Molly Maloy

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

CD34-Selected Hematopoietic Stem Cell Transplants Conditioned with Myeloablative Regimens and Antithymocyte Globulin for Advanced Myelodysplastic Syndrome: Limited Graft-versus-Host Disease without Increased Relapse.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for patients with myelodysplastic syndrome (MDS). Donor T cells are critical for the graft-versus-tumor effect but carry the risk of graft-versus-host disease (GVHD). CD34 selection with immunomagnetic beads has been an effective method of depleting alloreactive donor T cells from the peripheral blood graft and has been shown to result in significant reduction in acute and chronic GVHD. We analyzed the outcomes of 102 adults (median age, 57.6 years) with advanced MDS who received a CD34-selected allo-HSCT between January 1997 and April 2012 at Memorial Sloan Kettering Cancer Center. The cumulative incidences of grades II to IV acute GVHD were 9.8% at day 100 (95% confidence interval [CI], 5.0% to 16.5%) and 15.7% at day 180 (95% CI, 9.4% to 23.4%). The cumulative incidence of chronic GVHD at 1 year was 3.9% (95% CI, 1.3% to 9.0%). The cumulative incidences of relapse were 11.8% at 1 year (95% CI, 6.4% to 18.9%) and 15.7% at 2 years (95% CI, 9.4% to 23.4%). Forty-eight patients were alive with a median follow-up of 71.7 months. Rates of overall survival (OS) were 56.9% at 2 years (95% CI, 48% to 67.3%) and 49.3% at 5 years (95% CI, 40.4% to 60.2%). Rates of relapse-free survival (RFS) were 52.0% at 2 years (95% CI, 41.9% to 61.1%) and 47.6% at 5 years (95% CI, 37.5% to 56.9%). The cumulative incidences of nonrelapse mortality were 7.8% at day 100 (95% CI, 3.7% to 14.1%), 22.5% at 1 year (95% CI, 15.0% to 31.1%), and 33.4% at 5 years (95% CI, 24.2% to 42.6%) post-transplant. The incidence of chronic GVHD/RFS overlapped with RFS. These findings demonstrate that ex vivo T cell-depleted allo-HSCT by CD34 selection offers long-term OS and RFS with low incidences of acute and chronic GVHD and without an increased risk of relapse.

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.

Resistance to imatinib in patients with chronic myelogenous leukemia and the splice variant BCR-ABL135INS

PURPOSE In patients with chronic myelogenous leukemia (CML), point mutations in the BCR-ABL1 kinase domain are the most common cause of treatment failure with a tyrosine kinase inhibitor (TKI). It is not clear whether the splice variant BCR-ABL1(35INS) is also associated with treatment failure. PATIENTS AND METHODS We reviewed all CML patients who had BCR-ABL1 kinase mutation analysis performed between August 1, 2007, and January 15, 2014. Patients who had BCR-ABL1(35INS) detected had their medical records reviewed to determine response to TKI therapy. RESULTS Two hundred and eighty four patients had kinase mutation testing performed; of these, 64 patients (23%) had BCR-ABL1(35INS) detected. Forty-five patients were in chronic phase (70%), 10 were in accelerated phase (16%), 6 were in blastic phase (9%), and 3 were in other settings (5%). Of the 34 chronic phase patients who began therapy with imatinib, 23 patients (68%) failed therapy: 8 patients (24%) had primary refractory disease, 11 patients (32%) progressed, and 4 patients (12%) had disease progression after dose interruption. In contrast to the patients with disease progression or lack of response, none of 23 patients who were responding to imatinib had BCR-ABL1(35INS) detected. DNA sequencing of commonly mutated spliceosomal genes SF3B1, U2AF1, SRSF2, ZRSR2, SFA31, PRPF408, U2A565, and SF1 did not reveal mutations in seven BCR-ABL1(35INS) -positive patients tested. CONCLUSIONS The splice variant BCR-ABL1(35INS) is frequently found in patients who are resistant to imatinib. Mutations in the commonly mutated spliceosomal proteins do not contribute to this association.

Sirolimus, tacrolimus and low-dose methotrexate based graft-versus-host disease prophylaxis after non-ablative or reduced intensity conditioning in related and unrelated donor allogeneic hematopoietic cell transplant.

