Factors Associated With Upstaging of Melanoma Thickness on Final Excision.

INTRODUCTION: The incidence and risk factors associated with upstaging from initial biopsy to definitive excision in cutaneous melanoma have not been established. The aim of this study was to determine the incidence of tumor stage upstaging and associated risk factors using the National Cancer Database. METHODS: A retrospective study of the National Cancer Database between 2012 and 2016 was performed. The cohort of patients undergoing excision of melanoma with available data comprised 133,592 patients. Differences in characteristics for upstaging were determined using Wilcox rank-sum, chi-square, or Fisher's exact tests. Multivariable analysis was performed using logistic regression to determine factors associated with upstaging. RESULTS: Incidence of upstaging was 5.2%. Upstaged patients were older, male, of non-White race, and of lower education level (P < 0.001). Lesions of the head/neck and lower extremity had increased incidence of upstaging compared to the trunk (P < 0.001). Nodular and acral lentiginous melanoma was associated with higher incidence of upstaging compared to superficial spreading melanoma (P < 0.001). Patients with lymphovascular invasion had increased risk of upstaging (P < 0.001). CONCLUSIONS: Upstaging of melanoma is infrequent but is significantly more prevalent in non-White patients and those with lower educational status. Provider and patient education should include the higher risk of upstaging in these groups and the possible need for further surgical intervention, such as re-excision of margins and sentinel lymph node biopsy.

Real-world evaluation of the impact of two anti-SARS-CoV-2 monoclonal antibody regimens on COVID-19 hospitalizations in older adults.

Evidence from clinical trials suggest anti-SARS-CoV-2 monoclonal antibodies (mABs) may reduce coronavirus disease 2019 (COVID-19)-related hospitalizations. The purpose of this study was to assess the real-world impact of mAB administration on COVID-19 hospitalization among patients 65 years or older. This was a retrospective, propensity-matched cohort study that included patients aged 65 years and older who presented to the emergency department (ED) within 10 days of symptom onset of mild to moderate COVID-19 infection. Outcomes were compared between those who did and did not receive mAB therapy. The primary endpoint was the rate of hospitalization for COVID-19 within 30 days of index ED visit. A total of 137 patients receiving mABs were matched to 137 controls. Hospitalization occurred in 2.9% of mAB-treated patients compared to 14.6% of patients of the standard of care (SOC) arm (odds ratio: 0.20 [95% CI: 0.07-0.59]). There were zero intubations and zero deaths compared to 3 (2.2%) and 2 (1.5%) in the SOC group. Among the 223 patients receiving mAB in the overall cohort, adverse drug events occurred in 10 (4.5%). Treatment with mAB therapy for mild to moderate COVID-19 was associated with a substantially reduced risk of hospitalization among patients at least 65 years of age.

Long-term Outcomes After Lung Cancer Resection in Smokers: Analysis of the National Lung Screening Trial.

BACKGROUND: Smoking is a known risk factor for perioperative complications after lung resection; however, little data exists looking at the impact of smoking status (current versus former) on long-term oncologic outcomes after lung cancer surgery. We sought to compare overall survival (OS), progression-free survival (PFS), and cancer-specific mortality (CSM) in current and former smokers using data from the National Lung Screening Trial (NLST). Additionally, we performed subset analysis in current smokers in order to evaluate the effect of modern surgical techniques on long-term outcomes. METHODS: Patients with clinical stage IA or IB NSCLC who underwent upfront resection within 180 days of diagnosis were identified in the NLST database. Cox proportional hazard regression models were used to assess differences in patient and treatment characteristics with respect to OS and PFS, with a cause-specific hazard model used for CSM. RESULTS: A total of 593 patients were included in the study (269 former smokers, 324 current smokers). Lobar resection (LR) was performed more often than sublobar resection (SLR) (481 vs. 112), and thoracotomy was performed more often than thoracoscopy (482 vs. 86). Comparison of current versus former smokers showed no difference in OS or PFS after resection. Higher CSM was seen in current smokers (p = 0.049). Subset analysis of current smokers revealed no difference in OS or PFS between sub-lobar and lobar resection or thoracotomy and thoracoscopy. Although higher CSM was associated with thoracoscopy versus thoracotomy in this group, this finding was limited by a relatively small thoracoscopy sample size of 44 patients (p = 0.026). CONCLUSION: Our analysis of the NLST database shows no significant difference in OS and PFS when comparing current and former smokers undergoing resection for stage I NSCLC. Active smoking status was associated with higher CSM. Subset analysis of current smokers showed no difference in OS or PFS between sub-lobar and lobar resection or thoracotomy and thoracoscopy. Higher CSM was seen in current smokers who underwent thoracoscopy compared to thoracotomy; however, this finding was limited by a small sample size.

