Temporal Discordance Between Graft-versus-leukemia and Graft-versus-host Responses: a Strategy for the Separation of Graft-versus-leukemia/graft-versus-host Reactivity?

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Nov, 2004  |  Pubmed ID: 15505605

The graft-versus-leukemia (GVL) effect is often coexpressed with graft-versus-host disease (GVHD), although the temporal kinetics of these responses have not been critically examined. To evaluate this question in the absence of the confounding effects of the conditioning regimen, 23 patients who received donor lymphocyte infusions from HLA-identical siblings and subsequently developed GVHD and/or a GVL response were studied to determine whether these were temporally synchronous events. The GVL effect occurred significantly earlier than GVHD, being that 19 of 23 patients had a sustained GVL response that antedated the onset of clinical GVHD. The median difference between time to GVL and graft-versus-host (GVH) reactivity in the entire cohort was 14 days. There was no correlation between total T-cell dose and the relative onset of GVL versus GVH reactivity, indicating that temporal dissociation of GVL and GVH responses was not a function of the absolute number of infused donor T cells. These data support existing murine bone marrow transplantation studies indicating that GVL and GVH responses are not temporally synchronous events and raise the possibility that targeted elimination of alloreactive donor T cells after bone marrow transplantation may be an effective strategy for the separation of GVL/GVH reactivity.

Autologous or Allogeneic Stem Cell Transplantation in Patients with Waldenstrom's Macroglobulinemia

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Aug, 2006  |  Pubmed ID: 16864055

The role of hematopoietic stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. To determine the potential for long-term disease control using SCT in WM, we performed a retrospective review of 36 patients with WM who received autologous (n = 10) or allogeneic (n = 26) SCT and were reported to the Center for International Blood and Marrow Transplant Research between 1986 and 2002. The following outcomes were described: nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and overall survival (OS). Median age at the time of SCT was 51 years (range, 30-76 years), and median time from initial treatment to SCT was 29 months (range, 2-198 months). A total of 78% of the patients had 2 or more previous chemotherapy regimens, and 52% had disease resistant to salvage chemotherapy. In the allogeneic SCT group, 58% of the patients received myeloablative conditioning regimens containing total body irradiation (TBI), and of the allograft recipients, 19% received nonmyeloablative/reduced-intensity conditioning. After a median follow-up of 65 months, 15 of the 36 patients (42%) are alive. Primary disease accounted for 29% of the deaths in the allogeneic SCT group and 25% of the deaths in the autologous SCT group. The relapse rate at 3 years was 29% (95% confidence interval [CI], 14%-48%) in the allogeneic group and 24% (95% CI, 4%-54%) in the autologous group. PFS at 3 years was 31% (95% CI, 14%-50%) in the allogeneic group and 65% (95% CI, 32%-91%) in the autologous group; OS was 46% (95% CI, 27%-65%) in the allogeneic group and 70% (95% CI, 40%-93%) in the autologous group. NRM at 3 years was 40% (95% CI, 23%-59%) in the allogeneic group and 11% (95% CI, 0-36%) in the autologous group. Autologous SCT is a safe and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Allogeneic SCT carries a much higher (40%) risk of NRM and should not be considered outside the context of a clinical trial.

New Questions About Transplantation in Multiple Myeloma

Oncology (Williston Park, N.Y.). Sep, 2006  |  Pubmed ID: 17024872

Multiple myeloma is now the most common indication for autologous stem cell transplantation (ASCT) in North America, with over 5,000 transplants performed yearly (Center for International Blood and Marrow Transplant Research [CIBMTR] data). While the role of ASCT as initial therapy in multiple myeloma has been established by randomized studies, newer therapies are challenging the traditional paradigm. The availability of novel induction agents and newer risk stratification tools, and the increasing recognition of durability of remissions are changing the treatment paradigm. However, even with arduous therapy designed to produce more complete remissions-for example, tandem autologous transplants-we have seen no plateau in survival curves. A tandem autologous procedure followed by maintenance therapy may be performed in an attempt to sustain remission. Sequential autologous transplants followed by nonmyeloablative allotransplants are pursued with the hope of "curing" multiple myeloma. We examine how the key challenges of increasing the response rates and maintaining responses are being addressed using more effective induction and/or consolidation treatments and the need for maintenance therapies after ASCT. We argue that given the biologic heterogeneity of multiple myeloma, risk-adapted transplant approaches are warranted. While the role of curative-intent, dose-intense toxic therapy is still controversial, conventional myeloablative allogeneic transplants need to be reexamined as an option in high-risk aggressive myeloma, given improvements in supportive care and transplant-related mortality.

