ABSTRACT
This study aimed to compare the real-life results of TECAM, a thiotepa-based conditioning regimen consisting of thiotepa (40 mg/m2 days -5 to -2), etoposide (200 mg/m2 days -6 to -3), cytarabine (200 mg/m2 days -4 to -1), cyclophosphamide (60 mg/kg day -3), and melphalan (60 mg/m2 days -2 to -1) with that of the conventional carmustine-based regimen BEAM. We reviewed 125 consecutive patients who underwent a first autologous transplantation (ASCT) for B-cell lymphomas at a large tertiary transplantation center between 1999 and 2014. TECAM (n=65) and BEAM (n=60) had comparable results (3yPFS 49 vs 62%, P=0.16; 3yOS 64 vs 71%, P=0.44; TRM 1.6 vs 5%, P=0.35) without a difference in toxicity or time to engraftment. Notably, comparable outcomes were observed even though patients treated with TECAM were older (55 vs 44) and had a trend towards more prior lines of therapy (>2 prior lines: 43 vs 27%, P=0.08). In this regard, 23% of TECAM patients were over the age of 65 yet could withstand therapy with similar results to younger patients. We conclude that, replacing carmustine by thiotepa and cyclophosphamide for ASCT conditioning, has comparable efficacy and safety profiles with a possible advantage in older patients.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Carmustine/therapeutic use , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Hodgkin Disease/therapy , Lymphoma, Non-Hodgkin/therapy , Thiotepa/therapeutic use , Transplantation, Autologous/methods , Adult , Antineoplastic Agents, Alkylating/pharmacology , Carmustine/pharmacology , Cyclophosphamide/pharmacology , Female , Hodgkin Disease/mortality , Humans , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Progression-Free Survival , Retrospective Studies , Thiotepa/pharmacologyABSTRACT
OBJECTIVES: We aimed to study whether ciprofloxacin prophylaxis reduces infectious complications in patients undergoing autologous haematopoietic cell transplantation (AHCT). METHODS: This is a quasi-experimental, retrospective, before-after study. We compared the incidence of bacterial-related complications among 356 patients with multiple myeloma (MM) (n = 202) and lymphoma (n = 154) who underwent AHCT with (n = 177) or without (n = 179) ciprofloxacin prophylaxis between 03/2007 and 10/2012 and between 10/2012 and 07/2016, respectively, at a single centre. RESULTS: Febrile neutropaenia, bacteraemia, and pneumonia were significantly more common among patients who underwent AHCT during the second study period and did not receive antibacterial prophylaxis compared with patients who underwent AHCT during the first study period and received antibacterial prophylaxis (89.9% (161/179) vs. 83.1% (147/177), difference 6.9%, 95% CI 0-14.1%, P = 0.002; 15.1% (27/179) vs. 4.5% (8/177), difference 10.6%, 95% CI 4.4-16.9%, p < 0.0001; 12.3% (22/179) vs. 6.2% (11/177), difference 6.1%, 95% CI 0-12.3%, p = 0.04, respectively). The number-needed-to-treat to prevent one episode of bacteraemia, pneumonia, and febrile neutropaenia was 8.6, 8.5, and 13.7, respectively. Patients with ciprofloxacin prophylaxis had higher rates of ciprofloxacin-resistant bacteraemia (62.5% (5/8) vs. 18.5% (5/27), difference 44%, 95% CI 7-70%, p = 0.01). In multivariate analysis, ciprofloxacin prophylaxis significantly decreased the odds of bacteraemia (OR 0.19, 95% CI 0.07-0.52; p < 0.0001) and pneumonia (OR 0.37, 95% CI 0.16-0.85, p = 0.02). CONCLUSION: According to our single-centre experience, patients with MM and lymphoma undergoing AHCT may benefit from antibacterial prophylaxis with ciprofloxacin.