Impact of postoperative complications on long-term survival after esophagectomy in older adults: A SEER-Medicare analysis.

BACKGROUND: Esophagectomy is a complex procedure associated with a high rate of postoperative complications. It is not clear whether postoperative complications effect long-term survival. Most studies report the results from single institutions. METHODS: We examined the Surveillance, Epidemiology and End Results (SEER)-Medicare database to assess whether long-term overall and cancer-specific mortality of patients undergoing esophagectomy for cancer is impacted by postoperative complications. RESULTS: Nine hundred and forty patients underwent esophagectomy from 2007 to 2014, of which 50 died, resulting in a cohort of 890 patients. Majority were males (n = 764, 85.8%) with adenocarcinoma of the lower esophagus. Almost 60% of the group had no neoadjuvant therapy. Four hundred and fifty-five patients had no major complications (51.1%), while 285 (32.0%) and 150 (16.9%) patients had one, two, or more major complications, respectively. Overall survival at 90 days was 93.1%. Multivariate analysis of patients followed up for a minimum of 90 days demonstrated that the number of complications was significantly associated with decreased overall survival but no impact on cancer-specific survival. CONCLUSIONS: Our population-based analysis with its inherent limitations suggests that patients undergoing esophagectomy who experience complications have worse overall survival but not cancer-specific survival if they survive at least 90 days from the date of surgery.

Presalvage International Staging System Stage and Other Important Outcome Associations in CD34+-Selected Allogeneic Hematopoietic Stem Cell Transplantation for Multiple Myeloma.

Despite ongoing therapeutic advances, multiple myeloma (MM) remains largely incurable, and outcomes in patients who develop resistance to immunomodulatory drugs or proteasome inhibitors remain grim. Allogeneic hematopoietic cell transplantation (alloHCT) is an alternative option that may offer potential for cure. Although rates of transplantation-related morbidity and mortality have decreased in recent years, weighing this approach's potential benefits against nontransplantation therapies demands a thoroughly informed pre-alloHCT assessment. Here we assess the impact of pre-alloHCT variables on important clinical outcomes in a large cohort of relapsed refractory MM (RRMM) CD34+-selected alloHCT recipients. We included all patients with MM who underwent CD34+-selected alloHCT at our center between June 2010 and December 2015. Patients were conditioned with busulfan (0.8 mg/kg × 10), melphalan (70 mg/m2 × 2), and fludarabine (25 mg/m2 × 5), followed by infusion of a CD34+-selected peripheral blood stem cell graft, without post-alloHCT graft-versus-host disease (GVHD) prophylaxis. The 73-patient cohort had a median age of 55 years (range, 37 to 66 years). Overall survival (OS) and progression-free survival (PFS) rates were 70% and 53%, respectively, at 1 year (95% confidence interval [CI], 58% to 79% and 41% to 64%) and 50% and 30%, respectively, at 3 years (95% CI, 38% to 62% and 19% to 41%). The cumulative incidence of relapse was 25% at 1 year (95% CI, 15% to 35%) and 47% at 3 years (95% CI, 35% to 58%). Nonrelapse mortality at 1 year was 22% (95% CI, 13% to 32%). The cumulative incidence of grade II-IV acute GVHD (aGVHD) was 7% at 100 days (95% CI, 3% to 14%), and that of any chronic GVHD (cGVHD) was 8% at 1 year (95% CI, 3% to 16%). International Staging System (ISS) stage II-III assessed before salvage therapy was associated with poorer 3-year OS (30% versus 54%; P = .037) and 3-year PFS (9% versus 33%; P = .013), and increased 3-year relapse incidence (72% versus 39%; P = .004). Older age and GVHD before 6 months (aGVHD grade II-IV or cGVHD of any grade) were also associated with poorer OS, and a greater number of pre-alloHCT lines of therapy was also associated with increased relapse incidence. Our findings reinforce that CD34+-selected alloHCT can achieve prolonged disease control and long-term survival in high- risk, heavily treated refractory MM populations. We also identified numerous pre-alloHCT variables associated with OS, PFS, and relapse. Amongst these, presalvage ISS stage II-III was consistently associated with poorer survival and relapse outcomes. Given the lack of established alternate therapies for patients with RRMM, we advocate the identification of adverse pre-alloHCT variables to inform alloHCT decision making rather than to exclude patient cohorts from this potentially curative treatment option.

