A phase 1 study to evaluate the safety, pharmacology, and feasibility of continuous infusion nelarabine in patients with relapsed and/or refractory lymphoid malignancies.

BACKGROUND: Nelarabine is a purine nucleoside analogue prodrug approved for the treatment of relapsed and refractory T-cell acute lymphoblastic leukemia (R/R T-ALL) and lymphoblastic lymphoma (T-LBL). Although effective in R/R T-ALL, significant neurotoxicity is dose-limiting and such neurotoxicity associated with nucleoside analogues can be related to dosing schedule. METHODS: The authors conducted a phase 1 study to evaluate the pharmacokinetics and toxicity of nelarabine administered as a continuous infusion (CI) for 5 days (120 hours), rather than the standard, short-infusion approach. RESULTS: Twenty-nine patients with R/R T-ALL/LBL or T-cell prolymphocytic leukemia (T-PLL) were treated, with escalating doses of nelarabine from 100 to 800 mg/m2 /day × 5 days. The median age of the patients was 39 years (range, 14-77 years). The overall response rate was 31%, including 27% complete remission (CR) or CR with incomplete platelet recovery (CRp). Peripheral neuropathy was observed in 34% of patients, including four ≥grade 3 events related to nelarabine. Notably, there was no nelarabine-related central neurotoxicity on study. The maximum tolerated dose was not reached. Pharmacokinetic data suggested no relationship between dose of nelarabine and accumulation of active intracellular ara-GTP metabolite. Higher intracellular ara-GTP concentrations were statistically associated with a favorable clinical response. CONCLUSION: Preliminary evaluation of continuous infusion schedule of nelarabine suggests that the safety profile is acceptable for this patient population, with clinical activity observed even at low doses and could broaden the use of nelarabine both as single agent and in combinations by potentially mitigating the risk of central nervous system toxicities.

Early mortality in acute myeloid leukemia with KMT2A rearrangement is associated with high risk of bleeding and disseminated intravascular coagulation.

BACKGROUND: Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well-defined in this entity. METHODS: In a retrospective analysis, causes and rates of early mortality following induction treatment were compared between a cohort of adults with KMT2Ar AML (N = 172) and an age-matched cohort of patients with normal karyotype AML (N = 522). RESULTS: The 60-day mortality in patients with KMT2Ar AML was 15% compared with 7% with normal karyotype (p = .04). We found a significantly higher occurrence of major bleeding events (p = .005) and total bleeding events (p = .001) in KMT2Ar AML compared with diploid AML. Among evaluable patients with KMT2Ar AML, 93% exhibited overt disseminated intravascular coagulopathy compared with 54% of patients with a normal karyotype before death (p = .03). In a multivariate analysis, KMT2Ar and a monocytic phenotypic were the only independent predictors of any bleeding event in patients who died within 60 days (odds ratio, 3.5; 95% CI, 1.4-10.4; p = .03; odds ratio, 3.2; 95% CI, 1-1-9.4; p = .04, respectively). CONCLUSION: In conclusion, early recognition and aggressive management of disseminated intravascular coagulopathy and coagulopathy are important considerations that could mitigate the risk of death during induction treatment in KMT2Ar AML. PLAIN LANGUAGE SUMMARY: Acute myeloid leukemia (AML) with rearrangement of KMT2A is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well-defined in this entity. In this article, that KMT2A-rearranged AML is demonstrably associated with higher early mortality and an increased risk of bleeding and coagulopathy, specifically, disseminated intravascular coagulation, compared with normal karyotype AML. These findings emphasize the importance of monitoring and mitigating coagulopathy in KMT2A-rearranged leukemia similar to what is done in acute promyelocytic leukemia.

Pneumonitis after immune checkpoint inhibitor therapies in patients with acute myeloid leukemia: A retrospective cohort study.

