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We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients.
RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients.
PMCID: PMC3886623  PMID: 24161923
Myelofibrosis; allogeneic transplantation; reduced intensity; prognosis
2.  Simplified Validated Prognostic Model for Progression-Free Survival after Autologous Transplantation for Hodgkin Lymphoma 
Hodgkin Lymphoma (HL) prognostic models based on factors measured at time of autologous hematopoietic cell transplantation (AHCT) are limited by small sample sizes. Models based on information at diagnosis are often not uniformly collected or available at transplantation. We propose an easily implementable prognostic model for progression-free survival (PFS) post-AHCT based on factors available at transplantation in a large international cohort of HL patients. The outcomes of 728 AHCT recipients for relapsed/refractory HL were studied. Patients were randomly selected for model development (n=337) and validation (n=391).
The multivariate model identified four major adverse risk factors at the time of AHCT with the following relative weights: Karnofsky performance score <90 and chemotherapy resistance at AHCT were each assigned 1 point while ≥3 chemotherapy regimens pre-AHCT and extra-nodal disease at AHCT were each assigned 2 points. Based on the total score summed for the four adverse risk factors, three risk groups were identified: Low, (score=0), Intermediate, (score=1-3) or High, (score=4-6). The 4-year PFS (95% CI) for the Low (N=176), Intermediate (N=261) and High (N=283) risk groups were 71% (63-78%), 60% (53-66%), and 42% (36-49%), respectively. The prognostic model was validated in an independent cohort. The CIBMTR Model is based on factors easily available at the time of AHCT and discriminates patients with favorable post-AHCT outcomes as well as an intermediate risk group. This model should assist in the prospective evaluation of alternative treatment strategies.
PMCID: PMC3906436  PMID: 24096096
3.  Proceedings from the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation: Part II. Autologous Transplantation — Novel Agents and Immunomodulatory Strategies 
In the National Cancer Institute’s Second International Workshop on the Biology, Prevention, and Treatment of Relapse after Hematopoietic Stem Cell Transplantation, the Scientific/Educational Session on Autologous Transplantation addressed the role of novel agents and immunomodulatory strategies in management of relapse after autologous hematopoietic stem cell transplantation (AHSCT). Concepts were illustrated through in-depth discussion of multiple myeloma, with broader discussion of areas relevant for relapse of other malignancies as well as in the setting of allogeneic transplantation. Dr. Hari provided an overview of the epidemiology of relapse after AHSCT in multiple myeloma, addressing clinical patterns, management implications, and treatment options at relapse, highlighting the implications of novel therapeutic agents in initial, maintenance and relapse treatment. Dr. Avigan discussed current concepts in tumor vaccine design, including whole-cell and antigen-specific strategies, use of an AHSCT platform to reverse tumor-associated immunosuppression and tolerance, and combining vaccines with immunomodulatory agents to promote establishment of durable antitumor immunity. Dr. Hsu reviewed the immunogenetics of natural killer (NK) cells and general NK biology, the clinical importance of autologous NK activity (e.g., lymphoma and neuroblastoma), as well as the impact of existing therapies on promotion of NK-cell activity (e.g., immunomodulatory drugs, monoclonal antibodies) and strategies for enhancing autologous and allogeneic NK-cell effects through NK-cell gene profiling.
