Sustained Hematologic Remission Research Articles

Mechanisms of left ventricular systolic dysfunction in light chain amyloidosis: a multiparametric cardiac MRI study.

Cardiac systolic dysfunction is a poor prognostic marker in light-chain (AL) cardiomyopathy, a primary interstitial disorder; however, its pathogenesis is poorly understood. This study aims to analyze the effects of extracellular volume (ECV) expansion, a surrogate marker of amyloid burden on myocardial blood flow (MBF), myocardial work efficiency (MWE), and left ventricular (LV) systolic dysfunction in AL amyloidosis. Subjects with biopsy-proven AL amyloidosis were prospectively enrolled (April 2016-June 2021; Clinicaltrials.gov ID NCT02641145) and underwent cardiac magnetic resonance imaging (MRI) to quantify rest MBF by perfusion imaging, LV ejection fraction (LVEF) by cine MRI, and ECV by pre- and post-contrast T1 mapping. The MWE was estimated as external cardiac work from the stroke volume and mean arterial pressure normalized to the LV myocardial mass. Rest MBF in 92 subjects (62 ± 8 years, 52 men) with AL amyloidosis averaged 0.87 ± 0.21 ml/min/g and correlated with MWE (r = 0.42; p < 0.001). Rest MBF was similarly low in subjects with sustained hematologic remission after successful AL amyloidosis therapy (n = 21), as in those with recently diagnosed AL amyloidosis. Both MBF and MWE decreased by ECV tertile (p < 0.01 for linear trends). The association of ECV with MWE comprised a direct effect (84% of the total effect; p < 0.001) on MWE from adverse interstitial remodeling assessed by ECV and an indirect effect (16% of the total effect; p < 0.001) mediated by MBF. There was a significant base-to-apex gradient of rest MBF in subjects with higher amyloid burden. In AL amyloidosis, both MBF and MWE decrease as cardiac amyloid burden and ECV expansion increase. Both structural and vascular changes from ECV expansion and myocardial amyloid burden appear to contribute to lower MWE.

Sustained hematologic remission after discontinuation of sutimlimab treatment in patients with cold agglutinin disease.

Sustained hematologic remission after discontinuation of sutimlimab treatment in patients with cold agglutinin disease.

Long-Term Remission and Bone Marrow Findings in Children with Severe Aplastic Anemia Immunosuppressed with High Doses of Cyclophosphamide

Background: Most cases of aplastic anemia are acquired and of autoimmune etiology. Treatment of patients lacking a stem cell donor habitually consists of two curses of immunosuppression with anti-thymocyte globuline plus cyclosporine (ATG/CSA), whereas intensive immunosuppression consisting exclusively of high doses of cyclophosphamide (HDCY) has been successfully employed mostly in adults, detailed long-term information on children receiving HDCY is lacking. Patients and methods: Five children suffering from severe acquired aplastic anemia and without an HLAcompatible stem cell donor were immunosuppressed with high-dose cyclophosphamide (HDCY) at a total dose of 200 mg/kg over four days. Granulocyte colony-stimulating factor (G-CSF) was administered at 5 μg/kg/day until sustained neutrophil and platelet count recovery. The surviving patients were followed-up for twelve years and their bone marrows examined at this time. Results:Three of the five children obtained a complete sustained hematological remission. Current ages are 17, 19 and 27. After twelve years of follow-up two patients have normal hematological values, with no relapse nor clonal or displasic hematological disorders, their bone marrow aspirate was morphologically normal, whereas bone marrow trephine biopsy histopathology demonstrated a reduced cell content to about 60% of normal. One patient developed myelodisplasia 12 years after HDCY and currently he is being considered for a bone marrow transplant. Conclusions: Sustained long-term trilineage hematopoiesis can be rescued in children suffering from SAA employing HDCY as the only immunosuppressor; the bone marrow did not fully recuperate its normal cellularity after twelve years post-treatment, mielodysplasia can develop more than ten years after HDCY.

Successful heart transplantation following melphalan plus dexamethasone therapy in systemic AL amyloidosis

Recurrence in the allograft and progression in other organs increase mortality after cardiac transplantation in AL amyloidosis. Survival may be improved after suppression of monoclonal light chain (LC) production following high dose melphalan and autologous stem cell transplantation (HDM/ASCT). However, because of high treatment related mortality, this tandem approach is restricted to few patients without significant extra-cardiac involvement. A diagnosis of systemic AL amyloidosis was established in a 45-year old patient with congestive heart failure related to restrictive cardiomyopathy, nephrotic syndrome, peripheral neuropathy, postural hypotension, macroglossia, and lambda LC monoclonal gammopathy. After melphalan and dexamethasone (M-Dex) therapy, which resulted in 80% reduction of serum free lambda LC, he underwent orthotopic cardiac transplantation. Two years later, he remains in a sustained hematologic remission, with no evidence of allograft or extra-cardiac amyloid accumulation. M-Dex should be considered as an alternative therapy in AL amyloid heart transplant recipients ineligible for HDM/ASCT.

