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2.
Leukemia ; 31(6): 1408-1414, 2017 06.
Article in English | MEDLINE | ID: mdl-28119528

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.


Subject(s)
Cord Blood Stem Cell Transplantation , Graft vs Host Disease/prevention & control , Leukemia, Myeloid, Acute/mortality , Neoplasm Recurrence, Local/mortality , Adolescent , Adult , Aged , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Middle Aged , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Prognosis , Remission Induction , Retrospective Studies , Survival Rate , Transplantation Conditioning , Unrelated Donors , Young Adult
3.
Bone Marrow Transplant ; 52(4): 570-573, 2017 Apr.
Article in English | MEDLINE | ID: mdl-28067886

ABSTRACT

We developed a haploidentical transplantation protocol with post-transplant cyclophosphamide (CY) for in vivo T-cell depletion (TCD) using a novel adapted-dosing schedule (25 mg/kg on days +3 and +4) for Fanconi anemia (FA). With median follow-up of 3 years (range, 37 days to 6.2 years), all six patients engrafted. Two patients with multiple pre-transplant comorbidities died, one from sepsis and one from sepsis with associated chronic GVHD. Four patients without preexisting comorbidities and early transplant referrals are alive with 100% donor chimerism and excellent performance status. We conclude that adjusted-dosing post-transplant CY is effective in in vivo TCD to promote full donor engraftment in patients with FA.


Subject(s)
Cyclophosphamide/administration & dosage , Fanconi Anemia/therapy , Lymphocyte Depletion/methods , Transplantation, Haploidentical/methods , Child , Child, Preschool , Drug Administration Schedule , Fanconi Anemia/mortality , Female , Humans , Immunosuppressive Agents/administration & dosage , Male , T-Lymphocytes
4.
Bone Marrow Transplant ; 51(12): 1573-1578, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27479689

ABSTRACT

A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ⩽2.5 × 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1-8) years after transplantation. Chronic GvHD developed in 16% of patients given ⩽2.5 × 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD.


Subject(s)
Anemia, Aplastic/therapy , Bone Marrow Transplantation/methods , Cell Count , Graft vs Host Disease/prevention & control , Adolescent , Adult , Anemia, Aplastic/complications , Child , Child, Preschool , Female , Graft Survival , Histocompatibility Testing , Humans , Immunosuppression Therapy/methods , Male , Middle Aged , Siblings , Treatment Outcome , Young Adult
5.
Bone Marrow Transplant ; 51(10): 1350-1353, 2016 Oct.
Article in English | MEDLINE | ID: mdl-27214071

ABSTRACT

The 2005 NIH chronic GVHD (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0-3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were (i) not attributed to cGVHD or (ii) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities.


Subject(s)
Graft vs Host Disease/epidemiology , Severity of Illness Index , Adolescent , Adult , Aged , Child , Chronic Disease , Confounding Factors, Epidemiologic , Female , Gastrointestinal Diseases/etiology , Graft vs Host Disease/pathology , Humans , Lung Diseases/etiology , Male , Middle Aged , National Institutes of Health (U.S.) , Skin Diseases/etiology , United States , Young Adult
6.
Bone Marrow Transplant ; 50(3): 444-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25599167

ABSTRACT

Recent studies have reported that statin use may be associated with improved outcomes in patients with sepsis or respiratory viral infections. In the setting of allogeneic hematopoietic cell transplantation (HCT), it has been shown that donor and recipient statin use is associated with reduced risks of GVHD. We assessed in retrospective analysis whether donor or recipient statin use impacts infection risk after allogeneic HCT (n=1191). Although recipient statin use was associated with the increased incidence of Gram-negative bacteremia (adjusted hazard ratio (aHR) 2.22, (95% confidence interval (CI) 1.2-4.2), P=0.01) without affecting mortality, donor statin use was associated with an increased incidence of respiratory viral infections in recipients (aHR 2.84 (95% CI 1.3-6.0), P=0.007). The overall incidence of invasive fungal infections and CMV reactivation and CMV disease were not impacted by recipient or donor statin use. In conclusion, this study suggests that recipient or donor statin use may be associated with an increased incidence of some infections without adversely affecting mortality.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Adult , Aged , Cohort Studies , Female , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Retrospective Studies , Tissue Donors , Transplantation Conditioning/adverse effects , Transplantation Conditioning/methods , Transplantation, Homologous , Young Adult
7.
Leukemia ; 29(1): 137-44, 2015 Jan.
Article in English | MEDLINE | ID: mdl-24888275

