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1.  Reduced-Intensity Allogeneic Transplantation Using Alemtuzumab from HLA-Matched Related, Unrelated, or Haploidentical Related Donors for Patients with Hematologic Malignancies 
We present a comparative study on 124 patients with hematologic malignancies who had undergone reduced-intensity conditioning and then received a transplant from an HLA-matched related (MRD), an HLA-matched unrelated (MUD), or an HLA-haploidentical related (HAPLO) donor. The conditioning regimen, which consisted of fludarabine, melphalan or busulfan, and alemtuzumab was administered to patients with lymphoid (n = 62) or myeloid disease (n = 62). Mycophenolate mofetil was used as prophylaxis for graft-versus-host disease (GVHD), and 38, 58, and 33 patients received transplants from MRD, MUD, and HAPLO donors, respectively. Only 2 patients experienced primary graft failure (GF) after melphalan-based regimen, whereas 8 of the 17 patients who received a transplant from HAPLO donors experienced a primary GF after busulfan-based regimen. The cumulative incidence of grade III to IV acute GVHD in engrafted patients who had received transplants from MRD, MUD, or HAPLO donors was 3%, 11%, and 27%, respectively, and the 2-year overall survival (OS) rates were 51%, 22%, and 23%, respectively. According to multivariate analysis, transplantation from either MUD or HAPLO donors compared with MRD were adverse factors that affected the OS (P = .006 and P = .002, respectively). In conclusion, the reduced-intensity regimen that included fludarabine, busulfan, or melphalan and alemtuzumab using only mycophenolate mofetil as the GVHD prophylaxis conferred favorable outcomes in the MRD group but lower survival rates in the MUD and HAPLO groups. The busulfan-based regimen led to a high incidence of GF in the HAPLO group, suggesting the need for modification or intensification of immunosuppression.
PMCID: PMC4140655  PMID: 24269380
Reduced-intensity; Alemtuzumab; Matched-related; Matched-unrelated; Haploidentical
2.  Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia 
Nature genetics  2014;46(3):245-252.
Cell fate can be controlled through asymmetric division and segregation of protein determinants. But the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein binding protein Lis1 (Pafah1b1) is critically required for blood formation and hematopoietic stem cell function. Conditional deletion of Lis1 in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, the loss of Lis1 accelerated cell differentiation, in part through defects in spindle positioning and inheritance of cell fate determinants. Finally, deletion of Lis1 blocked propagation of myeloid leukemia and led to a marked improvement in animal survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells, and mark the directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development.
PMCID: PMC4267534  PMID: 24487275
3.  Clinical potential of elacytarabine in patients with acute myeloid leukemia 
Acute myeloid leukemia (AML) has been treated for over four decades with standard induction chemotherapy including seven days of cytosine arabinoside (cytarabine, ara-C) infusion. Cytarabine, while effective in killing leukemic cells, is subject to development of several resistance mechanisms rendering the drug ineffective in many patients. Elacytarabine, a lipophilic 5’-elaidic acid ester or nucleoside analogue of cytosine arabinoside, was created with the intent of overcoming resistance mechanisms including reduced expression of the human equilibrative nucleoside transporter 1 (hENT1) required for cytarabine entry into cells, as well as increased activity of cytidine deaminase (CDA) which breaks down the active metabolite of cytarabine, ara-CTP. Elacytarabine enters cells independently of transporters, has a longer half life compared with cytarabine and is not subject to deactivation by CDA. Preclinical data were encouraging although subsequent clinical studies have failed to show superiority of elacytarabine compared with standard of care as monotherapy in patients with AML. Clinical trials utilizing elacytarabine in combination with anthracyclines are ongoing. Use of hENT1 expression as a predictive marker for cytarabine or elacytarabine response has been studied with no conclusive validation to date. Despite promising early results, the jury is still out in regards to this novel agent as an effective alternative to standard cytarabine therapy in acute leukemias, especially in combination with additional agents such as anthracyclines.
