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Supplemental Table 1. Multivariate analysis of late relapse, transplant-related mortality, overall survival after HCT for each disease (AML, ALL, CML, MDS)

Purpose: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse, it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year after transplant at the time when acute GVHD is still active.Experimental Design: This study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7,489 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS), who were leukemia free at 12 months after myeloablative allogeneic HCT.Results: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on late relapse was present only in patients with CML [RR, 0.47; 95% confidence interval (CI), 0.37–0.59; P < 0.0001). cGVHD was significantly associated with higher risk of treatment-related mortality (TRM; RR, 2.43; 95% CI, 2.09–2.82; P < 0.0001) and inferior overall survival (RR, 1.56; 95% CI, 1.41–1.73; P < 0.0001) for all diseases. In patients with CML, all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse.Conclusions: These results indicate that clinically relevant antileukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL, or MDS. Chronic GVHD in patients who are 1-year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival. Clin Cancer Res; 21(9); 2020–8. ©2014 AACR.See related commentary by Gill, p. 1981

Supplemental Table 4. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival, overall survival in patients with AML, ALL, MDS who developed cGVHD

Supplemental Table 2. Multivariate analysis showing impact of cGVHD characteristics in CML patients on relapse

Supplemental Table 3. Multivariate analysis showing impact of cGVHD characteristics on treatment related mortality, disease free survival and overall survival in patients with CML who developed cGVHD

Supplemental Figure 1. Cumulative incidence of cGVHD, relapse and death in patients with AML, ALL, CML, MDS

The use of cyclophosphamide (CY) for bidirectional tolerization of recipient and donor T cells is associated with reduced rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after HLA-matched hematopoietic stem cell transplantation (HSCT). However, recurrent disease remains the primary barrier to long-term survival. We extended our 2-step approach to HLA-matched related HSCT using a radiation-based myeloablative conditioning regimen combined with a high dose of T cells in an attempt to reduce relapse rates while maintaining the beneficial effects of CY tolerization. After conditioning, patients received their grafts in 2 components: (1) a fixed dose of 2 × 108/kg T cells, followed 2 days later by CY, and (2) a CD34-selected graft containing a small residual amount of non-CY-exposed T cells, at a median dose of 2.98 × 103/kg. Forty-six patients with hematologic malignancies were treated. Despite the myeloablative conditioning regimen and use of high T cell doses, the cumulative incidences of grade II-IV acute GVHD, chronic GVHD, and NRM at 1 year and 5 years were very low, at 13%, 9%, and 4.3%, respectively. This contributed to a high overall survival of 89.1% at 1 year and 65.8% at 5 years. Relapse was the primary cause of mortality, with a cumulative incidence of 23.9% at 1 year and 45.7% at 5 years. In a post hoc analysis, relapse rates were significantly lower in patients receiving greater than versus those receiving less than the group median of non-CY-exposed residual T cells in the CD34 product (19.3% versus 58.1%; P = .009), without a concomitant increase in NRM. In its current form, this 2-step regimen was highly tolerable, but strategies to reduce relapse, potentially the addition of T cells not exposed to CY, are needed.

PURPOSE An important obstacle to cancer research is that nearly all academic cancer centers maintain substantial collections of highly duplicative, poorly quality-assured, nonintercommunicating, difficult-to-access data repositories. It is inherently clear that this state of affairs increases costs and reduces quality and productivity of both research and nonresearch activities. We hypothesized that designing and implementing a multipurpose cancer information system on the basis of the Biomedical Research Integrated Domain (BRIDG) model developed by the National Cancer Institute and its collaborators might lessen the duplication of effort inherent in capturing, quality-assuring, and accessing data located in multiple single-purpose systems, and thereby increases productivity while reducing costs. METHODS We designed and implemented a core data structure on the basis of the BRIDG model and incorporated multiple entities, attributes, and functionalities to support the multipurpose functionality of the system. We used the resultant model as a foundation upon which to design and implement modules for importing preexisting data, capturing data prospectively, quality-assuring data, exporting data to analytic files, and analyzing the quality-assured data to support multiple functionalities simultaneously. To our knowledge, our system, which we refer to as the Cancer Informatics Data System, is the first multipurpose, BRIDG-harmonized cancer research information system implemented at an academic cancer center. RESULTS We describe the BRIDG-harmonized system that simultaneously supports patient care, teaching, research, clinical decision making, administrative decision making, mandated volume-and-outcomes reporting, clinical quality assurance, data quality assurance, and many other functionalities. CONCLUSION Implementation of a highly quality-assured, multipurpose cancer information system on the basis of the BRIDG model at an academic center is feasible and can increase access to accurate data to support research integrity and productivity as well as nonresearch activities.

