Low-dose decitabine plus venetoclax as post-transplant maintenance for high-risk myeloid malignancies.

Relapse remains a major cause of treatment failure following allogeneic stem cell transplantation (allo-SCT) for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We retrospectively investigated low-dose decitabine and venetoclax (DEC/VEN) as post-transplant maintenance in 26 older patients with AML and MDS. The cumulative incidence of day 100 gIII-IV acute graft versus host disease (GVHD) and 1-year moderate-severe chronic GVHD was 5% and 26%, respectively. One patient relapsed 14 m after transplant. The 1-year non-relapse mortality and survival were 11% and 84%, respectively. DEC/VEN is a safe and potentially effective strategy to reduce the risk of post-transplant relapse.

Post-transplant cyclophosphamide or cell selection in haploidentical allogeneic hematopoietic cell transplantation?

BACKGROUND: One major limitation for broader applicability of allogeneic hematopoietic cell transplantation (allo-HCT) in the past was the lack of HLA-matched histocompatible donors. Preclinical mouse studies using T-cell depleted haploidentical grafts led to an increased interest in the use of ex vivo T-cell depleted (TCD) haploidentical allo-HCT. TCD grafts through negative (T-cell depletion) or positive (CD34+ cell selection) techniques have been investigated to reduce the risk of graft-versus-host disease (GVHD) given the known implications of alloreactive T cells. A more practical approach to deplete alloreactive T cells in vivo using high doses of cyclophosphamide after allografting has proved to be feasible in overcoming the HLA barrier. Such approach has extended allo-HCT feasibility to patients for whom donors could not be found in the past. Nowadays, haploidentical donors represent a common donor source for patients in need of an allo-HCT. The broad application of haploidentical donors became possible by understanding the importance of depleting alloreactive donor T cells to facilitate engraftment and reduce incidence and severity of GVHD. These techniques involve ex vivo graft manipulation or in vivo utilization of pharmacologic agents, notably post-transplant cyclophosphamide (PTCy). DISCUSSION: While acknowledging that no randomized controlled prospective studies have been yet conducted comparing TCD versus PTCy in haploidentical allo-HCT recipients, there are two advantages that would favor the PTCy, namely ease of application and lower cost. However, emerging data on adverse events associated with PTCy including, but not limited to cardiac associated toxicities or increased incidence of post-allograft infections, and others, are important to recognize.

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.

Highlights into historical and current immune interventions for cancer.

Immunotherapy is an additional pillar when combined with traditional standards of care such as chemotherapy, radiotherapy, and surgery for cancer patients. It has revolutionized cancer treatment and rejuvenated the field of tumor immunology. Several types of immunotherapies, including adoptive cellular therapy (ACT) and checkpoint inhibitors (CPIs), can induce durable clinical responses. However, their efficacies vary, and only subsets of cancer patients benefit from their use. In this review, we address three goals: to provide insight into the history of these approaches, broaden our understanding of immune interventions, and discuss current and future approaches. We highlight how cancer immunotherapy has evolved and discuss how personalization of immune intervention may address present limitations. Cancer immunotherapy is considered a recent medical achievement and in 2013 was selected as the "Breakthrough of the Year" by Science. While the breadth of immunotherapeutics has been rapidly expanding, to include the use of chimeric antigen receptor (CAR) T-cell therapy and immune checkpoint inhibitor (ICI) therapy, immunotherapy dates back over 3000 years. The expansive history of immunotherapy, and related observations, have resulted in several approved immune therapeutics beyond the recent emphasis on CAR-T and ICI therapies. In addition to other classical forms of immune intervention, including human papillomavirus (HPV), hepatitis B, and the Mycobacterium bovis Bacillus Calmette-Guérin (BCG) tuberculosis vaccines, immunotherapies have had a broad and durable impact on cancer therapy and prevention. One classic example of immunotherapy was identified in 1976 with the use of intravesical administration of BCG in patients with bladder cancer; resulting in a 70 % eradication rate and is now standard of care. However, a greater impact from the use of immunotherapy is documented by the prevention of HPV infections that are responsible for 98 % of cervical cancer cases. In 2020, the World Health Organization (WHO) estimated that 341,831 women died from cervical cancer [1]. However, administration of a single dose of a bivalent HPV vaccine was shown to be 97.5 % effective in preventing HPV infections. These vaccines not only prevent cervical squamous cell carcinoma and adenocarcinoma, but also oropharyngeal, anal, vulvar, vaginal, and penile squamous cell carcinomas. The breadth, response and durability of these vaccines can be contrasted with CAR-T-cell therapies, which have significant barriers to their widespread use including logistics, manufacturing limitations, toxicity concerns, financial burden and lasting remissions observed in only 30 to 40 % of responding patients. Another, recent immunotherapy focus are ICIs. ICIs are a class of antibodies that can increase the immune responses against cancer cells in patients. However, ICIs are only effective against tumors with a high mutational burden and are associated with a broad spectrum of toxicities requiring interruption of administration and/or administration corticosteroids; both of which limit immune therapy. In summary, immune therapeutics have a broad impact worldwide, utilizing numerous mechanisms of action and when considered in their totality are more effective against a broader range of tumors than initially considered. These new cancer interventions have tremendous potential notability when multiple mechanisms of immune intervention are combined as well as with standard of care modalities.

