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1.  Reduced intensity allogeneic hematopoietic stem cell transplantion for MDS using tacrolimus/sirolimus-based GVHD prophylaxis 
Leukemia research  2012;36(9):1152-1156.
We report a consecutive series of 59 patients with MDS who underwent reduced-intensity hematopoietic stem cell transplantation (RI-HSCT) with fludarabine/melphalan conditioning and tacrolimus/sirolimus-based GVHD prophylaxis. Two-year OS, EFS, and relapse incidences were 75.1%, 65.2%, and 20.9%, respectively. The cumulative incidence of non-relapse mortality at 100 days, 1 year, and 2 years was 3.4%, 8.5%, and 10.5%, respectively. The incidence of grade II-IV acute GVHD was 35.4%; grade III-IV was 18.6%. Forty of 55 evaluable patients developed chronic GVHD, 35 extensive grade. This RI-HSCT protocol produces encouraging outcomes in MDS patients, and tacrolimus/sirolimus-based GVHD prophylaxis may contribute to that promising result.
PMCID: PMC3433241  PMID: 22677229
myelodysplastic syndrome; sirolimus; tacrolimus; allogeneic hematopoietic cell transplantation
2.  Deferasirox: appraisal of safety and efficacy in long-term therapy 
Journal of Blood Medicine  2013;4:101-110.
Deferasirox is a once-daily, oral iron chelator that is widely used in the management of patients with transfusional hemosiderosis. Several Phase II trials along with their respective extension studies as well as a Phase III trial have established the efficacy and safety of this novel agent in transfusion-dependent patients with β-thalassemia, sickle-cell disease and bone marrow-failure syndromes, including myelodysplastic syndrome and aplastic anemia. Data from various clinical trials show that a deferasirox dose of 20 mg/kg/day stabilizes serum ferritin levels and liver iron concentration, while a dose of 30–40 mg/kg/day reduces these parameters and achieves negative iron balance in red cell transfusion-dependent patients with iron overload. Across various pivotal clinical trials, deferasirox was well tolerated, with the most common adverse events being gastrointestinal disturbances, skin rash, nonprogressive increases in serum creatinine, and elevations in liver enzyme levels. Longer-term extension studies have also confirmed the efficacy and safety of deferasirox. However, it is essential that patients on deferasirox therapy are monitored regularly to ensure timely management for any adverse events that may occur with long-term therapy.
PMCID: PMC3743529  PMID: 23966805
deferasirox; iron overload; thalassemia; sickle-cell disease; myelodysplastic syndrome
3.  Impact of graft cell dose on transplant outcomes following unrelated donor allogeneic peripheral blood stem cell transplantation: Higher CD34+ cell doses are associated with decreased relapse rates 
Peripheral blood stem cells (PBSC) have been increasingly used in the matched unrelated donor (MUD) transplant setting, but the impact of CD34+ cell dose on outcomes in this setting have not been well characterized. We analyzed 181 consecutive patients who underwent MUD-PBSC transplantation at City of Hope between August 2000 to December 2004. Patients were conditioned with either full-intensity regimen or reduced-intensity regimen. There was a significant inverse relationship between higher CD34+ cell dose and faster neutrophil engraftment (r= −0.16, p=0.035). By univariate analysis, a CD34+ cell dose ≥4.2x106/kg (above the lowest quartile) was associated with significantly lower relapse risk (HR=0.67; p=0.0126), with a trend for corresponding improvement for disease-free survival (HR=0.84; p=0.12) but not overall survival (HR=0.91; p=0.46). The impact of the CD34+ cell dose remained significant in multivariate analysis. The higher CD34+ cell dose was significantly associated with faster recovery of absolute lymphocyte counts on day +30 post-transplant. Subset analysis demonstrated that the higher CD34+ cell dose was associated with 1) greater reduction in relapse in myeloid malignancies than that in lymphoid malignancies, 2) greater reduction in reduced-intensity conditioning than in full-intensity conditioning, 3) greater reduction in relapse when there is a inhibitory killer-cell immunoglobulin-like receptor ligand (iKIRL)-mismatch in the GVH direction, and 4) greater reduction in relapse when there is a lack of iKIRL, suggesting that the protective effect of CD34+ cell dose against relapse may be immune-mediated, possibly through NK cell recovery.
PMCID: PMC3589832  PMID: 18342788
unrelated donor; peripheral blood hematopoietic cell transplantation; CD34+ cell dose
4.  CD154 expression is associated with neutralizing antibody titer levels post- Influenza vaccination in stem cell transplant patients and healthy adults 
We undertook a prospective longitudinal study to examine humoral and cellular immune responses to influenza vaccination in hematopoietic cell transplant (HCT) patients and healthy adults.
