hematopoietic stem cell transplantation

Natural killer (NK) cells, the third population of lymphoid cells, comprise 5%-25% of peripheral blood (PB) lymphocytes and represent the first line of defense against infections and tumors [1-7]. They can be derived from: bone marrow, PB, cryopreserved umbilical cord blood (UCB), human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs), and various cell lines such as NK-92 and KHYG-1 [1]. NK cells; which have been divided into cytotoxic, tolerant, and regulatory subsets; are classified into: (1) naïve CD56 bright CD 16 dim CD 3 dim cells, (2) mature CD56 dim CD16 bright CD3 dim cells, and (3) lymphoid tissue-resident CD69+/CXCR6+ NK cells [1,2,8-11]. Although NK cells have been traditionally considered as part of the innate immune system, they have recently been shown to exhibit many of the features associated with adaptive immunity [8,12]. The functions of NK cells which are influenced by several cytokines include: elimination of infected cells, destruction of cancer cells, reducing the incidence of graft versus host disease (GVHD) following hematopoietic stem cell transplantation (HSCT), and regulation of pregnancy outcome [10,11,13]. 

Natural killer cells represent the first line of defense against infections and tumors and can be derived from various sources including: bone marrow, peripheral blood, specific types of human stem cells, and certain cell lines. The functions of natural killer cells are influenced by: several cytokines, activating and inhibitory receptors, as well as other immune cells such as dendritic cells and mesenchymal stem cells. Natural killer cells are attractive candidates for adoptive cellular therapy in patients with hematologic malignancies and solid tumors in addition to recipients of various forms of hematopoietic stem cell transplantation as they enhance antitumor effects without causing graft versus host disease. Several clinical trials have shown safety and efficacy of natural killer cell products obtained from autologous as well as allogeneic sources and used in conjunction with cytotoxic chemotherapy, monoclonal antibodies and novel agents. The following review, which includes extensive literature review on several aspects of natural killer cells, will give particular attention to: the rising role of natural killer cell therapies in patients with malignant hematological disorders, solid tumors and in recipients of stem cell therapies; preparation and manufacture of natural killer cell products; challenges facing the utilization of this form of cellular therapy including evolution of resistance; and maneuvers that can be employed to enhance the efficacy of natural killer cell therapies as well as suggested solutions to resolve the remaining challenges.

ystemic sclerosis (SScl) is an autoimmune disorder of unknown aetiology, characterised by fibrosis and microvascular injury of the affected organs. The hallmark of the disease is thickening and tightness of the skin and the subcutaneous tissue. SScl can affect virtually any organ systems, most importantly the skin, blood vessels, lungs, kidneys, gastrointestinal tract, and the heart [1].

Background: Invasive fungal infections cause significant morbidity and mortality in patients with hematologic malignancies and in recipients of hematopoietic stem cell transplantation. Case: We report a patient with relapsed acute myeloid leukemia who developed disseminated Fusarium infection during the neutropenic period following the salvage cycle of chemotherapy given at King Fahad specialist Hospital in Dammam, Saudi Arabia. The invasive fungal infection was successfully managed with a combination of voriconazole and liposomal amphotericin-B. Discussion: Fusarium species can cause invasive infections that may become disseminated and life-threatening in patients with acute myeloid leukemia. Conclusion: Combined antifungal therapy and recovery of neutrophil count are essential to control invasive Fusarium infections

Varicella zoster virus (VZV), a double-stranded DNA virus, is a highly contagious human neurotropic virus that belongs to the alpha group of herpes viruses [1-4]. Primary VZV infection (chickenpox) occurs in childhood then the virus becomes latent in the nerve ganglia [1,5-7]. Reactivation of the virus may occur decades later and cause herpes zoster (HZ) which is manifested by a typical painful skin eruption that has characteristic dermatomal distribution [1,5]. Reactivation of VZV is usually predisposed to: old age; comorbid medical conditions such as diabetes mellitus, chronic obstructive airway disease, and end-stage renal disease; and immunosuppression due to malignancy, autoimmune disorders, immunosuppressive therapies, trauma, cytotoxic chemotherapy, hematopoietic stem cell transplantation (HSCT), and solid organ transplantation (SOT) [1,5-7].

