Treatment-Free Remission in Chronic Myeloid Leukemia.

With the discovery of tyrosine kinase inhibitors (TKIs), overall survival in patients with chronic myeloid leukemia (CML) now approaches that of the general population. While these TKIs have proven to be lifesaving, remaining on them lifelong creates both physical and financial burdens for patients. Recently, multiple trials have begun looking into the efficacy of trialing patients off these TKIs to see if they can sustain treatment-free remission (TFR). TFR eligibility is currently limited to a small population of patients with both robust and sustained responses to TKIs. Currently, for those who attempt a trial of TFR, the average success rates are promising, with anywhere from 38 to 54% of patients experiencing sustained TFR. For those who fail to maintain sustained TFR, safety results to date are reassuring, with almost all patients successfully responding to the re-initiation of TKIs, with death and disease progression being very rare complications. Moving forward, research is being conducted to more accurately risk stratify patients at diagnosis and pair them with optimized upfront treatment regimens aimed at increasing candidacy for the trial of TFR.

Addition of single dose gemtuzumab ozogamicin to intensive induction chemotherapy in core-binding factor acute myeloid leukemia.

In a meta-analysis of 5 trials, the addition of gemtuzumab ozogamicin (GO) to intensive induction chemotherapy led to a survival benefit in patients with core-binding factor (CBF) acute myeloid leukemia (AML). Given the heterogeneous incorporation of GO in clinical trials, the ideal dose and schedule remains unclear. We conducted a single-center retrospective analysis to compare outcomes of patients with CBF-AML treated with intensive induction chemotherapy, with or without a single dose of GO 3 mg/m2, during induction only. We included 87 patients (GO=32, control=55). The composite complete remission (cCR) rate was higher in the control group (93%) compared to the GO group (82%) (p<0.001). The rate of measurable residual disease (MRD) negative cCR, by flow cytometry, was similar between both groups. There were no significant differences between the two groups in terms of toxicity. The 3-year relapse-free survival (RFS) for both groups was similar (71% vs 68%, p=0.5). The 3-year overall survival (OS) for the GO group was 68%, compared to 66% for the control group (p=0.9).In multivariable analysis, age and MRD positive status were risk factors for inferior outcomes. We find that survival of patients with CBF-AML is favorable in the real-world setting. The addition of single-dose GO, during induction, did not lead to a higher remission rate or survival benefit, when compared to intensive chemotherapy without GO. Further investigation into the incorporation of GO in the treatment algorithm for CBF-AML is needed.

Integrating electronic geriatric assessment and frailty screening for adults with acute myeloid leukemia to drive personalized treatment decisions.

PURPOSE: Evidenced based guidelines for patients with Acute Myeloid Leukemia (AML) acknowledge increasing importance of frailty assessment when deciding on treatment, yet comprehensive geriatric assessment (GA) results are not easily incorporated into clinic workflows and the electronic health record. This study assessed the feasibility of electronic GA use in a real-world environment. METHODS: Patients with AML, ≥ 60 years and at a treatment decision-making point were recruited at three academic institutions. An electronic GA (eGA) was completed by patients prior to starting treatment. Results were immediately available on a dashboard. Data on feasibility, useability and acceptability of the intervention were collected immediately after the clinical visit. Patients completed follow up surveys at 3 months and chart reviews were done to capture treatment and toxicities. RESULTS: 77 patients were enrolled with a median age of 71 years (range=61-88). The eGA results were 25 fit (31.0 %), 22 (32.0 %) intermediate, and 23 (31.0 %) frail. There was 62.7 % (n = 47) provider concordance with the eGA result and 27 (36.0 %) post visit reports indicated that the eGA results influenced the treatment decision. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. CONCLUSION: Patients easily completed an eGA prior to starting treatment. Results were reviewed by the physician and considered in the decision for optimal treatment. One third of physician reports indicated the results were used to inform the treatment decision. Feasibility of completing the eGA in the clinic without workflow disruption and utility of the results was demonstrated.

Allogeneic hematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a CIBMTR analysis.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.

Utility of end of induction bone marrow biopsy and survival outcomes in acute promyelocytic leukemia treated with fixed-dose induction regimen.

Significant variations exist related to the end of induction practices in the management of Acute Promyelocytic Leukemia (APL). These variations include all-trans retinoic acid (ATRA)-arsenic trioxide (ATO) in fixed doses versus continuation until hematologic complete remission (CR) and performance versus omission of post-induction bone marrow biopsy to confirm morphological CR. A retrospective chart review was conducted of 61 patients (42 low/intermediate-risk and 19 high-risk) aged ≥ 18 years with newly diagnosed APL treated with fixed duration ATRA-ATO +/- cytoreduction at a tertiary medical center from December 2012 through March 2020. Of the 54 patients with post-induction bone marrow biopsy results, 52 (96%) demonstrated no morphologic evidence of APL while the remaining were equivocal. After 2.6 years median follow-up, no relapses occurred. The estimated 2-year overall survival rate of 95% suggests excellent outcomes with a fixed ATO induction regimen and safe omission of post-induction bone marrow biopsy irrespective of hematologic parameters.

