Immune reconstitution, vaccine responses, and rituximab use after ex-vivo CD34-selected myeloablative allogenic hematopoietic cell transplantation.

Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.

Application of the CIBMTR One Year Survival Outcomes Calculator as a tool for retrospective analysis.

The Web-based One Year Survival Outcomes Calculator developed by the Center for International Blood and Marrow Transplant Research (CIBMTR) applies large-scale registry data to generate individualized estimates of overall survival (OS) probability 1 year after first allogeneic hematopoietic cell transplant (HCT) and can therefore provide a data-driven foundation for personalized patient counseling. We assessed the calibration of the CIBMTR One Year Survival Outcomes Calculator when applied to retrospective data among adult recipients of first allogeneic HCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) with peripheral blood stem cell transplant (PBSCT) from a 7/8- or 8/8-matched donor from 2000 through 2015 at a single center. Predicted 1 year OS was estimated for each patient using the CIBMTR Calculator. Corresponding observed 1 year OS was estimated for each group by the Kaplan-Meier method. A weighted Kaplan-Meier estimator was used to visually display the average of observed 1 year survival estimates over the continuous range of predicted OS. In the first analysis of its kind, we demonstrated that the CIBMTR One Year Survival Outcomes Calculator could be applied to larger patient cohorts and predicted 1 year prognosis with general agreement between predicted and observed survival.

High-resolution analyses of associations between medications, microbiome, and mortality in cancer patients.

Discerning the effect of pharmacological exposures on intestinal bacterial communities in cancer patients is challenging. Here, we deconvoluted the relationship between drug exposures and changes in microbial composition by developing and applying a new computational method, PARADIGM (parameters associated with dynamics of gut microbiota), to a large set of longitudinal fecal microbiome profiles with detailed medication-administration records from patients undergoing allogeneic hematopoietic cell transplantation. We observed that several non-antibiotic drugs, including laxatives, antiemetics, and opioids, are associated with increased Enterococcus relative abundance and decreased alpha diversity. Shotgun metagenomic sequencing further demonstrated subspecies competition, leading to increased dominant-strain genetic convergence during allo-HCT that is significantly associated with antibiotic exposures. We integrated drug-microbiome associations to predict clinical outcomes in two validation cohorts on the basis of drug exposures alone, suggesting that this approach can generate biologically and clinically relevant insights into how pharmacological exposures can perturb or preserve microbiota composition. The application of a computational method called PARADIGM to a large dataset of cancer patients' longitudinal fecal specimens and detailed daily medication records reveals associations between drug exposures and the intestinal microbiota that recapitulate in vitro findings and are also predictive of clinical outcomes.

Emergence of human CMV-induced NKG2C+ NK cells is associated with CD8+ T-cell recovery after allogeneic HCT.

Cytomegalovirus (CMV) infection is associated with the expansion of a mature NKG2C+FcεR1γ- natural killer (NK) cell population. The exact mechanism underlying the emergence of NKG2C+ NK cells, however, remains unknown. Allogeneic hematopoietic cell transplantation (HCT) provides an opportunity to longitudinally study lymphocyte recovery in the setting of CMV reactivation, particularly in patients receiving T-cell-depleted (TCD) allografts. We analyzed peripheral blood lymphocytes from 119 patients at serial time points after infusion of their TCD allograft and compared immune recovery with that in samples obtained from recipients of T-cell-replete (T-replete) (n = 96) or double umbilical cord blood (DUCB) (n = 52) allografts. NKG2C+ NK cells were detected in 92% (45 of 49) of recipients of TCD HCT who experienced CMV reactivation. Although NKG2A+ cells were routinely identifiable early after HCT, NKG2C+ NK cells were identified only after T cells could be detected. T-cell reconstitution occurred at variable times after HCT among patients and predominantly comprised CD8+ T cells. In patients with CMV reactivation, recipients of TCD HCT expressed significantly higher frequencies of NKG2C+ and CD56neg NK cells compared with patients who received T-replete HCT or DUCB transplantation. NKG2C+ NK cells after TCD HCT were CD57+FcεR1γ+ and degranulated significantly more in response to target cells compared with the adaptive the NKG2C+CD57+FcεR1γ- NK cell population. We conclude that the presence of circulating T cells is associated with the expansion of a CMV-induced NKG2C+ NK cell population, a potentially novel example of developmental cooperation between lymphocyte populations in response to viral infection.

Characteristics of Distress and Support Group Participation in Caregivers of Older Allogeneic Hematopoietic Cell Transplantation Patients: A Single Institution Retrospective Review.

Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplant (allo-HCT). However, older patients often have increased comorbidities and thus may require an increased level of post-transplant care. These factors can contribute to increased caregiver distress, which has been associated with worsened health outcomes for caregivers and patients. To examine predictors of caregiver distress and support group participation in caregivers of older allo-HCT patients, we retrospectively reviewed charts of 208 patients aged 60 and older who underwent their first allo-HCT at our institution from 2014 through 2016. We systematically characterized and identified the incidence of caregiver distress and attendance in a caregiver support group from the start of conditioning through 1 year post allo-HCT. Evidence of caregiver distress and support group participation was recorded by reviewing clinical and/or social work documentation. We found that 20 caregivers (10%) endorsed stress and 44 caregivers (21%) attended our support group at least once. A patient's prior history of psychiatric diagnosis (p = .046) or the use of potentially inappropriate medications for older adults (p = .046) was found to be associated with caregiver stress. Caregivers who were spouses or partners of patients (p = .048) or caregivers of married patients were more likely to attend the support group (p = .007). While limited by retrospective design and likely underreporting, this study reveals factors associated with caregiver distress in the older allo-HCT caregiver population. This information can help providers identify caregivers at risk for distress and improve caregiver resources, which may improve both caregiver and patient outcomes.

EASIX score predicts inferior survival after allogeneic hematopoietic cell transplantation.

The Endothelial Activation and Stress Index (EASIX) is a prognostic tool that uses common clinical laboratory values and has been shown to predict non-relapse mortality (NRM) and overall survival (OS) at the onset of acute graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). We hypothesized that EASIX calculated at different time points pre- and post- HCT may predict NRM and OS, and that EASIX calculated at onset of GVHD may predict response to steroids. We evaluated the EASIX score pre- and post-HCT in 152 patients with lymphoid malignancies undergoing unmodified reduced intensity conditioning (RIC) alloHCT with uniform GVHD prophylaxis. In multivariate analysis, EASIX calculated pre-HCT was significantly associated with higher NRM (HR = 1.64, p = 0.009) and lower OS (HR = 1.33, p = 0.046). Furthermore, EASIX calculated at day 30 and at day 100 was associated with increased NRM (HR = 1.65, p < 0.001; and HR = 1.65, p < 0.001) and decreased OS (HR = 1.27, p = 0.018; and HR = 1.49, p < 0.001), independent of HCT-CI, disease and conditioning regimen. Our study shows that high EASIX scores at various time points pre- and post-HCT are significantly associated with poorer overall outcomes. EASIX provides an independent and easily accessible tool to predict outcomes that can be complementary to other measures of risk stratification for patients undergoing HCT.

Dynamic EASIX scores closely predict nonrelapse mortality after allogeneic hematopoietic cell transplantation.

Endothelial activation and stress index (EASIX) predicts nonrelapse mortality (NRM) when assessed before hematopoietic cell transplantation (HCT). We sought to determine whether changes in EASIX after HCT may be an informative marker of NRM. We evaluated 509 adults who underwent reduced intensity, unmodified (N = 149, 29%), or myeloablative ex vivo CD34+-selected allogeneic HCT (allo-HCT) (N = 306, 71%) between 2008 and 2016. Patients who underwent unmodified allo-HCT received tacrolimus-based graft-versus-host disease (GVHD) prophylaxis, whereas CD34+-selected patients received no planned immunosuppression. EASIX (lactate dehydrogenase × creatinine/platelet count) was calculated continuously until 1-year after HCT. Log transformation using base 2 (log2) was applied to all EASIX variables to reduce skew. In total, 360 patients (71%) received CD34+-selected and 149 (29%) unmodified allo-HCT. Among all patients, EASIX scores increased rapidly, peaked at day +8, then declined rapidly until day +33. Thereafter, scores declined gradually but remained above the pre-HCT baseline. In unmodified HCT, scores appeared higher over time than in CD34+-selected patients. EASIX discrimination of NRM was highest around day +180 (concordance index = 0.85) in both platforms, but the prognostic impact of EASIX across time points differed between the 2 platforms. Mean EASIX scores were higher in men (mean log2 +0.52) and in patients who developed grade 2 to 4 GVHD (+0.81) and lower in patients who received matched vs mismatched donors (-0.81, all P < .01). EASIX scores are dynamic and variably concordant with NRM when analyzed longitudinally, and patterns differ between HCT platforms. Compared to pre-HCT evaluation, post-HCT EASIX scores may better predict risk of NRM as patients acquire additional endothelial injury and toxicities.