Experience with allogeneic hematopoietic stem cell transplantation (HSCT) in mycosis fungoides/Sezary syndrome (MF/SS) is limited to a small number of case reports and case series [1,2]. The advantage of allogeneic HSCT has been indicated in progressive disease in the review of CIBMTR study groups [3]. A consensus is still not available about the intensity and the content of the conditioning regimen due to the rarity of the disease and heterogeneous patient groups.

Background: Aautologous hematopoietic stem cell transplants (HSCT) is the standard of care for newly diagnosed patients with multiple myeloma (MM) who are eligible for autologous transplantation. Although cryopreservation is routinely employed, autologous HSCT can be performed using non-cryopreserved stem cells.Methods and materials: A retrospective study of patients with MM who received autologous HSCT between the 10th of October 2010 and the 31st of January 2022 at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia was performed.Results: Over 11 years and 113 days, a total of 135 autologous HSCTs were performed for 119 patients with MM at our institution. Single autologous HSCTs were performed for 119 patients, while 16 of these patients received either planned tandem autologous transplants or second autografts due to either progression or relapse of their myeloma. The median age of patients with MM at autologous HSCT was 51.5 years. At presentation of their MM, the following high-risk (HR) features were encountered: stage III disease according to the revised international scoring system (RISS) in 12.3%; adverse cytogenetics in 31.93% of patients; advanced bone disease in 60.50%; and renal dysfunction or failure in 11.76% of patients. A total of 104 autologous HSCTs (77.04%) were performed without cryopreservation while 31 autografts (22.96%) were performed using cryopreserved apheresis stem cell products. Additionally, 54 autologous HSCTs (40.00%) were done at outpatient while 81 autografts (60.00%) were performed in an inpatient setting. Survival for 100 days post-HSCT for all patients with MM who received autologous transplants including those done at outpatient was 100%. The 4 years overall survival (OS) an progression-free survival (PFS) for patients with MM who received non- cryopreserved or fresh autologous HSCTs were 82% and 68% respectively.Conclusion: Autologous HSCT without cryopreservation is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation with cryopreservation. Non- cryopreserved autologous grafts allow the performance of autologous transplants in an outpatient setting to save beds and reduce costs.

Background: Autologous hematopoietic stem cell transplants (HSCT) is the standard of care for transplant-eligible patients with newly diagnosed multiple myeloma (MM) and patients with relapsed and refractory Hodgkin lymphoma (R/R-HL) who achieve chemosensitivity after salvage therapy. Although autologous HSCT is routinely performed in an  inpatient setting, the procedure can safely be performed in an  outpatient setting.Methods and materials: A retrospective study of patients with MM and R/R- HL who received outpatient autologous HSCT at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia between the first of April 2017 and the 31st of January 2022 was performed.Results: Over the study period of 4 years and 10 months, a total of 90 outpatient autologous HSCTs were performed for 79 patients (54 patients with MM; 4 of them received planned tandem autografts and 7 other myeloma patients received second autologous HSCTs for relapsed or progressive disease; and 25 patients with R/R-HL) at our institution. The median ages of patients with MM and those with R/R-HL at HSCT were 50.4 years and 27.8 years respectively.At the presentation of their MM, the following high-risk (HR) features were encountered: stage II and III diseases according to the revised international scoring system (RISS) in 53.7%; adverse cytogenetics in 42.6% and extensive bone involvement in 53.7% of patients. In patients with HL at presentation, 48% of patients had stage IV disease according to Ann Arbor staging classification and 84% of patients had B symptoms.Survival for 100 days post-HSCT for all patients with MM and HL who received outpatient autologous transplants was 100%. For patients with MM, the overall survival (OS) rates at 3 years and 4 years post-HSCT were 80% and 67%, while the progression-free survival (PFS) rates over 3 years and 4 years were 58% and 38% respectively. For patients with HL, the OS at 6 years post-HSCT was 95% while the PFS rates at 3 years and 6 years post-HSCT were 84% and 62% respectively.Conclusion: Outpatient autologous HSCT for patients with MM and HL is safe, and feasible and can lead to short-term as well as long-term outcomes that are comparable to autologous transplantation performed in an  inpatient setting. Additional benefits of outpatient autologous include saving beds and reducing hospital costs.

