Hematopoietic stem-cell transplantation in a zoo of multidrug-resistant organisms: Data from a cancer center in eastern India.

BACKGROUND: Infections by multidrug-resistant organisms (MDRO) are a major hurdle in hematopoietic stem-cell transplants (HSCTs). Conditioning regimens lead to mucosal barrier injury, which in-turn leads to transmigration of gut bacteria and sepsis. Pre-transplant stool and throat surveillance cultures can guide empirical antibiotic policy during the neutropenic period. In this paper, we document colonization with MDRO in pre-transplant surveillance cultures and the correlation with bloodstream infections in HSCT patients and analyze transplant outcomes with respect to these infections. METHODS: A single-center, retrospective study on HSCT was performed between January 2021 and December 2021. The incidence of bacterial infections, percentage of MDROs, correlation with pre-transplant stool/throat surveillance cultures, and their impact on overall 100-day and post-100-day to 6-month post-transplant survival were analyzed. RESULTS: Sixty-four patients were included in the study. Pre-transplant stool surveillance cultures were positive for MDRO in 85.9% of patients. Almost half (48.5%) of the isolates were positive for carbapenemase-producing genes (mainly New Delhi metallo-beta-lactamase-1 [NDM-1] and oxacillinase-48 [OXA-48]). Eighteen patients (18/64, 28%) had a positive blood culture for MDRO in the peri-engraftment neutropenic period. Correlation between surveillance and blood cultures was seen in 61% (11/18) of patients. All-cause mortality was 14.1% (9/64) and 25% (16/64) in patients at 100 days and 6 months post-HSCT, respectively. The 100-day and post-100-day all-cause mortality rates were higher in patients with Gram-negative MDRO bloodstream infections (p < .012 and <.008, respectively). CONCLUSION: MDRO infections can adversely affect HSCT outcomes. Pre-transplant stool and throat surveillance cultures may guide empirical antibiotic policy and lead to favorable transplant outcomes.

Bortezomib-based induction therapy followed by autologous hematopoietic cell transplantation in newly diagnosed multiple myeloma patients: A single-center experience and review of Indian literature.

INTRODUCTION: High-dose chemotherapy with melphalan, followed by autologous hematopoietic stem cell transplantation (AHCT) remains the standard of care for consolidation therapy of fit patients with newly diagnosed multiple myeloma (NDMM), for more than 20 years now. MATERIAL AND METHODS: This is a retrospective study of NDMM patients who underwent AHCT at our center from 2011 to 2018. Data was undertaken using the hospital electronic medical records (EMR). RESULTS: Among transplant eligible patients (which were 764), 78 patients (10.2%) underwent AHCT. The predominant stage in the study cohort was International Scoring System (ISS)-III (55%), and IgG-kappa (44%) was the commonest subtype of multiple myeloma (MM). Light chain myeloma was found in 23.5% of patients. Pretransplant, 42%, 48%, and 10% patients were in more than very good partial response (>VGPR), very good partial response (VGPR), and partial response (PR), respectively. The median duration of follow-up was 57.2 months (range: 12.1-120.2 months). The entire cohort's 5-year overall survival (OS) and progression-free survival (PFS) were 89.1% and 41.8%, respectively. CONCLUSION: Bortezomib based triplet induction regimens were effective and well tolerated in this retrospective analysis of Indian patients. We observed that AHCT effectively achieves deep and durable remission in MM.

Relapsed Refractory Hodgkin Lymphoma and Brentuximab Vedotin-Bendamustine Combination Therapy as a Bridge to Transplantation: Real-World Evidence From a Middle-Income Setting and Literature Review.

