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Abstract Despite advances in HLA matching, graft failure remains a serious complication after allogeneic hematopoietic cell transplantation (HCT). Pre-formed anti-HLA donor-specific antibodies (DSAs) have been associated with graft failure, but the impact of newly developing (de novo) anti-HLA antibodies on HCT outcomes remains unknown. Here, we present the first reported case of graft failure associated with de novo anti-HLA-DPB1 DSA after a 10/10 matched unrelated donor HCT. Based on this observation, testing for DSA should be considered in case of unexplained pancytopenia after allogeneic transplantation, especially after reduced intensity conditioning. [ABSTRACT FROM AUTHOR]

The clinical staging of acute graft-versus-host disease (GVHD) varies significantly among bone marrow transplant (BMT) centers, but adherence to long-standing practices poses formidable barriers to standardization among centers. We have analyzed the sources of variability and developed a web-based remote data entry system that can be used by multiple centers simultaneously and that standardizes data collection in key areas. This user-friendly, intuitive interface resembles an online shopping site and eliminates error-prone entry of free text with drop-down menus and pop-up detailed guidance available at the point of data entry. Standardized documentation of symptoms and therapeutic response reduces errors in grade assignment and allows creation of confidence levels regarding the diagnosis. Early review and adjudication of borderline cases improves consistency of grading and further enhances consistency among centers. If this system achieves widespread use it may enhance the quality of data in multicenter trials to prevent and treat acute GVHD. [ABSTRACT FROM AUTHOR]

Abstract: Arrhythmias, especially supraventricular arrhythmias, often complicate the clinical course during autologous hematopoietic cell transplantation (AHCT). We wanted to determine the incidence and risk factors for cardiac arrhythmias during AHCT. The study included 983 patients (median age, 58 years [range, 19 to 77]; 61% male) who underwent AHCT between August 2006 and December 2010 at a single institution and for whom all relevant medical records were available for review. AHCT was done for plasma cell disorders in 58% patients and for lymphoma or leukemia in the remaining. Overall, 92 patients (9.4%) developed a supraventricular tachyarrhythmia at a median of 9 days posttransplantation (range, 0 to 18) and with a median duration of less than 1 day (range, <1 to 17 days). Atrial fibrillation was the most common and seen in 71 patients (7%), followed by atrial flutter and supraventricular tachycardia in 12 (1%) and 8 (1%) patients, respectively. In multivariate analysis, age older than 63 years, presence of premature supraventricular complexes or atrioventricular conduction delay on pretransplantation electrocardiogram, and history of any prior arrhythmia increased the risk of arrhythmia. Development of arrhythmia resulted in longer outpatient follow-up after AHCT, with the median follow-up for those developing an arrhythmia of 22 days compared with 19 days for the rest; P < .001. In conclusion, 9% of patients undergoing ASCT developed supraventricular arrhythmias posttransplantation, and this risk was elevated among older patients, those with a prior history of arrhythmias, and those with pretransplantation electrocardiographic abnormalities. [Copyright &y& Elsevier]

Dogs given nonmyeloablative conditioning and marrow grafts from 2 dog leukocyte antigen (DLA)-identical littermate donors developed stable trichimerism and stably accepted a subsequent kidney graft from one of the marrow donors without the need for immunosuppression. In this study, we used trichimeras to evaluate strategies for adoptive immunotherapy to solid tumors, using the kidney as a tumor surrogate. Three DLA-identical trichimeric recipients were established by simultaneously infusing marrow from 2 DLA-identical donor dogs into a DLA-identical recipient conditioned with 2 Gy of total body irradiation (TBI) and given a short course of postgraft immunosuppression. After stable hematopoietic engraftment was confirmed, a kidney was transplanted from 1 of the 2 marrow donors into each respective trichimeric recipient. Peripheral blood lymphocytes from each kidney donor were then used to sensitize the alternate marrow donor. The trichimeric recipients were given donor lymphocyte infusions (DLIs) from the sensitized dogs and monitored for chimerism, graft-versus-host disease (GVHD), and kidney rejection. After DLI, we observed both prompt rejection of the transplanted marrow and donor kidney and disappearance of corresponding hematopoietic chimerism. Presumably due to shared minor histocompatibility antigens, host chimerism also disappeared, and GVHD in skin, gut, and liver developed. The native kidneys, although exhibiting lymphocytic infiltration, remained functionally normal. This study demonstrates that under certain experimental conditions, the kidney—an organ ordinarily not involved in graft-versus-host reactions—can be targeted by sensitized donor lymphocytes. [Copyright &y& Elsevier]

Patients with malignancies are subject to developing a unique set of complications that require emergent evaluation and treatment. With the Increasing incidence of cancer in the general population and improved survival, these emergencies will be more frequently encountered. Physicians must be able to recognize these conditions and institute appropriate therapy after a focused initial evaluation. The approach to definitive therapy is commonly multi-disciplinary, involving surgeons, radiation oncologists, medical oncologists, and other medical specialists. Prompt interventions can be lifesaving and may spare patients considerable morbidity and pain, in this review, we discuss the diagnosis of and initial therapy for common emergencies In hematology and oncology. [ABSTRACT FROM AUTHOR]

We studied the value of postgrafting immunosuppression with sirolimus (SRL) and cyclosporine (CSP) in enhancing engraftment of dog leukocyte antigen-identical littermate marrow after nonmyeloablative conditioning in a canine model. Dogs received either 2 Gy (n=7) or 1 Gy (n=5) total body irradiation (TBI), followed by postgrafting immunosuppression with SRL and CSP. In the first cohort, all 7 dogs showed rapid initial engraftment. One engrafted dog died on day 21 due to hemorrhagic pneumonitis. Durable engraftment was seen in 5 of 6 remaining dogs, with a median follow-up of >48 (range, >32 to >56) weeks. The sixth dog rejected the marrow graft (as assessed by variable number of tandem repeats) at 11 weeks; however, a subsequent skin graft from the same marrow donor did not undergo acute cellular rejection, suggesting donor-specific tolerance. In the second cohort, all 5 dogs rejected the marrow graft at a median of 9 weeks (range, 3–11 weeks). We conclude that SRL/CSP is as effective as a previously studied combination of mycophenolate mofetil and CSP at establishing durable marrow engraftment after sublethal conditioning. [Copyright &y& Elsevier]

A response by Thorvardur R. Halfdanarson, William J. Hogan, and Timothy J. Moynihan to a letter to the editor about their article that discussed the diagnosis and treatment of oncologic emergencies published in the June 2006 issue is presented.

Diffusing capacity (DLCO) measurements are affected by hemoglobin. Two adjustment equations are used: Cotes (recommended by ATS/ERS) and Dinakara (used in the hematopoietic stem cell transplantation comorbidity index [HCT-CI]). It is unknown how these methods compare, and which is better from a prognostication standpoint. This is a retrospective cohort of 1273 adult patients who underwent allogeneic HCT, completed a pre-transplant DLCO and had a concurrent hemoglobin measurement. Non-relapse mortality was measured using competing risk analysis. Patients had normal spirometry (FEV 1 99.7% [IQR: 89.4–109.8%; FVC 100.1% [IQR: 91.0-109.6%] predicted), left ventricular ejection fraction (57.2[6.7]%) and right ventricular systolic pressure (30.1[7.0] mmHg). Cotes-DLCO was 85.6% (IQR: 76.5-95.7%) and Dinakara-DLCO was 103.6% (IQR: 90.7-117.2%) predicted. For anemic patients (Hb<10g/dL), Cotes-DLCO was 84.2% (IQR: 73.9–94.1%) while Dinakara-DLCO 111.0% (97.3–124.7%) predicted. Cotes-DLCO increased HCT-CI score for 323 (25.4%) and decreased for 4 (0.3%) patients. Cotes-DLCO was superior for predicting non-relapse mortality: for both mild (66-80% predicted, HR 1.55 [95%CI: 1.26-1.92, p < 0.001]) and moderate (<65% predicted, HR 2.11 [95%CI: 1.55-2.87, p<0.001]) impairment. In contrast, for Dinakara-DLCO, only mild impairment (HR 1.69 [95%CI 1.26-2.27, p < 0.001]) was associated with lower survival while moderate impairment was not (HR 1.44 [95%CI: 0.64-3.21, p = 0.4]). In multivariable analyses, after adjusting for demographics, hematologic variables, cardiac function and FEV 1 , Cotes-DLCO was predictive of overall survival at 1-year (OR 0.98 [95%CI: 0.97-1.00], p = 0.01), but Dinakara-DLCO was not (OR 1.00 [95%CI: 0.98-1.00], p = 0.20). The ERS/ATS recommended Cotes method likely underestimates DLCO in patients with anemia, whereas the Dinakara (used in the HCT-CI score) overestimates DLCO. The Cotes method is superior to the Dinakara method score in predicting overall survival and relapse-free survival in patients undergoing allogeneic HCT. [ABSTRACT FROM AUTHOR]

