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Fluid overload (FO) grade ≥2 (more than 10% weight gain from baseline) has recently been recognized as an important toxicity associated with a high rate of nonrelapse mortality in recipients of allogeneic hematopoietic cell transplantation (AHCT). The causes for FO remain unclear. We hypothesized that endothelial damage, possibly due to treatments received prior to AHCT, may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index (EASIX) (defined as lactate dehydrogenase [U/L] × creatinine [mg/dL]/platelets [109 cells/L]) correlates with grade ≥2 FO in 2 cohorts of recipients of AHCT at our institution. We tested our hypothesis in a cohort of 145 consecutive recipients (study cohort) of AHCT transplant from HLA-haploidentical donors and validated the findings in a cohort of 449 (validation cohort) recipients of AHCT from HLA-matched donors who underwent transplantation between 2010 and 2015. Predictors of grade ≥2 FO were evaluated using competing risks regression in univariate analysis and classification and regression tree (CART) analysis in multivariate analysis. The cumulative incidence of grade ≥2 FO was estimated considering death as a competing risk. EASIX scores were evaluated based on log2-transformed values. Optimal predictive EASIX cutoff values were determined based on receiver operating characteristics curve analysis. Grade ≥2 FO occurred in 21% and 6% of the study and validation cohorts, respectively, with the majority of these cases being diagnosed before the day of AHCT. Median log2 EASIX score at admission was 2.4 (interquartile range [IQR], 1.3, 3.7) and 2.5 (IQR, 1.4, 3.9) in the 2 respective cohorts. In univariate analysis, high EASIX at admission was a significant predictor of grade ≥2 FO in the study (cutoff: 4.4, hazard ratio [HR] = 4.8, P 60 years (HR = 9.6, P = .04) in the validation cohort. At admission, the prevalence of EASIX score of >4.3 (18% versus 17%, P = .9) was not different between the diabetics and nondiabetics. EASIX score at admission is a significant predictor of grade ≥2 FO in recipients of AHCT from HLA-haploidentical or HLA-matched donors. Independently of EASIX, older patients with low weight were associated with increased risk of grade ≥2 FO for recipients of HLA-haploidentical transplants. For the HLA-matched cohort, diabetes and older age were associated with increased FO risk. These findings require validation in external cohorts.

Although bortezomib and rituximab have synergistic activity in patients with lymphoma, and can both attenuate graft-versus-host disease (GVHD), the drugs have not been used together in patients undergoing allogeneic stem-cell transplantation (alloSCT). In this phase 1/2 trial, we assessed the safety and activity of bortezomib added to the rituximab (R) plus BEAM (carmustine, etoposide, cytarabine, melphalan) regimen in patients with relapsed lymphoma undergoing alloSCT. Primary GVHD prophylaxis consisted of tacrolimus and methotrexate. Bortezomib (1 – 1.3 mg/m(2) per dose) was administered intravenously on days −13, −6, −1, and +2. We performed inverse probability weighting analysis to compare GVHD and survival results to a historical control group that received R-BEAM without bortezomib. Thirty-nine patients were assessable for toxic effects and response. The median age was 54 years. The most common diagnosis was diffuse large B-cell lymphoma (41%). Twenty-two patients (56%) and 17 patients (44%) received their transplants from matched related and unrelated matched donors, respectively. The maximum tolerated bortezomib dose was 1 mg/m(2). The weighted cumulative incidences of grade II-IV and grade III or IV acute GVHD were 50% and 34%, respectively; these incidences and survival rates were not significantly different from those of the control group. Median survival has not been reached in patients age ≤50 years and who had a long follow-up time of 60.7 months. The R-BEAM regimen has a survival benefit in lymphoma patients age ≤50 years undergoing alloSCT. The addition of bortezomib has no impact on survival or incidence of GVHD.

With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9). On multivariate analysis a low β2-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT.

We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.

In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34+ cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34+ cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with

Cytomegalovirus (CMV) infection can increase the morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Because of a higher degree of immunosuppression, haploidentical transplant recipients may be at an increased risk of viral infections, particularly CMV. We retrospectively analyzed 86 haploidentical HCT recipients at our institution to determine whether a more intensified antiviral strategy would reduce the incidence of CMV reactivation compared with a traditional antiviral prophylaxis regimen. According to practice changes over time in antiviral prophylaxis at our institution, patients were divided into the following 3 groups: hybrid (n = 15), traditional (n = 26), and intermediate dose (n = 45). The hybrid group received valganciclovir from admission to day −2 followed by standard-dose valacyclovir. The traditional group received standard-dose valacyclovir starting on day −1. The intermediate-dose group received ganciclovir from admission through day −2, followed by intermediate-dose valacyclovir. The hybrid and intermediate-dose groups were combined into an intensified group for further analysis. We found the cumulative incidence (CI) of CMV reactivation within 100 days post-HCT was higher for patients receiving the traditional strategy compared with the hybrid and intermediate-dose strategy groups (81% versus 53% versus 71%, respectively; P = .08) and was significantly higher when the traditional group was compared against the intensified group (81% versus 67%, respectively; P = .032). Median time to CMV reactivation was also shorter in the traditional group versus the intensified group (31 versus 41 days, respectively). Moreover, the CI of CMV disease by day 100 was significantly worse for patients receiving the traditional prophylaxis strategy among the 3 groups (8% traditional versus 0% hybrid versus 0% intermediate dose; P = .032). Renal toxicity did not differ between the traditional and intensified group. In conclusion, an intensified approach to prevention of CMV reactivation was associated with lower incidence of CMV reactivation and less CMV disease without increased toxicity. Because the most benefit was observed in the intensified group, further studies are needed to assess which antiviral intervention is the most beneficial on lowering the rates of CMV viremia and disease.