BACKGROUND: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality. METHODS: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were modeled as a time-dependent variable and incorporated a standard risk set modifying variables into the models. RESULTS: Thirty patients developed pneumonitis (12%). Of these, 17 had partial or complete resolution, whereas 13 patients died from pneumonitis. Increasing age (hazard ratio [HR], 1.04 per year; 95% confidence interval [CI], 1.00-1.08), and baseline shortness of breath increased pneumonitis risk (HR, 2.51; 95% CI, 1.13-5.55). Female sex (HR, 0.33; 95% CI, 0.15-0.70) and increasing platelet count (HR, 0.52 per log-unit increase; 95% CI, 0.30-0.92) decreased pneumonitis risk. In adjusted models, ICI-related pneumonitis significantly increased mortality (HR, 2.84; 95% CI, 1.84-4.37). CONCLUSIONS: ICI-related pneumonitis occurs at a high rate in AML patients and increases mortality. LAY SUMMARY: Immune checkpoint inhibitors (ICIs) remove inhibitory signals that reduce T-cell function and allow T-cells to better attack cancer cells. In acute myeloid leukemia (AML), the effectiveness of ICIs is limited in part by inflammation of the lung, called pneumonitis. This study reviewed 258 patients with AML who received ICIs and identified 30 patients who developed pneumonitis, nearly half of whom died. Older age and baseline shortness of breath increased pneumonitis risk, whereas female sex and higher baseline platelet counts decreased pneumonitis risk. Pneumonitis increased mortality by nearly 3-fold. This work highlights the significant harm imposed by pneumonitis after ICI therapies.

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.

Long-term results of a phase 2 trial of nilotinib 400 mg twice daily in newly diagnosed patients with chronic-phase chronic myeloid leukemia.

BACKGROUND: Nilotinib is a potent, second-generation inhibitor of BCR-ABL1 tyrosine kinase and has been approved as frontline and salvage therapy for patients with chronic-phase chronic myeloid leukemia (CP-CML). METHODS: In this single-institution, phase 2 study, 122 patients with newly diagnosed CP-CML received nilotinib 400 mg twice daily. The median follow-up on study was 78.3 months (interquartile range, 58.4-96.5 months). RESULTS: Fifty-six percent of patients remained on therapy at the last follow-up. Both the complete cytogenetic response rate and the major molecular response (MR) rate were 91%. Seventy-five percent and 59% of patients achieved a ≥4.5-log reduction in BCR-ABL1 transcripts (MR4.5) and a sustained MR4.5 beyond 2 years, respectively. The estimated event-free survival and overall survival rates at 5 years were 89% and 93%, respectively, and the corresponding rates at 10 years were 85% and 88%, respectively. Treatment discontinuation due to toxicity occurred in 19% of patients, mostly because of cardiovascular events (10%) and biochemical abnormalities (6%). The top 3 nonhematologic toxicities were rash (55%), elevated bilirubin (57%), and elevated aminotransferases (48%). Hematologic toxicity was transient and mild. Ischemic cardiovascular adverse events occurred in 8% of patients. Four patients (3%) progressed to accelerated or blast phase while on therapy, and 7 patients (6%) died on study. CONCLUSIONS: The current data confirm the long-term efficacy of nilotinib 400 mg twice daily in patients with CP-CML. A majority of patients can achieve sustained MR4.5.

A phase 2 study of ruxolitinib in combination with azacitidine in patients with myelofibrosis.

Ruxolitinib (RUX)-based combinations may provide benefit for patients with myelofibrosis (MF). In this open-label, nonrandomized, prospective phase 2 study, patients with MF initially received RUX twice per day continuously in 28-day cycles for the first 3 cycles. Azacitidine (AZA) 25 mg/m2 (days 1-5) was added starting with cycle 4 and could be subsequently increased to 75 mg/m2 (days 1-5). Forty-six patients were enrolled with a median follow-up of 28 months (range, 4-50+ months). An International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) response was achieved in 33 patients (72%), with a median time to response of 1.8 months (range, 0.7-19.0 months). One-fourth (7 of 33) of the IWG-MRT responses occurred after the addition of AZA. A reduction of >50% in palpable spleen length at 24 weeks and at any time on the study was achieved in 62% and 71% of the evaluable patients, respectively. Among patients who achieved a >50% reduction in spleen length at 24 weeks, 95% had maintained it at 48 weeks. Notably, improvements in bone marrow reticulin fibrosis grade occurred in 57% of the patients at 24 months. Treatment discontinuations as a result of drug-related toxicities occurred in 4 patients (9%), all as a result of cytopenias. New onset grade 3 to 4 anemia and thrombocytopenia occurred in 35% and 26% of patients, respectively. RUX and AZA were safe, with encouraging spleen response rates and improvement in bone marrow fibrosis in patients with MF. This trial was registered at www.clinicaltrials.gov as #NCT01787487.

