Determining treatment tolerance and fitness for intensive chemotherapy in older adults with AML: a call to action.

ABSTRACT: Determining fitness for intensive chemotherapy in an older adult with acute myeloid leukemia (AML) is an unanswered age-old question. Geriatric assessment captures any variation in multidimensional health, which can influence treatment tolerance. A prospective study is necessary to validate fitness criteria, determine whether geriatric assessment-based fitness performs superiorly to other criteria, and what components of geriatric assessment are associated with treatment tolerance. A validation study should enroll diverse patients from both academic and community centers and patients receiving intensive and lower-intensity chemotherapy. Geriatric assessment should include at minimum measures of comorbidity burden, cognition, physical function, and emotional health, which in previous smaller studies have shown to be associated with mortality in AML. These assessments should be completed before or within a few days of initiation of chemotherapy to reduce the influence of chemotherapy on the assessment results. Treatment tolerance has been measured by rates of toxicities in patients with solid malignancies; however, during the initial treatment of AML, rates of toxicities are very high regardless of treatment intensity. Early mortality, frequently used in previous studies, can provide a highly consequential and easily identifiable measure of treatment tolerance. The key end point to assess treatment tolerance, thus, should include early mortality. Other end points may include decline in function and quality of life and treatment modifications or cessation due to toxicities. Validating fitness criteria can guide treatment selection and supportive care interventions and are crucial to guide fitness-based trial eligibility, inform the interpretation of trial results, and facilitate drug labeling.

North American Blastic Plasmacytoid Dendritic Cell Neoplasm Consortium: position on standards of care and areas of need.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC's inaugural meetings are presented herein.

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Development and validation of the Therapy Preference Scale to understand patients´ systemic cancer treatment preferences.

We incorporated questions related to safety, effectiveness and other characteristics of systemic cancer treatment into a self-report questionnaire - the Therapy Preference Scale - that captures patients´ preferences. The authors asked 20 experts to assess content validity and an additional 20 experts, patients and community members to examine face validity and guide revisions. Key revisions included shortening the length, clarifying constructs and providing details to explain the context and trade-offs necessary to balance the risks and benefits of cancer treatment. The content validity index for the final questionnaire was 1.0, indicating that all questions were relevant. Reviewers expressed that the questionnaire would serve an important purpose. Experts, patients and community members guided revisions of the questionnaire and documented its value.

Risk Factors for Graft-versus-Host Disease in Haploidentical Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide.

Post-transplant cyclophosphamide (PTCy) has significantly increased the successful use of haploidentical donors with a relatively low incidence of graft-versus-host disease (GVHD). Given its increasing use, we sought to determine risk factors for GVHD after haploidentical hematopoietic cell transplantation (haplo-HCT) using PTCy. Data from the Center for International Blood and Marrow Transplant Research on adult patients with acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myeloid leukemia who underwent PTCy-based haplo-HCT (2013 to 2016) were analyzed and categorized into 4 groups based on myeloablative (MA) or reduced-intensity conditioning (RIC) and bone marrow (BM) or peripheral blood (PB) graft source. In total, 646 patients were identified (MA-BM = 79, MA-PB = 183, RIC-BM = 192, RIC-PB = 192). The incidence of grade 2 to 4 acute GVHD at 6 months was highest in MA-PB (44%), followed by RIC-PB (36%), MA-BM (36%), and RIC-BM (30%) (P = .002). The incidence of chronic GVHD at 1 year was 40%, 34%, 24%, and 20%, respectively (P < .001). In multivariable analysis, there was no impact of stem cell source or conditioning regimen on grade 2 to 4 acute GVHD; however, older donor age (30 to 49 versus <29 years) was significantly associated with higher rates of grade 2 to 4 acute GVHD (hazard ratio [HR], 1.53; 95% confidence interval [CI], 1.11 to 2.12; P = .01). In contrast, PB compared to BM as a stem cell source was a significant risk factor for the development of chronic GVHD (HR, 1.70; 95% CI, 1.11 to 2.62; P = .01) in the RIC setting. There were no differences in relapse or overall survival between groups. Donor age and graft source are risk factors for acute and chronic GVHD, respectively, after PTCy-based haplo-HCT. Our results indicate that in RIC haplo-HCT, the risk of chronic GVHD is higher with PB stem cells, without any difference in relapse or overall survival.

A precision medicine approach to management of acute myeloid leukemia in older adults.