PMCID: PMC3914636  PMID: 24018393
4.  Trends in Utilization and Outcomes of Autologous Transplantation as Early Therapy for Multiple Myeloma 
The impact of novel multiple myeloma (MM) drugs on the utilization and outcomes of autologous hematopoietic progenitor cell transplantation (AHPCT) is unknown. We reviewed characteristics and outcomes of 20,278 patients undergoing AHPCT within 12 months of MM diagnosis in the US and Canada and registered at the Center for International Blood and Marrow Transplant Research (CIBMTR) in 3 time cohorts: 1995–1999 (n=2226), 2000–2004 (n=6408) and 2005–2010 (n=11644), reflecting increasing availability of novel drugs. In the US, the number of AHPCT increased at a greater rate than new MM cases. Patients in recent cohorts were older, less likely to have stage 3 MM and more likely to have received prior thalidomide, lenalidomide or bortezomib. In multivariate analysis, transplant in the 2000–04 cohort (HR=0.77) or in the 2005–10 cohort (HR=0.68) were associated with lower risk of death. Survival at 60 months from AHPCT improved from 47% to 55% and 57%, led less by improvement in progression free survival (50% vs. 55% vs. 57% at 24 months) than by post relapse/progression survival (58% vs. 65% vs. 72% at 24 months). AHPCT and new biological agents are complementary, non-redundant therapies and should be combined in the management of suitable MM patients.
PMCID: PMC3952066  PMID: 23939198
5.  Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma 
Journal of Clinical Oncology  2013;31(25):3100-3109.
To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma.
Patients and Methods
Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes.
AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival.
These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.
PMCID: PMC3753702  PMID: 23897963
6.  Fludarabine/2 Gy TBI is Superior to 2 Gy TBI as Conditioning for HLA-Matched Related HCT: A Phase III Randomized Trial 
The risk/benefit of adding fludarabine to a 2 Gy total body irradiation nonmyeloablative regimen is unknown. For this reason we conducted a prospective randomized trial comparing 2 Gy TBI alone or in combination with 90mg/m2 fludarabine (FLU/TBI) before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n=44) or FLU/TBI (n=41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and GVHD were similar between groups. Three-year overall survival was lower in the TBI group (54% vs. 65%; hazard ratio (HR) 0.57; p=0.09), with higher incidences of relapse/progression (55% vs. 40%; HR 0.55; p=0.06) and relapse-related mortality (37% vs. 28%; HR 0.53; p=0.09), and a lower progression-free survival (36% vs. 53%; HR 0.56; p=0.05). Median donor T-cell chimerism levels were significantly lower in the TBI group at days 28 (61% vs. 90%; p<0.0001) and 84 (68% vs. 92%; p<0.0001), as was NK-cell chimerism on day 28 (75% vs. 96%, p=0.0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high level donor engraftment early post-transplant.
PMCID: PMC3755028  PMID: 23769990
Bone marrow transplantation  2013;49(3):416-421.
There is no standard therapy for multiple myeloma (MM) relapsing after an autotransplant. We compared the outcomes of a 2nd autotransplant (N=137) with those of an allotransplant (N=152) after non-myeloablative or reduced-intensity conditioning (NST/RIC) in 289 subjects reported to the CIBMTR from 1995–2008. NST/RIC recipients were younger (median age 53 vs. 56 years; p < 0.001) and had a shorter time to progression after their first autotransplant. Non-relapse mortality (NRM) at one-year post-transplant was higher in the NST/RIC cohort, 13% (95% CI, 8–19) vs. 2% (95% CI, 1–5, p = < 0.001). Three year progression-free survival (PFS) and overall survival (OS) for NST/RIC cohort were 6% (95% CI, 3–10%) and 20% (95% CI, 14–27%). Similar outcomes for the autotransplant cohort were 12% (95% CI, 7–19%, p = 0.038) and 46% (95% CI, 37–55%, p = 0.001). In multivariate analyses, risk of death was higher in NST/RIC recipients (HR 2.38 [95% CI, 1.79–3.16], p < 0.001), those with KPS < 90 (HR 1.96 [95% CI, 1.47–2.62], p < 0.001) and transplant before 2004 (HR 1.77 [95% CI, 1.34–2.35] p = < 0.001). In conclusion, NST/RIC was associated with higher TRM and lower survival than an autotransplant. Since disease status was not available for most allotransplant recipients, is not possible to determine which type of transplant is superior after autotransplant failure.
