Benefits Of Bone Marrow Transplantation Research Articles

Successful Autologous Bone Marrow Transplantation in Active COVID-19 Patients: Case Report

BackgroundPatients with hematologic malignancies are considered at high risk for COVID-19 infection either from the disease or the treatment. Hematopoietic stem cell transplantation, one of the approved therapies for hematologic malignancies, was performed worldwide during the COVID-19 era with some regulations, such as COVID-19 testing, before proceeding with transplantation or cellular therapy. To the authors’ knowledge, none have reported the result of autologous hematopoietic stem cell transplantation in an active COVID-19 patient. Case PresentationWe describe a successful clinical course of autologous bone marrow transplantation for 2 lymphoma patients who tested positive for COVID-19. A thorough discussion was conducted between multidisciplinary hemato-oncology, intensive care, and infectious diseases teams. The decision was to proceed toward bone marrow transplantation with some modifications in the transplantation protocol and close patient monitoring. ConclusionOur cases lend credence that successful autologous bone marrow transplantation is possible among active COVID-19 patients. The obstacles we faced could be overcome with collaboration between a highly qualified multidisciplinary team. Despite the potential complications, the benefits of bone marrow transplantation among patients with a high risk of relapse and who are still COVID-19-positive outweigh the risks. However, further studies are still recommended to support our inference.

Cellular immunotherapy for refractory hematological malignancies

BackgroundAcute myeloid leukemia (AML) and other aggressive refractory hematological malignancies unresponsive to upfront therapy remain difficult conditions to treat. Often, the focus of therapy is centered on achieving complete remission of disease in order to proceed with a consolidative stem cell transplant. At issue with this paradigm is the multitude of patients who are unable to achieve complete remission with standard chemotherapeutic options. A major benefit of transplantation is the graft versus tumor effect that follows successful engraftment. However, with this graft versus tumor effect comes the risk of graft versus host disease. Therefore, alternative treatment options that utilize immunotherapy while minimizing toxicity are warranted. Herein, we propose a novel treatment protocol in which haploidentical peripheral blood stem cells are infused into patients with refractory hematological malignancies. The end goal of cellular therapy is not engraftment but instead is the purposeful rejection of donor cells so as to elicit a potent immune reaction that appears to break host tumor tolerance.Methods/designThe trial is a FDA and institutional Rhode Island Hospital/The Miriam Hospital IRB approved Phase I/II study to determine the efficacy and safety of haploidentical peripheral blood cell infusions into patients with refractory hematological malignancies. The primary objective is the overall response rate while secondary objectives will assess the degree and duration of response as well as safety considerations. Patients with refractory acute leukemias and aggressive lymphomas over the age of 18 are eligible. Donors will be selected amongst family members. Full HLA typing of patients and donors will occur as will chimerism assessments. 1-2x108 CD3+ cells/kilogram will be infused on Day 0 without preconditioning. Patients will be monitored for their response to therapy, in particular for the development of a cytokine release syndrome (CRS) that has been previously described. Blood samples will be taken at the onset, during, and following the cessation of CRS so as to study effector cells, cytokine/chemokine release patterns, and extracellular vesicle populations. Initially, six patients will be enrolled on study to determine safety. Provided the treatment is deemed safe, a total of 25 patients will be enrolled to determine efficacy.DiscussionCellular Immunotherapy for Refractory Hematological Malignancies provides a novel treatment for patients with relapsed/refractory acute leukemia or aggressive lymphoma. We believe this therapy offers the immunological benefit of bone marrow transplantation without the deleterious effects of myeloablative conditioning regimens and minus the risk of GVHD. Laboratory correlative studies will be performed in conjunction with the clinical trial to determine the underlying mechanism of action. This provides a true bench to bedside approach that should serve to further enrich knowledge of host tumor tolerance and mechanisms by which this may be overcome.Trial registrationNCT01685606.

