Acute Lymphoblastic Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for acute lymphoblastic leukemia (ALL) provide recommendations for management of ALL, with a focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. This selection from the NCCN Guidelines for ALL focuses on treatment recommendations for adults with newly diagnosed Ph-negative ALL based on current evidence.

Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Nonperturbative Double Copy in Flatland.

We derive a nonperturbative, Lagrangian-level formulation of the double copy in two spacetime dimensions. Our results elucidate the field theoretic underpinnings of the double copy in a broad class of scalar theories which can include masses and higher-dimension operators. An immediate corollary is the amplitudes-level double copy at all orders in perturbation theory. Applied to certain integrable models, the double copy defines an isomorphism between Lax connections, Wilson lines, and infinite towers of conserved currents. We also implement the double copy at the level of nonperturbative classical solutions, both analytically and numerically, and present a generalization of the double copy map that includes a fixed tower of higher-dimension corrections given by the Moyal algebra.

NCCN Guidelines® Insights: Myelodysplastic Syndromes, Version 3.2022.

The NCCN Guidelines for Myelodysplastic Syndromes (MDS) provide recommendations for the evaluation, diagnosis, and management of patients with MDS based on a review of clinical evidence that has led to important advances in treatment or has yielded new information on biologic factors that may have prognostic significance in MDS. The multidisciplinary panel of MDS experts meets on an annual basis to update the recommendations. These NCCN Guidelines Insights focus on some of the updates for the 2022 version of the NCCN Guidelines, which include treatment recommendations both for lower-risk and higher-risk MDS, emerging therapies, supportive care recommendations, and genetic familial high-risk assessment for hereditary myeloid malignancy predisposition syndromes.

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.

Extended CCR5 Blockade for Graft-versus-Host Disease Prophylaxis Improves Outcomes of Reduced-Intensity Unrelated Donor Hematopoietic Cell Transplantation: A Phase II Clinical Trial.

Graft-versus-host disease (GVHD) remains the most common treatment-related complication after allogeneic hematopoietic cell transplantation (allo-HCT). Lymphocyte migration plays a critical role in the pathogenesis of GVHD. A previous phase I/II trial demonstrated that CCR5 blockade with maraviroc in the first 30days after allo-HCT resulted in a low incidence of early acute GVHD, primarily in visceral organs, but with no impact on late acute or chronic GVHD. We conducted a phase II trial to examine the efficacy of an extended course of maraviroc, administered through post-transplantation day +90 in addition to standard prophylaxis in 37 recipients of reduced-intensity-conditioned unrelated donor allo-HCT performed to treat hematologic malignancies. Extended maraviroc treatment was safe and feasible. The primary study endpoint, day +180 rate of grade II-IV acute GVHD, was 22 ± 7%, liver GVHD was not observed, and gut GVHD was uncommon. The day +180 rate of grade III-IV acute GVHD was 5 ± 4%. The 1-year rate of moderate to severe chronic GVHD was 8 ± 5% and that of disease relapse was 30 ± 8%. Overall survival at 1 year was 70 ± 8%. Compared with the previously studied short course of maraviroc, the extended course resulted in a significantly higher GVHD-free, relapse-free survival (adjusted hazard ratio [HR], .45; 95% confidence interval [CI], .25 to .82; P = .009) and overall survival (adjusted HR, .48; 95% CI, .24 to .96; P = .037). A combined analysis of both trials showed that high maraviroc trough concentrations on the day of hematopoietic cell infusion were associated with lower rates of acute GVHD. An extended course of maraviroc after reduced-intensity-conditioned unrelated donor allo-HCT is safe and effective in preventing acute and chronic GVHD and is associated with favorable survival.

Dose-related periorbital edema following sorafenib in a patient with acute myeloid leukemia.

We describe a case of dose-related periorbital edema in a patient with FLT3-mutated acute myeloid leukemia taking sorafenib and voriconazole that resolved following sorafenib dose reduction. We hypothesize that the mechanism of this adverse event may be related to the inhibition of platelet-derived growth factor receptor (PDGFR) by sorafenib. Clinicians should be aware of this possible dose-related adverse event and the potential role of sorafenib dose reduction when on concurrent voriconazole.

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

Differences in treatment goals and perception of symptom burden between patients with myeloproliferative neoplasms (MPNs) and hematologists/oncologists in the United States: Findings from the MPN Landmark survey.

