Reduced intensity conditioning and allogeneic stem-cell transplantation: determining its role in multiple myeloma.
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Hematopoietic Stem Cell Transplantation↗
Biomedical subjects
Stephen Mackinnon
Publications and source records attributed to Stephen Mackinnon.
Role of nonmyeloablative allogeneic stem-cell transplantation after failure of autologous transplantation in patients with lymphoproliferative malignancies.
PURPOSE: Conventional allogeneic stem-cell transplantation (SCT) after a prior failed autograft is associated with a transplant-related mortality rate of 50% to 80%. The aim of the current study was to evaluate the safety and efficacy of sibling, HLA-matched, nonmyeloablative allogeneic SCT with donor lymphocyte infusion (DLI) in patients with lymphoid malignancy after failure of autologous SCT. PATIENTS AND METHODS: A total of 38 patients with refractory, progressive, or relapsed disease after autologous SCT were entered onto this study. The conditioning regimen consisted of the humanized monoclonal antibody CAMPATH-1H, fludarabine, and melphalan. Fifteen of 35 assessable patients received DLI after SCT. RESULTS: Sustained neutrophil engraftment was achieved in 37 recipients, and platelet engraftment was achieved in 35 patients. The estimated transplant-related mortality was 7.9% at day 100 and 20% at 14 months, the median duration of follow-up. Eight patients experienced grade I/II acute graft-versus-host disease (GVHD) after transplantation, but no grade III/IV GVHD was observed in this setting. However, grade III/IV GVHD occurred in seven patients who received DLI. The actuarial overall survival at 14 months was 53%, with a progression-free survival of 50%. DLI produced a further response in three of 15 recipients. CONCLUSION: Nonmyeloablative allogeneic SCT after CAMPATH-1H-containing conditioning is a relatively safe option compared with conventional allogeneic transplantation for patients who have failed previous autologous SCT. The low incidence of early GVHD enabled the subsequent administration of DLI to improve further clinical responses in this poor-risk group of lymphoma and myeloma patients.
Adult↗
Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation.
We report the outcome of reduced-intensity allogeneic progenitor cell transplantation (alloPCT) for 188 patients with lymphoma from the Working Party Lymphoma of the European Group for Blood and Bone Marrow Transplantation (EBMT). The median age of the patients was 40 years, the median number of prior treatment courses was 3, and 48% of patients had undergone a prior autologous transplantation. Eighty-four percent of the patients received conditioning with fludarabine-based regimens and 10% with the BEAM (BCNU, etoposide, cytosine arabinoside, melphalan) protocol. Full donor chimerism was confirmed in 71% of 100 patients assessed. Acute graft-versus-host disease (GVHD) developed in 37% of patients and chronic GVHD in 17%. A disease response to donor leukocyte infusion (DLI) was seen in 10 of 14 patients. With a median follow-up of 283 days, the overall survival rates at 1 and 2 years were 62% and 50%, respectively. The 100-day and 1-year transplantation-related mortality (TRM) rates were 12.8% and 25.5%, respectively, and were significantly worse for older patients. The probability of disease progression at 1 year for patients with chemoresistant and chemosensitive disease were 75% and 25%, respectively (P =.001). The progression-free survival at 1 year was 46% and was significantly better for those with chemosensitive disease, Hodgkin disease (HD), and low-grade non-Hodgkin lymphoma (NHL). Patients with high-grade NHL, mantle cell lymphoma, or chemoresistant disease had a poor outcome. Reduced-intensity progenitor cell transplantation is associated with a reduced TRM and may control advanced HD and low-grade NHL. A longer period of follow-up is required to determine the benefit of DLI and the graft-versus-lymphoma effect.
Adult↗
High incidence of cytomegalovirus infection after nonmyeloablative stem cell transplantation: potential role of Campath-1H in delaying immune reconstitution.
Nonmyeloablative conditioning is increasingly used for transplantation in a wide range of diseases, but little is known about its impact on the incidence of infections and immune reconstitution. We examined the pattern and outcome of cytomegalovirus (CMV) infections monitored by polymerase chain reaction-based assays and treated preemptively in 101 patients following nonmyeloablative conditioning containing in vivo Campath-1H. Fifty-one patients (50%) had a CMV infection at a median of 27 days after transplantation with a probability of 84.8% in patients at risk of CMV infection. The probability of recurrence of CMV infection before and after 100 days was 53.6% and 46.6%, respectively, and was more common in unrelated donor transplant recipients. All 3 patients who developed CMV disease died of this complication. The 2 patients with late CMV disease had grade III to IV graft-versus-host-disease (GVHD), which occurred de novo in only 4% of patients and in another 10% following donor lymphocyte infusions. The median time to CD4(+) T-cell count more than 200/microL was 9 months in the 48 patients studied. The probabilities of overall survival and nonrelapse mortality at 18 months were 65% and 27.8%, respectively, with no significant difference in survival between CMV-infected and -uninfected patients. The use of Campath-1H appeared to be associated with a low incidence of GVHD but a high incidence of CMV infections and prolonged immune paresis.