PMCID: PMC4250268  PMID: 25469211
elacytarabine; acute myeloid leukemia; therapy
Prediction of subsequent leukemia-free survival (LFS) and chronic graft-versus-host disease (GVHD) in adults with acute leukemia who survived at least one year after allogeneic HCT is difficult. We analyzed 3339 patients with acute myeloid leukemia (AML) and 1434 with acute lymphoblastic leukemia (ALL) who received myeloablative conditioning and related or unrelated stem cells from 1990–2005. Most clinical factors predictive of LFS in one year survivors were no longer significant after two or more years. For AML, only disease status (beyond first complete remission) remained a significant adverse risk factor for LFS two or more years after transplantation. For ALL, only extensive chronic GVHD remained a significant adverse predictor of LFS in the second and subsequent years. For patients surviving for one year without disease relapse or extensive chronic GVHD, the risk of developing extensive chronic GVHD in the next year was 4% if no risk factors were present, and higher if non-cyclosporine-based GVHD prophylaxis, an HLA-mismatched donor, or peripheral blood stem cells were used. Estimates for subsequent LFS and extensive chronic GVHD can be derived for individual patients or populations using an online calculator ( This prognostic information is more relevant for survivors than estimates provided before transplantation.
PMCID: PMC3832127  PMID: 24018394
leukemia-free survival; chronic graft-versus-host disease; landmark analysis; survivorship; prognosis
5.  Elacytarabine has single-agent activity in patients with advanced acute myeloid leukaemia 
British journal of haematology  2012;158(5):581-588.
Elacytarabine is a novel cytotoxic nucleoside analogue, independent of nucleoside transporters (e.g. human Equilibrative Nucleoside Transporter 1 [hENT1]) for cell uptake, and mechanisms of action similar to those of cytarabine. This Phase II study assessed the efficacy and safety of elacytarabine in patients with advanced stage acute myeloid leukaemia (AML). Patients received 2000 mg/m2/day continuously i.v. during days 1-5 every 3 weeks. Patients were matched by six risk factors with historical controls; remission rate (assessed after 1 or 2 cycles) and 6-month survival were compared. 61 patients, median age 58 years, were enrolled; 52% had five or six risk factors. The remission rate was 18% (95% confidence interval: 9%-30%) vs. 4% in controls (p< 0.0001), 6-month survival rate was 43%, median overall survival was 5.3 months (vs. 1.5 months); 10 patients (16%) were referred for stem cell transplantation after treatment. Side effects were predictable and manageable. The most common grade 3/4 non-haematological adverse events were febrile neutropenia, hypokalemia, fatigue, hyponatraemia, dyspnoea and pyrexia. 30-day all-cause mortality, after start of treatment, was 13% vs. 25% in controls. Elacytarabine has monotherapy activity in patients with advanced AML. This study provides proof-of-concept that lipid esterification of nucleoside analogues is clinically relevant.
PMCID: PMC4191720  PMID: 22702906
Elacytarabine; nucleoside analogue; lipid esterification
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
7.  Elacytarabine, a novel 5′-elaidic acid derivative of cytarabine, and idarubicin combination is active in refractory acute myeloid leukemia 
Leukemia research  2012;36(4):e71-e73.
PMCID: PMC4104110  PMID: 22226018
Elacytarabine; idarubicin; refractory AML; phase I; pharmacokinetics
8.  Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment 
The Journal of Clinical Investigation  2014;124(7):3121-3128.
BACKGROUND. Delayed hematopoietic recovery is a major drawback of umbilical cord blood (UCB) transplantation. Transplantation of ex vivo–expanded UCB shortens time to hematopoietic recovery, but long-term, robust engraftment by the expanded unit has yet to be demonstrated. We tested the hypothesis that a UCB-derived cell product consisting of stem cells expanded for 21 days in the presence of nicotinamide and a noncultured T cell fraction (NiCord) can accelerate hematopoietic recovery and provide long-term engraftment.
METHODS. In a phase I trial, 11 adults with hematologic malignancies received myeloablative bone marrow conditioning followed by transplantation with NiCord and a second unmanipulated UCB unit. Safety, hematopoietic recovery, and donor engraftment were assessed and compared with historical controls.
RESULTS. No adverse events were attributable to the infusion of NiCord. Complete or partial neutrophil and T cell engraftment derived from NiCord was observed in 8 patients, and NiCord engraftment remained stable in all patients, with a median follow-up of 21 months. Two patients achieved long-term engraftment with the unmanipulated unit. Patients transplanted with NiCord achieved earlier median neutrophil recovery (13 vs. 25 days, P < 0.001) compared with that seen in historical controls. The 1-year overall and progression-free survival rates were 82% and 73%, respectively.