ABSTRACT

Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRD(neg) and MRD(pos) NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRD(neg) and MRD(pos) NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRD(neg) (30%) compared with MRD(pos) (10%) patients, whereas the reverse was found for MRD(neg) (7%) and MRD(pos) (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRD(pos) patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Neoplasm, Residual , Remission Induction , Transplantation Conditioning , Adult , Aged , Female , Graft vs Host Disease , Humans , Male , Middle Aged , Prognosis , Young Adult
8.
Bone Marrow Transplant ; 49(9): 1198-204, 2014 Sep.
Article in English | MEDLINE | ID: mdl-25046213

ABSTRACT

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with pentostatin and ECP). We failed to demonstrate a positive impact of ECP and pentostatin for the prevention of GVHD compared with historical control dogs.


Subject(s)
Antineoplastic Agents/pharmacology , Dog Diseases/therapy , Graft vs Host Disease/veterinary , Hematopoietic Stem Cell Transplantation/methods , Pentostatin/pharmacology , Photopheresis/veterinary , Transplantation Conditioning/methods , Animals , Dog Diseases/prevention & control , Dogs , Flow Cytometry , Graft vs Host Disease/prevention & control , Photopheresis/methods , Transplantation Chimera
9.
J Clin Pharmacol ; 53(4): 393-402, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23382105

ABSTRACT

We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.


Subject(s)
Antibiotics, Antineoplastic/pharmacokinetics , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/pharmacokinetics , Mycophenolic Acid/analogs & derivatives , Mycophenolic Acid/pharmacokinetics , Administration, Oral , Adolescent , Adult , Aged , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/blood , Child , Child, Preschool , Cyclosporine , Female , Humans , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/blood , Infant , Male , Middle Aged , Models, Biological , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/blood , Serum Albumin , Transplantation, Homologous , Young Adult
10.
Bone Marrow Transplant ; 48(6): 782-6, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23241738

ABSTRACT

Reduced-intensity conditioning (RIC) regimens in cord blood transplant (CBT) are increasingly utilized for older patients and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Antithymocyte globulin (ATG) has been incorporated into conditioning regimens in order to decrease the risk of graft failure; however, use of ATG is often associated with infusion reactions and risk of post-transplant complications. We report the results of a non-ATG-containing RIC regimen, where patients received 2 Gy TBI unless they were considered to be at higher risk of graft failure, in which case they received 3 Gy of TBI. Thirty patients underwent CBT using this protocol for high-risk hematological malignancies. There was only one case of secondary and no cases of primary graft failure. At 1 year, estimates of non-relapse mortality, OS and PFS were 29%, 53% and 45%, respectively. The cumulative incidences of grade III-IV acute and chronic GVHD were 14% and 18%, respectively. In summary, the results of this study demonstrate that this non-ATG-containing conditioning regimen provides a low incidence of graft failure without increasing regimen-related toxicity.


Subject(s)
Antilymphocyte Serum , Cord Blood Stem Cell Transplantation , Hematologic Neoplasms/therapy , Immunologic Factors , Transplantation Conditioning , Whole-Body Irradiation , Acute Disease , Adult , Aged , Chronic Disease , Female , Graft Rejection/epidemiology , Graft Rejection/prevention & control , Graft vs Host Disease/epidemiology , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/epidemiology , Humans , Incidence , Male , Middle Aged
11.
Pediatr Hematol Oncol ; 29(6): 568-78, 2012 Sep.
Article in English | MEDLINE | ID: mdl-22839094

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) is the only known cure for patients with Fanconi anemia (FA) who develop aplasia or leukemia. However, transplant regimens typically contain high-dose alkylators, which are poorly tolerated in FA patients. Furthermore, as many patients lack human leukocyte antigen (HLA)-matched family donors, alternative donors are used, which can increase the risk of both graft rejection and graft-versus-host disease (GVHD). To improve on these three concerns, we developed a multi-institutional clinical trial using a fludarabine (FLU)-based conditioning regimen with limited alkylators/low-dose radiation, HLA-haploidentical marrow, followed by reduced-dose cyclophosphamide (CY) to treat three FA patients with aplasia. All three patients engrafted with 100% donor CD3 chimerism at 1 month. One patient died early from disseminated toxoplasmosis infection. Of the two survivors, one had significant pretransplant co-morbidities and inadequate immunosuppression, and developed severe acute GVHD. The other patient had only mild acute and no chronic GVHD. With a follow-up of 2 and 3 years, respectively, both patients are doing well, are transfusion-independent, and maintain full donor chimerism. The patient with severe GVHD has resolving oral GVHD and good quality of life. We conclude that using low-intensity conditioning, HLA-haploidentical marrow, and reduced-dose CY for in vivo T-cell depletion can correct life-threatening aplasia in FA patients.


