Biomedical subjects

H M Lazarus

Publications and source records attributed to H M Lazarus.

At least 19 recordsLinked to original sources

PubMed2006

Outcome of adult umbilical cord blood transplant patients admitted to a medical intensive care unit.

Umbilical cord blood transplant (UCBT) has emerged as an alternate source of stem cells for transplantation in patients with hematologic malignancies. However, outcomes of adult UCBT patients requiring ICU admission remain unknown. In order to identify predictors of ICU transfer and mortality in UCBT patients, the course and outcome of all adult (> or = 16 years old) patients who underwent UCBT between 1 January 1998 and 31 December 2003 at University Hospitals of Cleveland were analyzed. Forty-four patients underwent UCBT during the study period and 25 (57%) required ICU transfer. Use of a myeloablative preparative regimen was a significant predictor of ICU transfer (P = 0.03). An infusion of higher numbers of nucleated cells was protective from ICU transfer (P = 0.05). For those patients transferred to the ICU, mortality was 72%. The univariate predictors of mortality, at the time of ICU admission were a high APACHE III score (P = 0.0004), use of vasopressors (P = 0.03), and a low platelet count (P = 0.03). We conclude that transfer of UCBT patients to an ICU may be predicted by their preparative regimen, while ICU mortality may be predicted by physiologic parameters upon admission.

APACHE↗

PubMed2006

Has allogeneic stem cell cryopreservation been given the 'cold shoulder'? An analysis of the pros and cons of using frozen versus fresh stem cell products in allogeneic stem cell transplantation.

Donor stem cells for allogeneic transplant traditionally are collected and transfused 'fresh' into the recipient on the day of transplant; alternatively such cells can be collected in advance and cryopreserved until needed. Most centers favor the former approach based on theoretical concerns that cryopreservation and thawing may worsen clinical outcomes. Limited published data from single institution retrospective studies show no significant impairment of engraftment or reduced day 100 survival for cryopreserved bone marrow recipients. There are no reported outcomes for recipients of cryopreserved peripheral blood allografts. Use of cryopreserved stem cells is associated with a higher incidence of adverse events (transfusion reactions, bacterial graft contamination and collection of grafts which are not utilized). Conversely, use of cryopreserved grafts introduces a greater flexibility into a stressed healthcare system and results in a more streamlined experience for the donor. Some data suggest that transplantation with a cryopreserved product may lower the incidence of acute graft-versus-host disease. We compare the pros and cons of using 'fresh' versus cryopreserved stem cell products for allogeneic transplantation and suggest that the current standard of using 'fresh' products may not be warranted. We also suggest future areas of exploration to better elucidate this issue.

Cell Survival↗

PubMed2006

Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options.

Myeloablative sibling-matched allogeneic transplantation for adult acute lymphoblastic leukaemia provides the best outcome, but most patients lack a suitable, related histocompatible donor. We reviewed three haematopoietic stem cell donor sources used for alternative donor transplantation pointing out drawbacks of these approaches including inherent selection bias. Matched unrelated donor allografts most often are performed in Philadelphia chromosome-positive disease and in second complete remission (CR2); a nearly 30% event-free survival (EFS) can be anticipated in select patients. Transplants using haploidentical donors are most successful if undertaken in CR1 and CR2 and appear to produce EFS rates of about 25%. Limited umbilical cord blood transplant data suggest efficacy, but marked patient and treatment heterogeneity hamper conclusions. Each of these three strategies has unique potential benefits and disadvantages. The growing use of minimal residual disease detection may identify subgroups of patients unlikely to be cured by chemotherapy alone; these patients are candidates for upfront high-dose chemoradiotherapy and cellular immunotherapy. These three approaches are plagued by treatment-related mortality and relapse rates as high as 40%, but advances in technology and supportive care may make each stem cell source more feasible and efficacious.

Adult↗

PubMed2006

Reduced-intensity conditioning for acute myeloid leukemia: is this strategy correct.

Allogeneic stem cell transplantation for acute myeloid leukemia (AML) using reduced-intensity conditioning (RIC) is based on the strategy of attaining donor cell engraftment with immunosuppressive agents. This approach, which relies predominantly on donor effector cells for anti-leukemic or graft-versus-leukemia effect, is being used with increased frequency. Treatment-related mortality appears less with RIC than that observed with conventional myeloablative regimens. Available data support the fact that a myeloablative regimen is not required for successful engraftment and some patients appear to be cured of their disease. Despite the plethora of clinical reports, however, no prospective studies have been conducted that establish this procedure as the preferred option in AML. On the other hand, patients formerly excluded from a myeloablative procedure such as the 'elderly' and those with significant comorbid conditions, often may be RIC transplant candidates. By using prospective controlled clinical trials, we will determine whether these encouraging RIC data are applicable to a nonselect population of AML. The transplant community now is poised to design and complete investigations to ascertain the true role of RIC in the treatment of AML.