Ex Vivo T Cell-Depleted Hematopoietic Stem Cell Transplantation for Adult Patients with Acute Myelogenous Leukemia in First and Second Remission: Long-Term Disease-Free Survival with a Significantly Reduced Risk of Graft-versus-Host Disease.

Large series of patients with acute myelogenous leukemia (AML) after ex vivo T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) have not been reported previously. We retrospectively analyzed the outcomes of 266 patients (median age, 54 years) with AML who received CD34-selected TCD allo-HSCTs while in first (75%) or second (25%) complete remission (CR1/CR2) at a single institution. The conditioning regimens were all myeloablative, and no additional graft-versus-host disease (GVHD) prophylaxis was given. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 180 days were 14% (95% confidence interval [CI], 10% to 18%) and 3% (95% CI, 1% to 5%), respectively. The cumulative incidence of chronic GVHD at 3 years was 3% (95% CI, 1% to 6%). The 3-year cumulative incidence of nonrelapse mortality was 21% (95% CI, 16% to 26%) and that of relapse was 21% (95% CI, 17% to 27%). Overall survival (OS) and disease-free survival (DFS) at 1, 3, and 5 years were 75%, 61%, and 56% and 68%, 57%, and 53%, respectively. There were no significant differences in OS, DFS, and relapse rates for patients who underwent transplantation in CR1 and those who did so in CR2. However, patients with high-risk cytogenetics at diagnosis had significantly poorer outcomes. The OS and DFS rates compare favorably with those for unmodified allo-HSCT, but with considerably lower rates of GVHD.

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation.

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.

Allogeneic haematopoietic cell transplantation impacts on outcomes of mantle cell lymphoma with TP53 alterations.

TP53 alterations portend extremely poor prognosis in patients with mantle cell lymphoma treated with standard treatment modalities. We reviewed outcomes of 42 patients with available TP53 status who had received a reduced-intensity or non-myeloablative allogeneic haematopoietic cell transplant at our institution. We demonstrated a 2-year overall survival and progression-free survival of 78% [95% confidence interval (CI) 60-88] and 61% (95% CI 43-75), respectively. The 2-year cumulative incidences of relapse and non-relapse mortality were 19% and 20%, respectively. Importantly, there is no significant difference among patients with and without TP53 alterations, suggesting for the first time a beneficial treatment modality for these high-risk patients.

Early Fluid Overload Is Associated with an Increased Risk of Nonrelapse Mortality after Ex Vivo CD34-Selected Allogeneic Hematopoietic Cell Transplantation.

In a recently published and validated definition of fluid overload (FO), grade ≥ 2 FO was significantly associated with an increased risk of nonrelapse mortality (NRM) after unmodified and haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) using calcineurin inhibitor (CNI)-based graft-versus-host disease (GVHD) prophylaxis. We evaluated the effect of FO on outcomes in 169 patients undergoing myeloablative-conditioned ex vivo CD34+ selected allo-HCT using the same grading scale. Thirty patients (17.8%) had grade ≥ 2 FO within the 30 days after ex vivo CD34+ selected allo-HCT with a median onset at day 11 (range, -8 to 28). Age ≥ 55 years (odds ratio, 3.43; P = .005) and chemotherapy-based conditioning (odds ratio, 3.89; P = .007) were associated with an increased risk of grade ≥ 2 FO. Patients with early grade ≥ 2 FO had a significantly higher NRM when compared with patients with grade < 2 FO (24.1% versus 3.6% at day 100, P = .01). The HCT-specific comorbidity index (HCT-CI) ≥ 3, FEV1 < 80, adjusted DLco < 80, and HLA mismatch were associated with an increased risk of NRM, whereas total body irradiation-based conditioning was associated with a reduced risk of NRM. In a multivariate analysis grade ≥ 2 FO was associated with increased NRM after adjusting for HCT-CI and HLA match (hazard ratio, 2.3; P = .014). There was a trend toward inferior relapse-free survival in patients with grade ≥ 2 FO compared with patients with grade < 2 FO, 62% versus 72% at 1 year (P = .07), and a trend toward inferior overall survival, 69% versus 79% at 1 year (P = 0.06), respectively. Our findings show that FO should be routinely assessed to identify patients at risk for NRM. Despite a CNI-free allo-HCT platform, regimen-related tissue and endothelial injury leads to FO in susceptible patients. FO is a highly relevant post-HCT toxicity that requires further inquiry.

