Impact of Induction Therapy on the Outcome of Immunoglobulin Light Chain Amyloidosis after Autologous Hematopoietic Stem Cell Transplantation.

With the availability of immunomodulatory imide drugs (IMiDs) and proteasome inhibitors (PI), most patients with immunoglobulin light chain amyloidosis (AL) receive induction therapy before autologous hematopoietic stem cell transplantation (auto-HCT). In this study we evaluated the type of induction therapy and its impact on the outcome of auto-HCT in AL. We identified 128 patients with AL who underwent high-dose chemotherapy and auto-HCT at our institution between 1997 and 2013. Patients were divided into 3 groups: no induction, conventional chemotherapy (CC)-based induction (melphalan, steroids), and IMiD/PI-based induction (thalidomide, lenalidomide, or bortezomib). The hematologic response (HR) and organ response were defined according to the established criteria. Median age at auto-HCT was 58 years (range, 35 to 75). Twenty patients (15.5%) received no induction, 25 (19.5%) received CC, and 83 (65%) received IMiDs/PIs. One, 2, or 3 or more organs were involved in 90 (70%), 20 (16%), and 18 (14%) patients, respectively. After auto-HCT 12 of 20 (60%), 15 of 24 (62%), and 72 of 83 (87%) assessable patients achieved HR at 100 days in no induction, CC, and IMiD/PI groups, respectively (P = .001). Organ response at 1 year after auto-HCT was seen in 7 of 18 (39%), 14 of 24 (58%), and 37 of 79 (47%) assessable patients in no induction, CC, and IMiD/PI groups, respectively (P = .3). Achieving a hematologic complete response was associated with a significantly higher probability of achieving an organ response (P = .02). After a median follow-up of 26 months, rates of 2-year progression-free survival were 67%, 56%, and 73% in no induction, CC, and IMiD/PI groups, respectively (P = .07; hazard ratio, .5; 95% confidence interval [CI], .3 to 1.1). Rates of 2-year overall survival were 73%, 76%, and 87% in no induction, CC, and IMiD/PI groups, respectively (P = .05; hazard ratio, .4; 95% CI, .2 to .9). On multivariate analysis a low ß2-microglobulin (P = .01; hazard ratio, .3; 95% CI, .1 to .7) and induction therapy with IMiD/PI (P = .01; hazard ratio, .3; 95% CI, .1 to .7) were associated with a better overall survival. Induction therapy with either CC or IMiDs/PIs is safe and feasible in selected patients with AL. IMiD/PI-based induction is associated with a longer overall survival compared with patients who received no induction or CC before auto-HCT.

Poor immune reconstitution is associated with symptomatic BK polyomavirus viruria in allogeneic stem cell transplant recipients.

BACKGROUND: BK polyomavirus (BKPyV) infections are known indicators of immune suppression in hematopoietic stem cell transplant (HSCT) recipients; they can lead to hemorrhagic cystitis, ureteral stenosis, renal dysfunction, and prolonged hospital stays. In this study, we determined transplant-associated variables and immune parameters that can predict for the risk of BKPyV viruria. We hypothesized that BKPyV infection is a marker of poor immune recovery. METHODS: We analyzed all engrafted patients undergoing first allogeneic HSCT at MD Anderson Cancer Center in Houston between January 2004 and December 2012. We evaluated their immune parameters and their transplant-associated factors. BKPyV positivity was defined as BKPyV detection in urine by polymerase chain reaction testing. Cox proportional hazards model, as well as competing risk analysis method using subdistribution hazard models with death as competing risk, were applied to assess risk of BKPyV viruria. RESULTS: We identified a total of 2477 patients with a median age of 52 years. BKPyV viruria was manifest in 25% (n=629) of the patients. The median time from transplantation to BKPyV viruria development was 42 days among the patients who had BKPyV viruria. On multivariate analysis, tumor type, acute GVHD, chronic GVHD, myeloablative conditioning regimen, cord blood as the graft source, CD3+ , CD4+ , CD8+ , CD56+ , NK counts, and low platelet count were shown to be significantly associated with BKPyV infection. These finding were further confirmed when models incorporating the competing risk of death yielded similar findings. CONCLUSION: In this study, we report significant associations between BKPyV reactivation following allogeneic HSCT and suppressed immune variables. In addition, this study provides valuable information on the immune status of HSCT recipients as a predictor of BKPyV infections that may in turn help us formulate plans for more effective prevention and treatment of this infection.