Abstract: CYP2B6, CYP2C19, ABCC4, and SOD2 have been implicated in adverse drug reactions and survival after cyclophosphamide (CPA) treatment. 110 BMT patients who received high dose CPA treatment were genotyped for variants in these genes and the results were correlated with toxicity and relapse. CYP2B6 genotype significantly influenced overall toxicity suggesting active CYP2B6 alleles led to higher rates of overall toxicity. The p.R487C deficiency allele was significantly associated with a lower rate of overall toxicity and a higher rate of relapse. SOD2 rs4880 V16A polymorphism was associated with significantly less CPA-related overall toxicity and significantly lower relapse rates by Kaplan–Meier analysis although the SOD2 finding regarding relapse was not significant when evaluated by the cumulative incidence function. [Copyright &y& Elsevier]

The prognostic impact of increased beta-2 microglobulin (B2M) in patients with light chain (AL) amyloidosis undergoing autologous stem cell transplantation (ASCT) is unknown. The Mayo 2012 stage and increased bone marrow plasma cell (BMPC) percentage are known predictors for survival. Increased B2M is predictive of survival in patients with multiple myeloma. We evaluated the prognostic role of B2M in patients with newly diagnosed AL undergoing ASCT. We retrospectively reviewed patients with a diagnosis of AL amyloidosis who were treated with ASCT between July 1996 and September 2017. Patients with a creatinine level >1.2 mg/dL were excluded, because that affects B2M levels. The receiver operator characteristic curve was used to determine the best cutoff for B2M before ASCT in predicting survival, which was 2.5 µg/mL, which was also the upper limit of normal in our laboratory. Baseline characteristics were compared between patients with B2M >2.5 µg/mL and ≤2.5 µg/mL. Progression-free survival (PFS) was defined as the time from ASCT to relapse or death, whichever occurred first. Overall survival (OS) was calculated from the time of ASCT to death of any cause. Univariate and multivariate analyses were done for OS. Five hundred and ten patients were identified, 222 of whom (44%) had a B2M >2.5 µg/mL. These patients were more likely to be older (median age, 61 versus 57 years; P =.0002), to have Mayo 2012 stage III/IV disease (33% versus 8%; P <.0001), to have more than 2 organs involved (25% versus 14%; P =.001), and to have ≥10% BMPCs (56% versus 40%; P =.0002) compared with patients with B2M ≤2.5 µg/mL. The median PFS and OS were shorter in patients with B2M >2.5 µg/mL (median PFS, 64 months versus 80 months P =.03]; median OS, 104.9 months versus 175.5 months P <.0001]). On univariate analysis, predictors for OS included age >60 years (hazard ratio [HR], 1.61; P =.001), Mayo 2012 stage III/IV (HR, 3.36; P <.0001), more than 2 organs involved (HR, 1.36; P =.07), ≥10% BMPCs (HR, 1.5; P =.005), melphalan conditioning with 200 mg/m2 (HR,.29; P <.0001), B2M >2.5 µg/mL (HR, 1.82; P <.0001), and transplantation during or after 2010 (HR,.4; P =.0006). On multivariate analysis, only Mayo 2012 stage III/IV (HR, 1.89; P =.005), melphalan conditioning with 200 mg/m2 (HR,.39; P <.0001), B2M >2.5 µg/mL (HR, 1.84; P =.003), and transplantation performed during or after 2010 (HR,.58; P =.03) remained independent predictors of OS. Our findings identify B2M >2.5 µg/dL before ASCT as an independent predictor for OS in patients with AL amyloidosis and normal kidney function and should be routinely measured. [ABSTRACT FROM AUTHOR]

• The high prevalence and severity of cardiac involvement are the main drivers for the poor outcome in patients who have 3 or more organs involved. • An NT-proBNP level of ≥2000 pg/mL was an independent predictor for shorter progression-free and overall survival. • Patients with ≥3 organs involved who have minimal cardiac involvement have good outcomes with ASCT and should be considered transplant eligible. Prior reports have suggested that 3 or more organs involved is a contraindication for autologous stem cell transplant (ASCT) in amyloid light chain (AL) amyloidosis. Therefore, most centers limit transplantation to patients who have no more than 2 organs significantly involved. We retrospectively reviewed all patients with AL amyloidosis with ≥3 involved organs and who had ASCT between 1996 and 2015 at Mayo Clinic, Rochester, Minnesota to assess transplant safety and outcomes. Seventy-five patients with ≥3 organs involved underwent ASCT. Median age at diagnosis was 54 years, and 67% were men. The heart was involved in 95%, followed by the kidneys (84%). Thirty-eight patients (51%) had no induction treatment before ASCT. Full-dose melphalan (200 mg/m2) was given in 45%, and the remainder received 140 mg/m2. Overall hematologic response rate was 75%. The median progression-free survival (PFS) and overall survival (OS) were 16 and 68 months, respectively. The 100-day mortality was 16%, and 44 patients (59%) died during follow-up. The most common causes of death were cardiovascular events (32%) and progressive amyloidosis (25%). On multivariable analysis, predictors for PFS were Mayo 2012 stage III/IV (relative risk [RR], 3.3; P =.0012) and hematologic response (at least very good partial response; RR,.4; P =.012). An N-terminal pro–brain natriuretic peptide (NT-proBNP) level of ≥2000 pg/mL was an independent predictor for shorter PFS (RR, 2.6; P =.013). Predictors for OS included any hematologic response (RR,.12; P =.0015), melphalan 200 mg/m2 (RR,.2; P =.014), and Mayo 2012 stage III/IV (RR, 7.7; P =.0002). An NT-proBNP level ≥ 2000 pg/mL was a powerful predictor of OS (RR, 4; P =.013). The number of organs involved (3 versus >3) did not significantly impact PFS or OS. We conclude that the high prevalence and severity of cardiac involvement are the main drivers for the poor outcome in patients who have ≥3 organs involved. Using selection criteria defined for safe transplantation in cardiac amyloidosis should result in low therapy-related mortality independent of the number of organs involved. The severity of cardiac involvement should be the major criterion for transplanting patients with AL amyloidosis that have ≥3 organs involved and not merely the number of organs involved. [ABSTRACT FROM AUTHOR]

• Fertility preservation counseling is an unmet need in women undergoing hematopoietic cell transplantation (HCT). • The rate of fertility preservation counseling is lower than expected. • Assisted reproductive technologies are underutilized in women undergoing HCT. • Menstrual recovery is rare but more likely after reduced-intensity conditioning. Iatrogenic menopause with consequent infertility is a major complication in reproductive-age women undergoing hematopoietic cell transplantation (HCT). Recent guidelines recommend a discussion of the possibility of infertility and the options for fertility preservation as part of informed consent before initiation of any cancer-directed therapy, including HCT. Women age 15 to 49 years at the time of allogeneic HCT, between the years 2001 and 2017, were identified from the Mayo Clinic Rochester institutional HCT database. One hundred seventy-seven women were eligible, of whom 49 (28%) were excluded due to documented postmenopausal state or prior hysterectomy. The median age of the cohort was 31 years (range, 15 to 49 years) with median gravidity and parity being G1P1 (range, G0 to G8, P0 to P6). Fifty-four (42%) women were nulligravid at the time of HCT. Eighty-two percent underwent myeloablative conditioning (MAC), whereas 18% underwent reduced-intensity conditioning (RIC). Only 34 women (27%) had documented fertility counseling within 72 hours of diagnosis, and a total of 61 (48%) received fertility counseling prior to HCT. Thirty-eight women (30%) were referred to a reproductive endocrinologist, of whom 13 (10%) underwent assisted reproductive technologies (ART; nine oocyte cryopreservation, four embryo cryopreservation). Of these, nine procedures yielded successful cryopreserved tissue (two completed at outside institutions). The median time to completion of the seven successful ART procedures at Mayo Clinic was 13 days (range, 9 to 15 days). The remainder of women referred to reproductive endocrinology did not undergo ART due to disease severity (68%), financial barriers (20%), and/or low antral follicle count (12%). Ninety-three women (73%) received leuprolide for ovarian suppression prior to conditioning. Three (4%) of 75 women who underwent MAC and were alive >365 days after HCT had spontaneous menstrual recovery after HCT (median time, 14 months; range, 6 to 21 months), in comparison to 10 (50%) of 20 women who underwent RIC and were alive >365 days after HCT (P <.01) (median, 21.5 months; range, 5 to 83 months). In the latter cohort, there were two spontaneous pregnancies, occurring at 71 and 72 months after HCT, respectively. Oncofertility is an emerging field due to an increasing number of young cancer survivors. Herein, we document that even at a large tertiary HCT center, the rate of documented fertility counseling and reproductive endocrinology referrals was low and the rate of ART was even lower. Spontaneous menstrual recovery was rare but more likely in the setting of nonmalignant disease and RIC HCT. A concerted multidisciplinary effort is needed to understand parenthood goals and to explore the impact of HCT on decision making about fertility preservation and parenthood. These efforts could improve oncofertility referral, ART utilization, and reproductive outcomes. [ABSTRACT FROM AUTHOR]