NF-kappaB As a Target for the Prevention of Graft-versus-host Disease: Comparative Efficacy of Bortezomib and PS-1145

Blood. Jan, 2006  |  Pubmed ID: 16174760

NF-kappaB is a transcription factor that controls the expression of a number of genes important for mediating immune and inflammatory responses. In this study, we examined whether bortezomib and PS-1145, each of which inhibits NF-kappaB, could protect mice from lethal graft-versus-host disease (GVHD), which is characterized by immune activation and proinflammatory cytokine production. When administered within the first 2 days after transplantation, bortezomib and PS-1145 both protected mice from fatal GVHD, did not compromise donor engraftment, and effected marked reduction in the levels of serum cytokines that are normally increased during GVHD. Extending the course of bortezomib administration or delaying the initiation of this agent for as few as 3 days after bone marrow transplantation (BMT), however, significantly exacerbated GVHD-dependent mortality because of severe pathological damage in the colon. In contrast, prolonged administration of PS-1145, which, unlike bortezomib, is a selective inhibitor of NF-kappaB, caused no early toxicity and resulted in more complete protection than that observed with an abbreviated PS-1145 treatment schedule. These results confirm a critical role for NF-kappaB in the pathophysiology of GVHD and indicate that targeted inhibition of NF-kappaB may have a superior therapeutic index and may constitute a viable therapeutic approach to reduce GVHD severity.

Reversible Posterior Leukoencephalopathy Syndrome and Bevacizumab

The New England Journal of Medicine. Mar, 2006  |  Pubmed ID: 16514715

Suppressive Anti-HCV Therapy for Prevention of Donor to Recipient Transmission in Stem Cell Transplantation

The American Journal of Gastroenterology. Feb, 2007  |  Pubmed ID: 17100972

A 48-yr-old man with acute myeloid leukemia (AML) required urgent allogeneic hematopoietic stem cell transplantation because of failed attempts to induce remission via chemotherapy. He had an HLA identical donor sister who was hepatitis C virus (HCV) RNA positive. In order to prevent HCV transmission to her brother, the donor was treated with weekly injections of pegylated interferon alfa-2b (150 mug subcutaneously every week) and daily ribavirin (1 g/day) for 5 wk at which time her qualitative polymerase chain reaction (PCR) was negative. Her stem cells were successfully grafted into the recipient. The recipient remained HCV PCR negative after transplant until death from relapsed AML.

Multiple Myeloma: Charging Toward a Bright Future

CA: a Cancer Journal for Clinicians. Sep-Oct, 2007  |  Pubmed ID: 17855486

Multiple myeloma (MM) is an incurable clonal B-cell malignancy with terminally differentiated plasma cells. It afflicts approximately 55,000 people in the United States. Over the past 5 years, significant progress has been made in the diagnosis and assessment of patients with MM. Significant advances include a simplified staging system, which has replaced the more cumbersome Durie-Salmon staging system; an updated uniform international response criteria; the development of a sensitive new serum test to detect free light chain production (free light chain assay); the recognition of specific adverse cytogenetic abnormalities; and the evolution of genomics, which will identify specific and targeted therapies for individual MM patients. For the first time in decades, major therapeutic advances have been implemented in the treatment of MM patients. These include 2 new classes of agent: immunomodulatory drugs and proteosome inhibitors. In addition, clinical trials have solidified the role of hematopoietic stem cell transplant and established the benefits of post-transplant maintenance therapy. Finally, a number of new agents are in development that specifically target the myeloma cells and/or the bone marrow microenvironment. These advances have resulted in expanded treatment options, prolonged disease control and survival, and improved quality of life for patients with MM.

Allogeneic Transplants in Follicular Lymphoma: Higher Risk of Disease Progression After Reduced-intensity Compared to Myeloablative Conditioning

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Feb, 2008  |  Pubmed ID: 18215784

Reduced-intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for FL in 208 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N = 120) or RIC (N = 88). Use of RIC regimens increased from <10% of transplants in 1997 to >80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 months (4-96 months) after myeloablative conditioning versus 35 months (4-82 months) after RIC (P < .001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63%-79%) and 62 (51%-72%; P = .15) and progression free survival (PFS), 67 (58%-75%) and 55 (44%-65%; P = .07), respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment-related mortality (TRM) and lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (relative risk = 2.97, P = .04). RIC has become the de facto standard in allogeneic HSCT for FL, and appears to result in similar long-term outcomes. Although disease-free survival (DPS) is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.

Second Autologous Stem Cell Transplantation for Relapsed Lymphoma After a Prior Autologous Transplant

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Aug, 2008  |  Pubmed ID: 18640574

We determined treatment-related mortality, progression-free survival (PFS), and overall survival (OS) after a second autologous HCT (HCT2) for patients with lymphoma relapse after a prior HCT (HCT1). Outcomes for patients with either Hodgkin lymphoma (HL, n = 21) or non-Hodgkin lymphoma (NHL, n = 19) receiving HCT2 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) were analyzed. The median age at HCT2 was 38 years (range: 16-61) and 22 (58%) patients had a Karnofsky performance score <90. HCT2 was performed >1 year after HCT1 in 82%. The probability of treatment-related mortality at day 100 was 11% (95% confidence interval [CI], 3%-22%). The 1-, 3-, and 5-year probabilities of PFS were 50% (95% CI, 34%-66%), 36% (95% CI, 21%-52%), and 30% (95% CI, 16%-46%), respectively. Corresponding probabilities of survival were 65% (95% CI, 50%-79%), 36% (95% CI, 22%-52%), and 30% (95% CI, 17%-46%), respectively. At a median follow-up of 72 months (range: 12-124 months) after HCT2, 29 patients (73%) have died, 18 (62%) secondary to relapsed lymphoma. The outcomes of patients with HL and NHL were similar. In summary, this series represents the largest reported group of patients with relapsed lymphomas undergoing SCT2 following failed SCT1, and with long-term follow-up. Our series suggests that SCT2 is feasible in patients relapsing after prior HCT1, with a lower treatment-related mortality than that reported for allogeneic transplant in this setting. HCT2 should be considered for patients with relapsed HL or NHL after HCT1 without alternative allogeneic stem cell transplant options.