Outcome of Patients with Immunoglobulin Light-Chain Amyloidosis with Lung, Liver, Gastrointestinal, Neurologic, and Soft Tissue Involvement after Autologous Hematopoietic Stem Cell Transplantation.

There is limited information on the outcome when organs other than heart or kidneys are involved by immunoglobulin light-chain amyloidosis (AL). We report the outcome of 53 patients with AL with gastrointestinal (GI), peripheral nerve (PN), liver, lung, or soft-tissue involvement, who underwent high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HCT) at our institution between 1997 and 2013. The median age at auto-HCT was 56 years (range, 35 to 74). One, 2, 3, or 4 organs were involved in 43%, 22%, 28%, and 4% of patients, respectively. Concurrent cardiac, renal, or both were involved in 24 (45%) patients. Forty-six patients received induction therapy before auto-HCT. The 100-day and 1-year treatment-related mortality (TRM) were 3.8% (n = 2) and 7.5% (n = 4), respectively. Forty-one (80%) patients achieved a hematologic response. Organ response at 1 year after auto-HCT was seen in 23 (57%) of the 40 evaluable patients. With a median follow-up of 24 months, the median progression-free survival and overall survival (OS) were 36 and 73 months, respectively. Auto-HCT was associated with a low TRM, durable organ responses, and a median OS of > 6 years in selected patients with AL and GI, PN, liver, lung, or soft-tissue involvement.

General and Virus-Specific Immune Cell Reconstitution after Double Cord Blood Transplantation.

Cord blood transplantation (CBT) is curative for many patients with hematologic malignancies but is associated with delayed immune recovery and an increased risk of viral infections compared with HLA-matched bone marrow or peripheral blood progenitor cell transplantation. In this study we evaluated the significance of lymphocyte recovery in 125 consecutive patients with hematologic malignancies who underwent double-unit CBT (DUCBT) with an antithymocyte globulin-containing regimen at our institution. A subset of 65 patients was prospectively evaluated for recovery of T, natural killer (NK), and B cells, and in 46 patients we also examined viral-specific T cell recovery against adenovirus, Epstein-Barr virus, cytomegalovirus, BK virus, respiratory syncytial virus, and influenza antigen. Our results indicate that in recipients of DUCBT, the day 30 absolute lymphocyte count is highly predictive of nonrelapse mortality and overall survival. Immune recovery post-DUCBT was characterized by prolonged CD8+ and CD4+ T lymphopenia associated with preferential expansion of B and NK cells. We also observed profound delays in quantitative and functional recovery of viral-specific CD4+ and CD8+ T cell responses for the first year post-CBT. Taken together, our data support efforts aimed at optimizing viral-specific T cell recovery to improve outcomes post-CBT.

Impact of ß-globin mutations on outcome of matched related donor hematopoietic stem cell transplantation for patients with ß-thalassemia major.

