History Of Graft-versus-host Disease Research Articles

Allergic Fungal Rhinosinusitis and Contralateral Chronic Granulomatous Invasive Fungal Sinusitis: A Case Report.

This case report describes rare concomitant allergic fungal rhinosinusitis (AFRS) and chronic granulomatous invasive fungal sinusitis (CGIFS) in a 34-year-old woman with acute lymphoblastic leukemia and graft-versus-host disease (GVHD) post bone marrow transplantation. Initially presenting with rhinorrhea and nasal obstruction, the patient was diagnosed with AFRS in the right maxillary sinus, followed by a postoperative course of CGIFS in the left nasal cavity, showcasing the unique occurrence. She was not immunocompromised during diagnosis. CGIFS may have occurred because of surgery; however, voriconazole led to significant improvement. This case highlights noninvasive and invasive fungal infections in patients with chronic rhinosinusitis and a history of GVHD and underscores the complexity of diagnosing and managing such cases.

Non-invasive Estimation of Microvasculopathy & Endothelial Dysfunction in Stem Cell Transplant Recipients and its Relationship with GVHD.

Microvasculopathy and endothelial dysfunction play important roles in the development of post-transplant complications, including graft-versus-host disease (GVHD). We assessed structural microvasculopathy by employing nailfold video capillaroscopy (NFVC) and endothelial dysfunction via flow-mediated dilatation (FMD) of the brachial artery in recipients of hematopoietic stem cell transplantation. Recipients of stem cell transplantation were included in this study post day+100 and divided into two cohorts. The first cohort consisted of 35 recipients of allogeneic hematopoietic stem cell transplantation (HCT) and the second cohort was comprised of 31 recipients of autologous HCT. A third cohort included 35 healthy individuals. NFVC was conducted on the second to fifth fingers of both hands using an Optilia video capillaroscope at 200× magnification, and the images were analyzed according to the European Alliance of Associations for Rheumatology (EULAR) criteria. The following parameters were used to measure vasculopathy: (a) median capillary density, derived from the capillary density of eight fingers, (b) median capillary diameter, derived from maximum capillary apical diameters of eight fingers, and (c) significant neoangiogenesis (neoangiogenesis present in ≥2 fingers). FMD of the right brachial artery was observed by high-resolution ultrasonography using the principle of post-occlusive reactive hyperemia, and video images were analyzed using edge-detecting software. The median capillary diameter was significantly higher in the allo-HCT cohort (20.56±5.17 micrometer) compared to the auto-HCT cohort (16.19±3.31 micrometer; p<0.001) and healthy controls (14.66±2.61 micrometer; p<0.001). The median capillary density was significantly lower in the allo-HCT cohort (median: 6 capillaries/mm, range: 5-9 capillaries/mm) compared to the auto-HCT cohort (median: 8.5 capillaries, range: 5-12 capillaries/mm; p<0.001) and healthy controls (median: 8 capillaries/mm, range: 7-10.5 capillaries/mm; p<0.001). The allo-HCT cohort had a higher proportion of patients with significant neoangiogenesis (86%) than the auto-HCT cohort (10%) and healthy controls (9%). The presence of significant neoangiogenesis was more frequent in the subgroup of patients with a history of GVHD (93%) compared to the subgroup of patients without any history of GVHD (57%; p=0.044). No significant differences in NFVC parameters or FMD were observed between recipients of myeloablative and reduced-intensity conditioning regimens. There was no significant difference in NFVC parameters between the auto-HCT cohort and healthy controls. There was no significant difference in FMD among the three cohorts; however, a higher proportion of patients in the allo-HCT cohort (28%) had lower FMD than those in the auto-HCT cohort (3%) and healthy controls (6%), suggesting endothelial dysfunction. Our findings demonstrate the presence of structural microvasculopathy in allo-HCT recipients and suggest a possible role of alloreactivity in the pathogenesis of post-HCT microvasculopathy.

Idecabtagene Vicleucel Is Well Tolerated and Effective in Relapsed/Refractory Myeloma Patients with Prior Allogeneic Stem Cell Transplantation

BCMA-specific chimeric-antigen receptor cells have led to high response rates and durable remissions in patients with relapsed refractory multiple myeloma. However, little data are available for patients after prior allogeneic transplantation, where patient T-cells are chimeric. Our objective was to assess safety and efficacy of patient-derived donor CAR-T cell treatment in myeloma patients with prior allogeneic stem cell transplantation, in particular with regard to Graft versus Host Disease (GvHD). We demonstrate a comprehensive clinical analysis of 3 patients, who had previously received allogeneic transplantation for high-risk myeloma, treated with idecabtagene vicleucel (ide-cel) at our institution. Ide-cel was well tolerated with no clinically relevant immune effector cell-associated neurotoxicity syndrome or cytokine release syndrome observed in any patient. Importantly, no new GvHD was observed although all patients had a history of GvHD. All patients responded to treatment with at least a very good partial remission. Two patients relapsed within 6 months and one patient is still in sCR. We demonstrate that treatment with ide-cel is feasible, very well tolerated and effective in patients with relapsed/refractory multiple myeloma after prior allogeneic stem cell transplantation.