Intraventricular Dyssynchrony in Light Chain Amyloidosis: a New Mechanism of Systolic Dysfunction Assessed by 3-dimensional Echocardiography

Cardiovascular Ultrasound. 2008  |  Pubmed ID: 18687125

Light chain amyloidosis (AL) is a rare but often fatal disease due to intractable heart failure. Amyloid deposition leads to diastolic dysfunction and often preserved ejection fraction. We hypothesize that AL is associated with regional systolic dyssynchrony. The aim is to compare left ventricular (LV) regional synchrony in AL subjects versus healthy controls using 16-segment dyssynchrony index measured from 3-dimension-al (3D) echocardiography.

Nonmyeloablative Conditioning for Relapsed Follicular Lymphoma

Blood. Sep, 2008  |  Pubmed ID: 18779408

Comparison of Twin and Autologous Transplants for Multiple Myeloma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2008  |  Pubmed ID: 18804041

Relapse is the overwhelming cause of treatment failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on posttransplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically identical twins versus autotransplants because confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Multivariate analysis was performed by fitting a Cox model stratified on matched pairs. The matched transplant patients studied were similar with respect to subject-, disease-, and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower, and progression-free survival (PFS) was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk [RR] = 0.49, 95% confidence interval [CI] 0.28-0.86, P = .011). Twin transplants have a significantly lower relapse risk than autotransplants in MM, suggesting that graft composition may impact outcomes following high-dose chemotherapy.

Comparable Outcomes in Nonsecretory and Secretory Multiple Myeloma After Autologous Stem Cell Transplantation

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Oct, 2008  |  Pubmed ID: 18804043

Nonsecretory myeloma (NSM) accounts for <5% of cases of multiple myeloma (MM). The outcome of these patients following autologous stem cell transplantation (ASCT) has not been evaluated in clinical trials. We compared the outcomes after ASCT for patients with NSM reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1989 and 2003, to a matched group of 438 patients (4 controls for each patient) with secretory myeloma (SM). The patients were matched using propensity scores calculated using age, Durie-Salmon stage, sensitivity to pretransplant therapy, time from diagnosis to transplant, and year of transplant. Disease characteristics were similar in both groups at diagnosis and at transplant except higher risk of anemia, hypoalbuminemia, and marrow plasmacytosis (in SM) and plasmacytoma (more in NSM). Cumulative incidence of treatment-related mortality (TRM), relapse, progression-free survival (PFS), and overall survival (OS) were similar between the groups. In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. In this large cohort of patients undergoing ASCT, we found no difference in outcomes of patients with NSM compared to those with SM.

Long-term Outcome of Patients with Multiple Myeloma After Autologous Hematopoietic Cell Transplantation and Nonmyeloablative Allografting

Blood. Apr, 2009  |  Pubmed ID: 19015394

Autologous hematopoietic cell transplantation (HCT) followed by nonmyeloablative allogeneic HCT (auto/alloHCT) provides cytoreduction and graft-versus-myeloma effects. We report on long-term outcomes of 102 patients with multiple myeloma who received auto/alloHCT with a median follow-up of 6.3 years. Treatment consisted of high-dose melphalan and autograft followed by 2-Gy total body irradiation, with or without fludarabine, and alloHCT from human leukocyte antigen-identical siblings. Postgrafting immunosuppressive agent was cyclosporine or tacrolimus and mycophenolate mofetil. Forty-two percent of patients developed grade 2 to 4 acute graft-versus-host disease (GVHD) and 74% extensive chronic GVHD. Five-year nonrelapse mortality after allografting was 18%, 95% related to GVHD or infections. Among 95 patients with detectable disease, 59 achieved complete remissions. Median time to progression was 5 years. Median overall survival (OS) was not reached. Median progression-free survival (PFS) was 3 years. Five-year OS and PFS were 64% and 36%, respectively. Seventy-three patients receiving autoHCT within 10 months from treatment initiation had 5-year OS of 69% and PFS of 37%. In multivariate analysis, beta-2-microglobulin of more than 3.5 microg/mL at diagnosis and auto/alloHCT more than 10 months after treatment initiation correlated with shorter OS (P = .03 and P = .02) and PFS (P = .04 and P = .03), whereas Karnofsky scores less than 90% at allotransplantation correlated with shorter PFS only (P = .005). Long-term disease control and GVHD remain key issues.