Introduction :The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and subsequent coronavirus-19 (COVID-19) pandemic has impacted hematologic malignancies (HM) care worldwide. Reported risk factors for severe COVID-19 presentation include older age, medical comorbidities, and cardiac disease - many of which apply to patients with HM (Guan et al., 2020; Zhou et al., 2020). Additionally, patients with HM may be at even higher risk of infections with or complications from SARS-CoV-2 due to immune dysfunction from their underlying disease or treatment (He et al., 2020). However, data regarding rates of infection and outcomes in this population are limited. Here we describe the demographic characteristics, coexisting conditions, presenting symptoms, treatment, and outcomes of a cohort of patients with HM and COVID-19 infection at network sites across the Sidney Kimmel Cancer Center- Jefferson Health. Methods : We created an HM-specific COVID-19 database within our health system. Patients were identified for inclusion in the database by physician referral and query of the electronic medical record. Epidemiological, clinical, and laboratory data, therapy details, and outcomes on patients were obtained by accessing electronic medical records. A retrospective study of patients with a diagnosis of a HM- within 5 years of COVID-19 diagnosis-and a confirmed diagnosis of COVID-19 were was conducted using this database. A confirmed diagnosis of COVID-19 was defined as a positive result on a real-time RT-PCR assay of a specimen collected by nasopharyngeal swab. Results: More than 3,000 telehealth or in-person patient visits were conducted for patients with HM in the Jefferson Health Network between March 9, 2020 and July 15, 2020. During that period, 21 patients with HM had a confirmed diagnosis of COVID-19. Median age was 67 years (range 21-89). The majority of patients (86%) had at least 1 comorbid medical condition, and 76% had a history of tobacco use. The most common HM was multiple myeloma (7/21, 33%), followed by diffuse large B-cell lymphoma (3/21, 14%). 12/21 (52%) patients were on active cancer treatment at the time of COVID-19 diagnosis, and patients had received a median of 2 lines of cancer therapy (range 0-6). All 12 patients who were on active therapy at the time of COVID-19 diagnosis experienced a treatment interruption. Two patients had undergone prior autologous stem cell transplant (SCT) and 1 had undergone prior allogeneic SCT. Details on HM diagnosis and treatment are presented in Table 1. Twenty patients required hospital admission at the time of COVID-19 diagnosis, 7/21 were admitted to the ICU, and 6/21 required intubation. The most common presenting symptoms were fever (48%), cough (43%), and shortness of breath (43%), and lymphopenia (absolute lymphocyte count (ALC) Conclusion : In contrast to published reports, we found that the number of confirmed COVID-19 in patients with HM at our center was surprisingly low, with only 21 cases in 4 months. Furthermore, the mortality rate of 14% was lower than expected when compared to published cohorts of similar patients, which have shown mortality rates as high as 40% (He et al., 2020; Malard et al., 2020; Martín-Moro et al., 2020). Postulated reasons for the low number of infections include the early adoption of universal masking and robust utilization of telehealth to promote social distancing. In our small cohort, multiple myeloma was the most frequent HM diagnosis associated with COVID-19 infection, but this may be related to the prevalence of MM in our geographic area. The vast majority of HM patients with symptomatic COVID-19 were former smokers. Disclosures Binder: Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy. Alpdogan:Seattle Genetics: Consultancy; Kiowa Kirin: Consultancy. Kasner:Otsuka Pharmaceutical: Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Martinez-Outschoorn:Otsuka Pharmaceutical: Research Funding. Palmisiano:Genentech: Research Funding; AbbVie: Research Funding. Flomenberg:Tevogen: Consultancy, Honoraria. Porcu:Cell Medica: Research Funding; Daiichi: Consultancy, Honoraria; Galderma: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Miragen: Research Funding; Verastem: Consultancy; Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding.

Plasma cell dyscrasias and myeloproliferative neoplasms (MPN) are hematologic malignancies arising from two distinct hematopoietic cell lineages. They rarely occur concomitantly. Here, we report a case of a patient with a recent diagnosis of a JAK2 V617F positive MPN who presented with a new diagnosis of plasma cell leukemia. The patient had presented to the hospital with a leukocytosis predominantly comprised of plasma cells, followed by work-up involving peripheral blood flow cytometry, FISH analysis, and bone-marrow biopsy. FISH analysis was suggestive of a common progenitor cell for these distinct hematologic malignancies. To our knowledge, this case represents the second reported instance of a concomitant JAK2 positive MPN with primary plasma cell leukemia.

Patients with autologous stem cell transplantation (ASCT) have a variable period of immune deficiency in the post-transplant period. Guidelines recommend revaccination of patients after ASCT as standard care. The response to vaccination may affect the outcome of the transplant patients. We aim to evaluate the vaccination response after ASCT. All myeloma and lymphoma patients with ASCT who had vaccination and measured vaccination response, were included in the study. We retrospectively evaluated 73 ASCT patients, 55 with multiple myeloma (MM) and 18 with lymphoma between 2013 and 2018. The current ASCT protocol for active immunization includes three doses of pneumococcal conjugate vaccine (PCV13) from 6-12 months after ASCT, followed by a 23-valent polysaccharide pneumococcal vaccine (PPSV23). Haemophilus Influenza B (HiB), hepatitis B, and TDAP/TD vaccines are administered within one year after initiation of vaccination. The responses to these vaccines were investigated by checking antibody titers at a minimum of two months after completion of vaccination. Both MM and lymphoma groups had similar pre-vaccination immunologic parameters, including IgG levels, absolute CD4+, and CD4+CD45RA+ cell counts (Table 1). Diphtheria and tetanus had 89% response rate to the vaccination in all patients (Table 2). Only half of the patients (47%) responded to hepatitis B vaccine. The response was higher but not statistically significant in the lymphoma group compared to the MM group (57 % versus 43.9 % P: NS). More than 80% of the patients had a response to H. Influenza vaccine. All patients had a 59% response to pneumococcal vaccination. We then analyzed the pneumococcal responses according to serotype. PCV13 includes vaccine against 13 serotypes of S. pneumonia (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, 18C, and 23F). PPSV23 contains additional 11 serotypes (2, 8, 9N, 10A, 11A, 12F, 15B, 17F, 20, 22F, 33F). 76 % of MM patients responded to PCV13 serotypes, while only 41 % responded to PPSV23 specific serotypes (p: In conclusion, ASCT patients respond well to most vaccinations except for Hepatitis B and PPSV23. Further studies may need to explore pathophysiology of vaccine failure. Strategies to enhance immune reconstitution may augment the immune response and improve the outcome of the patients with ASCT. Disclosures Alpdogan: Seattle Genetics: Research Funding. Binder:Sanofi: Consultancy; Janssen: Membership on an entity's Board of Directors or advisory committees. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding. Martinez-Outschoorn:Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Porcu:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Cell Medica: Research Funding; Daiichi: Consultancy, Honoraria; Galderma: Research Funding; Innate Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kiowa Kirin: Research Funding; Kura Oncology: Research Funding; Miragen: Research Funding; Verastem: Consultancy. Flomenberg:Tevogen: Consultancy, Honoraria.

The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. (C) 2016 American Society for Blood and Marrow Transplantation.