The clinical outcome of hematopoietic stem cell transplantation (HSCT) for patients with ß-thalassemia major (ß-TM) can be affected by several factors. We investigated the influence of ß-globin gene mutation in patients with ß-TM on the clinical outcome of HSCT and conducted a prospective study of consecutive ß-TM patients who underwent allogeneic HSCT at our center. Among 87 included patients, 62 (71%) had homozygous and 25 (29%) had compound heterozygous ß-globin gene mutations. Intervening sequence II-1 appeared to be the most common mutation, with an occurrence rate of 33% in ß-globin alleles. With a median follow-up of 12 months, the thalassemia-free survival and overall survival probabilities were 83% (standard error, 4%) and 90% (standard error, 3%), respectively. Overall survival was not found to be associated with the ß-globin gene mutation status, but thalassemia-free survival was significantly improved in patients with homozygous mutations compared with patients with compound heterozygous mutations in univariate (91.2% versus 64.0%, P = .009) and multivariable (hazard ratio, 3.83; P = .014) analyses. This is the first report on the impact of ß-globin mutation status on the outcome of ß-TM after allogeneic HSCT and helps to better illustrate the course and prognosis of ß-TM after transplantation.

Central nervous system relapse in adults with acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation.

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.

Similar transplantation outcomes for acute myeloid leukemia and myelodysplastic syndrome patients with haploidentical versus 10/10 human leukocyte antigen-matched unrelated and related donors.

Allogeneic stem cell transplantation for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) has been performed primarily with an HLA-matched donor. Outcomes of haploidentical transplantation have recently improved, and a comparison between donor sources in a uniform cohort of patients has not been performed. We evaluated outcomes of 227 patients with AML/MDS treated with melphalan-based conditioning. Donors were matched related (MRD) (n = 87, 38%), matched unrelated (MUD) (n = 108, 48%), or haploidentical (n = 32, 14%). No significant differences were found between haploidentical and MUD transplantation outcomes; however, there was a trend for improved outcomes in the MRD group, with 3-year progression-free survival for patients in remission of 57%, 45%, and 41% for MRD, MUD, and haploidentical recipients, respectively (P = .417). Recovery of T cell subsets was similar for all groups. These results suggest that haploidentical donors can safely extend transplantation for AML/MDS patients without an HLA-matched donor. Prospective studies comparing haploidentical and MUD transplantation are warranted.

Outcomes of adults with acute lymphoblastic leukemia relapsing after allogeneic hematopoietic stem cell transplantation.

For patients with acute lymphoblastic leukemia (ALL) who relapse after allogeneic hematopoietic stem cell transplantation (HSCT), treatment options are limited, and the clinical course and prognostic factors affecting outcome have not been well characterized. We retrospectively analyzed outcomes of 123 adult patients with ALL who relapsed after a first HSCT performed at our center between 1993 and 2011. First-line salvage included second HSCT (n = 19), donor lymphocyte infusion with or without prior chemotherapy (n = 11), radiation therapy (n = 6), cytoreductive chemotherapy (n = 30), mild chemotherapy (n = 27), or palliative care (n = 23), with median postrelapse overall survival (OS) of 10 months, 6.5 months, 3 months, 4 months, 4 months, and 1 month, respectively. Despite a complete remission rate of 38% after first-line salvage in the treated patients, the OS rate remained limited with 1- and 2- year OS rates of 17% (95% confidence interval, 13 to 29) and 10% (95% confidence interval, 6 to 20), respectively. On univariate analysis, adverse factors for OS included active disease at the time of first HSCT and short time to progression from first HSCT (<6 months). There was no difference in the 6-month survival postrelapse in patients with isolated extramedullary relapse (44%) compared with combined extramedullary and bone marrow relapse (29%) or those with isolated bone marrow relapse (34%) (P = .8). Our data provide more insight into the disease behavior and treatment outcomes of ALL at relapse after HSCT against which future trials may be compared.

Successful fludarabine-based hematopoietic stem cell transplantation in a pediatric patient with idiopathic CD4+ lymphocytopenia.

Idiopathic CD4+ lymphocytopenia (ICL) is a rare immunodeficiency disease with severe CD4 T-cell depletion, leading to serious opportunistic infections. The optimal treatment of ICL has not been determined, especially in severe form of the disease. Here, we report an eight-yr-old girl with ICL who was successfully treated with fludarabine-based conditioning HSCT. To the best of our knowledge, this is the first pediatric ICL case that was treated by HSCT. Allogeneic HSCT with a reduced intensity condition (RIC) regimen may be a feasible and curative treatment option in ICL patients with recurrent life-threatening complications.