Highlights • Autologous stem cell transplant is efficacious in patients with IgM-related AL amyloidosis. • A hematologic response is seen in approximately 90% of patients, with 76% of patients achieving at least a very good partial response. • Organ response is seen in approximately 60% of patients and predicts both progression-free and overall survival. Abstract IgM-related amyloid light-chain (AL) amyloidosis is a rare disease, with patients presenting with more renal and neurologic involvement and less cardiac involvement compared with those with non–IgM-related disease. We retrospectively reviewed 38 patients receiving autologous stem cell transplant (ASCT) for IgM-related AL amyloidosis at the Mayo Clinic between May 1999 and June 2018. Median age was 61years, and 71% were men. The most common organs involved were renal (63%), neurologic (32%), and cardiac (26%). The median difference between involved and uninvolved free light chains was 6.2mg/dL, and most patients had early Mayo stage disease (87% Mayo stage I 2004 and 74% Mayo stage I 2012). The overall response rate was 92%, with 76% of patients achieving at least a very good partial response. Renal response was seen in 65% of patients (15/23; median time, 18 months post-ASCT; range 3 to 52) and cardiac response in 60% of patients (6/10; median time, 12 months post-ASCT; range 10 to 35). Median progression-free survival (PFS) and overall survival (OS) was 48 and 106 months, respectively. Organ response predicted better PFS and OS (median PFS, 93 months for organ response versus 16 months for no organ response [ P =.0006]; and median OS, 123 months for organ response versus 41 months for no organ response [ P =.02]). Two patients died within 100days of transplant, representing a 5% 100-day mortality. ASCT is an effective therapy that can be safely delivered to carefully selected patients with IgM-related AL amyloidosis. [ABSTRACT FROM AUTHOR]

Highlights • A complete response after stem cell transplant is seen in approximately 40% of patients with AL amyloidosis. • Most patients achieving complete response will achieve a stringent complete response (undetectable clonal plasma cells). • Patients achieving a stringent complete response have improved progression-free survival. • Bone marrow examination is valuable in response assessment after stem cell transplant in AL amyloidosis. Abstract Hematologic response has emerged as a powerful prognostic factor for survival in patients with immunoglobulin light chain (AL) amyloidosis. Patients achieving a complete response (CR), based on serum and urine analysis, survive longest. However, data regarding the impact of bone marrow features post-therapy on response and survival are limited. We evaluated the impact of achieving a stringent CR (sCR), defined as undetectable bone marrow clonal plasma cells by flow cytometry, in patients with AL amyloidosis receiving an autologous stem cell transplant. A total of 573 consecutive patients transplanted for AL amyloidosis at the Mayo Clinic between April 2002 and August 2016 were included in the analysis. Of 540 patients in whom response was assessable, 220 patients (41%) achieved a CR, of whom 212 (96%) had a bone marrow biopsy at time of response assessment and were further analyzed for determination of sCR; 166 patients (78%) with a CR achieved an sCR, representing 31% of the whole cohort. Patients achieving a CR had a higher median percentage of bone marrow plasma cells (10% for CR versus 6% for sCR, P =.03), more patients with bone marrow plasma cells ≥ 10% (50% for CR versus 33% for sCR, P =.04), and were less likely to receive chemotherapy before transplantation (30% for CR versus 49% for sCR, P =.03) compared with those achieving sCR. Median overall survival for all patients achieving a CR was 175 months and was not statistically different between those achieving an sCR compared with those achieving a CR only (median not reached for sCR versus 175 months for CR, P =.65). Progression-free survival, however, was significantly shorter in patients failing to achieve an sCR (151 months for sCR versus 72 months for CR, P =.0003). Bone marrow examination post-transplant in AL amyloidosis is important and identifies patients who fail to achieve an sCR and progress earlier. [ABSTRACT FROM AUTHOR]

Highlights • ECP favorably impacts overall survival in HCT patients with BOS. • This survival benefit is independent of the ECP effect on measured pulmonary function. • The corticosteroid-sparing effect of ECP may be responsible for the improved survival. Abstract We carried out the first matched retrospective cohort study aimed at studying the safety and efficacy of extracorporeal photopheresis (ECP) for bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT). Medical records of 1325 consecutive adult patients who underwent HCT between 2005 and 2015 were reviewed. Seventy-four patients (median age, 51 years) with a diagnosis of BOS were included in the study. After propensity-score matching for BOS severity, 26 patients who underwent ≥3 months of ECP were matched to 26 non–ECP-treated patients, who were assigned an index date corresponding to the ECP start date for their matched pairs. The rate of decline in FEV 1 percentage predicted (FEV 1PP) decreased after ECP initiation (and after index date in the non-ECP group), with no significant difference between the 2 groups (P =.33). On a multivariable analysis that included baseline transplant and pulmonary function test variables, matched related donor HCT (HR,.1; 95% CI,.03 to.5; P =.002), ECP (HR,.1; 95% CI,.01 to.3; P =.001), and slower rate of decline in FEV 1PP before the ECP/index date (HR,.7; 95% CI,.6 to.8; P =.001) were associated with a better overall survival. At last follow-up, non–ECP-treated patients were more likely to be on >5 mg daily dose of prednisone (54% versus 23%; P =.04) and had a greater decline in their Karnofsky performance score (mean difference, −9.5 versus −1.6; P =.06) compared with ECP-treated-patients. In conclusion, compared with other BOS-directed therapies, ECP was found to improve survival in HCT patients with BOS, without significantly impacting measured pulmonary functions. These findings need prospective validation in a larger patient cohort. [ABSTRACT FROM AUTHOR]

Background Matching at the HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 loci is important in donor selection for patients undergoing unrelated allogeneic hematopoietic stem cell transplantation (ASCT). Additional matching across the MHC gamma region may further improve outcomes. Methods The MHC gamma region was retrospectively genotyped in 66 adult recipients of ASCT and their 10/10 matched unrelated donors. A chart review was performed to determine whether MHC gamma matching impacted survival, relapse, or graft-versus-host disease. Results Of 66 donor-recipient pairs, 26(39.4%) were gamma-type matches, 34(51.5%) were mismatches, and 6(9.1%) were “indeterminate.” Matching status was not associated with overall survival (p = 0.43), relapse (p = 0.21), acute GVHD (p = 0.43), severe aGVHD (p = 0.31), or chronic GVHD (p = 0.23) in univariate analyses, nor in multivariate analyses (p = 0.28, 0.13, 0.29, 0.16, and 0.67, respectively), with or without adjusting for HLA-DPB1 matching status. Conclusions In our single institution study, gamma-type matching status was not associated with outcomes of adult ASCT recipients. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (aGVHD) is the leading cause of morbidity and mortality after allogenic hematopoietic cell transplantation (HCT). Corticosteroids are the first-line treatment; however, less than one-half of patients achieve durable remission. Studies suggest that TNF-α, a cytokine released from the bone marrow during conditioning, is involved in the pathogenesis of aGVHD. We retrospectively evaluated the outcome of anti-TNF-α therapy with infliximab in 35 patients with steroid refractory (SR) aGVHD. Infliximab was administered intravenously at 10 mg/kg for a median of 4 doses (range, 1 to 6) on a weekly basis. The overall response rates were 40% (17% complete response [CR], 23% partial response [PR]) at 4 weeks, 23% (9% CR, 14% PR) at 8 weeks, and 17% (all CR) at 12 weeks. Twenty-nine (83%) patients had infectious complications within 12 weeks of initiation of infliximab. These infections included 40 bacterial infections, 6 invasive fungal infections, and 5 viral reactivations. Twelve patients (34%) died secondary to infections. Overall survival at 12 weeks and 6 months from the start of infliximab therapy was 37% (13 of 35) and 17% (6 of 35), respectively; with most deaths secondary to complications from GVHD and infections. In conclusion; the use of infliximab therapy in patients with SR-aGVHD is associated with a modest poorly sustained response along with a heightened risk of severe infections. Future studies with more effective and less toxic therapies are needed for these patients. [ABSTRACT FROM AUTHOR]