Subject(s)
Fanconi Anemia/therapy , Graft Rejection/prevention & control , Graft vs Host Disease/prevention & control , HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation , Lymphocyte Depletion , T-Lymphocytes/immunology , Vidarabine/analogs & derivatives , Adolescent , Antineoplastic Agents/therapeutic use , Child , Combined Modality Therapy , Fanconi Anemia/immunology , Female , Follow-Up Studies , Humans , Transplantation Chimera/immunology , Transplantation Conditioning , Transplantation, Homologous , Vidarabine/therapeutic use
12.
Bone Marrow Transplant ; 47(10): 1312-7, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22327126

ABSTRACT

Allogeneic stem cell transplant for multiple myeloma (MM) is one treatment associated with long-term disease-free survival. The high incidence of treatment-related mortality and relapses, however, are important reasons for controversy about the role of allografting in the management of MM. We reviewed our results of allografting for MM spanning a period of 34 years in order to better define long-term outcomes and identify areas of progress as well as areas requiring improvement. A total of 278 patients received allogeneic marrow or PBSCs after high-dose myeloablative (N=144) or reduced intensity, non-myeloablative (N=134) regimens. In multivariable analysis, adjusting for differences in patient groups, reduced intensity/non-myeloablative transplants were associated with significantly less acute GVHD, lower transplant mortality, better PFS and overall survival. There were no significant differences in relapse, progression or chronic GVHD, when adjusted. In multivariable analysis of patients receiving only non-myeloablative transplants, decreased overall survival and PFS were associated with relapse after a prior autograft and a ß2 microglobulin >4.0. Transplant mortality was reduced and only influenced by a prior tandem autograft.


Subject(s)
Multiple Myeloma/mortality , Multiple Myeloma/therapy , Stem Cell Transplantation , Transplantation Conditioning , Adult , Aged , Disease-Free Survival , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Rate , Time Factors , Transplantation, Homologous
13.
Bone Marrow Transplant ; 47(6): 804-9, 2012 Jun.
Article in English | MEDLINE | ID: mdl-21909142

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) can be curative for both myelodysplastic syndromes (MDS) and lymphoid malignancies. Little is known about the efficacy of allogeneic HCT in patients in whom both myeloid and lymphoid disorders are present at the time of HCT. We analyzed the outcomes in 21 patients with MDS and concurrent lymphoid malignancy when undergoing allogeneic HCT. A total of 17 patients had previously received extensive cytotoxic chemotherapy, including autologous HCT in 7, for non-Hodgkin lymphoma (NHL, n=7), Hodgkin lymphoma (HL, n=2), CLL (n=5), NHL plus HL (n=1), multiple myeloma (n=1) or T-cell ALL (n=1), and had presumably developed MDS as a consequence of therapy. Four previously untreated patients had CLL. A total of 19 patients were conditioned with high-dose (n=14) or reduced-intensity regimens (n=5), and were transplanted from HLA-matched or one Ag/allele mismatched related (n=10) or unrelated (n=9) donors; two patients received HLA-haploidentical related transplants, following a modified conditioning regimen. Currently, 2 of 4 previously untreated and 2 of 17 previously treated patients are surviving in remission of both MDS and lymphoid malignancies. However, the high non-relapse mortality among previously treated patients, even with reduced-intensity conditioning regimens, indicates that new transplant strategies need to be developed.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma , Multiple Myeloma , Myelodysplastic Syndromes , Transplantation Conditioning , Adult , Aged , Disease-Free Survival , Female , Histocompatibility Testing , Humans , Lymphoma/mortality , Lymphoma/therapy , Male , Middle Aged , Multiple Myeloma/mortality , Multiple Myeloma/therapy , Myelodysplastic Syndromes/mortality , Myelodysplastic Syndromes/therapy , Retrospective Studies , Survival Rate , Transplantation, Homologous
14.
Bone Marrow Transplant ; 46(4): 539-44, 2011 Apr.
Article in English | MEDLINE | ID: mdl-20581880