Novel developments in the prophylaxis and treatment of acute GVHD.

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic hematopoietic cell transplant. Traditional standard prophylaxis for aGVHD has included a calcineurin inhibitor plus an antimetabolite, whereas treatment has relied mainly on corticosteroids, followed by multiple nonstandard second-line options. In the past decade, this basic framework has been reshaped by approval of antithymocyte globulin products, the emergence of posttransplant cyclophosphamide, and recent pivotal trials studying abatacept and vedolizumab for GVHD prophylaxis, whereas ruxolitinib was approved for corticosteroid-refractory aGVHD treatment. Because of this progress, routine acute GVHD prophylaxis and treatment practices are starting to shift, and results of ongoing trials are eagerly awaited. Here, we review recent developments in aGVHD prevention and therapy, along with ongoing and future planned clinical trials in this space, outlining what future goals should be and the limitations of current clinical trial designs and end points.

The COVID-19 Pandemic and In-Person Visit Rate Disruptions Among Patients With Hematologic Neoplasms in the US in 2020 to 2021.

Importance: The COVID-19 pandemic has led to a reduction in routine in-person medical care; however, it is unknown whether there have been any changes in visit rates among patients with hematologic neoplasms. Objective: To examine associations between the COVID-19 pandemic and in-person visits and telemedicine use among patients undergoing active treatment for hematologic neoplasms. Design, Setting, and Participants: Data for this retrospective observational cohort study were obtained from a nationwide electronic health record-derived, deidentified database. Data for patients with hematologic neoplasms who had received at least 1 systemic line of therapy between March 1, 2016, and February 28, 2021, were included. Treatments were categorized into 3 types: oral therapy, outpatient infusions, and inpatient infusions. The data cutoff date was April 30, 2021, when study analyses were conducted. Main Outcomes and Measures: Monthly visit rates were calculated as the number of documented visits (telemedicine or in-person) per active patient per 30-day period. We used time-series forecasting methods on prepandemic data (March 2016 to February 2020) to estimate expected rates between March 1, 2020, and February 28, 2021 (if the pandemic had not occurred). Results: This study included data for 24 261 patients, with a median age of 68 years (IQR, 60-75 years). A total of 6737 patients received oral therapy, 15 314 received outpatient infusions, and 8316 received inpatient infusions. More than half of patients were men (14 370 [58%]) and non-Hispanic White (16 309 [66%]). Early pandemic months (March to May 2020) demonstrated a significant 21% reduction (95% prediction interval [PI], 12%-27%) in in-person visit rates averaged across oral therapy and outpatient infusions. Reductions in in-person visit rates were also significant for all treatment types for multiple myeloma (oral therapy: 29% reduction; 95% PI, 21%-36%; P = .001; outpatient infusions: 11% reduction; 95% PI, 4%-17%; P = .002; inpatient infusions: 55% reduction; 95% PI, 27%-67%; P = .005), for oral therapy for chronic lymphocytic leukemia (28% reduction; 95% PI, 12%-39%; P = .003), and for outpatient infusions for mantle cell lymphoma (38% reduction; 95% PI, 6%-54%; P = .003) and chronic lymphocytic leukemia (20% reduction; 95% PI, 6%-31%; P = .002). Telemedicine visit rates were highest for patients receiving oral therapy, with greater use in the early pandemic months and a subsequent decrease in later months. Conclusions and Relevance: In this cohort study of patients with hematologic neoplasms, documented in-person visit rates for those receiving oral therapy and outpatient infusions significantly decreased during the early pandemic months but returned to close to projected rates in the later half of 2020. There were no statistically significant reductions in the overall in-person visit rate for patients receiving inpatient infusions. There was higher telemedicine use in the early pandemic months, followed by a decline, but use was persistent in the later half of 2020. Further studies are needed to ascertain associations between the COVID-19 pandemic and subsequent cancer outcomes and the evolution of telemedicine use for care delivery.

Goals, preferences, and concerns of patients with acute myeloid leukemia at time of treatment decision.