Stem cell therapy: A novel & futuristic treatment modality for disaster injuries

Stem cell therapy hold the potential to meet the demand for transplant cells/tissues needed for treating damages resulting from both natural and man-made disasters. Pluripotency makes embryonic stem cells and induced pluripotent stem cells ideal for use, but their teratogenic character is a major hindrance. Therapeutic benefits of bone marrow transplantation are well known but characterizing the potentialities of haematopoietic and mesenchymal cells is essential. Haematopoietic stem cells (HSCs) have been used for treating both haematopoietic and non-haematopoietic disorders. Ease of isolation, in vitro expansion, and hypoimmunogenecity have brought mesenchymal stem cells (MSCs) into limelight. Though differentiation of MSCs into tissue-specific cells has been reported, differentiation-independent mechanisms seem to play a more significant role in tissue repair which need to be addressed further. The safety and feasibility of MSCs have been demonstrated in clinical trials, and their use in combination with HSC for radiation injury treatment seems to have extended benefit. Therefore, using stem cells for treatment of disaster injuries along with the conventional medical practice would likely accelerate the repair process and improve the quality of life of the victim.

Donor Lymphocyte Infusion: The Use of Alloreactive and Tumor-Reactive Lymphocytes for Immunotherapy of Malignant and Nonmalignant Diseases in Conjunction with Allogeneic Stem Cell Transplantation

Donor lymphocyte infusion (DLI), pioneered in Jerusalem in January 1987, represents the first proof of principle of the absolute efficacy of immunotherapy as a means of curing cancer. Immunotherapy with alloreactive donor lymphocytes can eliminate "the last tumor cell" even in patients with hematological malignancies resistant to maximally tolerated doses of chemoradiotherapy. Alloreactive lymphocytes that can mediate anti-tumor effects following induction of host-versus-graft tolerance induced by transplantation of donor stem cells, can induce graft-versus-malignancy (GVM) effects which are usually accompanied by graft-versus-host disease (GVHD). However, occasionally GVM effects may also be accomplished independently of clinically overt GVHD. Interestingly, allogeneic donor lymphocytes may also eliminate undesirable host-derived hematopoietic cells in a large number of nonmalignant indications including genetic diseases, diseases caused by deficiency of stem cell products, and autoimmune disorders mediated by self-reactive lymphocytes. The cumulative clinical experience suggests feasibility of effective induction of graft-versus-leukemia (GVL); graft-versus-lymphoma (GVLy); graft-versus-multiple myeloma, as well as graft-versus-solid tumors (GVT), well-documented in patients with renal and breast cancer, even in patients with resistant disease that have failed myeloablative chemoradiotherapy. These observations that suggested that cell therapy by donor lymphocytes is the main therapeutic benefit of bone marrow transplantation (BMT) led to development of the nonmyeloablative approach for safer allogeneic stem cell transplantation. Nonmyeloablative stem cell transplantation (NST) makes it possible to offer an option for cure to elderly patients with no upper age limit, as well as to patients with poor performance status not considered eligible for conventional BMT. Using well-tolerated NST regimen, allogeneic stem cell transplantation can be accomplished with minimal procedure-related toxicity and mortality, possibly even on an outpatient basis. Immunotherapy mediated by adoptive allogeneic cell-mediated immunotherapy can be further improved by utilizing specifically immune donor lymphocytes, thus maximizing their efficacy against undesirable target cells of host origin on the one hand, while minimizing their ontoward efficacy against normal cells of host origin that could result in GVHD on the other. Taken together, DLI and subsequently NST, may have opened new horizons for treatment of life-threatening malignant and nonmalignant disorders correctable by allogeneic stem cell transplantation. It is anticipated that further improvement of reactivity and specificity of donor lymphocytes will lead to safer clinical application of cell therapy for a larger number of indications toward improving disease-free survival in a large number of indications while minimizing immediate and late procedure-related complications.

Substrate-reduction therapy enhances the benefits of bone marrow transplantation in young mice with globoid cell leukodystrophy.

Globoid cell leukodystrophy is an autosomal recessive disease with progressive demyelination caused by a deficiency of the lysosomal enzyme galactosylceramidase. Bone marrow transplantation (BMT) is a therapeutic option for patients with late-onset disease and for patients with early onset disease that had an early diagnosis owing to an affected sibling. This therapy, however, typically is not effective for early onset disease when the diagnosis occurs after several months of life. In an effort to enable a broader range of patients to benefit from BMT, we tested whether combining substrate-reduction therapy with BMT would result in a greater benefit than either treatment alone in the twitcher mouse model of globoid cell leukodystrophy. Twitcher mice treated with L-cycloserine, an inhibitor of 3-ketodyhydrosphingosine synthase, and transplanted with 50 +/- 5 x 10(6) bone marrow cells on d 10 had a mean life-span of 112 d compared with 51 d for BMT alone (p < 0.001) or L-cycloserine alone, which was previously reported to be 56 d. L-Cycloserine treatment also was initiated neonatally to determine whether it would allow for a delayed BMT to have therapeutic value. Twitcher mice given only BMT at 18 d or only a short course of L-cycloserine died at 36 and 37 d, respectively. Twitcher mice given a short course of L-cycloserine + BMT at 18 d lived to 58 d (p = 0.0006). In conclusion, substrate-reduction therapy enhanced the value of BMT in twitcher mice, suggesting that this combination strategy might benefit patients with globoid cell leukodystrophy.