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged 59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

Background We previously reported that conditioning with Bu-Mel results in significantly longer PFS compared to Mel alone in patients with newly diagnosed multiple myeloma ([NDMM] Lancet Haematol 2019). Here we report the outcomes of the high-risk patients (based on chromosomal abnormalities as defined by IMWG) enrolled in this trial. Methods The primary objective was to compare PFS in NDMM patients who undergo auto-HCT with Bu-Mel versus Mel conditioning. Transplant eligible patients were randomly assigned (1:1) to treatment. Patients in Bu-Mel arm received test dose Bu 32 mg/m2 followed by PK adjusted Bu to achieve a target AUC of 5000 microMol-minute (days -7 to -4) and Mel 70 mg/m2 on days -2 and -1. Patients in Mel arm received Mel 200 mg/m2 on day -2. Results Sixty-two patients (Bu-Mel, n=32; Mel, n=30) were identified. Median age at transplant was 61 yrs in the Bu-Mel and 60 yrs in the Mel arm. Sixteen (50%) and 18 (60%) patients were male in the Bu-Mel and the Mel arm, respectively. The R-ISS stage was I in 6 (22%), II in 17 (63%), and III in 4 (15%) of 27 patients in the Bu-Mel arm versus I in 8 (38%), II in 9 (43%), and III in 4 (19%) of 21 patients in the Mel arm, p=0.39. There was no significant difference in the HCT-CI score, induction therapy, response to induction, number of patients receiving maintenance therapy, and other patients, disease, or treatment characteristics between the two treatment groups. The median time to neutrophil engraftment (ANC ≥500) was 11 days and 12 days in the Bu-Mel and Mel arms, respectively, p=0.002. The median time to platelet engraftment (platelet count ≥20K without transfusion support) was 10 days and 12.5 days in the Bu-Mel and Mel arms, respectively, p Conclusion Conditioning therapy with Bu-Mel before auto-HCT yields significantly longer PFS in high-risk myeloma patients compared with Mel alone. Longer follow-up is needed to characterize any OS benefit.

Introduction PTCy-based GVHD prophylaxis has emerged as an effective method in Allo-HCT. Cyclophosphamide has historically been associated with increased rates of cardiac toxicities. This potential complication plays a role in the choice of optimal GVHD prophylaxis. The cardiac toxicity profile of PTCy compared with non-PTCy GVHD prophylaxis in HLA-matched Allo-HCT setting is unclear. Methods We performed a retrospective analysis to evaluate cardiac toxicities after HLA-matched Allo-HCT between October 1, 2016 and April 1, 2019. Cardiac toxicity was defined as any documented arrhythmia, heart failure, cardiac event (cardiac arrest or myocardial infarction), pericarditis, or pericardial effusion that occurred between Day 0 and 100. Results A total of 585 consecutive adult patients met eligibility (Table 1). 38 unique patients developed a total of 52 cardiac toxicities. The median time to cardiac toxicity was 20 days in the PTCy and 15 days in the non-PTCy groups. Toxicities (Table 2) included arrhythmias (40%), heart failure (27%), pericardial effusions (19%), and cardiac events (13%). This distribution and severity of toxicity was comparable between groups. Similarly the cumulative incidence of cardiac toxicity was comparable between the PTCy and non-PTCy groups (7 vs. 6%, p=0.4). Predictors of cardiac toxicity are shown in table 1. In univariate analysis, the cardiac comorbidity composite (defined as the presence of arrhythmia, cardiac, or heart valve comorbidities obtained via HCT-CI score) was found to be the most significant predictor for the development of cardiac toxicity (p In multivariate analysis, the cardiac comorbidity composite maintained significance and this effect was augmented by the presence of diabetes and infection. Patients with the cardiac comorbidity composite who also had diabetes or infection had the highest incidence (37%, p Conclusion Our results demonstrate a low incidence of cardiac toxicity. Baseline cardiac comorbidities are associated with higher incidence of developing cardiac toxicities after Allo-HCT. PTCy-based GVHD prophylaxis does not appear to impact the development of cardiac toxicities after HLA-matched Allo-HCT and may be associated with survival benefit in patients who do experience toxicity.

Introduction Multiple myeloma (MM) remains incurable with only a small proportion of patients (pts) surviving over 10 years (long-term survivors). It has been over 3 decades since the first autologous stem cell transplantation (ASCT) was done for MM at the University of Texas MD Anderson Cancer Center (MDACC). We sought from this study to describe patient and disease characteristics of long-term MM survivors after ASCT. Methods We included consecutive pts who underwent their first ASCT at MDACC between January 1988 and December 2015. The primary objective was to assess and compare baseline characteristics and predictive factors for long-term vs short-term (died within10 years from diagnosis) MM survivors. We excluded MM survivors with 10 years were assessed by logistic regression models. Results Among 2176 pts who underwent their first ASCT during the study period, 1409 pts met the eligibility criteria of which 392 (28%) were long-term survivors and 1017 (72%) were short-term survivors. Only 24 and 43% of pts in the long-term and short-term survivor groups received proteasome inhibitor-based induction. Compared to short-term survivors, higher percentage of pts in the long-term survivor group were younger 10 years (Table). ISS Stage III (OR 0.45, 95% CI 0.19-1.05; p=0.08) showed a trend towards shorter OS. Maintenance treatment was not significantly associated with surviving > 10 years. Median follow-up from diagnosis for the long-term survivor group was 13 years (10-30 years); among this group, the 15-year PFS rate was 19% (95% CI 14% - 23%) and the 15-year OS rate was 62% (95% CI 56% - 68%) (Figure 1). The cumulative incidence rates of relapse at 1, 3, and 5 years in the short-term survival group were 9%, 63%, and 82%, respectively, compared to 2%, 20%, and 40%, respectively, in the long-term survivor group (p Conclusions ASCT is associated with durable responses and prolonged survival in a subgroup of MM pts irrespective of type of induction therapy and/or use of maintenance therapy. Duration of remission after transplant is the strongest predictor for long-term survival. Age