AML-528 Long-Term Outcomes After Haploidentical Stem Cell Transplantation (Haplo-SCT) for Hematologic Malignancies

Allogeneic SCT is curative for large proportion of patients with high-risk hematologic malignancies. The introduction of posttransplant cyclophosphamide (PTCy)-based graft versus host disease (GVHD) prophylaxis led to significant improvements in haplo-SCT outcomes and a remarkable increase in its use in the past decade. We aimed from this study to assess long-term outcomes of patients who underwent haplo-SCT. We included all consecutive adult patients who had their first haplo-SCT between 2/2009 and 3/2019. Long-term survivors defined as patients who were alive and disease free at 2 years after transplant. PFS and OS. cumulative incidence of relapse (CIR) and non-relapse mortality (NRM). Age, gender, KPS, DRI, HCT-CI, conditioning regimen, CMV status, and history of GVHD were included in the predictive risk-factor analysis for long-term outcomes. 336 patients were identified: AML/MDS, n=196; ALL, n=55; lymphoid malignancy, n=48; MPNs, n=37. Of these, 144 patients with a median age of 45 (range, 18-72) years were disease-free at 2 years after transplant. Thirty-three percent of patients with ≥55 years, 28% had high/very-high DRI, and 30% had high HCT-CI >3. Majority received reduced intensity conditioning (88%). Prior history of acute grades 2-4 and chronic GVHD were 54 (37%) and 28 (19%) patients, respectively. The 4-year PFS and OS for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survival group, the 4-year PFS and OS were 92% and 96%, respectively. The 4-year CIR and NRM were 4% and 3%, respectively. Age ≥ 55 was the only predictive factor in multivariate analysis for inferior PFS (HR 2.63, 95% CI: 1.01-6.84; p=0.047) and OS (HR 3.33, 95% CI: 1.08-12.23; p=0.036). Thirteen patients (9%) died in the long-term survivor group, only two of which died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n=4), 2 patients died from infection, 1 patient each from GVHD and sudden death, and 3 unknowns. Our findings suggest an excellent long-term survival for patients who were disease-free at 2 years after haplo-SCT. Late relapses were low, and age was the only predictive factor for survival.

Day 100 Levels of Blood Immune Cells Are Prognostic Biomarkers for Allogeneic Hematopoietic Stem Cell Transplant Outcomes: Results from BMT CTN 0201

Background: BMT CTN 0201 was a randomized trial of bone marrow (BM) vs. G-CSF mobilized blood (G-PB) grafts in 550 pediatric and adult patients with leukemia or MDS undergoing allogeneic hematopoietic stem cell transplantation from unrelated donors. Overall survival (OS) was equivalent between both arms, with more chronic graft-versus-host disease (GvHD) among recipients of G-PB grafts and more graft failure among recipients of BM grafts (Anasetti NEJM 2012; 367:1487-1496). We have previously reported donor plasmacytoid dendritic cell (pDC) content in BM grafts are linked with improved survival and less death from acute GvHD (Waller JCO 2014 32:2365-2372). Here, we compare the kinetics of immune cell reconstitution between BM and G-PB recipients to test the hypothesis that graft source leads to differences in blood levels of donor-derived immune cells, and that higher levels of dendritic cells are associated with lower GvHD-related death rates.Methods: Demographics among randomized patients were similar with respect to diagnosis, conditioning regimens, GvHD prophylaxis, and CMV serostatus. Flow cytometry measured immune cells in blood samples at 1, 3, 6, 12, and 24 months post-transplant in recipients of BM (N=161) or G-PB (N=147) grafts from unrelated donors. Univariate and multivariable analyses evaluated associations between donor immune cells and outcomes.Results: Reconstitution kinetics of immune cells at day +100 were associated with graft source, a history of GvHD, and subsequent GvHD-related death.G-PB recipients had higher 1 and 3-month levels of blood T cells and B cells than BM recipients, as well as higher numbers of γ/δ, CD4+ T-reg, CD4+ T cells at later time points (Table 1). In contrast, recovery kinetics for pDC, mDC,and immature CD56+CD16- NK cellswere similar between each graft arm (Table 1). B cell reconstitution kinetics were slower in BM recipients, especially in BM recipients who developed acute GvHD prior to day +100 as opposed to those who did not (in Figure 1, p < .001). No significant association existed between aGvHD history and lymphocyte reconstitution in G-PB recipients.Blood levels of immune cells at day +100 were associated both with a history of acute GvHD as well as subsequent 2-year OS, and GvHD-related death. All patients who developed grades 2-4 acute GvHD by day +100 had worse 2-year OS than non-GvHD patients (66% vs. 53%, p=.01). However, patients with a history of GvHD and >median numbers of blood mDC, CD4+, or CD8+ T cells at day +100 had better 2-year OS (95% CI): [mDC, 63 (51-74)% vs. 43 (32-55)% p=.02; CD4+ T cells, 64 (53-75)% vs. 42 (31-53)%, p=0.007; CD8+ T cells, 65 (54-76)% vs. 42 (31-53)%, p= 0.004] than GvHD-patients with <median numbers of these cells. Furthermore, significantly fewer GvHD-related deaths occurred in patients with >median numbers of mDC compared to in those with <median numbers of mDC (23% vs 40%, respectively, p<.05).In contrast, G-PB recipients with >median numbers of blood central memory CD8+ (p=.01), CD8+ (p=.004), and γ/δ T cells (p=.002) by day +100 had significantly higher 2-year OS compared to those with <median numbers of these cells. BM recipients with >median numbers of mDC had higher 2-year OS compared to those with <median numbers (p=.06).The content of blood mDC was prognostic for post-transplant outcomes for the entire cohort of patients and the subset of BM recipients. Significantly improved 2-year OS (95% CI) was observed in patients with >median numbers of mDC by day +100 post-transplant (68 (61-76)%) compared to those with <median numbers of mDC (51 (43-59)%; p=.008; Figure 2). Compared to the latter, the former also had significantly less (p=.04) treatment-related mortality at 2-years post-transplant (12 (8-18)% vs. 23 (17-31)%) and no difference in relapse (30 (23-38)%) vs. 29 (22-37)%).Conclusions: Graft source is associated with differences in reconstitution kinetics of T and B cells. Blood levels of immune cells at day +100 are cellular bio-markers for both GvHD-related death and OS in transplant recipients, and are correlated with a history of acute GvHD. Specific cell subsets prognostic for OS vary by graft source. Higher levels of blood mDC at day +100 in BM recipients are associated with improved OS, while higher numbers of T-cells predict better OS in GPB recipients. Compared to BM recipients, G-PB recipients have faster T and B cell reconstitution as well as greater resiliency of lymphogenesis following acute GvHD. [Display omitted] DisclosuresLee:Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Waller:Helocyte: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Research Funding; Coulter Foundation: Research Funding; Katz Foundation: Research Funding; Chimerix: Equity Ownership; AMGEN: Consultancy; Cambium Medical Technologies: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Celldex: Consultancy; Cerus: Equity Ownership; National Institutes of Health: Research Funding; PRA: Consultancy.

