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Qiuju Liu,1 Brittny Major,2 Jennifer Le-Rademacher,2 Aref A Al-Kali,3 Hassan Alkhateeb,3 Kebede Begna,3 Michelle A Elliott,3 Naseema Gangat,3 William J Hogan,3 C Christopher Hook,3 Scott H Kaufmann,3 Animesh Pardanani,3 Mrinal S Patnaik,3 Ayalew Tefferi,3 Alexandra P Wolanskyj-Spinner,3 Wei Wei,4 Mark R Litzow3 1Department of Cancer Center, Division of Hematology, Jilin University, Changchun, Jilin, People’s Republic of China; 2Department of Health Sciences Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, USA; 3Department of Internal Medicine, Division of Hematology, Mayo Clinic, Rochester, MN, USA; 4Department of Urology, Second Division, Jilin University, Changchun, Jilin, People’s Republic of ChinaCorrespondence: Mark R LitzowDivision of Hematology, Mayo Clinic, 200 First St, Rochester, MN 55902, USATel +1 507-284-2511Email litzow.mark@mayo.eduIntroduction: Obesity is a worldwide problem that is related to cardiac disease, thrombosis and cancer. However, little is known about the impact of obesity on the outcomes of adult acute lymphoblastic leukemia (ALL) patients.Methods: We retrospectively evaluated a cohort of 154 newly diagnosed adult ALL patients between 1994 and 2011 at Mayo Clinic (Rochester). According to the World Health Organization (WHO) international BMI classification, patients were stratified as underweight, normal weight, overweight, and obese. For some analyses, patients were also stratified according to a two-sided non-obese or obese classification.Results: The median follow-up time was 8.37 years. Obese patients were more likely to be women (p=0.024) and ≥ 60 years old (p=0.003). Five-year mortality rates were higher in obese patients than non-obese [HR 95% CI: 1.60 (1.03– 2.50) p=0.035]. This was also the case in subgroup analysis among T-cell patients although the number of patients was small [HR 95% CI: 5.42 (1.84– 15.98) p< 0.001]. There was no difference in mortality among the B-cell patients. After adjusting for baseline variables, the difference in mortality remained in several models. There was no difference in EFS or cumulative incidence of relapse rates between obese and non-obese patients among the overall population.Discussion: In conclusion, our study suggests that adult ALL patients with obesity have lower survival rates, especially in T-cell ALL.Keywords: acute lymphoblastic leukemia, obesity, overweight, B cell, T cell

Mehrdad Hefazi, Mark R Litzow Division of Hematology, Mayo Clinic, Rochester, MN, USA Abstract: Acute lymphoblastic leukemia (ALL) is a hematologic malignancy arising from precursors of the lymphoid lineage. Conventional cytotoxic chemotherapies have resulted in high cure rates of up to 90% in pediatric ALL, but the outcomes for adult patients remain suboptimal with 5-year survival rates of only 30%–40%. Over the last decade, major advances have been made in our understanding and management of ALL. Identification of new prognostic genomic markers and incorporation of minimal residual diseases’ assessment into therapeutic protocols have improved risk stratification and treatment strategies. The use of pediatric-inspired regimens for adolescent and young adults, and the advent of tyrosine kinase inhibitors and novel targeted therapies, including monoclonal antibodies and chimeric antigen receptor T cells, have redefined the therapeutic paradigm of ALL, and significantly improved the outcomes. In this article, we will provide an overview of the current knowledge regarding the biology and treatment of ALL, and highlight recent diagnostic and therapeutic advances made in this area over the past 5 years. Keywords: acute lymphoblastic leukemia, minimal residual disease, hematopoietic cell transplantation, Philadelphia chromosome, monoclonal antibodies

Theodora Anagnostou, Mark R Litzow Mayo Clinic Rochester, Rochester, MN, USA Abstract: Ponatinib, a third-generation tyrosine kinase inhibitor that inhibits BCR/ABL independent of the mutation status, is currently approved for the treatment of patients with chronic myeloid leukemia or acute lymphoblastic leukemia that are either resistant or unable to tolerate another tyrosine kinase inhibitor. Its US Food and Drug Administration approval was based on results from long-term follow-up of the pivotal Phase II PACE trial, which demonstrated deep and durable molecular responses in the treated patients. Despite the remarkable responses, ponatinib has been associated with high frequency of severe vascular events, which led to its withdrawal from the market in 2013. Following analysis of the risk factors of patients who developed vascular side effects, ponatinib was reintroduced in the market 1 year later with specific dose-reduction recommendations and carrying a black box warning. Thus, careful patient selection with identification of patients whose potential benefit from ponatinib exceeds the potential risks associated with its use is crucial. Ongoing and future studies are focusing on earlier detection of mutations, strategies to minimize side effects, and potential expansion of the treatment indications. Clinical trials testing the safety and efficacy of ponatinib as frontline therapy are ongoing. Keywords: ponatinib, acute lymphoblastic leukemia, chronic myeloid leukemia, patient selection

