Stem Cell Transplantation For Hematologic Malignancies Research Articles

D-Index-Guided Early Antifungal Therapy Versus Empiric Antifungal Therapy for Persistent Febrile Neutropenia: A Randomized Controlled Noninferiority Trial.

Empiric antifungal therapy (EAT) is recommended for persistent febrile neutropenia (FN), but in most patients, it is associated with overtreatment. The D-index, calculated as the area surrounded by the neutrophil curve and the horizontal line at a neutrophil count of 500/μL, reflects both the duration and depth of neutropenia and enables real-time monitoring of the risk of invasive fungal infection in individual patients at no cost. We investigated a novel approach for patients with persistent FN called D-index-guided early antifungal therapy (DET), in which antifungal treatment is postponed until a D-index reaches 5,500 or the detection of positive serum or imaging tests, and compared it with EAT in this multicenter open-label noninferiority randomized controlled trial. We randomly assigned 423 patients who underwent chemotherapy or hematopoietic stem-cell transplantation for hematologic malignancies to the EAT or DET group. The prophylactic use of antifungal agents other than polyenes, echinocandins, or voriconazole was allowed. Micafungin at 150 mg per day was administered as EAT or DET. In an intent-to-treat analysis of 413 patients, the incidence of probable/proven invasive fungal infection was 2.5% in the EAT group and 0.5% in the DET group, which fulfilled the predetermined criterion of noninferiority of the DET group (-2.0%; 90% CI, -4.0% to 0.1%). The survival rate was 98.0% versus 98.6% at day 42 and 96.4% versus 96.2% at day 84. The use of micafungin was significantly reduced in the DET group (60.2% v 32.5%; P < .001). A novel strategy, DET, decreased the use and cost of antifungal agents without increasing invasive fungal infections and can be a reasonable alternative to empiric or preemptive antifungal therapy.

Thiotepa 10 mg/kg Treatment Regimen Is Superior to Thiotepa 5 mg/kg in TBF Conditioning in Patients Undergoing Allogeneic Stem-Cell Transplantation

IntroductionThe optimal intensity of myeloablation with a reduced-toxicity conditioning regimen to decrease relapse rate after allogeneic stem-cell transplantation without increasing transplant-related mortality (TRM) has not been well established. Materials and MethodsWe compared outcomes between 5 mg/kg (T5) and 10 mg/kg (T10) thiotepa-based conditioning regimens in 29 adults who underwent allogeneic stem-cell transplantation for hematologic malignancies. ResultsAfter a median follow-up of 11 months, TRM was 0% and 14% at 100 days and 1 year, respectively, with TRM observed only in the T5 group (P = .016). The relapse incidence at 1 year was 20%. No patient had disease in first complete remission at the time of transplantation. At 1 year, progression-free and overall survival were 30% versus 87% (P = .012) and 46% versus 87% (P = .008) in the T5 and T10 groups, respectively. In univariate and multivariate analysis, only age at transplantation and total dose of thiotepa had a significant impact on TRM, overall, and progression-free survival. ConclusionPatients deemed fit to receive T10-based conditioning for allogeneic stem-cell transplantation to treat high-risk hematologic malignancies had better overall and progression-free survival than those who received T5 with no additional toxicities. Patients should be stratified before conditioning, and those judged fit should receive T10, while the others should consider alternative reduced-intensity conditioning regimens.

Toxicity of iron overload and iron overload reduction in the setting of hematopoietic stem cell transplantation for hematologic malignancies

Iron is an essential element for key cellular metabolic processes. However, transfusional iron overload (IOL) may result in significant cellular toxicity. IOL occurs in transfusion dependent hematologic malignancies (HM), may lead to pathological clinical outcomes, and IOL reduction may improve outcomes. In hematopoietic stem cell transplantation (SCT) for HM, IOL may have clinical importance; endpoints examined regarding an impact of IOL and IOL reduction include transplant-related mortality, organ function, infection, relapse risk, and survival. Here we review the clinical consequences of IOL and effects of IOL reduction before, during and following SCT for HM. IOL pathophysiology is discussed as well as available tests for IOL quantification including transfusion history, serum ferritin level, transferrin saturation, hepcidin, labile plasma iron and other parameters of iron-catalyzed oxygen free radicals, and organ IOL by imaging. Data-based recommendations for IOL measurement, monitoring and reduction before, during and following SCT for HM are made.