Background: MCL is an incurable, aggressive B-cell lymphoma. Allogeneic stem cell transplantation (allo-SCT) is often reserved for relapsed/refractory patients, but upfront allo-SCT transplant in younger patients is feasible and produces durable remissions in high-risk disease. Objective: To describe the SKCC experience with allo-SCT transplantation in MCL. Design: Retrospective data review of all consecutive MCL patients who underwent allo-SCT at SKCC between 1999 and 2019. Results: We identified 16 patients with MCL who underwent allo-SCT. Indications: blastoid variant (N=5), physician preference (n=5), relapse after auto-SCT (N=3), high-risk MIPI (N=2), inadequate autologous stem cell collection (N=1). The majority of patients were male (n=11, 69%) and Caucasian (n=14, 88%) with a median age at transplant of 50 years (range 40-69). Donor source was HLA haploidentical (n=8), matched-related (n=4), and matched-unrelated (n=4). The majority of haploidentical recipients were transplanted on our two-step T-cell tolerization approach. Conditioning was chemotherapy-based myeloablative (n=7) and reduced intensity (n=9); 69% were treated on clinical trial. Pretransplant induction regimens were heterogeneous over this span of time. Disease status at transplant: first complete remission (n=5), second complete remission (n=3), first relapse with chemosensitive disease (n=2), first relapse with chemoresistant disease (n=1), primary induction failure with chemosensitive disease (n=2), not evaluated (n=3). Median follow-up of surviving patients is 104 months (range 11-253). At 5 years, probability of overall survival is 52.5% and in haploidentical vs matched recipients is 73% vs 31%, respectively. Transplant-related mortality was 25% in the total cohort, all of which occurred in patients treated >15 years ago. Graft-vs-host disease (GVHD) occurred in 10/16 (63%) patients, with no GVHD-related death. Conclusions: For patients with aggressive MCL treated at SKCC on or off clinical trial, allo-SCT is feasible and effective, with evidence of a graft-vs-lymphoma effect. The increased tolerability of allo-SCT with recent approaches and the favorable outcomes with haploidentical donor source support the use of allo-SCT in high-risk MCL patients. TP53 gene status in this patient cohort is being evaluated to assess the effect of allo-SCT on outcomes and will be reported.

High dose chemotherapy followed by autologous stem cell transplantation (ASCT) offers a cure in the relapsed setting in both Hodgkin (HL) and non-Hodgkin lymphoma (NHL). Additionally, it remains a first-line standard of care in multiple myeloma (MM) patients whom are eligible for ASCT. However, the management of these hematologic malignancies continues to rapidly evolve with non-cytotoxic therapeutic options such as development of new cellular therapies. These developments underscore the importance of monitoring immune reconstitution after ASCT. Immune reconstitution panels (IRP) were evaluated retrospectively in all lymphoma and MM patients over a 6-year span (2012-2018) whom underwent ASCT at our institution. Patients were included if they had at least two IRP evaluations including (1) a pre-ASCT measured within 30 days of ASCT, (2) day 30-45, (3) day 60-90, and (4) at 1-year post-ASCT. Mononuclear cells from peripheral blood of treated patients were analyzed by flow cytometry for assessment of lymphocyte phenotype and numbers. The data on 110 patients were available for analysis (72 MM, 34 NHL, 4 HL). All lymphoma patients were conditioned with BEAM. All MM patients were conditioned with a standard high dose melphalan regimen. The median pre-ASCT absolute CD3 counts in the lymphoma cohort were significantly lower than the MM cohort at 1709 cells/μL vs 3309 cells/μL, respectively (P Impaired T-cell reconstitution in both lymphoma and MM continues through 1-year post-ASCT. As shown, a larger percent reduction in median CD3 and CD4 counts through day 365 was appreciated in MM compared to lymphoma. Impaired recovery of CD4+ T cells may increase the risk of opportunistic infections, decrease the response to vaccination, and lead to ineffective anti-tumor response. Further prospective and larger retrospective studies like this should continue in the modern-era as they may help predict responses to further interventions requiring a robust T-cell repertoire for maximal efficacy such as CAR-T cell and BiTE therapies.

Engraftment syndrome (ES) is a known complication of autologous hematopoietic stem cell transplant during neutrophil recovery. There is a limited amount of data available comparing the incidence of ES with post-transplant granulocyte colony-stimulating factor versus granulocyte macrophage colony-stimulating factor (GM-CSF), specifically in patients with multiple myeloma. Our retrospective review of 156 patients at a single center showed that GM-CSF was associated with a higher incidence of ES compared with G-CSF (32% versus 8% of patients, P.001) and that development of ES was associated with a 32.9% (P.001) longer hospital stay. This suggests that the choice of growth factor could possibly contribute to the development of ES and the associated costs of increased medical care.

Although transplant practices have changed over the last decades, no information is available on trends in incidence and outcome of chronic graft-versus-host disease (cGVHD) over time. This study used the central database of the Center for International Blood and Marrow Transplant Research (CIBMTR) to describe time trends for cGVHD incidence, nonrelapse mortality, and risk factors for cGVHD. The 12-year period was divided into 3 intervals, 1995 to 1999, 2000 to 2003, and 2004 to 2007, and included 26,563 patients with acute leukemia, chronic myeloid leukemia, and myelodysplastic syndrome. Multivariate analysis showed an increased incidence of cGVHD in more recent years (odds ratio = 1.19, P

Higher rates of relapse in maternal recipients of haploidentical hematopoietic stem cell transplantation from adult offspring donors for AML and myelodysplastic syndrome

Acquired uniparental disomy in chromosome 6p as a feature of relapse after T-cell replete haploidentical hematopoietic stem cell transplantation using cyclophosphamide tolerization

