Roy D. Baynes

Successful allogeneic bone marrow transplantation in selected patients over 50 years of age – a single institution’s experience

As allogeneic bone marrow transplantation (BMT) is a procedure with a higher risk of morbidity and mortality in older patients, many institutions place a limit of 50 to 55 years for allogeneic BMT. Consequently, older patients may not be offered potentially curative treatment for otherwise poor prognosis diseases such as AML or myelodysplastic syndrome. We compared the outcome of 59 patients aged over 50, 124 aged 40–50, and 253 aged 18–39 years who underwent allogeneic BMT in our institution between August 1987 and April 1996. Our results show little influence of age on outcome when comparing patients over 50 years with patients 40–50 years. Apart from an initial higher transplant mortality rate, overall survival was not significantly different between the three age groups. The 1-year and 2-year overall survival rates were 57% and 48%, 57% and 48%, and 62% and 58% for the >50 years, 40–50 years, and <40 years patients, respectively. the incidence of gvhd was also comparable. we conclude that allogeneic bmt can be performed in selected patients over the age of 50 years with acceptable morbidity and mortality and that older patients should not be denied this treatment based on age alone.

Recovery of lymphocyte and dendritic cell subsets after autologous CD34+ cell transplantation

Following high-dose chemotherapy (HDC) and peripheral blood progenitor cell transplantation (PBPCT), there are profound changes in leukocyte homeostasis and the immune system is compromised. Transplantation of purified CD34+ cells may further compromise immune recovery because the grafts are depleted of mature immune cells. However, a detailed monitoring of immune cell reconstitution has not been done. We monitored blood levels of antigen-presenting cells (APC) and of lymphocytes by multi-color flow cytometry at different times post CD34+ PBPCT. We found a rapid normalization of circulating levels of the antigen-presenting CD11c+ dendritic cells (defined as lineage− HLA-DR+ CD11c+ cells). There was a slight over-representation of lin− DR+ CD11c− cells at day 42 post transplantation suggesting that the composition of the APC population might be affected. Normal levels of total T, B and NK lymphocytes were rapidly achieved but the composition of the T cell population was abnormal. Patients had elevated levels of CD8+ T cells at early times and a persistent reduction in levels of naive CD8+ T cells (CD8+ CD4− CD45RA+ CD27+) and of naive CD4+ T cells (CD4+CD3+ CD8− CD45RA+). Thus, we found a rapid recovery of DC after CD34+ PBPCT but the specific numerical defects in naive T cells are likely to be a major cause of immune dysfunction in the patients. Bone Marrow Transplantation (2000) 25, 1249–1255.

Early intervention with antithrombin III therapy to prevent progression of hepatic venoocclusive disease

Venoocclusive disease (VOD) is the most frequent cause of early nonrelapse mortality among patients receiving high-dose chemoradiotherapy and hematopoietic stem cell transplantation. Endothelial injury of sinusoids and hepatic veins following chemotherapy is considered the initial event in the development of VOD. Activation of the coagulation cascade and inflammatory processes following endothelial injury results in a hypercoagulable state and a localized consumption of the natural anticoagulants, antithrombin III, protein C and protein S. The resultant coagulopathy can lead to multiorgan dysfunction and death. The objective was to retrospectively study the largest series of patients that has received antithrombin III for the treatment of VOD following hematopoietic stem cell transplantation. A total of 48 patients were diagnosed with VOD post hematopoietic stem cell transplantation (median age, 39 years; range, 1–69 years); 38 of the 48 received a nonradiation-based conditioning regimen and 21 of 48 received a transplant from an unrelated donor. Treatment was primarily directed at early intervention rather than prophylactic therapy to correct the antithrombin III deficiency associated with VOD. We attempted to achieve antithrombin III levels greater than 120%. There was no significant treatment-related morbidity. The overall 100-day mortality for the treatment cohort was 17%, with 10% for the mild/moderate group and 39% for the severe group, respectively. In conclusion, the encouraging results of this study suggest that this antithrombin III treatment should be further considered in patients with severe VOD.