PMCID: PMC3947725  PMID: 24270389
Multiple Myeloma; allogeneic; salvage transplant
British journal of haematology  2013;162(5):648-656.
Pre-existing central nervous system (CNS) involvement may influence referral for autologous haematopoietic cell transplantation (AHCT) for patients with non-Hodgkin lymphoma (NHL). The outcomes of 151 adult patients with NHL with prior secondary CNS involvement (CNS+) receiving an AHCT were compared to 4688 patients without prior CNS lymphoma (CNS−).
There were significant baseline differences between the cohorts. CNS+ patients were more likely to be younger, have lower performance scores, higher age-adjusted international prognostic index scores, more advanced disease stage at diagnosis, more aggressive histology, more sites of extranodal disease, and a shorter interval between diagnosis and AHCT. However, no statistically significant differences were identified between the two groups by analysis of progression-free survival (PFS) and overall survival (OS) at 5 years. A matched pair comparison of the CNS+ group with a subset of CNS− patients matched on propensity score also showed no differences in outcomes. Patients with active CNS lymphoma at the time of AHCT (n=55) had a higher relapse rate and diminished PFS and OS compared with patients whose CNS lymphoma was in remission (n=96) at the time of AHCT.
CNS+ patients can achieve excellent long-term outcomes with AHCT. Active CNS lymphoma at transplant confers a worse prognosis.
PMCID: PMC3766698  PMID: 23829536
CNS Involvement; Non-Hodgkin Lymphoma; Autologous transplantation; Outcomes
9.  Donor lymphocyte infusion for relapsed hematological malignancies after allogeneic hematopoietic cell transplantation: prognostic relevance of the initial CD3+ T cell dose 
The impact of donor lymphocyte infusion (DLI) initial cell dose on its outcome is known in patient with chronic myeloid leukemia, but limited in patients with other hematological malignancies. In this retrospective study, we evaluated the effect of initial DLI CD3+ cell dose on graft-versus-host disease (GVHD) and overall survival (OS) after DLI given for relapse of any hematological malignancies after allogeneic hematopoietic cell transplantation (HCT) with high or reduced intensity conditioning. The cohort included 225 patients. Initial DLI CD3+ cell dose/kg recipient body weight was ≤1×107 (n=84; Group A), >1.0 to <10 ×107 (n=58; Group B), and ≥ 10×107 (n=66; Group C). Cumulative incidence rates of GVHD at 12 months after DLI were 21%, 45% and 55% for Groups A, B, and C, respectively. Multivariate analysis showed that initial DLI CD3+ cell ≥1×107 dose/kg is associated with an increased risk of GVHD after DLI (p=0.03). Moreover, initial DLI CD3+ cell dose of 10×107 or higher did not decrease the risk of relapse and did not improve OS. Thus, these results support the use of less than 10×107 CD3+ cell/kg as the initial cell dose of DLI for treatment of persistent or recurrent hematological malignancy after HCT.
PMCID: PMC3846289  PMID: 23523892
donor lymphocyte infusion (DLI); hematopoietic cell transplantation (HCT); CD3+ T cells; graft-versus-host disease (GVHD); adoptive immunotherapy for relapse after HCT
Patients with chemorefractory non-Hodgkin lymphomas (NHL) generally have a poor prognosis. We used the observational database of the CIBMTR to study the outcome of 533 patients with refractory diffuse large B-cell lymphoma (DLBCL) or grade-III follicular lymphoma (FL-III) who underwent allogeneic transplantation (allo-HCT) using either myeloablative (MA; N=307) or reduced intensity/non-myeloablative conditioning (RIC/NST; N=226), between 1998-2010. We analyzed non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Only 45% of the patients at transplant had a Karnofsky performance score of ≥90%. Median follow-up of surviving patients after MA and RIC/NST allo-HCT is 35 months and 30 months, respectively. At 3years, MA allo-HCT was associated with a higher NRM compared to RIC/NST (53% vs. 42%; p=0.03), similar PFS (19% vs. 23%; p=0.40), and lower OS (19% vs. 28%; p=0.02), respectively. On multivariate analysis, FL-III histology was associated with lower NRM (relative-risk [RR]=0.52), reduced risk of relapse/progression (RR=0.42), superior PFS (RR=0.51) and OS (RR=0.53), while MA conditioning was associated with reduced risk of relapse/progression (RR=0.66). Despite a refractory state, a small subset of DLBCL and FL-III patients can attain durable remissions after allo-HCT. Conditioning regimen intensity was not associated with PFS and OS despite a higher risk of relapse/progression with RIC/NST allo-HCT.