Background Older patients undergoing allogeneic stem cell transplant (SCT) have inferior outcomes. They have limited physiological reserves, which makes them more susceptible to toxic effects of conditioning regimens. Supportive care directed at maintaining and augmenting their limited functional reserve may reduce non-relapse mortality (NRM). We studied impact of a multidisciplinary supportive care and prehabilitation program (ER-SCT) and compared one-year NRM with a historical control group. Methods Between 1/1/15 and 9/30/18, 204 patients ≥ 65 years old underwent allogeneic SCT at our institution. ER-SCT program started on 10/1/17 and 57 of 64(89%) eligible patients participated during the first year. All 64 patients were included in the ER-SCT cohort, while patients treated between 1/1/15-9/30/17 were in the control group. ER-SCT program consisted of a prehabilitation phase prior to admission. Patients were evaluated by a multidisciplinary team consisting of a geriatrician, physical medicine and rehabilitation physician, physical therapist, occupation therapist, dietician, nurse, and a pharmacist specializing in SCT. Preexisting chronic conditions were optimized and recommendations were made for nutrition, exercise, and coping strategies. During hospitalization, fluid usage and medication choice / doses were optimized for older patients to prevent side effects such as fluid overload and delirium. Physical therapy, occupational therapy and nutrition counselling was continued. The team continued to follow and intervene as needed after discharge from the hospital. Results Median age was 68 (65-79) with 36 (18%) patients >than 70 years. Diagnoses included AML 96 (47%), MDS 57(28%), MPD 26 (13%), ALL 8(4%), and other 17 (8%). 103 (51%) had high or very high disease risk index (DRI). HCT-CI score was >3 in 80 (39%). Donor types included 127 (62%) matched unrelated, 57(28%) matched related and 20(10%) haploidentical. The NRM at 1 year was 13% in ER-SCT cohort vs 26% (p=0.03) in the control cohort. Multivariate analysis adjusting for GVHD prophylaxis and conditioning regimen, age, DRI, HCT-CI, donor type and graft source showed that ER-SCT HR=0.4 (0.2-0.9, P=0.02), comorbidity score Conclusion Although the data from this retrospective sequential cohort analysis cannot be conclusive, they do suggest that a multidisciplinary supportive care program (ER-SCT) may reduce NRM in older patients undergoing allogeneic SCT.

The gain/amplification of the CKS1B gene on chromosome 1q21 region is associated with a poor outcome in patients with multiple myeloma (MM). However, there are limited data on the outcome of patients with CKS1B amplification after a single high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT). We retrospectively evaluated the outcome of patients with CKS1B amplification who received an auto-HCT between June 2012 and July 2014 at our institution. We identified 58 patients with MM and CKS1B gene amplification detected by fluorescent in situ hybridization (FISH). We compared their outcomes with a propensity score–matched control group of 58 patients without CKS1B amplification who were treated at approximately the same time. The primary objective was to compare the progression-free (PFS) and overall survival (OS) between the CKS1B and the control groups. Stratified log-rank test with the matched pairs as strata and double robust estimation under the Cox model were used to assess the effect of CKS1B gene amplification on PFS or OS in the matched cohort. Patients in the CKS1B and control groups were well matched for age, gender, disease status, year of auto-HCT, response to pretransplantation therapy, and baseline hemoglobin level. In both groups, 57% patients were in first remission and 43% had relapsed disease at auto-HCT. Twenty-seven (47%) patients with CKS1B amplification had concurrent monosomy 13 or 13q deletion; 6 (10%) by conventional cytogenetics only, 16 (28%) by FISH only, and 5 (9%) by both. Median follow-up after auto-HCT was 25.4 months. The median PFS of the CKS1B and the control groups were 15.0 months and 33.0 months (P = .002), respectively. The median OS have not been reached yet. The 2-year OS rates in the CKS1B and the control groups were 62% and 91% (P = .02), respectively. In conclusion, Patients with CKS1B amplification are more likely to have additional high-risk cytogenetic abnormalities and a shorter PFS and OS after an auto-HCT.

Allogeneic stem cell transplantation is an effective treatment for high-risk myeloid malignancies, but relapse remains the major post-transplantation cause of treatment failure. Alloreactive natural killer (NK) cells mediate a potent antileukemic effect and may also enhance engraftment and reduce graft-versus-host disease (GVHD). Haploidentical transplantations provide a setting in which NK cell alloreactivity can be manipulated, but they are associated with high rates of GVHD. We performed a phase I study infusing escalating doses of NK cells from an HLA haploidentical-related donor-selected for alloreactivity when possible-as a component of the preparative regimen for allotransplantation from a separate HLA-identical donor. The goal of infusing third-party alloreactive NK cells was to augment the antileukemic effect of the transplantation without worsening GVHD and, thus, improve the overall outcome of hematopoietic transplantation. Twenty-one patients with high-risk acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or chronic myelogenous leukemia refractory or beyond first remission received a preparative regimen with busulfan and fludarabine followed by infusion of apheresis-derived, antibody-selected, and IL-2-activated NK cells. Doses were initially based on total nucleated cell (TNC) content and later based on CD56(+) cells to reduce variability. CD56(+) content ranged from .02 to 8.32 × 10(6)/kg. IL-2, .5 × 10(6) units/m(2) subcutaneously was administered daily for 5 days in the final cohort (n = 10). CD3(+) cells in the NK cell product were required to be 10(5)/kg. Median relapse-free, overall, and GVHD-free/relapse-free survival for all patients enrolled was 102, 233, and 89 days, respectively. Five patients are alive, 5 patients died of transplantation-related causes, and 11 patients died of relapse. Despite the small sample size, survival was highly associated with CD56(+) cells delivered (P = .022) and development of ≥ grade 3 GVHD (P = .006). There were nonsignificant trends toward higher survival rates in those receiving NK cells from KIR ligand-mismatched donors and KIR-B haplotype donors. There was no association with disease type, remission at time of transplantation, or KIR content. GVHD was not associated with TNC, CD56(+), or CD3(+) cells infused in the NK cell product or the stem cell product. This trial demonstrates a lack of major toxicity attributable to third-party NK cell infusions delivered in combination with an HLA-compatible allogeneic transplantation. The infusion of haploidentical alloreactive NK cells was well tolerated and did not interfere with engraftment or increase the rate of GVHD after allogeneic hematopoietic transplantation. Durable complete remissions occurred in 5 patients at high risk for disease recurrence. This approach is being further developed in a phase I/II trial with ex vivo-expanded NK cells to increase the NK cell dose with the objective of reducing relapse and improving the outcome of allogeneic hematopoietic transplantation for AML/MDS.