Healthy volunteers and HCT patients had blood samples taken prior to influenza vaccination and 30, 90, and 180 days post-vaccination. Serum from pre and post-vaccination time points were tested for influenza A IgG and IgM by ELISA as well as tested for neutralizing antibody (NAb) titers via hemagluttination inhibition assay. Polychromatic flow cytometry was used to examine CD4+ T cells for levels of IFN-γ, TNF-α, and CD154 (CD40 ligand) expression after stimulation with inactivated flu virus.
In healthy subjects, we found a significant increase in Influenza A IgG and IgM levels as well as an increase in NAb titers pre and post-influenza vaccination. Notably, NAb titers of most HCT patients did not rise to a protective level post-vaccination. CD4+ T cell expression of CD154 and cytokine responses were significantly reduced in HCT recipients compared to healthy adults.
A lack of B cell reconstitution and dysfunctional CD4 T cell co-stimulation (as marked by low CD154 expression) is associated with low NAb levels post-vaccination in HCT patients.
PMCID: PMC2933414  PMID: 20457264
CD154; CD40L; Influenza; Vaccination; Stem Cell Transplant
5.  Phase II Study of Vorinostat for Treatment of Relapsed or Refractory Indolent Non-Hodgkin's Lymphoma and Mantle Cell Lymphoma 
Journal of Clinical Oncology  2011;29(9):1198-1203.
We performed a phase II study of oral vorinostat, a histone and protein deacetylase inhibitor, to examine its efficacy and tolerability in patients with relapsed/refractory indolent lymphoma.
Patients and Methods
In this open label phase II study (NCT00253630), patients with relapsed/refractory follicular lymphoma (FL), marginal zone lymphoma (MZL), or mantle cell lymphoma (MCL), with ≤ 4 prior therapies were eligible. Oral vorinostat was administered at a dose of 200 mg twice daily on days 1 through 14 of a 21-day cycle until progression or unacceptable toxicity. The primary end point was objective response rate (ORR), with secondary end points of progression-free survival (PFS), time to progression, duration of response, safety, and tolerability.
All 35 eligible patients were evaluable for response. The median number of vorinostat cycles received was nine. ORR was 29% (five complete responses [CR] and five partial responses [PR]). For 17 patients with FL, ORR was 47% (four CR, four PR). There were two of nine responders with MZL (one CR, one PR), and no formal responders among the nine patients with MCL, although one patient maintained stable disease for 26 months. Median PFS was 15.6 months for patients with FL, 5.9 months for MCL, and 18.8 months for MZL. The drug was well-tolerated over long periods of treatment, with the most common grade 3 adverse events being thrombocytopenia, anemia, leucopenia, and fatigue.
Oral vorinostat is a promising agent in FL and MZL, with an acceptable safety profile. Further studies in combination with other active agents in this setting are warranted.
PMCID: PMC3083875  PMID: 21300924
6.  Phase-2 Trial of an Intensified Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant for Poor-Risk Leukemia 
Bone marrow transplantation  2010;46(9):1256-1262.
Patients with poor-risk leukemia have a high relapse rate despite allogeneic transplant. We report on the phase II trial of an intensified allogeneic transplant regimen whose aim was tolerable toxicity and durable remission. Study patients (n=30) had unfavorable first remission cytogenetics, progression from myelodysplasia or active disease due to induction failure or relapse. Conditioning was intravenous busulfan, targeted to a first-dose plasma area under the curve (AUC) of 700–900 µM·min, VP-16 at 30 mg/kg of adjusted ideal body weight and fractionated total body irradiation (FTBI) at 1200 cGy in ten fractions. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine A and mycophenolate mofetil. Regimen-related toxicities (Bearman) included grade 3 mucositis in 29 patients (97%) and grade 4 in one, grade 2–3 sinusoidal obstructive syndrome in 2 patients (7%), and grade 2–3 skin toxicity in 8 patients (27%). The 30- and 100-day transplant-related mortalities were 0% and 7% respectively. The median follow-up was 83.7 months (60.7–96.4) for surviving patients. The 5-yr overall and disease-free survival was 40% for all patients. Cumulative 5-yr relapse incidence was 23% and transplant-related mortality was 37%. We have shown promising overall survival and relapse incidence in these poor-risk patients, who typically have few curative options.