Haploidentical Hematopoietic Stem-Cell Transplantation in Adults

Haploidentical hematopoietic stem-cell transplantation is an alternative transplant strategy for patients without an HLA-matched donor. Still, only half of patients who might benefit from transplantation are able to find an HLA-matched related or unrelated donor. Haploidentical donor is readily available for many patients in need of immediate stem-cell transplantation. Historical experience with haploidentical stem-cell transplantation has been characterised by a high rejection rate, graft-versus-host disease, and transplant-related mortality. Important advances have been made in this field during the last 20 years. Many drawbacks of haploidentical transplants such as graft failure and significant GVHD have been overcome due to the development of new extensive T cell depletion methods with mega dose stem-cell administration. However, prolonged immune deficiency and an increased relapse rate remain unresolved problems of T cell depletion. New approaches such as partial ex vivo or in vivo alloreactive T cell depletion and posttransplant cell therapy will allow to improve immune reconstitution in haploidentical transplants. Results of unmanipulated stem-cell transplantation with using ATG and combined immunosuppression in mismatched/haploidentical transplant setting are promising. This paper focuses on recent advances in haploidentical hematopoietic stem-cell transplantation for hematologic malignancies.

Impact of Delirium on Distress, Health-Related Quality of Life, and Cognition 6 Months and 1 Year after Hematopoietic Cell Transplant

Delirium commonly occurs during myeloablative hematopoietic cell transplantation (HCT). Little is known about how delirium during the acute phase of HCT affects long-term distress, health-related quality of life (HRQOL), and neurocognitive functioning. This prospective, cohort study examines these outcomes at 6 months and 1 year in 90 patients undergoing HCT. Patients completed a battery assessing distress, HRQOL, and subjective neuropsychological functioning before receiving their first HCT as well as at 6 months and 1 year. Patients with a delirium episode within the 4 weeks after HCT had significantly more distress and fatigue at 6 months (P < .004) and at 1 year (P < .03), compared with patients without delirium. At 1 year, patients with delirium also had worse symptoms of depression and post traumatic stress (P < .03). Patients with delirium had worse physical health on the SF-12 at 6 months (P < .03) and worse mental health on the SF-12 at 1 year (P < .03). At both 6 months and 1 year, patients with delirium after HCT reported worse memory (P < .009) and executive functioning (P < .006). Delirium during the acute phase of HCT is significantly associated with persistent distress, decreased HRQOL, and subjective neurocognitive dysfunction at both 6 months and 1 year.

ESMO special symposium: what is the role of high dose therapy and allografting stemcell transplantation for hematological malignancies in the era of “-nibs” and “-mabs”

ESMO special symposium: what is the role of high dose therapy and allografting stemcell transplantation for hematological malignancies in the era of “-nibs” and “-mabs”

Increased Risk of Cervical Dysplasia in Long-Term Survivors of Allogeneic Stem Cell Transplantation—Implications for Screening and HPV Vaccination

As more women survive allogeneic stem cell transplantation (SCT), the development of genital human papilloma virus (HPV)-related squamous intraepithelial lesions (SIL) warrants study. Thirty-five of 38 females followed prospectively long-term after SCT for hematological malignancies (median: 7 years posttransplant) were adults and had cervical cytology testing. Acute graft-versus-host-disease (aGVHD) occurred in 9 and chronic (cGVHD) in 34 patients. Six (17%) continued receiving systemic immunosuppressive therapy (IST) for cGVHD >3 years after SCT. Of 15 (43%) with abnormal cytology, 12 (34%) patients had HPV-related SIL (median time to SIL 51 months, range: 22-108) including high-grade SIL in 7 (20%). Patients requiring continued IST had the highest risk (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.1-16.4; P = .019). This high incidence of SIL in long-term SCT survivors underscores the importance of gynecologic assessment after transplantation, especially in those requiring IST. This may portend an increased risk of genital or other HPV-related malignancies.

The biology and therapeutic potential of natural regulatory T-cells in the bone marrow transplant setting

Graft-versus-host disease (GVHD) remains a major barrier to the long-term success of allogeneic hematopoietic stem-cell transplantation for hematologic malignancies. This has prompted a great deal of interest in the development of alternative GVHD management strategies such as the adoptive transfer of lymphocytes with immunosuppressant activity. This review will focus on the biology of thymically derived regulatory T-cells (Tregs) and their potential therapeutic role in human bone marrow transplantation. A discussion of their basic suppressive mechanisms and in vivo trafficking patterns will be presented, along with an overview of important preclinical studies using murine GVHD/tumor models. Currently available clinical data will also be discussed, including the contribution of Tregs to various transplant outcome parameters such as GVHD incidence and malignancy relapse rates.