Graft-Versus-Host Disease in Multiple Myeloma Patients Treated With Daratumumab After Allogeneic Transplantation

IntroductionAllogeneic hematopoietic cell transplantation (allo-HCT) represents an adoptive immunotherapy strategy for eliciting a graft-versus-myeloma, the effect for high-risk or relapsed multiple myeloma (MM). Allo-HCT recipients are at risk for graft-versus-host disease (GVHD) as well as associated increases in morbidity and mortality. Daratumumab, an anti-CD38 human immunoglobulin G1 kappa humanized monoclonal antibody, is used for treatment of MM. Daratumumab also affects CD38+ nonmyeloma cells, including T cells, which mediate GVHD. The use of daratumumab after allo-HCT has not been well described, and its potential impact on GVHD is unknown. Patients and MethodsIn a multicenter retrospective study, we evaluated incidence of GVHD in 34 patients with relapsed MM treated with daratumumab after allo-HCT. ResultsOverall response to daratumumab (partial response or better) was 41% (95% confidence interval, 24-59). Five patients (15%) developed acute GVHD after daratumumab therapy; no chronic GVHD events were observed after daratumumab therapy. One of these 5 patients had a history of chronic GVHD and developed a flare of acute GVHD during daratumumab therapy. The remaining 4 patients did not have a history of GVHD before daratumumab. ConclusionThe incidence of GVHD after daratumumab was low and did not result in increased exacerbation of GVHD in patients with a history of GVHD.

S1643 INCIDENCE, RISK FACTORS AND OUTCOMES OF THROMBOEMBOLISM EVENTS IN HAPLOIDENTICAL VS. MATCHED RELATED DONOR HEMATOPOIETIC STEM CELL TRANSPLANTATION

Background:Allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is regarded as a curative therapy for the majority of malignant hematologic diseases. Only 25–35% of recipients have an HLA‐identical sibling donor. For patients lacking an HLA‐identical donor, a haploidentical donor HSCT (HID‐HSCT) is an alternative option. Patients who undergo HSCT are at a high risk of suffering from thromboembolism events (TEEs) due to the conditioning regimen, immune‐modulatory drugs, graft versus host disease (GVHD) and prolonged hospital stays. However, no information is available on the TEE complication following HID‐HSCT.Aims:To compare discrepancies in the incidence, risk factors and clinical outcomes of TEEs between HID‐HSCT and matched related donor HSCT (MRD‐HSCT).Methods:We retrospectively analyzed data from 5471 HSCT recipients to identify the incidence, risk factors and mortality due to TEEs. TEEs were divided into venous thromboembolism events (VTE) and arterial thrombotic events (ATE). We recorded the incidence and manifestation times of TEEs during the course of HSCT. In the nested case‐based control study, potential risk factors affecting the occurrence of TEEs were identified using univariate and multivariate analyses. Overall survival (OS) was defined as the time elapsed between HSCT day 0 (HSC infusion) and death or the last follow up and was calculated by the Kaplan‐Meier method.Results:Among all 5471 consecutive allo‐HSCT recipients (HID‐HSCT = 3798, MRD‐HSCT = 1673), a total of 117 (2.2%) patients had VTE, including 85 patients after HID‐HSCT and 32 patients after MRD‐HSCT. The incidence of VTE was similar between the two groups (2.2% vs 1.9%). ATE occurred in 45 (0.8%) patients after allo‐HSCT at follow‐up, including 38 patients after HID‐HSCT and 7 patients after MRD‐HSCT. The median occurrence time of VTE after allo‐HSCT was 105 days (range 9–2051). Among the HID‐group, VTE occurred at a median time of 95 days (range 9–1511), which was significantly earlier than that of the MRD‐group (249.5 days, range 14–2053) (p &lt; 0.05). The median occurrence time of ATE after allo‐HSCT was 176 days (range 14–2623). No significant difference was found in the occurrence time of ATE between the MRD and HID‐HSCT groups (p = 0.098). In the univariate analysis, an age &gt;45 years, prior VTE, GVHD, cardiovascular factors and relapse were significantly associated with VTE. In the multivariate analyses, prior VTE, cardiovascular risk factors, aGVHD, and relapse were retained due to their associations with VTE. Both MRD‐HSCT and HID‐HSCT had the same risk factors associated with VTE in the multivariate analysis. The multivariate analysis showed that both a history of GVHD and cardiovascular risk factors were risk factors for ATE after allo‐HSCT. During follow‐up, the probability of overall survival (OS) was 47.1% among patients with TEEs and 76.4% among patients without TEEs (p &lt; 0.05). No significant difference in OS was found between the MRD‐HSCT and HID‐HSCT recipients with TEEsSummary/Conclusion:The incidence of TEEs was similar between MRD‐HSCT and HID‐HSCT. TEEs are highly significant complications for both HID‐HSCT and MRD‐HSCT and have been associated with shorter OS. Well‐designed clinical studies of TEEs prevention and treatment in HSCT recipients are urgently needed.

Emergency general surgery procedures in hematopoietic stem cell transplant recipients

BackgroundOutcomes of emergency general surgery (EGS) procedures on hematopoietic stem cell transplant (HST) recipients have not been defined in a large, national database. Whether EGS during HST engraftment admission, or in HST patients with graft versus host disease (GVHD) results in worse outcomes is unknown. MethodsThe National Inpatient Sample (NIS) was examined for patients with a history of BMT between 2001 and 2014. ResultsThere were 520,000 HST admissions meeting inclusion criteria, of which, 14,143 (2.7%) required EGS. Of those requiring EGS, 378 (2.7%) were during engraftment admission and 13,765 (97.3%) on subsequent admission. For those requiring EGS during subsequent admission, 9,920 (72.1%) had a history of GVHD and 3,845 (27.9%) did not. On multivariate analysis, requirement of EGS was associated with mortality (OR: 1.71, 95%CI: 1.47–1.99, p < 0.001). For patients requiring EGS, engraftment admission or GVHD was not associated with mortality. ConclusionsWhile EGS results in worse survival for the HST population, patients in their engraftment admission do not appear to be at increased mortality risk. In addition, GVHD does not worsen survival.

Venous Thromboembolism Is Associated with Graft-Versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation

▪Introduction: Although venous thromboembolism (VTE) after allogeneic hematopoietic stem cell transplantation (HSCT) is known to occur, there are currently limited data on its incidence, risk factors and outcomes. Studies that have examined VTE after HSCT have been small and not adequately able to address clinical risk factors including graft-versus-host disease (GVHD). We describe VTE incidence, characteristics, risk factors and outcomes in a large cohort of patients undergoing allogeneic HSCT.Methods: We identified all patients who underwent allogeneic HSCT between January 1, 2002 and December 31, 2013 at Dana Farber Cancer Institute/Brigham and Women's Hospital (DFCI/BWH). Using pharmacy records and medical chart review, patients who received systemic anticoagulation (low-molecular weight heparin, warfarin, fondaparinux, and dabigatran) for VTE were identified. All VTE events were confirmed by radiologic imaging (ultrasound, CT, MRI or V/Q scan). VTE was defined as catheter-associated, pulmonary embolism (PE), lower extremity deep vein thrombosis (DVT), upper extremity DVT, superior vena cava (SVC) thrombosis or other (pelvic, abdominal, or ventricular thrombosis).Results: 2276 patients who underwent initial allogeneic HSCT at DFCI/BWH were identified, with a median follow-up time of 50 months (range 4-146) among survivors. 190 patients (8.3%) developed VTE. The 1 and 2-year cumulative incidence of all VTE were 5.5% (95% CI 4.6-6.5%) and 7.1% (95% CI 6.1-8.2%) respectively. There was no difference in age, gender, body mass index, diagnosis, disease status at time of HSCT, conditioning regimen intensity, donor type (HLA matched/mismatched, related/unrelated, or cord blood), or graft source (bone marrow or peripheral blood) between HSCT recipients with and without VTE.Amongst the 190 patients who developed VTE, 65 (34.2%) were lower extremity DVT, 48 (25.3%) were catheter-associated, 45 (23.7%) were PE, 10 (5.3%) were PE and DVT, 9 (4.7%) were upper extremity DVT, 9 (4.7%) were other DVT, and 4 (2.1%) were SVC thrombosis. Catheter-associated DVT occurred at a median of 1.1 months (range 0.1-41.1) after HSCT, which was significantly shorter than other types of VTE (figure, p<0.0001). Only 9 patients (4.7%) were not on systemic immune suppression at time of VTE. 98 patients (51.6%) had active GVHD at time of VTE, while 28 (14.7%) had a history of GVHD, still on immune suppression at time of VTE. For patients with active or previous GVHD, the most prevalent organ involvement was skin (38.4%).In a multivariable Cox model treating VTE and GVHD as time-dependent variables, VTE was associated with increased non-relapse mortality (HR=1.47; 95% CI 1.07-1.98), but not relapse (HR=0.98, 95% CI 0.69-1.34), progression-free survival (HR=1.21, 95% CI 0.94-1.57) or overall survival (HR=1.07, 95% CI 0.86-1.34). Non-relapse mortality remained as a significant association with VTE when catheter-associated VTE were excluded (HR=1.67; 95% CI 1.14-2.37). In a multivariable model to identify potential risk factors for VTE, both acute and chronic GVHD were independently associated with developing VTE (see table). In patients who developed GVHD, 8% had a subsequent VTE: 7% non-catheter-associated and 1% catheter-associated.Conclusion: Venous thromboembolism is a prevalent complication of allogeneic HSCT that increases non-relapse mortality risk. Both acute and chronic GVHD are associated with an increased risk of developing VTE. Further analysis is needed to identify HSCT patients with the highest risk for VTE who might benefit from VTE prophylaxis.TableMultivariable Cox model stratified by conditioning intensity for identification of potential risk factors for VTEPrognostic FactorHR (95% CI)p-valueAge: >=70 years vs <70 years0.26 (0.04-1.85)0.18Male vs Female0.97 (0.72-1.29)0.81BMI: >=30 vs <301.07 (0.79-1.46)0.65Matched related vs unrelated donor1.09 (0.79-1.49)0.61Mismatched vs matched donor0.99 (0.62-1.59)0.96Myeloid diagnosis0.81 (0.60-1.10)0.18GVHD prophylaxis: Sirolimus vs No Sirolimus0.91 (0.68, 1.24)0.56Prior acute GVHD2.02 (1.47-2.77)<0.0001Prior chronic GVHD2.30 (1.52-3.48)<0.0001Median time to VTE: Catheter-associated=1.1 mos, PE=13 mos, lower extremity DVT=9 mos, upper extremity DVT=2.7 mos, PE and DVT=7.5 mos, SVC=37.3 mos and other DVT=7.8 mos (p<0.0001). [Display omitted] DisclosuresArmand:Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Infinity Pharmaceuticals: Consultancy.

Treatment with Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation

Treatment with Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (r/r ALL) Post-Allogeneic Hematopoietic Stem Cell Transplantation

Association of Graft-Versus-Host Disease and Immunosuppressive Treatment with Risks of Recurrent Malignancy and Mortality After Allogeneic Hematopoietic Cell Transplantation

AbstractAbstract 218 Background:Graft-versus-leukemia (GVL) effects are closely associated with graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). In a reexamination of GVL effects, we evaluated acute and chronic GVHD defined by NIH consensus criteria and immunosuppressive treatment (IST) as risk factors for recurrent malignancy after HCT. Patients and methods:We analyzed a cohort of 2656 consecutive patients with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN) who received allogeneic HCT after high-intensity conditioning between 1992 and 2005. The onset of NIH chronic GVHD was ascertained by retrospective chart review using follow-up information obtained by our Long Term Follow Up clinic. Rates and hazards of recurrent malignancy and mortality were analyzed according to GVHD and IST as time-varying covariates. To illustrate the effect of time-varying covariates, we calculated the rate of recurrent malignancy per patient-year according to prior GVHD within sequential 90-day intervals after HCT. Cox proportional hazard models were adjusted for potential factors affecting outcomes. Results:The median patient age at HCT was 39 years (range, 0 to 71 years). Donors were HLA-identical relatives (n=1088), HLA-matched unrelated volunteers (n=912), HLA-mismatched relatives (n=243), and HLA-mismatched unrelated volunteers (n=413). GVHD prophylaxis was mostly cyclosporine and methotrexate (n=1885, 71%). Relapse rates per patient-year declined from 3 months until at least 36 months after HCT for patients with prior acute GVHD or NIH chronic GVHD (Figure). Patients without prior GVHD showed a much less pronounced decline between 12 and 30 months after HCT. Adjusted Cox analysis showed that acute GVHD and NIH chronic GVHD were associated with statistically similar reductions in risk of late recurrent malignancy beyond 18 months after HCT, with no incremental effect of chronic GVHD in patients with prior acute GVHD (Table 1). GVL effects were demonstrable in patients with CML or AML but not in those with ALL or MDS/MPN. Discontinuation of IST was associated with a decreased risk of recurrent malignancy among patients without prior GVHD but not among those with prior GVHD (Table 2). Grades III–IV acute GVHD and NIH chronic GVHD with prior acute GVHD were associated with a statistically significant increase in risk of early mortality between 3 and 18 months, but grade II acute GVHD and NIH chronic GVHD without prior acute GVHD were not. [Display omitted] Conclusion:Both acute and NIH chronic GVHD are associated with potent GVL effects, but NIH chronic GVHD does not confer any incremental benefit after acute GVHD. Withdrawal of IST was associated with a reduction in risk of recurrent malignancy in patients without prior GVHD. Analyses of GVL effects should account for time from HCT, the history of GVHD, type of malignancy and IST. Immune manipulations such as prophylactic donor lymphocyte infusion or early withdrawal of IST may represent reasonable approaches to decrease the risk of recurrent malignancy in patients without prior GVHD, if the risk of GVHD could be minimized. Disclosures:No relevant conflicts of interest to declare.