Background: The initial treatment of FLT3 wild type acute myeloid leukemia (AML) has not significantly changed since induction therapy with Ara-C and anthracyclines was first developed. Preclinical data suggests constitutive activation of the AKT3/mammalian target of rapamycin (mTOR) pathway may play a role in pathogenesis of this disease in a subset of AML patients. Previous data from our group has shown that the presence of phosphorylated ribosomal S6 (pS6) in AML blasts as detected by flow cytometry may predict response to the combination of sirolimus and induction chemotherapy. Here we report the clinical and pharmacodynamics results of a phase II study of the combination of these drugs. Methods: Subjects had newly diagnosed AML based on WHO criteria. Subjects received oral sirolimus starting on day 1 (12 mg loading dose) then 4 mg daily on days 2-10 with idarubicin 12mg/m2 days 4-7 and cytarabine 100mg/m2 days 4-10. Clinical response was assessed at hematologic recovery or by day 42 using IWG for response. Samples for pharmacodynamic studies of blasts were drawn prior to treatment with sirolimus on day 1, and then again prior to dosing of idarubicin and cytarabine on day 4. Assessment of pS6 on gated blasts, a biomarker of mTORC1 activation, was assessed by flow cytometry using previously described methods. Results: 55 patients enrolled on this trial received sirolimus with an average age of 58 years. Toxicity was similar to published 7+3 data and prolonged aplasia without recovery was not observed. Twenty-nine patients (53%) had high risk cytogenetic or molecular mutations, 15 (27%) had intermediate risk disease, and 11 (20%) patients had lower risk disease. As a whole, 35 patients (64%) entered into CR or CRp, 1 had a PR, 17 (27%) were non-responders. Two (4%) patients (ages 64 and 71) died during induction. Thirteen (45%) patients with high risk disease had a CR or CRp, 14 (48%) were non-responders, and 2 died in induction. Of the 15 subjects with intermediate risk disease, 11 (79%) patients had a CR or CRp, 1 had a partial response, and 3 were non-responders. All low risk patients had a CR, and 9 of 11 are alive and in remission at the time of censoring of data with a median time on study of 674 days. One patient with low risk disease subsequently relapsed, went to stem cell transplant, and is currently in CR. Two patients with low risk disease refused to proceed with standard of care consolidation; of these, 1 is alive and in remission 946 days from study entry, and 1 died in relapse. Fifteen patients (27%) subsequently underwent allogeneic stem cell transplantation in CR, and 8 (53%) are still alive an average of 358 days after transplant. Thirty-seven of 55 patients had adequate samples for pharmacodynamic analysis. Surprisingly, all patients demonstrated activation of ribosomal S6 prior to therapy in contrast to 67% positivity seen in previous studies that focused on patients with relapsed AML. mTORC1 was inhibited greater than 40% in 28/37 (76%) of patients. Inhibition did not correlate with either overall survival or age of patients. Conclusions: Sirolimus and 7+3 is a well-tolerated regimen. mTORC1 appears to be activated in almost all patients at the time of diagnosis of AML as assessed by flow cytometric assessment of ribosomal S6. Inhibition of mTORC1 did not correlate with response, suggesting that AML cells may have redundant signaling pathways that regulate chemosensitivity when mTORC1 is inhibited. Given the large percentage of samples with mTORC1 activation in this upfront AML study, future research into dual mTORC inhibitors may prove valuable. Disclosures Carroll: Astellas Pharmaceuticals: Research Funding; Incyte Pharmaceuticals: Research Funding. Porcu: Innate Pharma: Research Funding; Kura: Research Funding; Miragen: Research Funding; Kiowa: Research Funding; Galderma: Research Funding; Tetralogic: Research Funding; Cell Medica: Research Funding; Celgene: Research Funding. Perl: Arog Pharmaceuticals: Consultancy; Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board; Seattle Genetics: Other: Advisory board; Asana Biosciences: Other: Scientific advisory board; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Actinium Pharmaceuticals: Other: Scientific Advisory Board.

Many hematopoietic stem cell programs capture transplant-related data into multiple data repositories simultaneously, including electronic medical record systems, repositories to support specific research projects, repositories to support specific quality management initiatives, repositories to track and guide the pre-transplant evaluation and workup, repositories to guide stem cell collection and harvest, repositories to support reporting to internal and external regulatory entities, and others. This state of affairs increases costs and decreases productivity as a result of marked duplication of data-capturing effort and poor quality, accessibility, and interoperability of captured data. An important barrier to addressing this issue is the fact that most data repositories in academic medical centers are based on different underlying data models, which constitutes a so-called "chasm of semantic despair" with regard to sharing and/or combining data residing in two or more data repositories, both within and between institutions. To address this issue, NCI, FDA, ISO, HL7, and C-DISC have developed a Biomedical Research Integrated Domain Group (BRIDG) Model. The purpose of the BRIDG model is to bridge the multiple chasms of semantic despair that exist between data repositories maintained by basic researchers, translational researchers, clinical researchers, pharmaceutical companies, and government regulators. To our knowledge, we are the first academic cancer center in the world to design and implement a cancer research system based on the NCI-BRIDG model. Important aspects of our implementation derived from the BRIDG model include extensive utilization of the NCI/BRIDG standard data elements, and resolution of the many-to-many relationship between patients and treatment protocols with a patient treatment course instance table. The latter feature provides powerful support for quality assurance of both clinical documentation and patient management by enabling our software to continually compare what is supposed to be happening to each patient, based on the treatment protocol or protocols on which the patient is registered, against what the clinical documentation indicates is happening to each patient. In addition to enhancing data sharing between researchers, we have also begun to use the system to support clinical decision-making, administrative decision-making, and clinical quality assurance.

International audience; Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least 1 year after allogeneic hematopoietic cell transplantation is difficult. We analyzed 3339 patients with acute myeloid leukemia and 1434 patients with acute lymphoblastic leukemia who received myeloablative conditioning and related or unrelated stem cells from 1990 to 2005. Most clinical factors predictive of LFS in 1-year survivors were no longer significant after 2 or more years. For acute myeloid leukemia, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS 2 or more years after transplantation. For lymphoblastic leukemia, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for 1 year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present and higher if noncyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator (http://www.cibmtr.org/LeukemiaCalculators). This prognostic information is more relevant for survivors than estimates provided before transplantation.

Several risk factors are associated with increased mortality in patients with chronic graft-versus-host disease (cGVHD), but there is considerable variability in the reported factors. Therefore, we evaluated patient, transplantation, and cGVHD characteristics to develop a risk score in 5343 patients with cGVHD. Ten variables were identified as being significant in multivariate analysis of overall survival and nonrelapse mortality (NRM): age, prior acute GVHD, time from transplantation to cGVHD, donor type, disease status at transplantation, GVHD prophylaxis, gender mismatch, serum bilirubin, Karnofsky score, and platelet count. These 10 variables were used to build a cGVHD risk score, and 6 risk groups (RGs) were identified. The 5-year NRM was 5% (1%-9%) in RG1, 20% (19%-23%) in RG2, 33% (29%-37%) in RG3, 43% (40%-46%) in RG4, 63% (53%-74%) in RG5, and 72% (59%-85%) in RG6. The 5-year overall survival was highest at 91% (95% confidence interval [CI]:85%-97%) in RG1, followed by 67% (65%-69%) in RG2, 51% (46%-55%) in RG3, 40% (37%-43%) in RG4, 21% (12%-30%) in RG5, and 4% (0%-9%) in RG6 (all P < .01). This analysis demonstrates the usefulness of data from a large registry to develop risk-score categories for major transplantation outcomes. Validation of this cGVHD risk score is needed in a different population to ensure its broad applicability.