Non-TBI hematopoietic stem cell transplantation in pediatric AML patients: a single-center experience.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) has been established as a promising treatment in acute myeloid leukaemia (AML). Several studies have been performed to minimize the toxicity of HSCT in children without impairing the efficacy. We report our long-term results of HSCT in pediatric AML patients using non-total body irradiation conditioning regimen. PROCEDURE: From May 1991 to June 2010, 133 pediatric patients with AML (age<15 y) who were referred to our institute underwent autologous (auto-) or allogeneic (allo-) HSCT. The conditioning regimen consisted of oral busulfan plus etoposide in auto-HSCT patients and oral busulfan plus cyclophosphamide in allo-HSCT patients. RESULTS: Overall survival (OS), leukemia-free survival (LFS), probability of relapse, and transplantation-related mortality at 3 years were 67.6%, 62.2.5%, 27.3%, and 10.1%, respectively. There was no significant difference between allo-HSCT and auto-HSCT groups. In multivariable analysis using Cox proportional hazards regression model, male sex was associated with significantly improved OS (P<0.001) and LFS (P=0.022). An age ≤3 years was associated with higher relapse (P=0.034) and worse OS (P=0.001) and LFS (P=0.014). CONCLUSIONS: The role of allo-HSCT in pediatric AML patients in first complete remission is uncertain. Further randomized studies are recommended to clarify the optimal postremission therapy in these patients.

Effects of zinc supplementation on antioxidant status and lipid peroxidation in hemodialysis patients.

OBJECTIVES: This study was designed to determine the effects of zinc supplementation on oxidative stress in hemodialysis (HD) patients through evaluating total antioxidant capacity (TAC), whole blood glutathione peroxidase (GSH) level, superoxide dismutase (SOD) activity, and malondialdehyde (MDA) level. DESIGN AND SETTING: Double-blinded randomized controlled trialfrom October 2006 to December 2007 at Tabriz Imam Khomeini Hospital. SUBJECTS: Sixty-five HD patients were randomly enrolled into 2 groups. INTERVENTION: Patients received placebo in group A and zinc (100 mg/day) in group B for 2 months. After a washout period for 2 months, the groups were crossed over and the study was continued for an additional 2 months. MAIN OUTCOME MEASURES: Serum zinc concentration was measured using atomic absorption spectrophotometry. TAC, GSH level, and SOD activity were determined by commercial enzyme-linked immunosorbent assay kits. MDA level was measured using a thiobarbituric acid method. RESULTS: The levels of serum zinc, TAC, GSH (P < .001 for all), and SOD activity (P < .001 for group A and P = .003 for group B) significantly increased after zinc supplementation whereas the serum level of MDA decreased after the same period (P = .003 for group A and P < .001 for group B). CONCLUSIONS: Zinc supplementation for 2 months improved the serum levels of zinc, antioxidant status, and lipid peroxidation in HD patients.

Adaptive therapy to circumvent drug resistance to tyrosine kinase inhibitors in cancer: is it clinically relevant?

INTRODUCTION: Cancer is highly adaptable and is constantly evolving against current targeted therapies such as tyrosine kinase inhibitors. Despite advances in recent decades, the emergence of drug resistance to tyrosine kinase inhibitors constantly hampers therapeutic efficacy of cancer treatment. Continuous therapy versus intermittent clinical regimen has been a debate in drug administration of cancer patients. An ecologically-inspired shift in cancer treatment known as 'adaptive therapy' intends to improve the drug administration of drugs to cancer patients that can delay emergence of drug resistance. AREAS COVERED: We discuss improved understanding of the concept of drug resistance, the basis of continuous therapy, intermittent clinical regimens, and adaptive therapy will be reviewed. In addition, we discuss how adaptive therapy provides guidance for future cancer treatment. EXPERT OPINION: The current understanding of drug resistance in cancer leads to poor prognosis and limited treatment options in patients. Fighting drug resistance mutants is constantly followed by new forms of resistance. In most reported cases, continuous therapy leads to drug resistance and an intermittent clinical regimen vaguely delays it. However, adaptive therapy, conceptually, exploits multiple parameters that can suppress the growth of drug resistance and provides safe treatment for cancer patients in the future.