INTRODUCTION: Despite high cure rates with standard treatment, 30% patients with Hodgkin lymphoma develop relapsed or refractory (R/R) disease. Salvage therapy followed by autologous hematopoietic cell transplantation (HCT) is considered standard of care. Brentuximab Vedotin (Bv) in combination with Bendamustine (B) has been tested in the salvage setting with promising results. MATERIALS AND METHODOLOGY: We conducted a single centre retrospective chart review of patients who received BBv salvage therapy to determine its activity and safety in patients with R/R classical Hodgkin lymphoma (HL). Between May 2011- December 2019, 179 patients were diagnosed with R/R HL. RESULTS: Thirty patients received BBv [median age: 30 (15-59) years, females (n=15)]. Primary refractory disease in 19 patients (63%), and 26 patients (87%) had advanced stage at treatment. Most patients received BBv after 2 prior lines of therapy [n=16 (53%)]. The median number of cycles of BBv were 3 (1-6). The number of BBv cycles delivered as outpatient was 63%. The most common Grade III/IV hematological adverse event was neutropenia [n=21, (70%)], while grade III/IV non-hematological toxicities included infections in 4 (13%), neuropathy in 4(13%), skin rash in 2 (7%), GI toxicities in 3 (10%) and liver dysfunction in 2 (7%) patients. The ORR and CR rates were 79% and 62%, respectively. Seventeen patients (57%) underwent an autologous HCT and 8 (26%) underwent an Allogeneic HCT (all haploidentical). The median follow up time from BBv administration was 12 months. Six patients died: 2 = disease progression, and 4 = non-relapse causes (Infection and sepsis = 2, GVHD=2). In addition to this, one patient progressed soon after HCT and another patient relapsed 22 months post HCT. Three year Overall survival (OS) and Event free survival (EFS) probability post-BBv treatment was 75% and 58%, respectively. OS and EFS analysis based on response (viz., CMR) to BBv demonstrated that patients in CMR had better survival probability [93% (p=0.0022) 3yr-OS and 72% (p=0.038) 3yr-EFS probability]. CONCLUSIONS: BBv is an active and well-tolerated salvage treatment for patients with R/R HL, even in refractory and advanced settings. In middle-income settings, cost constraints and access determine patient uptake of this regimen.

Impact of COVID-19 on peripheral stem cell collection and preservation at a hematopoietic cell transplant center in India: Experience 2020.

The prevailing corona virus disease 19 (COVID-19) pandemic has adversely affected the healthcare services globally. Hematopoietic cell transplantation (HCT) is considered as the preferred treatment option for several hematological malignancies, and HPC collection facilities have to function continuously along with implementing safety measures. Based on the national and international guidelines, we implemented additional measures and modifications to our standard operating procedure (SOP) to ensure secure HPC collection from patients as well as donors. Here, we report our experience with HPC collection and processing from 1st January, 2020 until 31st December, 2020. We collected 59 HPC products through apheresis and 41 cryopreservation procedures. Compared to 2019, there was a 33% decrease in the number of HPC transplants and 31% reduction in HPC collection procedures. However, we report an 86% (13 procedures) increase in the cryopreservation of HPC products from related donors, as several organizations recommend cryopreservation of HPC products. We report our institutional experience to better understand the impact of COVID-19 on HCT services in a tertiary care center in the developing world. It may also help in being prepared for any future waves of COVID-19 cases.

Thalidomide in Patients with Transfusion-Dependent E-Beta Thalassemia Refractory to Hydroxyurea: A Single-Center Experience.

Transfusion-dependent E-Beta (EB) thalassemia is one of the major causes of hereditary hemoglobinopathies in India. Hydroxyurea has been tried for HbF induction and amelioration of the transfusion frequency in EB thalassemia. The primary objective of this retrospective study, conducted between January 2017 and December 2018, was to determine the efficacy of thalidomide in reducing transfusion frequency in patients with EB thalassemia who have failed a reasonable trial of hydroxyurea. Of the 21 patients studied, 15 (71.4%) attained transfusion independence (complete responders) and 1 (4.7%) attained partial response (50% decrease in transfusion requirement) while 5 (23.9%) were non-responders. 12 patients attained their response within 1 month, 2 patients achieved within 1-3 months, and 1 patient beyond 3 months. Median time to transfusion independence in complete responders was 1 month. The median time on thalidomide for the complete responders and partial responders was 16.48 months. No major grade 3/4 toxicities were documented. This approach needs larger randomised controlled studies. Thalidomide is a safe and effective strategy at reducing or abrogating transfusion requirement in patients with EB thalassemia. This approach requires further testing in systematic clinical trials.

Ultrasonography of Knee Joint in Hemophilia A: What the Eyes Cannot See.

Haemophilia is the most common inherited coagulopathy. Approximately 94% patients suffer from joint disability. An imaging modality to detect joint damage can help in monitoring. Ultrasonography (USG) provides a low cost and reliable imaging alternative to magnetic resonance imaging. This study aims at the detection of subclinical knee-joint involvement by USG, in patients with moderate to severe Haemophilia. 27 patients suffering from moderate and severe Haemophilia and 27 age-matched controls were studied. USG of bilateral knee joints was done to analyse cartilage and synovial thickness, synovial vascularity and resistive index of vascular flow along with synovial collection. The relevant clinical parameters (age at diagnosis and study enrolment, severity of haemophilia A, annualized bleeding rates, total number of joint bleeds, spontaneous and provoked bleed, number of episodes treated with factor VIII injection) were noted. The USG findings were correlated to the clinical parameters and subclinical joint bleed detection looked for. 13 patients [18 out of 54 joints (33.33%)] showed increased vascular signals with mean resistive-index (RI) 0.67 (± 0.086; 95% CI: 0.62-0.70). The mean synovial thickness in persons with haemophilia (PwH) was higher than the control subset (p < 0.05 on all counts). The mean cartilage thickness was lower in PwH than in controls. On a subset analysis, there was significant difference between the mean cartilage thickness between moderate PwH and age matched controls (p < 0.0001). 3 patients (11.1%) showed evidence of joint collection (hemarthrosis) despite having no clinical evidence of joint involvement. Through the findings of our study, we do infer that ultrasonography can detect subclinical synovial inflammation and cartilage damage in haemophilia patients that may affect long term articular outcome. It is also a useful modality for detection of sub clinical joint bleed.