CONCLUSION. UCB-derived hematopoietic stem and progenitor cells expanded in the presence of nicotinamide and transplanted with a T cell–containing fraction contain both short-term and long-term repopulating cells. The results justify further study of NiCord transplantation as a single UCB graft. If long-term safety is confirmed, NiCord has the potential to broaden accessibility and reduce the toxicity of UCB transplantation.
FUNDING. Gamida Cell Ltd.
PMCID: PMC4071379  PMID: 24911148
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
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
Bone marrow transplantation  2011;47(6):810-816.
Allogeneic hematopoietic stem cell transplantation (HSCT) is curative treatment, albeit in a minority of patients with accelerated (AP) or blast phase (BP) chronic myeloid leukemia (CML). Imatinib (IM) has transient but significant activity in advanced phases of CML, which may permit early allografting for responding patients. To identify prognostic factors in allograft recipients previously treated with IM, we analyzed 449 allogeneic HSCT performed between 1999–2004 in advanced phase CML using data reported to the Center for International Blood and Marrow Transplant Research. CML patients in second chronic phase (CP2, n=184), AP (n=185), and BP (n=80) received HLA-identical sibling (27%), related (3%), or matched or mismatched unrelated donor (70%), peripheral blood (47%) or bone marrow (53%) HSCT after myeloablative (78%) or non-myeloablative (22%) conditioning. 52% in CP2, 49% in AP, and 46% in BP received IM pre-HSCT. Disease-free survival was 35–40% for CP2, 26–27% for AP and 8–11% for BP. Cumulative incidence of acute and chronic GVHD and TRM were not affected by stages of CML or pre-HSCT IM exposure. Multivariate analyses showed that conventional prognostic indicators remain the strongest determinants of transplant outcomes. In conclusion, there are no new prognostic indicators of outcomes of allogeneic HSCT for advanced phase CML in the IM era.
PMCID: PMC3896981  PMID: 21986636
Imatinib; allogeneic transplantation; chronic myeloid leukemia; accelerated phase; blast phase; outcomes
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
Bone marrow transplantation  2011;47(8):10.1038/bmt.2011.217.
Plerixafor, given on day 4 of G-CSF treatment is more effective than G-CSF alone in mobilizing hematopoietic progenitor cells. We tested a strategy of preemptive plerixafor use following assessment of the peak mobilization response to 5 days of G-CSF. Patients were eligible for plerixafor if, on day 5 of G-CSF, there were less than 7 circulating CD34+ cells/μl or if <1.3 × 106 CD34+ cells/kg were collected on the first day of apheresis. Plerixafor (0.24 mg/kg subcutaneous) was given on day 5 of G-CSF followed by apheresis on day 6. This was repeated for up to two additional doses of plerixafor. The primary endpoint of the study was the percentage of patients who collected at least 2 × 106 CD34+ cells/kg. Twenty candidates for autologous stem cell transplantation enrolled on the trial. The circulating CD34+ cell level increased a median of 3.1 fold (range 1–8 fold) after the first dose of plerixafor and a median of 1.2 fold (range 0.3–6.5 fold) after the second dose of plerixafor. Fifteen of 20 (75%) patients achieved the primary endpoint. In conclusion, the decision to administer plerixafor can be delayed until after the peak mobilization response to G-CSF has been fully assessed.
PMCID: PMC3877677  PMID: 22080963
15.  Adult Dual Umbilical Cord Blood Transplantation Using Myeloablative Total Body Irradiation (1350cGy) and Fludarabine Conditioning 
High treatment-related mortality and high graft failure rate are serious concerns in HLA-mismatched umbilical cord blood (UCB) transplantation with myeloablative conditioning. We conducted a prospective trial of dual UCB transplantation using modified myeloablation consisting of total body irradiation (TBI; 1350 cGy) and fludarabine (160 mg/m2). Twenty-seven patients (median age, 33 years; range, 20–58 years) with hematologic malignancies were enrolled. The median combined cryopreserved total nucleated cell (TNC) dose was 4.3 × 107/kg (range, 3.2–7.7 × 107/kg). The cumulative incidences of neutrophil (≥500/μl) and platelet (≥50,000/μl) engraftment were 80% (95% confidence interval (CI), 58–91%) and 68% (95% CI, 46–83%), respectively. Among engrafted patients, a single cord blood unit was predominant by 100 days post transplantation. A higher cryopreserved and infused TNC dose and infused CD3+ cell dose were significant factors associated with the predominant UCB unit (P = 0.032, 0.020, and 0.042, respectively). Treatment-related mortality and relapse rates at 2 years were 28% (95% CI, 12–47%) and 20% (95% CI, 7–37%), respectively. Cumulative incidences of grades II–IV and grades III–IV acute GVHD were 37% (95% CI, 20–55%) and 11% (95% CI, 3–26%), respectively, and that of chronic GVHD was 31% (95% CI, 15–49%). With a median follow-up of 23 months, overall and disease-free survival rates at 2 years were 58% (95% CI, 34–75%) and 52% (95% CI, 29–70%), respectively. This study supports the use of TBI 1350cGy/fludarabine as an alternative to conventional myeloablative conditioning for dual UCB transplantation.
