Treatment of Acute Promyelocytic Leukemia with High White Cell Blood Counts.

Acute promyelocytic leukemia (APL) with WBC above 10 G/L has long been considered, even in the all-trans retinoic acid (ATRA) era, to carry a relatively poor prognosis (compared to APL with WBC below 10 G/L), due to increased early mortality and relapse. However, early deaths can to a large extent be avoided if specific measures are rapidly instigated, including prompt referral to a specialized center, immediate onset of ATRA and chemotherapy, treatment of coagulopathy with adequate platelet transfusional support, and prevention and management of differentiation syndrome. Strategies to reduce relapse rate include chemotherapy reinforcement with cytarabine and/or arsenic trioxide during consolidation, prolonged maintenance treatment, especially with ATRA and low dose chemotherapy, and possibly, although this is debated, intrathecal prophylaxis to prevent central nervous system relapse. By applying those measures, outcomes of patients with high risk APL have considerably improved, and have become in many studies almost similar to those of standard risk APL patients

Autonomous growth potential of leukemia blast cells is associated with poor prognosis in human acute leukemias

We have described a severe combined immunodeficiency (SCID) mouse model that permits the subcutaneous growth of primary human acute leukemia blast cells into a measurable subcutaneous nodule which may be followed by the development of disseminated disease. Utilizing the SCID mouse model, we examined the growth potential of leukemic blasts from 133 patients with acute leukemia, (67 acute lymphoblastic leukemia (ALL) and 66 acute myeloid leukemia (AML)) in the animals after subcutaneous inoculation without conditioning treatment. The blasts displayed three distinct growth patterns: "aggressive", "indolent", or "no tumor growth". Out of 133 leukemias, 45 (33.8%) displayed an aggressive growth pattern, 14 (10.5%) displayed an indolent growth pattern and 74 (55.6%) did not grow in SCID mice. The growth probability of leukemias from relapsed and/or refractory disease was nearly 3 fold higher than that from patients with newly diagnosed disease. Serial observations found that leukemic blasts from the same individual, which did not initiate tumor growth at initial presentation and/or at early relapse, may engraft and grow in the later stages of disease, suggesting that the ability of leukemia cells for engraftment and proliferation was gradually acquired following the process of leukemia progression. Nine autonomous growing leukemia cell lines were established in vitro. These displayed an aggressive proliferation pattern, suggesting a possible correlation between the capacity of human leukemia cells for autonomous proliferation in vitro and an aggressive growth potential in SCID mice. In addition, we demonstrated that patients whose leukemic blasts displayed an aggressive growth and dissemination pattern in SClD mice had a poor clinical outcome in patients with ALL as well as AML. Patients whose leukemic blasts grew indolently or whose leukemia cells failed to induce growth had a significantly longer DFS and more favorable clinical course

Chronic myeloid leukemia in children and adolescents: The achilles heel of oncogenesis and tyrosine kinase inhibitors

Chronic myeloid leukemia (CML) is a rare disease in children and adolescents. The goal of therapy in children and adolescents is normal life expectancy, without compromising normal growth and development and potential for achievement of milestones in adult life. The perspective of cure is also reflected in the goal of treatment‐free remission, with its surrogate markers, such as deep molecular response, also becoming the new endpoints of therapy efficacy in children and ad-olescents. Chronic myeloid leukemia was a fatal disease to children and adolescents in the past. Following the treatment paradigm of imatinib, it became a chronic disease with the potential of complete remission and even cure without the long‐term hazards of allogeneic hematopoietic cell transplantation. The diagnosis and treatment of CML affect a child’s trajectory through life and important physiological events like development and procreation. © 2021 by the authors. Li-censee MDPI, Basel, Switzerland

PlGF and sFlt-1 levels in patients with non-transfusion-dependent thalassemia: Correlations with markers of iron burden and endothelial dysfunction

Background: Levels of the angiogenic cytokines placental growth factor (PlGF) and soluble Fms-like tyrosine kinase-1 (sFlt-1) and the angiogenic balance, expressed by sFlt-1/PlGF ratio, are perturbed in sickle-cell disease and iron overload, but they have not been evaluated in non-transfusion-dependent thalassemia (NTDT). Patients and Methods: We measured levels of PlGF, sFlt-1 and vWF:antigen in patients with NTDT of beta-thalassemia genotype, and correlated them with erythrocytic indices and markers of iron overload, inflammation, and tissue hypoxia. Thirty-four NTDT patients with mean hemoglobin level of 8.4 g/dL were included in the study along with 20 apparently healthy individuals who served as controls. Results: Ferritin, LDH, and hs-CRP were higher in patients as compared to controls. We found significant differences between patients and controls in regard to levels of PlGF (52.2 vs 17.2 pg/mL, P <.001), sFlt-1/PlGF (2 vs 4.7, P <.001), and vWF:antigen (88 vs 77.1 IU/dL, P <.01). There was a strong correlation of ferritin with PlGF (r =.653, P <.001) and with vWF:antigen (r =.503, P =.003). Conclusions: In this study, we demonstrated an association between increased PlGF and iron overload and the degree of tissue hypoxia in patients with NTDT. High vWF:antigen expressing endothelial damage may be associated with specific NTDT comorbidities. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Bone Marrow Failure in Fanconi Anemia: Clinical and Genetic Spectrum in a Cohort of 20 Pediatric Patients

Prognostic refinement in Fanconi anemia (FA) is needed, especially when considering allogeneic hematopoietic stem cell transplantation (HCT). We studied 20 children with FA and bone marrow failure from a single center. According to Hôpital Saint-Louis risk classification for FA, patients were classified in stage A (no or mild cytopenia/dysplasia), B (single non-high-risk cytogenetic abnormality), C (severe cytopenia and/or significant dysplasia and/or high-risk cytogenetic abnormality), and D (myelodysplastic syndrome with excess of blasts/acute myeloid leukemia) in 4, 2, 13, and 0 cases, respectively. Nine patients received androgens +/- steroids, with a response rate of 30%, and 11 patients underwent HCT. Ten-year cumulative incidence (CI) of myelodysplastic syndrome/acute myeloid leukemia and overall survival (OS) were 21.9% and 45.3%, respectively, in the entire cohort, whereas cumulative incidence of transplantation-related mortality and OS were 27% and 63%, respectively, in patients who underwent HCT. Patients with significant dysplasia at diagnosis (stages C and D) had significantly shorter OS post-HCT as compared with patients without dysplasia. All patients in stages C and D at diagnosis or during evolution died from their disease. HCT in recent years was associated with more favorable outcomes. Larger cohorts could validate homogenous reporting of risk and help decision-making, particularly for HCT. © 2019 Wolters Kluwer Health, Inc. All rights reserved

Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib-based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL-pPCL and 17 with secondary PCL-sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P=0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR-group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow-up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P<0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P<0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow-up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity. © 2013 Wiley Periodicals, Inc