Leukemia Lineage-Specific Chimerism Analysis and Molecular Monitoring Improve Outcome of Donor Lymphocyte Infusions

A retrospective analysis was performed of 118 patients with hematologic malignancies who received donor lymphocyte infusions (DLIs) after allogeneic stem cell transplantation (ASCT). Treatment was either given because of hematologic relapse (n = 44), molecular/cytogenetic relapse (n = 52), or other causes (n = 22). Molecular relapse was in most cases based on leukemia lineage-specific chimerism analysis. Patients with acute leukemia and myelodysplastic syndrome showed a 3-year survival of 42% if DLI treatment was given because ofmolecular relapse, compared to 16% in hematologic relapse (P < .006). In multivariate analysis, there was a correlation between response to DLI and nonhematologic relapse (risk ratio [RR] 3.36, P = .001), chronic graft-versus-host disease (cGVHD) (RR = 1.51, P = .005), and late relapse (RR = 2.06, P = .017). The overall incidences of acute GVHD (aGVHD) grades I-II and grades III-IV aGVHD were 33% and 8.5%, respectively. Probability of cGVHD was 33%. The development of aGVHD or cGVHD did not significantly influence the response of DLI in patients with molecular/cytogenetic relapse. However, the development of cGVHD was significantly associated with a better response in patients with hematologic relapse because only 4 of 29 patients without cGVHD responded compared to 7 of 12 with cGVHD (P = .007). The development of cGVHD increased significantly if DLI was given >12 months after ASCT (46% versus 27%, P = .04). In contrast, time between ASCT and start of DLI treatment had no significant influence on the risk of developing aGVHD. To conclude, monitoring of leukemia lineage-specific chimerism is of utmost importance for DLI response after ASCT.

Low Vitamin D Levels After Allogeneic Hematopoietic Stem Cell Transplant.

Abstract 3322Poster Board III-210▪▪This icon denotes an abstract that is clinically relevant. IntroductionVitamin D deficiency can cause osteomalacia, aching bone pain, muscle weakness, fatigue, increase risk of fracture and precipitate or exacerbate osteopenia and osteoporosis. Patients receiving chemotherapy for Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) may have limited exposure to sunlight (prolonged hospital stay, debilitation limiting outdoor activity, sunscreen use) and gastrointestinal side effects of chemotherapy may decrease their ability to ingest adequate amounts of Vitamin D. We hypothesized that patients with AML and ALL will have low Vitamin D levels after allogeneic hematopoietic stem cell transplant (AHSCT). We therefore studied Vitamin D level after AHSCT to determine the incidence of Vitamin D deficiency. Patients and Methods289 patients with AML or ALL underwent myeloblative or non-myeloablative AHSCT between January 1, 2000 and January 31, 2009 at our institution. Baseline demographic data, disease characteristics, transplant variables and outcomes data were obtained from the transplant database, which contains prospectively collected data on all patients transplanted at our center. These data were supplemented by retrospective chart review for post-transplant Vitamin D level, Vitamin D supplementation at the time of Vitamin D level, parathyroid hormone (PTH) level at the time of Vitamin D level, bone density result closest to the time of Vitamin D level (either before or after), and specialty of physician ordering Vitamin D level. Categories for Vitamin D level included sufficient (>30 ng/ml), insufficient (20-30 ng/ml), or deficient (<20 ng/ml). Categories for PTH level included normal (10-60 pg/ml), low (<10 pg/ml), and high (>60 pg/ml). Bone density results were recorded as normal (no osteopenia or osteoporosis) or abnormal (osteopenia or osteoporosis). Results58 (20.1%) patients had Vitamin D testing post AHSCT. The mean time from AHSCT to Vitamin D testing was 13.8 ± 18.0 months. Testing was ordered most commonly by physicians in the osteoporosis/metabolic disease clinic (79.3%) followed by the AHSCT physician (8.6%), women's health exam provider (3.4%), palliative medicine physician (3.4%), inpatient medicine team (1.7%), pulmonary physician (1.7%) and unknown provider (1.7%). Patients were more likely to have Vitamin D testing if they were female (27.7% versus 12.8% in males; P = 0.002) and if AHSCT was performed more recently (P<0.001). 52 (89.6%) patients who had Vitamin D testing had low levels and 6 (10.3%) had normal levels. Of those with low levels, 18 were insufficient and 34 were deficient. There was no significant difference between gender, age at transplant, diagnosis, type of transplant, year of transplant, or PTH level among the patients with low Vitamin D levels. Most patients with Vitamin D testing had graft versus host disease (GVHD) and were taking corticosteroids (94.8% and 98.2% respectively) and most of these patients had low Vitamin D levels (89%). Of the 49 patients with Vitamin D testing who also had bone density testing, 57% had abnormal scans. However, only 21% of patients with Vitamin D testing were taking Vitamin D supplements prior to testing. ConclusionsMost patients did not have Vitamin D testing post AHSCT, but those that did were very likely to have low levels. We observed that testing was done mostly in those with a history of GVHD and corticosteroid use, and usually by a provider other than their AHSCT physician. Also, patients with low Vitamin D levels were not likely to be on Vitamin D supplementation after AHSCT. Patients with low levels of Vitamin D had more abnormal than normal bone density results. Our study suggests a high incidence of Vitamin D deficiency among patients with GVHD taking corticosteroids. These patients are at risk for osteoporotic bone fracture and they often complain of bone pain, muscle weakness, and fatigue that may be amenable to Vitamin D supplementation. Vitamin D supplementation may be a low cost, easy to implement addition to routine post AHSCT care that might increase quality of life and reduce AHSCT associated morbidity in patients with GVHD on corticosteroids. DisclosuresNo relevant conflicts of interest to declare.