Phase 2 study of hyper-CMAD with liposomal vincristine for patients with newly diagnosed acute lymphoblastic leukemia.

Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper-CMAD). In a single-center, phase 2 study, patients ≥18 years with newly-diagnosed B-cell ALL were eligible to receive hyper-CMAD alternating with high-dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome-positive (Ph-positive) ALL. Thirty-one patients were enrolled, median follow-up of 59 months (0.3-70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph-positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph-positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow-up of 59 months, 21 (68%) patients are alive. The 5-year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post-transplant complications; four, relapse. Hyper-CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL.

Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome.

The Philadelphia chromosome resulting from t(9;22)(q34;q11.2) or its variants is a defining event in chronic myeloid leukemia. It is also observed in several types of de novo acute leukemia, commonly in B lymphoblastic leukemia, and rarely in acute myeloid leukemia, acute leukemia of ambiguous lineage, and T lymphoblastic leukemia. Acquisition of the Philadelphia chromosome during therapy of acute leukemia and myelodysplastic syndrome is rare. We reported 19 patients, including 11 men and 8 women with a median age of 53 years at initial diagnosis. The diagnoses at initial presentation were acute myeloid leukemia (n = 11), myelodysplastic syndrome (n = 5), B lymphoblastic leukemia (n = 2), and T lymphoblastic leukemia (n = 1); no cases carried the Philadelphia chromosome. The Philadelphia chromosome was detected subsequently at relapse, or at refractory stage of acute leukemia or myelodysplastic syndrome. Of 14 patients evaluated for the BCR-ABL1 transcript subtype, 12 had the e1a2 transcript. In 11 of 14 patients, the diseases before and after emergence of the Philadelphia chromosome were clonally related by karyotype or shared gene mutations. Of 15 patients with treatment information available, 7 received chemotherapy alone, 5 received chemotherapy plus tyrosine kinase inhibitors, 2 received tyrosine kinase inhibitors only, and 1 patient was not treated. Twelve patients had follow-up after acquisition of the Philadelphia chromosome; all had persistent/refractory acute leukemia. Thirteen of 15 patients died a median of 3 months after the emergence of the Philadelphia chromosome. In summary, secondary Philadelphia chromosome acquired during therapy is rare, and is associated with the e1a2 transcript subtype, terminal disease stage, and poor outcome.

Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: current treatments and future perspectives.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for approximately one-fourth of cases of adult ALL. It typically presents with an aggressive clinical course, responds poorly to standard chemotherapy, and carries a high risk for relapse. The landscape of Ph+ ALL therapy has changed favorably since the development of tyrosine kinase inhibitors (TKIs). With the successful incorporation of TKIs into chemotherapy regimens, remissions occur more frequently and patients live longer. Imatinib was the first TKI that targeted the BCR-ABL1 oncoprotein in Ph+ ALL. Since then, nilotinib, dasatinib, bosutinib, and ponatinib have been developed. Despite the significant progress that has been made in inducing remission, frequent relapses remain a challenge, especially among those with resistant BCR-ABL1 mutations. Still, the therapeutic armamentarium of ALL therapy is expanding at a breathtaking pace today compared with a decade ago. Novel drugs, such as potent later-generation TKIs, antibody-drug conjugates, bispecific monoclonal antibodies, and chimeric antigen receptor T-cell therapies, are being developed and investigated in patients with Ph+ ALL. In this review, we summarize the current treatment options for Ph+ ALL and highlight the therapies that may become the standard of care in the near future.

The evolution of arsenic in the treatment of acute promyelocytic leukemia and other myeloid neoplasms: Moving toward an effective oral, outpatient therapy.