INTRODUCTION: Current cancer value-based models require documentation of patient goals of care and an evidence-based treatment course commensurate with patient goals. This feasibility study assessed the utility of an electronic tablet-based questionnaire to elicit patient goals, preferences, and concerns at a treatment decision making time point in patients with acute myeloid leukemia. MATERIALS AND METHODS: Seventy-seven patients were recruited from three institutions prior to seeing the physician for treatment decision-making visit. Questionnaires included demographics, patient beliefs, and decision-making preferences. Analyses included standard descriptive statistics appropriate for the level of measurement. RESULTS: Median age was 71 (range = 61-88), 64.9% female, 87.0% white, and 48.6% college educated. On average, patients completed the surveys unassisted in 16.24 min and providers reviewed the dashboard in 3.5 min. All but one patient completed the survey prior to starting treatment (98.7%). Providers reviewed the survey results prior to seeing the patient 97.4% of the time. When asked their goals of care, 57 (74.0%) patients agreed with the statement "my cancer is curable" and 75 (97.4%) agreed that the treatment goal was to get rid of all cancer. Seventy-seven (100%) agreed the goal of care is to feel better and 76 (98.7%) agreed the goal of care is live longer. Forty-one (53.9%) indicated they wanted to make treatment decisions together with the provider. The top two concerns were understanding treatment options (n = 24; 31.2%) and making the right decision (n = 22; 28.6%). DISCUSSION: This pilot demonstrated the feasibility of using technology for decision-making at the point of care. Eliciting patient goals of care, treatment outcomes expectations, decision-making preferences, and top concerns may provide clinicians with information to inform the treatment discussion. A simple electronic tool may provide valuable insight into patient understanding of disease to better tailor patient-provider discussion and treatment decision-making.

Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease Prophylaxis.

BACKGROUND: In patients undergoing allogeneic hematopoietic stem-cell transplantation (HSCT), a calcineurin inhibitor plus methotrexate has been a standard prophylaxis against graft-versus-host disease (GVHD). A phase 2 study indicated the potential superiority of a post-transplantation regimen of cyclophosphamide, tacrolimus, and mycophenolate mofetil. METHODS: In a phase 3 trial, we randomly assigned adults with hematologic cancers in a 1:1 ratio to receive cyclophosphamide-tacrolimus-mycophenolate mofetil (experimental prophylaxis) or tacrolimus-methotrexate (standard prophylaxis). The patients underwent HSCT from an HLA-matched related donor or a matched or 7/8 mismatched (i.e., mismatched at only one of the HLA-A, HLA-B, HLA-C, and HLA-DRB1 loci) unrelated donor, after reduced-intensity conditioning. The primary end point was GVHD-free, relapse-free survival at 1 year, assessed in a time-to-event analysis, with events defined as grade III or IV acute GVHD, chronic GVHD warranting systemic immunosuppression, disease relapse or progression, and death from any cause. RESULTS: In a multivariate Cox regression analysis, GVHD-free, relapse-free survival was significantly more common among the 214 patients in the experimental-prophylaxis group than among the 217 patients in the standard-prophylaxis group (hazard ratio for grade III or IV acute GVHD, chronic GVHD, disease relapse or progression, or death, 0.64; 95% confidence interval [CI], 0.49 to 0.83; P = 0.001). At 1 year, the adjusted GVHD-free, relapse-free survival was 52.7% (95% CI, 45.8 to 59.2) with experimental prophylaxis and 34.9% (95% CI, 28.6 to 41.3) with standard prophylaxis. Patients in the experimental-prophylaxis group appeared to have less severe acute or chronic GVHD and a higher incidence of immunosuppression-free survival at 1 year. Overall and disease-free survival, relapse, transplantation-related death, and engraftment did not differ substantially between the groups. CONCLUSIONS: Among patients undergoing allogeneic HLA-matched HSCT with reduced-intensity conditioning, GVHD-free, relapse-free survival at 1 year was significantly more common among those who received cyclophosphamide-tacrolimus-mycophenolate mofetil than among those who received tacrolimus-methotrexate. (Funded by the National Heart, Lung, and Blood Institute and others; BMT CTN 1703 ClinicalTrials.gov number, NCT03959241.).

Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced-intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (fludarabine/ busulfan n=166, fludarabine/melphalan n=327) and 379 using MAC (fludarabine/busulfan n=247, busulfan/cyclophosphamide n=132). In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (hazard ratio [HR]=1.80; 95% confidenec interval [CI]: 1.15-2.81; P=0.009), higher early non-relapse mortality (HR=1.81; 95% CI: 1.12-2.91; P=0.01) and higher acute graft-versus-host disease (GvHD) (grade 2-4 HR=1.45; 95% CI: 1.03-2.03; P=0.03; grade 3-4 HR=2.21; 95%CI: 1.28-3.83; P=0.004) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GvHD (grade 2-4 HR=2.33; 95% CI: 1.67-3.25; P<0.001; grade 3-4 HR=2.31; 95% CI: 1.52-3.52; P<0.001) and inferior GvHD-free relapse-free survival (GRFS) (HR=1.94; 95% CI: 1.49-2.53; P<0.001) as compared to fludarabine/busulfan. Hence, our study suggests that fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GvHD) and MAC (lower acute GvHD and better GRFS) in myelofibrosis.

