Bone Marrow Disease In Patients Research Articles

Efficacy and Safety of Concomitant Use of Ravulizumab and IST in Patients with Paroxysmal Nocturnal Hemoglobinuria up to 52 Weeks

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disease characterized by uncontrolled complement activation on the surface of PNH blood cells, which can lead to hemolytic anemia. Aplastic anemia is a closely related rare bone marrow disorder and commonly treated with immunosuppressive therapy (IST), such as cyclosporine and anti-thymocyte globulin. Previous research has shown that IST is effective when used concomitantly with eculizumab, regardless of the sequence of treatment initiation with IST or eculizumab. However, there are little available data in patients with PNH who may require concomitant ravulizumab and IST. Aims: To evaluate the efficacy and safety of concomitant ravulizumab and IST use in patients with PNH who received ravulizumab up to 52 weeks and those who switched to ravulizumab following the 26 weeks of treatment with eculizumab during the primary evaluation period, and to assess the transfusion requirements in these patients. Methods: Patient data from Study 301 (Lee JW, et al. Blood. 2019;133[6]:530-539; NCT02946463) were stratified by concomitant IST use during the primary evaluation period and extension period of this phase 3, multicenter, randomized, active-controlled, open-label, multicenter study. The study consisted of a 26-week primary evaluation period in which patients ≥18 years old with a documented diagnosis of PNH received either ravulizumab or eculizumab, followed by an extension period of up to 5 years, during which all patients received ravulizumab. Efficacy data were collected at the end of the primary evaluation period (through week 26) and through week 52 of the extension period. Data from week 52 were then compared with week 26 data to assess for maintenance of treatment response. Maintenance of treatment response is defined as patients who achieved the primary and secondary efficacy endpoints at both 26 weeks and 52 weeks. Safety variables were also assessed. Descriptive statistics are provided; no tests for differences between treatment groups were performed. Results: There were 246 patients receiving either ravulizumab or eculizumab in the 26-week primary evaluation period of Study 301, and 243 of these patients then received ravulizumab during the extension period. Of these patients, 28 received concomitant IST and 215 did not. Efficacy data are described in Table 1. For lactate dehydrogenase (LDH) normalization (LDH levels < 1x upper limit of normal; ULN), 50.0% of patients on IST maintained the treatment response from week 26 to week 52 vs 75.5% of patients without IST. Patients on IST had a numerically lower mean change in LDH levels compared with patients without IST at week 26, compared with baseline (Table 2). A total of 75.0% of patients taking IST maintained transfusion avoidance through 52 weeks compared with 89.9% of patients without IST, which may also be caused by an underlying coexisting condition such as bone marrow disease in patients who required IST. A similar proportion of patients on IST and without IST maintained stabilized hemoglobin levels through week 52 (avoidance of >2 g/dL decrease in hemoglobin levels from baseline in the absence of transfusion): 88.9% and 87.6%, respectively. Furthermore, a higher proportion of patients who were treated with IST also required transfusions: 53.3-61.5% of patients on IST vs 21.1-38.7% of patients without IST through week 26 and week 52. Similarly, patients treated with IST received, on average, more transfusions than patients without IST (Table 3). Safety results were similar between the IST and non-IST patient subgroups (Table 4). Conclusions: Despite a limited number of patients with available data for evaluating the effects of IST, concomitant use of ravulizumab and IST was effective and well tolerated in patients with PNH. Furthermore, patients treated with ravulizumab for the whole 52-week treatment period and did not receive concomitant IST had numerically fewer pRBC/whole blood transfusions compared with patients treated with IST. Disclosures Schrezenmeier: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Lee:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hill:Alexion Pharmaceuticals Inc.: Current Employment. Ptushkin:Alexion Pharmaceuticals Inc.: Honoraria. Notaro:Alexion Pharmaceuticals Inc.: Honoraria, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Ogawa:Alexion Pharmaceuticals Inc.: Current Employment. Okamoto:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Peffault De Latour:Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees.