Abstract Encouraging results have been reported with sirolimus, tacrolimus and low-dose methotrexate after non-myeloablative allogeneic hematopoietic cell transplant. We conducted a retrospective analysis of 71 patients with lymphoid malignancies treated with this prophylaxis regimen after non-myeloablative or reduced intensity allogeneic hematopoietic cell transplant. Grafts were human leukocyte antigen (HLA)-matched related in 29 (41%), matched unrelated in 36 (51%) and 9/10 HLA-matched unrelated in six (8%) patients. The regimen was well tolerated and over 90% of patients completed the planned treatment. The cumulative incidences of 1-year grade B–D and C–D acute graft-versus-host disease (GVHD) were 0.28 (95% confidence interval [CI], 0.18–0.39) and 0.07 (95% CI, 0.03–0.15), respectively, and of 1- and 2-year chronic GVHD (National Institutes of Health criteria) in 70 evaluable patients were 0.15 (95% CI, 0.08–0.24) and 0.33 (95% CI, 0.22–0.44), respectively. The median day of onset of acute GVHD was 123 days (range, 17–268 days). Peri-transplant rituximab or anti-thymocyte globulin did not affect GVHD. The cumulative incidence of 1-year non-relapse mortality and relapse were 4% and 20%, respectively. With a median follow-up of 3.5 (range: 0.18–5.1) years, overall survival and progression-free survival at 2 years were 82% and 66%, respectively. This GVHD regimen results in a low incidence and severity of acute and chronic GVHD after reduced intensity and non-myeloablative allogeneic hematopoietic cell transplant for lymphoid malignancies. The study also highlights the incidence of late onset acute GVHD in non-myeloablative/reduced intensity conditioning, and the contribution of the new GVHD staging system that more accurately reflects clinical outcomes.

Short- and long-term outcomes of adult allogeneic hematopoietic stem cell transplant patients admitted to the intensive care unit in the peritransplant period

Abstract Survival of allogeneic hematopoietic stem cell transplant (aHSCT) recipients in the intensive care unit (ICU) has been poor. We retrospectively analyzed the short- and long-term outcomes of aHSCT patients admitted to the ICU over a 12-year period. Of 1235 adult patients who had aHSCT between 2002 and 2013, 161 (13%) were admitted to the ICU. The impact of clinical parameters was assessed and outcomes were compared for the periods 2002–2007 and 2008–2013. The ICU, in-hospital, 1- and 5-year survival rates were 64.6%, 46%, 33% and 20%, respectively. Mechanical ventilation and vasopressor use predicted for worse hospital- and overall survival (OS). After 2008, the requirement for mechanical ventilation and vasopressors, and the diagnosis of sepsis were reduced. While hospital mortality decreased from 69% to 44%, long-term survival (LTS) remained unchanged. Late deaths, due to causes not associated with the ICU such as relapse and graft-versus-host disease, increased. As thresholds for transplant are lowered, improvements in ICU outcomes for aHSCT recipients may be limited.

Effects of Late Toxicities on Outcomes in Long-Term Survivors of Ex-Vivo CD34+-Selected Allogeneic Hematopoietic Cell Transplantation

The late adverse events in long-term survivors after myeloablative-conditioned allogeneic hematopoietic cell transplantation (HCT) with ex vivo CD34+ cell selection are not well characterized. Using the National Cancer Institutes Common Terminology Criteria for Adverse Events, version 4.0, we assessed all grade ≥3 toxicities from the start of conditioning to the date of death, relapse, or last contact in 131 patients who survived >1 year post-HCT, identifying 285 individual toxicities among 17 organ-based toxicity groups. Pretransplantation absolute lymphocyte count >.5 K/µL and serum albumin >4.0 g/dL were associated with a reduced risk of toxicities, death, and nonrelapse mortality (NRM), whereas serum ferritin >1000 ng/mL was associated with an increased risk of toxicities and NRM after 1 year. An HCT Comorbidity Index (HCT-CI) score ≥3 was associated with an increased risk of all-cause death and NRM, but was not associated with a specific increased toxicity risk after 1 year. Patients who incurred more than the median number of toxicities (n = 7) among all patients within the first year subsequently had an increased risk of hematologic, infectious, and metabolic toxicities, as well as an increased risk of NRM and inferior 4-year overall survival (OS) (67% versus 86%; P = .003) after the 1-year landmark. The development of grade II-IV acute graft-versus-host disease (GVHD) within the first year was associated with incurring >7 toxicities within the first year (P = .016), and also with an increased risk of all-cause death and NRM after 1 year. In multivariate models, cardiovascular, hematologic, hepatic, infectious, metabolic, neurologic, and pulmonary toxicities incurred after 1 year were independently associated with increased risk of death and NRM when adjusting for both HCT-CI and grade II-IV acute GVHD within the first year. One-year survivors of ex vivo CD34+ selection had a favorable 4-year OS of 77%, although the development of grade ≥3 toxicities after the first year was associated with poorer outcomes, emphasizing the fundamental importance of improving survivorship efforts that may improve long-term toxicity burden and outcome.