Genetic determinants related to pharmacological induction of foetal haemoglobin in transfusion-dependent HbE-ß thalassaemia.

Thalassaemia are the most common inherited autosomal recessive single gene disorders characterized by chronic hereditary haemolytic anaemia due to the absence or reduced synthesis of one or more of the globin chains. Haemoglobin E-ß thalassaemia is the genotype responsible for approximately one half of all severe beta-thalassaemia worldwide. This study proposes to evaluate the effect of various molecular parameters on the response of hydroxyurea. Hydroxyurea was started at an initial dose of 10 mg/kg of body weight/day on 110 transfusion-dependent HbE-ß thalassaemia patients. HbF level was measured by HPLC analysis. ß-Thalassaemia mutations, XmnI and five other SNPs, and α-globin gene deletions and triplications were detected by ARMS-PCR, RFLP-PCR and Gap-PCR, respectively. Based on the factors for evaluating hydroxyurea-response, 42 patients were responders as they showed an increment of Hb from a mean baseline value of 6.45 g/dl (± 0.70) to 7.78 g/dl (± 0.72) post-therapy. Based on increase in HbF above the median value (14.72%) post-therapy, 78 patients were found to be responders. All the 78 responders showed mean decrease in transfusion of 74.26% (± 8.32) with a maximum decrease of 98.43%. There was a significant correlation between decrease in transfusion and increase in HbF level for all 78 responders. XmnI polymorphism showed the strongest association (p < 0.0001) with increase in HbF levels and Hb levels. Patients with α-globin gene deletions were better responders. It was concluded that hydroxyurea treatment is effective in transfusion-dependent HbE-ß thalassaemia patients and the response is best in patients having both XmnI polymorphism and α-deletion.

SWI/SNF subunit expression heterogeneity in human aplastic anemia stem/progenitors.

Acquired aplastic anemia (AA) is a bone marrow (BM) failure associated with autoimmune destruction of hematopoietic stem cells (HSCs). Although somatic mutations have been identified in AA patients, mutations alone do not explain AA pathophysiology. SWI/SNF is an evolutionarily conserved, multi-subunit, ATP-dependent chromatin-remodeling protein complex that plays an important role in mammalian hematopoiesis. Herein, gene expression analysis identified a significant loss of the SWI/SNF core component SMARCC1, along with ARID1B, ACTL6A, and SMARCD1, in human AA BM CD34+ HSCs and hematopoietic stem and progenitor cells (HSPCs) compared with normal HSPCs. However, expression of SMARCA4, SMARCB1, SMARCD3, and DPF2 remained intact in our AA cohort. PBRM1, BRD7, and SMARCA2 expression were significantly upregulated in both untreated and follow-up AA patients. Clonal hematopoiesis in AA is associated with evolution to late clonal disorders, including myelodysplastic syndromes (MDS). Apart from SMARCD1 loss, we did not observe significant alteration of SWI/SNF expression in MDS HSPCs, indicating SWI/SNF differential expression in AA and MDS. In addition, except for ACTL6A, SWI/SNF expression was unaltered in aged HSPCs. Importantly, our results provide evidence for loss of SWI/SNF in AA, and may implicate AA HSPC-autonomous defective SWI/SNF regulation as an integral component of BM failure, in addition to autoimmune destruction of AA HSCs. These findings illustrate for the first time SWI/SNF subunit expression heterogeneity in human AA HSPCs and require prognostic validation in a larger cohort.

Intracellular iron overload leading to DNA damage of lymphocytes and immune dysfunction in thalassemia major patients.

