. HRM was defined as del17p, t(4;14), t(14;16), hypodiploidy (<45 chromosomes excluding -Y) or chromosome 1 p and 1q abnormalities; all others were non-HRM. Among 125 HRM patients (17.5%), induction with bortezomib and immunomodulatory agents (imids) was higher compared with non-HRM (56% versus 43%, P < .001) with similar pretransplant complete response (CR) rates (14% versus 16%, P .1). At day 100 post-transplant, at least a very good partial response was 59% in HRM and 61% in non-HRM (P = .6). More HRM patients received post-transplant therapy with bortezomib and imids (26% versus 12%, P = .004). Three-year post-transplant progression-free (PFS) and overall survival (OS) rates in HRM versus non-HRM were 37% versus 49% (P < .001) and 72% versus 85% (P < .001), respectively. At 3 years, PFS for HRM patients with and without post-transplant therapy was 46% (95% confidence interval [CI], 33 to 59) versus 14% (95% CI, 4 to 29) and in non-HRM patients with and without post-transplant therapy 55% (95% CI, 49 to 62) versus 39% (95% CI, 32 to 47); rates of OS for HRM patients with and without post-transplant therapy were 81% (95% CI, 70 to 90) versus 48% (95% CI, 30 to 65) compared with 88% (95% CI, 84 to 92) and 79% (95% CI, 73 to 85) in non-HRM patients with and without post-transplant therapy, respectively. Among patients receiving post-transplant therapy, there was no difference in OS between HRM and non-HRM (P = .08). In addition to HRM, higher stage, less than a CR pretransplant, lack of post-transplant therapy, and African American race were associated with worse OS. In conclusion, we show HRM patients achieve similar day 100 post-transplant responses compared with non-HRM patients, but these responses are not sustained. Post-transplant therapy appeared to improve the poor outcomes of HRM.

Peridischarge prophylactic platelet transfusions after stem cell transplant: is a tranfusion trigger needed?

BACKGROUND: We examined the appropriateness of prophylactic peridischarge platelet (PLT) transfusions and the feasibility of lowering the prophylactic PLT transfusion threshold in transplant recipients within 24 hours of discharge at a National Cancer Institute-designated comprehensive cancer center. STUDY DESIGN AND METHODS: From April 2011 to June 2014, each prophylactic PLT transfusion that was administered to transplant recipients within 24 hours of discharge was identified. Each transfusion was reviewed to identify the indication and to determine if the transfusion adhered to institutional guidelines. RESULTS: Of the 187 transplant patients identified, 44 patients received a prophylactic PLT transfusion within 24 hours of discharge. Of these 44 patients, transfusions were administered to fulfill a PLT count of 20 × 10(9) /L required for discharge (n = 25 patients), for the removal of a tunneled central venous catheter (n = 16 patients), for active bleeding (n = 1 patient), or due to active anticoagulation (n = 2 patients). CONCLUSIONS: The majority of PLT transfusions (95%) were appropriate, and only 5% were avoidable. If the prophylactic PLT transfusion threshold was decreased to 15 × 10(9) /L from 20 × 10(9) /L for central line removal and to fulfill discharge PLT count criteria, 41% of the currently appropriate PLT transfusions could have been avoided. These results suggest that a risk-adapted method to select autologous transplant recipients for prophylactic PLT transfusions may be beneficial. A future study is needed to address this issue.

Successful implementation of a rural extracorporeal photopheresis program for the treatment of cutaneous T-cell lymphoma and chronic graft-versus-host disease in a rural hospital.

OBJECTIVE: Extracorporeal photopheresis (ECP) is currently standard therapy for cutaneous T-cell lymphoma (CTCL) and Graft-versus-host disease (GVHD). Of the many challenges associated with outpatient ECP treatments, commuter travel to capable facilities can fragment and compromise the patient care. In 2008, our hospital implemented an ECP program providing patients to a treatment center over 120 minutes away. This study was undertaken to describe our experience with the establishment of a regional ECP program. METHODS: A retrospective review using a standardized template was performed of patients treated from May 2008 to 2012. The response to treatment was analyzed after a minimum of eight procedures. A partial response to treatment in individuals with CTCL, was more than 50% skin improvement, and GVHD, a reduction in steroid dose by 50%, liver function test improvement or documented improvement in skin findings. RESULTS: Of the 34 patients treated, 11 were for CTCL and 23 for GVHD. 95.8% of the 1,071 planned procedures were successfully. The average procedure time was 186 min for the UVAR-XTSTM and 93 min for the CELLEXTM. Patients travelled a median of 65.7 miles (range 4-133 miles). The median duration of therapy was 6 months (range 2-23) for CTCL and 5 months (range 1-27) for GVHD. A clinical benefit was observed in 7 of 11 (63.6%) patients with CTCL and in 15 of 23 (65.2%) with GVHD. CONCLUSION: Our regional ECP program was a viable option in improving access to care for patients requiring treatment for CTCL and chronic GVHD.