Acute Disease↗

PubMed2006

Lack of isohemagglutinin production following minor ABO incompatible unrelated HLA mismatched umbilical cord blood transplantation.

While immune hemolysis due to donor isohemagglutinin (IH) production often complicates minor ABO incompatible peripheral blood hematopoietic stem cell transplantation (PBSCT), it is not known if this occurs with umbilical cord blood transplantation (UCBT). We compared IH production and hemolysis following minor ABO allogeneic PBSCT and UCBT. We reviewed 24 ABO minor incompatible allogeneic PBSCTs and 14 ABO minor incompatible UCBTs. Patients were evaluated for donor-derived IH by reverse ABO grouping. Evaluation of hemolysis was based on clinical and laboratory findings of anemia associated with increased RBC transfusion need, concomitant with the appearance of donor-derived IH. Of the 24 ABO minor incompatible allogeneic PBSCTs, 15 produced donor-derived IH from 6 to 88 days following transplantation, with seven of 15 patients exhibiting clinically evident hemolysis. There was no significant difference in days to leukocyte engraftment or infused CD34 cells in patients with or without donor-derived IH. None of the 14 patients receiving ABO incompatible UCBTs showed evidence of donor-derived IH following transplantation with a median follow-up of 60 days. We conclude that donor IHs are not produced in patients undergoing minor ABO incompatible UCBTs suggesting fundamental immunologic differences between allogeneic PBSCT and UCBT.

Adolescent↗

PubMed2006

Multiple myeloma-associated AL amyloidosis: is a distinctive therapeutic approach warranted?

The natural history of multiple myeloma (MM) was revolutionized by the introduction of haematopoietic stem cell transplantation to the treatment armamentarium of this disease. Defined subgroups of MM patients (such as the elderly or dialysis-dependent) have required an individualized approach in order to minimize the transplant-related mortality. Little, however, is known about the management of 12-30% of MM patients with coexistent AL amyloidosis as the amyloidopathy is often overlooked and when recognized these patients commonly are excluded from clinical trials. While occult amyloidosis appears to have no impact on the toxicity and outcome of MM patients, the presence of symptomatic amyloidopathy clearly worsens their prognosis. Use of induction chemotherapy drugs that can cause further damage to the heart (Adriamycin), nervous system (Vincristine) or kidneys should be avoided as should lengthy delays in proceeding to autograft. Further, refining the transplant eligibility criteria for this subgroup of patients with co-existent amyloidopathy to include the number of organs involved and the degree of cardiac involvement (NYHA class, Troponins and NT-pro-BNP levels) along with melphalan dose-adjustment will minimize the treatment-related toxicity and mortality and possibly allow a reversal of the organ damage induced by the amyloidogenic light chain.

Amyloidosis↗

PubMed2006

Transfer of the hematopoietic stem cell transplant patient to the intensive care unit: does it really matter?

We critically reviewed published English language literature and concluded that from 1998 onward the survival of hematopoietic stem cell transplant (SCT) patients who experienced intensive care unit (ICU) transfer has improved. The factors associated with increased mortality during ICU stay included increased patient age, allogeneic transplant, intubation/mechanical ventilation, multiorgan system failure (MOSF), presumed/documented infection, graft-versus-host disease, and higher APACHE and O-PRISM score at ICU transfer. This encouraging outcome trend reflects evolving advances such as use of recombinant hematopoietic growth factors, use of mobilized blood cells rather than marrow, protective strategies for acute lung injury and early goal-directed therapy for sepsis syndrome. Patient selection bias (which patients were transferred and which were not sent to an ICU) also plays a role in ICU survival rates. New strategies to improve upon SCT patient outcome include use of a scoring system to predict mortality, better therapies for MOSF and integration of ICU components and multispecialist involvement earlier in the clinical course to prevent severe complications such as respiratory failure. SCT recipients comprise a heterogeneous group; to further advance this field, prospective multicenter trials involving larger populations from many centers are needed to reduce the biases of retrospective and single-center reports.

