Mature T and natural killer (NK) cell non-Hodgkin lymphoma (T-NHL) has a poor prognosis. Data from existing retrospective and prospective studies have suggested that high-dose chemotherapy followed by autologous hematopoietic cell transplantation (auto-HCT) may improve the survival in patients with chemosensitive disease, either in the upfront or salvage setting. Auto-HCT is currently recommended to be used as frontline consolidation in peripheral T cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, anaplastic large cell lymphoma-anaplastic lymphoma kinase negative, NK/T cell (disseminated), and enteropathy-associated T cell lymphoma. However, about one-third of patients never reach transplantation because of early relapse or refractory disease. Allogeneic hematopoietic cell transplantation (allo-HCT), via its immunologic graft-versus-lymphoma effect, has been used to salvage patients with relapsed or refractory disease, resulting in long-term disease-free survival in a fraction of patients. However, the higher risk of transplant-related mortality due to regimen-related toxicities, graft-versus-host disease, and post-transplant infectious complications continues to limit the mainstream adoption of allo-HCT for this disease. Despite that, allo-HCT has been incorporated as part of the frontline treatment for aggressive subtypes of T-NHL, such as γδ T cell lymphoma and aggressive NK cell leukemia. Recent attempts to incorporate novel targeted T cell directed therapies into the treatment pathway of T-NHL may enhance treatment response and enable more patients to reach transplant, offering an alternative means of treating this disease.
Haematopoietic stem cell transplantation (HSCT) was started in Malaysia since 1993 and it has improved the survival of patients with otherwise fatal haematological diseases. This study was initiated because quality of life of these survivors is an important tool in assessing the outcome of this treatment modality. The secondary objective was to identify factors that influenced their quality of life. The European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-30) was used to assess the quality of life of eligible patients. A total of 62 patents were recruited. The mean global health score (QoL) was 71.2. The major symptoms faced by our patients were fatigue, financial difficulty and appetite loss. Appetite loss was an independent adverse factor for lower QoL.
The incidence of Non-Hodgkin's lymphomas (NHL) is rising worldwide and if not adequately treated carries a high mortality rate. The pattern and frequency of NHL vary in different populations and geographical regions. It has considerable biologic and clinical heterogeneity and a definitive diagnosis can be made only after histopathogical examination. The histology and the extent of the lymphoma are the major determinants of optimal therapeutic regimen and treatment outcome. Additionally, the overall treatment strategies should be tailored according to medical status and preference of the patient. A holistic approach provided by a multi-disciplinary team of health care professionals is the cornerstone of ensuring successful treatment outcome. Importantly, therapy should be expedited and where possible performed in experienced centers. Patients achieving remission would require long-term monitoring for disease recurrence and late effects of cytotoxic chemotherapy and radiotherapy. Hence, clinicians should have a fundamental understanding in the biology and the principles of treatment of NHL. This review provides an evidence-based and systematic approach in designing therapeutic strategies for individual patients with newly diagnosed and relapsed NHL focusing on the common types of NHL with particular reference to the current practice within the local settings. The role of standard and novel therapeutic modalities in treatment will be summarized.
The current treatment options for beta thalassaemia major patients include conservative treatment with blood cell transfusions and iron chelation or stem cell transplantation. Regular blood transfusions inevitably lead to multi-organ haemosiderosis and are attended by risks of blood-borne infections. Results from stem cell transplantation are good and suggest that this should be offered as first line therapy when a matched sibling donor is available because the patient is often cured and able to live a normal life. Of 38 Malaysian children who underwent bone marrow or cord blood transplantations using matched sibling donors, 29 (76%) are now cured.
Although survival rates for childhood cancers have improved steadily over the past two decades, the outcome for advanced stage solid tumours remains poor. Many of these tumours are chemosensitive but most chemotherapeutic regimens are limited by their haematological toxicities. Much attention is now focused on mega-dose chemotherapy followed by stem cell rescue in the treatment of disseminated neuroblastoma, rhabdomyosarcoma, germ cell tumour and brain tumours. There is a preferential shift towards peripheral blood stem cell transplantation instead of bone marrow transplantation because of its advantages of faster engraftment, decreased transfusion and antibiotic usage and shortened hospitalisation. This mode of therapy is dependent on technologies including peripheral blood stem cell harvesting, cell cryopreservation and thawing. These technologies were recently made available in Malaysia and we report our early experience.