PMCID: PMC3650915  PMID: 23380340
DLBCL; grade III follicular lymphoma; allogeneic transplantation; refractory; relapsed; graft-versus-host disease
11.  Allogeneic hematopoietic cell transplant for acute myeloid leukemia: Current state in 2013 and future directions 
World Journal of Stem Cells  2014;6(2):69-81.
Acute myeloid leukemia (AML) represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes. Though remission-induction is an important first step in the management of AML, additional treatment strategies are essential to ensure long-term disease-free survival. Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk. Allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions, with a demonstrable survival advantage in younger patients with intermediate- or poor-risk cytogenetics. Herein we review the published data regarding the role of allo-HCT in adults with AML. We searched MEDLINE/PubMed and EMBASE/Ovid. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. We discuss the role of allo-HCT in AML patients stratified by cytogenetic- and molecular-risk in first complete remission, as well as allo-HCT as an option in relapsed/refractory AML. Besides the conventional sibling and unrelated donor allografts, we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood. We also discuss conditioning regimens, including reduced intensity conditioning which has broadened the applicability of allo-HCT. Finally we explore recent advances and future possibilities and directions of allo-HCT in AML. Practical therapeutic recommendations have been made where possible based on available data and expert opinion.
PMCID: PMC3999783  PMID: 24772235
Acute myeloid leukemia; Allogeneic hematopoietic cell transplantation; Reduced intensity conditioning; Myeloablative conditioning; Haploidentical; Umbilical cord blood
12.  Graft-Versus-Host Disease and Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation 
Journal of Clinical Oncology  2012;31(12):1530-1538.
We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities.
Patients and Methods
Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years).
Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM.
Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.
PMCID: PMC3625710  PMID: 23478054
Patients with chemorefractory mantle cell lymphoma (MCL) have poor prognosis. We used the CIBMTR database to study the outcome of 202 patients with refractory MCL who underwent allogeneic hematopoietic cell transplantation (allo-HCT) using either myeloablative (MA) or reduced intensity/non-myeloablative conditioning (RIC/NST), during 1998–2010. We analyzed non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS). Seventy-four patients received MA, and 128 underwent RIC/NST. Median ages are 54 and 59 years for MA and RIC/NST allo-HCT recipients, respectively. Median follow-up after MA and RIC/NST allo-HCT is 35 months and 43 months, respectively. At 3 years, comparing MA with RIC/NST allo-HCT, no significant differences were found in terms of NRM (47% vs. 43%; p-value=0.68), relapse/progression (33% vs. 32%; p-value=0.89), PFS (20% vs. 25%; p=0.53), and OS (25% vs. 30%; p-value=0.45). On multivariate analysis no significant differences were observed in NRM, relapse, PFS and OS between MA and RIC/NST allo-HCT; however, receiving a bone marrow or T-cell depleted allograft was associated with an increased risk of NRM and inferior PFS and OS. Despite a refractory disease state, approximately a fourth of MCL patients can attain durable remissions after allo-HCT. Conditioning regimen intensity did not influence the outcomes of patients after allo HCT.