Cyclophosphamide (CY) toleration has been associated with low rates of graft versus host disease (GVHD) and non-relapse mortality after both HI and MR HSCT. At Jefferson, both recipient types undergo a 2 step approach to HSCT in which after myeloablative (MYA) or reduced intensity (RIC) conditioning, patients receive a fixed dose of 2 x 108/kg donor CD3+ T cells (DLI), followed 2 days later by CY daily x 2 for bidirectional tolerization. A CD34-selected stem cell product containing < 5 x 104/kg untolerized CD3 cells is infused 24 hours after CY. Mycophenolate mofetil and tacrolimus are started on day-1 for GVHD prophylaxis. The consistency of cell doses, conditioning, and GVHD prophylaxis in the approach provides an optimal platform for comparing patient outcomes. Because tolerance induction and sustained engraftment in CY-based HSCT approaches depends on elimination of donor and host alloreactive T cells, we hypothesized that engraftment in this model would be different between HI and MR recipients based on the lower proliferation of alloreactive T cells in major histocompatibility (MHC) MR versus HI donor-recipient pairs. Data for 292 consecutive patients (232 HI, 60 MR) treated on a 2-step trial were evaluated for incorporation into this analysis. To be included, patients were required to be in remission for 3 months post HSCT and have available d+28 and d+90 peripheral blood T cell chimerism data. Seven HI patients with graft rejection, 5/232 with early (2%-all MYA) and 2/232 with late (0.1%-1 MYA and 1 RIC), were not included in the analysis. No MR patients developed graft rejection. Days to ANC > 500 cells x 103/ul, CD3/4 and CD3/8 counts at d+28 and d+90, peak fever after DLI infusion as a rough measure of alloreactivity, and number of patients requiring post HSCT donor lymphocytes for mixed chimerism were also examined. Independent samples T test was used for chimerism and peak fever comparisons. The final study group contained 201 patients treated on a 2 step MYA [12 Gy total body irradiation (TBI)] or RIC (fludarabine/TBI based) regimen. Patients had various hematological malignancies and 6 had aplastic anemia. Data is contained in the table. Mean T cell chimerism was higher in HI versus MR recipients at d+28 and d+90 (p= 0.001 both time points). In 3 MR recipients, donor T cell chimerism was < 70% through d+90. Four (9%) MR versus no HI recipients received post HSCT DLI for mixed chimerism in the absence of recurrent disease. Chimerism differences did not affect time to myeloid engraftment or lymphoid reconstitution. While higher median peak temperatures after DLI were observed in HI versus MR recipients, some patients in the latter population were also highly febrile. Those MR recipients with higher fevers had a higher mean donor engraftment percentage at d+28 than those with lower fevers, but the difference was not significant (96.61% vs 93.95%, p=0.193). The data presented here supports the concept that MHC mismatching in HI HSCT is associated with a higher frequency of alloreactive T cells in the DLI which more efficiently eliminate residual host lymphocytes prior to CY administration resulting in more complete donor lymphoid chimerism. Interestingly, further support for this notion was provided by the MR recipient data where higher fevers, a surrogate for more robust immunologic activation, translated into the more rapid achievement of full donor chimerism. This finding was potentially due to higher alloreactivity between some MR recipient/donor pairs from non-MHC polymorphisms. Persistence of small numbers of host lymphocytes, which have also been rendered tolerant by CY administration, does not, in and of itself, lead to graft failure/rejection. However, concerns that low degree of chimerism might contribute to higher risk of relapse led to administration of post-transplant DLIs to push donor lymphoid chimerism closer to 100%. The impact if any, of delayed complete chimerism on GVHD and relapse requires further evaluation and may dictate changes to the 2 step regimen for the MR group. Table. Table. Disclosures Porcu: Innate Pharma: Consultancy.

Mortality from relapsed disease remains a significant barrier to long term survival (OS) after HI HSCT despite presumed heightened alloreactivity from the mismatched graft. The Jefferson group uses a 2 step approach to HI HSCT where patients are typically conditioned with 12 Gy total body irradiation (TBI) in 8 fractions of 1.5 Gy over 4 days, immediately followed by an infusion of 2 x 108/kg donor CD3+ cells (DLI). After 2 rest days, cyclophosphamide (CY) 60 mg/kg daily x 2 is given for bidirectional tolerization, followed a day later by a CD34 selected stem cell infusion. In an attempt to maximize graft versus tumor (GVT) effects, we changed the timing of the TBI in the 2 step approach. In this updated regimen, TBI was given in 6 fractions of 2.0 Gy over 3 days, resulting in a 24 hour delay between conditioning and DLI. Theoretically, the extra time reduced residual disease burden prior to the introduction of the DLI, in turn reducing the number of donor T cells activated by tumor, thus avoiding their elimination by CY. Major HSCT endpoints of OS (Kaplan Meier), relapse and non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) [cumulative incidence (CI)-EZR Software v 1.37] were assessed using this updated 2 step HI HSCT approach. Forty patients, median age 51 (range 19-65) years with AML (13), MDS (7), B ALL (7), PH+ ALL (4), T cell ALL (2), Burkitt (2), and other heme malignancy (5) with revised disease risk assessment scores of intermediate (21), high (17), and very high (2) were treated from 2013 to 2017. Median follow-up is 36 (range 15 to 56) months. At 24 months, probability of OS was 59%, CI NRM and relapse were 34% and 15% respectively. CI aGVHD (grades 2-4), (grades 3-4), and cGVHD were 38%, 5%, and 20%. Median d+28 T cell chimerism of 36 patients engrafted and alive was 100% (range 97% to 100%). Median CD3/4 and CD3/8 counts at d +28 were 49 (range 9-417) and 54 (8-1329) cells/ul. Of the 4 remaining patients, two without donor specific antibodies rejected their graft, one with a large burden of CMML at the time of HSCT. An additional patient relapsed prior to the attainment of sustained donor T cell chimerism and one patient died of sinusoidal obstructive syndrome prior to d+28. Causes of death were infection (7), regimen toxicity (4), GVHD (2), and disease (3). This updated 2 step regimen was associated with a highly acceptable 2 year OS rate and low rates of disease recurrence. Of the patients that died, cause of death was primarily due to NRM and not relapsed disease suggesting that the added extra day may have enhanced GVT effects. In the absence of donor specific antibodies, the 2 early and 1 late graft rejections are atypical for a 2 step MA HI HSCT approach and were potentially caused by a rebound recipient hematopoiesis allowed by the delay in the DLI in a minority of patients. While formal comparison to prior patient cohorts is not feasible, this relapse rate compares favorably to the 2 year 27% relapse rate in similar patients treated on our initial trial.(Grosso, et al., Blood, 2011, 118:47320). The concept of allowing time for malignancy burden to decline in high risk patients prior to introduction of DLI warrants further evaluation going forward in efforts to reduce relapse after HSCT. Table. Table. Disclosures Porcu: Innate Pharma: Consultancy.