ORIGINAL ARTICLE: Role of mean platelet volume as discriminating guide for bone marrow disease in patients with thrombocytopenia

SummaryRecently, platelet indices have been evaluated to determine their utility in knowing the mechanism of thrombocytopenia. This study was conducted to analyze the role of mean platelet volume (MPV) as a guide or an indicator for bone marrow disease in thrombocytopenic patients. All the patients with thrombocytopenia for various causes followed by bone marrow examination were divided into two groups, one group with and another without bone marrow disease, depending on pathophysiology. The MPV was statistically analyzed in both the groups to assess its role as guide for bone marrow disease in these patients. Mean MPV (average score of all individual mean values in patients) in the group with bone marrow disease was 7.3 fl, while in the group without bone marrow disease, it was 8.62 fl. Although the difference in MPV in the two groups of with (including megaloblastic anemia) and without bone marrow involvement was statistically significant (P value <0.001), its sensitivity and specificity scores as observed by receptor operating characteristic (ROC) curve at cut‐off of <8.15 fl were not highly sufficient (67.7% sensitive and 65% specific). The study concluded that although MPV can be used as an initial hint for bone marrow disease in thrombocytopenic patients, it has limited sensitivity and specificity. The differentiation of megaloblastic anemia from other causes of pancytopenia involving the marrow requires bone marrow examination rather than using MPV as an indicator. Bone marrow examination remains the gold standard for discriminating hypoproductive type of thrombocytopenia from the hyperdestructive one. In addition, the role of other platelet indices should also be assessed further to know a better indicator for bone marrow involvement in thrombocytopenic patients.

Magnetic resonance imaging of disseminated bone marrow disease in patients treated for malignancy

Magnetic resonance imaging (MRI) is a sensitive method for the diagnosis of bone marrow abnormalities, but its usefulness in detecting active disseminated cancer in this tissue in treated patients has not been determined. We therefore examined 14 children who had been treated for disseminated bone marrow involvement by neuroblastoma (n = 6), lymphoma (n = 3), Ewing's sarcoma (n = 3), osteosarcoma (n = 1), and leukemia (n = 1). MRI studies were performed at 21 marrow sites to evaluate residual or recurrent tumor and were correlated with histologic material from the same site. T1- and T2-weighted sequences were employed in 21 and 14 studies, respectively; short tau inversion recovery (STIR) in 18; and static gadolinium diethylene triamine pentaacetic acid (Gd-DPTA)-enhanced. T1-weighted sequences in 13. All MRI studies showed an altered bone marrow signal. Technetium 99m methylene diphosphonate (99mTc-MDP) bone scintigraphy was also performed (19 studies). On histologic examination, 7 marrow specimens contained tumor, and 14 did not. Of the 7 tumor-positive lesions, all T1-weighted, 4 of 6 T2-weighted, and all 6 STIR sequences showed abnormal signal; all 5 Gd-DTPA-enhanced. T1-weighted sequences showed enhancement of the lesion. However, abnormal signals were also observed on all T1-weighted, 6 of 8 T2-weighted, 11 of 12 STIR, and 5 of 8 Gd-DTPA-enhanced, T1-weighted images of the tumor-negative sites. In this clinical setting, MRI did not consistently differentiate changes associated with treatment from malignant disease.

Gene rearrangements as markers of clonal variation and minimal residual disease in acute lymphoblastic leukemia.

Immunoglobulin (Ig) heavy (H) and light (L) chain gene rearrangements were used as molecular markers of clonal evolution and minimal residual disease in B cell precursor acute lymphoblastic leukemia (ALL). All leukemic episodes within individual patients shared at least one identical Ig rearrangement and thus arose from a common clonal progenitor cell. Nine of 11 patients displayed completely identical patterns between leukemic episodes, while two of 11 patients demonstrated genetic progression between diagnosis and relapse as evidenced by additional rearrangements. These genetic changes marked the emergence of leukemic subclones. Ig gene rearrangements were also used as sensitive markers to identify clonal cell populations in ALL patients following induction or reinduction therapy and to search for residual bone marrow disease in patients in clinical remission or with isolated extramedullary relapse. DNA rearrangements provide tumor-specific markers to follow the genetic variation of ALL and may facilitate the early detection of recurrent disease.