Celalettin Ustun

Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Tyrosine kinase inhibitors in the treatment of systemic mastocytosis

Systemic mastocytosis (SM) is a heterogeneous disease, vast majority of these patients have a gain of function mutation in the gene encoding the tyrosine kinase KIT (KIT(D816V)). A small subset of SM patients with KIT(D816V) mutation require cytoreductive therapy. In these patients, tyrosine kinase inhibitors (TKIs) have been actively investigated over the last decade because of codon 816 KIT mutations causing constitutive activation of tyrosine kinase activity of the molecule. The main question has been whether the success story with imatinib in chronic myeloid leukemia (CML), another disease associated with a constitutively active tyrosine kinase, could be mimicked in mastocytosis. However, the results from various TKIs in SM with KIT(D816V) mutation have been disappointing to date. Only a few of the TKIs sufficiently block KIT(D816V) activity and have shown promising clinical results. The data from these studies indicate that, apart from KIT(D816V), other kinase targets and target pathways may play a role in disease evolution and progression, especially in patients with SM with an associated clonal hematological non-mast cell lineage disease (SM-AHNMD). Imatinib is effective in patients with increased mast cells and eosinophils associated with FIP1L1/PDGFRA+ (e.g., myeloid neoplasm with eosinophilia and rearrangement of PDGFRA) or rare patients with SM associated with KIT mutations outside of exon 17. This review will focus on the KIT receptor, KIT mutations, and the effects of the mutations in SM. The preclinical and clinical activities of FDA approved TKIs (for CML) as well as novel TKIs in SM will be evaluated.

Regulatory T cells in acute myelogenous leukemia: Is it time for immunomodulation?

The microenviroment of acute myelogenous leukemia (AML) is suppressive for immune effector cells. Regulatory T cells (Tregs) have been recognized as a contributor factor and may be recruited and exploited by leukemic cells to evade immunesurveillance. Studies have shown that the frequencies of marrow and blood Tregs are greater in patients with AML than in control patients. Although increased Tregs have been associated with a decreased risk of GVHD after allogeneic HCT and hence may impede the graft-versus-tumor effect, recent findings indicate that that this may not be the case. Because there is a need to improve outcomes of standard treatment (chemotherapy with or without allogeneic HCT) in AML, targeting Tregs present an outstanding opportunity in AML because discoveries may apply throughout its treatment. Here, we review data on the roles of Tregs in mediating immune system-AML interactions. We focused on in vitro, animal, and observational human studies of Tregs in AML biology, development, prognosis, and therapy in different settings (eg, vaccination and HCT). Manipulation of Tregs or other types of immunomodulation may become a part of AML treatment in the future.

Enterococcal Bacteremia Is Associated With Increased Risk of Mortality in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation

BACKGROUND Enterococci are an important cause of healthcare-associated infections. We retrospectively analyzed risk factors and outcome of vancomycin-resistant enterococci (VRE) and vancomycin-sensitive enterococci (VSE) infections. METHODS Seven hundred fifty-two patients who received hematopoietic stem cell transplants from 2004 through 2008 at the University of Minnesota were included. RESULTS Ninety-three patients had enterococcal bloodstream infection (BSI) during the first year after transplant. Vancomycin resistance was observed in 66% and 31% of isolates in adults and children, respectively. Cumulative incidence of VRE and VSE bacteremia was 6.6% (95% confidence interval [CI], 4.8%-8.4%) and 5.7% (95% CI, 4.0%-7.4%), respectively. Colonization with VRE before or after transplant was a risk factor for VRE bacteremia (odds ratio [OR], 3.3 [95% CI, 1.3-8.3] and 7.0 [95% CI, 4.0-14.8], respectively). Delay in engraftment increased the incidence of VRE bacteremia from 4.5% (95% CI, 2.9-6.6) if engrafted before day 21 and to 15% (95% CI, 3.2%-38%) if engrafted between days 36 and 42. In adults, mortality 30 days after infection was 38% for both VRE (95% CI, 25%-54%) and VSE cases (95% CI, 21%-62%). The hazard ratio for all-cause mortality up to 1 year after transplant was 4.2 (95% CI, 3.1-6.9) and 2.7 (95% CI, 1.4-5.1) for patients with VRE and VSE BSIs, respectively, compared to patients without enterococcal BSI. In pediatric patients, mortality 30 days after VRE and VSE bacteremia was 20% (95% CI, 5.4%-59%) and 4.5% (95% CI, .6%-28%), respectively. CONCLUSION High rates of vancomycin resistance and association of enterococcal infections with significant mortality warrant further efforts to optimize prevention and management of these infections.