Adolescent↗
Outcome of major ABO-incompatible nonmyeloablative hematopoietic stem cell transplantation may be influenced by conditioning regimen.
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ABO Blood-Group System↗
Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen.
A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days -8 to -4, 30 mg/m(2) fludarabine on days -7 to -3, and 140 mg/m(2) melphalan on day -2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.
Adolescent↗
Characterization of human cytomegalovirus peptide-specific CD8(+) T-cell repertoire diversity following in vitro restimulation by antigen-pulsed dendritic cells.
Under conditions of impaired T-cell immunity, human cytomegalovirus (HCMV) can reactivate from lifelong latency, resulting in potentially fatal disease. A crucial role for CD8(+) T cells has been demonstrated in control of viral replication, and high levels of HCMV-specific cytotoxic T-lymphocytes are seen in immunocompetent HCMV-seropositive individuals despite very low viral loads. Elucidation of the minimum portion of the anti-HCMV T-cell repertoire that is required to suppress viral replication requires further study of clonal composition. The ability of dendritic cells to take up and process exogenous viral antigen by constitutive macropinocytosis was used to study HCMV-specific T-cell memory in the absence of viral replication. The specificity and clonal composition of the CD8(+) T-cell responses were evaluated using HLA tetrameric complexes and T-cell receptor beta chain (TCRBV) spectratypic analyses. There was a skewed reactivity toward the matrix protein pp65, with up to 40-fold expansion of CD8(+) T cells directed toward a single peptide-MHC combination. Individual expansions detected on TCRBV spectratype analysis were HCMV-specific and composed of single or highly restricted numbers of clones. There was preferential TCRBV gene usage (BV6.1/6.2, BV8, and BV13 in HLA-A*0201(+) individuals) but lack of conservation of CDR3 length and junctional motifs between donors. While there was a spectrum of TCR repertoire diversity directed toward individual MHC-peptide combinations between donors, a relatively small number of clones appeared to predominate the response in each case. These data provide further insight into the range of anti-HCMV responses and will aid the design and monitoring of adoptive immunotherapy protocols.
Amino Acid Sequence↗
The prospective evaluation of a nested polymerase chain reaction assay for the early detection of Aspergillus infection in patients with leukaemia or undergoing allograft treatment.
Patients with acute leukaemia or undergoing allogenic bone marrow transplantation at University College London Hospital Trust were screened for the presence of aspergillosis by polymerase chain reaction (PCR). Aspergillus DNA, from whole blood samples, was amplified by nested PCR to detect a 135 bp fragment in the mitochondrial region of Aspergillus fumigatus or A. flavus (121 bp). One colony-forming unit (CFU) per 2 ml of blood or 1-10 fg DNA could be detected. Patients at risk of aspergillosis were classified as probable or possible based on the European Organization for Research and Treatment of Cancer definitions. Antifungal drugs given were recorded. In four of 17 patients studied, infection was not suspected and the PCR was negative. Four patients were considered to have possible aspergillosis infection and were PCR positive on at least one occasion. Of the three patients in the probable group, four of the nine samples tested PCR positive from one patient and in another patient only one of nine samples tested positive. The remaining six patients were not suspected of having fungal infection but each had one or two PCR-positive results. In summary, six of seven patients thought to have clinical evidence of infection were PCR positive on at least one occasion and treatment with antifungals may have reduced infection below detectable levels.
Acute Disease↗
Respiratory virus infections in transplant recipients after reduced-intensity conditioning with Campath-1H: high incidence but low mortality.
Respiratory virus infections can cause serious morbidity and mortality after conventional allogeneic stem cell transplantation. However, the incidence and outcome of these infections after reduced intensity conditioning has not been reported. Between 1997 and 2001, 35 episodes of respiratory virus infections were noted in 25 of 83 transplant recipients conditioned with fludarabine, melphalan and Campath-1H, and 80% of them received early antiviral therapy. Parainfluenza virus (PIV) 3 was the commonest isolate (45.7%) followed by respiratory syncytial virus (37%). Patients with myeloma were more susceptible to these infections [odds ratio (OR) 4.1, P = 0.01] which were often recurrent in patients with severe acute or chronic graft-versus-host disease (GVHD) (OR 10.6, P = 0.03). Infection within the first 100 d (OR 5.0, P = 0.05) and PIV 3 (OR 9.2, P = 0.01) isolation were risk factors for developing lower respiratory infection. Although more than half of the episodes progressed to lower respiratory infection, the mortality was only 8%. This could have been due to early initiation of antiviral therapy, but the attenuation of pulmonary damage due to the reduced-intensity conditioning, low incidence of GVHD and, paradoxically, the low CD4+ T-cell subset in this setting might also have been contributory factors.