Computed tomography-guided stereotactic biopsy of intracranial lesions in pediatric patients.

PURPOSE: The primary objective of this study was to report the results of author's 18-year experience of diagnostic stereotactic biopsy procedures in children with intracranial lesions. METHODS AND MATERIALS: A retrospective analysis was conducted on stereotactic procedures performed on children with brain tumor between 1989 and 2007. RESULTS: Stereotactic biopsy of intracranial tumors was performed in 172 children (69 girls, and 103 boys) with the mean age of 9.17 ± 3.66 years at the time of diagnosis. The most frequent anatomical location of lesions was brainstem (45.9%). Glioma was the most common diagnosis, represented in 90.7% of patients (156 patients). Other diagnosed tumors (4.7%) were classified as metastatic (1.7%), lymphomas (1.2%), oligodendroglioma (0.6%), craniopharyngioma (0.6%), and pineocytoma (0.6%). Nonneoplastic lesions were revealed in 4.7% of patients. CONCLUSION: The most frequent brain pathology of children is glioma, but the incidence of brain lesions other than gliomas and the frequency of brain lesions in the inoperable areas are compelling reasons to establish tissue diagnosis.

Relation between serum magnesium level and migraine attacks.

OBJECTIVE: The determination of serum magnesium levels in migraine. METHODS: In a case control study performed between January 2007 and December 2007 at Tabriz University of Medical Sciences, Tabriz, Iran, 140 migraine patients were enrolled and their level of serum magnesium was determined and the results were compared with 140 healthy people who did not have any headache, kidney, or gastrointestinal disorders, and no consumption of magnesium complements. RESULTS: Migraine patients (22 male, 118 female) with a mean age of 33.82+/-10.31 and 140 healthy people (26 male, 114 female) with a mean age of (34.19+/-9.95) were enrolled. Forty patients had aura and 100 patients did not have aura. The average serum magnesium level in the patient group (26.14+/-4.3) was significantly lower than the control (31.09+/-4.32) group (p=0.000). There was no significant difference between the mean level of serum magnesium in patients with migraine with aura and without aura, however, there was a significant linear relationship between the amount of serum magnesium and the frequency of headache. CONCLUSION: Serum magnesium in migraine patients was significantly lower than the normal population and related to the frequency of migraine attacks, supporting the use of magnesium in prevention and treatment of migraine.

HLA-DP mismatch and CMV reactivation increase risk of aGVHD independently in recipients of allogeneic stem cell transplant.

HLA-DP mismatched allogeneic hematopoietic stem cell transplantation (allo-HCT) is associated with increased risk of aGVHD and decreased risk of relapse with no effects on overall survival (OS). It has been proposed that CMV-reactivation induces expression of HLA-DP molecules on GVHD target tissues by releasing inflammatory cytokines. We hypothesized that the increased GVHD incidence in HLA-DP mismatched allo-SCTs correlates with recipient CMV serostatus or CMV reactivation. In addition, CMV reactivation is associated with increased risk of GVHD with an unknown mechanism. Here, we analyzed the association between HLA-DPB1 and CMV reactivation on cumulative incidence of aGVHD and relapse as well as OS in 613 patients with AML and MDS who underwent matched related or unrelated allo-HCT at MD Anderson Cancer Center from 2005 to 2011. In multivariable analysis, HLA-DPB1 mismatching was associated with increased risk of aGVHD (hazard ratio (HR): 1.53, P < 0.001) independent of CMV serostatus and CMV reactivation. Additionally, HLA-DPB1 mismatching was associated with decreased risk of relapse and no effect on OS. CMV reactivation increased risks of aGVHD (HR: 5.82, P < 0.001) independent of HLA-DP mismatching with no effect on relapse or OS. In conclusion, our data suggests that HLA-DPB1 mismatching and CMV reactivation increase risk of aGVHD independently.