BACKGROUND: This analysis of the myeloproliferative neoplasm (MPN) Landmark survey evaluated gaps between patient perceptions of their disease management and physician self-reported practices. METHODS: The survey included 813 patient respondents who had MPNs (myelofibrosis [MF], polycythemia vera [PV], or essential thrombocythemia [ET]) and 457 hematologist/oncologist respondents who treated patients with these conditions. RESULTS: Greater proportions of physician respondents reported using prognostic risk classifications (MF, 83%; PV, 59%; ET, 77%) compared with patient recollections (MF, 54%; PV, 17%; ET, 31%). Most physician respondents reported that their typical symptom assessments included asking patients about the most important symptoms or a full list of symptoms, whereas many patient respondents reported less specific assessments (eg, they were asked how they were feeling). Many patient respondents did not recognize common symptoms as MPN-related. For example, approximately one-half or more did not believe difficulty sleeping resulted from their MPN (MF, 49%; PV, 64%; ET, 76%). Physician respondents underestimated the proportion of patients who had symptomatic PV or ET at diagnosis compared with patient respondents. There was discordance regarding treatment goals: among patient respondents with MF or PV, "slow/delay progression of condition" was the most important treatment goal, whereas physician respondents reported "symptom improvement" and "prevention of vascular/thrombotic events," respectively. Finally, more than one-third of patient respondents were not "very satisfied" with their physician's overall management/communication. CONCLUSIONS: The care and satisfaction of patients with MPN may be improved with increased patient education and improved patient-physician communication. Cancer 2017;123:449-458. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.

Getting It Right the First Time: Defining Regionally Relevant Training Curricula and Provider Core Competencies for Point-of-Care Ultrasound Education on the African Continent.

Significant evidence identifies point-of-care ultrasound (PoCUS) as an important diagnostic and therapeutic tool in resource-limited settings. Despite this evidence, local health care providers on the African continent continue to have limited access to and use of ultrasound, even in potentially high-impact fields such as obstetrics and trauma. Dedicated postgraduate emergency medicine residency training programs now exist in 8 countries, yet no current consensus exists in regard to core PoCUS competencies. The current practice of transferring resource-rich PoCUS curricula and delivery methods to resource-limited health systems fails to acknowledge the unique challenges, needs, and disease burdens of recipient systems. As emergency medicine leaders from 8 African countries, we introduce a practical algorithmic approach, based on the local epidemiology and resource constraints, to curriculum development and implementation. We describe an organizational structure composed of nexus learning centers for PoCUS learners and champions on the continent to keep credentialing rigorous and standardized. Finally, we put forth 5 key strategic considerations: to link training programs to hospital systems, to prioritize longitudinal learning models, to share resources to promote health equity, to maximize access, and to develop a regional consensus on training standards and credentialing.

Myeloproliferative neoplasms (MPNs) have a significant impact on patients' overall health and productivity: the MPN Landmark survey.

BACKGROUND: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) negatively affect patient quality of life (QoL) and are associated with increased risk of mortality. METHODS: The MPN Landmark survey was conducted from May to July 2014 in patients with MF, PV, or ET under active management in the United States. The survey assessed respondent perceptions of disease burden and treatment management and included questions on overall disease burden, QoL, activities of daily living, and work productivity. Outcomes were further analyzed by calculated (ie, not respondent-reported) prognostic risk score and symptom severity quartile. RESULTS: The survey was completed by 813 respondents (MF, n = 207; PV, n = 380; ET, n = 226). The median respondent age in each of the 3 MPN subtypes ranged from 62 to 66 years; median disease duration was 4 to 7 years. Many respondents reported that they had experienced MPN-related symptoms ≥1 year before diagnosis (MF, 49 %; PV, 61 %; ET, 58 %). Respondents also reported that MPN-related symptoms reduced their QoL, including respondents with low prognostic risk scores (MF, 67 %; PV, 62 %; ET, 57 %) and low symptom severity (MF, 51 %; PV, 33 %; ET, 15 %). Many respondents, including those with a low prognostic risk score, reported that their MPN had caused them to cancel planned activities or call in sick to work at least once in the preceding 30 days (cancel planned activities: MF, 56 %; PV, 35 %; ET, 35 %; call in sick: MF, 40 %; PV, 21 %; ET, 23 %). CONCLUSIONS: These findings of the MPN Landmark survey support previous research about the symptom burden experienced by patients with MPNs and are the first to detail the challenges that patients with MPNs experience related to reductions in activities of daily living and work productivity.

Unrelated donors are associated with improved relapse-free survival compared to related donors in patients with myelodysplastic syndrome undergoing reduced intensity allogeneic stem cell transplantation.