PURPOSE: The recovery pace of absolute lymphocyte count (ALC) is prognostic after hematopoietic stem cell transplantation (SCT). Previous studies have evaluated a wide range of ALC cutoffs and time points to predict outcomes. We aimed to determine the optimal ALC measure for outcome prediction after SCT from bone marrow grafts (BMT). METHODS: 518 patients who underwent BMT for acute leukemia or myelodysplastic syndrome between 1999 and 2010 were divided into training and test sets to assess the prognostic values of ALC on days 30, 60, 90, 120, 180, as well as, the first post-transplant day on which a patient achieved ALC of 100, 200, 300, 400, 500, and 1000/μL. RESULTS: In the training set, the best predictor of overall survival (OS), relapse-free survival (RFS), and non-relapse mortality (NRM) was ALC on day 60. In the whole patient cohort, multivariable analyses demonstrated significantly better OS, RFS, NRM, and lower incidence of graft-versus-host disease among patients with ALC >300/μL on day 60, both including and excluding patients who had developed graft-versus-host disease prior to day 60. Among the patient-, disease-, and transplant-related factors assessed, only busulfan-based conditioning was significantly associated with higher ALC counts on day 60 in both cohorts. CONCLUSION: The optimal ALC cutoff to predict outcomes after BMT is ALC of 300/μL on day 60 post-transplant.

Background Fluid overload (FO) grade ≥ 2 (more that 10% weight gain from baseline) has recently been recognized as an important toxicity associated with non-relapse mortality in recipients of allogeneic stem cell transplantation (alloSCT).1 The causes for fluid accumulation remain unclear. We hypothesized that endothelial damage due to treatments received prior to alloSCT may be associated with this toxicity and sought to determine whether the Endothelial Activation and Stress Index2 (EASIX), (defined as lactate dehydrogenase (U/L) × creatinine (mg/dL)/ thrombocytes (109 cells per L), correlates with grade ≥ 2 FO and overall survival (OS) in 2 cohorts of recipients of alloSCT at our institution. The first cohort included 145 recipients of haploidentical (haplo) transplantation, and the second 449 recipients of alloSCT from HLA-matched donors, as previously described.1 Methods Predictors (listed in table) of grade ≥ 2 FO and 6-months OS were evaluated using Cox's proportional hazards regression analysis on univariate analysis, and classification and regression tree (CART) analysis on multivariate (MV) analysis. EASIX scores were evaluated based on log2 transformed values. Results Median log2 EASIX score in the 2 cohorts was 2.4 (IQR: 1.3, 3.7) and 2.5 (IQR 1.4, 3.9) at admission, and 3.1 (IQR 2.2, 3.9) and 2.8 (IQR 1.7, 3.9) at transplant, respectively. CART analysis identified EASIX > 4.4 at admission to be an independent predictor of grade ≥ 2 FO in the haplo (HR=7.5, p 55 years recipients in the haplo cohort, and diabetes (HR=35, p=0.001) and age >60 years (HR=8.1, p=0.06) in the matched cohort. In patients with grade ≥ 2 FO, EASIX >4.4 at SCT was the only significant predictor of OS (HR=4.1, p=0.002). This effect was consistent in both cohorts (Figure A). In patients with grade 0-1 FO, MV analysis showed EASIX >3, comorbidity index score >3, and active disease at SCT to be independent adverse predictors of OS. OS was lowest (60%, reference) in patients with EASIX> 3 and comorbidity score >3, and this effect was consistent in both cohorts (Figure B). OS was significantly higher in patients with EASIX >3 and comorbidity score ≤3 (73%, p

Background Post transplant cyclophosphamide (PTCy), tacrolimus, and MMF GvHD prophylaxis makes transplantation from haploidentical donors feasible without T cell depletion. In matched donor transplant recipients, cumulative incidences of grades II-IV acute, grades III-IV acute, and chronic GVHD were 51%, 15%, and 14%, respectively when single agent PTCy was used (Kanakry et al JCO 2014 32:3497-3505). However; as a single agent it was inferior to tacrolimus and methotrexate in another study (Alousi etal BBMT 2015, 906-912). We therefore hypothesized that addition of tacrolimus to PTCy may be needed to prevent severe acute GVHD and improve transplant outcomes. Methods All patients with AML undergoing first allogeneic transplant from matched sibling or at least 9/10 matched unrelated donor between 1/1/2011 to 4/30/2018 were eligible for this retrospective study if they received a melphalan or timed sequential busulfan (course AUC 20,000 umol/min) based conditioning regimen. GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on day 1, 3, 6, and 11 in the Tac/MTX cohort (n=140); and cyclophosphamide 50mg/kg given on days 3 and 4 and tacrolimus in the PTCy cohort (n=76). Results Patient characteristics were similar in both cohorts except that patients in PTCy cohort were younger with a median age of 59 years versus 63.5 years (P Outcomes and results of univariate analysis are summarized in Table1. Conclusion Tacrolimus and PostCy based GVHD prophylaxis reduces severe GVHD and improves survival.