Allogeneic Stem Cell Transplantation for Advanced Myelodysplastic Syndrome: Comparison of Outcomes between CD34+ Selected and Unmodified Hematopoietic Stem Cell Transplantation.

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 <10% blasts before HSCT (n = 145). Two groups were defined: low risk, with low- and intermediate-risk cytogenetics (CD34+, n = 39; unmodified, n = 46), and high risk: poor and very poor risk cytogenetics (CD34+, n = 19; unmodified, n = 41). In the low-risk group, the incidence of grade II-IV acute graft-versus-host disease (aGVHD) at 1 year post-transplantation was 18% in the CD34+ subgroup versus 41.3% in the unmodified subgroup (P = .015). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of chronic graft-versus-host disease (cGVHD) at 3 years in the 2 subgroups was 5.3% and 56%, respectively (P < .001). At 3 years post-transplantation, relapse, overall survival (OS), and relapse-free survival (RFS) were similar in the CD34+ and unmodified subgroups: 8.1% versus 19.4% (P = .187), 58.5% versus 53.7% (P = .51), and 59.5% versus 52.4% (P = .448). However, the composite outcome combining extensive cGVHD-free status and relapse-free status (CRFS) at 3 years was 59.5% in the CD34+ group versus 19.2% in the unmodified group (P < .001). In the high-risk group, grade II-IV aGVHD at 1 year was 31.6% in the CD34+ subgroup versus 24.4% in the unmodified subgroup (P = .752). There were no differences between the subgroups in the incidence of grade III-IV aGVHD. The incidence of cGVHD at 3 years in the 2 subgroups was 0% versus 27.6% (P = .013). At 3 years post-transplantation, relapse, OS, RFS, and CRFS in the 2 subgroups were 31.6% versus 69.3% (P = .007), 35.5% versus 14.5% (P = .068), 31.6% versus 10.7% (P = .045), and 31.6% versus 6.1% (P = .001), respectively. Cytogenetic abnormalities at diagnosis and transplant type had significant univariate associations with RFS in the high-risk cohort. Only cytogenetics (P = .03) remained associated with this outcome in a multivariate model. OS was similar in the 2 transplant groups; however, CRFS was superior in the CD34+ cell-selected transplant group.

Insulin and glucose homeostasis in childhood cancer survivors treated with abdominal radiation: A pilot study.

BACKGROUND: Childhood cancer survivors exposed to abdominal radiation (abdRT) are at increased risk for both insulin-dependent and non-insulin-dependent diabetes. We sought to clarify the pathophysiology of diabetes after abdRT by performing dynamic studies of insulin and glucose and testing for type 1 diabetes-associated autoantibodies. PROCEDURE: Cross-sectional analysis of 2-year childhood cancer survivors treated with abdRT at age ≤21 years who underwent oral glucose tolerance testing and assessment of diabetes-related autoantibodies from December 2014 to September 2016. Prevalence of insulin/glucose derangements, indices of insulin sensitivity/secretion (homeostatic model assessment of insulin resistance [HOMA-IR], whole-body insulin sensitivity, insulinogenic index), autoantibody positivity, and treatment/demographic factors associated with adverse metabolic outcomes were assessed. RESULTS: Among 40 participants previously exposed to abdRT (57.5% male; median age at cancer diagnosis, 3.3 years [range, 0.5-20.1]; median age at study 14.3 years [range, 8.3-49.8]; none with obesity), 9 (22.5%) had glucose derangements (n = 4 with impaired fasting glucose [≥100 mg/dL]; n = 4 with impaired glucose tolerance [2-hour glucose 140-199 mg/dL]; n = 1 with previously unrecognized diabetes [2-hour glucose ≥200 mg/dL]). Three of the four individuals with impaired fasting glucose also had insulin resistance, as measured by HOMA-IR; an additional four subjects with normal glucose tolerance were insulin resistant. The subject with diabetes had normal HOMA-IR. No participant had absolute insulinopenia or >1 positive diabetes-related autoantibody. CONCLUSIONS: This study suggests that radiation-induced damage to the insulin-producing ß-cells is an unlikely explanation for the early derangements in glucose metabolism observed after abdRT. Research into alternative pathways leading to diabetes after abdRT is needed.