Age Factors↗

PubMed2006

Pre-mobilization therapy blood CD34+ cell count predicts the likelihood of successful hematopoietic stem cell mobilization.

We examined pre-mobilization blood CD34+ cell count to predict ability to mobilize adequate peripheral blood progenitor cells (PBPC) in 106 cancer patients and 36 allogeneic donors. Mean pre-mobilization therapy blood CD34+ cell count was 3.1 cells x 10(6)/l (s.d. = 3.9, r = 0.3-37) and mean CD34+ cells collected were 5.3 x 10(6) cells/kg/leukapheresis procedure (s.d. = 7.0, r = 0.03-53). Yields correlated with pre-mobilization CD34+ cells x 10(6)/l (r = 0.37, P-value < 0.0001); correlation was stronger in allogeneic donors (r = 0.56, P-value = 0.0004) and males (r = 0.46, P-value < 0.0001). Based on classification and regression tree multivariate analysis, the predictive value of pre-mobilization blood CD34+ cell count was confounded by other variables, including age, gender, mobilization regimen and malignancy type. We generated an algorithm to predict a minimum PBPC yield of 1 x 10(6) CD34+ cells/kg/leukapheresis procedure after mobilization. A threshold pre-mobilization blood CD34+ cell count of 2.65 cells x 10(6)/l was the most important decision point in predicting successful mobilization. Only 2% of subjects with pre-mobilization blood CD34+ cell counts > 2.65 cells x 10(6)/l did not achieve the minimum per apheresis, whereas 24% with pre-mobilization values below threshold had inadequate mobilization. Prospectively identifying individuals at risk for mobilization failure would allow for improved treatment planning, resource utilization and time saving.

Adolescent↗

PubMed2005

Immune restoration following hematopoietic stem cell transplantation: an evolving target.

Hematopoietic stem cell transplantation (HSCT) is the definitive cure for many malignant and nonmalignant diseases. However, delays in immune reconstitution (IR) following HSCT significantly limit the success of transplantation and increase the risk for infection and disease relapse in the transplant recipient. Therefore, ways to measure and to manipulate immune recovery following HSCT are emerging and their success depends directly upon an enhanced understanding for the underlying mechanisms responsible for reconstituted immunity and hematopoiesis. Recent discoveries in the activation, function, and regulation of dendritic cell (DC), natural killer (NK) cell, and T-lymphocyte subtypes have been critical in developing immunotherapies used to prevent graft-versus-host disease and to enhance graft-versus-leukemia. For example, regulatory T cells that induce tolerance and NK receptor-tumor ligand disparities that result in tumor lysis are being used to minimize GVHD and tumor burden, respectively. Furthermore, expansion and modulation of immune effector cells are being used to augment hematopoietic and immune recovery and to decrease transplant-related toxicity in the transplant recipient. Specifically, DC expansion and incorporation into antitumor and anti-microbial vaccines is fast approaching application into clinical trials. This paper will review our current understanding for IR following HSCT and the novel ways in which to restore immune function and decrease transplant-related toxicity in the transplant recipient.

Graft vs Host Disease↗

PubMed2005

Total parenteral nutrition and hematopoietic stem cell transplantation: an expensive placebo?

SUMMARY: A majority of patients undergoing hematopoietic stem cell transplantation (HSCT) suffer from severe mucositis and enteritis due to cytotoxic therapy and immune dysregulation, resulting in prolonged decreased oral intake, nausea, vomiting and diarrhea. While total parenteral nutrition (TPN) is often given to patients in order to maintain their nutritional status during the peritransplant period, there is conflicting evidence to support its routine use. We evaluated the small number of prospective randomized and nonrandomized controlled trials that assessed important clinical outcomes such as time to engraftment, rates of infection, overall survival and length of hospitalization. We believe that the data do not support the routine use of parenteral nutrition as first-line therapy but should be reserved for those patients who are unable to tolerate enteral feedings. We also believe that glutamine supplementation cannot be recommended to all HSCT recipients as it has been shown to increase morbidity and mortality rates in autologous transplant patients. Further investigations that test accurate monitoring assessments and incorporate specific substrates such as lipids with parenteral and enteral nutrition are warranted. Novel therapies such as recombinant human keratinocyte growth factor and glucagon-like peptide show future promise in modulating the severity and duration of mucositis, minimizing further the need for TPN.

Glutamine↗

PubMed2005

Comorbidity indices in hematopoietic stem cell transplantation: a new report card.