The natural killer-activating receptor, NKG2D, on CD3+CD8+ T cells plays a critical role in identifying and killing autologous myeloma cells.

BACKGROUND: The NKG2D receptor, one of the natural killer (NK) cell-activating receptors, is expressed on the surface of CD3+CD8+ T cells, γδ+ T cells, NK cells, NKT cells, and a few CD4+ T cells. We show, for the first time, a critical role for the NKG2D receptor on CD3+CD8+ T cells isolated from myeloma patients, in identifying and killing autologous myeloma cells isolated from the same patients' marrow. We also show that blocking NKG2D using anti-NKG2D reverses the cytotoxicity while blocking HLA-I using antibodies does not have the same effect, showing that the autologous cytotoxicity is NKG2D dependent and major histocompatibility complex (MHC)-I independent. We further confirmed the NKG2D specificity by small interfering RNA (siRNA) down regulation of NKG2D receptor. STUDY DESIGN AND METHODS: Using ex vivo expansion methods that enrich for NKG2D+CD3+CD8+ T cells, we investigated whether these ex vivo expanded NKG2D+CD3+CD8+ T cells would recognize and lyse autologous and allogeneic myeloma cells, independent of T-cell receptor or MHC-I expression. RESULTS: Myeloma cell lysis by the NKG2D+CD3+CD8+ T cells correlated with the amount of NKG2D ligand expression. With receptor-ligand interaction, interferon-γ and tumor necrosis factor-α were released. Blocking the NKG2D receptor by using either monoclonal antibodies or siRNAs inhibited the receptor's function and prevented myeloma cell lysis. CONCLUSION: Clinical trials are ongoing to determine a correlation with the number and function of NKG2D+CD3+CD8+ T cells and clinical outcomes in transplanted myeloma patients, including lymphocyte recovery following transplant and overall survival.

Porcine-human glioma xenograft model. Immunosuppression and model reproducibility.

BACKGROUND: Glioblastoma is the most common primary malignant and treatment-resistant human brain tumor. Rodent models have played an important role in understanding brain cancer biology and treatment. However, due to their small cranium and tumor volume mismatch, relative to human disease, they have been less useful for translational studies. Therefore, development of a consistent and simple large animal glioma xenograft model would have significant translational benefits. METHODS: Immunosuppression was induced in twelve standard Yucatan minipigs. 3 pigs received cyclosporine only, while 9 pigs received a combined regimen including cyclosporine (55 mg/kg q12 h), prednisone (25 mg, q24 h) and mycophenolate (500 mg q24 h). U87 cells (2 × 106) were stereotactically implanted into the left frontal cortex. The implanted brains were imaged by MRI for monitoring. In a separate study, tumors were grown in 5 additional pigs using the combined regimen, and pigs underwent tumor resection with intra-operative image updating to determine if the xenograft model could accurately capture the spatial tumor resection challenges seen in humans. RESULTS: Tumors were successfully implanted and grown in 11 pigs. One animal in cyclosporine only group failed to show clinical tumor growth. Clinical tumor growth, assessed by MRI, progressed slowly over the first 10 days, then rapidly over the next 10 days. The average tumor growth latency period was 20 days. Animals were monitored twice daily and detailed records were kept throughout the experimental period. Pigs were sacrificed humanely when the tumor reached 1 - 2 cm. Some pigs experienced decreased appetite and activity, however none required premature euthanasia. In the image updating study, all five pigs demonstrated brain shift after craniotomy, consistent with what is observed in humans. Intraoperative image updating was able to accurately capture and correct for this shift in all five pigs. CONCLUSION: This report demonstrates the development and use of a human intracranial glioma model in an immunosuppressed, but nongenetically modified pig. While the immunosuppression of the model may limit its utility in certain studies, the model does overcome several limitations of small animal or genetically modified models. For instance, we demonstrate use of this model for guiding surgical resection with intraoperative image-updating technologies. We further report use of a surrogate extracranial tumor that indicates growth of the intracranial tumor, allowing for relative growth assessment without radiological imaging.

Adoptive cellular therapy using cells enriched for NKG2D+CD3+CD8+T cells after autologous transplantation for myeloma.