A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Delirium in Critically Ill Cancer Patients With COVID-19.

BACKGROUND: COVID-19 has been a devastating pandemic with little known of its neuropsychiatric complications. Delirium is one of the most common neuropsychiatric syndromes among hospitalized cancer patients with incidence ranging from 25% to 40% and rates of up to 85% in the terminally ill. Data on the incidence, risk factors, duration, and outcomes of delirium in critically ill cancer patients with COVID-19 are lacking. OBJECTIVE: To report the incidence, risks and outcomes of critically ill cancer patients who developed COVID-19. METHODS: This is a retrospective single-center study evaluating delirium frequency and outcomes in all critically ill cancer patients with COVID-19 admitted between March 1 and July 10, 2020. Delirium was assessed by Confusion Assessment Method for Intensive Care Unit, performed twice daily by trained intensive care unit (ICU) nursing staff. Patients were considered to have a delirium-positive day if Confusion Assessment Method for Intensive Care Unit was positive at least once per day. RESULTS: A total of 70 patients were evaluated. Of those 70, 53 (75.7%) were found to be positive for delirium. Patients with delirium were significantly older than patients without delirium (median age 67.5 vs 60.3 y, P = 0.013). There were no significant differences in demographic characteristics, chronic medical conditions, neuropsychiatric history, cancer type, or application of prone positioning between the 2 groups. Delirium patients were less likely to receive cancer-directed therapies (58.5% vs 88.2%, P = 0.038) but more likely to receive antipsychotics (81.1% vs 41.2%, P = 0.004), dexmedetomidine (79.3% vs 11.8%, P < 0.001), steroids (84.9% vs 58.8%, P = 0.039), and vasopressors (90.6% vs 58.8%, P = 0.006). Delirium patients were more likely to be intubated (86.8% vs 41.2%, P < 0.001), and all tracheostomies (35.9%) occurred in patients with delirium. ICU length of stay (19 vs 8 d, P < 0.001) and hospital length of stay (37 vs 12 d, P < 0.001) were significantly longer in delirium patients, but there was no statistically significant difference in hospital mortality (43.4% vs 58.8%, P = 0.403) or ICU mortality (34.0% vs 58.8%, P = 0.090). CONCLUSIONS: Delirium in critically ill cancer patients with COVID-19 was associated with less cancer-directed therapies and increased hospital and ICU length of stay. However, the presence of delirium was not associated with an increase in hospital or ICU mortality.

Impact of Exercise on Susceptibility and Severity of COVID-19 in Patients with Cancer: A Retrospective Study.

BACKGROUND: Modifiable lifestyle-related factors heighten the risk and severity of coronavirus disease 2019 (COVID-19) in patients with cancer. Whether exercise lowers susceptibility or severity is not known. METHODS: We identified 944 cancer patients from Memorial Sloan Kettering Cancer Center (mean age: 64; 85% female; 78% White) completing an exercise survey before receiving a confirmed positive or negative SARS-CoV-2 test. Exercise was defined as reporting moderate-intensity ≥5 days per week, ≥30 minutes/session or strenuous-intensity ≥3 days per week, ≥20 minutes/session. Multivariable logistic regression was used to determine the relationship between exercise and COVID-19 susceptibility and severity (i.e., composite of hospital admission or death events) with adjustment for clinical-epidemiologic covariates. RESULTS: Twenty-four percent (230/944) of the overall cohort were diagnosed with COVID-19 and 35% (333/944) were exercisers. During a median follow-up of 10 months, 26% (156/611) of nonexercising patients were diagnosed with COVID-19 compared with 22% (74/333) of exercising patients. The adjusted OR for risk of COVID-19 was 0.65 [95% confidence interval (CI), 0.44-0.96, P = 0.03] for exercisers compared with nonexercisers. A total of 20% (47/230) of COVID-19 positive patients were hospitalized or died. No difference in the risk of severe COVID-19 as a function of exercise status was observed (P > 0.9). CONCLUSIONS: Exercise may reduce the risk of COVID-19 infection in patients with a history of cancer, but not its severity. IMPACT: This study provides the first data showing that exercise might lower the risk of COVID-19 in cancer patients, but further research is required.