Subject(s)
Antibiotic Prophylaxis , Ciprofloxacin/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Lymphoma/surgery , Multiple Myeloma/surgery , Postoperative Complications/prevention & control , Transplantation, Autologous/adverse effects , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Bacteremia/etiology , Bacteremia/microbiology , Bacteremia/prevention & control , Controlled Before-After Studies , Febrile Neutropenia/etiology , Febrile Neutropenia/prevention & control , Female , Humans , Israel , Male , Middle Aged , Pneumonia/etiology , Pneumonia/microbiology , Pneumonia/prevention & control , Postoperative Complications/microbiology , Retrospective Studies , Young AdultABSTRACT
BACKGROUND: The best current xenograft model of multiple myeloma (MM) in immune-deficient non-obese diabetic/severe-combined immunodeficient mice is costly, animal maintenance is complex and several weeks are required to establish engraftment and study drug efficacy. More practical in vivo models may reduce time and drug development cost. We recently described a rapid low-cost xenograft model of human blood malignancies in pre-immune turkey. Here, we report application of this system for studying MM growth and the preclinical assessment of anticancer therapies. METHODS: Cell lines and MM patient cells were injected intravenously into embryonic veins on embryonic day 11 (E11). Engraftment of human cells in haematopoietic organs was detected by quantitative real-time polymerase chain reaction, immunohistochemistry, flow cytometry and circulating free light chain. RESULTS: Engraftment was detected after 1 week in all embryos injected with cell lines and in 50% of those injected with patient cells. Injection of bortezomib or lenalinomide 48 h after cell injection at therapeutic levels that were not toxic to the bone marrow dramatically reduced MM engraftment. CONCLUSION: The turkey embryo provides a practical, xenograft system to study MM and demonstrates the utility of this model for rapid and affordable testing therapeutics in vivo. With further development, this model may enable rapid, inexpensive personalised drug screening.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Screening Assays, Antitumor/methods , Multiple Myeloma/drug therapy , Xenograft Model Antitumor Assays/methods , Animals , Bone Marrow/drug effects , Boronic Acids/pharmacology , Bortezomib , Cell Line, Tumor , Embryo, Nonmammalian , Flow Cytometry/methods , Humans , Neoplasm Transplantation , Pyrazines/pharmacology , Real-Time Polymerase Chain Reaction/methods , TurkeysSubject(s)
Immunocompromised Host , Influenza A Virus, H1N1 Subtype , Influenza, Human/complications , Peripheral Blood Stem Cell Transplantation/adverse effects , Fatal Outcome , Humans , Influenza A Virus, H1N1 Subtype/isolation & purification , Influenza, Human/immunology , Influenza, Human/microbiology , Israel , Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Male , Middle AgedABSTRACT
The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of acute myeloblastic leukemia (AML) cells within the bone marrow microenvironment and their release into the circulation. AML cells also constitutively express SDF-1-dependent elastase, which regulates their migration and proliferation. To study the molecular events and genes regulated by the SDF-1/CXCR4 axis and elastase in AML cells, we examined gene expression profiles of the AML cell line, U937, under treatment with a neutralizing anti-CXCR4 antibody or elastase inhibitor, as compared with non-treated cells, using DNA microarray technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or elastase inhibitor-treated cells, as compared with control. Pathway and functional analysis showed a greater tendency toward differentiation in cells under either one of both treatment modalities. Thus given, we further analyzed the effects of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in AML cell lines and triggered changes that mimicked differentiation, including morphological changes and the expression of myeloid differentiation antigens. Inhibition of elastase also triggered the differentiation of AML cells. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.
Subject(s)
Gene Expression Regulation, Leukemic/drug effects , Heterocyclic Compounds/pharmacology , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Receptors, CXCR4/antagonists & inhibitors , Receptors, CXCR4/metabolism , Antibodies, Monoclonal/pharmacology , Benzylamines , Cell Differentiation/drug effects , Cell Division/drug effects , Cell Survival/drug effects , Chemokine CXCL12/metabolism , Cyclams , Granulocytes/cytology , Granulocytes/drug effects , Granulocytes/physiology , HL-60 Cells , Humans , Leukemia, Myeloid, Acute/metabolism , Oligonucleotide Array Sequence Analysis , Pancreatic Elastase/antagonists & inhibitors , Pancreatic Elastase/metabolism , Receptors, CXCR4/immunology , U937 CellsABSTRACT
BACKGROUND: The clinical impact of fused PET/CT data on staging and patient management of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) was assessed. PATIENTS AND METHODS: A total of 103 consecutive patients with newly diagnosed NHL (n = 68) and HD (n = 35) were assessed retrospectively. Three comparisons were carried out in an attempt to assess the added value of each modality. RESULTS: For NHL patients, there were significant differences between staging by CT versus PET/CT (P = 0.0001). Disease was upstaged by PET/CT in 31% (mostly in stages I and II) and downstaged in only 1% of patients. In 25% of the patients, the treatment approach was changed according to CT versus PET/CT findings. For HD patients, disease was upstaged by PET/CT in 32% and downstaged by PET/CT in 15% (P = NS). As for NHL, upstaging by PET/CT versus CT was evident mostly for stages I and II. The treatment strategy was altered as determined by CT versus PET/CT in 45% of the patients. CONCLUSIONS: The addition of PET/CT to CT changed the management decisions in approximately a quarter of NHL and a third of HD patients, mostly in early disease stages. Thus, PET/CT performed as the initial staging procedure may well obviate the need for additional diagnostic CT in the majority of patients.
