Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia.

Transcriptome sequencing has identified multiple subtypes of B-progenitor acute lymphoblastic leukemia (B-ALL) of prognostic significance, but a minority of cases lack a known genetic driver. Here, we used integrated whole-genome (WGS) and -transcriptome sequencing (RNA-seq), enhancer mapping, and chromatin topology analysis to identify previously unrecognized genomic drivers in B-ALL. Newly diagnosed (n = 3221) and relapsed (n = 177) B-ALL cases with tumor RNA-seq were studied. WGS was performed to detect mutations, structural variants, and copy number alterations. Integrated analysis of histone 3 lysine 27 acetylation and chromatin looping was performed using HiChIP. We identified a subset of 17 newly diagnosed and 5 relapsed B-ALL cases with a distinct gene expression profile and 2 universal and unique genomic alterations resulting from aberrant recombination-activating gene activation: a focal deletion downstream of PAN3 at 13q12.2 resulting in CDX2 deregulation by the PAN3 enhancer and a focal deletion of exons 18-21 of UBTF at 17q21.31 resulting in a chimeric fusion, UBTF::ATXN7L3. A subset of cases also had rearrangement and increased expression of the PAX5 gene, which is otherwise uncommon in B-ALL. Patients were more commonly female and young adult with median age 35 (range,12-70 years). The immunophenotype was characterized by CD10 negativity and immunoglobulin M positivity. Among 16 patients with known clinical response, 9 (56.3%) had high-risk features including relapse (n = 4) or minimal residual disease >1% at the end of remission induction (n = 5). CDX2-deregulated, UBTF::ATXN7L3 rearranged (CDX2/UBTF) B-ALL is a high-risk subtype of leukemia in young adults for which novel therapeutic approaches are required.

Hypomethylating agents are associated with high rates of hematologic toxicity in patients with secondary myeloid neoplasms developing after acquired aplastic anemia.

Not available.

Obesity in adult acute myeloid leukemia is not associated with inferior response or survival even when dose capping anthracyclines: An ECOG-ACRIN analysis.

BACKGROUND: Obesity (body mass index [BMI] ≥30 kg/m2 ) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. METHODS: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). RESULTS: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate-risk cytogenetics group (p = .008), poorer performance status (p = .01), and a trend toward older age (p = .06). Obesity was not associated with somatic mutations among a selected 18-gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high-dose (90 mg/m2 ) daunorubicin arm (p = .002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90-2.13; p = .14). CONCLUSIONS: Obesity is associated with unique clinical and disease-related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area-based dosing is not necessary because dose adjustments do not affect outcomes.

Molecular classification improves risk assessment in adult BCR-ABL1-negative B-ALL.

Genomic classification has improved risk assignment of pediatric, but not adult B-lineage acute lymphoblastic leukemia (B-ALL). The international UKALLXII/ECOG-ACRIN E2993 (#NCT00002514) trial accrued 1229 adolescent/adult patients with BCR-ABL1- B-ALL (aged 14 to 65 years). Although 93% of patients achieved remission, 41% relapsed at a median of 13 months (range, 28 days to 12 years). Five-year overall survival (OS) was 42% (95% confidence interval, 39, 44). Transcriptome sequencing, gene expression profiling, cytogenetics, and fusion polymerase chain reaction enabled genomic subtyping of 282 patient samples, of which 264 were eligible for trial, accounting for 64.5% of E2993 patients. Among patients with outcome data, 29.5% with favorable outcomes (5-year OS 65% to 80%) were deemed standard risk (DUX4-rearranged [9.2%], ETV6-RUNX1/-like [2.3%], TCF3-PBX1 [6.9%], PAX5 P80R [4.1%], high-hyperdiploid [6.9%]); 50.2% had high-risk genotypes with 5-year OS of 0% to 27% (Ph-like [21.2%], KMT2A-AFF1 [12%], low-hypodiploid/near-haploid [14.3%], BCL2/MYC-rearranged [2.8%]); 20.3% had intermediate-risk genotypes with 5-year OS of 33% to 45% (PAX5alt [12.4%], ZNF384/-like [5.1%], MEF2D-rearranged [2.8%]). IKZF1 alterations occurred in 86% of Ph-like, and TP53 mutations in patients who were low-hypodiploid (54%) and BCL2/MYC-rearranged (33%) but were not independently associated with outcome. Of patients considered high risk based on presenting age and white blood cell count, 40% harbored subtype-defining genetic alterations associated with standard- or intermediate-risk outcomes. We identified distinct immunophenotypic features for DUX4-rearranged, PAX5 P80R, ZNF384-R/-like, and Ph-like genotypes. These data in a large adult B-ALL cohort treated with a non-risk-adapted approach on a single trial show the prognostic importance of genomic analyses, which may translate into future therapeutic benefits.