Background: Measurable residual disease (MRD) status before allogeneic hematopoietic stem cell transplantation (AHSCT) is commonly associated with a high risk of relapse. It is still uncertain whether AHSCT could overcome the negative impact of MRD positivity (MRD+), especially in patients with high-risk Philadelphia negative acute lymphoblastic leukemia (Ph-negative ALL). Materials and methods: An observational retrospective study was conducted on patients with high-risk Ph-negative ALL who underwent AHSCT between January 2005 and June 2022. The patients selected were in complete remission (CR): with 80% in CR1 (n = 69) and 20% in CR2 (n = 17). Graft sources were bone marrow (BM) in 71% of patients and peripheral blood stem cells in 29% of patients. The conditioning regimen was TBI or chemotherapy-based (CT). Bone marrow MRD level was quantified using 4-6 color multiparametric flow cytometry (MFC). The threshold for MRD positivity was ≥ 0.1%. Results: The study included 86 patients (45 B-ALL and 41 T-ALL) with a median age of 18 years (range, 4–55 years). The median level of MRD pre-AHSCT (pre-MRD) was 0.4×10-3 (range, 0.01-75.6×10-3). After a median follow-up of 25 months (range 1-205 months), the cumulative incidence of relapse (CIR) was significantly higher in the MRD+ group (39% vs. 20%, p = 0.04). The median time of relapse post-AHSCT was 14 months (range, 1-203 months) in the MRD+ group and 32 months (range, 4-209 months) in the MRD- group (p = 0.28). Non-relapse mortality (NRM) was 15% in both groups (p = 0.97). The 2-year estimated overall survival (OS) and event-free survival (EFS) were 61% vs. 74% (p = 0.07) and 58% vs. 70% (p = 0.10) in the MRD+ and MRD- groups, respectively. A subgroup analysis in MRD+ patients showed that a TBI-based conditioning regimen was distinctly associated with lower CIR (22% vs. 60% respectively, p = 0.04), improved OS (82% vs. 36% respectively, p = 0.007) and better EFS (73% vs. 38%, p = 0.04) compared to CT-based. In a multivariate analysis, pre-AHSCT MRD+ status and non-TBI-based conditioning were significantly associated with inferior OS (OR, 2.30; 95% CI, [1.027-5.168], p = 0.04 and OR, 3.91; 95% CI, [1.624-9.418], p = 0.002, respectively). The only predicting factor of lower EFS was the non-TBI-based regimen (OR, 2.82; 95% CI, [1.308-6.097], p = 0.008). Non-TBI-based and CR2 were significantly associated with higher CIR (OR, 6.25; 95% CI, [1.947-20.055], p = 0.002 and OR, 4.74; 95% CI, [1.197-18.791], p = 0.03, respectively). Peripheral stem cell source was significantly associated with higher NRM (OR, 6.55; 95% CI, [1.488-28.820], p = 0.01). Conclusion: High-risk Ph-negative ALL patients with MRD ≥ 10-3 prior AHSCT had lower OS compared to MRD- patients and may benefit from TBI as a conditioning regimen before AHSCT.