The therapeutic potential of arsenic derivatives has long been recognized and was recently rediscovered in modern literature. Early studies demonstrated impressive activity of this compound in patients with relapsed acute promyelocytic leukemia (APL). Over the last 2 decades, intravenous arsenic trioxide has been used successfully, both alone and in combination with other agents, for the treatment of APL and, with some success, of other myeloid neoplasms. Arsenic trioxide is currently part the standard of care for patients with APL. More recently, oral formulations of this compound have been developed and are entering clinical practice. In this review, the authors discuss the evolution of arsenic in the treatment of APL and other myeloid neoplasms.

Augmented Berlin-Frankfurt-Münster therapy in adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL).

BACKGROUND: Various trials have reported improved outcomes for adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) who received treatment with pediatric-based regimens. Those reports prompted the current investigation of the pediatric augmented Berlin-Frankfurt-Münster (ABFM) regimen in AYA patients. The results were compared with those from a similar population that received the hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) regimen. METHODS: Eighty-five patients ages 12 to 40 years who had Philadelphia chromosome (Ph)-negative ALL received the ABFM regimen from October 2006 through April 2012. Their outcome was compared with outcomes in 71 historic AYA patients who received hyper-CVAD from the authors' institution. Patient and disease characteristics, as well as minimal residual disease status, were analyzed for their impact on outcomes. RESULTS: The complete response rate with ABFM was 94%. The 3-year complete remission duration (CRD) and overall survival (OS) rates were 70% and 74%, respectively. For patients aged ≤21 years, the 3-year CRD and OS rates were 72% and 85%, respectively; and, for patients ages 21 to 40 years, the respective rates were 69% and 60%. The initial white blood cell count was an independent predictive factor of OS and CRD. The minimal residual disease status on days 29 and 84 of therapy also were predictive of long-term outcomes. Severe regimen toxicities included transient hepatotoxicity in 35% to 39% of patients, pancreatitis in 11% of patients, osteonecrosis in 11% of patients, and thrombosis in 22% of patients. The 3-year OS rate was 74% in the ABFM group versus 71% in the hyper-CVAD group, and the corresponding 3-year CRD rate was 70% versus 66%, respectively. CONCLUSIONS: ABFM was tolerable in AYA patients with ALL but was not associated with significant improvements in CRD and OS compared with hyper-CVAD.

Anorectal Infections in Neutropenic Leukemia Patients: A Common Clinical Challenge.

Anorectal infections in neutropenic leukemia patients are a significant and potentially life-threatening complication. The pathogenesis of this condition is not entirely understood and believed to be multifactorial, including mucosal injury as a result of cytotoxic drugs, profound neutropenia and impaired host defense. Establishing an early diagnosis is key and often made clinically on the basis of signs and symptoms, but also from imaging studies demonstrating perianal inflammation or fluid collection. The management of anorectal infections in neutropenic leukemia patients is not straightforward, as there are no well-conducted studies on this entity. This review seeks to provide a framework into the pathophysiology and clinical presentation of anorectal infections in neutropenic leukemia patients, propose a diagnostic approach and to discuss controversies in the management of this condition.

Transglutaminase 2 expression in acute myeloid leukemia: association with adhesion molecule expression and leukemic blast motility.

Acute myeloid leukemia (AML) is a heterogenous disease with differential oncogene association, outcome and treatment regimens. Treatment strategies for AML have improved outcome but despite increased molecular biological information AML is still associated with poor prognosis. Proteomic analysis on the effects of a range of leukemogenic oncogenes showed that the protein transglutaminase 2 (TG2) is expressed at greater levels as a consequence of oncogenic transformation. Further analysis of this observation was performed with 511 AML samples using reverse phase proteomic arrays, demonstrating that TG2 expression was higher at relapse than diagnosis in many cases. In addition elevated TG2 expression correlated with increased expression of numerous adhesion proteins and many apoptosis regulating proteins, two processes related to leukemogenesis. TG2 has previously been linked to drug resistance in cancer and given the negative correlation between TG2 levels and peripheral blasts observed increased TG2 levels may lead to the protection of the leukemic stem cell due to increased adhesion/reduced motility. TG2 may therefore form part of a network of proteins that define poor outcome in AML patients and potentially offer a target to sensitize AML stem cells to drug treatment.