Background At our center, we observed a series of patients who developed transudative refractory ascites secondary to non-cirrhotic non-veno-occlusive disease (NC-nVOD) portal hypertension after allogeneic transplant (allo-SCT). The natural history, pathogenesis and etiology of this phenomenon is not well characterized nor well studied in the literature. Objectives To study and analyze the clinical characteristics and outcome of myeloid and lymphoid malignancy patients who developed IPHRA post allo-HCT. Methods In this retrospective study, we analyzed age>18 myeloid and lymphoid malignancy patients who developed IPHRA post allo-HCT. IPHRA was defined as NC-nVOD intrahepatic portal hypertension (serum ascites albumin gradient ≥ 1.1 or hepatic venous pressure gradient (HVPG) >5) and related refractory ascites in the absence of pre and post-hepatic etiologies of portal hypertension. Results We identified 24 patients who developed IPHRA post allo-HCT from our database. Median age at the time of allo-HCT was 52 yrs (range, 23-67). 23/24 did not have elevated LFT (Transaminases> 2.5 ULN/Bilirubin>1.5 ULN) before allo-HCT. Median time to development of IPHRA after allo-HCT was 95 days (range, 21-576 days). A median number of paracentesis that these patients had was 2 (range, 1-11); 5 had an intraperitoneal catheter placed, and 2 had TIPS to decrease the portal pressure. Portal pressures were measured in 15 patients, 9 had moderate portal hypertension (HVPG 5-10), and 6 had severe portal hypertension (HVPG >10). Liver biopsy was done in 20 patients, and for 3 patients we had autopsy results available. None of the patients met either the histological or clinical criteria of VOD or cirrhosis. 19 patients (79 %) died, and the median survival after development of IPHRA was 5.2 months (range, 0.7-49). The most common cause of death were complications of ascites/liver failure (n=7, 37%), and infectious causes (n=7, 37%). Conclusion IPHRA is an unrecognized fatal entity post-allo-HCT and has a high mortality rate. Further investigation is necessary to establish prognostic criteria for patients at risk of this serious complication.

Background The cell of origin (COO) classification has been shown to predict survival outcomes in de-novo diffuse large B-cell lymphoma (DLBCL), however, it is unclear if this holds true following high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in relapsed DLBCL patients. The current analysis aims to compare survival outcomes based on COO classification in relapsed DLBCL patients who received auto-HCT. Methods This retrospective study includes relapsed/refractory DLBCL patients, aged 18 and above, who received auto-HCT with standard of care conditioning from January 2007 to December 2016 at our institution. Hans algorithm using CD10, BCL6 and MUM1 markers was performed to classify patients as per COO into the GCB and non-GCB types. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Results A total of 122 DLBCL (71 GCB, 51 non-GCB) patients were analyzed. Detailed patient characteristics are provided in Table 1. Except for GCB cohort being older (64 vs. 58 years, p 70 (HR=2.9, p=0.03) and IPI score 0 (HR=0.3, p=0.005) were significant variables in predicting PFS. After adjusting for these variables, no significant differences were seen in PFS between two groups. The median OS has not yet been reached in both groups therefore a difference in OS cannot be analyzed. Conclusion Our results suggest that cell of origin is not prognostic for patients with relapsed/refractory DLBCL treated with high dose chemotherapy followed by auto-SCT.

Introduction Graft-versus-host disease (GVHD) of the lung, also known as bronchiolitis obliterans syndrome (BOS), is associated with high mortality, but treatment with the combination of fluticasone, azithromycin, and montelukast (FAM) stabilizes lung function in the majority of patients. Recently, a randomized controlled trial evaluating azithromycin given at the time of conditioning for GVHD prevention was closed prematurely due to an increased risk of cancer relapse in azithromycin recipients. We evaluated whether exposure to azithromycin after allogeneic hematopoietic cell transplantation (allo-HCT), primarily for treatment of BOS, was also associated with a higher rate of cancer progression. Methods We conducted a retrospective study of patients who underwent allo-HCT and experienced a significant decline in pulmonary function from pre-HCT values (decrease in forced expiratory volumes in 1 second of ≥10% OR mid-flow rates of ≥25%) between 2005 and 2015. Risk factors for cancer progression were examined using cause-specific univariate and multivariate Cox regression analysis with azithromycin exposure evaluated as a time-dependent covariate. Results Among 672 eligible allo-HCT recipients with pulmonary decline, 9% (n=63) received azithromycin, including 41 patients for BOS and 22 patients for chronic treatment for mycobacterial infection or bacterial prophylaxis. Table 1 shows characteristics of the entire study cohort. No patients with chronic lymphocytic or myeloid leukemia (n=13) or lymphoma (n=12) who were exposed to azithromycin experienced cancer progression during the study period. Therefore, we evaluated the impact of azithromycin exposure on the rate of cancer progression in the subset of patients with acute myeloid leukemia or myelodysplastic syndrome (AML/MDS, n-327) or acute lymphoblastic leukemia (ALL, n=91). The median follow-up since allo-HCT in this subgroup was 73 months (range 5-148 months). 38 of these patients were exposed to azithromycin at a median time of 25 months (interquartile range 11-46 months) after allo-HCT. In multivariate analysis, azithromycin (HR 3.7, 95% CI 1.5-9.4, p=0.005) and unfavorable cytogenetics (HR 1.7, 95% CI 1.2-2.5, p=0.004) were associated with increased rates of cancer progression. Median time to cancer progression from time of allo-HCT was 8 months (range 1-98 months) for the entire cohort, while the median time to cancer progression was later in those exposed to azithromycin (median 21 months, range 4-25 months). The median time to cancer progression after exposure to azithromycin was 51 days (range 17-847 days). Conclusion Our findings show that recipients of allo-HCT for treatment of AML/MDS or ALL, exposure to azithromycin for BOS or infections is associated with an increased rate of cancer progression.

Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation.

We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate-I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age ≥ 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/−5 and abnl(17p) had the worse transplant outcomes, with 3-year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes.

We studied the roles of autologous (A) and allogeneic (allo) stem cell transplantation (SCT) in the treatment of 134 patients with T cell lymphoma (TCL) at our center. For frontline SCT, 58 patients were studied. The 4-year overall survival (OS) rates for ASCT (n = 47; median age, 49 years) and alloSCT (n = 11; median age, 55 years) groups were 76% and 54%, respectively (P > .05). The 4-year OS rates for first complete remission (CR1) patients were 84% and 83%, respectively. For SCT for relapsed disease, 76 patients were studied (41 with ASCT and 35 with alloSCT). The 4-year OS rates were 50% and 36% for ASCT and alloSCT patients with chemosensitive disease, respectively (P > .05). Those who were in CR2 and CR3 had 4-year OS rates of 59% and 53%, respectively. Similar results were also observed in patients with refractory disease (29% and 35%, respectively). These data suggest that a pre-SCT CR is associated with improved outcomes in TCL patients after SCT. Considering the 84% 4-year OS rates in CR1 patients and the unpredictable responses in patients with relapsed disease, we favor the use of ASCT as consolidation therapy after CR1. AlloSCT did not result in a superior outcome compared with ASCT.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been performed primarily with an HLA-matched donor. Outcomes of haploidentical transplantation have recently improved, and a comparison between donor sources in a uniform cohort of patients has not been performed. We evaluated outcomes of 227 patients with AML/MDS treated with melphalan-based conditioning. Donors were matched related (MRD) (n = 87, 38%), matched unrelated (MUD) (n = 108, 48%), or haploidentical (n = 32, 14%). No significant differences were found between haploidentical and MUD transplantation outcomes; however, there was a trend for improved outcomes in the MRD group, with 3-year progression-free survival for patients in remission of 57%, 45%, and 41% for MRD, MUD, and haploidentical recipients, respectively (P = .417). Recovery of T cell subsets was similar for all groups. These results suggest that haploidentical donors can safely extend transplantation for AML/MDS patients without an HLA-matched donor. Prospective studies comparing haploidentical and MUD transplantation are warranted.

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.

Background High-dose melphalan 200 mg/m2 (Mel200) is the standard preparative regimen for multiple myeloma (MM). Reduced-dose melphalan 140 mg/m2 (Mel140) is frequently used as an alternative for older patients (pts), or those at higher risk of toxicity. There is conflicting data regarding the efficacy of Mel140 compared to Mel200. A recent report by EBMT suggested no survival advantage for Mel200 vs Mel140 except for a subset of pts with pretransplant suboptimal response to induction therapy. Objectives To assess treatment outcomes for MM pts who underwent ASCT by Mel200 vs Mel140. Methods Patients with newly diagnosed MM who underwent frontline ASCT using single agent melphalan conditioning regimen were included. To correct for potential bias in the melphalan dose comparisons, propensity score analysis was used for matching (by age, ISS, cytogenetic risk status, serum creatinine, induction and maintenance therapy), within response to induction at ASCT (PR or less vs VGPR or better). Primary endpoints were PFS and OS. Secondary endpoints included cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM). Results A total of 1628 consecutive pts were identified during study period; 1525 (94%) received Mel200 and 103 (6%) received Mel140. Propensity score matching resulted in 3:1 matches for a total of 312 pts (234 in the Mel200 group and 78 in the Mel140 group). The majority of pts were older with a median age of 69.6 (range: 43.3 – 80.6) years. For all matched pts, there was a statistically significant OS advantage for Mel200 with a HR of 0.46 (95% CI: 0.26, 0.80; P=0.006), but no significant differences in PFS (HR 0.87; 95% CI: 0.58, 1.31; P=0.51), CIR (HR 0.96; 95% CI: 0.66, 1.39; P=0.83) or NRM (HR 0.57; 95% CI: 0.22, 1.49; P=0.25). In pts with VGPR or better, PFS, OS, CIR, and NRM were not significantly different between the Mel200 (n=111) and Mel140 (n=37) groups. However, for pts with PR or less, there was significantly better OS for Mel200 (n=123) compared to Mel140 (n=41) (HR 0.39; 95% CI: 0.19, 0.82; P=0.013), but no significant differences in PFS, CIR, or NRM. The adjusted 3-year PFS with Mel200 and Mel140 for the matched pts were 13% and 14% (P=0.25), respectively, and adjusted 3-year OS were 67% and 46% (P=0.007). Additionally, multivariable regression models were fit using all the data adjusting the models with the same measures that were used in the matching. The results and conclusions between the two methods were consistent. Conclusion Mel200 remains standard of care with superior survival in patients with PR or worse, however Mel140 is a suitable alternative for patients in VGPR or better. Depth of response prior to transplantation is a strong predictor for selecting melphalan dose intensity and treatment outcomes. Our findings highlight the importance of improving remission status prior to transplant. Prospective randomized trials are needed to define the optimal melphalan dose.