Targeting levels or oligomerization of nucleophosmin 1 induces differentiation and loss of survival of human AML cells with mutant NPM1

Nucleophosmin 1 (NPM1) is an oligomeric, nucleolar phosphoprotein that functions as a molecular chaperone for both proteins and nucleic acids. NPM1 is mutated in approximately one-third of patients with AML. The mutant NPM1c+ contains a 4-base insert that results in extra C-terminal residues encoding a nuclear export signal, which causes NPM1c+ to be localized in the cytoplasm. Here, we determined the effects of targeting NPM1 in cultured and primary AML cells. Treatment with siRNA to NPM1 induced p53 and p21, decreased the percentage of cells in S-phase of the cell cycle, as well as induced differentiation of the AML OCI-AML3 cells that express both NPMc+ and unmutated NPM1. Notably, knockdown of NPM1 by shRNA abolished lethal AML phenotype induced by OCI-AML3 cells in NOD/SCID mice. Knockdown of NPM1 also sensitized OCI-AML3 to all-trans retinoic acid (ATRA) and cytarabine. Inhibition of NPM1 oligomerization by NSC348884 induced apoptosis and sensitized OCI-AML3 and primary AML cells expressing NPM1c+ to ATRA. This effect was significantly less in AML cells coexpressing FLT3-ITD, or in AML or normal CD34+ progenitor cells expressing wild-type NPM1. Thus, attenuating levels or oligomerization of NPM1 selectively induces apoptosis and sensitizes NPM1c+ expressing AML cells to treatment with ATRA and cytarabine.

Hematopoietic Stem-Cell Transplantation for Advanced Systemic Mastocytosis

PURPOSE Advanced systemic mastocytosis (SM), a fatal hematopoietic malignancy characterized by drug resistance, has no standard therapy. The effectiveness of allogeneic hematopoietic stem-cell transplantation (alloHCT) in SM remains unknown. PATIENTS AND METHODS In a global effort to define the value of HCT in SM, 57 patients with the following subtypes of SM were evaluated: SM associated with clonal hematologic non-mast cell disorders (SM-AHNMD; n = 38), mast cell leukemia (MCL; n = 12), and aggressive SM (ASM; n = 7). Median age of patients was 46 years (range, 11 to 67 years). Donors were HLA-identical (n = 34), unrelated (n = 17), umbilical cord blood (n = 2), HLA-haploidentical (n = 1), or unknown (n = 3). Thirty-six patients received myeloablative conditioning (MAC), and 21 patients received reduced-intensity conditioning (RIC). RESULTS Responses in SM were observed in 40 patients (70%), with complete remission in 16 patients (28%). Twelve patients (21%) had stable disease, and five patients (9%) had primary refractory disease. Overall survival (OS) at 3 years was 57% for all patients, 74% for patients with SM-AHNMD, 43% for those with ASM, and 17% for those with MCL. The strongest risk factor for poor OS was MCL. Survival was also lower in patients receiving RIC compared with MAC and in patients having progression compared with patients having stable disease or response. CONCLUSION AlloHCT was associated with long-term survival in patients with advanced SM. Although alloHCT may be considered as a viable and potentially curative therapeutic option for advanced SM in the meantime, given that this is a retrospective analysis with no control group, the definitive role of alloHCT will need to be determined by a prospective trial.

Similar Overall Survival Using Sibling, Unrelated Donor, and Cord Blood Grafts after Reduced-Intensity Conditioning for Older Patients with Acute Myelogenous Leukemia