Significance of deeper molecular responses in patients with chronic myeloid leukemia in early chronic phase treated with tyrosine kinase inhibitors.

Most patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with tyrosine kinase inhibitors (TKI) achieve complete cytogenetic response (CCyR). An increasing number of patients also achieve deep molecular responses (MR). We determined the frequency and significance of deep MR after TKI therapy for CML in CP. MR included: major molecular response (MMR), MR4, MR4.5, and undetectable transcripts (UND), i.e., BCR-ABL/ABL of ≤0.1, ≤0.01, ≤0.0032%, and undetectable transcripts, respectively. Four hundred eighty-three patients received imatinib 400 mg/day (IM400, 71, July 2000 to April 2001), imatinib 800 mg/day (IM800, 204, June 2001 to July 2005), nilotinib (106, July 2005 to date), or dasatinib (102, November 2005 to date). UND rates at 36 months were 18.1, 30.6, 29.2, and 28.6%, respectively. Patients achieving UND have superior transformation-free survival (TFS) and overall survival (OS) versus those obtaining ≤MMR, but not other MR levels. At the 18- and 24-month landmark analysis, patients achieving UND have no advantage in TFS and OS compared to those achieving a lesser degree of MR. Among patients achieving MR4.5, those who maintain it for ≥2 years (susMR4·5) have no additional benefit in TFS or OS. Most patients with early CP CML receiving TKI achieve MMR. BCR-ABL transcripts become undetectable in a significant fraction of them. Deeper MR at 18 or 24 months are not associated with a benefit in TFS or OS. Furthermore, achieving susMR4·5 does not appear to further reduce the risk of transformation or death.

Non-intensive acute myeloid leukemia therapies for older patients.

INTRODUCTION: Acute myeloid leukemia (AML) is an aggressive disease predominantly affecting the elderly population. The elderly population represents a challenging group to treat and the prognosis is generally poor with significantly worse treatment outcomes compared to the younger population. While the goal of treatment for younger fit patients is cure and includes intensive chemotherapy and stem cell transplantation, these strategies are not always feasible for elderly unfit patients due to increased frailty, co-morbidities, and, subsequently, an increased risk of treatment-related toxicity and mortality. AREAS COVERED: This review will discuss both patient- and disease-related factors, outline prognostication models and summarize current treatment options, including intensive and less intensive treatment strategies and novel agents. EXPERT OPINION: Although recent years have seen major advances in the development of low-intensity therapies, there is still a lack of consensus on the optimal treatment for this patient group. Because of the heterogeneity of the disease, personalizing the treatment strategy is important and curative-oriented approaches should be selected wisely, rather than following a rigid hierarchical algorithm.

SOHO State of the Art Updates and Next Questions |The Role of Maintenance Therapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive disease predominantly affecting the elderly population. Although, up to 65% of patients with AML achieve a complete remission with standard induction chemotherapy, the majority of patients will relapse and succumb to the disease. Although maintenance therapy is a component of standard management for various hematological malignancies, such as acute lymphoblastic leukemia (ALL), acute promyelocytic leukemia (APL) or multiple myeloma, past studies investigating the role of maintenance therapy in AML were unable to demonstrate an advantage in overall survival, and therefore, it has not been an established practice in the treatment of AML. For patients, who are not candidates for stem cell transplant, effective AML maintenance therapies are needed in order to reduce the risk of relapse. Over the past decades, many investigators have examined the role of various maintenance strategies in AML; with the intention to prolong remission and overall survival. This review will provide an overview of prior and ongoing approaches and strategies to maintenance therapy for AML.

Neutropenic Enterocolitis: An Uncommon, but Fearsome Complication of Leukemia.

Neutropenic enterocolitis (NEC) is a life-threatening condition occurring in severely neutropenic patients, following intensive chemotherapy for leukemia. Its pathogenesis is not entirely understood and believed to be multifactorial, including mucosal injury as a result of cytotoxic drugs, profound neutropenia, impaired host defense and possibly microbiota changes. Establishing an early diagnosis is key. The management of NEC remains undefined due to lack of high-quality clinical data. With a better understanding of the disease, a more conservative approach is preferred over surgical intervention. The involvement of a multi-disciplinary team, consisting of the oncologist, infectious diseases specialists and surgeons is highly recommended. This review aims to delineate insights into the pathophysiology and clinical presentation of NEC and to emphasize the diagnostic and therapeutic approach to this condition.