Allogeneic Hematopoietic Stem Cell Transplantation Recipients Have Defects of Both Switched and IgM Memory B Cells

Allogeneic hematopoietic stem cell transplant (HSCT) recipients were assessed to elucidate memory B cell defects underlying their increased susceptibility to infections, particularly by encapsulated bacteria. Circulating IgM memory B cells (CD19+, CD27+, IgM+) and switched memory B cells (CD19+, CD27+, IgM(-)) were enumerated in allogeneic HSCT recipients (n = 37) and healthy controls (n = 35). T lymphocyte subpopulations and serum levels of immunoglobulins, including IgG subclasses, and antibodies to pneumococcal polysaccharides were also assayed. Allogeneic HSCT recipients were deficient in both switched memory and IgM memory B cells compared to healthy controls (both P < .0001), irrespective of time post-HSCT. Switched memory B cell deficiency correlated with CD4+ T cell deficiency, and both correlated with serum levels of IgG1 (P < .0001), possibly reflecting impaired B cell isotype switching in germinal centres. "Steady-state" serum levels of antibodies to pneumococcal polysaccharides did not correlate with circulating memory B cells. Graft-versus-host disease (GVHD) was associated with lower IgM memory B cell counts and lower serum levels of IgG2, IgG4, IgA, and pneumococcal antibodies. The increased susceptibility of allogeneic HSCT patients to infection may reflect a combination of memory B cell defects, which are most common in patients with a history of GVHD.

Defective Anti-Bacterial Carbohydrate Antibody Production after Unrelated HSC Transplantation.

Protective levels of anti-bacterial carbohydrate antibodies are necessary to protect HSC transplantation recipients from severe infections with encapsulated bacteria. Recipients of unrelated HSC transplants are at increased risk of severe infections regardless of their history of graft versus host disease (GVHD). Antibodies to a naturally occurring, prototypic bacterial carbohydrate antigen, polyribose phosphate (PRP), present in Hemophilus influenza type b and K100 stains of E. coli, were measured in the recipients of unrelated bone marrow (UBMT) and unrelated cord blood transplants (UCBT). UBMT and UCBT recipients, who were not on immunosuppressive therapy, were analyzed with follow-ups of 12 and 7 years, respectively. Of 20 UBMT recipients, only 3 had protective anti-PRP antibody levels. All 3 recipients with protective antibody levels were younger than 1 year old at the time of transplantation and did not have a history of GVHD. No recipients, who were older than 1 year old at the time of transplantation, had protective levels of anti-carbohydrate antibody. Of 16 UCBT recipients, 7 had protective antibody levels, including recipients as old as 53 at the time of UCBT. All unrelated recipients, who did not have protective levels of anti-carbohydrate antibodies, were able to produce protective levels of antibodies to a protein antigen, tetanus toxoid, after immunization. Therefore, the inability of the recipients of unrelated HSC to produce protective levels of anti-bacterial carbohydrate antibody is not part of a generalized antibody deficiency state, but is a specific defect. Since bacterial carbohydrate antigens are T lymphocyte-dependent antigens in humans, the results indicate that thymic and T lymphocyte function are greater in UCBT recipients than in UBMT recipients (p=.008 for protective anti-PRP antibody levels in recipients older than age 1). Defects in protective anti-bacterial carbohydrate antibody production are common in the recipients of HSC unrelated transplants regardless of the source of HSC. The recipients of unrelated HSC transplants, especially UBMT, should be tested for their capacity to produce anti-carbohydrate antibody, and, if deficiencies are detected, appropriate prophylactic measures undertaken to reduce the likelihood of severe bacterial infections.

Bone mineral density and osteonecrosis in survivors of childhood allogeneic bone marrow transplantation.

