Meeting Challenges in the Long-Term Care of Children, Adolescents, and Young Adults with Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: To discuss the long-term view of treating and following pediatric, adolescent, and young adult patients with acute lymphoblastic leukemia (ALL) - with review of what can be done to prevent, monitor for, and treat complications of therapy. RECENT FINDINGS: Pediatric, adolescent, and young adult oncology patients, including those with ALL, are living longer with higher overall survival rates as treatments and supportive care for these patients continue to improve. These patients are burdened by the risk of significant health and quality of life consequences as a result of their treatment.. For these patients, the late effects of treatment can be life-threatening, such as secondary cancers or cardiotoxicity, or life-altering with respect to quality of life. The goal of this paper is to review the current literature, research, and surveillance guidelines regarding the late effects of ALL therapy, to outline what can be done to mitigate the toxic effects of oncology treatment, and to extend life expectancy and improve quality of life for our patients. We review risk factors and interventions available to prevent and treat cardiovascular disease, secondary malignancies, endocrine complications (obesity, osteoporosis, infertility, and premature menopause), cognitive effects, and effects on functioning and mortality.

Diagnosis and Management of Atypical Chronic Myeloid Leukemia with a t(2;13)(q33;q12) Translocation.

Atypical chronic myeloid leukemia (aCML) is a rare myeloproliferative disorder that shares clinical features with chronic myeloid leukemia but lacks the classic t(9;22) BCR-ABL1 translocation and features prominent dysgranulopoiesis and granulocytic dysplasia. Challenges of this diagnosis include clinical and biologic heterogeneity, the high risk of transformation to acute myeloid leukemia, and the lack of standard treatment options. Allogeneic hematopoietic stem cell transplant is likely the preferred treatment, but this can be limited by patient psychosocial support, age, concomitant medical conditions, and availability of an appropriate donor. We report the case of a 61-year-old male with no significant past medical history diagnosed with aCML with a rare t(2;13)(q33;q12). He presented with weight loss, night sweats, splenomegaly, hyperleukocytosis, a leukoerythroblastic differential with a predominant neutrophilia, anemia, and thrombocytopenia. Subsequent peripheral blood and bone marrow studies lead to the diagnosis of aCML. He was recommended to undergo an allogeneic stem cell transplant evaluation and declined. He was initially treated with hydroxyurea and imatinib to which he responded for approximately three years. After clinical progression, he was treated with sorafenib, a multiprotein kinase inhibitor more commonly used in the treatment of hepatocellular and renal cell carcinoma due to its off target FLT3 inhibition. The patient achieved complete hematologic response which has been sustained for 7 years with tolerable side effects.

Diagnostic approach to the evaluation of myeloid malignancies following CAR T-cell therapy in B-cell acute lymphoblastic leukemia.

Immunotherapeutic strategies targeting B-cell acute lymphoblastic leukemia (B-ALL) effectively induce remission; however, disease recurrence remains a challenge. Due to the potential for antigen loss, antigen diminution, lineage switch or development of a secondary or treatment-related malignancy, the phenotype and manifestation of subsequent leukemia may be elusive. We report on two patients with multiply relapsed/refractory B-ALL who, following chimeric antigen receptor T-cell therapy, developed myeloid malignancies. In the first case, a myeloid sarcoma developed in a patient with a history of myelodysplastic syndrome. In the second case, two distinct events occurred. The first event represented a donor-derived myelodysplastic syndrome with monosomy 7 in a patient with a prior hematopoietic stem cell transplantation. This patient went on to present with lineage switch of her original B-ALL to ambiguous lineage T/myeloid acute leukemia. With the rapidly evolving field of novel immunotherapeutic strategies, evaluation of relapse and/or subsequent neoplasms is becoming increasingly more complex. By virtue of these uniquely complex cases, we provide a framework for the evaluation of relapse or evolution of a subsequent malignancy following antigen-targeted immunotherapy.

Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFbeta.

The two subunits of core binding factor (Runx1 and CBFbeta) play critical roles in hematopoiesis and are frequent targets of chromosomal translocations found in leukemia. The binding of the CBFbeta-smooth muscle myosin heavy chain (SMMHC) fusion protein to Runx1 is essential for leukemogenesis, making this a viable target for treatment. We have developed inhibitors with low micromolar affinity which effectively block binding of Runx1 to CBFbeta. NMR-based docking shows that these compounds bind to CBFbeta at a site displaced from the binding interface for Runx1, that is, these compounds function as allosteric inhibitors of this protein-protein interaction, a potentially generalizable approach. Treatment of the human leukemia cell line ME-1 with these compounds shows decreased proliferation, indicating these are good candidates for further development.