Heterogenous lung inflammation CT patterns distinguish pneumonia and immune checkpoint inhibitor pneumonitis and complement blood biomarkers in acute myeloid leukemia: proof of concept.

Background: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers. Materials and methods: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add diagnostic value. Results: Habitat imaging revealed intrinsic lung inflammation patterns by identifying 5 distinct subregions, correlating to lung parenchyma, consolidation, heterogenous ground-glass opacity (GGO), and GGO-consolidation transition. Consequently, our proposed habitat model (accuracy of 79%, sensitivity of 48%, and specificity of 88%) outperformed the clinical-blood model (accuracy of 68%, sensitivity of 14%, and specificity of 85%) for classifying pneumonia versus pneumonitis. Integrating imaging and blood achieved the optimal performance (accuracy of 81%, sensitivity of 52% and specificity of 90%). Using this imaging-blood composite model, the post-test probability for detecting pneumonitis increased from 23% to 61%, significantly (p = 1.5E - 9) higher than the clinical and blood model (post-test probability of 22%). Conclusion: Habitat imaging represents a step forward in the image-based detection of pneumonia and pneumonitis, which can complement known blood biomarkers. Further work is needed to validate and fine tune this imaging-blood composite model and further improve its sensitivity to detect pneumonitis.

IDH1/IDH2 Inhibition in Acute Myeloid Leukemia.

Recently, the discovery of biological and clinical properties of mutated isoforms 1 and 2 mutations of isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with acute myeloid leukemia (AML), lead to the development of an individualized treatment strategy. Promoting differentiation and maturation of the malignant clone targeting IDH is an emerging strategy to promote clinical responses in AML. Phase I/II trials have shown evidence of safety, tolerability, and encouraging evidence of efficacy of two small molecule inhibitors targeting IDH2 and IDH1 gene mutations, respectively enasidenib and ivosidenib. In this review, the contribution of IDH1/IDH2 mutations in leukemogenesis and progress of targeted therapeutics in AML will be highlighted.

Acute erythroid leukemia as defined in the World Health Organization classification is a rare and pathogenetically heterogeneous disease.

The diagnostic criteria for acute erythroid leukemia have been controversial since this disease was initially described. Using the current World Health Organization classification criteria, we retrospectively reviewed cases of acute myeloid leukemia or myelodysplastic syndrome in which erythroid precursors were >or=50% of the bone marrow nucleated cell population and the diagnosis of erythroleukemia was considered using older classification schemes. We collected 90 cases and separated them into four diagnostic groups: acute erythroid leukemia, erythroleukemia or erythroid/myeloid type (n=20); acute myeloid leukemia with myelodysplasia-related changes (n=22); therapy-related acute myeloid leukemia (n=32); and refractory anemia with excess blasts and preceding or concurrent history of erythropoietin therapy for anemia (n=16). Patients with acute erythroid leukemia were the youngest patient group and had the best overall survival. There was a statistically significant difference in overall survival between patients with acute erythroid leukemia versus acute myeloid leukemia with myelodysplasia-related changes (P=0.003) and between patients with acute erythroid leukemia versus therapy-related acute myeloid leukemia (P<0.0001). The presence of complex cytogenetic abnormalities (>3) was the only statistically significant independent variable that adversely affected survival in the acute erythroid leukemia group. Monosomy 5/del(5q) and monosomy 7/del(7q) were overrepresented in the context of complex chromosomal abnormalities. Our data suggest that acute erythroid leukemia, as currently defined in the World Health Organization classification, has become a rare disease. A majority of the cases reported previously as erythroleukemia are now classified as other entities. In addition, our data suggest that the current definition of acute erythroid leukemia, erythroleukemia type remains heterogeneous. One subset of acute erythroid leukemia patients has relatively low blast counts and are diploid. The prognosis of this patient subset is relatively good. The other subset has cytogenetic abnormalities similar to those in myelodysplastic syndromes and a poor prognosis.