Subject(s)
Hodgkin Disease/pathology , Lymphoma, Non-Hodgkin/pathology , Positron-Emission Tomography/methods , Adult , Aged , Aged, 80 and over , Female , Fluorodeoxyglucose F18 , Follow-Up Studies , Hodgkin Disease/diagnostic imaging , Humans , Lymphoma, Non-Hodgkin/diagnostic imaging , Male , Middle Aged , Neoplasm Staging , Prognosis , Radiopharmaceuticals , Retrospective Studies , Tomography, X-Ray ComputedSubject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/enzymology , Protein-Tyrosine Kinases/biosynthesis , T-Lymphocytes/enzymology , Aged , Disease Progression , Female , Flow Cytometry , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/diagnosis , Male , Neoplasm Staging , Survival Analysis , ZAP-70 Protein-Tyrosine KinaseABSTRACT
Our objectives were to assess survival and predictors for survival among lymphoma patients whose disease had progressed after autologous bone marrow (ABMT) or stem cell transplantation (ASCT). Patients transplanted at Hadassah University Hospital between October 1983 and February 1999 were included. We compared survival of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) after relapse or progression. Predictors for survival were assessed in a multivariate model. Of 88 transplanted patients with HD and 152 with NHL, relapse/progression occurred in 27 (31%) and 75 (49%), respectively. Median survival postrelapse was 25 months for HD and 7.5 months for NHL (P=0.12). Seven relapsed patients with HD (26%) and 10 (13%) with NHL survived >4 years. In NHL, longer postrelapse survival was associated with indolent histologies (P=0.007). On multivariate analysis, factors associated with survival included attainment of remission postrelapse (for both diseases), use of prophylactic immunotherapy (for HD), LDH level and time from transplant to relapse (for NHL). The short-term prognosis for patients with disease progression postautologous transplant may be somewhat better for HD compared to NHL. Long-term survival is poor in both diseases. However, the survival times in the current study are twice as long as those previously reported. Treatment regimens with the potential for achieving remission may have an impact on survival.
Subject(s)
Hematopoietic Stem Cell Transplantation/mortality , Hodgkin Disease/mortality , Hodgkin Disease/therapy , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/therapy , Disease-Free Survival , Female , Humans , Male , Prognosis , Recurrence , Survival Analysis , Transplantation, AutologousABSTRACT
We have investigated the immune status of patients with hematologic malignancies treated with a low intensity conditioning in preparation for allogeneic stem cell transplantation. Conditioning consisted of fludarabine, anti-T lymphocyte globulin and low-dose busulfan, followed by infusion of allogeneic blood stem cells. This protocol resulted in rapid engraftment and complete replacement of host with donor hematopoietic cells. Immunological parameters of these patients were compared to those patients who were conditioned by an aggressive myeloablative regimen. Distribution of cell surface markers of lymphocyte subsets from both groups of patients was similar, but different from that of normal control cells. Reduced intensity or non-myeloablative conditioning prior to allogeneic stem cell transplantation (NST), hardly lowered the normal T cell-dependent mitogenic response even during the early period following transplant, while the myeloablative treatments resulted in a suppressed mitogenic reaction and in slow immune recovery. Reactivity of non-MHC restricted cytotoxic T cells was also at a normal level in patients who were treated with NST. We conclude that stem cell engraftment following reduced conditioning may result in early reconstitution of immune responses assessed in vitro. We hypothesize that clinical application of NST may lead to faster development of effective immune responses against residual host-type malignant and abnormal non-malignant hematopoietic cells, although the role of fludarabine on post-transplant infections remains to be investigated in a larger cohort of patients.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Hematopoietic Stem Cell Transplantation/methods , Immune System/drug effects , Transplantation Conditioning/methods , Adolescent , Adult , Antilymphocyte Serum/administration & dosage , Antilymphocyte Serum/toxicity , Antineoplastic Combined Chemotherapy Protocols/toxicity , Busulfan/administration & dosage , Busulfan/toxicity , Case-Control Studies , Cell Culture Techniques , Child , Child, Preschool , Cytotoxicity, Immunologic , Female , Hematologic Neoplasms/complications , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immune System/cytology , Infections/chemically induced , Killer Cells, Lymphokine-Activated/cytology , Killer Cells, Lymphokine-Activated/immunology , Lymphocyte Activation/drug effects , Male , Middle Aged , Phytohemagglutinins/pharmacology , T-Lymphocyte Subsets/drug effects , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Transplantation Conditioning/standards , Transplantation, Homologous/adverse effects , Transplantation, Homologous/methods , Vidarabine/administration & dosage , Vidarabine/analogs & derivatives , Vidarabine/toxicityABSTRACT
Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.