PURPOSE OF REVIEW: Therapy selection in older adults with acute myeloid leukemia (AML) can be challenging because of a higher incidence of high-risk cytogenetic and molecular features conferring chemoresistance and poor functional status leading to increased treatment-related toxicities. The purpose of this review is to highlight the recent advances in precision medicine in AML that have shown promise to improve outcomes of older adults. RECENT FINDINGS: The utilization of next generation sequencing to identify and target actionable mutations can influence therapy selection in one-third of patients and can result in higher response rates as well as survival compared with those who do not receive targeted therapy. Oral targeted agents are available for AML with IDH 1, IDH2, or FLT3 mutations. Low-intensity venetoclax-based regimens have shown high rates of responses in AML, particularly among those with NPM1 and IDH2 mutations; responses are often durable and associated with minimal residual disease (MRD) negativity. Multiple studies have demonstrated the prognostic significance of flow cytometric MRD, with potential implications for subsequent therapy. SUMMARY: Novel approaches for AML risk-stratification, MRD assessment, and a precision medicine approach offer significant promise to improve survival and quality of life of older adults.

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (P=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (P=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.

Hematopoietic Cell Transplantation, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology

Hematopoietic cell transplantation (HCT) involves the infusion of hematopoietic progenitor cells into patients with hematologic disorders with the goal of re-establishing normal hematopoietic and immune function. HCT is classified as autologous or allogeneic based on the origin of hematopoietic cells. Autologous HCT uses the patient's own cells while allogeneic HCT uses hematopoietic cells from a human leukocyte antigen-compatible donor. Allogeneic HCT is a potentially curative treatment option for patients with certain types of hematologic malignancies, and autologous HCT is primarily used to support patients undergoing high-dose chemotherapy. Advances in HCT methods and supportive care in recent decades have led to improved survival after HCT; however, disease relapse and posttransplant complications still commonly occur in both autologous and allogeneic HCT recipients. Allogeneic HCT recipients may also develop acute and/or chronic graft-versus-host disease (GVHD), which results in immune-mediated cellular injury of several organs. The NCCN Guidelines for Hematopoietic Cell Transplantation focus on recommendations for pretransplant recipient evaluation and the management of GVHD in adult patients with malignant disease.

Venous Thromboembolism in COVID-19: Towards an Ideal Approach to Thromboprophylaxis, Screening, and Treatment.

PURPOSE OF REVIEW: Novel coronavirus disease 2019 (COVID-19) has been associated with an increased risk of arterial and venous thromboembolic (VTE) diseases. However, there is a limited amount of data regarding the prevention and management of VTE in severe hospitalized COVID-19 patients. RECENT FINDINGS: In this article, we review currently available clinical data, and mechanisms for COVID-associated coagulopathy, and propose algorithms for screening, prevention (including extended-duration prophylaxis), and treatment of these patients. Although these recommendations are subject to change given rapidly evolving data, we provide a framework that can guide clinicians in managing thrombotic complications in this challenging condition.

Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation.

Data on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.

Acute Myeloid Leukemia, Version 3.2019, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. Recent advances have resulted in an expansion of treatment options for AML, especially concerning targeted therapies and low-intensity regimens. This portion of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for AML focuses on the management of AML and provides recommendations on the workup, diagnostic evaluation and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.

Effects of center type and socioeconomic factors on early mortality and overall survival of diffuse large B-cell lymphoma.

Aim: To examine whether the center type and socioeconomic factors significantly impact 1-month mortality and overall survival (OS) of patients with diffuse large B-cell lymphoma (DLBCL). Methods: National Cancer Database (NCDB) was used to identify patients diagnosed with diffuse large B-cell lymphoma from 2006 to 2012 (postrituximab era). Results: Among 185,183 patients, 33% were treated at academic centers. The receipt of therapy at larger volume centers was associated with improved 1-month mortality. Academic centers had better OS than nonacademic centers in univariable analysis. Younger age, private insurance, lower Charlson comorbidity score and lower lymphoma stage were associated with improved 1-month mortality and OS. Conclusion: The receipt of therapy at larger volume centers and socioeconomic factors were associated with improved survival.

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.

Initial management of immune thrombocytopaenia in adults based on risk stratification.

Patients with immune thrombocytopaenia (ITP) have a wide spectrum of disease severity and bleeding risk even at similar platelet counts. Hence, additional clinical and laboratory factors may be considered in the evaluation of bleeding risk in ITP. Risk stratification based on predicted bleeding risk may help to identify high-risk patients and guide the initial management of ITP in adults requiring treatment. Recent evidence supports the use of high-dose dexamethasone therapy over prednisone in the initial management of ITP because of improved initial response rates, shorter median time to response and better safety profile. A risk-stratified approach to management of ITP is hoped to reduce bleeding complications in high-risk patients; however, the outcomes of such management approach need to be studied prospectively. Additionally, whether therapy intensification or combination of dual therapy such as intravenous immunoglobulin or rituximab in combination with dexamethasone can reduce bleeding complications in high-risk ITP should be studied in the future.