PMCID: PMC3640440  PMID: 23333532
Mantle cell lymphoma; allogeneic transplantation; chemotherapy unresponsive; graft-versus-host disease
Trends in utilization and outcomes after autologous or allogeneic hematopoietic cell transplantation (HCT) for Burkitt Lymphoma (BL) were analyzed in 241 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1985 and 2007. The autologous HCT cohort had a higher proportion with chemotherapy sensitive disease, peripheral blood grafts and HCT in first complete remission (CR1). The use of autologous HCT has declined over time with only 19% done after 2001. Overall survival (OS) at 5 years for the autologous cohort was 83% for those in CR1, and 31% for non-CR1 recipients. Corresponding progression free survival (PFS) was 78% and 27%, respectively. After allogeneic HCT, OS at 5 years was 53% and 20% for the CR1 and non-CR1 cohorts while PFS was 50% and 19%, respectively. The most common cause of death was progressive lymphoma. Allogeneic HCT performed in a higher risk subset (per NCCN guidelines) resulted in a 5 year PFS of 27%. Autologous HCT, resulted in a 5 year PFS of 44% in those transplanted in second CR.
PMCID: PMC3553321  PMID: 23200705
alloHCT; autoHCT; Burkitt lymphoma
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 yrs); 31% had a Karnofsky performance score <90. Follicular NHL (43%) was the major histology. Incidence of grades II–IV acute graft-versus-host disease (GVHD) was 43% at 100 days; and chronic GVHD was 44% at three 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 anti-thymocyte globulin (ATG) and HLA mismatch were associated with increased TRM. High-grade histology, ATG use and chemotherapy resistance were associated with lower progression-free survival (PFS). Older age, shorter interval from diagnosis to HCT, non-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.
PMCID: PMC3894923  PMID: 22155506
16.  Salvage Second Hematopoietic Cell Transplantation in Myeloma 
Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM.
PMCID: PMC3816739  PMID: 23298856
Second autologous; transplantation; Multiple myeloma; Relapsed multiple myeloma
17.  Protective role of clusterin in preserving endothelial function in AL amyloidosis 
Atherosclerosis  2012;225(1):220-223.
Misfolded immunoglobulin light chain proteins (LC) in light chain amyloidosis (AL) are toxic to vascular tissues. We tested the hypothesis that chaperone protein clusterin preserves endothelial function and cell survival during LC exposure.
LC (20 μg/mL) were given to human aortic endothelial cells (EC) for 24-hours and clusterin protein/gene expression and secretion were measured. DNA fragmentation was measured with/without recombinant clusterin (Clu, 300 ng/mL). Adipose arterioles (non-AL subjects) were tested for dilator responses to acetylcholine/papaverine at baseline and after 1-hour of LC±Clu.
LC reduced EC clusterin secretion, protein and gene expression while increasing DNA fragmentation. Clu attenuated LC-induced DNA fragmentation and restored dilator response to acetylcholine (logEC50: control −7.05±0.2, LC+Clu −6.53±0.4, LC −4.28±0.7, p<0.05 vs. control, LC+Clu).
LC induced endothelial cell death and dysfunction while reducing clusterin protein/gene expression and secretion. Exogenous clusterin attenuated LC toxicity. This represents a new pathobiologic mechanism and therapeutic target for AL amyloidosis.
PMCID: PMC3478430  PMID: 22981431
amyloid; endothelial function; chaperone protein
18.  Characteristics of CliniMACS® System CD34-Enriched T Cell-Depleted Grafts in a Multi-Center Trial for Acute Myeloid Leukemia-Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0303 
Eight centers participated in 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 transplant 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 × 106 CD34+ cells/kg with a target of 5.0 × 106 CD34+ cells/kg and <105 CD3+ T cells/kg. Up to three 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 regards to total nucleated cells, CD34+ cells and CD3+ T cells which could in part be ascribed to a higher dose of G-CSF 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 negatively associated with the starting number of CD34+ cells (p=0.02). Median purity of the CD34-enriched fraction was 96.7% (61.5 to 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.