ABSTRACT

A nonmyeloablative conditioning regimen consisting of fludarabine (FLU) and 2 Gy TBI has been used extensively and with substantial engraftment success without promoting excessive nonrelapse mortality in medically infirm patients requiring hematopoietic cell transplantation. In this paper, we studied this same low-toxicity regimen as a means of promoting engraftment of unrelated donor hematopoietic cell transplantation in patients with Fanconi anemia (FA). All patients tolerated the regimen well with no mucositis or other severe toxicities. Of six patients transplanted, five achieved stable mixed or full donor chimerism. Acute and chronic GVHD occurred in four and three patients, respectively. Three patients are alive and well at a median of 45.9 (range, 20.9-68.1) months after transplant. In summary, this FLU-based regimen facilitates stable engraftment of unrelated PBSCs, but is associated with significant chronic GVHD.


Subject(s)
Fanconi Anemia/therapy , Hematopoietic Stem Cell Transplantation/methods , Transplantation Conditioning/adverse effects , Vidarabine/analogs & derivatives , Whole-Body Irradiation , Child , Fanconi Anemia/drug therapy , Female , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Survival Rate , Tissue Donors , Transplantation Chimera , Transplantation Conditioning/methods , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/toxicity , Whole-Body Irradiation/adverse effects
15.
Bone Marrow Transplant ; 46(10): 1382-8, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21151184

ABSTRACT

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects, but have not been evaluated for their ability to enhance engraftment of hematopoietic stem cells. We evaluated, in a canine model of dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT), whether ECP in combination with pentostatin could enhance engraftment using a nonmyeloablative regimen consisting of 100 cGy TBI and postgrafting immunosuppression with mycophenolate mofetil and CYA. We have shown previously that with 100 cGy TBI alone as conditioning, all of the six dogs rejected their grafts 2-12 weeks after HCT. With the addition of pentostatin to 100 cGy TBI, 6 of 10 dogs rejected their graft. We now tested the additional use of ECP alone (n=2) or ECP and 3-6 doses of pentostatin (n=7) before 100 cGy TBI and HCT. Eight out of nine dogs rejected their grafts within 6-11 weeks after HCT. Compared with data without ECP, we failed to demonstrate a positive impact of the use of either ECP or pentostatin for prevention of rejection.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Pentostatin/pharmacology , Photopheresis , Transplantation Conditioning/methods , Animals , Dogs , Histocompatibility Antigens/immunology , Immunomodulation , Transplantation, Homologous
16.
Bone Marrow Transplant ; 41(10): 887-93, 2008 May.
Article in English | MEDLINE | ID: mdl-18209720

ABSTRACT

We previously reported a 25% incidence of serious graft-versus-host disease (GVHD) (that is, acute or chronic GVHD that caused death, lengthy hospitalization or disability, or resulted in recurrent major infections) among 171 hematopoietic cell transplantation (HCT) recipients after nonmyeloablative (NMA) regimen. Here we present a retrospective study applying the same criteria to 264 recipients of peripheral blood HCT after myeloablative (MA) regimen, and compare the results with the previous study after additional follow-up. The MA group was younger and had lower comorbidity scores at HCT than those in the NMA group. The overall incidence of serious GVHD was 17% (44/264) in the MA group versus 28% (48/171) in the NMA group. The adjusted hazard ratio (HR) of serious GVHD in the MA group compared to the NMA group was 0.65 (95% CI, 0.4-1.1); P=0.13, and if follow-up was censored at the onset of recurrent or progressive malignancy, HR was 0.67 (95% CI, 0.4-1.3), P=0.22. We conclude that the choice between MA and NMA regimens does not greatly affect the risk of serious GVHD as an overall indicator of outcomes related to either acute or chronic GVHD. Serious GVHD may be considered as an endpoint in clinical trials with GVHD-related outcomes.