Comorbid conditions have not been studied systematically for impact upon patient outcome in the setting of hematopoietic stem cell transplantation (HSCT). Patients formerly excluded from myeloablative transplant due to comorbid illnesses now receive reduced-intensity conditioning regimens; hence, the incidence of comorbid conditions in HSCT recipients is expected to increase. Comorbid grading systems developed without regard for oncology patients have been applied in retrospective fashion to HSCT patients. Two commonly used scales (Charlson Comorbidity Index and the Adult Comorbidity Inventory-27) fail to include critical information: tumor and histologic type/stage, extent of prior treatment, donor stem cell source and cell type and preparative regimen. Further, data are reported in retrospective rather than prospective fashion. Despite limitations, however, such grading systems exhibit ease and utility for evaluation and may have predictive value for patient outcome. Modifying such approaches to include additional factors and appropriate weighting of components may enable an improved comparison of techniques and study results. These scoring systems may elucidate predictors of outcome and disease natural history and enhance statistical efficiency methods of HSCT. Refined scoring could be used effectively to assign patients to differing transplant conditioning regimens, that is, myeloablative vs reduced intensity. Prospective validation of such grading systems is encouraged.

Comorbidity↗

PubMed2005

Stem cell transplantation for mantle cell lymphoma: if, when and how?

Although the prognosis for mantle cell lymphoma (MCL) patients has improved in recent years, the outlook for those with advanced or recurrent disease remains poor. High-dose chemotherapy and autografting performed early in responding patients appears to be a method to extend progression-free survival (PFS) and overall survival (OS). The use of monoclonal antibody therapy added into the initial therapy and in the peritransplant period may improve on these results. Myeloablative allogeneic transplant appears to be a modality capable of providing curative therapy, but is plagued by a high treatment-related mortality, especially in older patients. Reduced-intensity conditioning allografting have fewer problems associated with the initial phase of transplant and hence may be preferred for those patients for whom an allograft is considered but have comorbid conditions or age issues that preclude a full allograft. Long-term results are lacking and the side effects associated with chronic GVHD may be as significant and debilitating. Trials designed to look at newly diagnosed patients with MCL examining the outcomes after planned autologous and allogeneic transplant as part of the initial management are needed to confirm the role of these various modalities in the overall therapy of this poor-outcome lymphoma.

Clinical Trials as Topic↗

PubMed2004

A multicenter phase 2 trial of stem cell transplantation for immunoglobulin light-chain amyloidosis (E4A97): an Eastern Cooperative Oncology Group Study.

Stem cell transplantation was introduced as a new therapeutic modality for amyloidosis. The purpose of the current study was to determine the feasibility and toxicity of stem cell transplantation for amyloidosis in a cooperative group setting in which most participating institutions would have limited experience in managing the disorder. A total of 30 patients with biopsy-proven amyloidosis shown to be immunoglobulin light-chain type were enrolled on this trial. The protocol required mobilization of a minimum of 6 x 10(8) mononuclear cells/kg or 5 x 10(6) CD34(+) cells/kg ideal body weight. These targets had to be achieved within seven collections. Patients with advanced hepatic, renal, or cardiac failure were excluded. End points included objective response rate and overall survival. The secondary end point of the protocol was nonhematologic toxicity. Accrual to the study was faster than expected. The overall response rate (hematologic and organ) was 64%, with three treatment-related deaths. Another patient died before day 30 of sudden cardiac death not treatment related. The median follow-up of surviving patients is 30.3 months. Median survival has not been reached. Stem cell transplantation for selected patients with amyloidosis is feasible in a cooperative group setting. A multicenter phase 3 trial of high-dose therapy is indicated.

Adult↗

PubMed2004

Transmission of donor illness by stem cell transplantation: should screening be different in older donors?

With increasing donor age, the potential of transmitting diseases from donor to recipient reaches new dimensions. Potentially transmittable diseases from donors include infections, congenital disorders, and acquired illnesses like autoimmune diseases or malignancies of hematological or nonhematological origin. While established nonmalignant or malignant diseases might be easy to discover, early-stage hematological diseases like CML, light-chain multiple myelomas, aleukemic leukemias, occult myelodysplastic syndromes and other malignant and nonmalignant diseases might not be detectable by routine screening but only by invasive, new and/or expensive diagnostic tests. In the following article, we propose recommendations for donor work-up, taking into consideration the age of the donors. In contrast to blood transfusions, stem cells from donors with abnormal findings might still be acceptable for HCT, when no other options are available and life expectancy is limited. This issue is discussed in detail in relation to the available donor and stem cell source. Finally, the recommendations presented here aim at harmonized worldwide work-up for donors to insure high standard quality.