PMCID: PMC3762249  PMID: 21875505
19.  Lenalidomide after Stem-Cell Transplantation for Multiple Myeloma 
The New England journal of medicine  2012;366(19):1770-1781.
Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma.
Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15).
The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P<0.001); of the remaining 128 patients who received placebo and who did not have progressive disease, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 86 of 231 patients who received lenalidomide (37%) and 132 of 229 patients who received placebo (58%) had disease progression or had died. The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). A total of 35 patients who received lenalidomide (15%) and 53 patients who received placebo (23%) died (P=0.03). More grade 3 or 4 hematologic adverse events and grade 3 non-hematologic adverse events occurred in patients who received lenalidomide (P<0.001 for both comparisons). Second primary cancers occurred in 18 patients who received lenalidomide (8%) and 6 patients who received placebo (3%).
Lenalidomide maintenance therapy, initiated at day 100 after hematopoietic stem-cell transplantation, was associated with more toxicity and second cancers but a significantly longer time to disease progression and significantly improved overall survival among patients with myeloma. (Funded by the National Cancer Institute; number, NCT00114101.)
PMCID: PMC3744390  PMID: 22571201
20.  Outcome of Lower-Intensity Allogeneic Transplantation in non-Hodgkin Lymphoma After Autologous Transplant Failure 
We studied the outcome of allogeneic transplantation after lower-intensity conditioning regimens (reduced-intensity [RIC] and non-myeloablative [NST]) in non-Hodgkin lymphoma (NHL) relapsing after autologous transplantation. Non-relapse mortality (NRM), lymphoma progression/relapse, progression-free survival (PFS) and overall survival (OS) were analyzed in 263 NHL patients. All had relapsed after a prior autologous transplant and then received allogeneic transplantation from related (n = 26) or unrelated donors (n= 237) after RIC (n = 128) or NST (n = 135), and were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1996 and 2006. Median follow-up of survivors was 68 months (range, 3–111). Three-year NRM was 44% (95% CI, 37%–50%). Lymphoma progression/relapse at three years was 35% (95% CI, 29%–41%). Three-year probabilities of PFS and OS were 21% (95% CI, 16%–27%) and 32% (95% CI, 27%–38%) respectively. Superior performance score, longer interval between transplants, total-body irradiation-based conditioning regimen and lymphoma remission at transplantation correlated with improved PFS. Allogeneic transplantation after lower-intensity conditioning is associated with significant NRM, but can result in long-term PFS. We describe a quantitative risk model based on pretransplant risk factors in order to identify those likely to benefit from this approach.
PMCID: PMC3376237  PMID: 22198543
Non-Hodgkin Lymphoma; Allogeneic; Relapse
21.  Tocilizumab for the Treatment of Steroid Refractory Graft-versus-Host Disease 
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.
PMCID: PMC3716013  PMID: 21745454
Graft-versus-host disease; Interleukin 6; Tocilizumab; Steroid refractory
22.  Tandem Autologous versus Single Autologous Transplantation Followed by Allogeneic Hematopoietic Cell Transplantation for Patients with Multiple Myeloma: Results from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 Trial 
The lancet oncology  2011;12(13):1195-1203.
Autologous hematopoietic cell transplantation (HCT) improves survival in patients with multiple myeloma, but disease progression remains a challenge. Allogeneic HCT (alloHCT) has the potential to reduce disease progression through graft-versus-myeloma effects. The aim of the BMT CTN 0102 trial was to compare outcomes of autologous HCT (autoHCT) followed by alloHCT with non-myeloablative conditioning (auto-allo) to tandem autoHCT (auto-auto) in patients with standard risk myeloma. Patients in the auto-auto arm were randomized to one year of thalidomide and dexamethasone (Thal-Dex) maintenance therapy or observation (Obs).