The impact of depth of response and minimal residual disease (MRD) status on survival is not well defined in multiple myeloma (MM) with high-risk (HR) cytogenetics because of the low representation of such patients in clinical trials. We have evaluated the impact of post-transplant stringent complete response (sCR) and MRD status on progression-free survival (PFS) and overall survival (OS) in 185 consecutive MM patients with HR fluorescence in situ hybridization cytogenetics undergoing upfront autologous stem cell transplantation between 2007 and 2015 in our institution. The median age at transplant was 61 years. Post-transplant sCR was achieved by 42 patients (23%). Patients achieving sCR had a superior PFS (median, 38 versus 21 months) compared with those who did not ( P  = .002). One hundred three patients (56%) were MRD negative on day 100 by 6- or 7-color flow cytometry. Patients achieving MRD negativity had a superior PFS (median, 26 versus 17 months; P  < .001) and superior OS (5-year OS rate, 64% versus 41%; P  = .023) compared with MRD-positive patients. In the subgroups with deletion(17p) (n = 84) and those with ≥2 HR cytogenetic abnormalities (n = 32), sCR and MRD negativity did not translate into a superior PFS or OS. In patients with t(4;14) (n = 65), sCR post-transplant led to a trend toward superior PFS and MRD negativity translated into significantly superior PFS and OS. Depth of response and MRD status are important surrogate markers for survival in patients with HR cytogenetics, except in the subgroups with deletion(17p) and ≥2 HR abnormalities, where sCR and MRD negativity post-transplant did not translate into a superior survival. [ABSTRACT FROM AUTHOR]

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV 1 ). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases and included studies that compared azithromycin with placebo or no intervention in the treatment of OB or bronchiolitis obliterans syndrome (BOS) in patients who had undergone allogeneic HSCT. Ninety-one unique publications were identified, and 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV 1 were measured between 12 and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV 1 of 30 mL (95% confidence interval, −260 to +330 mL; P  = .82) after initiation of azithromycin. One patient death was reported but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS after HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting. [ABSTRACT FROM AUTHOR]

A variety of interstitial Lung Diseases (ILD) have been described in patients with myelodysplastic syndromes (MDS) with possible etiologies including autoimmunity, drug related toxicity, and recurrent infections. A comprehensive study of ILD in MDS patients has not been previously performed. Out of 827 consecutive biopsy proven MDS patients seen at our institution from June 1970–May 2010, 18 (2%) were found to have ILD. There was no statistical significance in baseline characteristics between patients with ILD (ILD +) vs those without ILD (ILD−). Cytogenetic studies were reported in 14 ILD + patients out of whom 43% had 5q- abnormalities (21% isolated and 22% part of complex karyotype). Prevalence of high risk MDS was similar between both groups (22% vs 29% in ILD−) with similar overall survival. ILD was diagnosed prior to MDS in the majority of cases (72%) with a median time to MDS diagnosis of 22.3 months. Our study suggests that ILD are present in a higher percentage than anticipated in the MDS population. Deletion 5q was frequent in ILD+ cases and this requires further study. Prior MDS treatment and autoimmunity seemed to play no significant role in ILD development. [ABSTRACT FROM AUTHOR]

Highlights • Autologous stem cell transplantation can be safely performed in carefully selected patients aged 70 or older. • The overall response rate is 75% in this cohort. • Progression-free and overall survival are encouraging for a population with competing risks for death. Abstract Autologous stem cell transplantation (ASCT) has been used in treatment for immunoglobulin light chain (AL) amyloidosis for over 2 decades and is generally reserved for patients younger than 70 years. Herein we report on outcomes of ASCT in a cohort of patients with AL amyloidosis aged 70 years or older. Between August of 2002 and April of 2017, 34 patients aged 70 years or older, with biopsy-proven AL amyloidosis, received an ASCT at the Mayo Clinic Rochester. Seventy percent of patients (n = 24) were transplanted within 6 months of diagnosis, and 74% (n = 25) received reduced-intensity conditioning with melphalan <200 mg/m2. Sixty-five percent of patients (n = 22) required hospitalization with a median duration of hospital admission of 8 days. Common reasons for hospitalization included fever or infection (14%), cardiac arrhythmia (14%), nutritional support (24%), and volume overload (19%). Overall response rate was 75%, with a complete response seen in 25% of patients. Overall survival and progression-free survival for the cohort were 66 months and 40 months, respectively. One patient died within 100 days of transplant, representing a 3% 100-day mortality rate. ASCT is safe and efficacious in carefully screened patients aged 70 or above. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for patients with blood disorders and genetic diseases. Approximately 70% of the HSCTs currently performed in the United States use stems cells from an unrelated donor who donated voluntarily. Medical students (MS) are a young, diverse, influential population whose willingness to engage in altruistic acts, such as donating stem cells, may be correlated with knowledge on the topic. A literature gap exists in MS perspectives towards HSCT and the bone marrow registry (BMR) and prior studies suggest that misconceptions about donation deter MS from participation on the BMR, which may decrease opportunities to educate other potential donors. We performed a cross-sectional survey among the 4-year cohort of MS at Mayo Medical School in Rochester, Minnesota. The questionnaire evaluated multiple areas including whether MS were current members of the BMR and/or prior blood donors, MS current knowledge on donor eligibility (DE) and the donation process (DP), MS familiarity with HSCT and the DP, and MS attitudes towards joining the BMR and towards donating stem cells. The responses were analyzed and assessed alongside a self-reported, standardized scale measuring students' altruistic behaviors. There were 99 out of 247 potential respondents (40%), with 45% (n = 44) of MS in preclinical years 1 or 2, 37% (n = 37) in clinical years 3 or 4, and 18% (n = 18) in research or alternative portions of their training, of which 43% (n = 41) in total were current BMR members. BMR status correlated positively with prior blood donation ( P  = .015) and female sex ( P  = .014). Respondents had a 57.7% and 63.7% average correct response rate regarding knowledge of DE and DP, respectively, with knowledge of DE not surprisingly higher in BMR members ( P  < .0001). The majority of MS surveyed, 68% (n = 65), had learned about HSCT during medical school. BMR status correlated with the following attitudes towards donating stem cells: lower concern with all evaluated aspects of HSCT—time, cost, pain, and side effects (for all subsections, P  < .05) but not with the altruism score ( P  = .32). The mean altruism score for respondents was 59.9 ± 11.3 (of a possible 100 points) with no significant difference in age, race, sex, level of training, or participation in the BMR. Altruism scores did not directly correlate with lower concern with aspects of time, cost, and pain of HSCT but did with long-term side effects ( P  = .021). This latter correlation was regardless of BMR status. Among MS, positive predictors for participation in the BMR included prior blood donation and female sex. BMR status did not ensure knowledge of all aspects of donating stem cells, but it correlated with less concern regarding the DP and was unrelated to altruism score. Improving knowledge gaps regarding the BMR and HSCT for the next generation of physicians and health care providers through expanded medical education curriculum may be beneficial to for the recruitment and retention of donor populations to the BMR. [ABSTRACT FROM AUTHOR]

Employment after hematopoietic stem cell transplantation (HSCT) is an indicator of post-transplantation recovery and function, with economic and social implications. As survival rates for HSCT continue to improve, greater emphasis can be placed on factors affecting the quality of post-transplantation survival, including the ability to resume employment. A sample of recipients of autologous or allogeneic HSCT was accrued (n = 1000) to complete a longitudinal lifestyle survey before transplantation and at 1 year after transplantation. The present study examines associations between employment and patient characteristics, disease variables, illness status, and quality of life among 1-year survivors (n = 702). Participants had a mean age of 55 years (range, 18 to 78) and were predominately male (59.7%), married/partnered (77.1%), and non-Hispanic Caucasian (89.5%); most (79.4%) had received autologous transplantation. Of the 690 participants reporting some form of employment before illness diagnosis, 62.4% had returned to work by 1 year after HSCT. Full-time employment at 1 year after HSCT was significantly associated with remission of illness, improved illness, fewer post-transplantation hospitalizations, less fatigue and pain, higher quality of life, and higher rating of perceived health. Those unemployed because of their health reported the highest rates of fatigue and pain and lowest quality of life, and they were most likely to report poor perceived health. These findings highlight work reintegration as an important outcome and marker of survivors’ overall adjustment after transplantation. Identifying factors affecting post-transplantation employment offers opportunities for behavioral interventions to target modifiable risk factors to optimize post-transplantation survivorship, inclusive of increased rates of return to work and decreased rates of associated disability. [ABSTRACT FROM AUTHOR]

Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively ( P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively ( P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB ( P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR. [ABSTRACT FROM AUTHOR]

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all-cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with an estimated prevalence of MetS of 31% to 49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors. [ABSTRACT FROM AUTHOR]

Oral mucositis (OM) is a debilitating early adverse effect of allogeneic hematopoietic stem cell transplantation (HSCT). The intensity of the conditioning regimen correlates with the incidence and severity of OM, but no studies have analyzed this relationship among various conditioning regimens. We performed a systematic review on the incidence and outcomes of OM in allogeneic HSCT patients and analyzed this association. A comprehensive search of several databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Cochrane CRCT, Cochrane DSR, Scopus) from 1990 to 2014 for studies of OM in allogeneic HSCT patients was conducted. Professional societies' meeting abstracts were also searched. Grade of OM was analyzed based on the World Health Organization (WHO) or National Cancer Institutes (NCI) Common Terminology Criteria for Adverse Events scales. Severe mucositis was defined as either grades 2 to 4 or grades 3 and 4, depending on the studies' definition of severity. Cohorts were analyzed based on regimen intensity; ie, reduced-intensity conditioning (RIC) (including nonmyeloablative) and myeloablative (MA). Random effect (RE) and standard logistic models weighted by the number of patients in each cohort were used for comparisons. A total of 624 studies were generated from the search. Of the 395 patients in 8 eligible MA regimen studies, 73.2% experienced any OM, whereas in 245 patients in the 6 eligible RIC regimen studies, 86.5% experienced any OM (chi-square P < .0001; RE, P = .05). Severe (grades 2 to 4) OM occurred among 79.7% of the WHO/NCI-graded MA patients and 71.5% of RIC patients (chi-square, P = .0421; RE, P < .01). In comparing graft-versus-host disease (GVHD) prophylaxis, only 55.4% of patients receiving nonmethotrexate regimens experienced OM; this was lower (chi-square, P < .0001; RE, P = .06) than that found among patients who received methotrexate (83.4%), either standard or reduced dose. Besides NCI and WHO grading scales, other scales included in the studies were Oral Mucositis Index, the Southwest Oncology Group Criteria, and Eastern Cooperative Oncology Group scale. To our knowledge, this is the first analysis on OM in allogeneic HSCT patients with respect to conditioning regimens, and we observed that RIC regimens led to a high incidence of OM similar to that of MA regimens. Clinical trials on treatment of OM are lacking, emphasizing the essential need for prospective studies in this arena. A significant variance in the criteria for grading OM underscores the importance of establishing a standard grading system for OM measurement in future allogeneic HSCT clinical trials. [ABSTRACT FROM AUTHOR]

Supportive care guidelines recommend antimold prophylaxis in hematopoietic stem cell transplant (HSCT) recipients deemed to have high risk for invasive fungal infection, leading to long-term use of voriconazole after allogeneic HSCT in patients who remain immunocompromised. Voriconazole has been associated with periostitis, exostoses, and fluoride excess in patients after solid organ transplantation, HSCT, and leukemia therapy. The aims of this study were to describe the frequency and clinical presentation of patients presenting with pain and fluoride excess among allogeneic HSCT patients taking voriconazole, to identify when a plasma fluoride concentration was measured with respect to voriconazole initiation and onset of pain, and to describe the outcomes of patients with fluoride excess in the setting of HSCT. A retrospective review was conducted of all adult allogeneic HSCT patients receiving voriconazole at Mayo Clinic in Rochester, Minnesota, between January 1, 2009 and July 31, 2012. Of 242 patients included, 32 had plasma fluoride measured to explore the etiology of musculoskeletal pain. In 31 patients with fluoride measurement while on voriconazole, 29 (93.5%) had elevated levels. The median plasma fluoride was 11.1 μmol/L (range, 2.4 to 24.7). The median duration of voriconazole was 163 days (range, 2 to 1327). The median time to fluoride measurement was 128 days after voriconazole initiation (range, 28 to 692). At 1 year after the start of voriconazole after HSCT, 15.3% of patients had developed pain associated with voriconazole use and 35.7% developed pain while on voriconazole after 2 years. Of the patients with an elevated fluoride level, 22 discontinued voriconazole; pain resolved or improved in 15, stabilized in 3, and worsened in 4 patients. Ten patients continued voriconazole; pain resolved or improved in 7, was attributable to alternative causes in 2, and undefined in 1. Serum creatinine, estimated glomerular filtration rate, alkaline phosphatase, and voriconazole concentration did not predict for fluoride excess and associated pain. Periostitis due to fluoride excess is a common adverse effect of voriconazole that should be considered in patients presenting with pain and is often reversible after drug discontinuation. Alternative antifungal agents with a lower risk for fluoride excess should be considered in patients receiving voriconazole who develop fluoride excess and pain. [ABSTRACT FROM AUTHOR]

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation. [ABSTRACT FROM AUTHOR]

Introduction The 2016 World Health Organization (WHO) classification of myeloid neoplasms reclassified patients with myelodysplastic syndromes (MDS) with multilineage dysplasia (MLD) based on the presence or absence of ring sideroblasts (RS). We performed this study to validate this change in the context of relevant gene mutations. Methods WHO-defined MDS and MLD were identified with detailed clinical, cytogenetic and outcomes data. A 32-gene targeted exome sequencing panel was performed on bone marrow samples obtained at diagnosis. Results Ninety eight patients were included; 59 (60%) MDS-MLD and 39 (40%) MDS-RS-MLD. There were no significant differences in the median overall survival (OS) in the two groups (25 months each, p = 0.6). Among the myeloid-relevant gene mutations, presence of ASXL1 (HR 2.5, p = 0.005) was identified as an adverse prognostic factor in a multivariate analysis. Conclusion While segregation of MDS-MLD based on RS holds little prognostic relevance, ASXL1 mutational status significantly and independently predicts poor outcomes. [ABSTRACT FROM AUTHOR]

Infused autograft absolute lymphocyte count is a prognostic factor for survival after autologous peripheral hematopoietic stem cell transplantation (APHSCT) for diffuse large B cell lymphoma (DLBCL). CD14 + HLA-DR low/neg immunosuppressive monocytes affect tumor growth by suppressing host antitumor immunity. Thus, we set out to investigate if the infused autograft lymphocyte to monocyte ratio (A-LMR), as a biomarker of host immunity (ie, lymphocytes) and immunosuppression (ie, monocytes), affects survival after APHSCT. From 1994 to 2012, 379 DLBCL patients who underwent APHSCT were studied. The 379 patients were randomly divided into a training set (n = 253) and a validation set (n = 126). Receiver operating characteristic and area under the curve identified an A-LMR ≥1 as the best cut-off value, which was validated by the k-fold cross-validation in the training set. Multivariate analysis showed A-LMR to be an independent prognostic factor for survival in the training set. Patients with an A-LMR ≥ 1.0 experienced superior overall survival (OS) compared with patients with an A-LMR <1.0 (median OS: 167.2 versus 17.6 months; 5-year OS: 73% [95% confidence interval (CI), 63% to 80%] versus 30% [95% CI, 2% to 38%], P < .0001, respectively) in the training set. In the validation set, an A-LMR ≥ 1 showed a median OS of 181.2 months versus 19.5 months for an A-LMR <1, and 5-year OS rates of 67% (95% CI, 52% to 79%) versus 35% (95% CI, 25% to 47%), P < .0001, respectively. The A-LMR provides a platform to engineer immunocompetent autograft to improve clinical outcomes in DLBCL patients undergoing APHSCT. [ABSTRACT FROM AUTHOR]