Impact of pre-transplant individual comorbidities on risk of ICU admission and survival outcomes following allogeneic hematopoietic stem cell transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (allo-hsct) can require intensive care unit (ICU) admission in the post-transplant period. Whereas outcomes of ICU admission are poor, little is known about the pre-transplant risk factors leading to them. We conducted a retrospective analysis to investigate the impact of pre-transplant individual comorbidities on acute inpatient complications, focusing on ICU admission, ventilator support and multi-system organ failure, following allo-hsct. During the initial hospitalization, 33 (11%) patients required ICU admission, 29 (10%) required ventilator support and 33 (11%) developed multi-system organ failure. Risk factors for ICU admission and ventilator support included pre-transplant infection, pre-transplant diabetes, time to neutrophil engraftment, donor type and older transplant decade (2008-2010). Risk factors for multi-system organ failure included pre-transplant diabetes, time to neutrophil engraftment and older transplant decade (2008-2010). For ICU patients, the 60-day and 6-month mortality was 58% and 67%, respectively and the median overall survival was 1.4 months. Patients with diabetes and infection at the time of HSCT and longer time to neutrophil engraftment during transplant are at an increased risk for ICU admission, ventilator support and multi-system organ failure. Patients admitted to the ICU are also at a high risk for mortality leading to poor survival.

Impact of pre-transplant induction and consolidation cycles on AML allogeneic transplant outcomes: a CIBMTR analysis in 3113 AML patients.

We investigated the impact of the number of induction/consolidation cycles on outcomes of 3113 adult AML patients who received allogeneic hematopoietic cell transplantation (allo-HCT) between 2008 and 2019. Patients received allo-HCT using myeloablative (MAC) or reduced-intensity (RIC) conditioning in first complete remission (CR) or with primary induction failure (PIF). Patients who received MAC allo-HCT in CR after 1 induction cycle had 1.3-fold better overall survival (OS) than 2 cycles to CR and 1.47-fold better than ≥3 cycles. OS after CR in 2 or ≥3 cycles was similar. Relapse risk was 1.65-fold greater in patients receiving ≥3 cycles to achieve CR. After RIC allo-HCT, the number of induction cycles to CR did not affect OS. Compared to CR in 1 cycle, relapse risk was 1.24-1.41-fold greater in patients receiving 2 or ≥3 cycles. For patients receiving only 1 cycle to CR, consolidation therapy prior to MAC allo-HCT was associated with improved OS vs. no consolidation therapy. Detectable MRD at the time of MAC allo-HCT did not impact outcomes while detectable MRD preceding RIC allo-HCT was associated with an increased risk of relapse. For allo-HCT in PIF, OS was significantly worse than allo-HCT in CR after 1-3 cycles.

Adaptation of Remote Symptom Monitoring Using Electronic Patient-Reported Outcomes for Implementation in Real-World Settings.

PURPOSE: Despite evidence of clinical benefits, widespread implementation of remote symptom monitoring has been limited. We describe a process of adapting a remote symptom monitoring intervention developed in a research setting to a real-world clinical setting at two cancer centers. METHODS: This formative evaluation assessed core components and adaptations to improve acceptability and fit of remote symptom monitoring using Stirman's Framework for Modifications and Adaptations. Implementation outcomes were evaluated in pilot studies at the two cancer centers testing technology (phase I) and workflow (phase II and III) using electronic health data; qualitative evaluation with semistructured interviews of clinical team members; and capture of field notes from clinical teams and administrators regarding barriers and recommended adaptations for future implementation. RESULTS: Core components of remote symptom monitoring included electronic delivery of surveys with actionable symptoms, patient education on the intervention, a system to monitor survey compliance in real time, the capacity to generate alerts, training nurses to manage alerts, and identification of personnel responsible for managing symptoms. In the pilot studies, while most patients completed > 50% of expected surveys, adaptations were identified to address barriers related to workflow challenges, patient and clinician access to technology, digital health literacy, survey fatigue, alert fatigue, and data visibility. CONCLUSION: Using an implementation science approach, we facilitated adaptation of remote symptom monitoring interventions from the research setting to clinical practice and identified key areas to promote effective uptake and sustainability.