Allogeneic haemopoietic stem cell transplantation was initially considered as a means of delivering supralethal doses of chemotherapy with or without total body irradiation for the treatment of malignancy. However, it has become clear that this mode of therapy does not eradicate the malignancy in many patients and its benefit is largely due to the immune mediated graft versus malignancy effect. This has led to development of alternative strategy to utilize a less intensive preparative regimen pre-transplantation that provides sufficient immunosuppression to achieve engraftment of an allogeneic stem cell graft, thus allowing the evolution of a graft versus malignancy effect post-transplantation. Since September 1999, we had carried out 10 cases of allogeneic peripheral blood stem cell transplantation: one case of aplastic anaemia, four cases of acute myeloid leukemia (AML) in first remission, and five cases of chronic myeloid leukemia (CML) in chronic phase. The preparative regimen was non-myeloablative comprising Fludarabine with Cyclophosphamide or Busulphan. Recovery from transplantation was rapid with no or brief period of neutropenia or thrombocytopenia. Engraftment was established by determining donor's short tandem repeats in the recipient's bone marrow at day 30, 60 and 100 post-transplantation. Seven cases (70%) show partial or complete donor's chimerism by day 30 indicating successful engraftment. No treatment mortality was noted at day 100. Graft versus host disease was generally limited. Up to the date of reporting, two patients with CML had graft failure, one was successfully re-transplanted later. Two patients with AML had since relapsed and passed away. The others remain alive and well. The cost of transplantation on average was estimated to be about a quarter of that using a myeloablative regimen. It appears that this treatment strategy is a promising approach for the management of blood disorders.
Immune Thrombocytopenia Purpura (ITP) secondary to vaccinations is rare, especially after autologous hematopoietic stem cell transplantation (HSCT). A 31-yearold female received autologous HSCT for relapsed Hodgkin Disease, with platelet engraftment at Day+14. One week after receiving second scheduled vaccinations, she developed severe thrombocytopenia (3x109/L) associated with pharyngeal hematoma. Bone marrow (BM) examinations were consistent with ITP, possibly secondary to Influenza vaccine. Platelet increment was poor despite high dose corticosteroids, intravenous immunoglobulin (IVIG), Danazol and Eltrombopag. A repeated BM biopsy was in agreement with ITP. Re-treatment with tapering doses of prednisolone resulted in stable platelet counts at 120x109/L a year later.
Peripheral blood stem cells (PBSC) mobilised with growth factor with or without chemotherapeutic regimens, are used increasingly in both autologous and allogeneic transplantation. Previously, many PBSC harvests are used directly without ex vivo manipulation, and these PBSC have been shown to be contaminated with tumour cells, which may contribute to subsequent relapses post transplantation. Therefore, requirement for purging of malignant cells from the harvest has initiated the use of various methods to reduce tumour cell contamination of the graft by the positive selection of CD34+ progenitor cells or negative selection of tumour cells using other cell-specific antigens. We report here our local experience with the CliniMACS (magnetic-activated cell separation system) in eight adult patients with haematologic malignancies.
Allogeneic bone marrow or peripheral blood stem cell transplantation traditionally uses myeloablative regimen for conditioning to enable grafting of donor's stem cells. Animal experiments have shown that a milder non-myeloablative conditioning regimen does allow engraftment to occur. Nonmyeloablative conditioning regimens are low-intensity immunosuppressive treatment given to the recipient before infusion of donor's stem cells. It was reported to have decreased immediate procedural mortality, in particular those secondary to acute graft versus host reaction. However, it did give rise to higher risks of graft rejection, tumour tolerance and disease progression. Fortunately, appropriately administered donor lymphocyte infusion has been shown to establish full donor chimerism (complete donor stem cell grafting in the recipient's bone marrow) and potentiate antitumour effect (graft versus tumour reaction). The reduction of immediate transplant mortality allows the procedure to be carried out in older age groups, patients with concomitant diseases that otherwise would have made the patients unfit for the procedure, patients with non-malignant disorders such as congenital immune deficiencies, autoimmune disorders or thalassaemia majors. The regimen also allows transplantation of genetically manipulated haemopoietic stem cells (gene thrapy) to be carried out more readily in the immediate future. Lastly, the regimen may serve as a platform for immunotherapy using specific T cell clones for anti-tumour therapy with or without the knowledge of known tumour antigen.