Abstract: Historically, up to 30% of patients were unable to collect adequate numbers of peripheral blood stem cells (PBSCs) for autologous stem cell transplantation (ASCT). Plerixafor in combination with granulocyte colony-stimulating factor (G-CSF) has shown superior results in mobilizing peripheral blood (PB) CD34+ cells in comparison to G-CSF alone, but its high cost limits general use. We developed and evaluated risk-adapted algorithms for optimal utilization of plerixafor. In plerixafor-1, PBSC mobilization was commenced with G-CSF alone, and if PB CD34 on day 4 or day 5 was <10/μL, plerixafor was administered in the evening, and apheresis commenced the next day. In addition, if on any day, the daily yield was <0.5 × 106 CD34/kg, plerixafor was added. Subsequently, the algorithm was revised (plerixafor-2) with lower thresholds. If day-4 PB CD34 <10/μL for single or <20/μL for multiple transplantations, or day-1 yield was <1.5 × 106 CD34/kg, or any subsequent daily yield was <0.5 × 106 CD34/kg, plerixafor was added. Three time periods were analyzed for results and associated costs: January to December 2008 (baseline cohort; 319 mobilization attempts in 278 patients); February to November 2009 (plerixafor-1; 221 mobilization attempts in 216 patients); and December 2009 to June 2010 (plerixafor-2; 100 mobilization attempts in 98 patients). Plerixafor-2 shows a significant improvement in PB CD34 collection, increased number of patients reaching minimum and optimal goals, fewer days of apheresis, and fewer days of mobilization/collection, albeit at increased costs. In conclusion, although the earlier identification of ineffective PBSC mobilization and initiation of plerixafor (plerixafor-2) increases the per-patient costs of PBSC mobilization, failure rates, days of apheresis, and total days of mobilization/collection are lower. [Copyright &y& Elsevier]

Many previous studies of immune reconstitution (IR) postallogeneic hematopoietic stem cell transplantation (HSCT) have focused on lymphocyte recovery. Recognizing that IR involves complex interactions between innate and adaptive immune networks, we hypothesized that patterns of both monocyte and lymphocyte recovery could provide additional prognostic information. To test our hypothesis, we analyzed data from 135 consecutive patients undergoing myeloablative allogeneic HSCT for acute myeloid (AML) and lymphoblastic leukemia (ALL) from 2001 to 2010. The absolute lymphocyte and monocyte counts (ALC and AMC, respectively) were determined longitudinally at days +15, +30, +60, and +100, and correlated with clinical outcomes. At the day +30 time point, both ALC and AMC >0.3 × 109 cells/L were strongly associated with improved survival (overall survival [OS] 29.6 months versus 5.4 months, P = .006 and 25.3 months versus 5.1 months, P = .01 respectively), a pattern that generally continued through the day +100 evaluation. Multivariate analysis revealed the following independent prognostic factors: early disease status at transplantation, the development of chronic GVHD, the day +30 AMC, day +100 AMC, and day +100 ALC. To further explore whether any inherent patterns in the timing of lymphocyte and monocyte recovery had prognostic value post-HSCT, we performed unsupervised hierarchical clustering on the longitudinal hematopoietic parameters studied in this cohort. Four clusters of patients were identified: clusters A-D. Patient clusters B and D both demonstrated improved ALC and AMC recovery at the day +60 and day +100 time points and had significantly improved OS compared with clusters A and C (57.8 months versus 19.7 and 4.4 months, respectively, P < .001). Our data suggest that patients with poor lymphocyte and monocyte recovery beyond the day +60 time points may be at risk for poorer outcomes, and that further investigation into lymphoid/myeloid interactions in developing individualized immunotherapy is warranted. [Copyright &y& Elsevier]

Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients. [Copyright &y& Elsevier]

A specific predictor during routine follow-up to ascertain risk for postautologous peripheral blood hematopoietic stem cell transplantation (post-APHSCT) relapse in non-Hodgkin lymphoma (NHL) has not been identified. Thus, we studied if new-onset lymphopenia measured by the absolute lymphocyte count (ALC) was a marker of post-APHSCT NHL relapse. ALC was obtained at the time of confirmed relapse, and at last follow-up with no relapse. From 1993 until 2005, 269 patients treated with APHSCT for diffuse large B-cell lymphoma (DLBCL) were included in this study. Patients at last follow-up without relapse (N=137) had a higher ALC compared with those with low ALC at the time of confirmed relapsed (N=132) (median ALC ×109/L of 1.66 versus 0.71, P < .0001, respectively). ALC at follow-up was a strong predictor for relapse with an area under the curve (AUC)=0.86 (P < .0001). An ALC <1.0×109/L at the time of confirmed relapse had a positive predictive value of 89% and a positive likelihood ratio of 8.4 to predict relapse post-APHSCT. Patients with an ALC ≥1.0×109/L (N=147) had a cumulative incidence of relapse of 19% versus 92%, with an ALC <1.0×109/L (N=122) (P < .0001). This study suggests that new-onset lymphopenia measured by ALC can be used as marker to assess risk of DLBCL relapse during routine follow-up for after APHSCT. [Copyright &y& Elsevier]

We report on the feasibility of outpatient transplant in 716 patients undergoing autologous stem cell transplant for multiple myeloma at Mayo Clinic's site in Rochester, MN, from January 1, 2000, through October 31, 2007. We also report on the development and effect of a multidisciplinary quality initiative implemented by the Mayo Clinic Blood and Marrow Transplant Program involving physicians, nurses, pharmacists, dietitians, and financial specialists for outpatient management of patients undergoing stem cell transplant. This approach uses an electronic ordering system for diagnostic tests and chemotherapy to minimize medical errors. Analysis of hospitalization trends since inception of the program showed that 278 (39%) of the 716 patients treated completed the transplant procedure as outpatients. The median duration of hospitalization for all patients was 4 days; age and serum creatinine levels were predictive of the need for and duration of hospitalization. We also assessed recent treatment-related mortality rates during a 33-month period after implementation of the program (between January 1, 2005, and October 1, 2007). The 100-day survival rate was 99.5% for patients with low-risk myeloma (transplant during first plateau; n=201) and 97.2% for patients with high-risk myeloma (refractory, relapsing or second or greater plateau; n=71). The overall 100-day survival rate was 98.9%. Our experience shows that outpatient transplant is feasible for all patients with multiple myeloma and results in shorter hospital stays and low treatment-related mortality rates. [ABSTRACT FROM AUTHOR]

The national shortage of oral (PO) and intravenous (IV) tacrolimus, as well as the undesirable sequelae of IV administration, call for innovative solutions to conserve existing supply and optimize safety and efficacy of medication delivery. Sublingual (SL) administration of tacrolimus is widely used as an alternative to the IV route in the solid organ transplant population and similar benefits may be appreciated by patients undergoing hematopoietic cell transplant (HCT). The most widely accepted SL:PO dose conversion ratio has been 0.5 based on available evidence. We sought to demonstrate feasibility of SL tacrolimus use and estimate a SL:PO conversion ratio in the HCT setting. Ten adults (median age 60.5 years) undergoing allogeneic HCT received tacrolimus 0.04 mg/kg/dose, based on ideal body weight, twice daily beginning 3 days prior to transplant. Initial doses were given via SL route and a steady state trough level was collected after 4 consecutive doses. Participants were then switched to tacrolimus PO, the dose was adjusted for a goal trough 8-12 ng/mL, and another steady state trough was drawn (Figure 1). Trough concentration was divided by total daily dose for each route to determine the dosing ratio of SL:PO (Table 1). Median trough level following SL administration was 11.3 ng/mL. Three of these were within goal, 3 were low (4.7-6.4 ng/mL) and 4 were elevated (15.9-18.6 ng/mL). Median SL:PO ratio was 0.99. In 5 patients the SL:PO ratio was <1 (range 0.52-0.91) and in 5 the ratio was ³1 (1.07-1.76). No significant barriers or intolerance to SL tacrolimus use were noted. Results demonstrate reliable absorption with SL tacrolimus use in patients undergoing HCT. This represents an alternative drug delivery method in patients with barriers to PO administration or in the setting of limited availability of the IV product. This preliminary experience identified an SL:PO ratio of 0.99 with some degree of variability. Fluctuating clinical status and changes in interacting medications are important to consider when adjusting doses or converting between routes and may influence this ratio. Further study is needed to better elucidate the a more precise SL:PO dose conversion ratio and understand the impact of various drug-drug interactions. [ABSTRACT FROM AUTHOR]