We examined the efficacy of reduced-intensity conditioning (RIC) and compared outcomes of 93 patients older than 16 years after RIC with 1428 patients receiving full-intensity conditioning for allografts using sibling and unrelated donors for Philadelphia-negative acute lymphoblastic leukemia (ALL) in first or second complete remission. RIC conditioning included busulfan 9 mg/kg or less (27), melphalan 150 mg/m2 or less (23), low-dose total body irradiation (TBI; 36), and others (7). The RIC group was older (median 45 vs 28 years, P < .001) and more received peripheral blood grafts (73% vs 43%, P < .001) but had similar other prognostic factors. The RIC versus full-intensity conditioning groups had slightly, but not significantly, less acute grade II-IV graft-versus-host disease (39% vs 46%) and chronic graft-versus-host disease (34% vs 42%), yet similar transplantation-related mortality. RIC led to slightly more relapse (35% vs 26%, P = .08) yet similar age-adjusted survival (38% vs 43%, P = .39). Multivariate analysis showed that conditioning intensity did not affect transplantation-related mortality (P = .92) or relapse risk (P = .14). Multivariate analysis demonstrated significantly improved overall survival with: Karnofsky performance status more than 80, first complete remission, lower white blood count, well-matched unrelated or sibling donors, transplantation since 2001, age younger than 30 years, and conditioning with TBI, but no independent impact of conditioning intensity. RIC merits further investigation in prospective trials of adult ALL.

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P 50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT. American Society for Blood and Marrow Transplantation. All rights reserved.

BACKGROUND: The impact of donor-recipient ABO matching on outcomes after allogeneic stem cell transplantation has been a matter of controversy. STUDY DESIGN AND METHODS: Individual patient data–based meta-analysis was conducted with a pooled data set provided through six published and one unpublished cohorts. Outcomes in recipients of peripheral blood or bone marrow transplantation for hematologic malignancies were evaluated. A multivariate Cox model was used to adjust differences in outcomes of patients receiving ABO-matched grafts with those receiving major, minor, or bidirectional mismatched grafts. Considering multiple testing, p values of less than 0.05 and 0.001 were considered significant for the primary and secondary endpoints, respectively. RESULTS: In all, 1208 cases, including 697 ABOmatched and 202 major, 228 minor, and 81 bidirectional mismatched transplants, were analyzed. Overall, adverse impact of ABO matching on overall survival (OS), as a primary endpoint, was not observed (adjusted hazard ratios [95% confidence intervals]: major, 1.03 [0.82-1.30], p = 0.81; minor, 1.19 [0.971.47], p = 0.10; bidirectional, 1.25 [0.91-1.72], p = 0.17). Among related stem cell recipients, ABO matching had no significant influence on OS, while the minor and bidirectional mismatched groups among unrelated stem cell recipients exhibited lower OS with marginal significance, especially in patients with acute leukemia, patients who received transplants after 1998, and patients who underwent transplants at Asian centers. CONCLUSIONS: Our meta-analysis demonstrates no adverse association between any ABO mismatching and survival. However, marginally lower OS found in recipients of minor or bidirectional mismatched grafts from unrelated donors suggested the need for larger studies focusing on unrelated transplants. A

We report the retrospective outcomes of unrelated donor (URD) transplants in 169 patients with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) who received transplants between 1995 and 2004. Median age was 33 years (range, 16-59 years). A total of 50% had a white blood cell count (WBC) more than 30 × 109/L, 18% extramedullary disease, 42% achieved CR more than 8 weeks from diagnosis, 25% had adverse cytogenetics, and 19% had T-cell leukemia. A total of 41% were HLA well-matched, 41% partially matched with their donors, and 18% were HLA-mismatched. At 54-month median follow-up, incidences of acute grade 2-IV, III to IV, and chronic graft-versus-host disease were 50%, 25%, and 43%, respectively. Five-year treatment-related mortality (TRM), relapse, and overall survival were 42%, 20%, and 39%, respectively. In multivariate analyses, TRM was significantly higher with HLA-mismatched donors and T-cell depletion. Relapse risk was higher if the diagnostic WBC was more than 100 × 109/L. Factors associated with poorer survival included WBC more than 100 × 109/L, more than 8 weeks to CR1, cytomegalovirus seropositivity, HLA mismatching, and T-cell depletion. Nearly 40% of adults with ALL in CR1 survive 5 years after URD transplantation. Relapse risks were modest; TRM is the major cause of treatment failure. Selecting closely HLA-matched URD and reducing TRM should improve results.

Background Donor lymphocyte infusion (DLI) has been used with variable success in a variety of hematologic malignancies. Patients and Methods We conducted a retrospective analysis of all patients who were treated with DLI for persistent or relapsed disease at the Temple University Bone Marrow Transplant Unit from July 1, 1993 to December 31, 2013 to evaluate the effect of the type of DLI (fresh vs. cryopreserved) on event-free survival (EFS) and overall survival (OS). Median follow-up was 64.8 months (range, 0.3-142.6 months). Results We found that EFS and OS were similar between patients receiving cryopreserved cells and those receiving fresh DLI (median OS for cryopreserved cells, 0.39 years; median OS for fresh cells, 0.32 years; P = .793; median EFS for cryopreserved cells, 0.410 years; median EFS for fresh cells, 0.420 years; P = .4264). In the setting of relapsed disease, treatment with any chemotherapy regimen before receiving DLI did not significantly impact OS (n = 63; P = .2203) or EFS (n = 40; P = .542). A subgroup analysis limited to patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) (32 patients) showed that differences in OS and EFS between cryopreserved and fresh DLI approached significance (median OS for cryopreserved cells, 0.34 years; median OS for fresh cells, 0.17 years; P = .16; median EFS for cryopreserved cells, 0.37 years; median EFS for fresh cells, 0.094 years; P = 0.11). Conclusion We conclude that the use of fresh cells versus cryopreserved cells does not have an impact on outcomes, and selected patients can achieve long-term survival with DLI for treatment of relapse after transplantation, although the overall outcomes remain dismal.