High-dose Chemotherapy and Adoptive Immunotherapy in the Treatment of Recurrent Pediatric Brain Tumors

Pediatric patients with recurrent brain tumors have a poor prognosis and limited therapeutic options. We investigated the use of high-dose chemotherapy with adoptive immunotherapy for recurrent brain tumors. Three pediatric patients with recurrent brain tumors received high-dose chemotherapy. This was followed by adoptive transfer of ex-vivo expanded T-cells. The T-cells were generated from peripheral blood after immunization with autologous cancer cells. The objectives of this study included (1) establishing the safety and feasibility of this potential treatment, (2) measuring changes in immune response after high-dose chemotherapy and adoptive immunotherapy, and (3) determining whether adoptive immunotherapy would be able to translate into a clinical response. Immune function was tested in all patients at the time of enrollment into the study. Humoral responses to recall antigens delayed-type hypersensitivity (DTH) were intact in all patients. After immunizing patients with autologous cancer cells, peripheral blood lymphocytes were harvested and activated with anti-CD3, expanded in-vitro, and infused post-autologous transplant. Patients received at least three doses of the vaccine, each consisting of an intradermal administration near a draining lymph node at biweekly intervals. Toxicity was limited and well tolerated in all patients. All three patients showed a tumor-specific immune response by serial imaging. Responses were durable at 16, 23, and 48 months, respectively.

Low Infectious Morbidity after Intensive Chemotherapy and Autologous Peripheral Blood Progenitor Cell Transplantation in the Outpatient Setting for Women with Breast Cancer

Autologous peripheral blood progenitor cell (PBPC) transplantation is increasingly employed in the outpatient setting, yet data on early complications following PBPC transplantation are scant. We evaluated 105 women with high-risk primary or metastatic breast cancer who were treated at a single institution during 1996--1997. The mean duration of neutropenia (absolute neutrophil count, <500 cells/mm(3)) was 7.5 days. Twenty-nine percent of women remained afebrile throughout the neutropenic period. Of the remaining 71%, most (64 of 75) had fever of unknown origin. Infections, mostly of mild severity, occurred in 34% of women; these infections included bacteremia due to gram-positive organisms, catheter site infection, cellulitis, pneumonia, oral candidiasis, herpes simplex virus infection, and vaginitis. Fifty percent of PBPC transplant recipients required hospital admission, usually because of persistent fever; the mean duration of hospitalization was 3 days. No deaths or serious adverse events occurred. Such reduced infectious morbidity may be a consequence of minimal oral and/or gastrointestinal mucositis associated with the conditioning regimen and broad-spectrum antimicrobial prophylaxis used for this patient population.

Nonablative allogeneic hematopoietic stem cell transplantation.

During the past few years there has been an explosion of knowledge in nonablative allogeneic stem cell transplantation. This approach to transplantation relies more on the creation of “immunologic space” for engraftment rather than the more traditional approach of creating “physical space” by the application of either intensive radiation or chemical therapy. Nonablative allogeneic stem cell transplantation holds the promise of allowing powerful alloimmune responses to eradicate disease processes while minimizing the initial treatment-related morbidity and mortality, and it appears to be the necessary enabling platform by which to apply allogeneic cellular therapy. Intuitively, this approach should broaden the eligibility for potentially curative allogeneic transplantation in various disease categories, reduce initial hospitalization costs, and at the same time have a positive impact on quality of life. We review the current published data relating to this approach including the underlying principles, the preparative regimen, disease indications, preliminary results in hematologic and solid malignancies, and certain correlative immunologic evaluations.

High-dose chemotherapy and hematopoietic stem cell transplantation for breast cancer: past or future?

Given that each year in the United States 180,000 new cases of breast cancer are diagnosed, with about 44,000 women succumbing to the disease, and that breast cancer is the second leading cause of cancer-related death in women, it is clear that existing therapy fails a large number of patients. Recently, a number of novel strategies have been developed in attempts to improve survival. These include agents used at very high dose requiring stem cell support. High-dose chemotherapy (HDC) with hematopoietic stem cell transplantation (HSCT), most frequently in the form of peripheral blood progenitor cell transplantation (PBPCT), is an highly active treatment approach in appropriate patients and the current data relating to this modality will be reviewed here. This article will attempt to place the recent randomized studies in perspective, to highlight the strengths and limitations of the data, and to offer some thoughts on future directions for the field.

