Improved Outcome of Refractory/Relapsed Acute Myeloid Leukemia after Post-Transplantation Cyclophosphamide-Based Haploidentical Transplantation with Myeloablative Conditioning and Early Prophylactic Granulocyte Colony-Stimulating Factor-Mobilized Donor Lymphocyte Infusions.

We carried out post-transplantation cyclophosphamide (PTCy)-based haploidentical peripheral blood stem cell transplantation in 51 patients with refractory/relapsed acute myeloid leukemia not in remission. The first 10 patients received nonmyeloablative conditioning followed by planned granulocyte colony-stimulating factor (G-CSF)-mobilized donor lymphocyte infusions (DLIs) on days 35, 60, and 90. No patient developed graft-versus-host disease (GVHD), but 90% had disease progression between 3 and 6 months. A subsequent 41 patients received myeloablative conditioning (MAC); the first 20 patients did not receive DLIs (MAC group) and the next 21 patients received G-CSF-mobilized DLIs (G-DLI) on days 21, 35, and 60 (MAC-DLI group). The incidence of disease progression and progression-free survival at 18 months were 66% and 25% in the MAC group compared with 21.4% and 61.9% in the MAC-DLI group (P = .01). Chronic GVHD but not acute GVHD was increased in the MAC-DLI group (41.2% versus 11%, P = .05). Natural killer cell alloreactive donor was associated with lower incidence of disease progression in the MAC but not in MAC-DLI group. The only factor favorably influencing disease progression and progression-free survival was administration of G-DLI after myeloablative conditioning. Our study shows that early administration of G-DLI is feasible after PTCy-based haploidentical hematopoietic stem cell transplantation for refractory/relapsed acute myeloid leukemia and might be associated with improved survival after MAC.

Genetic defects in Indian Wilson disease patients and genotype-phenotype correlation.

Wilson disease (WD) is caused by defects in ATP7B gene due to impairment of normal function of the copper transporting P-type ATPase. This study describes a comprehensive genetic analysis of 199 Indian WD patients including mutations detected in our previous studies, undertakes functional assessment of the nucleotide variants in ATP7B promoter and correlates genotype with disease phenotype. The patient cohort harbors a total of 10 common and 48 rare mutations in the coding region of ATP7B including 21 novel changes. The common mutations represent 74% of characterized coding mutant alleles with p.C271X (63/260) and p.G1101R (7/31) being the most prevalent in eastern and western Indian patients, respectively. The mutation spectrum between east and west is mostly different with only three mutations (p.G1061E, p.N1270S and p.A1049A-fs) being shared between both the groups. Eight novel and 10 reported variants have been detected in the promoter and non-coding regions (5' and 3'UTRs) of ATP7B. Promoter reporter assay demonstrated that 3 novel variants and 5 reported polymorphisms alter the gene expression to a considerable extent; hence might play important role in ATP7B gene regulation. We devised the neurological involvement score to capture the spectrum of neurological involvement in WD patients. By utilizing the age at onset, neurological involvement score and ATP7B mutation background, we generated a genotype-phenotype matrix that could be effectively used to depict the phenotypic spectra of WD affected individuals and serve as a platform to identify prospective "outliers" to be investigated for their remarkable phenotypic divergence.

A novel COMMD1 mutation Thr174Met associated with elevated urinary copper and signs of enhanced apoptotic cell death in a Wilson Disease patient.

Wilson disease (WD) results from accumulation of copper and caused due to mutations in ATP7B, a copper transporting ATPase. Besides regular hepatic and neurological symptoms, WD patients occasionally manifest atypical symptoms due to unknown cause. To understand the molecular etiology of atypical WD manifestations, we screened COMMD1, a gene implicated in canine copper toxicosis, in 109 WD patients including those with atypical symptoms. In a patient showing apoptotic symptoms and high urinary copper surpassing normal WD levels, we identified a novel, putative mutation in COMMD1. Two other changes were also identified in the gene. We have examined genotype-phenotype correlation between the detected changes and the atypical presentation of the WD patient.