Subject(s)
Anemia, Aplastic/etiology , Anemia, Aplastic/virology , Hepatitis Viruses/isolation & purification , Hepatitis, Viral, Human/complications , Hepatitis, Viral, Human/virology , Adolescent , Adult , Anemia, Aplastic/therapy , Bone Marrow Transplantation , Child , Child, Preschool , Female , Humans , Male , Transplantation, Homologous , Treatment OutcomeABSTRACT
OBJECTIVE: Matched unrelated bone marrow transplantation (BMT) for patients with hematological malignancies is associated with a high incidence of transplant-related complications due to high doses of chemoradiotherapy administered pre-BMT to ensure engraftment. The aim of this study was to investigate the feasibility of low-intensity conditioning for BMT from matched unrelated donors. MATERIALS AND METHODS: Sixteen patients with hematologic malignancies underwent non-T-cell-depleted BMT following a low-intensity conditioning regimen consisting of fludarabine monophosphate 30 mg/m(2)/day for 6 days, busulfan 4 mg/kg/day for 2 days, anti-T lymphocyte globulin 10 mg/kg/day for 4 days. Seven of the patients suffered from chronic myelogenous leukemia, four from acute lymphoblastic leukemia, four from acute myelogenous leukemia, and one from Ki-1 non-Hodgkin's lymphoma. Three of the patients had secondary leukemia and two were post-autologous BMT (ABMT). All patients were transplanted from fully matched unrelated donors. RESULTS: Fifteen of the 16 patients had 100% donor chimerism; no graft rejection was observed. None of the patients developed >Grade II veno-occlusive disease, sepsis, multiorgan failure, or renal or pulmonary toxicity. Four patients died posttransplant; one of thrombocytopenia and severe hemorrhagic cystitis, one of central nervous system toxicity, one of Grade IV graft-vs-host disease, and one following relapse (9 months post-BMT). Survival and disease-free survival at 36 months are 75% (95% confidence interval 46-90%) and 60% (95% confidence interval 30-80%), respectively. CONCLUSION: These results indicate that low-intensity conditioning is sufficient to ensure stable engraftment of bone marrow grafts in a matched unrelated setting.
