Refractory Hydroa Vacciniforme-like Lymphoma: Biological Insights from Morphoproteomic Analysis.

T-cell/natural killer cell lymphoproliferative disorders are rare, associated with poor overall survival, and have limited treatment options. We report a case of a patient who developed hydroa vacciniforme-like lymphoma (HVLL, an EBV-peripheral T-cell lymphoma), refractory to multiple lines of systemic therapy including methotrexate, mycophenolate mofetil, dapsone, thalidomide, prednisone, and romidepsin. We conducted morphoproteomic analysis of the patient's tumor which provided important biological insights. Histopathology showed primarily lymphohistiocytic infiltrates strongly positive EBV expression with a Ki-67 of >50% in the pretreatment biopsy and approximately 90% in the post-treatment biopsy, strong expression of Enhancer of Zester Homolog 2 (EZH2), a constitutively active mTOR pathway, 50% cytoplasmic BCL-2 expression; largely negative PD-1 positive CD8 T-cells. Based on this morphoproteomic analysis and published literature, we postulated that novel agents, including venetoclax, tazemetostat, and other agents may provide a targeted approach for treating HVLL. This case illustrates the use of morphoproteomic analysis to better understand the biology of tumors.

Clinical Outcomes of Patients With Newly Diagnosed Acute Lymphoblastic Leukemia in a County Hospital System.

BACKGROUND: Major advances in the treatment of acute lymphoblastic leukemia (ALL) over the past decade have resulted in 5-year overall survival (OS) rates of 80% in mature B cell ALL, 50% in precursor B cell ALL, 50% to 60% in T cell ALL, and 60% to 70% in Philadelphia chromosome-positive (Ph+) ALL, as reported in studies from large, specialized centers. However, many patients treated in the community have limited access to novel therapies and stem cell transplantation (HSCT). PATIENTS AND METHODS: The purpose of this retrospective cohort analysis was to evaluate the clinical outcomes of patients ≥ 16 years with newly diagnosed ALL treated from October 2007 to June 2019 in the Harris County Health System, Houston, TX. RESULTS: One hundred forty-six patients were included, with newly diagnosed pre-B-ALL (n = 127), T-ALL (n = 18), and chronic myeloid leukemia and/or lymphoid blast crisis (n = 1). Median age was 35 years (16-82) at diagnosis, and 81(55%) were male. The majority of patients with pre-B ALL identified as Hispanic (n = 118, or 92%). Ninety-eight (67%) of patients were uninsured or indigent, receiving care under the county's financial assistance programs. Hyper-CVAD-based induction chemotherapy was administered in 134 (92%) of patients, while 9 (6%) were treated on different protocols, and 3 (2%) were not treated due to early death, or patient refusal. Imatinib was the most common TKI used in 17 of 30 or 57% of patients with Ph+ disease. Out of 137 evaluable for response patients, 117 (85%) achieved complete remission (CR + CRi), 19 (14%) had refractory disease, and 1 (1%) died within 4 weeks of diagnosis. Median follow-up time was 50 months (1.5-135). For the entire study cohort, the median duration of CR/CRi was 15.4 months. Out of 62 patients who were eligible for consolidative HSCT at first CR, 52 (89%) did not receive it, with lack of insurance being the most common reason (n = 29, or 56%). Barriers to utilization of novel therapies such as blinatumomab or CAR-T were also observed. Patient-caused delays in administration of chemotherapy and treatment interruptions of at least 30 days were seen in 31(23%) patients. At 1, 2, and 5 years, relapse rates were 37%, 56%, and 70%. Recurrent and/or refractory disease was the cause of death in most patients (n = 69 [85%]). Five-year EFS and OS rates were 22% and 38% for patients with pre-B ALL, 24% and 44% for patients with T ALL, and 13% and 27% for patients with Ph+ ALL. Median OS was significantly increased (not reached [NR] vs. 24 months; P = .00088) in patients with an indication for HSCT in first CR due to high-risk features who underwent HSCT, versus those who did not. CONCLUSION: Addressing barriers raised by socioeconomic disparities, increasing access to effective therapies, and including patients with ALL treated in the community in clinical trials may improve survival for underserved populations.

Phase II study of sunitinib in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis.

BACKGROUND: Changes in the bone marrow microenvironment in myelofibrosis are triggered by a cytokine burst and consist of fibrosis, osteosclerosis, and angiogenesis. Sunitinib is a multitargeted small-molecule inhibitor of the receptor tyrosine kinases involved in cell proliferation and angiogenesis, including vascular endothelial growth factor receptors. PATIENTS AND METHODS: Fourteen patients with myelofibrosis were treated with sunitinib at a daily continuous dose of 37.5 mg orally. The median duration of sunitinib treatment was 5.2 months (range, 1-18 months). RESULTS: One patient (7%) showed a clinical improvement of anemia (increase in hemoglobin of 4 g/dL), with improvement in anemia-associated symptoms. The time to response was 6 months, and the benefit was sustained for 12 months. However, 8 patients (57%) experienced a total of 13 incidents of significant (grade 3-4) adverse events possibly related to sunitinib (fatigue, gastrointestinal disturbances, anemia, leukopenia, and thrombocytopenia were the most common). In 7 patients (50%), sunitinib was held, and subsequently the dose was reduced to 25 mg daily. Overall, 29% of patients withdrew from the study because of toxicity. CONCLUSION: Sunitinib therapy, as applied here, was not well-tolerated by patients with myelofibrosis, and the benefits were minimal. Our experience with sunitinib combined with previous experience with other antiangiogenic medications suggest that this class of drugs may have limited usefulness in myelofibrosis when used as a single-agent therapy.