For older patients with acute myeloid leukemia (AML), allogeneic hematopoietic cell transplantation (HCT) provides the best chance of long-term survival. A formal comparison between matched sibling (SIB), unrelated donor (URD), or umbilical cord blood (UCB) transplantation has not yet been reported in this setting. We compared reduced-intensity conditioning HCT in 197 consecutive patients 50 years and older with AML in complete remission from SIB (n = 82), URD (n = 35), or UCB (n = 80) transplantation. The 3-year cumulative incidences of transplantation-related mortality were 18%, 14%, and 24% with SIB, URD, and UCB transplantation, respectively (P = .22). The 3-year leukemia-free survival rates were 48%, 57%, and 33% with SIB, URD, and UCB transplantation, respectively (P = .009). In multivariate analysis, poor-risk cytogenetics was associated with relapse (hazard ratio, 1.7 [95% confidence interval, 1.0 to 3.0]; P = .04) and worse leukemia-free survival (hazard ratio, 1.6 [95% confidence interval, 1.0 to 2.5]; P = .03), whereas donor choice had no significant impact on overall survival (P = .73). Adjusted 3-year overall survival rates were 55% with SIB, 45% with URD, and 43% with UCB transplantation (P = .26). Until prospective studies are completed, this study supports the recommendation to consider SIB donor, URD, or UCB for HCT for older patients with AML in complete remission.

Alternative donor transplantation for older patients with acute myeloid leukemia in first complete remission: a center for international blood and marrow transplant research-eurocord analysis.

We studied patients with acute myeloid leukemia (AML) over age 50 and in first complete remission (CR1) after adult unrelated donor (URD) (n = 441, 8/8 HLA matched; n = 94, 7/8 HLA matched) or umbilical cord blood (UCB; n = 205) transplantations. UCB recipients achieved CR1 within 8 weeks less often, and received reduced-intensity conditioning and cyclosporine-based graft-versus-host disease (GVHD) prophylaxis more often. Neutrophil recovery was slower in UCB (69% by day 28) compared with 8/8 HLA-matched URD (97%) and 7/8 HLA-matched (91%) (P < .001) recipients. Three-year transplantation-related mortality (TRM) was higher and leukemia-free survival (LFS) lower with UCB (35% and 28%, respectively) versus 8/8 HLA-matched URD (27% and 39%, respectively). TRM was higher in 7/8 HLA-matched URD (41%, P = .01), but LFS was similar at 34% (P = .39). Three-year chronic GVHD was the lowest in UCB (28%) versus 53% and 59% in 8/8 and 7/8 HLA-matched URD recipients, respectively. Three-year survival was 43% in 8/8 HLA-matched URD (95% confidence interval [CI], 38% to 48%), 30% in UCB (95% CI, 23% to 37%) (P = .002) and 37% in 7/8 URD (95% CI, 27 to 46). Allotransplantation for AML in CR1 with any of these grafts extends LFS for over one third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.

Human Herpesvirus 6 Infection after Hematopoietic Cell Transplantation: Is Routine Surveillance Necessary?

Human herpesvirus 6 (HHV6) may be an important pathogen following allogeneic hematopoietic cell transplantation (HCT). We prospectively evaluated weekly HHV6 viremia testing after allogeneic HCT using a quantitative polymerase chain reaction (PCR)-based assay. HHV-6 viremia was detected in 46 of 82 (56%) patients at a median of 23 days post-HCT (range: day +10 to +168). More males (65% vs females 39%, P = .03) and recipients of umbilical cord blood (UCB 69% vs unrelated donor [URD], 46% vs sibling donor [20%] grafts, P = 0.01) reactivated HHV-6. Patients with HHV6 viremia had more cytomegalovirus (CMV) reactivation (26% vs 5.5%, P = .01) and unexplained fever and rash (23.9% vs 2.7%, P = .01) compared with patients without HHV6 viremia. High-level HHV6 (≥ 25,000 copies/mL) versus lower levels were associated with more culture-negative pneumonitis (72.7% vs 22.8%, P = .01). Twenty HHV6-positive patients were treated with foscarnet, ganciclovir, or cidofovir for HHV6 or other coexistent viruses. Within 2 weeks, HHV6 viremia resolved more commonly in treated (65%) than untreated patients (31%), P = .02. Survival at 3 months was similar in treated and untreated patients (90% vs 81%, P = .4). Survival at 3 and 6 months post-HCT were not affected by HHV6 positivity (3 months HHV6+ 85% vs 78%, P = .46; 6 months HHV6+ 70% vs 72%, P = .89) or by HHV6 level (3-month high level 73% vs 89%, P = .23; 6-month high level 64% vs 71%, P = .54). Neither the occurrence of HHV6, degree of viremia, nor use of antiviral drugs influenced short-term survival after HCT.

Reduced-Intensity Hematopoietic Cell Transplantation for Patients with Primary Myelofibrosis: A Cohort Analysis from the Center for International Blood and Marrow Transplant Research

We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients.