Bone Marrow Transplantation Therapy Research Articles

Alpha-Mannosidosis: Therapeutic Strategies.

Alpha-mannosidosis (α-mannosidosis) is a rare lysosomal storage disorder with an autosomal recessive inheritance caused by mutations in the gene encoding for the lysosomal α-d-mannosidase. So far, 155 variants from 191 patients have been identified and in part characterized at the biochemical level. Similarly to other lysosomal storage diseases, there is no relationship between genotype and phenotype in alpha-mannosidosis. Enzyme replacement therapy is at the moment the most effective therapy for lysosomal storage disease, including alpha-mannosidosis. In this review, the genetic of alpha-mannosidosis has been described together with the results so far obtained by two different therapeutic strategies: bone marrow transplantation and enzyme replacement therapy. The primary indication to offer hematopoietic stem cell transplantation in patients affected by alpha-mannosidosis is preservation of neurocognitive function and prevention of early death. The results obtained from a Phase I–II study and a Phase III study provide evidence of the positive clinical effect of the recombinant enzyme on patients with alpha-mannosidosis.

Clinical units to set up chimeric antigen receptor T-cell therapy (CAR T-cells): Based on the recommendations of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) hold its eighth practice harmonization workshops on September 2017. In a workshop dedicated to chimeric antigen receptor T-cell therapy (CAR T-cells), the society issued recommendations regarding the prerequisite for hematopoietic cellular therapy programs to set up CAR T-cell therapy. In this article we focused on the prerequisite needed, in France, for a hematopoietic transplantation unit to start a CAR T-cell program with industrial manufactured cells within investigational products or after market access authorization.

Genetics and Therapies for GM2 Gangliosidosis.

Tay-Sachs disease, caused by impaired β-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from disease-causing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses.

Total body irradiation in allogeneic bone marrow transplantation conditioning regimens: A review.

Hematologic malignancies may require, at one point during their treatment, allogeneic bone marrow transplantation. Total body irradiation combined with chemotherapy or radiomimetic used in allogeneic bone marrow transplantation is known to be very toxic. Total body irradiation (TBI) induces immunosuppression to prevent the rejection of donor marrow. TBI is also used to eradicate malignant cells and is in sanctuary organs that are not reached by chemotherapy drugs. TBI has evolved since its introduction in the late fifties, but acute and late toxicities remain. Helical tomotherapy, which is widely used for some solid tumors, is a path for the improvement of outcomes and toxicities in TBI because of its sparing capacities. In this article, we first review the practical aspects of TBI with patient positioning, radiobiological considerations and total dose and fractionation prescriptions. Second, we review the use of intensity modulated radiation therapy in bone marrow transplantation with a focus on helical tomotherapy TBI, helical tomotherapy total marrow irradiation (TMI) and total marrow and lymphoid irradiation (TMLI) and their dosimetric and clinical outcomes. Finally, we review the perspective of dose escalation and the extension to older patients and patients with comorbidity who do not benefit from a standard bone marrow transplantation conditioning regimen.

Better outcome with haploidentical over HLA-matched related donors in patients with Hodgkin's lymphoma undergoing allogeneic haematopoietic cell transplantation-a study by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

The question of the best donor type between haploidentical (HAPLO) and matched-related donors (MRD) for patients with advanced HL receiving an allogeneic hematopoietic cell transplantation (allo-HCT) is still debated. Given the lack of data comparing these two types of donor in the setting of non-myeloablative (NMA) or reduced-intensity (RIC) allo-HCT, we performed a multicentre retrospective study using graft-vs.-host disease-free relapse-free survival (GRFS) as our primary endpoint. We analysed the data of 151 consecutive HL patients who underwent NMA or RIC allo-HCT from a HAPLO (N = 61) or MRD (N = 90) between January 2011 and January 2016. GRFS was defined as the probability of being alive without evidence of relapse, grade 3-4 acute GVHD or chronic GVHD. In multivariable analysis, MRD donors were independently associated with lower GRFS compared to HAPLO donors (HR = 2.95, P < 0.001). Disease status at transplant other than CR was also associated with lower GRFS in multivariable analysis (HR = 1.74, P = 0.01). In addition, the administration of ATG was independently linked to higher GRFS (HR = 0.52, P = 0.009). In summary, we observed significantly higher GRFS in HL patients receiving an allo-HCT using the HAPLO PT-Cy platform compared to MRD.