CD34+ -selected hematopoietic stem cell transplant conditioned with a myeloablative regimen in patients with advanced myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (Allo-HCT) remains the only curative treatment for myelofibrosis (MF). Transplantation in patients with MF is mostly done using a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. Here we sought to evaluate outcomes of patients who underwent an ex vivo CD34+ -selected allo-HCT using myeloablative conditioning (MAC). Twenty-seven patients were included in this retrospective analysis. All patients were conditioned with busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Median follow-up among survivors was 50.6 months. The estimated 3-year overall survival, relapse free survival and the combined endpoint of GVHD/relapse free survival were 88% (95% CI, 75-100%), 80% (95% CI, 66-98%) and 74% (95% CI, 59-93%), respectively. The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 16.4-51.3%), and two patients suffered chronic GVHD. There were no cases of primary graft failure. However, delayed graft failure occurred in two patients. We conclude that CD34+ selected allo-HCT with a MAC resulted in high survival rates in this cohort of patients with MF.

Low-dose unfractionated heparin prophylaxis is a safe strategy for the prevention of hepatic sinusoidal obstruction syndrome after myeloablative adult allogenic stem cell transplant.

Hepatic sinusoidal obstruction syndrome (SOS) is a serious complication after allogeneic stem cell transplantation (allo-HCT). However, there is no uniform consensus on the optimal strategy for SOS prevention. Ursodeoxycholic acid is the most used regimen, even though its administration is challenging in recipients unable to tolerate oral medication. Defibrotide was recently studied in a phase 3 trial, but enrollment was stopped early due to futility. Low-dose unfractionated heparin (UFH) is an alternative strategy. However, its efficacy is reputed but unproven increased risk of bleeding has not been fully established. We evaluated 514 adult allo-HCT recipients who received SOS prophylaxis with low-dose UFH. Bleeding complications occurred in 12 patients 2.3% of patients of which only 2 (0.4%) had significant grade 3 bleeding. Only 14 patients were diagnosed with hepatic SOS. Univariate analysis showed that day 100 SOS was higher in recipients of unmodified grafts when compared to CD34+ selected ex vivo T-cell depleted grafts (p ≤ 0.001), and patients with hepatitis B and/or C exposure pre-HCT (p = 0.028). Overall, UFH was well tolerated and associated with a low incidence of subsequent hepatic SOS. Low-dose UFH prophylaxis can be considered in select patients who cannot tolerate oral ursodiol.

Impact of omitting post-transplant minidose-methotrexate doses in allogeneic hematopoietic cell transplantation.

Given prophylactic methotrexate (MTX) is often held in the setting of toxicity we investigated the impact of omitting minidose-MTX dose(s). Outcomes were compared between patients who had 1-3 doses omitted and those who received all four planned doses of minidose-MTX. Of 370 consecutive patients, 50 had MTX dose(s) omitted. When MTX was omitted, initial management was mycophenolate mofetil (MMF; 36/50 patients) with or without corticosteroids (14/50 patients). Rates of grade 3-4 acute GVHD were similar between groups. Omission of minidose-MTX resulted in an increased risk of chronic GVHD (cGVHD; HR 2.27; p = .024) and decreased overall survival (HR 1.61; p = .024). However, other transplant-related outcomes were comparable. In summary, omission of minidose-MTX doses was not associated with an increased risk of acute GVHD when an alternative was added (e.g. MMF ± corticosteroids). This did not abrogate the increased risk of cGVHD or decreased overall survival.

Outcomes of Patients with COVID-19 from a Specialized Cancer Care Emergency Room.

PURPOSE: Our goal was to identify discrete clinical characteristics associated with safe discharge from an emergency department/urgent care for patients with a history of cancer and concurrent COVID-19 infection during the SARS-CoV-2 pandemic and prior to widespread vaccination. PATIENTS AND METHODS: We retrospectively analyzed 255 adult patients with a history of cancer who presented to Memorial Sloan Kettering Cancer Center (MSKCC) urgent care center (UCC) from March 1, 2020 to May 31, 2020 with concurrent COVID-19 infection. We evaluated associations between patient characteristics and 30-day mortality from initial emergency department (ED) or urgent care center (UCC) visit and the absence of a severe event within 30 days. External validation was performed on a retrospective data from 29 patients followed at Fred Hutchinson Cancer Research Center that presented to the local emergency department. A late cohort of 108 additional patients at MSKCC from June 1, 2020 to January 31, 2021 was utilized for further validation. RESULTS: In the MSKCC cohort, 30-day mortality and severe event rate was 15% and 32% respectively. Using stepwise regression analysis, elevated BUN and glucose, anemia, and tachypnea were selected as the main predictors of 30-day mortality. Conversely, normal albumin, BUN, calcium, and glucose, neutrophil-lymphocyte ratio <3, lack of (severe) hypoxia, lack of bradycardia or tachypnea, and negative imaging were selected as the main predictors of an uneventful course as defined as a Lack Of a Severe Event within Thirty Days (LOSETD). Utilizing this information, we devised a tool to predict 30-day mortality and LOSETD which achieved an area under the operating curve (AUC) of 79% and 74% respectively. Similar estimates of AUC were obtained in an external validation cohort. A late cohort at MSKCC was consistent with the prior, albeit with a lower AUC. CONCLUSION: We identified easily obtainable variables that predict 30-day mortality and the absence of a severe event for patients with a history of cancer and concurrent COVID-19. This has been translated into a bedside tool that the clinician may utilize to assist disposition of this group of patients from the emergency department or urgent care setting.