Allogeneic HCT is a potentially curative strategy for SAA. In combination with fludaribine, anti-thymocyte globulin (ATG) or alemtuzumab, low-dose (2 Gy) total body irradiation (TBI) has been incorporated in the conditioning regimen for matched unrelated donors (MUD) for SAA, with the intention of reducing the cyclophosphamide dose and rate of graft failure. Progressive telomeric shortening in SAA can theoretically increase the risk of radiation injury in affected patients. Outcomes between TBI and non-TBI containing conditioning regimens in SAA have not been systematically compared. After regulatory approval, clinical and outcomes data for patients with SAA treated with allogeneic HCT from 1998-2018 were collected, and compared between TBI and non-TBI groups. Fifty seven patients were included in the study, median age 25 (range: 1-63) years; 23 (40%) < 18 years, 44 (77%) < 40 years and 29 (51%) patients were male. Forty five (80%) patients received prior immunosuppressive therapy (IST); 19 (68%) horse ATG; 2 (7%) rabbit ATG. Median time from SAA diagnosis to transplant was <6 months in 18 (32%) patients, and >12 months in 28 (49%) patients. Graft source was bone marrow (BM) in 48 (84%) patients, followed by peripheral blood in 8 (14%), and cord blood in 1 patient. Twenty-nine (51%) patients were transplanted with matched sibling donors (MSD), followed by 20 (35%) MUD, and 13 (23%) others (cord/mismatch/haplo). TBI-containing regimens were used in 30 (53%) patients [MUD-20 (67%), mismatch-5 (17%)], while non-TBI regimens were used in 27 (47%) patients [MSD-24 (89%), mismatch-3 (11%)]. Although the rate of RBC (P = 0.02) and platelet transfusion dependence (P = 0.04) was higher in the TBI group, presence of clinically significant HLA alloantibodies prior to transplant (MFI>1000) was not different (P = 0.07). At a median follow-up of 77 (95% CI 63-95) months, there were 11 (19%) deaths [TBI-8 (27%), non-TBI-3 (11%), p = 0.1]. Median overall survival (OS) was lower in the TBI group among MSD donors (163 mo v/s median NR, P = 0.01), and MSD+MUD donors (93 mo v/s NR, P = 0.0002, figure 1). The two groups did not significantly differ in terms of rates of graft failure (P = 0.7), acute (P =0.2), and chronic GVHD (P =0.6), and documented infections (P =0.5). Based on prior knowledge of adverse prognostic factors in SAA and limited events, a Cox proportional hazard model was designed with three variables; age at transplant, donor source and TBI-use. Only TBI use was independently associated with poor OS (HR 6, 95% CI 1-33, P = 0.05). In our limited series, low-dose TBI use as part of pre-transplant conditioning regimen for SAA was associated with poor overall survival, despite no significant differences in rates of post-transplant graft failure, GVHD, and infections. Prospective validation of this finding in larger cohorts is needed. [ABSTRACT FROM AUTHOR]

Abstract: We investigated whether pretransplantation immunosuppression with canine-specific rabbit antithymocyte globulin (ATG), combined with a suboptimal dose of 1 Gy of total body irradiation (TBI), would permit engraftment of canine dog leukocyte antigen-identical marrow. Cumulative ATG doses of 2 to 5 mg/kg produced a T-cell depletion of 1 log in the peripheral blood and 50% in the lymph nodes. Serum levels of ATG peaked on days 4 to 6 after initiation of therapy and became undetectable by day 13 as a result of canine antibody responses to ATG. ATG prolonged allogeneic skin graft survival to 14 days (n = 5), compared with 8 days in control dogs (P = .0003). Five dogs were given marrow transplants after ATG (3.5¿5 mg/kg) and 1 Gy of TBI. Posttransplantation immunosuppression consisted of mycophenolate mofetil and cyclosporine. All dogs showed initial engraftment, with maximum donor chimerism levels of 25%. However, only 1 dog achieved sustained engraftment, and 4 rejected their grafts. The duration of engraftment ranged from 8 to =36 weeks (median, 11 weeks), and this is comparable to that in 6 historical controls not given ATG (range, 3¿12 weeks; median, 10 weeks; P = .20). The total nucleated cell doses in the marrow grafts had the highest correlation coefficient with the duration of engraftment: 0.82 (P = .09). We concluded that administering ATG before an otherwise suboptimal conditioning dose of 1 Gy of TBI failed to secure uniform stable hematopoietic engraftment. [Copyright &y& Elsevier]

Background Patients with immunoglobulin light chain (AL) amyloidosis often present with organ dysfunction secondary to the deposition and aggregation of the amyloidogenic light chain. Renal involvement typically presents as proteinuria, however renal dysfunction manifesting as reduced creatinine clearance (CrCL) may also be seen, often contributed to by other comorbidities and can complicate therapy for these patients. Patients and methods We retrospectively reviewed all patients receiving an autologous stem cell transplant (ASCT) for AL amyloidosis at the Mayo Clinic Rochester between 19th May 1999 and 30th of September 2017, to identify the impact of impaired renal function (CrCL<45 ml/min/SA) on post-transplant outcomes. Patients were grouped into two cohorts, those with normal renal function (NRF) CrCl ≥45 ml/min (n=556) and those with impaired renal function (IRF) CrCl <45 ml/min (n=84). Patients on dialysis prior to ASCT or without available data on CrCl prior to ASCT were excluded. Results Baseline characteristics for each cohort are summarized in Table 1. Median age and the proportion of males in each cohort were similar. Predictably renal amyloidosis was more common in the IRF group (90% IRF cohort vs 60% NRF cohort, p<0.0001). Disease stage according to the Mayo 2004 and Mayo 2012 staging systems were similar in both cohorts. The majority of patients in the IRF cohort received reduced intensity conditioning with melphalan <200mg/m^2 (73% for IRF vs 22% for NRF, p<0.0001). Overall response rate (ORR) was similar in both cohorts (ORR 85% for NRF vs 78% for IRF, p=0.17), Figure 1A. Renal outcomes are summarized in Table 2. The number of patients requiring dialysis within 100 days post ASCT was higher in the IRF cohort (14% (n=12) for IRF vs 6% (n=31) for NRF, p<0.0078). Seventeen patients have received a kidney transplant (12% (n=10) of IRF cohort vs 1% (n=7) of NRF cohort, p<0.0001). Median progression free survival (PFS) and overall survival (OS) was similar for both cohorts (PFS: median 65 months for IRF vs 69 months for NRF, p=0.89; OS: median 118 months for IRF vs 126 months for NRF, p=0.23), Figure 1B. The all-cause mortality at 100 days post ASCT was higher amongst patients with IRF (13% for IRF vs 6% for NRF, p0.01). Conclusions ASCT is an effective therapy in patients with AL amyloidosis and impaired renal function. Although PFS and OS in this cohort are similar to those with normal renal function, the 100 day mortality and proportion of patients requiring dialysis post ASCT are higher and need to be considered prior to recommendation of this therapy for patients. [ABSTRACT FROM AUTHOR]

IgM related AL amyloidosis is a rare disease with patients presenting with more renal and neurological involvement and less cardiac involvement compared to those with non-IgM related disease. We retrospectively reviewed 38 patients receiving autologous stem cell transplant (ASCT) for IgM related AL amyloidosis at the Mayo Clinic between May 1999 and June 2018. Median age was 61 years and 71% were male. The most common organs involved were renal (63%), neurological (32%) and cardiac (26%). The median difference between involved and uninvolved free light chains (dFLC) was 6.2 mg/dL and most patients had early mayo stage (87% Mayo Stage I 2004 and 74% Mayo Stage I 2012). The overall response rate (ORR) was 92% with 76% of patients achieving at least a very good partial response (VGPR). Renal response was seen in 65% (15/23) of patients (median time 18 months post ASCT, range 3-52 months) and cardiac response was seen in 60% (6/10) of patients (median time 12 months post ASCT, range 10-35 months). Median progression free and overall survival was 48 and 106 months respectively, Figure 1. Organ response predicted better PFS and OS (median PFS 93 months for organ response vs 16 months for no organ response, p=0.0006 and median OS 123 months for organ response vs 41 months for no organ response, p=0.02), Figure 2. Two patients died within 100 days of transplant representing a 5% 100 day mortality. ASCT is an effective therapy that can be safely delivered to carefully selected patients with IgM related AL amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction Reduced-intensity conditioning (RIC) regimens have expanded allogeneic hematopoietic stem cell transplantation (allo-HSCT) to patients (pts) with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who are unfit for myeloablative regimens. Several RIC regimens are typically used. We and others have previously shown that fludarabine-melphalan (FM) has a lower risk of relapse compared to fludarabine-busulfan (FB). Objectives Herein, we re-examine these findings with a larger cohort and longer follow-up. We also compare the composite endpoint graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS), and elucidate factors that predict for relapse and NRM. Methods After IRB approval, we conducted a study of pts (age ≥18) diagnosed with AML or MDS who underwent allo-HSCT from January 1st, 2008 to March 1st 2017 at Mayo Clinic Rochester. Only pts who received FM (melphalan 140 mg/m2) or FB (busulfan 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L[min]) were included. Grade III-IV acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death counted as events for GRFS. Statistical analyses were performed using JMP 13 and EZR 1.36. Results We identified 184 pts who underwent RIC allo-HSCT: 135 with AML and 49 with MDS. The median age for the entire cohort was 61 (range, 18-74). FM was used in 123 pts, while 61 received FB. Baseline characteristics were comparable (Table 1a). The median follow-up was 5 years (95% CI, 4-5.6). In line with previous findings, the cumulative incidence of relapse (CI-R) was significantly higher with FB compared to FM: 3-year CI-R was 31.7% for FB vs. 17.3% for FM (p=.04)(Figure 1a). On the other hand, there was a nonsignificant trend towards an increased CI-NRM in the FM group; at Day +100, CI-NRM was 6.5% for FM vs. 1.6% for FB (p=.24). Acute and chronic GHVD were comparable (Table 1b). The median GRFS for the entire cohort was 7.3 months (95% CI, 6.1-8.4); there was no difference between the two regimens (p=.94). Overall survival (OS) was comparable (p=.61), as were causes of death (Figure 1b). In a multivariate Fine-Gray proportional hazard model for relapse vs. NRM, which included factors in Table 2 ; disease status (CR1 vs. CR2 or active disease) predicted relapse (HR 0.42, 95% CI 0.21-0.84, p=.01). There was also a trend towards a decreased risk of relapse with FM (HR 0.54, 95% CI 0.28-1.03, p=.06). On the other hand, age was predictive of NRM (HR 1.05 per year, 95% CI 1.01-1.09, p=.01). Conclusion In the present follow-up study, there were no significant differences in GRFS or OS between FM and FB regimens for RIC allo-HSCT in AML/MDS, despite FB having a significantly higher risk of relapse. Likely, the OS was balanced by continuing NRM after FM conditioning, particularly in older pts. Further studies, ideally prospective, are required to elucidate the optimal RIC regimen matched to disease biology and pt fitness. [ABSTRACT FROM AUTHOR]