Introduction: Thalassemia is an inherited blood disorder of haemoglobin (Hb) synthesis, which affects different regions around the world. India has the largest number of children with beta-thalassemia major in the world, particularly in the tribal population. Heterozygous conditions are milder and even go unreported than the condition of homozygous where regular blood transfusion is required.Case report: This report focuses on a case of major beta-thalassemia in a child, whose parents are beta thalassemia minor to intermediate conditions, and who was treated by blood transfusion once a month. However, Thalassemia may be cured by allogeneic hematopoietic stem cell transplantation, although not everyone is a good candidate. Genetic counselling, prenatal diagnosis, and selective termination of affected fetuses are effective ways to control thalassemia.Discussion and conclusion: The paper reports a unique case of Thalassemia in rural India. The blood disorder while commonly presented in a juvenile whose parents were Thalassemia positive resulted in the termination of a fetus diagnosed with it. It archives the story of the parents who are now in the process of planning future offspring while mitigating disease risk. The case leads the way for effective management and containment of hereditary genetic disorders through carrier detection while planning alliances and offspring.

Graft Versus Host Disease (GVHD) is a major limitation to the success of allogeneic Hematopoietic Stem Cell Transplantation (HSCT) as Steroid-Refractory (SR) acute GVHD carries poor prognosis due to the absence of an efficacious second-line therapy. Mesenchymal Stem Cells (MSCs) which have immunosuppressive, immunomodulatory, and regenerative properties may become a highly effective therapeutic modality for SR-GVHD in the near future. MSCs have already been approved to treat childhood SR-GVHD in Japan, and they have been conditionally licensed in New Zealand and Canada. It is expected that MSCs will be approved for the treatment of SR-GVHD in adults in Europe, North America, and other parts of the world within a few years. Utilization of the recently introduced techniques including the use of MSC products such as exosomes and Extracellular Vesicles (ECVs) instead of the parent MSCs, robotic manufacturing technology, and genetic engineering of MSCs will ultimately overcome the remaining obstacles facing the widespread utilization of MSCs and their products as therapeutics not only in HSCT but also in other medical fields. The aim of this review is to provide an update on the remarkable progress achieved in the use of MSCs and their products in the field of HSCT.

Mesenchymal stem cells are heterogenous adult multipotent stromal cells that can be isolated from various sources including bone marrow, peripheral blood, umbilical cord blood, dental pulp, and adipose tissue. They have certain regenerative, anti-inflammatory, immunomodulatory, immunosuppressive, antimicrobial, and other properties that enable them to have several therapeutic and clinical applications including treatment of various autoimmune disorders; role in hematopoietic stem cell transplantation and regenerative medicine; treatment of skin, pulmonary and cardiovascular disorders; treatment of neurological and eye diseases; as well as treatment of various infections and their complications. Different factors including donor age, biological source, route of administration, and signaling pathways have an impact on the functions and consequently the clinical applications of mesenchymal stromal cells. The products of mesenchymal stem cells such as extracellular vesicles and exosomes reproduce the biological effects and most of the therapeutic actions of the parent stem cells. Genetic engineering and the use of specific mesenchymal stromal cell products have improved their clinical efficacy and decreased their adverse effects. However, despite the recent progress in the use of mesenchymal stem cells, the clinical application of these cells in the treatment of several diseases still faces real challenges that need to be resolved. The current status of mesenchymal stem cells and the controversies related to their clinical utilization in various disease conditions will be thoroughly discussed in this review.

