Concetta Ditto

Phase II Study of Bortezomib as a Single Agent in Patients with Previously Untreated or Relapsed/Refractory Acute Myeloid Leukemia Ineligible for Intensive Therapy.

We explored the safety and efficacy of bortezomib given as single agent in patients with untreated or relapsed/refractory acute myeloid leukemia (AML), unfit for conventional chemotherapy. Fourteen patients were treated with bortezomib 1.5 mg/m2 administered twice weekly for two weeks, every 3 weeks. Median age was 70 years (range 60–81) and the median number of cycles delivered was 2 (range 1–4). Of 13 evaluable patients, in 8 (61%), the administration of bortezomib resulted in an antileukemic effect as demonstrated by peripheral blood and/or bone marrow blast reduction. In 4 (50%) of these 8, a decrease by 37% of transfusion requirement was also observed (P = 0.009). Overall median survival was 4 months (range 0.25–10). Neurotoxicity was the most frequent adverse event with 7 of 13 (54%) patients experiencing grades 3-4 peripheral neuropathy. Neurotoxicity led to treatment discontinuation in 4 (57%) of 7. In conclusion, the observed anti-leukemic activity of bortezomib indicates that there is room for designing additional studies in which combination with other chemotherapeutic agents should be considered. Clinical registration no.: EUDRACT 2006-006923-38.

Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia

Despite progress in treatment and supportive therapies, outcome of high-risk adult AML remains dismal with ~ 20% of patients becoming long-term survivors. Since the pretreatment genetics/cytogenetics of AML do not always anticipate the individual outcome, there is a strong rationale to implement laboratory techniques capable of exploring the quality of CR and allowing post-remission therapy to be optimally directed. In this view, minimal residual disease (MRD) assessment promises to be a robust approach. It captures the diversities of the underlying genetic/cytogenetic features of AML and recapitulates other patient heterogeneities regarding drug bioavailability, metabolism and resistance. Multiparametric flow cytometry (MFC) is one of the leading techniques successfully exploited to quantify MRD in AML expressing leukemia-associated immunophenotypes (LAIP). This assay applies to the vast majority of patients after chemotherapy-induced morphologic CR and has been shown to predict the clinical outcome when measured at several time points, potentially prompting prospective treatment adjustments. Recent studies have demonstrated that pretransplant MRD levels negatively affect post-transplant outcome. Years ago, we showed that MRD persistence at the end of consolidation was associated with an unfavorable outcome and that autologous stem cell transplantation (AuSCT) was not able to alter such an unfavorable course. More recently, other authors have extended this observation to either pediatric or adult patients receiving allogeneic stem cell transplantation (ASCT), showing that pretransplant MRD is a major determinant of prognosis, regardless of the occurrence of graft-versus-leukemia (GVL). Nevertheless, whether MRD positivity is an indication or a contraindication to deliver ASCT is still a matter of debate. On the basis of these premises, we analyzed a retrospective series of MRD-positive adults with AML who were submitted to ASCT. Our aim was to evaluate the impact of pretransplant MRD status on overall survival (OS) and DFS. We analyzed 230 consecutive patients achieving CR after the induction cycle of intensive EORTC/GIMEMA protocols and who harbored in their leukemic cells a LAIP suitable for MRD monitoring. The present series represents an extension of a cohort of patients already analyzed for different purposes and reported previously. Following our previous experience, MRD positivity was defined if ⩾ 3.5 × 10 4 (0.035%) residual leukemic cells (RLCs) were detected in the BM upon full hematological recovery after consolidation cycle. According to this definition, 176/230 patients (76.5%) were classified as MRD positive (MRD) and 54/230 (23.5%) as MRD negative (MRD). In the overall series, 84/230 patients (36.5%) received no transplant because of age, poor performance status or insufficient stem cell harvest, 28/230 (12.2%) relapsed before transplant delivery whereas 118/230 (51.3%) underwent ASCT (N= 50) or AuSCT (N= 68) in first CR. For the purpose of the present analysis, we focused on the 81 patients who tested MRD and who were submitted to ASCT (N= 45) or AuSCT (N= 36), respectively. The same analysis was not feasible for MRD patients due to the low numbers in the ASCT group (N= 5), preventing any statistical significance from being demonstrated. The clinico-biological characteristics of the patients are detailed in Table 1. The two groups were balanced regarding white blood cell count (WBCc), ELN risk category, FLT3 and NPM1 mutational status. Karyotypic analysis was available in 77 (95%) out of 81 patients. Intermediate risk category accounted for 78%

Minimal residual disease as biomarker for optimal biologic dosing of ARA-C in patients with acute myeloid leukemia