Modified EASIX predicts severe cytokine release syndrome and neurotoxicity after chimeric antigen receptor T cells.

Patients who develop chimeric antigen receptor (CAR) T-cell-related severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial Activation and Stress Index) score (lactate dehydrogenase [LDH; U/L] × creatinine [mg/dL]/platelets [PLTs; 109 cells/L]) is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low PLTs have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and 2 new modified EASIX formulas (simplified EASIX, which excludes creatinine, and modified EASIX [m-EASIX], which replaces creatinine with CRP [mg/dL]), calculated peri-CAR T-cell infusion, would be associated with development of severe (grade ≥ 3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene ciloleucel or tisagenlecleucel. The 3 formulas showed similar predictive power for severe CRS and ICANS. However, low PLTs and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (area under the curve [AUC] at lymphodepletion, 80.4%; at day -1, 73.0%; and at day +1, 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC, 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cell-related toxicities.

Fractionated Infusion of Hematopoietic Progenitor Cells Does Not Improve Neutrophil Recovery or Survival in Allograft Recipients.

Allogeneic hematopoietic cell transplantation (HCT) offers a potentially curative therapy in patients with hematologic malignancies; however, nonrelapse mortality (NRM) remains a concern. Strategies to improve neutrophil recovery and immune reconstitution are needed to decrease NRM. Murine models of allogeneic HCT suggest that fractionated hematopoietic progenitor cell (HPC) infusion may improve engraftment through improved access of HPCs to a viable hematopoietic niche. The primary objective of the present study was to determine the impact of fractionated infusion versus unfractionated (bulk) infusion of HPCs on the time to achieve neutrophil engraftment. Secondary objectives included the effect of fractionated versus bulk infusion of HPCs on platelet engraftment, immune reconstitution, the incidence of acute graft-versus-host disease (GVHD) grade II-IV, NRM, and overall survival (OS). In this randomized phase 2 study, patients with hematologic malignancies undergoing allogeneic HCT were randomized to receive HPC infusion as a bulk (bulk arm) or in fractions (fractionated arm): 4 × 106 CD34+ cells/kg recipient weight infused on day 0, with the remaining HPCs CD34+ cell-selected then infused in equally distributed aliquots on days 2, 4, and 6 post-HCT. Randomization was stratified by type of transplant, unmodified (i.e. T cell-replete graft) versus CD34+ cell-selected (T cell-depleted graft). Patients whose donor failed to collect at least 7 × 106 CD34+ cells/kg of recipient weight received bulk HPC infusions regardless of randomization, for safety. These patients continued the HCT process on study but were replaced until each arm reached the prespecified accrual target. Per protocol, these patients were not included in this modified intention-to-treat analysis. A total of 116 patients were enrolled. Donors of 42 patients failed to mobilize the minimum CD34+ cell dose (7 × 106 cells/kg recipient weight) and were excluded from the analysis. The 74 evaluable patients included 38 randomized to the bulk arm and 36 randomized to the fractionated arm. All patients engrafted. The median time to an absolute neutrophil count of ≥0.5 × 109/L was 11 days on both arms. The day +180 median CD4+ cell count was 179 cells/µL in the bulk arm and 111 cells/µL in the fractionated arm (P = .779). The cumulative incidence of grade II-IV acute GVHD on post-transplant day +100 was 32% in the bulk arm and 17% in the fractionated arm (P = .131). Two patients in the bulk arm, but none in the fractionated arm, experienced grade III-IV GVHD. The 4-year OS was 60% in the bulk arm and 62% in the fractionated arm (P = .414), whereas the 4-year cumulative incidences of NRM and relapse were similar in the 2 arms. Fractionated infusion of HPCs in allogeneic HCT recipients did not impact neutrophil or CD4+ cell recovery, NRM, relapse, or OS when compared with bulk HPC infusion. We also observed that with current mobilization techniques, it was unlikely that more than 60% of healthy donors would be able to collect >7 × 106 CD34+ cells/kg recipient weight for adult recipients. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Reduced-intensity conditioning hematopoietic stem cell transplantation for chronic lymphocytic leukemia and Richter's transformation.