Real-world effectiveness of intensive chemotherapy with 7&3 versus venetoclax and hypomethylating agent in acute myeloid leukemia.

Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)-derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60-75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40-0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53-0.94). A sub-group of patients with equipoise, likelihood at least 30%-70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75-1.6). Regarding safety outcomes, 60-day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real-word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.

Which Second-Line Tyrosine Kinase Inhibitor(s) for Chronic Myeloid Leukemia?

OPINION STATEMENT: In patients with chronic myeloid leukemia who require second-line tyrosine kinase inhibitor therapy, many options exist. These treatments include alternate generation tyrosine kinase inhibitors and in some cases consideration of allogeneic transplant. Although efficacious, each tyrosine kinase inhibitor possesses distinct side effects and pharmacological profiles that prevent a generalizable treatment approach. Furthermore, there is limited head-to-head trial data that would suggest the superiority of one tyrosine kinase inhibitor over another to help guide treatment decisions in specific clinical settings. Therefore, we treat each patient independently. A patient's treatment plan must be personalized by a variety of clinical factors to optimize response and tolerability. Our general approach is to first examine the reason for treatment failure, which may be due to either intolerance or relapse. Second, we consider the age and patient's comorbidities such as lung disease, diabetes, or cardiovascular disease. In patients who have inadequate responses, we analyze the patient's BCR-ABL1 mutational profile, which is beneficial if that patient harbors a specific tyrosine kinase inhibitor responsive mutation, such as T315I. Using these steps, we can provide a generalizable approach to choosing the appropriate second-line tyrosine inhibitor for chronic myeloid leukemia.

One versus two sets of busulfan therapeutic drug monitoring in myeloablative allogeneic hematopoietic cell transplant.

INTRODUCTION: Busulfan is a common component of allogeneic hematopoietic cell transplant (alloHCT) conditioning, however interpatient pharmacokinetic variability can result in enhanced toxicity or increased relapse risk. Therapeutic drug monitoring (TDM) can minimize variability, yet the optimal frequency of TDM is unknown. We compared outcomes for patients with one versus two sets of busulfan TDM during myeloablative conditioning (MAC) prior to alloHCT. METHODS: We analyzed the impact of busulfan TDM frequency and dose adjustments, with the primary outcome being relapse-free survival (RFS). Other outcomes included the incidence of acute and chronic graft versus host disease (GVHD), oral mucositis, pulmonary toxicity, sinusoidal obstruction syndrome (SOS), the cumulative incidence of relapse (CIR), and overall survival (OS). RESULTS: Twenty-two patients underwent one set of sampling while 53 patients underwent two sets. Similar baseline characteristics were observed between the groups. There were no significant differences observed in RFS by day +180 (77.3% vs. 79.2%, p = 1.0), CIR by day +180 (18.2% vs. 17.8%, p = 0.74), or OS (p = 0.73). The incidences of acute GVHD, chronic GVHD, SOS, and severe mucositis were also similar. In each group, 63% received busulfan dose adjustments after one set, with 52.8% receiving further dose adjustments following the second set. CONCLUSION: We observed no significant difference in alloHCT outcomes between patients who underwent one versus two sets of busulfan TDM sampling, suggesting that a single-time TDM and dose adjustment may be adequate to maximize outcomes after MAC alloHCT.