Role of myeloid-derived suppressor cells in tumor recurrence.

The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically.

Enrichment of innate immune cells from PBMC followed by triple cytokine activation for adoptive immunotherapy.

Innate immune cells [Natural killer (NK) and gamma-delta (γδ) T-cells] have the advantage of mediating graft versus leukemia (GVL) without graft versus host disease (GVHD). Therefore, the infusion of activated innate immune cells post allogenic hematopoietic stem transplant (AHSCT) is a promising adoptive immunotherapy strategy for relapsed and/or refractory myeloid malignancies. Microbead depletion of T-cells and B-cells has been used as a graft manipulation method to prevent GVHD post haploidentical AHSCT. These grafts are enriched for NK and γδ T-cell receptor (TCR+) cells. Brief ex vivo activation of purified NK cells with interleukin (IL)-12, IL-18, and IL-15 [triple cytokines (TC)] has been shown to produce cells with a memory like function and significantly enhanced leukemia cytotoxicity. In our studies we depleted αß TCR+ and CD19+ B-cells from healthy donors' peripheral blood mononuclear cells (PBMC) using microbeads; enriching the frequency of NK and γδ TCR+ cells. Following overnight TC incubation, we observed that these innate immune cells were activated based on phenotypic expression of CD69 and CD25. Further, we observed increased cytotoxicity of TC activated innate immune cells against NK sensitive and NK refractory leukemic cell targets. Further, the presence or absence of monocytes did not alter activation marker expression or in vitro cytotoxicity of innate immune cells. Additionally, we observed correlation between target cytotoxicity and mature activated NK phenotypes (CD56dim or CD56dim with co-expression of the activation markers CD69+ and/or CD25+). This approach of depleting T- and B-cells from PBMCs, combined with overnight TC activation, provides a novel cell population for donor lymphocyte infusion (DLI) post AHSCT.

Integrating geriatric assessment and genetic profiling to personalize therapy selection in older adults with acute myeloid leukemia.

INTRODUCTION: Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection. MATERIALS AND METHODS: In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418). In the present report, we demonstrate feasibility of this approach. RESULTS: Broad eligibility criteria and co-management of patients with community oncologists allowed enrollment of 45% of all patients with AML treated at our center during the study period. The median time from enrollment to therapy initiation was two days (range 0-9). Over half of the trial patients had a score of ≥3 on hematopoietic cell transplantation comorbidity index, impairment in physical function (Short Physical Performance Battery), and Montreal Cognitive Assessment. Three fit patients received intensive chemotherapy, whereas other patients received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 3.7% (95% confidence interval [CI] 0.7-18.3%) and at 90 days was 29.6% (95% CI 15.9-48.5%). One-year overall survival was 66% (95% CI 60-87%). DISCUSSION: Our data demonstrate the feasibility of integrating geriatric assessment in precision oncology trials to define fitness for intensive chemotherapy. Broad eligibility criteria and academic-community collaboration can expand access to clinical trials.