Cardiovascular Risk Factors in Survivors of Childhood Hematopoietic Cell Transplantation Treated with Total Body Irradiation: A Longitudinal Analysis.

Hematopoietic cell transplantation (HCT) survivors treated with total body irradiation (TBI) are known to be at increased risk for the development of cardiovascular risk factors (CVRFs). We sought to characterize the incidence of CVRFs in a TBI-exposed survivor cohort and to describe prognostic indicators of their development through a retrospective analysis of CVRFs in 1-year survivors of leukemia or lymphoma treated with TBI at Memorial Sloan Kettering between April 1987 and May 2011. Eligible participants were age ≤21 years at the time of TBI and were not receiving glucocorticoid therapy at the time of entry to long-term follow-up. Survivors were assessed for obesity (body mass index ≥95th percentile for age ≤ 20 years and ≥30 kg/m2 for age >20 years), elevated blood pressure, dyslipidemia (elevated triglycerides [TG], low high-density lipoprotein [HDL]), and glucose intolerance (fasting glucose ≥100 mg/dL); those with ≥3 risk factors were deemed to have a CVRF cluster, a surrogate for metabolic syndrome. Cox regression models were used to estimate hazard ratios (HRs) for factors associated with each CVRF. To compare the prevalence of CVRFs in HCT survivors and the general population, survivors were compared with age-, sex-, and race-matched controls from the National Health and Nutrition Examination Survey. A total of 123 survivors were evaluated (62.6% males). The median age at TBI was 11.8 years (range, 1.6 to 21.9 years). The median duration of follow-up was 8.0 years (range, 1.01 to 24.6 years), and the median age at last follow-up was 20.1 years (range, 4.0 to 41.3 years). The 5-year cumulative incidence was 14.7% for elevated blood pressure, 10.5% for elevated glucose, 26.8% for low HDL, 39.2% for hypertriglyceridemia, and 16.0% for obesity, and corresponding 10-year cumulative incidences of 28.8%, 33.1%, 52.0%, 65.0%, and 18.6%. The median cumulative incidence of a CVRF cluster rose from 10.6% (range, 5.6% to 17.5%) at 5 years to 28.4% (range, 18.8% to 38.7%) at 10 years. In multivariate analysis, growth hormone (GH) deficiency (hazard ratio [HR], 8.6; 95% confidence interval [CI], 2.1 to 34.4; P = .002), history of cranial radiation (HR, 4.0; 95% CI, 1.7 to 9.6; P = .002), and grade II-IV acute graft-versus-host disease GVHD (HR, 4.2; 95% CI, 1.5 to 12.2; P = .008) were associated with the risk of developing a CVRF cluster. Compared with a random sample of matched population controls, HCT survivors had an increased prevalence of hypertriglyceridemia and low HDL, but not of glucose intolerance, elevated blood pressure, or CVRF cluster. Given the young age of this HCT survivor cohort, these data highlight the importance of routine screening for CVRF starting in childhood in individuals exposed to TBI.

Allogeneic Hematopoietic Stem Cell Transplantation Is Underutilized in Older Patients with Myelodysplastic Syndromes.