Allogeneic hematopoietic stem cell transplantation (HSCT) may potentially cure patients with chronic lymphocytic leukemia (CLL) and Richter's transformation (CLL-RT) or CLL without RT, but the impact of novel agents on HSCT is unclear. CLL-RT patients have a grave prognosis, and their outcomes after HSCT are uncertain. We conducted a retrospective analysis of all 58 CLL patients, including 23 CLL-RT patients, who underwent reduced intensity conditioning (RIC) HSCT at Memorial Sloan Kettering Cancer Center (New York, NY) between September 2006 and April 2017. With a median follow-up of 68 months (range, 24-147 months), 5-year progression-free survival (PFS) was 40% (95% confidence interval [CI], 28%-56%), and overall survival (OS) was 58% (95% CI, 48%-74%). The 1-year graft-versus-host disease/relapse-free survival (GRFS) was 38% (95% CI, 25%-50%). Patients with CLL-RT and CLL patients without RT had comparable outcomes. In both cohorts, treatment-sensitive response and ≤3 previous lines of therapy produced superior PFS and OS. Outcomes were agnostic to adverse cytogenetic and molecular features. Novel agents did not have a negative impact on HSCT outcomes. Total body irradiation (TBI)-containing RIC yielded inferior PFS, OS, and GRFS. CLL-RT patients older than age 55 years who had an HSCT Comorbidity Index score of ≥2 demonstrated inferior OS. This study, which is the largest series of RIC-HSCT for patients with CLL-RT, provides evidence supporting RIC-HSCT in early remission courses for patients with CLL-RT and poor-risk CLL patients. TBI-containing RIC should be considered with caution.

The post-transplant scoring system (PTSS) is associated with outcomes in patients with MDS after CD34+selected allogeneic stem cell transplant.

The post-transplant scoring system (PTSS), developed by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy, is based on three independent post-transplant risk factors: grade of acute graft-versus-host disease, lack of platelet recovery before day 100, and relapse before day 100; discriminating low- (0), intermediate- (1-3), and high-risk (4-8) patients. We investigated the prognostic value of the PTSS in a cohort of patients with MDS who underwent myeloablative CD34-selected TCD transplants. From 2008 to 2018, 109 patients underwent a first TCD-HCT for MDS at our center. We used Cox proportional hazards models and different landmark analyses to evaluate the association of categorized PTSS score risk groups with overall survival (OS). Patients with an intermediate/ high risk PTSS score had decreased OS at day 180 (univariate HR 3.25 [95% CI 1.60, 6.60], p = 0.001) and at day 365 (univariate HR 5.42 [95% CI 2.21, 13.3], p < 0.001) compared to low risk PTSS scores. This association remained significant after adjusting for HCT-CI. PTSS score calculated at day 100 was not associated with OS, even after adjusting for HCT-CI subgroups. In summary, the PTSS predicted survival at day 180 and day 365 in recipients of T-cell-depleted allografts for myelodysplastic syndrome.

Neutropenia in adult acute myeloid leukemia patients represents a powerful risk factor for COVID-19 related mortality.

Patients with hematological malignancies are at risk for poor outcomes when diagnosed with coronavirus disease 2019 (COVID-19). It remains unclear whether cytopenias and specific leukemia subtypes play a role in the clinical course of COVID-19 infection. Here, we report outcomes and their clinical/laboratory predictors for 65 patients with acute and chronic leukemias diagnosed with COVID-19 between 8 March 2020 and 19 May 2020 at Memorial Sloan Kettering Cancer Center in New York City. Most patients had CLL (38%) or AML (26%). A total of 14 (22%) patients required high flow nasal cannula or were intubated for mechanical ventilation and 11 patients (17%) died. A diagnosis of AML (OR 4.7, p=.028), active treatment within the last 3 months (OR 5.22, p=.047), neutropenia within seven days prior and up to 28 days after SARS-CoV-2 diagnosis (11.75, p=.001) and ≥3 comorbidities (OR 6.55, p=.019) were associated with increased odds of death.