The Missing LNK: Evolution from Cytosis to Chronic Myelomonocytic Leukemia in a Patient with Multiple Sclerosis and Germline SH2B3 Mutation.

Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis.

Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized.

Phase II clinical trial using anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) consolidation therapy for HER2 negative (0-2+) metastatic breast cancer.

BACKGROUND: Metastatic human epidermal growth receptor II (HER2) negative breast cancer remains incurable. Our phase I study showed that anti-CD3 × anti-HER2 bispecific antibody armed activated T cells (HER2 BATs) may be effective against HER2-tumors. This phase II trial evaluates the efficacy and immune responses of HER2 BATs given to patients with metastatic HER2-estrogen and/or progesterone receptor positive (HR+) and triple negative breast cancer (TNBC) as immune consolidation after chemotherapy. The primary objective of this study was to increase the traditional median time to progression after failure of first-line therapy of 2-4 months with the secondary endpoints of increasing overall survival (OS) and immune responses. METHODS: HER2- metastatic breast cancer (MBC) patients received 3 weekly infusions of HER2 BATs and a boost after 12 weeks. RESULTS: This phase II study included 24 HER2-HR+ and 8 TNBC patients who received a mean of 3.75 and 2.4 lines of prior chemotherapy, respectively. Eight of 32 evaluable patients were stable at 4 months after the first infusion. There were no dose limiting toxicities. Tumor markers decreased in 13 of 23 (56.5%) patients who had tumor markers. The median OS was 13.1 (95% CI 8.6 to 17.4), 15.2 (95% CI 8.6 to 19.8), and 12.3 (95% CI 2.1 to 17.8) months for the entire group, HER2-HR+, and TNBC patients, respectively. Median OS for patients with chemotherapy-sensitive and chemotherapy-resistant disease after chemotherapy was 14.6 (9.6-21.8) and 8.6 (3.3-17.3) months, respectively. There were statistically significant increases in interferon-γ immunospots, Th1 cytokines, Th2 cytokines, and chemokines after HER2 BATs infusions. CONCLUSIONS: In heavily pretreated HER2-patients, immune consolidation with HER2 BATs after chemotherapy appears to increase the proportion of patients who were stable at 4 months and the median OS for both groups as well as increased adaptive and innate antitumor responses. Future studies combining HER2 BATs with checkpoint inhibitors or other immunomodulators may improve clinical outcomes.

Usefulness of Charlson Comorbidity Index to Predict Early Mortality and Overall Survival in Older Patients With Acute Myeloid Leukemia.

INTRODUCTION: Older adults with acute myeloid leukemia (AML) often have significant comorbidities. We hypothesized that greater comorbidity burden predicts worse 1-month mortality and overall survival (OS) in patients ≥60 years with AML. MATERIALS AND METHODS: We included 50,668 patients ≥60 years diagnosed between 2004 and 2014 from the National Cancer Database; patients were divided into 3 groups with Charlson comorbidity index (CCI) 0, 1, and ≥2. Chi-square tests were used to examine the association between CCI and different variables. We used logistic regression and Cox proportional hazard models to determine predictors of 1-month mortality and OS, respectively. RESULTS: Among the entire cohort, 65% had CCI 0, 24% had CCI 1, and 11% had CCI ≥2. Thirty-four percent did not receive chemotherapy. Patients with CCI 0 were more likely to receive chemotherapy, especially multiagent chemotherapy and undergo upfront hematopoietic cell transplantation. In multivariate analyses, 1-month mortality and OS were significantly worse with CCI 1 or ≥2, compared with CCI 0 in the entire cohort, as the subgroup of only those patients who received chemotherapy. Younger age, male gender, higher annual income, academic facility, longer travel distance, and acute promyelocytic leukemia were associated with improved OS. CONCLUSION: In one of the largest real-world studies of older adults with AML, we demonstrated that greater comorbidity, measured by higher CCI, independently predicted worse early mortality and OS in older patients with AML. Higher CCI was more common with increasing age and correlated with lower likelihood of receiving chemotherapy and hematopoietic cell transplantation. Whether optimal comorbidity management and supportive care may improve outcomes needs to be studied further.