Adolescent↗
Adoptive cellular therapy: a therapeutic reality?
The past decade has seen numerous lines of evidence emerging that suggest human malignancies may be sensitive to the effects of cellular immunotherapy. An increasing understanding of the nature of the effector cells and their target antigens is now leading to more focused efforts to harness these responses for therapeutic benefit. However, clinical application has proven more challenging than initially envisaged. Advances in the setting of allogeneic stem cell transplantation now allow attempts to augment both immunological recovery and anti-tumour activity. Some of the most attractive targets here are allospecific rather than truly tumour-specific. Application outside of this setting is based on attempts to delineate further tumour-specific or, increasingly, tumour-selective targets. This review summarizes these developments and highlights some of the issues that remain to be resolved.
Animals↗
Non-myeloablative transplantation.
The concept of utilizing enhanced immunosuppression rather than myeloablative cytotoxic conditioning has allowed the engraftment of allogeneic stem cells from related and unrelated donors with lower early transplant-related mortality (TRM) and morbidity. This approach shifts tumor eradication to the graft-vs-host immune response directed against minor histocompatibility antigens expressed on tumor cells. This is not without risk, as the long-term effects of graft-versus-host disease (GVHD), it's treatment, or resulting complications and immunodeficiency may be life threatening. However, this approach does allow the application of a potentially curative procedure to elderly or medically infirm patients who would not tolerate high-dose conditioning regimens. Section I, by Dr. Sandmaier, describes the current use of nonmyeloablative regimens and matched related or unrelated donors for the treatment of patients with CLL, CML, acute leukemia, MDS, lymphoma, and myeloma. In Section II, Dr. Maloney discusses the use of cytoreductive autologous followed by planned non-myeloablative allografts as treatment for patients with myeloma or NHL. This tandem transplant approach has a lower TRM than conventional high dose allografting. The nonmyeloablative allograft may allow the graft-versus-tumor (GVT) immune response to eradicate the minimal residual disease that causes nearly all patients with low-grade NHL or myeloma to relapse following autologous transplantation. In Section III, Dr. Mackinnon discusses the risks and benefits of T cell depletion strategies to prevent acute GVHD, while retaining GVT activity by planned donor lymphocyte infusions. Finally, in Section IV, Dr. Shizuru discusses the relationship between GVHD and GVT activity. Future studies, employing a greater understanding of these issues and the separation of GVHD from GVT activity by immunization or T cell cloning, may allow nonmyeloablative allogeneic transplantation to be safer and more effective.
Alemtuzumab↗
Clinical evidence of a graft-versus-Hodgkin's-lymphoma effect after reduced-intensity allogeneic transplantation.
BACKGROUND: In patients with multiply relapsed Hodgkin's lymphoma allogeneic stem-cell transplantation has been limited by prohibitive non-relapse-related mortality rates and by a lack of definitive evidence for a therapeutic graft-versus-tumour effect. Therefore, we aimed to assess the graft-versus-tumour effect of reduced-intensity allogeneic transplantation. METHODS: We undertook reduced-intensity transplantation in 49 patients with multiply relapsed Hodgkin's lymphoma, 44 (90%) of whom had progression of disease after previous autologous transplantation (median age 32 years [range 18-51], number of previous treatment courses was five [range 3-8], and time from diagnosis 4.8 years [range 0.6-4.8]). 31 patients had HLA matched donors who were related and 18 had donors who were unrelated. Median follow-up was 967 days (range 102-2232). The primary endpoints were engraftment, toxic effects, non-relapse-related mortality, incidence of graft-versus-host disease (GVHD), and the toxic effects of adjuvant donor-lymphocyte infusion. FINDINGS: All patients engrafted. Eight of 49 (16%) had grade II-IV acute GVHD and seven (14%) had chronic GVHD before donor-lymphocyte infusion. 16 (33%) patients received donor-lymphocyte infusion from 3 months after transplantation for residual disease or progression. Six (38%) of the 16 developed grade II-IV acute GVHD and five developed chronic GVHD. Nine (56%) showed disease responses after infusion (eight complete, one partial). Non-relapse-related mortality was 16.3% at 730 days (7.2% for patients who had related donors vs 34.1% for those with unrelated donors, p=0.0206). Projected 4 year overall and progression-free survival were 55.7% and 39.0%, respectively (62.0% and 41.5% for related donors). INTERPRETATION: These data show the potential for durable responses in patients who have previously had substantial treatment for Hodgkin's lymphoma. The low non-relapse-related mortality suggests the procedure could be undertaken earlier in the course of the disease.
Adolescent↗