Follow-up of nine patients with Hurler syndrome after bone marrow transplantation.

We report our experience in nine patients with Hurler syndrome (six with a severe and three with an intermediate phenotype) who successfully engrafted after bone marrow transplantation. The donor was a human leukocyte antigen-identical sibling in six cases, the human leukocyte antigen-identical father in one case, and an unrelated donor in two cases. One patient with Hurler syndrome and an intermediate phenotype received two successive grafts from the same donor. There was a beneficial effect of bone marrow transplantation on visceral features (hepatosplenomegaly, obstruction of the upper airway, and coarse facies); however, dysostosis multiplex worsened. All patients but one required surgery for carpal tunnel syndrome. Visual acuity was low because of corneal clouding, and two patients had glaucoma several years after the graft. Five patients had normal hearing before the graft that remained normal, and four had hearing impairment that improved. All patients had learning difficulties, but none had severe mental retardation (IQ ranging from 75 to 103). The follow-up of patients with severe Hurler syndrome engrafted for more than 10 years emphasizes the limits and benefits of bone marrow transplantation.

Bone-marrow transplantation in Hurler's syndrome. Effect on skeletal development

Between 1980 and 1988, displacement bone-marrow transplantation was performed on 25 children with Hurler's syndrome (type-1 mucopolysaccharidosis). We describe the musculoskeletal development of 11 of the 12 surviving children and the orthopaedic procedures undertaken to treat progressive thoracolumbar kyphosis, hip subluxation and carpal tunnel syndrome. We found abnormal bone modelling, focal failures of ossification and an avascular disorder of the femoral head in every patient and offer an explanation for these phenomena. Increasing valgus deformity of the knees and progressive generalised myopathy caused loss of mobility as the children entered adolescence. The benefit of bone-marrow transplantation as a treatment for the skeletal disorders of Hurler's syndrome is limited by the poor penetration of the musculoskeletal tissues by the enzyme derived from the leucocytes.

Bone-marrow transplantation for congenital erythropoietic porphyria

Congenital erythropoietic porphyria, a disorder of haem synthesis, is caused by uroporphyrinogen III synthase deficiency in bone-marrow normoblasts. Uroporphyrins and coproporphyrins accumulate and cause oxidative damage to cells exposed to sunlight. Uroporphyrin overproduction was greatly reduced and skin changes reversed in a girl who received a bone-marrow graft from an HLA-identical sibling at 10 years of age. The patient died 11 months after transplantation because of severe progressive pneumonitis and encephalopathy associated with cytomegalovirus infection, but the encouraging response up to 8 months after engraftment indicates a possible benefit of bone-marrow transplantation in the treatment of this rare but usually fatal inherited disease.

Allogeneic Marrow Transplantation for Chronic Granulocytic Leukemia&lt;xref ref-type="fn" rid="FN1"&gt;1&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;

A retrospective analysis is presented of results obtained with allogeneic bone marrow transplantation (BMT) in three phases of Philadelphia chromosome-positive chronic granulocytic leukemia. At BMT, 23 patients were in blastic phase (BP), 33 were in accelerated phase (AP), and 45 were in chronic phase (CP). With a follow-up time of 1-8 years after BMT, the probability of long-term survival was 14, 10, and 58%, respectively, for patients transplanted in BP, AP, or CP. The probability of cytogenetic relapse with or without clinical hematologic relapse at 3 years after BMT was 80, 38, and 31%, respectively, for patients transplanted in BP, AP, or CP. Splenectomy did not influence posttransplant survival. Given the dismal prognosis on conventional therapy, patients younger than 50 in BP or AP should be considered for BMT. For the patient in CP, BMT offers the possibility of cure but with a significant risk of early death. Patients under 40 who fully understand the risks and potential benefits of BMT should be offered BMT early in CP before any change to AP occurs.