PMCID: PMC3877679  PMID: 20868761
adult; dual umbilical cord blood transplantation; myeloablative; fludarabine; total body irradiation
16.  Haploidentical Transplantation for Leukemia 
Current oncology reports  2010;12(5):10.1007/s11912-010-0113-4.
Hematopoietic stem cell transplantation from human leukocyte antigen (HLA)-haploidentical family members offers a potential cure for patients in need of allogeneic immunotherapy who have no immediate access to an HLA-matched donor. The use of ex vivo T-cell-depleted stem cells combined with immuno-myeloablative conditioning has enabled durable donor engraftment with a low incidence of acute graft-versus-host disease despite the HLA disparity. Moreover, additional transplant techniques involving in vivo T-cell-depletion and reduced-intensity conditioning have further minimized the risks. However, a major drawback is delayed immune reconstitution leading to infections and high relapse rates, prompting significant research efforts focused on improving recovery in the post-transplant period. Infusions with donor lymphocytes are common, though newer manipulations with a focus on donor natural killer cells hold great promise as does other modified donor T-cell infusions. Success of these new procedures will make haploidentical transplants safer and more effective, further broadening its appeal.
PMCID: PMC3874937  PMID: 20602183
haploidentical transplantation; T-cell-depletion method; immune recovery; donor lymphocyte infusion; KIR ligand mismatch; NK cell infusion; interleukin-2
17.  New approaches to manipulate minimal residual disease after allogeneic stem cell transplantation 
International journal of hematologic oncology  2013;2(1):10.2217/ijh.13.4.
Minimal residual disease (MRD) is a complex topic that has been studied extensively in hematologic malignancies given its clinical implications related to prognosis. However, methods to monitor and treat MRD, especially after stem cell transplantation, are not well defined and vary in different disease processes. Alternative transplant strategies, such as reduced-intensity conditioning, have altered the way we assess and address MRD after transplantation. Development of new diagnostic tools have allowed for higher sensitivity and specificity of testing. Both targeted chemotherapeutic agents and immunotherapies have been developed to treat MRD in hopes of improving patient outcomes. This article aims to address ways to define and manipulate MRD specifically after stem cell transplantation.
PMCID: PMC3841006  PMID: 24303095
18.  Comparison of Reduced-Intensity Hematopoietic Cell Transplantation with Chemotherapy in Patients Aged 60–70 Years with Acute Myeloid Leukemia in First Remission 
We compared the outcomes of acute myeloid leukemia (AML) patients aged 60–70 years receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (CIBMTR) (N=94) with outcomes in patients treated with induction and post-remission chemotherapy on Cancer and Leukemia Group B (CALGB) protocols (N=96). All patients included had remained in CR1 for at least 4 months. HCT recipients were slightly younger than chemotherapy patients (median ages: 63 v 65 years; P<0.001), with no significant differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for HCT recipients (median: 44 v 38 days; P=0.031). Allogeneic HCT was associated with significantly lower risk of relapse (32% v 81% at 3 years; P<0.001), higher non-relapse mortality (36% v 4% at 3 years; P<0.001), and longer leukemia-free survival (32% v 15% at 3 years; P=0.001). Although overall survival was longer for HCT recipients, this was not statistically significant (37% v 25% at 3 years; P=0.08). RIC allogeneic HCT in CR1 AML patients aged 60–70 years reduces relapse and improves leukemia-free survival. Strategies that reduce non-relapse mortality may yield significant improvements in overall survival.