Unrelated Donor Reduced-intensity Allogeneic Hematopoietic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jan, 2009  |  Pubmed ID: 19135949

Myeloablative allogeneic hematopoietic cell transplantation (HCT) may cure patients with relapsed or refractory Hodgkin lymphoma (HL), but is associated with a high treatment-related mortality (TRM). Reduced-intensity and nonmyeloablative (RIC/NST) conditioning regimens aim to lower TRM. We analyzed the outcomes of 143 patients undergoing unrelated donor RIC/NST HCT for relapsed and refractory HL between 1999 and 2004 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Patients were heavily pretreated, including autologous HCT in 89%. With a median follow-up of 25 months, the probability of TRM at day 100 and 2 years was 15% (95% confidence interval [CI] 10%-21%) and 33% (95% CI 25%-41%), respectively. The probabilities of progression free survival (PFS) and overall survival (OS) were 30% and 56% at 1 year and 20% and 37% at 2 years. The presence of extranodal disease and the Karnofsky Performance Scale (KPS) <90 were significant risk factors for TRM, PFS, and OS, whereas chemosensitivity at transplantation was not. Dose intensity of the conditioning regimen (RIC versus NST) did not impact outcomes. Unrelated donor HCT with RIC/NST can salvage some patients with relapsed/refractory HL, but relapse remains a common reason for treatment failure. Clinical studies should be aimed at reducing the incidence of acute graft-versus-host disease (GVHD) and relapse.

Unrelated Donor Hematopoietic Cell Transplantation for Non-hodgkin Lymphoma: Long-term Outcomes

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. May, 2009  |  Pubmed ID: 19361747

We analyzed the outcomes of 283 patients receiving unrelated donor allogeneic hematopoietic cell transplantation for non-Hodgkin lymphoma (NHL) facilitated by the Center for International Blood and Marrow Transplant Research/National Marrow Donor Program (CIBMTR/NMDP) between 1991 and 2004. All patients received myeloablative conditioning regimens. The median follow-up of survivors is 5 years. Seventy-three (26%) patients are alive. The day 100 probability of death from all causes is estimated at 39%. The cumulative incidence of developing grade III-IV acute graft-versus-host disease (aGVHD) at day 100 is 25%. The estimated 5-year survival and failure free survival are 24% (95% confidence interval [CI]: 19-30) and 22% (95% CI: 17-28), respectively. Factors adversely associated with overall survival (OS) included increasing age, decreased performance status, and refractory disease. Follicular lymphoma (FL) and peripheral T cell lymphoma had improved survival compared to aggressive B cell lymphomas. Factors adversely associated with progression-free survival (PFS) included performance status, histology, and disease status at transplant. Long-term failure-free survival is possible following unrelated donor transplantation for NHL, although early mortality was high in this large cohort.

Prognostic Implication of Late Gadolinium Enhancement on Cardiac MRI in Light Chain (AL) Amyloidosis on Long Term Follow Up

BMC Medical Physics. 2009  |  Pubmed ID: 19416541

Light chain amyloidosis (AL) is a rare plasma cell dyscrasia associated with poor survival especially in the setting of heart failure. Late gadolinium enhancement (LGE) on cardiac MRI was recently found to correlate with myocardial amyloid deposition but the prognostic role is not established. The aim is to determine the prognostic significance of LGE in AL by comparing long term survival of AL patients with and without LGE.

Phenotyping Studies of Clonotypic B Lymphocytes from Patients with Multiple Myeloma by Flow Cytometry

Archives of Pathology & Laboratory Medicine. Oct, 2009  |  Pubmed ID: 19792049

Clonotypic B lymphocytes, monoclonal B lymphocytes sharing identical, rearranged IGH-CDR3 sequences with the patient's myeloma cells, have been detected in the peripheral blood of patients with multiple myeloma. These cells have been postulated to act as a therapy-resistant tumor reservoir that drives recurrence.

Impact of Pre-transplant Rituximab on Survival After Autologous Hematopoietic Stem Cell Transplantation for Diffuse Large B Cell Lymphoma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Nov, 2009  |  Pubmed ID: 19822306

Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens to treat diffuse large B cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, however, many patients develop refractory or recurrent DLBCL and then undergo autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes after AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n = 176; +R cohort) or was not (n = 818; -R cohort) administered with front-line or salvage therapy before AuHCT. The +R cohort had superior progression-free survival (PFS; 50% vs 38%; P = .008) and overall survival (OS; 57% vs 45%; P = .006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Nonrelapse mortality (NRM) did not differ significantly between the 2 cohorts. In multivariate analysis, the +R cohort had improved PFS (relative risk of relapse/progression or death, 0.64; P < .001) and improved OS (relative risk of death, 0.74; P = .039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival after AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM.