Effects of Distance From Academic Cancer Center on Overall Survival of Acute Myeloid Leukemia: Retrospective Analysis of Treated Patients.

INTRODUCTION: Patients living farther away from academic centers may not have easy access to resources for management of acute myeloid leukemia (AML). We aimed to analyze the effect of distance traveled on overall survival (OS) of AML patients treated at an academic center. PATIENTS AND METHODS: AML patients diagnosed at the University of Nebraska Medical Center were divided into 4 groups according to the shortest distance between the cancer center and patients' residence (<25, 25-50, 50-100, and > 100 miles). Chi-square test and ANOVA were used to examine the association of distance with patient characteristics. OS, defined as the time from diagnosis of AML to death from any cause, was determined by the Kaplan-Meier method. Comparison of survival curves was done by the log-rank test. Multivariable analysis using Cox regression was performed to detect the survival effect of distance from the cancer center. RESULTS: The total number of patients was 449. Median distance was 85 miles (interquartile range, 20-180). OS at 1 year for < 25, 25-50, 50-100, and > 100 miles was 45%, 55%, 38%, and 40% respectively (P = .6). In a Cox regression analysis, distance from treatment center, as a continuous variable, was not a significant factor for death (hazard ratio, 1.001; 95% confidence interval, 1.000-1.001). Multivariable analysis showed nonsignificant trend of increased mortality for patients traveling > 100 miles to a cancer center. CONCLUSION: This study did not demonstrate an association between distance from an academic cancer center and OS in AML. This finding should provide some assurance to patients who live farther away from academic centers.

Prevalence and effects of polypharmacy on overall survival in acute myeloid leukemia.

Polypharmacy, usually defined as taking ≥5 prescribed medications, increases chances of drug-drug interactions and toxicities, and may harm cancer patients who need multiple chemotherapeutic agents and supportive medications. We analyzed the effects of polypharmacy in overall survival (OS) in acute myeloid leukemia (AML). A total of 399 patients were divided into two groups: patients with polypharmacy (≥5 medications) versus without polypharmacy (<5 medications). Polypharmacy was associated with age ≥60 years, Karnofsky Performance Status of ≤80, hematopoietic cell transplant (HCT) comorbidity index of ≥5, and adverse cytogenetics. Patients with polypharmacy were less likely to receive intensity chemotherapy or HCT. One-year OS of patients with polypharmacy versus those without polypharmacy was 29 vs. 49% (p<.001). Polypharmacy conferred worse OS in patients <60 years (37 vs. 65% at 1 year, HR 1.95, 95% CI 1.21-3.15) but not in patients ≥60 years (26 vs. 27% at 1 year, HR 1.12, 95% CI 0.81-1.57). Thus, polypharmacy has negative impact on OS in AML, particularly among patients aged <60 years.

Survival of Older Adults With Newly Diagnosed Acute Myeloid Leukemia: Effect of Using Multiagent Versus Single-agent Chemotherapy.

BACKGROUND: Controversy exists regarding the optimal chemotherapy regimen for older adults with acute myeloid leukemia (AML). PATIENTS AND METHODS: We analyzed data from the US National Cancer Data Base of 25,621 patients aged 60 to 79 years, with a diagnosis of AML from 2004 to 2014, who had received single-agent versus multiagent chemotherapy. A Cox proportional hazard model was used for overall survival (OS) analysis for the entire study cohort and separately for patients who had received single-agent (n = 6743) versus multiagent (n = 6743) chemotherapy, matched for age, Charlson comorbidity index, and AML subtype. RESULTS: The use of multiagent chemotherapy was high overall (70%) but declined with factors, such as increasing age, Charlson comorbidity index, AML subtype other than good risk, academic center, lower rate of high school graduation, and more recent year of diagnosis. Patients treated with multiagent chemotherapy had greater 1-year OS (43% vs. 28%), especially for patients aged 60 to 69 years and those with good-risk AML or Charlson comorbidity index of 0 to 1. OS (hazard ratio, 1.32; 95% confidence interval, 1.28-1.36) remained more favorable for the multiagent chemotherapy group on multivariable analysis. This was confirmed in a matched cohort analysis. CONCLUSIONS: To the best of our knowledge, this is the largest real-world study that has demonstrated an association between factors such as age, comorbidity, and AML subtype and the use of multiagent chemotherapy. The use of multiagent chemotherapy was associated with improved OS, especially for patients aged <70 years, those with good-risk AML, and those with a low Charlson comorbidity index.