The number of circulating lymphocytes on day 15 after transplantation correlates with improved survival in patients with myeloma, but the lymphocyte subset responsible is unknown. NKG2D is a natural killer (NK) cell activating receptor that mediates non-MHC restricted and TCR-independent cell lysis. Our preliminary results indicate that CD3(+)CD8(+) T cells expressing NKG2D may be a critical lymphocyte population. A phase II trial examined the feasibility of infusing ex vivo-expanded cells enriched for NKG2D(+)CD3(+)CD8(+) T cells at weeks 1, 2, 4, and 8 after an autologous transplantation. In addition, low-dose IL-2 (6 × 10(5) IU/m(2)/day) was administered for 4 weeks, beginning on the day of transplantation. Twenty-three patients were accrued and 19 patients are evaluable. There were no treatment-related deaths. All patients completed their course of IL-2 and demonstrated normal engraftment. When compared with patients with myeloma who underwent transplantation not receiving posttransplantation immune therapy, the treated patients demonstrated an increase in the number of circulating NKG2D(+)CD3(+)CD8(+) T cells/µL (P < .004), CD3(+)CD8(+) T cells/µL (P < .04), CD3(+)CD8(+)CD56(+) T cells/µL (P < .004), and NKG2D(+)CD3(-)CD56(+) T cells/µL (P < .003). Myeloma cell-directed cytotoxicity by the circulating mononuclear cells increased after transplantation (P < .002). When compared to posttransplantation IL-2 therapy alone in this patient population, the addition of cells enriched for NKG2D(+)CD3(+)CD8(+) T cells increased tumor-specific immunity, as demonstrated by enhanced lysis of autologous myeloma cells (P = .02). We postulate that this regimen that increased the number and function of the NKG2D(+)CD3(+)CD8(+) T cells after transplantation may improve clinical outcomes by eliminating residual malignant cells in vivo.

Trends in utilization and outcomes of autologous transplantation as early therapy for multiple myeloma.

The impact of novel drugs for treating multiple myeloma (MM) on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients who underwent AHPCT within 12 months of diagnosis of MM in the United States and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts reflecting the increasing availability of novel drugs: 1995 to 1999 (n = 2226), 2000 to 2004 (n = 6408), and 2005 to 2010 (n = 11,644). In the United States, the number of AHPCTs performed increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM, and more likely to have received previous thalidomide, lenalidomide, or bortezomib. On multivariate analysis, AHPCT in the 2000 to 2004 cohort (HR = 0.77) or in the 2005 to 2010 cohort (HR = 0.68) were associated with lower risk of death. Survival at 60 months post-AHPCT improved from 47% in 1995 to 1999 to 55% in 2000 to 2004 and to 57% in 2005 to 2010, owing less to improvement in progression-free survival (50% versus 55% versus 57% at 24 months) than to postrelapse/progression survival (58% versus 65% versus 72% at 24 months). AHPCT and new biological agents are complementary, nonredundant therapies and should be combined in the management of MM in suitable patients.

Salvage second hematopoietic cell transplantation in myeloma.

Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM.

Trends in allogeneic stem cell transplantation for multiple myeloma: a CIBMTR analysis.

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).

Harnessing the Collective Expertise of Patients, Care Partners, Clinical Teams, and Researchers Through a Coproduction Learning Health System: A Case Study of the Dartmouth Health Promise Partnership.

The coproduction learning health system (CLHS) model extends the definition of a learning health system to explicitly bring together patients and care partners, health care teams, administrators, and scientists to share the work of optimizing health outcomes, improving care value, and generating new knowledge. The CLHS model highlights a partnership for coproduction that is supported by data that can be used to support individual patient care, quality improvement, and research. We provide a case study that describes the application of this model to transform care within an oncology program at an academic medical center.

The practical application of chimerism analyses in allogeneic stem cell transplant recipients: blood chimerism is equivalent to marrow chimerism.

BACKGROUND: Chimerism defines the amount of donor versus recipient hematopoiesis following allogeneic stem cell transplant (SCT). PCR-based analyses of short tandem repeats (STRs) are commonly used and are accurate and applicable to allogeneic transplant recipients. These analyses are performed on blood and marrow aspirates, but it is unknown if analyses of both are required. We performed a retrospective analysis of 42 consecutive adult allogeneic SCT recipients at our institution to determine if both sample types are needed. METHODS: Chimerism status was determined by multiplex PCR and capillary electrophoresis of STRs. Analyses were performed at 30, 60, and 90days after SCT on both unfractionated blood and unfractionated marrow aspirate. RESULTS: PCR analyses of STRs for chimerism performed on unfractionated blood highly correlated with results obtained using unfractionated marrow aspirates at 30, 60, or 90days following transplant (p<0.0001 for each time point). Overall and relapse-free survival of patients experiencing full donor chimerism was not statistically different from patients demonstrating mixed chimerism at days 30, 60, and 90 following SCT. CONCLUSIONS: PCR-based chimerism analyses on blood provide similar information as marrow aspirate analyses. These are unique results suggesting that chimerism analyses may be assessed on peripheral blood alone.