Mark R LitzowMayo Clinic, Rochester, MN, USAAbstract: Acute lymphoblastic leukemia (ALL) arises from immature B and T lymphoblasts. An increasing array of cytogenetic and molecular markers have been identified in ALL, which allows for increasingly sophisticated prognostication, as well as identification of potential new targets for therapy. The treatment of ALL in children has shown astounding success in the last 50 years, with more than 90% of children now able to be cured of their ALL. In adults, these success rates have not been duplicated. However, the use of pediatric-intensive regimens in young adults has shown increasing success. The use of monoclonal antibodies conjugated to drugs, immunotoxins, and cells also has shown early success and promises to enhance the outcome of newly diagnosed patients. Blinatumomab, a bispecific T-cell engager antibody, brings a malignant B cell in proximity to a T cell with redirected lysis. This antibody construct has shown promising results in patients with relapsed and refractory disease and is entering randomized clinical trials in newly diagnosed patients. The addition of monoclonal antibody therapy to chemotherapy in adults promises to enhance outcomes while hopefully not increasing toxicity. After many years of stagnation, it appears that the therapy of adults with ALL is showing significant improvement.Keywords: acute lymphoblastic leukemia, chemotherapy, monoclonal antibodies, CD19, blinatumomab

Anagnostou T, Litzow MR. Blood Lymphat Cancer.2018;8:1–9.On page 2, Table 1 was incorrectly presented. Read the original article

Obesity is becoming more prevalent worldwide and is a major risk factor for cancer development. Acute myeloid leukemia (AML), the most common acute leukemia in adults, remains a frequently fatal disease. Here we investigated the molecular mechanisms by which obesity favors AML growth and uncovered the fatty acid-binding protein 4 (FABP4) and DNA methyltransferase 1 (DNMT1) regulatory axis that mediates aggressive AML in obesity. We showed that leukemia burden was much higher in high-fat diet-induced obese mice, which had higher levels of FABP4 and interleukin (IL)-6 in the sera. Upregulation of environmental and cellular FABP4 accelerated AML cell growth in both a cell-autonomous and cell-non-autonomous manner. Genetic disruption of FABP4 in AML cells or in mice blocked cell proliferation in vitro and induced leukemia regression in vivo. Mechanistic investigations showed that FABP4 upregulation increased IL-6 expression and signal transducer and activator of transcription factor 3 phosphorylation leading to DNMT1 overexpression and further silencing of the p15INK4B tumor-suppressor gene in AML cells. Conversely, FABP4 ablation reduced DNMT1-dependent DNA methylation and restored p15INK4B expression, thus conferring substantial protection against AML growth. Our findings reveal the FABP4/DNMT1 axis in the control of AML cell fate in obesity and suggest that interference with the FABP4/DNMT1 axis might be a new strategy to treat leukemia.

Background: Patients with newly diagnosed acute myeloid leukemia (AML) often have residual leukemia in the bone marrow 10 to 14 days after the start of induction therapy. Some cooperative groups administer a second cycle of similar induction therapy on Day 14 if there is residual leukemia. It is a common perception that the presence of residual leukemia at that point predicts a worse prognosis irrespective of the therapy received. The objective of this study was to determine whether patients who required a second cycle of induction (given on or about Day 14) to achieve complete remission (CR) had a worse prognosis than patients who achieved CR after only 1 cycle, because a worse prognosis may alter postremission therapy.Methods: Patients who were enrolled on 6 consecutive studies for AML that were conducted by the Eastern Cooperative Oncology Group (ECOG) between 1983 to 1993 received induction therapy. If residual leukemia was present in the bone marrow on the Day 14 after the start of induction, then patients were to receive a second cycle of identical induction therapy. All patients who achieved CR after 1 or 2 cycles received the identical postremission therapy.Results: In each of the 6 ECOG studies, the long-term outcome was similar for patients who required 1 or 2 cycles of induction therapy to achieve CR, and their outcome was independent of other prognostic variables, such as age or karyotype.Conclusions: The presence of residual leukemia in bone marrow 10 to 14 days after induction therapy did not predict a worse prognosis if patients received second, similar cycle of induction therapy and achieved CR. [ABSTRACT FROM AUTHOR]