OBJECTIVES: To investigate the cause and effects of intracellular iron overload in lymphocytes of thalassemia major patients. METHODS: Sixty-six thalassemia major patients having iron overload and 10 age-matched controls were chosen for the study. Blood sample was collected, and serum ferritin, oxidative stress; lymphocyte DNA damage were examined, and infective episodes were also counted. RESULTS: Case-control analysis revealed significant oxidative stress, iron overload, DNA damage, and rate of infections in thalassemia cases as compared to controls. For cases, oxidative stress (ROS) and iron overload (serum ferritin) showed good correlation with R2  = 0.934 and correlation between DNA damage and ROS gave R2  = 0.961. We also demonstrated that intracellular iron overload in thalassemia caused oxidative damage of lymphocyte DNA as exhibited by DNA damage assay. The inference is further confirmed by partial inhibition of such damage by chelation of iron and the concurrent lowering of the ROS level in the presence of chelator deferasirox. CONCLUSION: Therefore, intracellular iron overload caused DNA fragmentation, which may ultimately hamper lymphocyte function, and this may contribute to immune dysfunction and increased susceptibility to infections in thalassemia patients as indicated by the good correlation (R2  = 0.91) between lymphocyte DNA damage and rate of infection found in this study.

Ultrasonography as a useful modality for documenting sacroiliitis in radiographically negative inflammatory back pain: a comparative evaluation with MRI.

OBJECTIVES: The aims of this study were to identify and characterize features of sacroiliitis in patients with non-radiographic inflammatory low back pain by ultrasonography (USG) and to correlate the findings with that of MRI. METHODS: MRI and USG of SI joints were performed on 29 patients who fulfilled the definition of inflammatory low back pain according to the Assessment of SpondyloArthritis International Society 2009 criteria for axial SpA but were X-ray negative for sacroiliitis. Increased vascularity, low resistive index (RI) and hyperechogenicity of the joint space were considered USG features of sacroiliitis. The findings were compared with those of 32 controls. USG features of sacroiliitis were compared with MRI by κ statistics. RESULTS: Receiver operating characteristic analysis revealed cut-off values for flow signals and RI of 3 and 0.605, respectively. There was a significant difference in the number of flow signals, RI and echogenicity of the SI joint between MRI-proven cases and controls. The Cohen's κ for flow signals, RI and hyperechogenicity when compared with MRI were 0.816 (95% CI 0.676, 0.937) and 0.821 (95% CI 0.662, 0.965) and 0.403 (95% CI 0.108, 0.695). Taking both flow signals and RI parameters as criteria for determining sacroiliitis, comparison with MRI returned a κ of 0.816 (95% CI 0.601, 0.963). CONCLUSION: Three or more flow signals and a RI ≤0.605 can be applied as USG criteria for sacroiliitis. USG can be a cost-effective and non-inferior modality compared with MRI in documenting sacroiliitis in early SpA.

Unilateral sternocostoclavicular hyperostosis in a patient with ankylosing spondylitis: A case report with color Doppler ultrasonogram findings.

Sternocostoclavicular hyperostosis is a chronic inflammatory disorder affecting the sternoclavicular joint and upper ribs. There is a strong association with seronegative spondyloarthropathy in which bilateral involvement is common. Ultrasonography and Color Doppler findings of this entity have not been described previously, to the best of our knowledge. We describe the findings in a patient of ankylosing spondylitis who was referred for unilateral sternoclavicular joint swelling.

Development of a colour Doppler ultrasound scoring system in patients of Takayasu's arteritis and its correlation with clinical activity score (ITAS 2010).

OBJECTIVES: The objectives of this study were to develop a scoring system with colour Doppler ultrasound (CDUS) in patients with Takayasu's arteritis, to correlate the CDUS score with the Indian Takayasu's Activity Score (ITAS) and to assess the degree of agreement between CDUS and angiogram in the diagnosis of Takayasu's arteritis. METHODS: Nineteen angiographically confirmed Takayasu's arteritis patients fulfilling three or more of the 1990 ACR criteria were evaluated. Their ITASs were recorded. A CDUS scoring system, CDUS-Kolkata (CDUS-K), was devised based on the presence of stenosis and altered flow patterns. It was then correlated with the ITAS. An inter-rater agreement analysis was done between the CDUS-K scores and angiographic scores in selected arterial sites. RESULTS: We found a significant degree of correlation between the ITAS and the CDUS-K score (r = 0.7144, 95% CI 0.3852, 0.8823, P = 0.0006). A high degree of correlation was found between the CDUS-K and angiographic scores in the selected arterial sites (κ-value = 0.725 on inter-rater agreement analysis). CONCLUSION: CDUS imaging may be used as an objective tool for assessing disease severity in Takayasu's arteritis. Development of a CDUS-K scoring system would be a supplementary tool to clinical scoring and the ITAS. CDUS imaging could be a cost-effective, non-invasive and reliable substitute for angiogram, especially for follow-up in Takayasu's arteritis patients.