Cyclophosphamide and paclitaxel as initial or salvage regimen for the mobilization of peripheral blood progenitor cells

Peripheral blood progenitor cells are now commonly used for hematologic reconstitution after myelosuppressive chemotherapy for hematologic and solid malignancies. The purpose of this study was to evaluate the activity of paclitaxel 170 mg/m2 and cyclophosphamide 2 g/m2 (CP) with filgrastim (human G-CSF) for mobilization of PBPCs as the first or second maneuver after failure with filgrastim alone. Sixty-four patients with stage II–IV breast cancer received (CP) followed by filgrastim (10 μg/kg/day). In 35 (55%) this was the first maneuver while it was for salvage in 29 (45%) patients. The median number of aphereses was two (range, 1–7). In 83% of the patients apheresis was initiated on days 10–11 following chemotherapy. The median numbers of CD34+ cells/kg, CD34+ cells/apheresis/kg and total nucleated cells/kg collected were 8.7 × 106 (2.11–73.5), 3.97 × 106 (0.3–36.75) and 164.15 × 108(9–660), respectively. All the patients yielded at least 2 × 106 CD34+ cells/kg. CP mobilization salvaged the 29 patients who failed mobilization with filgrastim alone. When used as first-line mobilization the yield of CD34+ cells × 106/kg was higher than in the salvage group (16.93 vs 3.94, P < 0.001). patients receiving cp as salvage reached the target of 5 × 106 CD34+ cells/kg in only 45% (13/29) of cases vs 94.3% as first maneuver. CP followed by filgrastim is a safe and effective regimen for the mobilization of PBPCs in patients with breast cancer and shows significant activity in patients who failed to mobilize with filgrastim, suggesting a higher mobilization potential.

High-Dose Chemotherapy and Autologous Stem Cell Transplantation for Breast Cancer

The frequent use of high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT) in the treatment of metastatic breast cancer and high-risk primary breast cancer reflects frustration with the outcomes obtained using conventional therapies and the reproducible and generally favorable results being reported from phase 11. single institution phase 111, and registry data. Indeed, transplantation for breast cancer is the leading indication in the United States for stem cell-supported transplantation. Breast cancer is the second leading cause of cancer death among women in the United States, with 180,000 new cases diagnosed annually and 44,000 deaths ( 1 ) . Early detection, surgery, radiation therapy, and chemotherapy have improved the survival expectations of patients with early-stage breast cancer. During the past decade, the paradigm for the conventional treatment of

Cardiac sequelae of doxorubicin and paclitaxel as induction chemotherapy prior to high-dose chemotherapy and peripheral blood progenitor cell transplantation in women with high-risk primary or metastatic breast cancer.

Doxorubicin plus paclitaxel has been shown to be an active regimen for metastatic breast cancer and is now frequently used as adjuvant therapy for high-risk primary breast cancer. Initial studies reported a higher than expected rate of cardiac toxicity with this regimen. We studied 105 patients with either high-risk primary breast cancer or metastatic breast cancer who were treated with doxorubicin (60 mg/m2) and 3-h infusions of paclitaxel (175 mg/m2) cycled every 3 weeks. Patients received three cycles of chemotherapy for high-risk primary or four cycles for metastatic disease. Patients then proceeded to high-dose chemotherapy (HDC) (STAMP I cyclophosphamide, cisplatin and carmustine) and peripheral blood progenitor cell transplantation (PBPCT). Patients underwent radionuclide multi-gated angiograms (MUGA) before and following induction chemotherapy and following HDC. During induction chemotherapy 40 (38%) of the patients had a reduction in left ventricular ejection fraction (LVEF). Fourteen had a decrease of 20% or greater and two were mildly symptomatic from CHF. There was additional reduction in the LVEF after HDC with a median value for LVEF of 59% (range, 20–78%). During HDC 10 patients developed clinical signs of congestive heart failure (CHF). Five patients responded to diuretic therapy and did not require any additional treatment. Four patients responded to vasodilation and/or digoxin with improvement in cardiac function. A clinically significant decrease in cardiac function was found in a small number of patients after induction chemotherapy and HDC with PBPCT. The majority of the patients tolerated this regimen without problems. Although there was a decline in LVEF as measured by radionuclide MUGA this did not prevent the majority of patients from proceeding with HDC. Bone Marrow Transplantation (2000) 25, 1047–1052.