Reduced intensity allogeneic stem cell transplantation (RI alloSCT) is a potentially curative treatment approach for patients with myelodysplastic syndrome (MDS). It is currently unclear if older related donors are better than younger unrelated donors for patients with MDS undergoing RI alloSCT. We retrospectively studied 53 consecutive MDS patients who underwent RI alloSCT between April 2007 and June 2014 and evaluated associations between donor type and outcomes with adjustment for significant covariates. 34 patients (median age: 64 years) and 19 patients (median age: 60 years) received allografts from unrelated and related donors, respectively. Unrelated donors were younger than related donors (median age: 32 vs. 60 years, P < 0.0001). There were no significant differences in baseline disease characteristics of patients receiving allografts from related or unrelated donors. Patients who received allografts from unrelated donors had a lower relapse risk (adjusted hazard ratio [aHR] = 0.35, P = 0.012) and improved relapse-free survival (aHR = 0.47, P = 0.018). HLA mismatched unrelated donors were associated with a higher risk of grade 2-4 acute graft versus host disease (GVHD) (HR = 4.64, P = 0.002) without an accompanying increase in the risk of non-relapse mortality (P = 0.56). Unrelated donors provided a higher mean CD8 cell dose (P = 0.014) and were associated with higher median donor T cell chimerism at day 60 (P = 0.003) and day 100 (P = 0.03). In conclusion, patients with MDS who received allografts from unrelated donors had a lower risk of relapse and improved relapse-free survival when compared to patients who received allografts from related donors. These findings should be confirmed in a prospective study. Am. J. Hematol. 91:883-887, 2016. © 2016 Wiley Periodicals, Inc.

Infusion of CD3/CD28 costimulated umbilical cord blood T cells at the time of single umbilical cord blood transplantation may enhance engraftment.

Limited cell numbers in umbilical cord blood (UCB) grafts present a major impediment to favorable outcomes in adult transplantation, largely related to delayed or failed engraftment. The advent of UCB transplantation (UCBT) using two grafts successfully circumvents this obstacle, despite the engraftment of only one unit. Preclinical models suggested that the addition of UCB T cells at the time of transplant can enhance engraftment. We tested whether ex vivo activation by CD3/CD28 costimulation and expansion of T cells from a single UCB graft would be safe and feasible in adults with advanced hematologic malignancies, with an overall objective of optimizing engraftment in single unit UCBT. In this phase 1 study, recipients of single UCB units were eligible if the unit was stored in two adequate fractions. Dose limiting toxicity was defined as grade 3 or grade 4 GVHD within 90 days of UCBT. Four patients underwent UCBT; all were treated at the first dose level (10(5) cells/kg). At the 10(5) cells/kg dose level two subjects experienced grade 3 intestinal GVHD, thus meeting stopping criteria. For three subjects, neutrophil engraftment was early (12, 17, and 20 days), while one subject experienced primary graft failure. We observed early donor T cell trafficking and found that expanded T cells produced supraphysiologic levels of cytokines relevant to engraftment and to lymphoid differentiation and function. Taken together, these preliminary data suggest rapid engraftment in recipients of a single UCBT combined with relatively low doses of activated T cells, though potentially complicated by severe GVHD.

Approach to patients with primary refractory acute myeloid leukemia.

PURPOSE OF REVIEW: Despite successful remission induction in 60-80% of patients with newly diagnosed acute myeloid leukemia, there remain a significant number of patients who exhibit primary refractory disease. Here we examine the data for predicting likelihood of having refractory disease, available therapeutic options, and how to decide the appropriate treatment option for a patient. RECENT FINDINGS: Recently identified recurrent molecular mutations and early response to chemotherapy as determined by kinetics of peripheral blast clearance or nadir bone marrow biopsy assist in determining the likelihood of primary refractory disease. Newer cytotoxic agents, used as salvage chemotherapy, or in novel conditioning regimens for hematopoietic stem cell transplant may represent improvement over prior regimens. FMS-like tyrosine kinase 3 gene inhibitors and other targeted therapies currently in clinical trials show promise for select patients. Hypomethylating agents provide benefit to patients who are not candidates for other therapies. SUMMARY: Recent advances in understanding the pathogenesis of acute myeloid leukemia have not yet translated to a significantly improved outlook for patients with refractory disease. While there are several therapeutic options, outcomes remain poor and further studies are needed to identify and validate novel approaches.

Acute cholecystitis is a common complication after allogeneic stem cell transplantation and is associated with the use of total parenteral nutrition.