The Impact of Toxicities on First-Year Outcomes after Ex Vivo CD34+–Selected Allogeneic Hematopoietic Cell Transplantation in Adults with Hematologic Malignancies

Factors that impact first-year morbidity and mortality in adults undergoing myeloablative allogeneic hematopoietic cell transplantation with ex vivo CD34+ selection have not been previously reported. We assessed all toxicities ≥ grade 3 from the start of conditioning to date of death, relapse, or last contact in 200 patients during the first year after transplantation, identifying 1885 individual toxicities among 17 organ-based toxicity groups. The most prevalent toxicities in the first year were of infectious, metabolic, hematologic, oral/gastrointestinal, hepatic, cardiac, and pulmonary etiologies. Renal complications were minimal. Grades II to IV and III and IV acute GVHD at day 100 were 11.5% and 3%, respectively. In separate multivariate models, cardiovascular, hematologic, hepatic, neurologic, pulmonary, and renal toxicities negatively impacted nonrelapse mortality (NRM) and overall survival during the first year. A higher-than-targeted busulfan level, patient cytomegalovirus seropositivity, and an Hematopoietic Cell Transplantation-Specific Comorbidity Index of ≥3 were associated with increased risk of NRM and all-cause death. Ex vivo CD34+ selection had a favorable 1-year OS of 75% and NRM of 17% and a low incidence of sinusoidal obstruction syndrome. These data establish a benchmark to focus efforts in reducing toxicity burden while improving patient outcomes.

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.

Adenovirus Viremia in Adult CD34+ Selected Hematopoietic Cell Transplant Recipients: Low Incidence and High Clinical Impact

Adenovirus (ADV) infections after hematopoietic cell transplantation (HCT) range in severity from self-limited to fatal. We have previously reported high mortality rates in CD34(+) selected T cell-depleted (TCD) HCT recipients using symptomatic testing and culture methods for ADV detection. We report rates and outcomes of ADV viremia in 215 adult recipients of TCD HCT using the CliniMACS CD34(+) selection system. This was a prospective observational study of adults transplanted from March 21, 2012 through November 30, 2014 at Memorial Sloan-Kettering Cancer Center. TCD was performed using CliniMACS CD34(+) cell selection. Patients were monitored for ADV by whole blood PCR assay from +14 to +100 days post-transplant. ADV viremia was defined as ≥1 PCR above the lower limit of quantitation. ADV disease was defined per European Group for Blood and Marrow Transplantation guidelines. Treatment for ADV was at the clinicians discretion. Competing risk regression analyses were used to identify predictors for ADV viremia and overall survival. The median age was 55 years (range, 22 to 72); 215 patients underwent TCD. All patients received myeloablative conditioning. Eighteen patients (8% of cohort) had ADV viremia at a median onset of 57 days (interquartile range [IQR], 23 to 79) and with a median viral load at first detection of 2.6 log10 copies/mL (IQR, 2.5 to 4.0). The median maximal viral load was 4.5 log10 copies/mL (IQR, 3.5 to 5.9). No significant risk factor was identified for ADV viremia by univariate analysis. Six patients (3% of total cohort, 33% of viremic patients) developed ADV disease (3 colitis, 2 nephritis/cystitis, 1 pneumonitis). ADV viremia preceded onset of ADV disease a median of 11 days from the first positive quantitative PCR (range, +3 to +37) except in 1 patient with nephritis. Overall, 12 of 18 viremic patients (67%) received antiviral treatment (5 cidofovir only, 7 brincidofovir ± cidofovir). All patients with ADV disease were treated, and 6 patients were preemptively treated for ADV. Among the 18 viremic patients, 8 (44%) died during the study period, and, of those, 4 (22%) died of ADV. Early ADV viremia was infrequent (8%) among adult HCT recipients of CD34(+) selected allografts. Among viremic patients, rate of ADV disease was 33% and ADV attributable mortality was 22%. Further studies are needed to assess the impact of preemptive treatment with brincidofovir on improving outcomes of ADV infections in this patient population.