Subject(s)
Antilymphocyte Serum/administration & dosage , Bone Marrow Transplantation/methods , Busulfan/administration & dosage , Transplantation Conditioning/methods , Transplantation, Homologous/methods , Vidarabine/analogs & derivatives , Vidarabine/administration & dosage , Adolescent , Adult , Bone Marrow Transplantation/adverse effects , Bone Marrow Transplantation/mortality , Cell Count , Child , Cohort Studies , Disease-Free Survival , Female , Graft Survival , Histocompatibility , Humans , Leukemia/mortality , Leukemia/therapy , Life Tables , Lymphoma, Large-Cell, Anaplastic/therapy , Male , Middle Aged , Recurrence , Survival Analysis , T-Lymphocytes , Transplantation Conditioning/adverse effects , Transplantation, Homologous/adverse effects , Transplantation, Homologous/mortality , Treatment OutcomeABSTRACT
Patients who undergo autologous bone marrow transplantation for acute leukemia are at high risk for relapse. We have evaluated the feasibility of administering cell-mediated immunotherapy with family-related haploidentical lymphocytes following autologous bone marrow transplantation in order to evoke a graft-vs-leukemia effect in the autologous setting.Twenty-six patients aged 1.5-48 years were enrolled in this study. Eighteen suffered from acute myeloid leukemia, seven from acute lymphoblastic leukemia, and one from myelodysplastic syndrome. Eleven patients were transplanted in first remission, six in second remission, one in fourth remission, and eight in relapse. Conditioning consisted of Busulfan/Cyclophosphamide or Busulfan/Thiotepa/Cyclophosphamide. Nineteen patients (Group A) were treated with gradual increments of haploidentical donor T cells, starting on day +1, with an additional course of T cells plus intravenous recombinant human interleukin-2 one month later if no signs of graft-vs-host disease developed in the interim. Seven patients (Group B) were treated with high-dose haploidentical T cells on day +1 in conjunction with intravenous recombinant human interleukin-2. Donor cells were detected in the peripheral blood of both groups 12-48 hours post-cell-mediated immunotherapy, peaking at 48 hours. Three patients in Group A developed transient Grade I graft-vs-host disease. One patient in Group B developed Grade I, and three Grade IV, graft-vs-host disease. Group A patients engrafted normally, but the Group B patients with Grade IV graft-vs-host disease showed no signs of engraftment. Our results show that it is feasible to induce graft-vs-host disease in the autologous stem cell transplantation setting. However, the high-dose regimen of haploidentical T cells in conjunction with interleukin-2 results in severe toxicity and nonengraftment.
Subject(s)
Bone Marrow Transplantation , Immunotherapy, Adoptive , Leukemia/immunology , Leukemia/therapy , Lymphocytes/immunology , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/therapy , Acute Disease , Adolescent , Adult , Child , Child, Preschool , Combined Modality Therapy , Female , Humans , Lymphocyte Transfusion , Male , Middle Aged , Transplantation, Autologous , Transplantation, HomologousABSTRACT
OBJECTIVE: Second allogeneic stem cell transplants for hematological malignancies are associated with a high incidence of transplant-related mortality due to the cumulative incidence of toxicity of the high-dose chemoradiotherapy traditionally used as an essential component of the conditioning. We have demonstrated previously that nonmyeloablative conditioning for primary allogeneic transplants from both sibling and unrelated donors results in minimal transplant-related toxicity and excellent stem cell engraftment. This study explores the possibility of using nonmyeloablative conditioning to minimize transplant-related toxicity in patients who have undergone second allogeneic transplants. PATIENTS AND METHODS: Twelve high-risk, heavily treated patients-five with acute myelogenous leukemia (AML); five with non-Hodgkin's lymphoma (NHL); one with Burkitt's lymphoma, and one with acute lymphoblastic leukemia (ALL)-underwent second allogeneic nonmyeloablative stem cell transplantation (NST) from human leukocyte antigen (HLA)-matched donors, 29 (median) (range 3-57) months following their first transplantation procedure. The conditioning consisted of fludarabine 30 mg/m(2) daily for 6 days, busulfan 4 mg/kg daily for 2 days, and anti-T-lymphocyte globulin 10 mg/kg daily for 4 days. Anti-graft-vs-host disease (anti-GVHD) prophylaxis consisted of cyclosporine A alone, 3 mg/kg. RESULTS: Engraftment was observed in all recipients, with complete and stable chimerism. None of the patients developed veno-occlusive disease of the liver or multi-organ failure. Five very high-risk patients with NHL (n = 3), Burkitt's lymphoma (n = 1), and AML (n = 1) relapsed 2 to 6 months post-transplant, and four of them died. Six patients appear to be disease-free after median follow-up of 23 months. One additional patient died from grade IV hemorrhagic cystitis. Actuarial survival and disease-free survival at 34 months are 56% and 50% respectively, with 95% confidence interval (25-78%). CONCLUSION: These results suggest that nonmyeloablative conditioning significantly reduces transplant-related toxicity, thus making a second transplant feasible.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Neoplasms, Second Primary/therapy , Transplantation Conditioning/methods , Actuarial Analysis , Adolescent , Adult , Animals , Cause of Death , Child , Disease-Free Survival , Female , Graft Survival , Graft vs Host Disease/drug therapy , Graft vs Host Disease/pathology , Graft vs Tumor Effect , Hematologic Neoplasms/complications , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Male , Middle Aged , Neoplasms, Second Primary/complications , Recurrence , Survival Rate , Transplantation Chimera , Transplantation Conditioning/adverse effects , Transplantation, Autologous/adverse effects , Transplantation, Homologous , Treatment OutcomeABSTRACT