This study was conducted to retrospectively compare the clinical outcomes after transplantation of T cell–depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N = 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)+thiotepa+fludarabine; HFTBI+thiotepa+cyclophosphamide; or i.v. busulfan+melphalan+fludarabine. TCD was performed by 1 of 2 immunomagnetic CD34+ cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood cell–rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N = 181) after conditioning with busulfan+fludarabine and GVHD prophylaxis with tacrolimus+mini-methotrexate. Patients with unrelated or human leukocyte antigen–mismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P = not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD.

More active high-dose chemotherapy (HDC) regimens are needed for refractory Hodgkin's lymphoma (HL). We report a cohort analysis of 180 consecutive patients with primary refractory or poor-risk relapsed HL treated with busulfan-melphalan (Bu-Mel) (n = 39), gemcitabine-busulfan-melphalan (Gem-Bu-Mel) (n = 84), or BEAM (BCNU, etoposide, ara-C, melphalan; n = 57) between 2005 and 2010. Their pre-HDC positron emission tomography (PET) scans were interpreted prospectively. Despite more prevalent poor-risk features in the Gem-Bu-Mel cohort, such as PET-positive tumors at HDC, tumors growing at HDC, extranodal disease, or bulky tumors at prior relapse, this cohort had improved outcomes compared with the Bu-Mel and BEAM cohorts, with event-free survival (EFS) rates of 57%, 33%, and 39%, respectively (P = .01), at median follow-up of the whole population of 36 months (range, 3 to 72). Their respective overall survival (OS) rates were, respectively, 82%, 52%, and 59% (P = .04). Secondary acute myelogenous leukemia was seen in 5 patients after BEAM but was not seen in Gem-Bu-Mel and Bu-Mel cohorts (P = .004). Multivariate analyses showed independent adverse effects of an HDC regimen different from Gem-Bu-Mel (hazard ratio [HR] for EFS = 2.3, P = .0008; HR for OS = 2.7, P = .0005), positive PET at HDC (HR for EFS = 2.2, P = .004, HR for OS = 3.1, P = .0001), and >1 previous salvage line (HR for EFS = 1.9, P = .008, HR for OS = 1.8, P = .07). Gem-Bu-Mel improved outcomes in this cohort analysis of patients with refractory/poor-risk relapsed HL and merits evaluation in randomized phase III trials.

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT. With median follow-up of 5 years among survivors (range: 1.1-20.4 years), overall survival (OS) was significantly better for patients transplanted in first remission compared with HSCT in advanced disease: 43% versus 16%, P = .002. Disease stage and age at time of HSCT, the development of acute graft-versus-host disease (aGVHD), and decade of HSCT were found to significantly impact OS, progression-free survival (PFS), and nonrelapse mortality (NRM) in multivariate analyses. Allogeneic HSCT provides durable remission for patients with Ph+ ALL in first remission. Neither TKI use pre- nor post-HSCT were found to significantly impact transplant outcomes in univariate and multivariate analyses.

Complete remission (CR) is the gold standard for assessing outcomes following chemotherapy for acute myelogenous leukemia (AML). "CRp," a response criterion defined as fulfillment of all criteria for CR except platelet count recovery to ≥100 × 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo-SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and ≥CR2) and 78 in CRp (CR1p and ≥CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or ≥CR2) compared with CRp (CR1p or ≥CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT.

BK virus (BKV) is a human polyomavirus which remains latent in the urinary tract epithelium in most individuals. However, in immunocompromised states, including post hematopoietic stem cell transplantation (HSCT), BKV may reactivate and cause infection, predominantly affecting the bladder, commonly manifested as hemorrhagic cystitis. Renal insufficiency, occasionally requiring hemodialysis, is not uncommon, and was previously attributed to medications or the development of tubulointestitial nephritis. We report a series of 6 HSCT recipients who developed obstructive uropathy of the upper urinary tract system secondary to inflammation and hemorrhage involving the upper uroepithelium, causing ureteral stenosis. Temporary percutaneous nephrostomy catheter placement relieved the obstruction and improved significantly the kidney function, successfully preventing progression to more advanced renal disease in these patients.

Alternative donor stem cell transplantation from cord blood or haploidentical peripheral blood donors is increasingly being used for patients who lack a matched related or unrelated donor. A higher nonrelapse mortality (NRM) rate has been noted with these 2 types of transplants, primarily because of infectious complications. Here, we hypothesized that the time to lymphocyte recovery (absolute lymphocyte count [ALC] of ≥ 1000/μL for the first 3 consecutive days) after transplant correlates with outcomes. We retrospectively analyzed 65 consecutive patients treated at our institution with cord blood (n = 37) and haploidentical (n = 28) transplantation with myeloablative fludarabine, melphalan, and thiotepa conditioning. Patients with lymphocyte recovery at day 60 posttransplant were more likely to survive long term than those without lymphocyte recovery. In multivariate analysis, ALC recovery was the only independent prognostic factor associated with mortality; patients without ALC recovery were 10.5 times (95% confidence interval [CI]: 4.3–25.4) more likely to die than those with ALC recovery (P < .0001). This difference appeared to be related to NRM (hazard ratio [HR] =0.1, 95% CI: 0.02–0.6, P = .008), whereas ALC recovery did not influence the rate of disease relapse. These results suggest that ALC recovery is an important prognostic indicator for patients treated with cord blood and T cell–depleted peripheral haploidentical transplants.

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted.