PMCID: PMC3203202  PMID: 21151180
7.  Improved Outcomes Using Tacrolimus/Sirolimus for Graft Versus Host Disease prophylaxis with a Reduced Intensity Conditioning Regimen for Allogeneic Hematopoietic Cell Transplant as treatment of Myelofibrosis 
Allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we (1) and others have reported. Non-relapse mortality (NRM) from Graft vs. Host Disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/− methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CSA)/mycophenolate (MMF) +/− MTX, and the current series of 14 patients who received tacrolimus/sirolimus +/− MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow up for alive patients was 29.0 months (9.5–97.0). The estimated 2 yr overall survival (OS) for the CSA/MMF cohort was 55.6 % (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (p=0.047). The probability of grade III or IV acute GVHD was 60% for the CSA/MMF patients, and 10% for the tacrolimus/sirolimus group (p=0.0102). No significant differences were seen for grade II to IV acute GVHD in the two groups. We conclude that the combination of tacrolimus/sirolimus +/− MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe acute GVHD and NRM, and leads to improved OS compared to CSA/MMF +/− MTX.
PMCID: PMC2819616  PMID: 19786111
Myelofibrosis; reduced intensity conditioning; allogeneic transplantation; tacrolimus/sirolimus
8.  Iron Overload in Patients Undergoing Hematopoietic Stem Cell Transplantation 
Advances in Hematology  2010;2010:345756.
Recipients of hematopoietic stem cell transplantation (HSCT) frequently have iron overload resulting from chronic transfusion therapy for anemia. In some cases, for example, in patients with myelodysplastic syndromes and thalassemia, this can be further exacerbated by increased absorption of iron from the gut as a result of ineffective erythropoiesis. Accumulating evidence has established the negative impact of elevated pretransplantation serum ferritin, a surrogate marker of iron overload, on overall survival and nonrelapse mortality after HSCT. Complications of HSCT associated with iron overload include increased bacterial and fungal infections as well as sinusoidal obstruction syndrome and possibly other regimen-related toxicities. Based on current evidence, particular attention should be paid to prevention and management of iron overload in allogeneic HSCT candidates, especially in patients with thalassemia and myelodysplastic syndromes. The pathophysiology of iron overload in the HSCT patient and optimum strategies to deal with iron overload during and after HSCT require further study.
PMCID: PMC2943091  PMID: 20871852
9.  Therapy‐related, mixed‐lineage leukaemia translocation‐positive, monoblastic myeloid sarcoma of the uterus 
Journal of Clinical Pathology  2007;60(5):562-564.
Myeloid sarcomas are tumour masses of myeloid leukaemic cells at extramedullary sites. These tumours can, on occasion, occur without concurrent or antecedent leukaemia. Myeloid sarcomas have been described at unusual locations including the female genital tract. An unusual case of therapy‐related acute myeloid leukaemia (t‐AML) presenting as isolated monoblastic myeloid sarcoma of the uterus in a patient who had received adjuvant chemotherapy for breast cancer is presented. Fluorescence in situ hybridisation analysis performed on paraffin‐wax‐embedded tumour tissue revealed a mixed‐lineage leukaemia (MLL) gene rearrangement, supporting the association of this malignancy with prior chemotherapy. This case illustrates that t‐AML can rarely present as isolated extramedullary tumours, and the detection of specific chromosomal abnormalities in these myeloid sarcomas can be useful for risk assessment and guiding definitive therapy.
PMCID: PMC1994540  PMID: 17513515
10.  Systemic mastocytosis associated with t(8;21)(q22;q22) acute myeloid leukemia 
Journal of Hematopathology  2009;2(1):27-33.
Although KIT mutations are present in 20–25% of cases of t(8;21)(q22;q22) acute myeloid leukemia (AML), concurrent development of systemic mastocytosis (SM) is exceedingly rare. We examined the clinicopathologic features of SM associated with t(8;21)(q22;q22) AML in ten patients (six from our institutions and four from published literature) with t(8;21) AML and SM. In the majority of these cases, a definitive diagnosis of SM was made after chemotherapy, when the mast cell infiltrates were prominent. Deletion 9q was an additional cytogenetic abnormality in four cases. Four of the ten patients failed to achieve remission after standard chemotherapy and seven of the ten patients have died of AML. In the two patients who achieved durable remission after allogeneic hematopoietic stem cell transplant, recipient-derived neoplastic bone marrow mast cells persisted despite leukemic remission. SM associated with t(8;21) AML carries a dismal prognosis; therefore, detection of concurrent SM at diagnosis of t(8;21) AML has important prognostic implications.
PMCID: PMC2713498  PMID: 19669220
Systemic mastocytosis; Acute myeloid leukemia; KIT mutations; Pathogenesis; Translocation (8;21); Prognosis

Results 1-10 (10)