Currently, the indications to perform reduced-intensity conditioning allogeneic hematopoietic stem cell transplant (RIC-HCT) are based on data derived mainly from large registry and single-centre retrospective studies. Thus, at the present time, there is limited direct evidence supporting the current practice in selecting patients with acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) for RIC versus myeloablative conditioning (MAC) transplants. To determine the relationship between dose intensity of conditioning regimen and survival outcomes after allografting in AML/ALL patients, we performed a meta-analysis of 23 clinical trials reported between 1990 and 2013 involving 15,258 adult patients that compare survival outcomes after RIC-HCT versus MAC-HCT. RIC-HCT resulted in comparable <2-year and 2-6 year overall survival (OS) rates post-transplantation even though the RIC-HCT recipients were older and had more active disease than MAC-HCT recipients. The 2-6 year progression-free survival (PFS), nonrelapse mortality, acute graft-versus-host disease (GvHD) and chronic GvHD rates were reduced after RIC-HCT, but relapse rate was increased. Similar outcomes were observed regardless of disease type and status at transplantation. Odds ratio for all outcomes remained comparable with or without performing separate analyses for the year of HCT and for retrospective versus prospective studies. Among RIC-HCT recipients, survival rates were superior if patients were in CR at transplantation. Significant inter-study heterogeneity for aGvHD data and publication bias for PFS data were observed. This meta-analysis showed no OS benefit of MAC-HCT over RIC-HCT across the entire cohort of patients suggesting that RIC-HCT could be an effective therapeutic option for AML/ALL patients who are ineligible for MAC-HCT and CR status is preferred before RIC-HCT.
Allogeneic hematopoietic stem cell transplantation (HSCT) remains a potential curative option for many patients with hematological malignancies (HM). However, the high rate of transplantation-related mortality (TRM) restricted the use of standard myeloablative HSCT to a minority of young and fit patients. Over the past few years, it has become evident that the alloreactivity of the immunocompetent donor cells mediated anti-malignancy effects independent of the action of high dose chemoradiotherapy. The use of reduced intensity conditioning (RIC) regimens has allowed a graft-versus-malignancy (GvM) effect to be exploited in patients who were previously ineligible for HSCT on the grounds of age and comorbidity. Retrospective analysis showed that RIC has been associated with lower TRM but a higher relapse rate leading to similar intermediate term overall and progression-free survivals when compared to standard myeloablative HSCT. However, the long term antitumor effect of this approach is less well established. Prospective studies are ongoing to define which patients might most benefit from reduced toxicity stem cell transplant (RT-SCT) and which transplant protocols are suitable for the different types of HM. The advent of RT-SCT permits the delivery of a potentially curative GvM effect to the majority of patients with HM whose outcome with conventional chemotherapy would be dismal. Remaining challenges include development of effective strategies to reduce relapse rates by augmenting GvM effects without increasing toxicity.
Primary oesophageal lymphoma is a very rare entity, with fewer than 30 reported cases worldwide. It represents an important cause of dysphagia. Most of the oesophageal lymphomas are diffuse large B-cell type, with only one reported case of anaplastic large cell lymphoma (ALCL) of T-cell phenotype. Primary oesophageal lymphomas that are not associated with an immunocompromised state tend to affect elderly patients. We describe the first case of primary oesophageal Ki (CD30)-positive ALK+ALCL of T-cell phenotype in a 34-year-old immunocompetent woman, who presented with a two-year history of dysphagia. She was treated with chemotherapy and endoscopic oesophageal dilations and stenting, resulting in complete remission of the lymphoma and resolution of the dysphagia. She then underwent autologous peripheral blood haematopoietic stem cell transplantation and remained disease-free two years after the diagnosis.
The follow-up of chimerism status after allogeneic haematopoietic stem cell transplantation (HSCT) is essential to predict successful engraftment to assess the development of graft-versus-host disease, graft rejection and disease relapse. Analysis of short tandem repeats (STR) via polymerase chain reaction is frequently used for chimerism determination. However, most commercially-available kits have been designed for forensic purposes and may not be optimal for chimerism analysis. The present study aims to identify suitable STR markers for patient-donor pairs of predominantly Malay and Chinese ethnicity using two commercially-available forensic kits.
Human glioma is a highly fatal tumor with a significant feature of immune suppression. The functions of PD-L1 refer to co-simulation and immune regulation. To investigate expression and functional activity of PD-L1 in human glioma cell in vivo and in vitro. Expressions of PD-L1mRNA and protein in the human glioma cell line were analyzed with quantitative RT-PCR and flow cytometer; and then expression of PD-L1 in tissue specimens of 10 glioma patients was treated with immunohistochemical analysis; glioma cell and allogeneic CD4+ and CD8+ T cells were co-cultured, and cytokine IFN-γ, IL-2 and IL-10 in cultured supernatant fluid were determined with ELISA; upon blocking the interaction between glioma cell and the immune cell with PD-L1 monoclonal antibody (5H1), surface markers on immune cells were analyzed using flow cytometer. All human glioma cell lines constitutively expressed PD-L1, and IFN-γ induced glioma cell to highly express PD-L1. It was shown through immunohistochemical analysis that glioma specimen expressed PD-L1, while expression of PD-L1 was not observed in normal tissue and normal human brain near the tumor location. The release of IFN-γ and IL-2 was inhibited, while IL-10 was increased slightly. Glioma cell may escape from immune recognition and injury with the help of PD-L1, which is a significant pathogenic mechanism of glioma.