Utility of CD56 Immunohistochemical Studies in Follow-up of Plasma Cell Myeloma

American Journal of Clinical Pathology. Jul, 2009  |  Pubmed ID: 19864234

Although 70% to 80% of plasma cell myelomas (PCMs) express CD56, few data are available on the usefulness of CD56 immunohistochemical analysis in assessing residual disease. We retrospectively reviewed 127 PCM posttreatment bone marrow (BM) specimens, classifying them as positive or negative for residual disease (independent of CD56 immunohistochemical studies) based on abnormal plasma cell (PC) morphologic features or flow cytometry (FC) and/or light chain restriction by immunohistochemical studies (conventional criteria). CD56 immunohistochemical analysis was performed on these and 20 negative lymphoma staging BM specimens. Of 127 BM specimens, 74 were positive and 53 were negative for residual PCM by conventional criteria. Of 74 BM specimens positive by conventional criteria, 59 (80%) demonstrated CD56 (strong+) PCs in clusters and/or with cytologic atypia. Of the 53 BM specimens negative by conventional criteria, 3 showed CD56 (strong+) morphologically atypical PCs in clusters or scattered. CD56 immunohistochemical analysis is useful for detecting residual PCM, particularly in morphologically equivocal cases in which light chain restriction cannot be demonstrated, and may serve as a potential response criterion.

Left Ventricular Ejection Time on Echocardiography Predicts Long-term Mortality in Light Chain Amyloidosis

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Dec, 2009  |  Pubmed ID: 19880277

Light chain amyloidosis (AL) is associated with high mortality. The aim was to identify echocardiographic parameters that predict AL long-term mortality.

Race and Outcomes of Autologous Hematopoietic Cell Transplantation for Multiple Myeloma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Mar, 2010  |  Pubmed ID: 19922808

Blacks are twice as likely to develop and die from multiple myeloma (MM), and are less likely to receive an autologous hematopoietic-cell transplant (AHCT) for MM compared to Whites. The influence of race on outcomes of AHCT for MM is not well described. We compared the probability of overall survival (OS), progression-free survival (PFS), disease progression, and nonrelapse mortality (NRM) among Black (N=303) and White (N=1892) recipients of AHCT for MM, who were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1995 to 2005. The Black cohort was more likely to be female, and had better Karnofsky performance scores, but lower hemoglobin and albumin levels at diagnosis. Black recipients were younger and more likely to be transplanted later in their disease course. Disease stage and treatment characteristics prior to AHCT were similar between the 2 groups. Black and White recipients had similar probabilities of 5-year OS (52% versus 47%, P=.19) and PFS (19% versus 21%, P=.64) as well as cumulative incidences of disease progression (72% versus 72%, P=.97) and NRM (9% versus 8%, P=.52). In multivariate analyses, race was not associated with any of these endpoints. Black recipients of AHCT for MM have similar outcomes compared to Whites, suggesting that the reasons underlying lower rates of AHCT in Blacks need to be studied further to ensure equal access to effective therapy.

A Comparison of HLA-identical Sibling Allogeneic Versus Autologous Transplantation for Diffuse Large B Cell Lymphoma: a Report from the CIBMTR

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Jan, 2010  |  Pubmed ID: 20053330

We compared outcomes of 916 diffuse large B cell lymphoma (DLBCL) patients aged >or=18 years undergoing first autologous (n = 837) or myeloablative (MA) allogeneic hematopoietic cell transplant (HCT) (n = 79) between 1995 and 2003 reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Median follow-up was 81 months for allogeneic HCT versus 60 months for autologous HCT. Allogeneic HCT recipients were more likely to have high-risk disease features including higher stage, more prior chemotherapy regimens, and resistant disease. Allogeneic HCT was associated with a higher 1 year treatment-related mortality (TRM) (relative risk [RR] 4.88, 95% confidence interval [CI], 3.21-7.40, P < .001), treatment failure (RR 2.06, 95% CI, 1.54-2.75, P < .001), and mortality (RR 2.75, 95% CI, 2.03-3.72, P < .001). Risk of disease progression was similar in the 2 groups (RR 1.12, 95% CI, 0.73-1.72, P = .59). In fact, for 1-year survivors, no significant differences were observed for TRM, progression, progression-free (PFS) or overall survival (OS). Increased risks of TRM and mortality were associated with older age (>50 years), lower performance score, chemoresistance, and earlier year of transplant. In a cohort of mainly high-risk DLBCL patients, upfront MA allogeneic HCT, although associated with increased early mortality, was associated with a similar risk of disease progression compared to lower risk patients receiving autologous HCT.

Efficacy and Safety of Long-term (>7 Year) Alemtuzumab Therapy for Refractory T-cell Large Granular Lymphocytic Leukaemia

British Journal of Haematology. Aug, 2010  |  Pubmed ID: 20456357

Light Chain Amyloidosis Circa 2010: Six Prognostic Markers and One Sobering Reality

Journal of the American Society of Echocardiography : Official Publication of the American Society of Echocardiography. Jun, 2010  |  Pubmed ID: 20497862

Access to Hematopoietic Stem Cell Transplantation: Effect of Race and Sex

Cancer. Jul, 2010  |  Pubmed ID: 20564154

The purpose of the current study was to determine whether the use of hematopoietic stem cell transplantation (HCT) to treat leukemia, lymphoma, or multiple myeloma (MM) differs by race and sex.