Introduction There have been considerable advances in the understanding of molecular markers in acute myeloid leukemia(AML). It is widely accepted that internal tandem duplication (ITD) in the juxta membrane domain of the fms-like tyrosine kinase-3 (FLT3) gene in patients with AML is associated with an increased risk of relapse and reduced overall survival. In several studies, alloSCT performed in first complete remission (CR) from matched-related donors (MRDs) has been shown to result in an improved survival. There is also evidence that alloSCT improves OS in high allelic ratio FLT3-ITD AML and in patients with low allelic ratio FLT3-ITD AML and wild-type nucleophosmin (NPM1) but not in mutated NPM1 with low FLT3 ITD ratio. We wanted to validate these findings in our own cohort. Methods We retrospectively reviewed 723 consecutive patients (>18 years) with newly diagnosed AML treated at Mayo clinic between January 2007 and July 2016. Patients with intermediate-risk cytogenetics and known NPM1 and FLT3 molecular genetics were included in the study (n =198). Patients who had M3 AML, who were lost to follow up and without molecular data were excluded. We analyzed outcomes based on therapy and molecular mutations. Results Baseline characteristics are listed in Table 1. As expected patients receiving alloSCT were younger and a higher proportion received high intensity induction therapy. The majority of patients were transplanted in CR 1 (72%, n=55), Table 2. Median time to transplant was 4.6 months (range 2-64 months). Median follow up for the entire cohort was 62 months. At last follow up 117 (59%) of patients have died. Median OS for the whole cohort was 27 months. OS was longer in patients receiving alloSCT (median OS 87 months vs 16 months for No SCT, p=0.0001)(Figure 1A). This survival advantage remained significant amongst patients achieving CR1 (Figure 1B). Molecular mutations predicted survival based on FLT3 and NMP1 status primarily amongst the non-transplant cohort (Figure 1C). Patients receiving SCT had a similar survival irrespective of molecular mutation profile(Figure 1D). Amongst the FLT3+ cohort, data on subtype and ITD allelic ratio were available in 47 patients (FLT3 ITD low allelic ratio (<0.5), n=13, FLT3 ITD high allelic ratio (≥0.5), n=26 and FLT3 TKD, n=8). Patients with a high allelic ratio FLT3 ITD mutation appeared to have the worst survival, although this did not meet statistical significance (median OS 69 months for FLT3 ITD low vs 21 months for FLT3 ITD high, p=0.16). Conclusion In our cohort, patients with intermediate risk AML achieving CR1 benefited from alloSCT. The poor prognostic impact of FLT3 mutations in this cohort may be abrogated by alloSCT. The FLT3 mutation burden (allelic ratio) may help further prognosticate this category of patients with intermediate risk AML. [ABSTRACT FROM AUTHOR]

Acute GVHD biomarkers predict long-term outcomes after GVHD diagnosis. Our group has validated the MAGIC algorithm which uses the concentrations of 2 GVHD biomarkers, ST2+REG3a, to predict lethal GVHD (defined as death from GVHD without relapse) [Hartwell 2017]. Other published biomarker combinations that predict GVHD outcomes include ST2+ REG3a+TNFR1 [Levine 2015], ST2+TIM3 [Abu Zaid 2017], ST2+TNFR1 [McDonald 2015], TIM3+TNFR1+IL6 [McDonald 2015], as well as AREG alone [Holtan 2018]. It is not clear which biomarker combination best predicts lethal GVHD because these algorithms were developed using different patient cohorts with different endpoints. To answer this question, we compared the predictive accuracy of different biomarker combinations as well as these six specific combinations in the same patient cohort. We studied 522 patients with serum samples at GVHD diagnosis who were transplanted at 19 Mount Sinai Acute GVHD International Consortium (MAGIC) centers between January 1, 2004 and April 30, 2017. Patients were divided into training (n = 253) and validation (n = 269) sets; validation patients were transplanted after November 1, 2015 and had not previously been used to generate an algorithm. Biomarkers were measured by ELISA and log-transformed values were used to predict 1-year lethal GVHD by competing risk regression. Four of the 6 biomarkers (ST2, REG3a, TNFR1, and TIM3) independently predicted lethal GVHD in the training set. We then developed algorithms that predicted lethal GVHD using all possible combinations of these 4 biomarkers as well as the published combination of TIM3+TNFR1+IL6 and AREG alone. The best algorithms of 1-4 biomarkers for predicting lethal GVHD were REG3a alone, ST2+REG3a, ST2+REG3a+TNFR1, and ST2+REG3a+TNFR1+TIM3. While ST2+REG3a was the most accurate combination based on the lowest Akaike Information Criterion (AIC), the other published biomarker combinations produced similar AICs. Therefore, we used the independent validation set to compare all six published algorithms. We generated area under the receiver operating characteristic curves (AUC) for each algorithm (FIG 1). We next determined the threshold that maximized sensitivity and specificity for each algorithm and calculated the cumulative incidence of lethal GVHD in the resulting high and low risk strata (FIG 2). Highly similar results were obtained when the cumulative incidence of non-relapse mortality was used as the endpoint. In a validation set of previously unanalyzed patients, several biomarker combinations reproducibly stratified patients with GVHD for risk of death. The best 4 algorithms, all of which included ST2, produced comparable outcomes. Adding TNFR1 to ST2+ REG3a did not improve accuracy. The ST2+REG3a algorithm best identifies patients at onset of GVHD for high risk of lethal GVHD and NRM, and thus remains a standard for biomarker-based risk prediction. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT) is the standard-of-care for fit/younger patients with multiple myeloma. Outcomes are heterogeneous for those achieving less than a complete response (CR) after transplant; novel predictors of early relapse are needed to guide consolidation, maintenance and disease monitoring strategies. The post-ASCT proliferative index of clonal plasma cells (cPC) predicts for survival.1 In the present study, we evaluated nonmalignant proliferating polyclonal plasma cells (pPC) for an independent effect on outcome. From January 1 2013 to January 1 2014, 176 consecutive patients with multiple myeloma underwent their first ASCT at our institution and had a bone marrow (BM) specimen collected approximately 100 days post-ASCT. All BM was subject to multi-parametric flow cytometry using a BD FACS Canto IITM as previously described. Briefly, proliferating (S-phase) pPC were classified using DAPI staining and reported as a percentage of total pPC, which was calculated if there were at least 150 pPC/500000 events (Figure 1). Those with less than 150 pPC were deemed "non-evaluable." Time to next therapy (TNT) was calculated from ASCT Day 0 to the initiation of a new therapy (not including maintenance or consolidation), with patients censored at time of last follow-up or death without further therapy. Overall survival (OS) was calculated from Day 0 to death, with living patients censored at time of last follow-up. Statistics were performed using R 3.5.2. Responses at Day 100 were as follows: 71 (40%) CR, 48 (27%) very good partial response, 57 (33%) partial response or less. Among the 77 of 105 (73%) patients with