Allogeneic hematopoietic stem cell transplantation (HCT) is the only curative treatment for myelodysplastic syndrome (MDS). The proportion of MDS patients referred for transplantation evaluation, those undergoing transplantation, and the reasons for not undergoing transplantation are unknown. In this retrospective analysis, predefined HCT eligibility and indications criteria were applied to 362 unselected patients with newly diagnosed MDS seen by leukemia faculty between 2008 and 2015 at Memorial Sloan Kettering Cancer Center. Two hundred ninety-four patients (81%) were deemed eligible for transplantation and among these, transplantation was considered indicated in 244 (83%). Of these, 158 of 244 (65%) were referred for transplantation evaluation at a median of 3.9 months from diagnosis. Overall 120 of 362 (33%) underwent transplantation at a median of 7.7 months from diagnosis. Metastatic solid-organ malignancy was the major reason for transplantation ineligibility (54%), and death due to MDS, which occurred in 41% of candidates who did not undergo transplantation, was the major reason for not undergoing transplantation. Factors associated with a lower likelihood of referral for transplantation evaluation included age ≥65 (P < .001), ≥2 comorbidities (P = .008), intermediate-1/low risk MDS (P < .001), <5% blasts at diagnosis (overall P < .001), having Medicare/Medicaid health insurance (P < .001), not being married (P = .017), and diagnosis between 2008 and 2011 (P = .035). On multivariate analysis adjusting for all of the previous factors, diagnosis between 2008 and 2011 (P < .001), age ≥65 (P = .001), and <5% blasts at diagnosis (overall P = .031) were associated with a lower likelihood of referral for transplantation evaluation. Factors associated with a lower likelihood of undergoing transplantation included age ≥65 (P < .001), ≥2 comorbidities (P = .003), intermediate-1/low risk MDS (P < .001), <5% blasts (overall P < .001), very low/low/intermediate risk International Prognostic Scoring System-revised karyotype (P = .018), and having Medicare/Medicaid health insurance (P < .001). In multivariate analysis adjusting for all of the previous factors, age ≥65 (P = .021), presence of ≥2 comorbidities (P = .018), and <5% blasts (overall P = .011) were associated with a lower likelihood of undergoing transplantation. The results highlight that transplantation for MDS remains underutilized, particularly for candidates over the age of 65.

T Cell Depletion as an Alternative Approach for Patients 55 Years or Older Undergoing Allogeneic Stem Cell Transplantation as Curative Therapy for Hematologic Malignancies.

T cell-depleted (TCD) allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment for hematologic malignancies in adults, shown to reduce graft-versus-host disease (GVHD) without increased relapse. We retrospectively reviewed a single-center, 11-year experience of 214 patients aged ≥ 55 years to determine tolerability and efficacy in the older adult. Most patients (70%) had myeloid diseases, and most acute leukemias were in remission. Median age was 61 years, with related and unrelated donors ≥8/10 HLA matched. Hematopoietic cell transplantation-specific comorbidity index scores were intermediate and high for 84%. Conditioning regimens were all myeloablative. Grafts were peripheral blood stem cells (97%) containing CD3 dose ≤103-4/kg body weight, without pharmacologic GVHD prophylaxis. With median follow-up of 70 months among survivors, Kaplan-Meier estimates of overall and relapse-free survival were 44% and 41%, respectively (4 years). Cumulative incidence of nonrelapse mortality at day +100 was only 10%. Incidence of GVHD for acute (grades II to IV) was 9% at day +100 and for chronic was 7% at 2 and 4 years (8 extensive, 1 overlap). Median Karnofsky performance status for patients > 2 years post-transplant was 90%. As 1 of the largest reports for patients ≥2 aged ≥55 years receiving TCD HSCTs, it demonstrates curative therapy with minimal GVHD, similar to that observed in a younger population.

A Chemotherapy-Only Regimen of Busulfan, Melphalan, and Fludarabine, and Rabbit Antithymocyte Globulin Followed by Allogeneic T-Cell Depleted Hematopoietic Stem Cell Transplantations for the Treatment of Myeloid Malignancies.