Outcome of Patients with IgD and IgM Multiple Myeloma Undergoing Autologous Hematopoietic Stem Cell Transplantation: a Retrospective CIBMTR Study

Clinical Lymphoma, Myeloma & Leukemia. Dec, 2010  |  Pubmed ID: 21156462

Immunoglobulin D (IgD) and IgM multiple myeloma represent uncommon immunoglobulin isotypes, accounting for 2% and 0.5% of cases, respectively. Limited information is available regarding the prognosis of these isotypes, but they have been considered to have a more aggressive course than the more common immunoglobulin G (IgG) and IgA isotypes. In particular, the outcome after autologous hematopoietic stem cell transplantation (auto-HCT) has not been well defined.

Systemic and Microvascular Oxidative Stress Induced by Light Chain Amyloidosis

International Journal of Cardiology. Nov, 2010  |  Pubmed ID: 19446898

Light chain amyloidosis (AL) is a plasma cell dyscrasia associated with production of amyloidogenic immunoglobulin light chains (LC). Despite its often fatal course, the mechanism of injury remains unknown. We tested the hypothesis that AL is associated with oxidative stress by comparing serum protein carbonyl (a marker of protein oxidation and oxidative stress) in AL subjects (n=23, 60 ± 11 years) vs. controls (n=9, 54 ± 2 years); we also measured superoxide production (n=11) and dilator response to sodium nitroprusside (SNP, n=6) in isolated non-AL human adipose arterioles exposed to LC (20 μg/mL) purified from AL subjects for 1 h vs. control. Protein carbonyl was higher in AL patients (0.19 ± 0.04 vs. 0.003 ± 0.003 nmol/mg control, p=0.002). Post-exposure to LC proteins, arteriole superoxide was higher (1.89 ± 0.36 times control, p=0.03) with impaired dilation to SNP (10(-4) M, 54 ± 6 vs. 86 ± 4%, p=0.01, logEC50 -3.7 ± 0.2 vs. -6.7 ± 0.6, p=0.002). AL is associated with systemic oxidative stress and brief acute exposure to AL light chain proteins induces oxidative stress and microvascular dysfunction in human adipose arterioles. This novel mechanism of injury may be important in AL pathophysiology.

CD200 Expression in Plasma Cell Myeloma

British Journal of Haematology. May, 2011  |  Pubmed ID: 21275968

Low Risk of Chronic Graft-versus-host Disease and Relapse Associated with T Cell-depleted Peripheral Blood Stem Cell Transplantation for Acute Myelogenous Leukemia in First Remission: Results of the Blood and Marrow Transplant Clinical Trials Network Protocol 0303

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Sep, 2011  |  Pubmed ID: 21320619

Graft-versus-host disease (GVHD) is most effectively prevented by ex vivo T cell depletion (TCD) of the allograft, but its role in the treatment of patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia (AML) in complete remission (CR) remains unclear. We performed a phase 2 single-arm multicenter study to evaluate the role of TCD in AML patients in CR1 or CR2 up to age 65 years. The primary objective was to achieve a disease-free survival (DFS) rate of >75% at 6 months posttransplantation. A total of 44 patients with AML in CR1 (n = 37) or CR2 (n = 7) with a median age of 48.5 years (range, 21-59 years) received myeloablative chemotherapy and fractionated total body irradiation (1375 cGy) followed by immunomagnetically selected CD34-enriched, T cell‒depleted allografts from HLA-identical siblings. No pharmacologic GVHD prophylaxis was given. All patients engrafted. The incidence of acute GVHD grade II-IV was 22.7%, and the incidence of extensive chronic GVHD was 6.8% at 24 months. The relapse rate for patients in CR1 was 17.4% at 36 months. With a median follow-up of 34 months, DFS for all patients was 82% at 6 months, and DFS for patients in CR1 was 72.8% at 12 months and 58% at 36 months. HCT after myeloablative chemoradiotherapy can be performed in a multicenter setting using a uniform method of TCD, resulting in a low risk of extensive chronic GVHD and relapse for patients with AML in CR1.

Effect of Obesity on Outcomes After Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 21624486

Obesity has implications for chemotherapy dosing and selection of patients for therapy. Autologous hematopoietic stem cell transplant (AutoHCT) improves outcomes for patients with multiple myeloma, but optimal chemotherapy dosing for obese patients is poorly defined. We analyzed the outcomes of 1087 recipients of AutoHCT for myeloma reported to the CIBMTR between 1995 and 2003 who received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal, overweight, obese, or severely obese. There was no overall effect of BMI on progression-free survival (PFS), overall survival (OS), progression, or nonrelapse mortality (NRM). In patients receiving melphalan and TBI conditioning, obese and severely obese patients had superior PFS and OS compared with normal and overweight patients, but the clinical significance of this finding is unclear. More obese patients were more likely to receive a reduced dose of melphalan, but there was no evidence that melphalan or TBI dosing variability affected PFS. Therefore, current common strategies of dosing melphalan do not impair outcomes for obese patients, and obesity should not exclude patients from consideration of autologous transplantation. Further research is necessary to optimize dosing of both chemotherapy and radiation in obese patients.