Effects of Obesity on Overall Survival of Adults With Acute Myeloid Leukemia.

BACKGROUND: The role of obesity in prognosis of acute myeloid leukemia (AML) is debatable. Our retrospective study aimed to determine the effect of obesity on overall survival (OS) in AML. PATIENTS AND METHODS: AML patients diagnosed at University of Nebraska Medical Center were divided into 3 groups according to body mass index (BMI): normal (18.5-25 kg/m2) or underweight (< 18.5 kg/m2); overweight (25-30 kg/m2); and obese (≥ 30 kg/m2). Chi-square test, Kruskal-Wallis test, and ANOVA were used to examine the association of BMI with baseline characteristics. Mann-Whitney test was used for pairwise comparisons of hematopoietic cell transplantation (HCT) comorbidity index. Bonferroni correction was used to adjust P values. OS, defined as time from diagnosis to death from any cause, was determined by the Kaplan-Meier method; comparisons of survival curves were done using log-rank test. Cox regression analysis was performed to detect the effect of BMI on OS. RESULTS: Of 314 patients, 38% were obese, 68% received intensive chemotherapy, and 30% underwent HCT. Patient characteristics for all BMI groups were similar except greater HCT comorbidity index in obese patients. Actual body weight was used to calculate the chemotherapy dose in 92% of obese patients. The rates of receipt of HCT in normal, overweight, and obese groups were 33%, 32%, and 25%, respectively (P = .6). One-year OS values for normal/underweight, overweight, and obese groups was 42%, 45%, and 39%, respectively (P = .31). On multivariate analysis, obesity was associated with worse OS compared to normal-weight (hazard ratio = 0.6; 95% confidence interval, 0.4-0.9; P = .03) but not overweight patients. CONCLUSION: Obesity confers worse prognosis in AML. Differences in OS were not the result of differences in chemotherapy dose or receipt of HCT.

Summary of the Third Annual Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling.

The third annual Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling was held on November 29, 2018, at the American Society of Hematology (ASH) annual meeting. This workshop featured the latest research focused on minimal residual disease (MRD) assessment and immune profiling (IP) in myeloma as well as discussion of the statistical and regulatory issues intrinsic to the development of MRD as a surrogate endpoint. In this report, we provide a summary of the workshop and focus on the integration of MRD and IP assessment into trial design and clinical practice.

Intensity of chemotherapy for the initial management of newly diagnosed acute myeloid leukemia in older patients.

Aim: This study evaluated the overall survival (OS) of older patients (≥60 years) with acute myeloid leukemia based on the intensity of treatment. Methods: This single center, retrospective study included 211 patients diagnosed between 2000 and 2016, who received 10-day decitabine, low-intensity therapy or high-intensity therapy. Cox regression examined the impact of therapy on OS. Results: Younger patients were more likely to receive high-intensity therapy. Patients who received low-intensity therapy had worse OS compared with high-intensity therapy (median OS: 1.2 vs 8.5 months; p < 0.01). OS was similar with 10-day decitabine (median OS of 6.3 months) compared with either low-intensity therapy or high-intensity therapy. Conclusion: Ten-day decitabine is an effective alternative in older patients with newly diagnosed acute myeloid leukemia.

Three prophylaxis regimens (tacrolimus, mycophenolate mofetil, and cyclophosphamide; tacrolimus, methotrexate, and bortezomib; or tacrolimus, methotrexate, and maraviroc) versus tacrolimus and methotrexate for prevention of graft-versus-host disease with haemopoietic cell transplantation with reduced-intensity conditioning: a randomised phase 2 trial with a non-randomised contemporaneous control group (BMT CTN 1203).

BACKGROUND: Prevention of graft-versus-host disease (GvHD) without malignant relapse is the overall goal of allogeneic haemopoietic cell transplantation (HCT). We aimed to evaluate regimens using either maraviroc, bortezomib, or post-transplantation cyclophosphamide for GvHD prophylaxis compared with controls receiving the combination of tacrolimus and methotrexate using a novel composite primary endpoint to identify the most promising intervention to be further tested in a phase 3 trial. METHODS: In this prospective multicentre phase 2 trial, adult patients aged 18-75 years who received reduced-intensity conditioning HCT were randomly assigned (1:1:1) by random block sizes to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide (cyclophosphamide 50 mg/kg on days 3 and 4, followed by tacrolimus starting on day 5 and mycophenolate mofetil starting on day 5 at 15 mg/kg three times daily not to exceed 1 g from day 5 to day 35); tacrolimus, methotrexate, and bortezomib (bortezomib 1·3 mg/m2 intravenously on days 1, 4, and 7 after HCT); or tacrolimus, methotrexate, and maraviroc (maraviroc 300 mg orally twice daily from day -3 to day 30 after HCT). Methotrexate was administered as a 15 mg/m2 intravenous bolus on day 1 and 10 mg/m2 intravenous bolus on days 3, 6, and 11 after HCT; tacrolimus was given intravenously at a dose of 0·05 mg/kg twice daily (or oral equivalent) starting on day -3 (except the post-transplantation cyclophosphamide, as indicated), with a target level of 5-15 ng/mL. Tacrolimus was continued at least until day 90 and was tapered off by day 180. Each study group was compared separately to a contemporary non-randomised prospective cohort of patients (control group) who fulfilled the same eligibility criteria as the trial, but who were treated with tacrolimus and methotrexate at centres not participating in the trial. The primary endpoint (GvHD-free, relapse-free survival [GRFS]) was defined as the time from HCT to onset of grade 3-4 acute GvHD, chronic GvHD requiring systemic immunosuppression, disease relapse, or death. The study was analysed by modified intention to treat. The study is closed to accrual and this is the planned analysis. This trial is registered with ClinicalTrials.gov, number NCT02208037. FINDINGS: Between Nov 17, 2014, and May 18, 2016, 273 patients from 31 US centres were randomly assigned to the three study arms: 89 to tacrolimus, methotrexate, and bortezomib; 92 to tacrolimus, methotrexate, and maraviroc; 92 to tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; and six were excluded. Between Aug 1, 2014, and Sept 14, 2016, 224 controls received tacrolimus and methotrexate. Controls were generally well matched except for more frequent comorbidities than the intervention groups and a different distribution of types of conditioning regimens used. Compared with controls, the hazard ratio for GRFS was 0·72 (90% CI 0·54-0·94; p=0·044) for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide, 0·98 (0·76-1·27; p=0·92) for tacrolimus, methotrexate, and bortezomib, and 1·10 (0·86-1·41; p=0·49) for tacrolimus, methotrexate, and maraviroc. 238 patients experienced grade 3 or 4 toxicities: 12 (13%) had grade 3 and 67 (73%) grade 4 events with tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; ten (11%) had grade 3 and 68 (76%) had grade 4 events with tacrolimus, methotrexate, and bortezomib; and 18 (20%) had grade 3 and 63 (68%) had grade 4 events with tacrolimus, methotrexate, and maraviroc. The most common toxicities were haematological (77 [84%] for tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide; 73 [82%] for tacrolimus, methotrexate, and bortezomib; and 78 [85%] for tacrolimus, methotrexate, and maraviroc) and cardiac (43 [47%], 44 [49%], and 43 [47%], respectively). INTERPRETATION: Tacrolimus, mycophenolate mofetil, and post-transplantation cyclophosphamide was the most promising intervention, yielding the best GRFS; this regimen is thus being prospectively compared with tacrolimus and methotrexate in a phase 3 randomised trial. FUNDING: US National Health, Lung, and Blood Institute; National Cancer Institute; National Institute of Allergy and Infectious Disease; and Millennium Pharmaceuticals.