PMCID: PMC3817558  PMID: 21699879
acute myeloid leukemia; allogeneic; reduced-intensity transplantation
19.  Immune Recovery in Adult Patients Following Myeloablative Dual Umbilical Cord Blood, Matched Sibling, and Matched Unrelated Donor Hematopoietic Cell Transplantation 
Immunologic reconstitution following allogeneic hematopoietic cell transplantation (HCT) is a critical component of successful outcome. Umbilical cord blood (UCB) transplantation in adult recipients is associated with slow and often inadequate immune recovery. We characterized the kinetics and extent of immune recovery in 95 adult recipients following a dual UCB (n=29), and matched sibling (MSD) (n=33) or unrelated donor (MUD) (n=33) transplantation. All patients were treated with myeloablative conditioning. There were no differences in the immune recovery profile of MSD and MUD recipients. Significantly lower levels of CD3+, CD4+ and CD8+ T-cells were observed in UCB recipients until 6 months following transplantation. Lower levels of regulatory T-cells persisted until 1 year following transplantation. Thymopoiesis as measured by T-cell receptor rearrangement excision circle (TREC) was comparable among all recipients by 6 months following transplantation. In a subset of patients 1 year following transplantation with similar levels of circulating T-cells and TREC, there was no difference in T-cell receptor diversity. Compared to HLA-identical MSD and MUD adult HCT recipients, quantitative lymphoid recovery in UCB transplant recipients is slower in the first 3 months, but these differences disappeared by 6–12 months following transplantation.
PMCID: PMC3472115  PMID: 22698485
adult; dual umbilical cord blood transplantation; matched sibling transplantation; matched unrelated donor transplantation; immune recovery; T-cell receptor excision DNA circles (TRECs); post-thymic T-cell reconstitution
21.  Re-induction therapy decisions based on day 14 bone marrow biopsy in acute myeloid leukemia 
Leukemia research  2012;37(1):28-31.
The decision to re-induce patients with acute myeloid leukemia (AML) based on results of the day 14 bone marrow (BM) biopsy is variable and lacks evidence based data. The aim of our review was to evaluate the accuracy of a day 14 BM biopsy in determining the need for re-induction chemotherapy.
Seventy-four patients with newly diagnosed de novo AML treated with induction chemotherapy were retrospectively reviewed for the purpose of evaluating treatment decisions and outcomes based on their day 14 BM biopsy. Response to therapy in this analysis was based on morphology alone.
Of the 74 patients undergoing standard induction, 45 patients (61%) had no evidence of leukemia on their day 14 BM biopsy. Eighteen patients (24%) had definitive residual disease (RD), and 11 patient’s (15%) were classified as indeterminate response (IR). Fifteen patients with RD and one with IR underwent re-induction chemotherapy. However, thirteen patients (3 RD and 10 IR) were observed until count recovery without any re-induction therapy. Eleven of these 13 patients who were observed eventually attained a morphologic complete remission (CR), including two patients with RD.
A day 14 BM biopsy may have suboptimal sensitivity for the detection of residual leukemia. Some patients with an IR on day 14 may not require re-induction chemotherapy, but instead, may benefit from careful observation until count recovery to avoid the mortality and morbidity associated with re-induction chemotherapy.
PMCID: PMC3753071  PMID: 23046833
AML; D14 BM biopsy; Re-induction
22.  Pre-engraftment syndrome after myeloablative dual umbilical cord blood transplantation: Risk factors and response to treatment 
Bone marrow transplantation  2013;48(7):926-931.
High fever and/or rash prior to neutrophil engraftment are frequently observed after umbilical cord blood (UCB) transplantation, and the condition is referred to as pre-engraftment syndrome (PES). Few studies have evaluated the risk factors for and treatment response to PES. Therefore, we retrospectively characterized PES in 57 consecutive engrafted patients (≥12 years old) who received myeloablative dual UCB transplantation. All patients received TBI (≥13.2Gy)-based myeloablative conditioning. Tacrolimus (n=35) or cyclosporine (n=22) combined with mycophenolate mofetil was used as GVHD prophylaxis. PES was defined as the presence of non-infectious fever (≥38.5°C) and/or rash prior to or on the day of neutrophil engraftment. The incidence (95% CI) of PES was 77% (66%–88%). The incidence of PES was significantly higher in patients who received cyclosporine as a GVHD prophylaxis than those who received tacrolimus (P<0.001), and this association was confirmed in the multivariate analysis. The occurrence of PES did not impact overall survival or tumor relapse, although it may have increased non-relapse mortality (P=0.071). The incidence of acute GHVD or treatment-related mortality was not influenced by the choice to use corticosteroids to treat PES. This study suggests that use of cyclosporine for GVHD prophylaxis increases the risk of PES following dual umbilical cord blood transplantation.