We sought to develop a myeloablative chemotherapeutic regimen to secure consistent engraftment of T-cell depleted (TCD) hematopoietic stem cell transplantations (HSCT) without the need for total body irradiation, thereby reducing toxicity while maintaining low rates of graft-versus-host disease (GVHD) and without increasing relapse. We investigated the myeloablative combination of busulfan (Bu) and melphalan (Mel), with the immunosuppressive agents fludarabine (Flu) and rabbit antithymocyte globulin (r-ATG) as cytoreduction before a TCD HSCT. No post-transplantation immunosuppression was administered. Between April 2001 and May 2008, 102 patients (median age, 55 years) with a diagnosis of primary or secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) underwent cytoreduction with Bu/Mel/Flu, followed by TCD grafts. TCD was accomplished by CD34+-selection followed by E-rosette depletion for peripheral blood stem cell grafts and, for bone marrow grafts, by soybean agglutination followed by E-rosette depletion. Donors included matched and mismatched, related and unrelated donors. Risk stratification was by American Society for Blood and Marrow Transplantation risk categorization for patients with primary disease. For patients with secondary/treatment-related MDS/AML, those in complete remission (CR) 1 or with refractory anemia were classified as intermediate risk, and all other patients were considered high risk. Neutrophil engraftment occurred at a median of 11 days in 100 of 101 evaluable patients. The cumulative incidences of grades II to IV acute and chronic GVHD at 1 year were 8.8% and 5.9%, respectively. Overall- and disease-free survival (DFS) rates at 5 years were 50.0% and 46.1%, respectively, and the cumulative incidences of relapse and treatment-related mortality were 23.5% and 28.4%, respectively. Stratification by risk group demonstrated superior DFS for low-risk patients (61.5% at 5 years) compared with intermediate- or high-risk (34.2% and 40.0%, respectively, P = .021). For patients with AML, those in CR1 had superior 5-year DFS compared with those in ≥CR2 (60% and 30.6%, respectively, P = .01), without a significant difference in incidence of relapse (17.1% and 30.6%, respectively, P = .209). There were no differences in DFS for other patient, donor, or disease characteristics. In summary, cytoreduction with Bu/Mel/Flu and r-ATG secured consistent engraftment of TCD transplantations. The incidences of acute/chronic GVHD and disease relapse were low, with favorable outcomes in this patient population with high-risk myeloid malignancies.

Hematopoietic Cell Transplantation Comorbidity Index Predicts Outcomes in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndromes Receiving CD34+ Selected Grafts for Allogeneic Hematopoietic Cell Transplantation.

To evaluate the association between the hematopoietic cell transplantation-comorbidity index (HCT-CI) and the recently developed age-adjusted HCT-CI (HCT-CI/age) and transplant outcomes in the setting of CD34-selected allogeneic HCT, we analyzed a homogeneous population of patients undergoing allogeneic HCT with CD34-selected grafts for acute myeloid leukemia and myelodysplastic syndrome (n = 346). Median HCT-CI and HCT-CI/age scores were 2 (percentile 25 to 75, 1 to 4) and 3 (percentile 25 to 75, 1 to 5), respectively. Higher HCT-CI and HCT-CI/age scores were associated with higher nonrelapse mortality (NRM) and lower overall survival (OS). The HCT-CI distinguished 2 risk groups (0 to 2 versus ≥3), whereas, with the HCT-CI/age, there was a progressive increase in NRM and decrease in OS with increasing scores in all 4 groups (0 versus 1 to 2 versus 3 to 4 versus ≥5). Higher scores in both models were associated with lower chronic graft-versus-host disease relapse-free survival but not with higher relapse. Both models showed a promising predictive accuracy for NRM (c- = .616 for HCT-CI and c- = .647 for HCT-CI/age). In conclusion, the HCT-CI and HCT-CI/age predict transplant outcomes in CD34-selected allo-HCT, including NRM, OS, and chronic graft-versus-host disease relapse-free survival and may be used to select appropriate patients for this approach.

Ex Vivo CD34+-Selected T Cell-Depleted Peripheral Blood Stem Cell Grafts for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Leukemia and Myelodysplastic Syndrome Is Associated with Low Incidence of Acute and Chronic Graft-versus-Host Disease and High Treatment Response.