Trends in Allogeneic Stem Cell Transplantation for Multiple Myeloma: a CIBMTR Analysis

Blood. Aug, 2011  |  Pubmed ID: 21690560

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).

Tocilizumab for the Treatment of Steroid Refractory Graft-versus-host Disease

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 21745454

Corticosteroid refractory graft-versus-host disease (GVHD) is one of the major challenges in the management of allogeneic stem cell transplant recipients. Although numerous agents have been employed to treat this patient population, no standardized second-line therapy exists. In this study, we report our experience with the administration of tocilizumab, an anti-interleukin 6 receptor antibody, in the treatment of steroid refractory GVHD. Tocilizumab was administered to 8 patients with refractory acute (n = 6) or chronic GVHD (cGVHD) (n = 2) once every 3 to 4 weeks. The majority of patients with acute GVHD (aGVHD) had grade IV organ involvement of the skin or gastrointestinal tract, whereas both patients with cGVHD had long-standing severe skin sclerosis at the time of treatment. There were no allergic or infusion-related adverse events. Treatment was discontinued in one patient over concerns that tocilizumab may have worsened preexisting hyperbilirubinemia. Several patients also had transient elevations in serum transaminase values. Infections were the primary adverse events associated with tocilizumab administration. Four patients (67%) with aGVHD had either partial or complete responses apparent within the first 56 days of therapy. One patient with cGVHD had a significant response to therapy, whereas the second had stabilization of disease that allowed for a modest reduction in immune suppressive medications. These results indicate that tocilizumab has activity in the treatment of steroid refractory GVHD and warrants further investigation as a therapeutic option for this disorder.

Detection of Amyloid in Abdominal Fat Pad Aspirates in Early Amyloidosis: Role of Electron Microscopy and Congo Red Stained Cell Block Sections

CytoJournal. 2011  |  Pubmed ID: 21760829

Fine-needle aspiration biopsy (FNA) of the abdominal fat pad is a minimally invasive procedure to demonstrate tissue deposits of amyloid. However, protocols to evaluate amyloid in fat pad aspirates are not standardized, especially for detecting scant amyloid in early disease.

Characteristics of CliniMACS(®) System CD34-Enriched T Cell-Depleted Grafts in a Multicenter Trial for Acute Myeloid Leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Aug, 2011  |  Pubmed ID: 21875505

Eight centers participated in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) protocol 0303 to determine the effect of extensive T cell depletion (TCD) on the outcome of HLA matched sibling donor transplantation for acute myeloid leukemia. One goal of the study was to determine if TCD could be performed uniformly among study sites. TCD was achieved using the CliniMACS(®) CD34 Reagent System for CD34 enrichment. Processed grafts needed to contain ≥2.0 × 10(6) CD34(+)cells/kg with a target of 5.0 × 10(6) CD34(+) cells/kg and <10(5) CD3(+) T cells/kg. Up to 3 collections were allowed to achieve the minimum CD34(+) cell dose. In total, 86 products were processed for 44 patients. Differences in the starting cell products between centers were seen in regard to total nucleated cells, CD34(+) cells, and CD3(+) T cells, which could in part be ascribed to a higher dose of granulocyte-colony stimulating factor used for mobilization early in the trial. Differences between centers in processing outcomes were minimal and could be ascribed to starting cell parameters or to differences in graft analysis methods. Multivariate analysis showed that CD34(+) cell recovery (66.1% ± 20.3%) was inversely associated with the starting number of CD34(+) cells (P = .02). Median purity of the CD34 enriched fraction was 96.7% (61.5%-99.8%) with monocytes and B cells the most common impurity. All patients received the minimum CD34(+) cell dose, and 39 patients (89%) came within 10% or exceeded the target CD34(+) cell dose without exceeding the maximum T cell dose. All patients proceeded to transplantation and all achieved initial engraftment. Products processed at multiple centers using the CliniMACS System for CD34 enrichment were comparably and uniformly highly enriched for CD34(+) cells, with good CD34(+) cell recovery and very low CD3(+) T cell content.

Autologous Haemopoietic Stem-cell Transplantation Followed by Allogeneic or Autologous Haemopoietic Stem-cell Transplantation in Patients with Multiple Myeloma (BMT CTN 0102): a Phase 3 Biological Assignment Trial

The Lancet Oncology. Dec, 2011  |  Pubmed ID: 21962393

Autologous haemopoietic stem-cell transplantation (HSCT) improves survival in patients with multiple myeloma, but disease progression remains an issue. Allogeneic HSCT might reduce disease progression, but can be associated with high treatment-related mortality. Thus, we aimed to assess effectiveness of allogeneic HSCT with non-myeloablative conditioning after autologous HSCT compared with tandem autologous HSCT.

Human Microvascular Dysfunction and Apoptotic Injury Induced by AL Amyloidosis Light Chain Proteins

American Journal of Physiology. Heart and Circulatory Physiology. Dec, 2011  |  Pubmed ID: 21963839

Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 μg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.