Atypical chronic myeloid leukemia: a rare entity with management challenges.

The aim of our study was to review the clinicopathologic features and management of atypical chronic myeloid leukemia (aCML). Relevant manuscripts published in English were searched using PubMed. aCML is diagnosed as per WHO 2016 classification in the presence of leukocytosis ≥13 × 109/l with circulating neutrophil precursors ≥10%, monocytes less than 10%, minimal basophils, hypercellular bone marrow with granulocytic proliferation and dysplasia, bone marrow blast less than 20% and absence of BCR/ABL fusion gene. Common cytogenetic features and mutations include trisomy 8, and mutations in SETBP1 and ETNK1. Median survival is 1-2 years. Hematopoietic stem cell transplant may be the only curative option. Ruxolitinib and dasatinib are emerging therapeutic options. Thus, aCML is a rare entity with poor survival. Novel therapies are needed.

Central nervous system complications after allogeneic hematopoietic stem cell transplantation.

Allogenic hematopoietic stem cell transplant (alloSCT) is a potentially curative modality of treatment for patients with hematological malignancies. However, CNS complications following transplant pose a risk to survival of the patients. Early recognition and management of these complications are crucial to reduce morbidity and mortality of patients following transplant. Early CNS complications associated with alloSCT are infection, cerebrovascular events, chemotherapy and radiation-induced toxicities while late complications include post-transplant lymphoproliferative disorder, CNS relapse of underlying malignancy and viral and fungal infections. Development of graft-versus-host disease can further increase the risk of CNS complications and outcomes after alloSCT. Strategies aimed to reduce the risk of CNS complications and early management may ameliorate the morbidity and mortality in transplant recipients.

Leukemic transformation in patients with myeloproliferative neoplasms: a population-based retrospective study.

AIM: This study determined the epidemiology of developing leukemic transformation in patients with myeloproliferative neoplasms (MPN). METHODS: We utilized the Surveillance, Epidemiology and End Results 13 database to identify 83 cases of leukemic transformation in MPN (n = 9335). RESULTS: The 5-year cumulative incidence of leukemic transformation was higher in male versus female (2.17 vs 1.09%; p < 0.001), and in myelofibrosis (2.19%; 95% CI: 1.36-3.34%), compared with essential thrombocythemia (0.37%; 95% CI: 0.19-0.65%) and polycythemia vera (0.72%; 95% CI: 0.46-1.07%; p < 0.001). Patients had a median survival of 2 months after leukemic transformation, worse in older patients and without any impact of prior MPN subtypes. CONCLUSION: Myelofibrosis has a higher risk of leukemic transformation. Overall survival is dismal regardless of MPN subtypes.

Outcomes of haploidentical transplant compared with matched donor allogeneic stem cell transplant.

The risk of acute and chronic graft-versus-host disease (GVHD) with haploidentical transplant with post-transplant high-dose cyclophosphamide may be lower compared with matched unrelated donor transplant and largely similar to matched related donor transplant. The lower probability of GVHD with the haploidentical donor may result in a risk of nonrelapse mortality that is at least similar to or even lower than the matched donor. The incidence of relapse and survival are also largely similar to different donor types. Haploidentical transplant may be associated with slower engraftment. Given a lower risk of GVHD, haploidentical transplant has gained popularity. Additionally, the use of post-transplant high-dose cyclophosphamide has been extended to lower the risk of GVHD with matched donor and mismatched unrelated donor transplant.

Time to Insurance Approval in Private and Public Payers Does Not Influence Survival in Patients Who Undergo Hematopoietic Cell Transplantation.

In the United States, insurance status has been implicated as a barrier to obtaining timely treatment. In this retrospective cohort study of 521 patients who underwent first hematopoietic cell transplantation (HCT), we investigated the association between timeliness of HCT and overall survival. Timeliness was operationally defined in the following 3 ways: (1) payer approval, from request for approval to actual payer approval; (2) transplantation speed, from payer approval to time of actual HCT; and (3) total time, from request for approval to HCT. Patients with private insurance had longer time to payer approval (P < .0001) than those with public payers but shorter time from approval to actual HCT (P < .0001) and total time to HCT (P < .0001). Multivariate Cox regression showed no significant differences in risk of death between slow and fast times in the 3 indices of timeliness in the models that used all patients (n = 509), autologous HCT in lymphoma (n = 278), and autologous HCT in multiple myeloma (n = 121). Additional studies to evaluate the effect of insurance timeliness on all patients for whom HCT is recommended, not just those who undergo HCT, should be conducted.