We assessed by flow cytometry minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) given standard‐dose (SDAC) and high‐dose ARA‐C (HDAC) regimens. Of 163 patients enrolled, 130 (median age, 45 years; range, 18–59 years) qualified for analysis, all achieving complete remission after treatment with SDAC (n = 78) or HDAC (n = 52) plus etoposide and daunorubicin. Consolidation consisted of intermediate‐dose ARA‐C and daunorubicin. MRD negativity was significantly more frequent in the SDAC vs. HDAC arm after both induction (37% vs. 15%, P = 0.007) and consolidation (44% vs. 18%, P = 0.002). Respective median residual leukemic cell counts with SDAC and HDAC use were 1.5 × 10−3 and 4 × 10−3 (P = 0.033) after induction and 5.7 × 10−4 and 2.9 × 10−3 (P = 0.008) after consolidation. Based on ARA‐C schedule and post‐consolidation MRD status, the four patient groups (SDAC‐MRD−, HDAC‐MRD−, SDAC‐MRD+, and HDAC‐MRD+) displayed 5‐year overall survival rates of 60%, 33%, 24%, and 42% (P = 0.007), respectively, with 24%, 35%, 74%, and 48% (P < 0.0001) respective cumulative incidence of relapse estimates. MRD may serve as a biomarker for optimal biologic dosing of ARA‐C, and SDAC regimen appears to yield more frequent MRD negativity. Am. J. Hematol. 90:125–131, 2015.

Thoracic Cord Compression Caused by Epidural Extramedullary Hematopoiesis During Erythroid-Stimulating Agent Therapy in Two Patients With Myelodysplastic Syndromes

Introduction Proliferation of extramedullary hematopoiesis (EMH) is a rare event that complicates chronic anemic states. The largest series published to date included 24 cases, all of which were reported in association with hematologic disorders, in which compensatory or inappropriate increase of blood formation (eg, thalassemia, myeloproliferative disorders, sickle cell anemia, and so on) can reactivate unusual hematopoietic sites. Abnormal EMH usually occurs in sites that are involved in hematopoiesis during fetal development, such as the spleen, liver, and kidneys; however, even ectopic locations, such as the paraspinal tissue, may be frequently involved, which results in neurologic symptoms, pain, and spinal cord compression. The epidural block has been often described as midthoracic, probably because of the narrow course of the thoracic epidural space at this level. Few patients (Table 1) have been reported to have a spinal block caused by EMH in association with myelodysplastic syndromes (MDSs), but to our knowledge, none of these patients was receiving erythroidstimulating agents (ESAs) when symptoms occurred. ESAs are universally recognized as first-line treatment for patients with low-risk MDSs who are transfusion dependent. Erythropoietin alpha, erythropoietin beta, and more recently, darbepoetin, have been found to increase hemoglobin levels and ameliorate transfusion dependence in 19% to 68% of patients with MDSs. Despite concern of a detrimental effect on tumor progression in patients with solid cancers, in MDSs, several meta-analyses that have included thousands of patients showed only sporadic thromboembolic events, and no episodes of neurologic or cardiovascular complications that were directly related to the drug have been documented. We report two patients who were treated with ESAs; both patients were diagnosed as having an EMH mass that caused thoracic cord compression. In both patients, ESA withdrawal resulted in rapid relief of symptoms and mass resolution with no need of laminectomy or radiotherapy. Case Reports In March 2002, a 69-year-old woman with a diagnosis of anemia was referred to our clinic. Laboratory studies showed leucopenia (WBC count, 3.3 10/L; absolute neutrophil count, 1.8 10/L) and normochromic/normocytic anemia (hemoglobin [Hb], 8.0 mg/ dL). Bone marrow aspirate showed less than 5% blasts and karyotype was normal. The final diagnosis was refractory anemia (low risk per the International Prognostic Scoring System). Because the decreasing level of Hb required a program of regular packed red cell unit (PRCU) transfusions, in October 2002, we initiated erythropoietin alpha (10,000 UI three times per week). The therapy was administered for 30 months with good tolerance and no relevant adverse effect. In March 2005, because of an increase in the transfusion requirement from two to five PRCU transfusions per month, we incrementally increased the erythropoietin alpha dosage to 40,000 UI twice per week. A significant reduction in transfusion support was gained. In December 2007, the patient reported persistent thoracic pains spreading to the epigastric region. A total-body computed tomography (CT) scan showed an epidural mass at the D8-D9 vertebrae level, with no bone erosion. Erythropoietin alpha was stopped and the symptoms subsided within a few days. A CT-guided biopsy was performed and histologic examination revealed EMH. The patient is alive, receives erythropoietin alpha at a dose of 40,000 UI once per week, and is transfusion free. In August 2008, a 75-year-old man with a diagnosis of chronic anemia was referred to our clinic. Laboratory studies showed a WBC count of 3.4 10/L, absolute neutrophil count of 1.95 10/L, normochromic/normocyticanemia(Hb,9.5mg/dL),andmildthrombocytopenia (platelets, 95 10/L). Bone marrow aspirate showed less than 5% blasts and cytogenetic analysis demonstrated a chromosome 11 monosomy. The final diagnosis was refractory cytopenia with multilineage dysplasia (International Prognostic Scoring System risk: Intermediate-1). In November 2008, high doses of erythropoietin alpha therapy were initiated (40,000 UI twice per week) because the patient began requiring transfusion support. Erythropoietin alpha treatment was continued for 26 months with good tolerance and no relevant adverse effect. After 8 months of such therapy, the transfusion need decreased from a median number of two to 0.7 PRCU transfusions per month. In January 2011, the patient presented with complaints of persistent, intense pains that spread from the retrosternal to