We present a case of abdominal gastric band-associated Mycobacterium abscessus infection, manifesting after the onset of acute myeloid leukemia, complicated by immune reconstitution inflammatory syndrome (IRIS), and cured while receiving an allogeneic hematopoietic stem cell transplant. IRIS should be considered in less classical situations where there is unexplained clinical deterioration.
Mantle cell lymphoma (MCL) is a rare, aggressive subtype of non-Hodgkin lymphoma with a poor prognosis and high recurrence rate. It seldom affects the Waldeyer's ring let alone the nasopharynx. Patients usually present at late stages of the disease leading to poor failure-free and overall survival rates. Intensive chemotherapy regimes and autologous stem cell transplantation have reported increased survival rates. We report a relapsed case of nasopharyngeal MCL, which previously occurred in the gastrointestinal tract. The patient had undergone a hemicolectomy for colon intussusception secondary to the intraluminal lymphoma mass. He was unable to complete the treatment regime for MCL due to the adverse side effects. Oropharyngeal mass was discovered during routine outpatient follow-up, which was confirmed as nasopharyngeal MCL. We discuss the prognosis, disease progression, and possible treatments.
Stem cell transplantation is a generic term covering different techniques. However there is argument over the pros and cons of autologous and allogeneic transplants of mesenchymal stem cells (MSCs) for regenerative therapy. Given that the MSCs have already been proven to be safe in patients, we hypothesize that allogeneic transplantation could be more effective and cost-effective as compared to autologous transplantation specifically in older subjects who are the likely victims of degenerative diseases. This analysis is based on the scientific logic that allogeneic stem cells extracted in large numbers from young and healthy donors could be physiologically, metabolically and genetically more stable. Therefore stem cells from young donors may be expected to exhibit higher vigor in secreting trophic factors leading to activation of host tissue-specific stem cells and also be more efficient in remodeling the micro-environmental niche of damaged tissue.
Primary immunodeficiency disease (PID) or inborn error of immunity is a heterogeneous group of inherited diseases affecting the immune system resulting in increased susceptibility to infections, immune dysregulation, autoimmune manifestations, lymphoproliferation and malignancy. Cases of PIDs have been reported in Malaysia since 1977 and the numbers of reported cases steadily increased for the past 30 years with more trained clinical immunologist available, better immunodiagnostic facilities, wider immunoglobulin replacement therapy availability and improved techniques in haematopoietic stem cell transplantation for PIDs. In this article, we highlight some of the limitations and challenges in the diagnosis and therapy of PID, and more recent efforts to establish PID services in Malaysia.
Inherited thalassaemia disease is commonly found in many countries of the world. Care of the disease requires comprehensive management strategies comprising of clinical management of both transfusion dependant thalassaemia (TDT) and non-transfusion dependant thalassaemia (NTDT). It also includes preventive measures such as screening programmes and genetic counseling in order to contain the genetic transmission. At the moment, the only cure is through haematopoeitic stem cell transplant (HSCT). This report illustrates thalassaemia disease prevalence in the Terengganu state and the evolution of care since National Thalassaemia Programme was launched in 2009.
Introduction: During the last three decades hematopoietic stem cell transplantation (HSCT) has become a well-established treatment for many hematologic malignancies. The most important limitation for HSC transplantation is the low number of hematopoietic stem cells (HSC) that can lead to delayed engraftment or graft failures. Numerous attempts have been made to improve in vitro HSC expansion via optimization of various methods such as isolation techniques, supplementing with growth factors, utilizing stromal cells as feeder layer and other culture conditions. Objective: This project is aimed to decipher the efficiency of an isolation technique and retrieval of culture expanded HSC from feeder layer using two different harvesting methods. Materials and Methods: Hematopoietic stem cells from human umbilical cord blood were isolated via MACS mediated CD34+ double sorting. Then, the cells were cultured onto MSC feeder layer for 3 and 5 days. Culture expanded cells were harvested using two different harvesting method namely cell aspiration and trypsinization methods. Hematopoietic stem cell expansion index were calculated based on harvesting methods for each time point. Results: The numbers of HSC isolated from human umbilical cord blood were 1.64 x 106 and 1.20 x106 cells at single and double sortings respectively. Although the number of sorted cells diminished at the second sorting yet the yield of CD34+ purity has increased from 43.73% at single sorting to 81.40% at double sorting. Employing the trypsinization method, the HSC harvested from feeder layer showed a significant increase in expansion index (EI) as compared to the cell aspiration harvesting method (p≤ 0.05). However, the purity of CD34+ HSC was found higher when the cells were harvested using aspiration method (82.43%) as compared to the trypsinization method (74.13%). Conclusion: A pure population of CD34+ HSC can be retrieved when the cells were double sorted using MACS and expanded in culture after being harvested using cell aspiration method.