The incidence and risk factors for acute cholecystitis after allogeneic hematopoietic stem cell transplantation (HSCT) are not well defined. Of 644 consecutive adult transplants performed at our institution between 2001 and 2011, acute cholecystitis occurred in the first year of transplant in 32 patients (5.0%). We conducted 2 retrospective case-control studies of this population to determine risk factors for cholecystitis after HSCT and to evaluate the performance of different methods of imaging to diagnosis cholecystitis in patients undergoing HSCT compared with non-HSCT patients. In the HSCT population, development of cholecystitis was associated with an increased 1-year overall mortality rate (62.5% versus 19.8%, P < .001). The risk of developing cholecystitis was higher in patients who received total parenteral nutrition (TPN) (adjusted odds ratio, 3.41; P = .009). There was a trend toward more equivocal abdominal ultrasound findings in HSCT recipients with acute cholecystitis compared with nontransplant patients (50.0% versus 30.6%, P = .06). However, hepatobiliary iminodiacetic acid (HIDA) scans were definitively positive for acute cholecystitis in most patients in both populations (80.0% of HSCT recipients versus 77.4% of control subjects, P = .82). In conclusion, acute cholecystitis is a common early complication of HSCT, the risk is increased in patients who receive TPN, and it is associated with high 1-year mortality. In HSCT recipients with findings suggestive of acute cholecystitis, especially those receiving TPN, early use of HIDA scan may be considered over ultrasound.

Early donor chimerism levels predict relapse and survival after allogeneic stem cell transplantation with reduced-intensity conditioning.

The success of hematopoietic stem cell transplantation (HSCT) with reduced-intensity conditioning (RIC) is limited by a high rate of disease relapse. Early risk assessment could potentially improve outcomes by identifying appropriate patients for preemptive strategies that may ameliorate this high risk. Using a series of landmark analyses, we investigated the predictive value of early (day-30) donor chimerism measurements on disease relapse, graft-versus-host disease, and survival in a cohort of 121 patients allografted with a uniform RIC regimen. Chimerism levels were analyzed as continuous variables. In multivariate analysis, day-30 whole blood chimerism levels were significantly associated with relapse (hazard ratio [HR] = .90, P < .001), relapse-free survival (HR = .89, P < .001), and overall survival (HR = .94, P = .01). Day-30 T cell chimerism levels were also significantly associated with relapse (HR = .97, P = .002), relapse-free survival (HR = .97, P < .001), and overall survival (HR = .99, P = .05). Multivariate models that included T cell chimerism provided a better prediction for these outcomes compared with whole blood chimerism. Day-30 chimerism levels were not associated with acute or chronic graft-versus-host disease. We found that high donor chimerism levels were significantly associated with a low lymphocyte count in the recipient before transplant, highlighting the impact of pretransplant lymphopenia on the kinetics of engraftment after RIC HSCT. In summary, low donor chimerism levels are associated with relapse and mortality and can potentially be used as an early predictive and prognostic marker. These findings can be used to design novel approaches to prevent relapse and to improve survival after RIC HSCT.

Results from phase 1 of the MANIFEST clinical trial to evaluate the safety and tolerability of pelabresib in patients with myeloid malignancies.

Pelabresib (CPI-0610), a BET protein inhibitor, is in clinical development for hematologic malignancies, given its ability to target NF-κB gene expression. The MANIFEST phase 1 study assessed pelabresib in patients with acute leukemia, high-risk myelodysplastic (MDS) syndrome, or MDS/myeloproliferative neoplasms (MDS/MPNs) (NCT02158858). Forty-four patients received pelabresib orally once daily (QD) at various doses (24-400 mg capsule or 225-275 mg tablet) on cycles of 14 d on and 7 d off. The most frequent drug-related adverse events were nausea, decreased appetite, and fatigue. The maximum tolerated dose (MTD) was 225 mg tablet QD. One patient with chronic myelomonocytic leukemia (CMML) showed partial remission. In total, 25.8% of acute myeloid leukemia (AML) patients and 38.5% of high-risk MDS patients had stable disease. One AML patient and one CMML patient showed peripheral hematologic response. The favorable safety profile supports the ongoing pivotal study of pelabresib in patients with myelofibrosis using the recommended phase 2 dose of 125 mg tablet QD.CLINICAL TRIAL REGISTRATION: NCT02158858.

IDH2-mutated near ETP-ALL with aggressive leukemia cutis and brisk response to venetoclax and decitabine.

Near early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a rare hematologic malignancy, for which second line therapeutic options are limited. T-cell leukemias are also rarely associated with leukemia cutis, which is more often seen in leukemias of myeloid origin. We present the case of an adult male diagnosed with near ETP-ALL, with IDH2 and DNMT3A mutations, suggestive of a myeloid origin, and leukemia cutis. After the patient progressed on hyper-CVAD and nelarabine, we treated him with the BCL-2 inhibitor venetoclax and the hypomethylating agent decitabine. The regimen induced a rapid bone marrow response and resolution of the leukemia cutis.