Background: Patients with acute and chronic leukemia presenting with hyperleukocytosis are at risk of developing leukostasis which has serious and life-threatening complications. Leukapheresis is usually performed to reduce the complications of leukostasis in patients presenting with hyperleukocytosis and clinical manifestations compatible with leukostasis. Methods and materials: A retrospective study of patients with acute and chronic leukemia who received leukapheresis for hyperleukocytosis between the 1st of January 2013 and the 31st of December 2023 at King Fahad Specialist Hospital (KFSH) in Dammam, Saudi Arabia was performed. Results: Over a period of 11 years, a total of 50 patients with acute and chronic leukemia presenting with hyperleukocytosis and clinical manifestations of leukostasis; 32 patients with acute leukemia (AL) and 18 patients with chronic myeloid leukemia (CML); received leukapheresis at our institution. Among the 32 patients with AL who received leukapheresis, 24 patients (75%) had acute myeloid leukemia (AML), 7 patients (21.88%) had acute lymphoblastic leukemia (ALL) and 1 patient (3.13%) had bilineage acute leukemia (BAL). At presentation of their AL: 3 patients (9.38%) had fever, 9 patients (28.13%) had infections, 4 patients (12.5%) had palpable spleen or liver, 6 patients (18.75%) had palpable external lymph nodes, and 9 patients (28.13%) had extramedullary disease (EMD). After receiving induction and consolidation cycles of chemotherapy, 11 patients (34.38%) of AL patients received allogeneic hematopoietic stem cell transplantation (HSCT). At the end of the follow-up, 17 patients (53.1%) with AL were alive while 15 patients (46.9%) were dead. The 8-year overall survival (OS) for all patients with AL subjected to leukapheresis was 47%. The 5 years OS for patients with AL who subsequently received HSCT and those who did not receive allogeneic HSCT were 70% and 40% respectively. The mean white blood cell (WBC) count of CML patients subjected to leukapheresis was 465.5 × 109/L, 11 patients (61.11%) had clear signs of leukostasis, and 8 patients (44.44%) had splenomegaly at presentation. Regarding the disease stage at presentation, 14 CML patients (77.78%) had chronic phase (CP), 2 patients (11.11%) had accelerated phase (AP) and 2 patients (11.11%) had blast phase (BP). Regarding the fate of CML patients at the end of the study were: 15 (83.33%) were alive, 1 (5.56%) dead, and 2 (11.11%) were unknown as they lost follow-up. However, the 10-year OS of patients with CML subjected to leukapheresis was 90%. Conclusion: Patients with acute or chronic leukemia presenting with hyperleukocytosis and either ongoing or impending leukostasis should have urgent cytoreductive chemotherapy and leukapheresis to prevent life-threatening complications. Although the outcome of AL patients presenting with leukostasis is generally poor, prompt cytoreductive therapy and leukapheresis, followed by induction chemotherapy and allogeneic HSCT may improve the outcome. Also, urgent cytoreduction including leukapheresis improves the outcome of patients with CML presenting with hyperleukocytosis and leukostasis.

Background: Adult patients with Acute Myeloid Leukemia (AML) have traditionally been hospitalized for the duration of intensive consolidation chemotherapy until blood count recovery to avoid complications. Recently, there has been a trend to shift the care of AML patients treated with intensive chemotherapy from inpatient to outpatient settings to reduce treatment costs and save beds. Methods and materials: A retrospective study of AML patients who received cytarabine consolidation chemotherapy between the 1st of August 2016 and the 31st of December 2023 at King Fahad Specialist Hospital in Dammam, Saudi Arabia was performed. Results: Over a period of 7 years and 4 months, 62 patients received a total of 127 cycles of intensive consolidation chemotherapy at outpatient setting. At diagnosis: 12 patients had extramedullary disease, and 17 patients had adverse cytogenetic abnormalities. Following the 127 cycles of chemotherapy, 38 episodes of febrile neutropenia were encountered, and 46 hospital admissions were required. No complications were encountered following 62.2% of the cycles of consolidation therapy and no early mortality due to intensive consolidation therapy was reported. Out of 62 patients studied, 36 patients underwent various forms of hematopoietic stem cell transplantation. Disease relapses were encountered in 24 patients and the 5-year incidence of relapse for the entire group of patients was 42%. The 5-year leukemia-free survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 43%, 38%, and 50% respectively. The 5-year overall survival for the: entire study patients, transplanted patients, and non-transplanted patients were: 44%, 34%, and 65% respectively. At the end of follow-up: 37 patients (59.68%) were alive, 24 patients (38.71%) were dead, and the fate of 1 patient (1.61%) was unknown as the patient moved to another hospital. Conclusion: Administration of intensive consolidation chemotherapy for patients with AML at outpatient setting is safe, feasible, and cost-effective. The incidence of infectious complications was relatively low. No early treatment-related mortality due to intensive consolidation therapy was encountered. Outpatient administration of intensive consolidation therapy can save beds, reduce hospital costs, and is associated with short-term and long-term outcomes that are comparable to inpatient administration of consolidation therapy. 