Relationship Between Longitudinal Coping Strategies and Outcomes in Patients With Acute Myeloid Leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) face an abrupt life-threatening illness and experience immense physical and psychological symptoms. However, no data describe how patients with AML cope longitudinally with their illness or the relationship between longitudinal coping and outcomes. METHODS: We conducted a secondary analysis of longitudinal data from 160 patients with high-risk AML enrolled in a supportive care intervention trial to describe coping strategies longitudinally across the illness course. We used the Brief COPE questionnaire, the Hospital Anxiety and Depression Scale, the Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, and the Functional Assessment of Cancer Therapy-Leukemia to measure coping strategies, psychological distress, and quality of life (QoL) at baseline and at weeks 2, 4, 12, and 24 after diagnosis. Electronic health records were used to assess healthcare utilization and end-of-life (EoL) outcomes, and multivariate analyses were used to assess the relationship between coping and outcomes. RESULTS: Longitudinal utilization of approach-oriented coping strategies was significantly associated with less distress (anxiety: ß, -0.18; P<.001; depression symptoms: ß, -0.42; P<.001; PTSD symptoms: ß, -0.60; P<.001) and better QoL (ß, 2.00; P<.001). Longitudinal utilization of avoidant coping strategies was significantly associated with greater distress (anxiety: ß, 0.64; depression symptoms: ß, 0.54; PTSD symptoms: ß, 2.13; P<.001 for all) and worse QoL (ß, -4.27; P<.001). Although the use of approach-oriented and avoidant coping strategies was not significantly associated with hospitalization, chemotherapy administration, or hospice use in the last 30 days of life, approach-oriented coping was associated with lower odds of ICU admissions (odds ratio, 0.92; P=.049). CONCLUSIONS: Longitudinal use of approach-oriented coping strategies was associated with less psychological distress, better QoL, and a lower likelihood of ICU admission, suggesting a possible target for supportive oncology interventions. Coping strategies did not impact EoL outcomes, and further research is needed to elucidate which patient factors impact EoL decision-making.

Pentosan polysulfate for the treatment of hemorrhagic cystitis after allogeneic hematopoietic cell transplant.

INTRODUCTION: Hemorrhagic cystitis can commonly occur following an allogeneic hematopoietic cell transplant and treatment options are currently limited. Pentosan polysulfate, a heparin-like, sulfated polysaccharide, is used to relieve bladder pain and discomfort associated with interstitial cystitis. Initial reports in patients with hemorrhagic cystitis demonstrate that pentosan polysulfate may hasten hemorrhagic cystitis resolution and control symptoms. METHODS AND RESULTS: This report includes a retrospective case series of six patients who received pentosan polysulfate for the treatment of hemorrhagic cystitis following an allogeneic hematopoietic cell transplant. Pentosan polysulfate was initiated at a median of 4.5 days (range: 3-18) following hemorrhagic cystitis onset and continued for a median duration of 17.5 days (range: 7-64). Four patients were tested for BK virus and all were found to have BK viremia and viruria around the time of pentosan polysulfate initiation. The median number of red blood cell transfusions seemed to decrease in the patients initiated on pentosan polysulfate. All patients received a multi-agent treatment regimen, which included pentosan polysulfate, and half the patients had symptom resolution. The median time to symptom resolution from pentosan polysulfate initiation was 9 days (range: 7-10). CONCLUSION: Pentosan polysulfate was well-tolerated and seemed to assist with symptom resolution. Future studies are needed to confirm the impact of pentosan polysulfate on the treatment of hemorrhagic cystitis.

Day 4 vs. day 12 G-CSF administration following reduced intensity peripheral blood allogeneic stem cell transplant.

INTRODUCTION: Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis. METHODS: We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017-2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis. RESULTS: Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19-32) with day + 4 initiation vs. 24 days (21-30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups. CONCLUSION: Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.