Relapse is a serious complication following high-dose therapy and autologous bone marrow transplantation (ABMT) for malignant lymphoma (ML). Allogeneic transplantation (alloSCT) is a therapeutic option. However, it is associated with a high incidence of transplant-related organ toxicity and mortality. We recently reported fast engraftment and minimal transplant-related toxicity, using fludarabine-based conditioning with reduced amounts of chemotoxic drugs prior to alloSCT. We now present our experience with 23 heavily treated high risk ML patients who underwent matched alloSCT following the same low intensity conditioning. The patients (20 male, three female) were aged 13-63 years. Nineteen had NHL and four HD (resistant disease 12, partial remission 11). Five were post ABMT. Twenty-two patients had fully matched sibling donors, and one a fully matched unrelated donor. Engraftment was fast. There was no rejection or non-engraftment. Organ toxicity was moderate with no liver or renal toxicity >grade II. Four patients developed >grade II graft-versus-host disease (GVHD). Seven patients died - four of grade III-IV GVHD and severe infections, two of bacterial sepsis, one of pulmonary failure. Ten patients are alive after 22.5 (15-37) months. Survival and disease-free survival at 37 months are both 40%. Probability of relapse is 26%. These encouraging results suggest that alloSCT following fludarabine-based low intensity conditioning in high-risk patients merits further evaluation. Bone Marrow Transplantation (2000).
Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Hematopoietic Stem Cell Transplantation , Immunosuppressive Agents/administration & dosage , Lymphoma/therapy , Salvage Therapy , Transplantation Conditioning/methods , Vidarabine/analogs & derivatives , Adolescent , Adult , Antilymphocyte Serum/administration & dosage , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow Transplantation , Busulfan/administration & dosage , Disease-Free Survival , Female , Graft Survival , Graft vs Host Disease/etiology , Graft vs Host Disease/mortality , Granulocyte Colony-Stimulating Factor/administration & dosage , Hematopoietic Stem Cell Mobilization , Hematopoietic Stem Cell Transplantation/adverse effects , Hematopoietic Stem Cell Transplantation/mortality , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Infections/etiology , Infections/mortality , Life Tables , Lymphoma/drug therapy , Lymphoma/mortality , Lymphoma/radiotherapy , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/mortality , Lymphoma, Non-Hodgkin/radiotherapy , Lymphoma, Non-Hodgkin/therapy , Male , Middle Aged , Neoplasm Recurrence, Local , Remission Induction , Survival Analysis , Transplantation Conditioning/adverse effects , Transplantation, Homologous/adverse effects , Transplantation, Homologous/mortality , Treatment Outcome , Vidarabine/administration & dosage , Vidarabine/adverse effects , Vidarabine/therapeutic useABSTRACT
Graft versus host disease (GVHD) and recurrence of basic disease are major obstacles to a successful allogeneic bone marrow transplantation (BMT) outcome. One of the possibilities of maintaining the therapeutic potential of marrow allografting in the absence of GVHD is to intensify the conditioning regimen administered pre-T-cell depleted BMT in order to compensate for the loss of GVH related graft versus leukemia (GVL) effect. In order to do so we used a preparative regimen consisting of three alkylating agents-Busulfan (BU), Thiotepa (TTP) and Cyclophosphamide (CY)-for T-cell depleted allogeneic stem cell transplantation (SCT) instead of the standard BU-CY protocol. The effect of this intensified regimen was investigated in 30 consecutive leukemia patients who underwent T-cell depleted SCT from HLA identical siblings. Sixteen of the patients were males and 14 females, of median age 24 (5-43) years. Fourteen patients had acute myelogenous leukemia (AML), ten acute lymphoblastic leukemia (ALL), four chronic myelogenous leukemia (CML) and two myelodysplastic syndrome. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was normal, with WBC >1.0x10(9)/l at day +18 (10-32), ANC >0.5x10(9)/l at day +21 (9-33) and platelets >25x10(9)/l at day +30 (14-69). Regimen related toxicity (RRT) was moderate and transplant related complications comparable to other conventional conditioning protocols. Overall survival and disease free survival (DFS) at 60 months follow up was 50%. Only three patients (10%), with ALL, relapsed and subsequently died. From the current data it would appear that TTP does not significantly improve BMT outcome in patients with leukemia, when compared to the standard BU-CY conditioning. However, our results with the BU-TTP-CY combination followed by T-cell depleted allogeneic SCT could provide the basis for a prospective randomized study comparing this protocol with the standard BU-CY regimen.
Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Busulfan/therapeutic use , Cyclophosphamide/therapeutic use , Hematopoietic Stem Cell Transplantation , Leukemia/therapy , Thiotepa/therapeutic use , Adolescent , Adult , Antineoplastic Agents, Alkylating/administration & dosage , Busulfan/administration & dosage , Child , Child, Preschool , Combined Modality Therapy , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Leukemia/mortality , Leukemia/physiopathology , Lymphocyte Depletion , Male , Middle Aged , Survival Analysis , Thiotepa/administration & dosage , Transplantation, HomologousABSTRACT
Chronic granulomatous disease (CGD) is a primary immunodeficiency disease symptomized by failure to generate superoxide and recurrent bacterial and fungal infections. Allogeneic bone marrow transplantation (BMT) is one of the therapeutic options available. However, it presents considerable risk to the recipient, especially if the patient is already at an advanced stage of disease, after repeated bacterial and fungal infections and organ damage. We present a case report of a 6-year-old child with long-standing CGD, severe clubbing, and jeopardized pulmonary function after multiple bacterial pulmonary infectious episodes, who had failed treatment with sulphamethazole trimethoprim, multiple antibiotic courses, itraconazole, as well as steroid and interferon-y therapy. He underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from his HLA-matched MLC non-reactive sister following non-myeloablative conditioning. His ANC did not fall below 0.2 x 10(9)/l, his lowest WBC was 0.6 x 10(9)/l, and his platelets did not fall below 28 x 10(9)/l. He had normal engraftment, with no mucositis or organ toxicity. Neither parenteral nutrition nor platelet infusions were necessary. Partial donor chimerism following alloPBSCT was converted to full donor chimerism and superoxide production reverted to normal after donor lymphocyte infusions (DLI) from his HLA-matched sister. Twenty four months post transplant the patient is well, with stable and durable engraftment, 100% donor chimerism, normal superoxide production, no GVHD, and stabilization of his pulmonary condition. We suggest that alloPBSCT preceded by non-myeloablative conditioning and followed by DLI may constitute a successful mode of therapy for patients suffering from advanced CGD with recurrent infectious episodes resulting in organ dysfunction, enabling them to achieve full donor chimerism and normal superoxide production with minimal risk of transplant-related toxicity and GVHD.
Subject(s)
Granulomatous Disease, Chronic/therapy , Hematopoietic Stem Cell Transplantation , Lymphocyte Transfusion , Child , Humans , Male , Transplantation Conditioning , Transplantation, HomologousABSTRACT
We have analyzed the factors associated with engraftment in 216 recipients of T-cell depleted allogeneic HLA identical sibling marrow transplants using Campath 1 monoclonal antihuman lymphocyte (CD52) antibodies. The patient population consisted of 168 patients with hematologic malignancies, 26 with severe aplastic anemia (SAA), and 22 with hemoglobinopathies, half of whom received marrow treated in vitro with Campath-1M (IgM) and half received marrow with Campath-1G (IgG2b isotype). Patients with durable engraftment had fast hematopoietic recovery: SAA patients reached ANC > 0.5 x 10(6)/L on Day 14; those with leukemia attained ANC > 0.5 x 10(6)/L on Days 18, 17, and 15 for ANLL, ALL and CML respectively, while patients with thalasemia reached ANC > 0.5 x 10(6)/L on Day 21. Overall, 24 patients (17 with leukemia, 4 with SAA, and 3 with thalassemia) suffered graft failure: 10 patients (all grafted with Campath-1M) rejected their grafts, while 14 others (9 grafted with Campath-1M, and 5 with 1G isotype) never engrafted (p = 0.009). Multivariate analysis revealed that neither pretransplant protocol, nor stage of disease or type of antibody used, donor sex and ABO match had any impact on engraftment. The variables favorably associated with engraftment were older age (p = 0.030, RR = 1.016) and CFU-GM number (p = 0.013, RR = 1.001). Patients with ANLL or SAA had a better chance to engraft (p = 0.027, RR = 1.400; and p = 0.003, RR = 2.677, respectively) compared to patients with thalassemia (p = 0.001, RR = 0.551). A higher concentration of Campath-1 antibody in vitro and in vivo adversely affected engraftment. Our data show that satisfactory engraftment can be achieved in patients transplanted with Campath-1 treated marrow allografts. However, despite the measures undertaken to prevent rejection, graft failure still poses a problem. Further pretransplant immunosuppression and perhaps more selective T-cell depletion may reduce the increased graft failure in these patients.