Percussion Hemoglobinuria - a Novel Term for Hand Trauma-induced Mechanical Hemolysis: a Case Report

Journal of Medical Case Reports. 2011  |  Pubmed ID: 21982397

ABSTRACT:

Long-term Outcomes Among Older Patients Following Nonmyeloablative Conditioning and Allogeneic Hematopoietic Cell Transplantation for Advanced Hematologic Malignancies

JAMA : the Journal of the American Medical Association. Nov, 2011  |  Pubmed ID: 22045765

A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions.

Alternate Donor Hematopoietic Cell Transplantation (HCT) in Non-Hodgkin Lymphoma Using Lower Intensity Conditioning: A Report from the CIBMTR

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 22155506

We analyzed the outcomes of 248 (61% male) adult recipients of HLA-matched unrelated and HLA-mismatched related donor hematopoietic cell transplantation (HCT) for non-Hodgkin lymphoma (NHL) after reduced or lower intensity conditioning (RIC), reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from 1997 to 2004. Median age was 52 (range: 18-72 years); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II-IV acute graft-versus-host disease (aGVHD) was 43% at 100 days; and chronic GVHD (cGVHD) was 44% at 3 years. Treatment-related mortality (TRM) at 100 days was 24%. Three-year overall survival (OS) and progression-free survival (PFS) were 41% and 32%, respectively. In multivariate analysis, use of antithymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use, and chemotherapy resistance were associated with lower PFS. Older age, shorter interval from diagnosis to HCT, non-total body irridiation (TBI) conditioning regimens, ex vivo T cell depletion, and HLA-mismatched unrelated donors were associated with mortality. GVHD did not influence relapse or PFS. Older age, aggressive histology, and chemotherapy resistance correlated with poorer survival. For selected patients with NHL, lack of an available sibling donor should not be a barrier to allogeneic HCT.

Outcome of Lower-Intensity Allogeneic Transplantation in Non-Hodgkin Lymphoma After Autologous Transplantation Failure

Biology of Blood and Marrow Transplantation : Journal of the American Society for Blood and Marrow Transplantation. Dec, 2011  |  Pubmed ID: 22198543

We studied the outcome of allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning regimens (reduced-intensity conditioning and nonmyeloablative) in patients with non-Hodgkin lymphoma who relapsed after autologous hematopoietic stem cell transplantation. Nonrelapse mortality, lymphoma progression/relapse, progression-free survival (PFS), and overall survival were analyzed in 263 patients with non-Hodgkin lymphoma. All 263 patients had relapsed after a previous autologous hematopoietic stem cell transplantation and then had undergone allogeneic hematopoietic stem cell transplantation from a related (n = 26) or unrelated (n = 237) donor after reduced-intensity conditioning (n = 128) or nonmyeloablative (n = 135) and were reported to the Center for International Blood and Marrow Transplant Research between 1996 and 2006. The median follow-up of survivors was 68 months (range, 3-111 months). Three-year nonrelapse mortality was 44% (95% confidence interval [CI], 37%-50%). Lymphoma progression/relapse at 3 years was 35% (95% CI, 29%-41%). Three-year probabilities of PFS and overall survival were 21% (95% CI, 16%-27%) and 32% (95% CI, 27%-38%), respectively. Superior Karnofsky Performance Score, longer interval between transplantations, total body irradiation-based conditioning regimen, and lymphoma remission at transplantation were correlated with improved PFS. Allogeneic hematopoietic stem cell transplantation after lower-intensity conditioning is associated with significant nonrelapse mortality but can result in long-term PFS. We describe a quantitative risk model based on pretransplantation risk factors to identify those patients likely to benefit from this approach.

Immunophenotypic Stability of Sezary Cells by Flow Cytometry: Usefulness of Flow Cytometry in Assessing Response to and Guiding Alemtuzumab Therapy

American Journal of Clinical Pathology. Mar, 2012  |  Pubmed ID: 22338052

Flow cytometry (FC) is frequently used to detect aberrant peripheral blood (PB) T cells ("Sézary cells") in patients with mycosis fungoides (MF) and Sézary syndrome (SS). However, immunophenotypic stability of MF/SS over time is not well characterized. We analyzed 141 PB samples from 9 cases (2 SS, 7 MF). At diagnosis, there were 3 to 5 immunophenotypic aberrancies per case (median, 4), including dim or absent CD2, CD3, CD4, CD5, CD7, or CD26 and bright CD45RO. Of 9 patients, 7 had a subsequent change in immunophenotype. All patients retained multiple aberrancies at follow-up (median, 3 per analysis; range, 2-6), of which 22.0% (81/369) were new. In 5 patients, a more than 99% decrease in absolute Sézary cell (ASC) counts by FC after alemtuzumab therapy or total skin electron beam radiation was associated with clinical improvement. We observed minor immunophenotypic changes over time in most patients with MF/SS; however, the Sézary clones maintain persistently aberrant immunophenotypes and seem amenable to follow-up with limited FC panels. ASC counts by FC correlated well with clinical response.