Posttraumatic stress disorder symptoms in patients with acute myeloid leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) receiving intensive chemotherapy face a life-threatening illness, isolating hospitalization, and substantial physical and psychological symptoms. However, data are limited regarding risk factors of posttraumatic stress disorder (PTSD) symptoms in this population. METHODS: The authors conducted a secondary analysis of data from 160 patients with high-risk AML who were enrolled in a supportive care trial. The PTSD Checklist-Civilian Version was used to assess PTSD symptoms at 1 month after AML diagnosis. The Brief COPE and the Functional Assessment of Cancer Therapy-Leukemia were to assess coping and quality of life (QOL), respectively. In addition, multivariate regression models were constructed to assess the relation between PTSD symptoms and baseline sociodemographic factors, coping, and QOL. RESULTS: Twenty-eight percent of patients reported PTSD symptoms, describing high rates of intrusion, avoidance, and hypervigiliance. Baseline sociodemographic factors significantly associated with PTSD symptoms were age (B = -0.26; P = .002), race (B = -8.78; P = .004), and postgraduate education (B = -6.30; P = .029). Higher baseline QOL (B = -0.37; P ≤ .001) and less decline in QOL during hospitalization (B = -0.05; P = .224) were associated with fewer PTSD symptoms. Approach-oriented coping (B = -0.92; P = .001) was associated with fewer PTSD symptoms, whereas avoidant coping (B = 2.42; P ≤ .001) was associated with higher PTSD symptoms. CONCLUSIONS: A substantial proportion of patients with AML report clinically significant PTSD symptoms 1 month after initiating intensive chemotherapy. Patients' baseline QOL, coping strategies, and extent of QOL decline during hospitalization emerge as important risk factors for PTSD, underscoring the need for supportive oncology interventions to reduce the risk of PTSD in this population.

Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).

BACKGROUND: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML. METHODS: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796). RESULTS: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017). CONCLUSIONS: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.

Prognostic effect of gender on outcome of treatment for adults with acute myeloid leukaemia.

There are conflicting reports in the literature suggesting that one gender or the other has a better survival with acute myeloid leukaemia (AML). The present study was done in an attempt to resolve the issue. The effect of gender was examined on 3546 newly diagnosed patients with AML, including 548 patients with acute promyelocytic leukaemia (APL) enrolled in 10 multi-institutional treatment studies from March 1984 to November 2008. Kaplan-Meier estimates were used to estimate event-time distributions for survival and multivariate models were used to examine the gender effect after adjusting for multiple risk factors. P values were based on two-sided tests. Non-APL female patients had a significantly better overall (OS) but not disease-free survival (DFS) than males, irrespective of age, initial white blood cell count, or dose of daunorubicin. No differences were observed for obese or FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD)-positive patients. Female patients with APL had a significantly better OS and DFS than male patients with APL, and differences in survival were greater for patients with t(15;17) + other cytogenetic abnormalities compared with those with t(15;17) only. Gender is an independent prognostic variable in patients with AML. Whether these survival differences are due to hormonal, genetic or pharmacokinetic differences between the sexes or differential toxin exposure such as smoking is unknown. However, the former seems less likely as patient age did not influence the survival advantage for female patients.

A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children's Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Dose intensity for induction in acute myeloid leukemia: what, when, and for whom?

Intensive chemotherapy has been the backbone of the treatment of acute myeloid leukemia (AML) for decades. However, an increase in novel targeted agents, which has been brought about in part by a deeper understanding of the genetic makeup of AML, has led to remission-inducing regimens that do not require traditional cytotoxic agents. Combinations of a hypomethylating agent (HMA) and venetoclax have doubled the chance of remission for patients considered unfit for induction chemotherapy who would have traditionally been offered singleagent HMA. In fact, this regimen may rival the complete remission rate achieved with induction chemotherapy for certain populations such as the very elderly and those with secondary AML, but equivalency has yet to be established. Further advances include the addition of gemtuzumab ozogamicin and FLT3 inhibitors to induction chemotherapy, which improves survival for patients with core-binding factor and FLT3-mutated AML, respectively. Still, much work is needed to improve the outcomes of the highest-risk subgroups: frail patients and those with high-risk cytogenetics and/or TP53 mutations. Promisingly, the landscape of AML therapy is shifting dramatically and no longer is intensity, when feasible, always the best answer for AML.

Tacrolimus induced pseudogout following allogeneic hematopoietic cell transplant.