Recent Developments in Adolescent and Young Adult (AYA) Acute Lymphoblastic Leukemia.

PURPOSE OF REVIEW: Adolescent and Young Adult (AYA) Oncology is a relatively new field encompassing research in the unique pathophysiology, clinical care, and psychosocial issues facing patients between the ages of 15 and 40 with cancer. About 100,000 of the approximately 1.5 million people diagnosed annually with cancer in the USA are in this age range. This chapter will review notable new developments in the care of adolescents and young adults with acute lymphoblastic leukemia (ALL) within the last 3 years. RECENT FINDINGS: The preponderance of data favors the treatment of AYA ALL patients with pediatric-inspired treatment regimens due to better relapse-free and overall survival. Minimal residual disease (MRD) measurement is emerging as an important prognostic factor and can serve as a new measure of efficacy of the addition of novel therapies to the treatment of patients with new diagnoses. There have been several treatment advances ranging from new cytotoxic agents for ALL to new antibody-based therapy to novel immune therapies such as CAR-T cells. The care of AYA ALL patients is improving as the unique issues for this patient population are addressed.

A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma.

Purpose: Genetic and preclinical studies have implicated FGFR signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor of FGFR activity, may be active in ACC.Experimental Design: In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500 mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate and change in tumor growth rate. Progression-free survival, overall survival, metabolic response, biomarker, and quality of life were secondary endpoints.Results: Of 34 evaluable patients, 2 (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on treatment (P < 0.001). Toxicity was moderate; 63% of patients developed grade 3-4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3 of 15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with overexpression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib.Conclusions: Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably with those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine whether FGFR signaling is a valid therapeutic target in ACC. Clin Cancer Res; 23(15); 4138-45. ©2017 AACR.

Effect of lysophosphatidic acid acyltransferase-beta inhibition in acute leukemia.

Phosphatidic acid (PA) is an important component of mammalian target of rapamycin (mTOR) signaling and in the recruitment of Raf to the cell membrane. PA can be produced by several mechanisms, including by a series of lysophosphatidic acid acyl transferases (LPAATs). LPAAT-beta is an isoform that is overexpressed in some human cancers and its inhibition has been investigated as a potential targeted cancer therapy. We report that LPAAT-protein and enzyme activity in acute leukemia cell lines and blasts from patient samples are equivalent to levels in normal mononuclear cells. Treatment with the LPAAT-beta inhibitor CT-32228 (Cell Therapeutics, Seattle, WA) uniformly induces apoptosis in multiple leukemia cell lines. In patient samples, however, apoptosis was variably induced by CT-32228 and appeared to be related to the degree of cellular proliferation. The growth inhibitory effect of CT-32228 on normal hematopoietic progenitors was more pronounced in cells induced to proliferate by growth factors. These data suggest that CT-32228 may have potential in the treatment of acute leukemias, but that efficacy is more directly related to the degree of cell proliferation rather than to the level of LPAAT-beta expression or activity.

Primary nasopharyngeal interdigitating dendritic cell tumor presentation and response to radiation therapy.

We report the case of a primary nasopharyngeal interdigitating dendritic cell tumor (IDDCT). A 25-year old male presented with bilateral decreased hearing, double vision, and ataxia. Flexible nasopharyngoscopy reviewed a large mass obstructing and filling the entire nasopharynx. MRI and PET-CT confirmed the presence of the primary tumor and demonstrated bilateral cervical lymphadenopathy. Biopsy of the nasopharynx revealed a hematolymphoid neoplasm with dendritic cell differentiation, most consistent with an IDDCT. The lesion was unresectable. The patient was treated with definitive radiotherapy to 66 Gy to the primary tumor and 50 Gy to the bilateral cervical lymphatics using an IMRT technique. A complete response was achieved and the patient remains disease free at the primary site 23 months after completion of radiotherapy.

Neuroleukemiosis: case report of leukemic nerve infiltration in acute lymphoblastic leukemia.

We describe a patient in remission from acute lymphoblastic leukemia who developed a painless common peroneal neuropathy. Magnetic resonance imaging (MRI) revealed nerve thickening and enhancement, while a positron emission tomography (PET) scan demonstrated increased fluorodeoxyglucose uptake in a large segment of the neurovascular bundle, suggesting peripheral nerve infiltration. Both findings resolved following treatment with chemotherapy that crossed the blood-nerve barrier. In selected patients presenting with peripheral neuropathy, MRI and PET scan can be helpful in the diagnosis of peripheral nerve infiltration.