Acid-base disturbances in acute poisoning and their association with survival.

PURPOSE: The purpose was to investigate the association between acid-base disturbances and mortality in acute poisoning. MATERIALS AND METHODS: We performed a retrospective cross-sectional exploratory study on all acutely poisoned patients older than 12 years who had been admitted to the main tertiary toxicology hospital in Tehran between March and August 2010. RESULTS: Of a total of 1167 patients (median age=25 years, 50.9% male), 98 died (74.5% male). Psychotropic medications were the most common cause of poisoning (36.5%), whereas narcotics and psychodysleptics were the most common cause of death (23.5%). Mixed respiratory alkalosis and metabolic acidosis with normal pH were the most common acid-base status (333, 28.5%). However, patients with primary metabolic acidosis and respiratory compensation had significantly higher mortality (31 cases, 18.8%). Logistic regression analysis identified age (odds ratio [OR], 1.051; 95% confidence interval [CI], 1.031-1.070; P<.001), intensive care unit admission (OR, 12.405; 95% CI, 7.178-21.440; P<.001), consciousness level (OR, 1.752; 95% CI, 1.301-2.359; P<.001), hospitalization period (OR, 1.1361; 95% CI, 1.079-1.195; P<.001), severe metabolic acidosis (OR, 6.016; 95% CI, 1.647-21.968; P=.007), and primary respiratory alkalosis (OR, 5.579; 95% CI, 1.353-23.001; P=.017) as death predictors during hospitalization (P<.001). CONCLUSION: On-arrival acid-base status predicts survival and can be used in prognostication of the poisoned patients.

Systemic juvenile xanthogranuloma with multiple central nervous system lesions.

Juvenile xanthogranulomatosis (JXG) is an uncommon histiocytic disorder that is usually benign and limited to the skin. The systemic form of JXG is rare and may be associated with severe morbidity and mortality especially in central nervous system (CNS) involvement. Here, we describe a six-year-old boy with disseminated skin lesions and neurological signs and symptoms. Diagnostic work up revealed multiple brain lesions. A skin biopsy and a stereotactic brain biopsy considered suggestive of systemic JXG. Treatment with prednisolone, vinblastine and methotrexate was successful with regression of skin and CNS lesions. The patient has been in remission for almost three years.

On-versus Off-Pump Coronary Artery Bypass Grafting: No Difference in Early Postoperative Kidney Function Based on TNF-α or C-Reactive Protein.

BACKGROUND/AIMS: There are controversial data about renal function following off-pump coronary artery bypass grafting (CABG). The present study aimed to evaluate renal function changes 24 h after on- and off-pump CABG, as well as renal function correlated with high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α). METHODS: Ninety patients with coronary artery disease referred to our center for CABG from July 2006 to November 2007 were enrolled in the study. Patients were equally and randomly divided in two groups, on- and off-pump. Serum levels of creatinine (Cr), blood urea nitrogen, creatinine clearance (CrCl), hs-CRP, and TNF-α were determined immediately before and 24 h after surgery. RESULTS: Cr and CrCl changes after surgery were not significantly different between the two groups; however, blood urea nitrogen levels after surgery were significantly higher in the on-pump group (p = 0.035). No statistically significant difference was noted between the two groups in terms of changes in levels of hs-CRP and TNF-α (p = 0.350 and 0.805, respectively). The changes in CrCl levels had no significant correlation with hs-CRP and TNF-α. CONCLUSIONS: The early Cr and CrCl levels after surgery are not significantly different in on- and off-pump groups. The early renal function after on- or off-pump CABG is not correlated with the levels of inflammatory markers including hs-CRP and TNF-α.