Outcomes After Hematopoietic Stem-Cell Transplantation for Hematologic Malignancies in Patients With or Without Advance Care Planning

Engagement in advance care planning (ACP) is viewed as a way to prepare for possible death. In patients undergoing hematopoietic stem-cell transplantation (HSCT), an aggressive but possibly curative procedure for cancer, encouraging engagement in ACP is difficult. We conducted this analysis to determine if engagement in ACP among patients who undergo HSCT is associated with adverse outcomes. Adult patients who were undergoing their first HSCT for hematologic malignancies between 2001 and 2003 were included. ACP was defined as having a living will, a power of attorney for health care, or life-support instructions. Outcomes assessed included the length of hospital stay, in-hospital mortality, and overall survival. Of the 343 patients, 172 did not have ACP, whereas 171 did have ACP, and 127 of those were reviewable. Of those with reviewable ACP, 28 patients (22%) completed ACP before cancer diagnosis, 87 (68%) completed ACP after the cancer diagnosis but before HSCT, and 12 (10%) engaged in ACP after HSCT. Patients without ACP before HSCT had a significantly greater risk of death compared with patients with ACP (hazard ratio, 2.11; 95% CI, 1.34 to 3.33; P = .001) while adjusting for statistically significant factors. Our study demonstrated that lack of engagement in ACP is associated with adverse outcomes after HSCT. Thus, the patients least likely to have planned for poor outcomes are the ones most likely to face them. Additional studies should evaluate the nature of this association and should seek modifiable explanatory factors that could be the target of interventions.

Case-referent comparison of cognitive functions in patients receiving haematopoietic stem-cell transplantation for haematological malignancies: Two-year follow-up results

During bone marrow or haematopoietic stem-cell transplantation (HSCT), potentially neurotoxic treatments are used. Previous studies identified cognitive disturbances in patients treated with HSCT, but prospective studies with longitudinal assessment are sparse. We examined cognitive functions up to 20 months after a first baseline assessment in 101 patients undergoing HSCT and in 82 reference patients with a haematological malignancy treated with non-myeloablative cancer therapies. Baseline findings revealed no between-group differences and demonstrated mild cognitive impairments in both groups. Follow-up analyses showed no significant changes over time, though poorer performance in attention and executive function, and psychomotor function was found in HSCT patients. Our results suggest limited HSCT-related cognitive dysfunctions. Additional follow-up is necessary to assess long-term effects.

Case-Control Comparison of At-Home to Total Hospital Care for Autologous Stem-Cell Transplantation for Hematologic Malignancies

One of the most significant limitations of at-home autologous stem-cell transplantation (ASCT) is the necessity for hospital readmission. We developed an at-home ASCT program in which prophylactic ceftriaxone and treatment of febrile neutropenia with piperacillin and tazobactam was introduced to minimize the readmission rate. Between November 2000 and February 2005, 178 consecutive patients underwent ASCT for a hematologic malignancy. Of these, 50 patients fulfilled the requirements for at-home ASCT. Results were compared with those observed in a control group of 50 patients individually matched to the group of patients treated at home for age, sex, diagnosis, stage of disease, conditioning, and source of stem cells. Febrile neutropenia occurred in fewer patients in the at-home group as compared with the hospitalized group (76% v 96%: P = .008), and duration of fever was also shorter in the at-home group (median, 2 and 6 days, respectively; range, 1 to 11 and 1 to 20 days, respectively; P = .00003). Hospital readmission in the at-home group was required in only four cases (8%). This resulted in a reduction of 18.6 days of hospitalization per patient. Likewise, total median charges were approximately half in the at-home group as compared with the in-hospital group (3,345 euro v 6,250 euro, respectively; P < .00001). Results of at-home ASCT with prophylactic administration of ceftriaxone and domiciliary treatment of febrile neutropenia with piperacillin and tazobactam are highly satisfactory and significantly cheaper compared with those obtained with conventional in-hospital ASCT.

Factors influencing haematological recovery following high-dose chemotherapy and peripheral stem-cell transplantation for haematological malignancies: 1-year analysis

Peripheral blood counts and factors influencing haematological recovery in 98 patients with a relapse-free survival of ⩾1 year treated with high-dose chemotherapy (HDC) and peripheral stem-cell transplantation (PSCT) for haematological malignancies were analysed. One year after PSCT full haematological recovery was demonstrated for haemoglobin (Hb) in 47% of patients, for the white blood cell count (WBC) in 94%, and for platelets in 64%; 39% had a trilineage recovery. In the multivariate analysis, recovery was influenced by age (P=0.002), number of reinfused CD34+ cells (P=0.016), Hb at start of HDC (P=0.001), and platelets at start of HDC (P=0.008). One year following PSCT, 61% of patients still have subnormal values in one or more haematopoietic cell lineage, suggesting a limited bone-marrow reserve. Long-term recovery is highly dependent on age, blood counts at start of HDC and number of reinfused CD34+ cells without a threshold, all reflecting the residual function of bone marrow before HDC. Reinfusing more CD34+ cells can accelerate long-term haematological recovery.