PMCID: PMC3701735  PMID: 23334274
pre-engraftment syndrome; dual umbilical cord blood transplantation; myeloablative
23.  The genetic landscape of mutations in Burkitt lymphoma 
Nature genetics  2012;44(12):1321-1325.
Burkitt lymphoma is characterized by deregulation of MYC, but the contribution of other genetic mutations to the disease is largely unknown. Here, we describe the first completely sequenced genome from a Burkitt lymphoma tumor and germline DNA from the same affected individual. We further sequenced the exomes of 59 Burkitt lymphoma tumors and compared them to sequenced exomes from 94 diffuse large B-cell lymphoma (DLBCL) tumors. We identified 70 genes that were recurrently mutated in Burkitt lymphomas, including ID3, GNA13, RET, PIK3R1 and the SWI/SNF genes ARID1A and SMARCA4. Our data implicate a number of genes in cancer for the first time, including CCT6B, SALL3, FTCD and PC. ID3 mutations occurred in 34% of Burkitt lymphomas and not in DLBCLs. We show experimentally that ID3 mutations promote cell cycle progression and proliferation. Our work thus elucidates commonly occurring gene-coding mutations in Burkitt lymphoma and implicates ID3 as a new tumor suppressor gene.
PMCID: PMC3674561  PMID: 23143597
24.  Response and toxicity of donor lymphocyte infusions following T cell depleted non-myeloablative allogeneic hematopoietic stem cell transplantation from 3–6/6 HLA matched donors 
Bone marrow transplantation  2008;43(4):327-333.
We report the outcome of early donor lymphocyte infusions (DLI) following T-cell depleted non-myeloablative transplantation using stem cells from human leukocyte antigen (HLA) matched or mismatched donors.
Patients and Methods
Sixty-nine patients with high risk hematologic malignancies received DLI following fludarabine, cyclophosphamide, and alemtuzumab with infusion of stem cells from a matched sibling (52) or partially matched family member donor (17).
Patients received the first infusion a median of 50 days following transplant and doses ranged from 1×104 CD3+ cells/kg to 3.27 ×108 CD3+ cells/kg, depending on clinical status and physician’s discretion. A median cell dose of 1× 105 CD3+ cells/kg in the mismatched setting and 1×106 CD3+ cells/kg in the matched sibling setting appears safe with only 1/7 (14%) and 4/31 (13%) respectively experiencing severe aGVHD at these doses. Importantly, 38% of patients with persistent disease prior to DLI attained a remission following infusion. Nine of the 69 remain alive and disease free 32–71 months following the first DLI infusion.
Low doses of DLI can be safely provided soon after T-cell depleted non-myeloablative therapy and provide a chance of remission. However, long term survival still remains poor due primarily to relapse in these patients however.
PMCID: PMC3635807  PMID: 18850014
DLI; haploidentical donors; Non-myeloablative Allogeneic Transplantation; Leukemia/Lymphoma
25.  Differential Impact of Inhibitory and Activating Killer Immunoglobulin-Like Receptors (KIR) in High Risk Patients with Myeloid and Lymphoid Malignancies Undergoing Reduced Intensity Transplantation from Haploidentical Related Donors 
Bone marrow transplantation  2011;47(6):817-823.
Impact of activating (aKIR) and inhibitory (iKIR) on overall survival (OS), relapse-related mortality (RRM), and acute graft-vs.-host disease (aGVHD) were studied in 84 adults with high risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic stem cell transplantation (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM was more dependent on graft-vs-leukemia (GVL) effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (p=0.009) and RRM lower (p=0.036) in patients missing HLA-C group2 ligand to donor inhibitory KIR. OS was higher if patients had >1 missing ligand (p=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was longer with donor activating KIR 2DS2 (p=0.028). There was a trend toward shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes are too small to provide inferential statistics. These results suggest that absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.
PMCID: PMC3629554  PMID: 22139069
KIR; Activating KIR; Inhibitory KIR; Haploidentical; Reduced Intensity Conditioning (RIC); Hematopoietic Stem Cell Transplantation (HSCT)

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