Unusual clinical presentation in a patient with myelodysplastic syndrome, with subsequent hematological remission and suppression of the malignant clone following treatment with cyclosporine A, erythropoietin and granulocyte colony-stimulating factor

A 35-year-old female presentedwith isolated thrombocytopenia of autoimmune origin. One and a half years later, hypoplastic myelodysplastic (MDS) was diagnosed. Following treatment with cyclosporin A, erythropoietin and granulocyte colony-stimulating factor, the patient has achieved a sustained hematological remission which is still ongoing after 3 years. Furthermore, to the best of our knowledge, this is the third case described in the literature where treatment with cytokines alone or in combination with immunosuppressive agents has resulted in a long standing cytogenetic response in MDS.

Long-Term Interferon-Alpha 2A Does not Induce Sustained Hematologic Remission in Younger Patients with Essential Thrombocythemia

The ability of Interferon alpha (α-IFN) to alter the natural history of essential thrombocythemia (ET) and induce sustained hematologic remission would provide further impetus to consider this agent in younger patients with this disease and may influence the decision to commence treatment in asymptomatic patients. This study has failed to demonstrate any sustained hematologic remissions after cessation of long-term (2 years) a-IFN administration in a group of 34 female patients with a median age of 41 years (range 14–68) who were considered at intermediate to high risk of thrombotic complications. In the twenty-one patients completing two years of therapy, 13 (62%) had complete hematological responses (CHR; platelet count <400 × 109/L), 7 (33%) partial hematological responses (PI-R; platelet count 400–600 × 109/L) and no thrombotic or hemorrhagic complications occurred. In all patients who discontinued a-IFN at 2 years, platelet counts rose above the normal range within 1–4 months and the majority required reinstitution of some form of therapy. The inability of long-term α-IFN to induce sustained, unmaintained hematologic remission argues strongly against any significant effect on the neoplastic clone at the doses used in this study. This study does, however, confirm the efficacy of long-term α-IFN in younger female patients with ET, a group not previously well represented in clinical trials of the agent.

Mutation of Ki-ras and N-ras Oncogenes in Myelodysplastic Syndromes

Somatic mutation of the N-ras oncogene occurs frequently in de novo acute myeloid leukemia (AML). By virtue of their relation to AML, myelodysplastic syndromes (MDS) provide an in vivo model of human leukemogenesis. By using a strategy for analysis of gene mutation based on in vitro amplification of target sequences by the polymerase chain reaction (PCR) and selective oligonucleotide hybridization we analyzed the mutational status of codons 12, 13, and 61 of Ha-ras, K-ras, and N-ras in peripheral blood (PB) and/or bone marrow (BM) in 34 cases of primary MDS. Mutations at codon 12 of Ki-ras or N-ras were detected in three cases (9%): one of six cases of refractory anemia with excess blasts (RAEB) and two of nine cases of chronic myelomonocytic leukemia (CMML). The nucleotide substitution differed in each. In all cases the mutant allele was detectable in PB cells. A sustained hematologic remission was achieved after low-dose cytarabine therapy in the case of RAEB. Neither case of CMML exhibited signs of disease progression during follow-up at 7 and 12 months. In contrast, four of 31 patients without the ras mutation underwent transformation to AML within 12 months of genetic analysis. We conclude that ras mutations in MDS are heterogeneous and may develop at an early stage during the evolution of MDS. Their detection in PB cells illustrates the potential utility of ras mutation as a clonal marker in myeloid malignancy.

Mutation of Ki-ras and N-ras oncogenes in myelodysplastic syndromes

Somatic mutation of the N-ras oncogene occurs frequently in de novo acute myeloid leukemia (AML). By virtue of their relation to AML, myelodysplastic syndromes (MDS) provide an in vivo model of human leukemogenesis. By using a strategy for analysis of gene mutation based on in vitro amplification of target sequences by the polymerase chain reaction (PCR) and selective oligonucleotide hybridization we analyzed the mutational status of codons 12, 13, and 61 of Ha-ras, K-ras, and N- ras in peripheral blood (PB) and/or bone marrow (BM) in 34 cases of primary MDS. Mutations at codon 12 of Ki-ras or N-ras were detected in three cases (9%): one of six cases of refractory anemia with excess blasts (RAEB) and two of nine cases of chronic myelomonocytic leukemia (CMML). The nucleotide substitution differed in each. In all cases the mutant allele was detectable in PB cells. A sustained hematologic remission was achieved after low-dose cytarabine therapy in the case of RAEB. Neither case of CMML exhibited signs of disease progression during follow-up at 7 and 12 months. In contrast, four of 31 patients without the ras mutation underwent transformation to AML within 12 months of genetic analysis. We conclude that ras mutations in MDS are heterogeneous and may develop at an early stage during the evolution of MDS. Their detection in PB cells illustrates the potential utility of ras mutation as a clonal marker in myeloid malignancy.