JAK2 inhibitors: A reality? A hope?

Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated.

del(15q) is a recurrent minor-route cytogenetic abnormality in the clonal evolution of chronic myelogenous leukemia.

The del(15q) chromosomal abnormality is known to occur in acute leukemias, but has rarely been described in chronic myelogenous leukemia (CML). Described here are five cases of CML associated with del(15q): four men and one woman. Bone marrow aspirate smears showed increased blasts in all cases at the time of del(15q) detection, in accelerated phase in two cases and myeloid blast phase in three. Conventional cytogenetic analysis showed t(9;22) and del(15q), as well as other inconsistent clonal abnormalities. All patients received imatinib mesylate; four received additional chemotherapy, and two had allogeneic stem cell transplantation (ASCT). Of the three patients who did not receive ASCT, one died, one was in persistent blast phase, and one was in clinical remission with molecular evidence of residual disease at 16, 6, and 34 months, respectively, after identification of the del(15q). Of the two patients who had ASCT, one died and one was in clinical remission with molecular evidence of disease at 15 and 64 months, respectively, after identification of the del(15q). These findings indicate that del(15q) is a recurrent cytogenetic abnormality that may be seen at initial presentation of advanced disease or may emerge during disease progression. Del(15q) appears to be associated with a poor prognosis in CML.

Treatment of acute lymphoblastic leukaemia : a new era.

Acute lymphocytic leukaemia (ALL) is a heterogeneous group of disorders that result from the clonal proliferation and expansion of malignant lymphoid cells in the bone marrow, blood and other organs. Distinct clinicopathological ALL entities have been identified, resulting in the adoption of risk-oriented treatment approaches. Advances in ALL therapy have led to long-term survival rates of >80% in children. However, only approximate, approximately 30-40% of adults achieve long-term disease-free survival. Contemporary ALL treatment programmes include induction, intensified consolidation, maintenance phases and CNS prophylaxis. The optimal treatment of Philadelphia chromosome-positive patients requires the addition of BCR-ABL tyrosine kinase inhibitors, such as imatinib, whereas allogeneic stem-cell transplantation remains the preferred approach for high-risk patients in first remission. Since only approximate, approximately 38% of adult ALL patients are free of disease 5 years after diagnosis and the outcome of salvage chemotherapy is very poor (complete remission rates of 20-30%, median survival of 3-6 months), novel agents are desperately required. Of those currently in clinical studies, the outlook for sphingosomal vincristine, pegylated asparaginase (pegaspargase), liposomal annamycin, ABT-751, pemetrexed, talotrexin, nelarabine and the novel BCR-ABL kinase inhibitors is discussed.

Emerging therapeutic options for Philadelphia-positive acute lymphocytic leukemia.

Acute lymphocytic leukemia (ALL) is a heterogeneous group of disorders that are associated with a cure rate of > 80% in children. The prognosis in adults is considerably inferior, with age, disease bulk, leukemia karyotype and immune phenotype being prognostically relevant. Adult ALL treatment programs include induction, intensified consolidation and maintenance phases with CNS prophylaxis. The addition of imatinib in patients with BCR-ABL-positive ALL has improved the prognosis of this subgroup, but their survival is still poor. Initial data on the second-generation BCR-ABL inhibitors, dasatinib and nilotinib, indicate a potentially greater efficacy than imatinib, but the improvement is likely to be modest. The overall efforts in terms of developmental therapeutics in ALL are very modest and not in keeping with the urgent need for improvement. Most agents being investigated have mechanisms of action similar to those of existing agents for ALL therapy and thus represent modest opportunities to improve results. Of such agents, data on BCR-ABL inhibitors, sphingosomal vincristine, pemetrexed, talotrexin, annamycin and ABT-751 are reviewed.

Troxacitabine in leukemia.

Troxacitabine (Troxatyl; BCH-4556; (-)-2'-deoxy-3'-oxacytadine) is the first synthetic l-nucleoside enantiomer to demonstrate broad spectrum cytotoxic activity. It was obtained by exchanging the sulphur endocyclic atom with oxygen in the structure of lamivudine, following the discovery that this agent had cytotoxic, as well as anti-viral activity. The unique "unnatural" stereochemistry of troxacitabine has produced impressive cytotoxic potency against a wide range of malignancies in the laboratory which led to its selection for clinical development. The initial trials with troxacitabine have established its efficacy in both solid and haematological malignancies, including those resistant to ara-C (cytarabine). This review will consider troxacitabine in terms of its pharmacology, mode of action, pharmacokinetics, toxicities, and clinical efficacy.