We reviewed our outcomes of patients with relapsed/refractory Hodgkin Lymphoma treated with autologous stem cell transplant over a 30-year period, 1992 to 2022 and are reporting 15-year Disease-Free Survival (DFS) and Overall Survival (OS) of the 36 patients treated (19 men, 17 women, median age 41). Over the years there were different preparative regimens employed (carmustine, etoposide, melphalan and BCNU, etoposide, cytarabine, and melphalan) as well as post-transplant consolidation therapy (brentuximab). With a median follow-up of 15 years, the DFS is 52% and OS is 64%. Long-term complications include cardiomyopathy and second malignancies.The use of better salvage regimens and post-transplant consolidation therapy should lead to better outcomes.

Pure Red Cell Aplasia (PRCA) is a well-recognized complication of Major ABO-incompatible allogeneic stem cell transplantation. It is featured by anemia, Reticulocytopenia, and the absence of erythroblasts in a normal-appearing bone marrow biopsy. The mechanism for PRCA is presumed to be the persistence of recipient isoagglutinins, produced by residual host B lymphocytes or plasma cells, which probably interfere with the engraftment of donor erythroid cells. Several risk factors for PRCA have been reported, such as the presence of Anti-A Isoagglutininsbefore transplantation, reduced intensity conditioning, absence of Graft Versus Host Disease (GVHD), sibling donor and Cyclosporin A(CsA) as GVHD prophylaxis. PRCA is not a barrier to going ahead with Hematopoietic Stem Cell Transplantation (HSCT). There are many therapeutic options however few recover spontaneously, among the available options include high-dose steroids, Erythropoietin(EPO), Plasma exchange, Donor lymphocyte Infusion (DLI), treatment with Rituximab, Bortezomib, Daratumumab and tapering or discontinuation of immunosuppression. All these options have variable success in the literature ranging from 30% - 70%, Non-responders become red cell transfusion dependent and their quality of life is impaired. We are reporting a novel therapeutic option, Ibrutinib as an armamentarium in treating the PRCA post-HSCT, which works by blocking the Bruton Tyrosine Kinase (BTK) pathway thereby inhibiting the host B cell isoagglutinins production and good clinical response.

Autologous Hematopoietic Stem Cell Transplantation (AHSCT) performed after induction therapy is the standard of care for newly diagnosed Multiple Myeloma (MM) patients who qualify. Our institution has performed AHSCT for MM since 1991, and in this study, we sought to retrospectively examine the outcomes of 303 MM patients who underwent AHSCT from 1991-2021. We focused on Overall Survival (OS) and Progression-Free Survival (PFS) in patients in addition to Landmark survival (1-year post-transplantation). We found that in elderly patients > 70 years of age there was no significant difference in OS at 12 years, with 51% for patients < 70 years of age and 50% > 70; these were the same numbers for PFS at 12 years as well. We also found that median overall survival is improving overall with each decade in our transplanted MM patients with patient survival improved to over > 80% regardless of age at 7 years, when the previous median overall survival was 6 - 6.6 years before 2001. Given our findings, supported by others, we show that survival is continually improving over time in MM AHSCT patients and that AHSCT can be performed safely with equivalent landmark and long-term PFS and OS in patients of advanced age.