Survey of quality of life and its influencing factors in patients with hematopoietic stem cell transplantation at different time points

Objective To investigate the dynamic changes and analyze the influencing factors of quality of life (QOL) among adult patients undergoing hematopoietic stem cell transplantation (HSCT). Methods Totally 143 HSCT patients were investigated by the common questionnaire, the Perceived Social Support Scale (PSSS) and the Functional Assessment in Cancer Therapy—Bone Marrow Transplant (FACT-BMT) before checked in the purification bin,1 month post transplantation and 3 months post transplantation. Results The QOL were different among different time points of HSCT patients (P<0.05). Multiple factors analysis showed that the factors before checked in the purification bin including social support (OR=4.480, P=0.019), residence (OR=3.167, P=0.036) and disease diagnosis (OR=0.036, P=0.042). The factors 1 month post transplantation included social support (OR=3.573, P=0.018), whether or not the platelets were reconstructed during storage (OR=2.735, P=0.018) and whether there were transplant related complications (OR=0.214, P=0.016). The factors 3 month post transplantation included social support (OR=9.639, P<0.01) and whether there were transplant related complications (OR=0.167, P=0.003). Conclusions The QOL was low among HSCT patients, and it dynamically changed at different points. Social support is the only sustainable influencing factor of quality of life. This prompts us that we should pay abundant attention on social support and use it to improve the QOL of HSCT patients. Key words: Hematopoietic stem cell transplantation; Quality of life; Longitudinal studies; Influencing factors

Stratégies préventives et thérapeutiques de la rechute après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Disease relapse remains the first cause of mortality of hematological malignancies after allogeneic hematopoietic stem cell transplantation (allo-HCT). The risk of recurrence is elevated in patients with high-risk cytogenetic or molecular abnormalities, as well as when allo-HCT is performed in patients with refractory disease or with persistent molecular or radiological (PET-CT scan) residual disease. Within the frame of the 7thannual workshops of the francophone society for bone marrow transplantation and cellular therapy, the working group reviewed the literature in order to elaborate unified guidelines for the prevention and treatment of relapse after allo-HCT. For high risk AML and MDS, a post transplant maintenance strategy is possible, using hypomethylating agents or TKI anti-FLT3when the target is present. For Philadelphia positive ALL, there was a consensus for the use of post-transplant TKI maintenance. For lymphomas, there are no strong data on the use of post-transplant maintenance, and hence a preemptive strategy is recommended based on modulation of immunosuppression, close follow-up of donor chimerism, and donor lymphocytes infusion. For multiple myeloma, even though the indication of allo-HCT is controversial, our recommendation is post transplant maintenance using bortezomib, due to its a good toxicity profile without increasing the risk of GVHD.

Prise en charge de la maladie du greffon contre l’hôte chronique : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The Francophone society of bone marrow transplantation and cellular therapy (SFGM-TC) organized the 7thallogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September2016in Lille, France. The objective of our workshop is to discuss chronic graft versus host disease and to provide recommendations for the indications and treatment of this condition.

Adaptation des doses de médicament des conditionnements de greffe de cellules souches hématopoïétiques dans des populations avec comorbidité : obésité, maladie rénale chronique ou hépatopathie : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th Allogeneic Stem Cell Transplantation Clinical Practices Harmonization Workshop Series. Our work group focused on chemotherapy drug dose adaptation for hematopoietic stem cell transplantation patients presenting a comorbidity. The purpose of this workshop was to provide recommendations on chemotherapy drug dose adaptation for patient populations receiving hematopoietic stem cell transplantation who also had the following comorbidities: obesity, chronic kidney disease and hepatopathy.

Allogreffe de cellules souches hématopoïétiques dans la lymphome de Hodgkin, le lymphome du manteau et autres hémopathies lymphoïdes rares : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic haematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript specifically reports on our conclusions regarding Hodgkin's lymphoma as well as rarer entities, such as T cell lymphomas.

Indications et suivi des autogreffes de cellules souches hématopoïétiques dans les maladies auto-immunes et auto-inflammatoires : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2017 in Lille, France and updated recommendations for indications and follow-up in autologous hematopoietic stem cell transplantation in autoimmune and autoinflammatory diseases, previously published under the auspices of SFGM-TC.

Allogreffe de cellules souches hématopoïétiques dans les lymphomes indolents : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This paper specifically reports on our conclusions regarding indolent lymphomas, mainly follicular lymphoma and chronic lymphocytic leukemia.

Allogreffe de cellules souches hématopoïétiques dans les lymphomes diffus à grandes cellules B : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly in the case of after autologous stem cell transplantation if remission can be achieved. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This section specifically reports on our conclusions regarding diffuse large B cell lymphoma.

Conservation/congélation des greffons de CSH dans un contexte pédiatrique : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allogeneic hematopoietic stem cell transplantation clinical practices harmonization workshop series in September 2016 in Lille, France. The objective of our workshop is to provide a discussion on the conservation and congelation of hematopoietic stem cells in a pediatric setting as well as our recommendations for this technique.

Utilisation des donneurs alternatifs avant allogreffe de cellules souches hématopoïétiques dans les hémopathies lymphoïdes : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation (allo-HCT) is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allo-HCT for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript reports on general considerations regarding allo-HCT for lymphoma and elaborates on the use of alternative donors in this setting.

Carnet national destiné aux patients autogreffés : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

In an attempt to harmonize clinical practices among French hematopoietic stem cell transplantation centers, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held its seventh annual workshop series in September 2016in Lille. This event brought together practitioners from across the country. Our workshop discusses the creation of a patient care logbook for patients undergoing autologous hematopoietic cell transplantation.