Summary:Autologous stem cell transplant (SCT) improves survival in multiple myeloma (MM) and remains the standard of care for eligible patients. Nearly a third of patients with newly diagnosed MM fail initial therapy aimed at reducing tumor burden preceding SCT (primary refractory). It is unclear if an initial response is important for successful SCT. We evaluated our experience with SCT in 50 patients with primary refractory MM and compared it to 101 patients with chemosensitive disease receiving SCT. The study cohort had a median age of 56 years (range 29-72) consisting of 87 males (58%). A total of 46 patients (92%) in the refractory group and 100 (99%) in the chemosensitive group had a response to transplant (50% or greater reduction in the M-protein). In all, 10 refractory patients (20%) and 35 (35%) in the chemosensitive group achieved a CR (P=0.06). The 1-year estimated progresion-free survival from the time of transplant for the refractory group was 70% compared to 83% for the chemosensitive group (P=0.65). The lack of response to initial induction therapy does not appear to preclude a good response to SCT. We recommend that patients with primary refractory MM be offered early SCT.Bone Marrow Transplantation (2004) 34, 161-167. doi:10.1038/sj.bmt.1704545 Published online 10 May 2004 [ABSTRACT FROM AUTHOR]

We report on the feasibility of outpatient transplant in 716 patients undergoing autologous stem cell transplant for multiple myeloma at Mayo Clinic's site in Rochester, MN, from January 1, 2000, through October 31, 2007. We also report on the development and effect of a multidisciplinary quality initiative implemented by the Mayo Clinic Blood and Marrow Transplant Program involving physicians, nurses, pharmacists, dietitians, and financial specialists for outpatient management of patients undergoing stem cell transplant. This approach uses an electronic ordering system for diagnostic tests and chemotherapy to minimize medical errors. Analysis of hospitalization trends since inception of the program showed that 278 (39%) of the 716 patients treated completed the transplant procedure as outpatients. The median duration of hospitalization for all patients was 4 days; age and serum creatinine levels were predictive of the need for and duration of hospitalization. We also assessed recent treatment-related mortality rates during a 33-month period after implementation of the program (between January 1, 2005, and October 1, 2007). The 100-day survival rate was 99.5% for patients with low-risk myeloma (transplant during first plateau; n=201) and 97.2% for patients with high-risk myeloma (refractory, relapsing or second or greater plateau; n=71). The overall 100-day survival rate was 98.9%. Our experience shows that outpatient transplant is feasible for all patients with multiple myeloma and results in shorter hospital stays and low treatment-related mortality rates. [ABSTRACT FROM AUTHOR]

Several factors are responsible for the occurrence of cardiac complications after bone marrow transplantation (BMT). These factors include the cardiotoxic effects of radiation therapy, antineoplastic and immunosuppressive drugs, abnormal immunologic reactions associated with graft-vs-host disease, and infectious agents. We report the case of a 45-year-old woman with T-cell prolymphocytic leukemia and no prior risk factors for coronary artery disease in whom sudden cardiac death occurred 2 1/2 years after allogeneic BMT from an unrelated male donor. Autopsy revealed severe 3-vessel coronary disease with grade 4/4 stenosis. This process was primarily nonatherosclerotic, with intimal hyperplasia of undetermined etiology. Furthermore, fluorescence in situ hybridization to identify the donor Y chromosome with simultaneous immunofluorescence labeling of smooth muscle actin suggested the presence of donor cells that transformed into myocytes. Coronary artery disease is an important, albeit rare, complication of BMT. Donor hematopoietic cells may contribute to its pathogenesis. [ABSTRACT FROM AUTHOR]

Although complete remission rates in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) have improved over the last two decades, it is still inferior to that of the pediatric population and once in remission, the risk of relapse is still high. Furthermore, while pediatric-inspired chemotherapy regimens have improved long-term outcomes for adolescents and young adults, these intensive chemotherapy regimens are not well tolerated in older patients and are associated with higher morbidity and mortality. Immunotherapeutic agents offer a potential opportunity to improve response and decrease relapse without increasing toxicity. The incorporation of rituximab (anti-CD20 monoclonal antibody) into chemotherapy regimens has been shown to improve outcomes. The treatment of BCP-ALL in adults has been transformed with the approval of inotuzumab ozogamicin (anti-CD22 antibody drug conjugate), blinatumomab (CD3/CD19 bispecific antibody construct), and CAR T-cells for relapsed or refractory disease, and of blinatumomab for measurable residual disease (MRD)-positive remission. More recently, studies of inotuzumab and blinatumomab have shown promising results when used upfront either with or without multiagent chemotherapy. Blinatumomab has also been shown in a randomized trial to provide a survival benefit in patients with MRD-negative first remission when added to chemotherapy which recently led to its additional FDA approval for use in consolidation. In this review, we highlight the evolution of chemoimmunotherapy-based treatment approaches in the management of treatment-naïve BCP-ALL., (Copyright © 2024 American Society of Hematology.)

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