Age Factors↗

PubMed2004

Choices aplenty: antifungal prophylaxis in hematopoietic stem cell transplant recipients.

The incidence of invasive fungal infection (IFIs) in hematopoietic stem cell transplantation (HSCT) recipients ranges from 10 to 25% with an overall case fatality rate of up to 70-90%. Candida and Aspergillus genera remain the two most common pathogens. Although fluconazole prophylaxis in this population has been moderately effective in reducing mortality due to invasive candidiasis, this agent does not have activity against invasive aspergillosis (IA) and other mould. Several new agents such as voriconazole and caspofungin have enhanced potency and broad-spectrum antifungal activity and show promising results against yeasts and filamentous fungi when given as therapy and as chemoprophylaxis. Further, new diagnostic tools to detect circulating fungal antigens in biological fluids and PCR-based methods to detect species or genus-specific DNA or RNA have been developed. Incorporating these techniques along with clinical criteria appear to improve the accuracy of preclinical diagnosis of IFIs. Such approaches may alter the current treatment strategy from prophylaxis to pre-emptive therapy, thereby potentially decreasing cost and toxicity in high-risk patients.

Antifungal Agents↗

PubMed2004

Stem cell transplantation in follicular lymphoma: progress at last?

Follicular non-Hodgkin's lymphomas usually present in advanced stage and although frequently are chemotherapy-sensitive remain incurable using conventional approaches. Treatment options are evolving rapidly and now include targeted therapies such as monoclonal antibodies. Recent studies, including the EBMTR-sponsored 'CUP Trial' (conventional Chemotherapy, Unpurged autograft, Purged autograft), demonstrate that for patients under age 60 years with recurrent chemotherapy-sensitive disease, autologous stem cell transplantation (ASCT) provides a survival benefit over conventional therapy. Allogeneic stem cell transplantation (alloSCT) has become a more effective option. Although incorporation of TBI into the preparative regimen may increase treatment-related mortality (TRM), relapses appear to be reduced compared to a chemotherapy-alone regimen. Reduced-intensity alloSCT procedures are now being performed at an increasing rate, in part due to a lower risk for TRM. Until more data are available, however, reduced-intensity alloSCT should be considered only in cases where myeloablative conditioning is contra-indicated. There are no clear means for choosing ASCT vs alloSCT, a decision influenced by the amount of residual tumor, disease-responsiveness, degree of marrow involvement and extent of prior chemotherapy. ASCT or alloSCT in first remission remains an investigational procedure. Future considerations include incorporation of novel preparative regimens, in vitro purging techniques, antilymphoma vaccines, post transplant immunotherapy and ex vivo-manipulated donor lymphocyte infusions.

Female↗

PubMed2003

Mucosal injury in patients undergoing hematopoietic progenitor cell transplantation: new approaches to prophylaxis and treatment.

Hematopoietic progenitor cell transplantation is often associated with severe mucosal toxicity. The need for parenteral analgesics and parenteral nutrition are evidence of the severity of the problem in individual patients. However, the increased risk for systemic infection related to bacteremia associated with the breakdown of mucosal barriers is a significant cause of morbidity and mortality as well. There is a multitude of grading scales, demonstrating the lack of consensus among clinicians in this area. Multiple agents have been used prophylactically and therapeutically to address mucositis. While efforts have been less successful in the past, the advent of newer agents including amifostine, keratinocyte growth factor, transforming growth factor beta and interleukin-11 provides hope that this toxicity will be significantly decreased in the near future.

Amifostine↗

PubMed2003

Clinical application of hematopoietic progenitor cell expansion: current status and future prospects.

In the past decade, we have witnessed significant advances in ex vivo hematopoietic stem cell culture expansion, progressing to the point where clinical trials are being designed and conducted. Preclinical milestone investigations provided data to enable expansion of portions of hematopoietic grafts in a clinical setting, indicating safety and feasibility of this approach. Data derived from current clinical trials indicate successful reconstitution of hematopoiesis after myeloablative chemoradiotherapy using infusion of ex vivo-expanded perfusion cultures. Future avenues of exploration will focus upon refining preclinical and clinical studies in which cocktails of available cytokines, novel molecules and sophisticated expansion systems will explore expansion of blood, marrow and umbilical cord blood cells.

Cell Culture Techniques↗