Ex vivo CD34+-selected T cell depletion (TCD) has been developed as a strategy to reduce the incidence of graft-versus-host disease (GVHD) after allogeneic (allo) hematopoietic stem cell transplantation (HSCT). Clinical characteristics, treatment responses, and outcomes of patients developing acute (aGVHD) and chronic GVHD (cGVHD) after TCD allo-HSCT have not been well established. We evaluated 241 consecutive patients (median age, 57 years) with acute leukemia (n = 191, 79%) or myelodysplastic syndrome (MDS) (n = 50, 21%) undergoing CD34+-selected TCD allo-HSCT without post-HCST immunosuppression in a single institution. Cumulative incidences of grades II-IV and III-IV aGVHD at 180 days were 16% (95% confidence interval [CI], 12 to 21) and 5% (95% CI, 3 to 9), respectively. The skin was the most frequent organ involved, followed by the gastrointestinal tract. Patients were treated with topical corticosteroids, poorly absorbed corticosteroids (budesonide), and/or systemic corticosteroids. The overall day 28 treatment response was high at 82%. The cumulative incidence of any cGVHD at 3 years was 5% (95% CI, 3 to 9), with a median time of onset of 256 days (range, 95 to 1645). The 3-year transplant-related mortality, relapse, overall survival, and disease-free survival were 24% (95% CI, 18 to 30), 22% (95% CI, 17 to 27), 57% (95% CI, 50 to 64), and 54% (95% CI, 47 to 61), respectively. The 1-year and 3-year probabilities of cGVHD-free/relapse-free survival were 65% (95% CI, 59 to 71) and 52% (95% CI, 45 to 59), respectively. Our findings support the use of ex vivo CD34+-selected TCD allograft as a calcineurin inhibitor-free intervention for the prevention of GVHD in patients with acute leukemia and MDS.

Prognostic value of FDG-PET prior to autologous stem cell transplantation for relapsed and refractory diffuse large B-cell lymphoma.

High-dose chemotherapy (HDT) plus autologous stem cell transplantation (ASCT) is the standard of care for chemosensitive relapsed and refractory diffuse large B-cell lymphoma (rel/ref DLBCL). Interim restaging with functional imaging by positron emission tomography using (18)F-deoxyglucose (FDG-PET) has not been established after salvage chemotherapy (ST) and before HDT-ASCT by modern criteria. Herein, we evaluated 129 patients with rel/ref DLBCL proceeding to HDT-ASCT, with ST response assessment by FDG-PET according to the contemporary Deauville 5-point scale. At 3 years, patients achieving a Deauville response of 1 to 3 to ST experienced superior progression-free survival (PFS) and overall survival (OS) rates of 77% and 86%, respectively, compared with patients achieving Deauville 4 (49% and 54%, respectively) (P < .001). No other pre-HDT-ASCT risk factors significantly impacted PFS or OS. Despite achieving remission to ST, patients with Deauville 4 should be the focus of risk-adapted investigational therapies.

High day 28 ST2 levels predict for acute graft-versus-host disease and transplant-related mortality after cord blood transplantation.

While cord blood transplantation (CBT) is an effective therapy for hematologic malignancies, acute graft-versus-host disease (aGVHD) is a leading cause of transplant-related mortality (TRM). We investigated if biomarkers could predict aGVHD and TRM after day 28 in CBT recipients. Day 28 samples from 113 CBT patients were analyzed. Suppressor of tumorigenicity 2 (ST2) was the only biomarker associated with grades II-IV and III-IV aGVHD and TRM. Day 180 grade III-IV aGVHD in patients with high ST2 levels was 30% (95% confidence interval [CI], 18-43) vs 13% (95% CI, 5-23) in patients with low levels (P = .024). The adverse effect of elevated ST2 was independent of HLA match. Moreover, high day 28 ST2 levels were associated with increased TRM with day 180 estimates of 23% (95% CI, 13-35) vs 5% (95% CI, 1-13) if levels were low (P = .001). GVHD was the most common cause of death in high ST2 patients. High concentrations of tumor necrosis factor receptor-1, interleukin-8, and regenerating islet-derived protein 3-α were also associated with TRM. Our results are consistent with those of adult donor allografts and warrant further prospective evaluation to facilitate future therapeutic intervention to ameliorate severe aGVHD and further improve survival after CBT.

The potential benefit of allogeneic over autologous transplantation in patients with very early relapsed and refractory follicular lymphoma with prior remission duration of ≤12 months.

Early relapsed or refractory follicular lymphoma (FL) warrants consolidation with transplantation, though graft source modality remains controversial. We analysed the outcomes of 44 patients transplanted with either autologous or allogeneic graft sources in the post-rituximab era. No difference in event-free (EFS) or overall survival (OS) was observed between allogeneic (81% and 81%) and autologous transplantation (64% and 70%) at 3 years. There was a significant difference in EFS between allogeneic and autologous transplantation patients with previous remission duration of ≤12 months (80% and 42% at 3 years, P < 0·015). Very early relapsed FL may warrant consideration of allogeneic over autologous transplantation in the appropriate setting.