Subject(s)
Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Myeloablative Agonists/therapeutic use , Transplantation Conditioning/methods , Acute Disease , Adolescent , Adult , Aged , Chronic Disease , Cohort Studies , Female , Graft vs Host Disease/epidemiology , Humans , Incidence , Infant , Male , Middle Aged , Retrospective Studies , Transplantation Conditioning/adverse effects
17.
Leukemia ; 20(10): 1690-700, 2006 Oct.
Article in English | MEDLINE | ID: mdl-16871276

ABSTRACT

Allogeneic hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning has been extensively evaluated in patients with hematologic malignancies who are ineligible for conventional HCT because of age or medical comorbidities. Nonmyeloablative regimens have led to an initial state of mixed hematopoietic chimerism defined as coexistence of donor- and host-derived hematopoiesis. While nonmyeloablative regimens have been associated with reduced regimen-related toxicities in comparison with conventional myeloablative conditioning, graft rejection, graft-versus-host disease (GVHD), and disease progression have remained significant challenges. In this article, after briefly introducing current techniques for chimerism assessment, we describe factors affecting donor chimerism levels after nonmyeloablative conditioning, and then review data suggesting that chimerism assessment early after HCT might help identify patients at risk for graft rejection, GVHD and relapse/progression. Finally, we discuss how these observations have opened the way to further research protocols evaluating manipulation of postgrafting immunosuppression, and/or infusion of donor immune cells.


Subject(s)
Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Transplantation Chimera , Transplantation Conditioning/methods , Humans , Transplantation, Homologous , Treatment Outcome
18.
Am J Transplant ; 6(1): 89-94, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16433761

ABSTRACT

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Kidney Failure, Chronic/epidemiology , Kidney Failure, Chronic/etiology , Adolescent , Adult , Aged , Calcineurin Inhibitors , Cohort Studies , Female , Humans , Hypertension, Renal/epidemiology , Hypertension, Renal/etiology , Incidence , Kidney/radiation effects , Male , Middle Aged
19.
Leukemia ; 20(1): 128-35, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16270037

ABSTRACT

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P<0.001), more frequently had progressed to tAML (53 vs 31%, P=0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P=0.004), had higher transplant specific comorbidity indices (68 vs 42%, P=0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P=0.56)), progression-free survival (28%/4 44%, (P=0.60)), and nonrelapse mortality (41%/34%, (P=0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR=0.9, P=0.84) and progression-free survivals (HR=1, P=0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.


Subject(s)
Hematopoietic Stem Cell Transplantation , Leukemia, Myeloid, Acute/therapy , Myeloablative Agonists/therapeutic use , Myelodysplastic Syndromes/therapy , Transplantation Conditioning/methods , Transplantation, Homologous , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cell Lineage , Disease Progression , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/therapy , Graft vs Leukemia Effect , Humans , Leukemia, Myeloid, Acute/complications , Male , Middle Aged , Myelodysplastic Syndromes/complications , Prognosis , Retrospective Studies , Survival Rate , Transplantation, Homologous/adverse effects , Treatment Outcome
20.
Leukemia ; 19(6): 990-7, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15800667

ABSTRACT

A total of 24 patients (median age 58; range, 27-71 years) with chronic myeloid leukemia (CML) in first chronic (CP1) (n=14), second chronic (n=4), or accelerated phase (n=6) who were not candidates for conventional hematopoietic cell transplantation (HCT), received nonmyeloablative HCT from HLA-matched siblings a median of 28.5 (range, 11-271) months after diagnosis. They were conditioned with 2 Gy total body irradiation (TBI) alone (n=8) or combined with fludarabine, 90 mg/m(2) (n=16). Postgrafting immunosuppression included cyclosporine and mycophenolate mofetil. All patients initially engrafted. However, 4 of 8 patients not given fludarabine experienced nonfatal rejection while all others had sustained engraftment. With a median follow-up of 36 (range, 4-49) months, 13 of 24 patients (54%) were alive and in complete remission. There were five (21%) deaths from nonrelapse mortality, one (4%) during the first 100 days after transplant. The proportions of grade II, III, and IV acute GVHD were 38, 4, and 8%, respectively. The 2-year estimate of chronic GVHD was 32%. The 2-year survival estimates for patients in CP1 (n=14) and beyond CP1 (n=10) were 70 and 56%, respectively. This study shows encouraging remission rates for patients with CML not eligible for conventional allografting.


Subject(s)
Hematopoietic Stem Cell Transplantation , Histocompatibility Testing , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy , Tissue Donors , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Female , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Male , Middle Aged , Radiation Dosage , Siblings , Transplantation Chimera , Transplantation Conditioning/mortality , Transplantation, Homologous , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/adverse effects , Whole-Body Irradiation/methods
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