Our purpose was to evaluate frequency and severity of bone mineral decrements and frequency of osteonecrosis in survivors of pediatric allogeneic bone marrow transplantation (alloBMT). We retrospectively reviewed demographic information, treatment, magnetic resonance (MR) imaging studies (hips and knees), and bone mineral density (BMD) studies of 48 patients as measured by quantitative computed tomography (QCT). In all, 24 patients were male; 37 were Caucasian. Median age at alloBMT was 10.3 years (1.6-20.4 years). Of the 48 patients, 43 underwent QCT. Median time between alloBMT and imaging was 5.1 years (1.0-10.2 years). Median BMD Z-score was -0.89 (-4.06 to 3.05). BMD Z-score tended to be associated with female sex (P=0.0559) but not with age at BMT, race, primary diagnosis, time from alloBMT, T-cell depletion of graft, total-body irradiation, or acute/chronic graft-versus-host disease (GVHD). MR showed osteonecrosis in 19 of 43 (44%). We found no associations between osteonecrosis and sex, race, diagnosis, age at BMT, history of GVHD, time from BMT, or T-cell depletion. Seven patients (15%) had MR changes of osteonecrosis and BMD Z-scores of less than -1 s.d. We conclude that pediatric alloBMT survivors have decreased BMD and are at risk of osteonecrosis. They should be monitored to assure early intervention that may ameliorate adverse outcomes.

Factors affecting thymic function after allogeneic hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation (HSCT) is followed by profound immunodeficiency. Thymic function is necessary for de novo generation of T cells after HSCT. Circulating CD45RA(+) naive T-cell levels are predictive of antigen-specific T-cell responses in the absence of graft-versus-host disease (GVHD). These T cells may not represent recent thymic emigrants, since naive T cells may maintain this phenotype if not antigen-activated. To accurately measure thymic output after HSCT and determine the factors that influence thymic function, T-cell receptor excision circles (TRECs) were examined in CD4(+) and CD8(+) cells from a cross-section of patients following HSCT. TREC levels rose weeks after HSCT and could be detected in patients 6 years after HSCT. TREC levels correlated with the frequency of phenotypically naive T cells, indicating that such cells were not expanded progeny of naive T cells present in the donor graft. Chronic GVHD was the most important factor that predicted low TREC levels even years after HSCT. Patients with a history of resolved GVHD had decreased numbers of TREC, compared with those with no GVHD. Because few adults had no history of GVHD, it was not possible to determine whether age alone inversely correlated with TREC levels. Recipients of cord blood grafts had no evidence of decreased TREC induced by immunosuppressive prophylaxis drugs. Compared with unrelated donor grafts, recipients of matched sibling grafts had higher TREC levels. Collectively, these data suggest that thymopoiesis is inhibited by GVHD. Larger studies will be needed to determine the independent contributions of age and preparative regimen to post-transplant thymopoietic capacity.

Effect of low-dose interleukin-2 on disease relapse after T-cell- depleted allogeneic bone marrow transplantation

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2–4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10- fold without any significant change in T-cell number. Of the 25 patients who received &gt; or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.

Effect of Low-Dose Interleukin-2 on Disease Relapse After T-Cell-Depleted Allogeneic Bone Marrow Transplantation

T-cell depletion of donor bone marrow has been associated with an increased risk of disease relapse after allogeneic bone marrow transplantation (BMT). Recombinant interleukin-2 (IL-2), which is capable of increasing the antileukemic activity of peripheral blood lymphocytes obtained from patients who have undergone BMT, has been proposed as a potentially useful agent to reduce the risk of relapse post-BMT. We have previously shown that IL-2 administered to patients at very low doses after BMT is both clinically tolerable and immunologically active. We now report on the clinical outcome of 29 patients treated with low-dose IL-2 after CD6-depleted allogenic BMT for hematologic malignancy. IL-2 was administered by continuous infusion for up to 3 months beginning at a median of 67 days post-BMT. Eligibility requirements for IL-2 therapy included demonstration of stable engraftment and absence of acute grade 2-4 graft-versus-host disease (GVHD). Low-dose IL-2 was well tolerated by the majority of patients, with only 4 of 29 subjects withdrawn early. Acute GVHD developed in only one individual. After 12 weeks of treatment, the mean number of circulating natural killer cells in patients increased 10-fold without any significant change in T-cell number. Of the 25 patients who received > or = 1 month of IL-2, only 6 have relapsed. Relapse rate and disease-free survival (DFS) were determined in the 25 patients who completed at least 4 weeks of IL-2 treatment and compared with historical controls transplanted at our institution for the same conditions and treated with an identical ablative regimen and method of T-cell depletion. Only control patients who had survived disease free for 100 days post-BMT were included in this analysis. Cox's proportional hazards regression model suggested that, compared with control patients without a history of GVHD, patients treated with IL-2 had a lower risk of disease relapse (hazard ratio 0.34; range, 0.14 to 0.82) and superior DFS (hazard ratio 0.39; range 0.18 to 0.87). A randomized controlled trial of IL-2 immunotherapy after T-cell-depleted BMT should now be undertaken.