Un support d’information pour les donneurs apparentés de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC)

Providing information to living donors is first and foremost a legal obligation as well as an ethical one, not to mention necessary to health care provision. It's been shown that quality of information concerning the procedure's practical aspects, scheduling of clinical tests and examinations, withdrawing stem cells for the donation, post-donation symptoms, and support provided by healthcare teams, directly impacts the donor's quality of experience. Taking this into consideration our group decided it was essential to create an informational support for donors in the form of a booklet to be provided in different hematopoietic stem cell transplant centers across France. In September 2016 in Lille, France, the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 7th allergenic hematopoietic stem cell transplantation clinical practices harmonization workshops. As part of these workshops, our group worked collectively to develop a basis of indispensable information to be included in the booklet and presented using clear and accessible language.

Retroviral Transduction of Quiescent Murine Hematopoietic Stem Cells.

Hematopoietic stem cells (HSCs) represent an important target cell population in bone marrow transplantation, cell and gene therapy applications, and the development of leukemia models for research. Because the hematopoietic progeny carries the genetic information of HSCs and replenishes the blood and immune system, corrective gene transfer into HSCs provides an ideal therapeutic approach for many monogenic hematological diseases and a useful tool for studies of HSC function and blood formation in normal and malignant hematopoiesis. However, the efficiency of gene transfer into HSCs has been limited by several features of viral vectors, viral titer, methods of viral transduction, and the property of stem cell quiescence. In this chapter, we describe the production of retrovirus using murine stem cell virus (MSCV)-based retroviral vectors and purification and transduction of murine HSCs.

A Comparative Assessment of Quality of Life in Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplantation Through an Outpatient and Inpatient Model

Outpatient autologous stem cell transplantation (ASCT) has proven to be feasible in terms of physical morbidity and mortality outcomes, but little data exist on the impact of this procedure on quality of life (QoL). The purpose of this prospective, observational, longitudinal cohort study was to compare the effects of inpatient (n = 76) and outpatient (n = 64) modes of care on QoL in patients with multiple myeloma who underwent ASCT. Patients were treated according to their preference for the inpatient or outpatient model. QoL was assessed using the Functional Assessment of Cancer Therapy–Bone Marrow Transplantation (FACT-BMT) at baseline (7 days before ASCT; T1) and at days +7 (T2) and +30 (T3) after ASCT. Overall, inpatients achieved higher mean values at each time point (86.05 ± 15.54 at T1, 89.23 ± 19.19 at T2, and 87.96 ± 13.6 at T3) compared with outpatients (85.62 ± 14.51 at T1, 87.42 ± 23.41 at T2, and 83.98 ± 20.2 at T3), although the differences did not reach statistical significance. Inpatients showed higher mean scores than outpatients in physical well-being (7.67 ± 5.7, 15.44 ± 6.34, and 12.96 ± 6.03, respectively, versus 5.89 ± 4.33, 13.92 ± 7.05, and 8.84 ± 6.33, respectively; P < .05). Mean scores on social/family well-being were significantly higher in the outpatient group compared with the inpatient group (22.93 ± 13.29, 21.14 ± 5.31, and 21.64 ± 4.58, respectively, versus 20.59 ± 3.79, 19.52 ± 5.12, and 20.01 ± 3.97, respectively; P = .003). There were no significant between-group differences with respect to functional well-being and emotional status. Among adults at a single institution undergoing ASCT for MM, the use of outpatient care compared with standard transplantation care did not result in improved QoL during transplantation. Further research is needed for replication and to assess longer-term outcomes and implications.

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OBJECTIVES/SPECIFIC AIMS: To date, only 1 documented case of an individual cured of HIV has been reported. He received an allogeneic bone marrow transplant with cells harboring an HIV-resistant genotype. To mimic this result, we have initiated a Phase I to evaluate the safety of an autologous stem cell gene therapy bone marrow transplant in HIV-related lymphoma patients. METHODS/STUDY POPULATION: The first cohort of patients will receive a 1:1 ratio of unmanipulated CD34 hematopoietic stem cells (HSC) and lentivector modified CD34 HSC expressing a combination of HIV-resistant genes and a selectable marker for cell sorting prior to transplantation. Safety of the HIV-resistant stem cells will be assessed by evaluating engraftment, expression of the anti-HIV genes, and the stability and sequence of the vector. RESULTS/ANTICIPATED RESULTS: One patient has been enrolled and transplanted with the HIV-resistant stem cells. After 1 and 2 months post-transplant, patient blood samples were received, processed for genomic DNA, analyzed by quantitative PCR (qPCR), and displayed successful engraftment of 16 and 12 vector copies per 100 cells, respectively. Expression of all anti-HIV genes was confirmed by qPCR. PCR on genomic DNA confirmed the correct sizes and sequences of the integrated vector and confirmed the successful engraftment of our gene modified cells. Currently, we are enrolling more patients into the trial. DISCUSSION/SIGNIFICANCE OF IMPACT: If successful, this therapy has the potential to change HIV treatment.