We previously reported a risk score that predicted mortality in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (HCT) between 1995 and 2004 and reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We sought to validate this risk score in an independent CIBMTR cohort of 1128 patients with CGVHD who underwent transplantation between 2005 and 2007 using the same inclusion criteria and risk score calculations. According to the sum of the overall risk score (range, 1 to 12), patients were assigned to 4 risk groups (RGs): RG1 (0 to 2), RG2 (3 to 6), RG3 (7 to 8), and RG4 (9 to 10). RG3 and RG4 were combined, as RG4 accounted for only 1% of the total cohort. Cumulative incidences of nonrelapse mortality (NRM) and probability of overall survival were significantly different between each RG (all P

Reports have shown a worse outcome for donor-recipient pairs mismatched for ABO blood groups in bone marrow transplantation (BMT). These studies, however, included small and heterogenous study populations, and not all considered bidirectional ABO incompatibility separately. Because the issue remains controversial, we analyzed the effect of ABO mismatch on the overall survival, transplant-related mortality, and occurrence of acute and chronic graft-versus-host disease (GVHD) in a large homogenous group of patients undergoing allogeneic BMT. A total of 3103 patients with early-stage leukemia who underwent transplantation between 1990 and 1998 with bone marrow from an HLA-identical sibling and who were reported to the Center for International Blood and Marrow Transplant Research were studied. The median follow-up was 54 months. A total of 2108 (67.9%) donor-recipient pairs were ABO identical, 451 (14.5%) had a minor mismatch, 430 (13.9%) had a major mismatch, and 114 (3.7%) had a bidirectional ABO mismatch. The groups did not differ significantly in patient or donor characteristics except for more female-to-male sex mismatch in the bidirectional ABO mismatch group (P = .017). In multivariate models of overall survival, transplant-related mortality, and grade II to IV acute GVHD, there were no significant differences among the 4 groups. Bidirectional ABO mismatch was associated with a significantly higher risk of grade III or IV acute GVHD (hazard ratio, 1.869; 95% confidence interval, 1.192-2.93; P = .006). Patients with major ABO mismatch received red blood cell transfusions (P = .001) for a longer timer after transplantation and had a slightly slower neutrophil recovery (P < .001). There was no evidence of a substantial effect of ABO blood group incompatibility on the outcome of conventional BMT among patients with leukemia.

Post-transplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus (EBV) associated malignancy that occurs in the setting of pharmacologic immunosuppression used after organ transplantation. The presence of monoclonal gammopathy (MG) after organ transplantation is a risk factor for the development of PTLD. We retrospectively explored the characteristics of serum protein electrophoresis (SPEP) in 38 adult solid organ transplant patients with biopsy proven PTLD and SPEP. Twenty-three (61%) had MG with nine (24%) showing multiple MG. Background gammaglobulin levels were abnormal in 13 (34%) patients with five (13%) and eight (21%) having polyclonal hypergammaglobulinemia or hypogammaglobulinemia, respectively. Hypogammaglobulinemia was correlated with the presence of MG (p = 0.01) and polymorphic B-cell hyperplasia histology (p = 0.01). No correlation between SPEP findings and overall survival were noted. With median follow-up of 116 wk (range 2-261 wk), 21 (55%) patients are alive with 20 (53%) in complete remission. Response to reduction in immunosuppression was correlated with improved overall survival (262 wk vs. 68 wk, p = 0.003). Persistence of MG after complete response of the PTLD did not predict relapse. There is a high incidence of MG and gammaglobulin abnormalities in patients with PTLD.

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in patients with lymphoma who experience disease relapse after autologous hematopoietic stem cell transplantation (auto-HSCT) because the allograft is tumor free and may induce a graft-versus-tumor effect. We analyzed 114 patients treated with this approach from 1990 to 1999 to assess disease progression, progression-free survival (PFS), and overall survival (OS). Cumulative incidence of disease progression at 3 years was 52%, whereas treatment-related mortality was 22%, lower than previously reported. Three-year probabilities of OS and PFS were 33% and 25%, respectively. With prolonged follow-up, however, nearly all patients experienced disease progression, and 5-year probabilities were 24% and 5%, respectively. Complete remission at the time of allo-HSCT and use of total body irradiation (TBI) in patients with non-Hodgkin lymphoma (NHL) were associated with lower rates of disease progression and higher rates of OS. In summary, allo-HSCT is feasible for patients with lymphoma who have relapses after auto-HSCT and can result in prolonged survival for some, but it is usually not curative. Most likely to benefit are patients who have HLA-matched sibling donors, are in remission, and have good performance status.

This study was conducted to determine if the accelerated telomere attrition that occurs as a consequence of allogeneic stem cell transplantation leads to measurable functional defects. Telomere lengths in mononuclear leukocytes obtained from 15 long-term allogeneic stem cell transplant recipients and their respective donors were determined by Southern hybridization and densitometric analysis. Functional assays evaluated the ability of these cells to proliferate in response to a mitogenic stimulus and to differentiate under appropriate cytokine stimulation. Lymphocyte proliferation in response to phytohemagglutinin was determined by measurement of (3)[H]thymidine uptake. The ability of circulating myeloid cells to differentiate was determined after incubation of peripheral blood mononuclear cells with IL-3 and GM-CSF. A total of 13 patients demonstrated telomeric loss, ranging from 0.1 to 3.7 kbp. Strikingly, lymphocytes from 14 of the 15 patients demonstrated a significant decrease in proliferation when compared to their respective donors (68%+/-22, P=0.001). All patients demonstrated at least a 50% decrease in the number of myeloid colony-forming units when compared to their respective donors (P0.0001). A decreased ability of hematopoietic cells to proliferate and differentiate is phenotypically consistent with an aged immune system. This may correlate with diminished clinically relevant immune responses to infection or vaccination, as seen in the elderly.

Ibritumomab tiuxetan is a novel radioimmunotherapeutic agent that has a high response rate in relapsed or chemotherapy-refractory CD20+ B-cell non-Hodgkin's lymphoma. Whereas chemotherapy agents can successfully be used multiple times in a given patient, there are few data on the repeated use of radioimmunotherapy in terms of efficacy or morbidity, and no reports as yet involving radioconjugates that target different antigens We report on a patient who was treated successfully with yttrium-90-labeled humanized anti-CD22 monoclonal antibody (90Y-epratuzumab). Upon relapse 3 years later, the patient was treated again with radioimmunotherapy consisting of 90Y-ibritumomab tiuxetan anti-CD20 monoclonal antibody, with a good response and acceptable bone marrow suppression. This case report demonstrates the potential for repeated treatments with radioimmunotherapy agents in patients with chemotherapy-refractory non-Hodgkin's lymphoma.