Subject(s)
Antibodies, Monoclonal/pharmacology , Bone Marrow Purging , Bone Marrow Transplantation , Graft Survival/drug effects , Graft vs Host Disease/prevention & control , Lymphocyte Depletion/methods , Transplantation, Homologous , ABO Blood-Group System/genetics , Age Factors , Alemtuzumab , Anemia, Aplastic/therapy , Animals , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm , Female , Graft Rejection , Humans , Immunosuppression Therapy , Leukemia/therapy , Leukemia, Myeloid, Acute/therapy , Male , Multivariate Analysis , Nuclear Family , Rats , Sex Factors , Transplantation Conditioning , Treatment Outcome , beta-Thalassemia/therapyABSTRACT
Allogeneic peripheral blood stem cell transplantation (allo PBSCT) is a recognized treatment modality for hematological malignancies resistant to conventional chemoradiotherapy. The post-transplant immune-mediated graft-versus-leukemia effect has major curative potential. In this case presentation, the allogeneic approach to resistant recurrent primary central nervous system (CNS) lymphoma using peripheral blood stem cells from an HLA identical sibling after immuno-suppressive non-myeloablative conditioning, was examined clinically. The patient in question had relapsing refractory primary CNS lymphoma and is the first to be treated with this modality. She developed early skin and liver-localized grade II graft-versus-host disease after allo PBSCT, which then responded to short-term treatment. Chimeric studies at the time showed 100% donor cells and repeated magnetic resonance imaging of the brain revealed gradual shrinkage of the tumor. Three months after transplant the cerebral mass was no longer evident and currently, 30 months after transplantation, the patient continues to be disease free. The absence of any signs of malignancy suggests the development of a durable graft-versus-lymphoma effect in this brain tumor and indicates that this effect may be achieved even after non-myeloablative conditioning.
Subject(s)
Brain Neoplasms/therapy , Graft vs Tumor Effect , Hematopoietic Stem Cell Transplantation , Lymphoma, B-Cell/therapy , Adult , Brain Neoplasms/immunology , Female , Humans , Lymphoma, B-Cell/immunology , Neoplasm Recurrence, Local/immunology , Neoplasm Recurrence, Local/therapy , Transplantation, HomologousABSTRACT
Graft-versus-host disease (GVHD), graft rejection, disease recurrence and long-term toxicity remain significant obstacles to successful allogeneic bone marrow transplantation (BMT) in children with genetic diseases. In an attempt to improve results, we used a preparative regimen consisting of three alkylating agents, busulfan (BU), thiotepa (TTP) and cyclophosphamide (CY), for T cell-depleted allogeneic bone marrow transplantation instead of the conventional BU-CY protocol. The effect of this intensified regimen was investigated in 26 consecutive children with genetic diseases who underwent T cell-depleted BMT from HLA-identical siblings. Sixteen patients were males and 10 females, of median age 5 (0.2-14) years. The diseases included beta-thalassemia major, osteopetrosis, severe combined immunodeficiency, Wiskott-Aldrich syndrome, familial agranulocytosis, congenital idiopathic hemolytic anemia (CIHA), Gaucher's disease, Niemann-Pick disease, Hurler's syndrome, and adrenoleukodystrophy. The conditioning regimen consisted of BU 4 mg/kg x 4 days (-8 to -5), TTP 5 mg/kg x 2 days (-4 and -3), and CY 60 mg/kg x 2 days (-2 and -1). Engraftment was as expected, with WBC >1.0 x 10(9)/l at day +19 (10-33), ANC >0.5 x 10(9)/l at day +22 (10-56) and platelets >25 x 10(9)/l at day +32 (18-131). Transplant-related mortality was 19%. Overall survival and disease-free survival (DFS) at 60 months follow-up were both 77%. Our results with the BU-TTP-CY regimen followed by T cell-depleted BMT in genetic diseases may provide a basis for prospective comparison with the standard conditioning regimen of BU-CY in the management of children suffering from these conditions.