Nonrelapse mortality (NRM) after reduced-intensity allogeneic transplants is likely to be influenced by abnormalities in renal function. We studied 141 patients diagnosed with acute myelogenous leukemia (AML) (n = 131) or high-risk myelodysplastic syndrome (MDS) (n = 10) who underwent allogeneic transplantation with fludarabine (Flu)/melphalan (Mel)-based regimens and hypothesized that moderate to mild renal function impairment increases NRM in this setting. Flu dose consisted of 25-30 mg/m2 for 4 days and Mel dose was 100-180 mg/m2. Donors were HLA-compatible siblings (n = 69) and matched unrelated donors (n = 72). Disease status at transplantation was complete remission (n = 56, 40%) or active disease (n = 85, 60%). The influence of the estimated glomerular filtration rate (GFR) measured before transplantation on outcomes was analyzed. GFR was estimated by both the Cockcroft-Gault (CG) and the modified diet in renal disease (MDRD) equations, using the creatinine value obtained prior to starting chemotherapy. Evaluated outcomes were overall survival (OS), NRM, and treatment-related mortality (TRM) at day 100 and 1-year posttransplantation. Median age was 55 years (range: 21-74 years); 59% of the patients were male. Estimated GFR by CG was ≥90 for 45 (32%), 60-89 for 78 (55%), and .05). There were no differences in OS and NRM at day 100 and 1-year posttransplantation in the 3 groups by any GFR estimation method. In conclusion, a mild to moderate decrease in GFR was not associated with an increase in NRM.

The purpose of this study was to determine the effect of alemtuzumab on treatment-related mortality (TRM), relapse, overall survival (OS), and disease-free survival (DSF) in patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) undergoing reduced intensity conditioning (RIC). We compared the outcome of 95 patients treated at the University of Chicago with fludarabine melphalan (Flu + Mel) + alemtuzumab conditioning and 59 patients treated at the M.D. Anderson Cancer Center with Flu + Mel conditioning. Both groups had similar patient and donor characteristics. There were no significant differences in TRM, relapse, survival, and DFS between the 2 groups. The incidence of acute graft-versus-host disease (aGVHD) grade II-IV (relative risk [RR] 5.5, P < .01) and chronic GVHD (cGVHD) (RR 6.6, P < .01) were significantly lower in patients receiving alemtuzumab. The addition of alemtuzumab to an RIC regimen dramatically reduces the incidence of aGVHD and cGVHD in patients with AML and MDS undergoing allogeneic transplantation. TRM, relapse risk, OS and DFS are not affected.

In this study, we evaluated the influence of nonmyeloablative and ablative conditioning regimens on the occurrence of acute and chronic graft-versus-host disease (GVHD). One hundred thirty-seven patients undergoing matched-related sibling transplantations received the same GVHD prophylaxis. Myeloablative regimens included intravenous busulfan/cyclophosphamide (n = 45) and fludarabine/melphalan (n = 29). Patients in the nonmyeloablative group (n = 63) received fludarabine/idarubicin/cytarabine, cisplatin/fludarabine/idarubicin, and fludarabine/cyclophosphamide. The actuarial rate of grade II to IV acute GVHD was significantly higher (hazard ratio, 3.6; 95% confidence interval, 1.5–8.8) in patients receiving ablative regimens (36%) compared with the nonmyeloablative group (12%). The cumulative incidence of chronic GVHD was higher in the ablative group (40%) compared with the nonmyeloablative group (14%). The rates were comparable within the first 200 days and were significantly higher in the ablative group beyond day 200 (hazard ratio, 5.2; 95% confidence interval, 1.2–23.2). Nonrelapse and GVHD-related mortality were relatively low in both groups. The use of the described nonmyeloablative preparative regimens was associated with a reduced incidence of grade II to IV acute GVHD and chronic GVHD compared with the busulfan/cyclophosphamide and fludarabine/melphalan transplant regimens. It is interesting to note that nonrelapse mortality with nonmyeloablative regimens in older and more debilitated patients was low (14%) and comparable to that achieved with standard high-dose regimens in younger patients

This phase I/II dose-escalation study examined the safety and efficacy of recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF) for postchemotherapy mobilization of peripheral blood progenitor cells (PBPCs) in patients with advanced breast cancer. Patients received cyclophosphamide, etoposide, and cisplatin (CVP) followed by G-CSF (6 microg/kg twice a day) and rhTPO (0.6, 1.2, 2.4, or 3.6 microg/kg as a single dose on day 5 or as 3 doses on days 5, 7, and 9 after chemotherapy). PBPCs were collected by daily leukapheresis when the postnadir white blood cell count reached > or = 2 x 10(9)/L; leukapheresis was continued until acquisition of a target dose of > or = 5 x 10(6) CD34+ cells/kg. Mobilized PBPCs were transplanted into patients after additional high-dose chemotherapy with cyclophosphamide, carmustine, and thiotepa (CBT). Comparisons were made with contemporaneously treated, nonrandomized, control patients who received the same chemotherapy regimens and G-CSF support but who did not receive rhTPO. Of 32 evaluable patients receiving rhTPO and G-CSF after CVP, 91% required only 1 leukapheresis to achieve a target PBPC graft; by contrast, only 69% of 36 of the control patients achieved the target graft with just 1 leukapheresis (P = .026). A median of 26.7 x 10(6) CD34 cells/kg per leukapheresis was obtained from the rhTPO-treated patients compared with 11.5 x 10(6) cells/kg per leukapheresis from the controls (P = .09). Higher rhTPO doses appeared to yield more CD34+ cells. When PBPCs were infused after high-dose CBT chemotherapy, the median times to return of an absolute neutrophil count of 0.5 x 10(9)/L and a platelet count of 20 x 10(9)/L were 15 and 16 days, respectively; these values did not differ from those in the control group (15 days for both neutrophil and platelets). No patient developed anti-TPO antibodies. These results indicate that rhTPO safely and effectively augments the number of PBPCs mobilized with chemotherapy and G-CSF and can reduce the required number of leukaphereses. Further studies are also warranted in patients who are likely to experience suboptimal PBPC mobilization when treated with currently available techniques.Biol Blood Marrow Transplant 2002;8(10):550-6.