Purpose: Malignancy relapse remains a major obstacle for successful allogeneic hematopoietic cell transplantation (HCT). Chronic graft-versus-host disease (cGVHD) is associated with fewer relapses. However, when studying effects of cGVHD on relapse, it is difficult to separate from acute GVHD effects as most cases of cGVHD occur within the first year after transplant at the time when acute GVHD is still active. Experimental Design: This study based on CIBMTR registry data investigated cGVHD and its association with the incidence of late relapse and survival in 7,489 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndromes (MDS), who were leukemia free at 12 months after myeloablative allogeneic HCT. Results: Forty-seven percent of the study population was diagnosed with cGVHD at 12 months after transplant. The protective effect of cGVHD on late relapse was present only in patients with CML [RR, 0.47; 95% confidence interval (CI), 0.37–0.59; P < 0.0001). cGVHD was significantly associated with higher risk of treatment-related mortality (TRM; RR, 2.43; 95% CI, 2.09–2.82; P < 0.0001) and inferior overall survival (RR, 1.56; 95% CI, 1.41–1.73; P < 0.0001) for all diseases. In patients with CML, all organ sites and presentation types of cGVHD were equally associated with lower risk of late relapse. Conclusions: These results indicate that clinically relevant antileukemia effects of cGVHD on late relapses are present only in CML but not in AML, ALL, or MDS. Chronic GVHD in patients who are 1-year survivors after myeloablative allogeneic HCT is primarily associated with higher TRM and inferior survival. Clin Cancer Res; 21(9); 2020–8. ©2014 AACR. See related commentary by Gill, p. 1981

BACKGROUND : In recent years, decreasing financial resources led to the use of lower-dose platelet components. However, the economic consequences of the use of such components have not been carefully studied. STUDY DESIGN AND METHODS: A formal economic analysis was conducted of a recently reported, prospective, randomized, double-blind study examining the platelet dose–response relationship in nonrefractory patients. The economic analysis used a decision analysis model, conducted from the hospital's perspective and based directly on the observed clinical data and on institutional cost structures. RESULTS : The decision analysis model estimated that a 38-percent reduction in mean platelet dose, within the commonly prescribed dose range, would result in the average patient's requiring approximately 60 percent more transfusions in the posttransplant period (8 vs. 5; p = 0.05), which would result in an estimated 60-percent increase in the median cost to the hospital ($4486/patient vs. $2804/patient [in 1996 US dollars], p = 0.05). CONCLUSION: Efforts to decrease costs by utilizing lower-dose single-donor platelet transfusions are predicted to result in a disproportionate increase in the number of transfusions per patient, with a corresponding increase in overall hospital transfusion costs.

Background We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. Methods Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. Results The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem ce...

BACKGROUND: The dose-response relationship for platelet transfusion has become increasingly important as the use of platelet transfusion has grown. STUDY DESIGN AND METHODS: One hundred fifty-eight prophylactic apheresis platelet transfusions were administered to 46 patients undergoing high-dose therapy followed by hematopoietic progenitor cell transplantation in a prospective, randomized, double-blind, multiple-crossover study. Transfusions were administered in pairs, differing only in platelet content. Each pair consisted of a lower-dose platelet component (LDP) and a higher-dose platelet component (HDP) administered in random order to the same patient. LDPs contained a mean of 3.1 × 1011 platelets (range, 2.3-3.5 × 1011), and HDPs contained a mean of 5.0 × 1011 platelets (range, 4.5-6.1 × 1011). Patients with active bleeding and those who were refractory to platelet transfusions were excluded. RESULTS: The mean posttransfusion platelet count increment with LDP was 17,010 per μL, and that with HDP was 31,057 per μL (p20,000 per μL, a shorter transfusion-free interval, and a greater relative risk per day of requiring additional transfusions.

Seventy women with high-risk stage II (n = 10), IIIA (n = 12), IIIB (n = 11), or IV (n = 37) breast cancer received cyclophosphamide 6000 mg/m2, etoposide 2400 mg/m2, and carboplatin 1200 mg/m2 followed by infusion of autologous hematopoietic stem cells (AHSC). Women with high-risk stage II disease had eight or more involved axillary lymph nodes (n = 9) or axillary and breast relapse following lumpectomy, chemotherapy, and radiation therapy (n = 1). Women with measurable stage III or stage IV disease were required to demonstrate complete or partial response to conventional-dose chemotherapy prior to transplant. The overall (complete plus partial) response rate for the 31 patients not in complete remission at the time of transplant was 55%. With a median follow-up of 545 days, the 2-year actuarial progression-free survival rates for patients with stage II, IIIA, IIIB and IV are 86, 75, 42 and 13%, respectively. Factors independently predictive of longer progression-free survival by multivariate analysis included lower stage disease, status of disease at transplant (in CR vs not in CR), and positive estrogen receptor status. Factors predictive of more rapid neutrophil engraftment by multivariate analysis included post-transplant administration of hematopoietic growth factors, greater number of infused CFU-GM, mobilization with G-CSF or cyclophosphamide/G-CSF (vs mobilization with GM-CSF or no mobilization), and lower stage disease. Only one patient (1.4%) died prior to day 100 from any cause. High-dose cyclophosphamide, etoposide, and carboplatin followed by infusion of AHSC constitutes an active and well-tolerated regimen in the treatment of women with high-risk non-metastatic or metastatic breast cancer.

The implementation of electronic medical records (EMR) systems was mandated by the U.S. federal government in large part due to research indicating that difficulty accessing clinical data was one of the most common causes of preventable deaths. Several assumptions were implicit in this mandate, including the assumption that the implementation of EMR would indeed improve clinicians’ access to clinical data, that implementation of EMR would pose little to no risk to patients, and that the clinical benefit of improved access to clinical data would outweigh any risks that might arise. As detailed in this review, both formal research and extensive experiential observation have called all three assumptions into question. Specifically, as detailed below, there is clear evidence that EMR systems are associated with multiple specific risks to patients, whereas few, if any, scientifically rigorous outcomes-based studies have demonstrated that the potential benefits of EMR outweigh the known risks. In addition, there is currently little to no scientifically rigorous evidence that EMR systems constitute a cost-effective methodology for improving patient outcomes.

A 62-year-old male with a myoepithelioma of the right parotid gland was treated with surgical excision followed by adjuvant radiation therapy. Prior to the completion of radiation therapy, the patient developed progressive disease at local, regional, and distant metastatic sites. Combined modality treatment with radiation and chemotherapy resulted in a significant but transient shrinkage of the tumours at all sites. The patient succumbed to metastatic disease 212 days following the diagnostic biopsy. This case illustrates several of the distinctive clinical and pathological characteristics of this rare tumour.