INTRODUCTION: Crystalline arthritis (CA), characterized by acute joint pain and erythema secondary to calcium pyrophosphate deposition (CPPD, or pseudogout) or monosodium urate crystals (gout), is a potentially underreported complication following allogeneic hematopoietic cell transplant (alloHCT). Graft-versus-host disease prophylaxis with calcineurin inhibitors (CNIs) causes hypomagnesemia and hyperuricemia, resulting in CA. CA related to tacrolimus has yet to be characterized following alloHCT. CASE REPORT: We retrospectively reviewed records of 450 consecutive patients undergoing alloHCT and identified 15 (3.3% incidence) who developed CA on tacrolimus. Large joints were involved in 10 (66.7%) patients, all patients had recent hypomagnesemia, and no patient had hyperuricemia, suggesting CPPD was the most likely etiology.Management and outcome: Eleven (73.3%) patients received systemic corticosteroids; 6 as initial therapy and 5 added to or substituted for colchicine in the setting of slow or inadequate response. The median duration of corticosteroid therapy was 6 days, however 2 patients (13.3%) required prolonged maintenance due to recurrence. Eleven (73.3%) patients received colchicine; 9 as initial therapy and 2 added to or substituted for corticosteroids in the setting of slow or inadequate response. The median duration of colchicine therapy was 18 days. The median time to symptom resolution was 21 days. DISCUSSION: Patients on tacrolimus following alloHCT presenting with acute joint pain and erythema should be evaluated for CPPD. Hypomagnesemia secondary to CNIs is likely the precipitating factor for CPPD in this population. Patients can effectively be managed with systemic corticosteroids and/or colchicine, however prolonged duration of treatment and even maintenance may be necessary. Based on the Naranjo Algorithm, CPPD secondary to tacrolimus induced hypomagnesemia is a possible adverse drug event, with a score of 3-4.

At three years, patients with acute lymphoblastic leukaemia are still at risk for relapse. Results of the international MRC UKALLXII/ECOG E2993 trial.

Late relapse [>3 years from complete remission (CR)] in acute lymphoblastic leukaemia (ALL), is unusual. Data from the MRC UKALLXII/ECOG E2993 trial are presented to evaluate the incidence and characteristics of late relapse in adult ALL. Of 1,909 patients, 1,752 (92%) achieved CR and among these 757 (43·2%) relapsed; 691 (91·3%) within three years and 66 (8·7%) beyond. Among these 66 patients, median time to relapse was 47 (37-144) months. Relapse beyond three years occurred in 3·8% of all who achieved CR. The cumulative risk of relapse was 40%, 43% and 45% at three, five and ten years respectively. Out of the 1 752 patients who achieved CR, 11·7% underwent autologous and 40·6% allogeneic transplant, while in CR1. Of the autologous patients, 43·2% relapsed early and 3·4% relapsed late. However, among the allogeneic patients, 13·2% relapsed early and only 1·3% late. The five-year overall survival from relapse was 5·8% and 20% in the early and late relapse patients respectively. In conclusion, late relapse in adults with ALL is not uncommon, and is associated with better outcome after relapse compared to early relapse.

Incorporation of extracorporeal photopheresis into a reduced intensity conditioning regimen in myelodysplastic syndrome and aggressive lymphoma: results from ECOG 1402 and 1902.

BACKGROUND: Extracorporeal photopheresis (ECP) is an immunomodulatory cellular therapy which has been shown to induce a tolerogenic state in patients with acute and chronic graft-vs-host disease. ECOG-ACRIN explored the activity of ECP as a part of a reduced intensity conditioning regimen in two multicenter trials in patients with MDS (E1902) and lymphomas (E1402). While both studies closed before completing accrual, we report results in 23 patients (17 MDS and 6 lymphoma). STUDY DESIGN AND METHODS: Patients received 2 days of ECP followed by pentostatin 4 mg/m2 /day for two consecutive days, followed by 600 cGy of total body irradiation prior to stem cell infusion. Immunosuppression for aGVHD was infusional cyclosporine A or tacrolimus and methotrexate on day +1, +3, with mycophenolate mofetil starting on day 100 for chronic GVHD prophylaxis. RESULTS: All patients engrafted, with median time to neutrophil and platelet engraftment of 15-18 days and 10-18 days respectively. Grade 3 or 4 aGVHD occurred in 13% and chronic extensive GVHD in 30%. CONCLUSIONS: These studies demonstrate that ECP/pentostatin/TBI is well tolerated and associated with adequate engraftment of neutrophils and platelets in patients with lymphomas and MDS.

Risk of invasive fungal infections in patients with high-risk MDS and AML receiving hypomethylating agents.

Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre-specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold-active prophylaxis can be considered in patients who are neutropenic at the start of therapy.

Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.