Patients with multiple myeloma within 10 months from initiation of induction therapy were classified as standard (SRD) or high risk (HRD) disease based on cytogenetics and beta-2-microglobulin levels. Assignment to auto-allo HCT was based on availability of an HLA-matched sibling donor. Primary endpoint was three-year progression-free survival (PFS) according to intent-to-treat analysis.
710 patients were enrolled completed a minimum of 3-year follow up. Among 625 SRD patients, 189 and 436 were assigned to auto-allo and auto-auto, respectively. Seventeen percent (33/189) of SR patients in the auto-allo arm and 16% (70/436) in the auto-auto arm did not receive a second transplant. Thal-Dex was not completed in 77% (168/217) of assigned patients. PFS and overall survival (OS) did not differ between the Thal-Dex (49%, 80%) and Obs (41%, 81%) cohorts and these two arms were pooled for analysis. Three year PFS was 43% and 46% (p=0·671) and three-year OS was 77% and 80 % (p=0·191) with auto-allo and auto-auto, respectively. Corresponding progression/relapse rates were 46% and 50% (p=0·402); treatment-related mortality rates were 11% and 4% (p<0·001), respectively. Auto/allo patients with chronic graft-vs-host disease had a decreased risk of relapse. Most common grade 3 to 5 adverse events in auto-allo was hypebilirubenemia (21/189) and in the auto-auto was peripheral neuropathy (52/436). Among 85 HRD patients (37 auto-allo), three PFS was 40% and 33% (p=0·743) and three-year OS was 59% and 67% (p=0·460) with auto-allo and auto-auto, respectively.
Thal-Dex maintenance was associated with poor compliance and did not improve PFS or OS. At three years there was no improvement in PFS or OS with auto-allo compared to auto-auto transplantation in patients with standard risk myeloma. Decisions to proceed with alloHCT after an autoHCT in patients with standard risk myeloma should take into consideration results of the current trial. Future investigation of alloHCT in myeloma should focus to minimize TRM and maximize graft-versus myeloma effects. This trial was registered in (NCT00075829) and was funded by the National Heart, Lung and Blood Institute and National Cancer Institute.
PMCID: PMC3611089  PMID: 21962393
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 receiving 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 non-relapse 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.
PMCID: PMC3175301  PMID: 21624486
obesity; myeloma; autologous transplantation; chemotherapy; radiation therapy; melphalan
24.  Effect of acute and chronic graft-versus-host disease on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma 
Bone Marrow Transplantation  2011;47(6):831-837.
We evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on relapse and survival after allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005 following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (grades I–IV) was 42% (95% confidence interval (CI) 35 – 49%) and of chronic GVHD at five years was 59% (95% CI 49 – 69%), with 70% developing extensive chronic GVHD. In multivariate analysis, acute GVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42; p=0.016), whereas limited chronic GVHD significantly decreased the risk of myeloma relapse (RR=0.35, p=0.035) and was associated with superior event-free survival (RR=0.40, p=0.027). Acute GVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52; p=0.001). The reduction in relapse risk associated with chronic GVHD is consistent with a beneficial graft-versus-myeloma effect, but this did not translate into a survival advantage.
PMCID: PMC3369112  PMID: 21946381
Graft-versus-host disease; reduced intensity; allogeneic; myeloma
25.  Hematopoietic Cell Transplantation for Primary Plasma Cell Leukemia: Results from the Center for International Blood and Marrow Transplant Research 
Leukemia  2011;26(5):1091-1097.
There is limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT respectively. Progression-free survival (PFS) at 3 years was 34% (95% CI, 23%-46%) in the autologous group and 20% (95% CI, 10%-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48%-72%) in the autologous group and 38% (95% CI, 25%-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52%-75%) in the autologous group and 39% (95% CI, 26%-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28%-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no overall survival benefit.
PMCID: PMC3274611  PMID: 22042147
primary plasma cell leukemia; stem cell transplant; overall survival

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