Esteban Abella

Assessment of optimal size and composition of the U.S. National Registry of hematopoietic stem cell donors.

Background. The National Marrow Donor Program (NMDP) receives federal funding to operate a registry of over 4 million volunteer donors for patients in need of a hematopoietic stem cell transplant. Because minority patients are less likely to find a suitably matched donor than whites, special efforts have been aimed toward recruitment of minorities. Significant financial resources are required to recruit and tissue type additional volunteer donors. Methods. Population genetics models have been constructed to project likelihoods of finding a human leukocyte antigen (HLA)-matched donor for patients of various racial/ethnic groups. These projections have been made under a variety of strategies for expansion of the NMDP Registry. Cost-effectiveness calculations incorporated donor unavailability and other barriers to transplantation. Results. At current recruitment rates, the probability of an available HLA-A,B,DRB1 matched donor is projected to increase from 27% to 34%; 45% to 54%; 75% to 79%; and 48% to 55%, for blacks, Asians/Pacific Islanders, whites and Hispanics, respectively, by the year 2007. Substantial increases in minority recruitment would have only modest impacts on these projections. These projections are heavily affected by donor availability rates, which are less than 50% for minority volunteers. Conclusions. Continued recruitment of additional volunteers can improve the likelihood of finding an HLA-matched donor, but will still leave significant numbers of patients of all racial/ethnic groups without a match. Efforts to improve donor availability (especially among minorities) and to increase the number of patients with access to the NMDP Registry may prove to be more cost-effective means of increasing transplants.

Mixed hematopoietic chimerism at day 90 following allogenic myeloablative stem cell transplantation is a predictor of relapse and survival

We retrospectively analyzed the prognostic significance of mixed chimerism and associated clinical parameters in 80 patients following unmanipulated allogenic stem cell transplantation. Chimerism studies were performed on marrow aspirates using fluorescent in situ hybridization and variable number tandem repeats techniques at day +30, day +90 and +12 months. The median overall survival (OS) was 24 months (range, 1–56 months). Mixed chimerism was found in 23, 28 and 14% of patients at day +30 (1 month), +90 (3 months), and +12 months, respectively. Day +30 chimerism studies failed to provide any prognostic information. Day +90 mixed chimeras (MC) had significantly higher relapse rates compared to day +90 complete chimeras (CC) at 6 months (P=0.03) and 18 months when compared to MC (P=0.03) following transplant. The median OS in day +90 MC and day+90 CC were, respectively (95% CI, 2–35 months), compared to 47 months (95% CI, 20–74 months) (P=0.02). In conclusion, chimerism studies on day +30 could be reserved for patients who fail to demonstrate engraftment. Day +90 MC had higher relapse rates and lower OS, and therefore may be considered for novel therapies and future studies.

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.

Prevention of Hemorrhagic Cystitis Following Allogeneic Bone Marrow Transplant Preparative Regimens With Cyclophosphamide and Busulfan: Role of Continuous Bladder Irrigation

High dose cyclophosphamide and/or busulfan conditioning treatment of recipients of bone marrow transplants proved to be highly effective but associated with substantial and sometimes life threatening hemorrhagic cystitis. To prevent this complication, a prophylactic continuous bladder irrigation program was instituted in patients receiving cyclophosphamide and/or busulfan in preparation for bone marrow transplantation. Retrospective analysis of 199 patients who underwent allogeneic bone marrow transplantation revealed that continuous bladder irrigation significantly decreased the frequency of hemorrhagic cystitis in patients receiving busulfan and cyclophosphamide (continuous bladder irrigation 23% versus no bladder irrigation 53%, p < 0.004). There was no difference in the frequency of hemorrhagic cystitis between the different preparative regimens in patients who underwent continuous bladder irrigation. There was no relationship between the incidence of hemorrhagic cystitis and the severity of graft-versus-host disease or the time to engraftment. The duration of hemorrhagic cystitis and overall survival rates were similar in both groups, and there was no increase in complications related to catheterization. In general, continuous bladder irrigation was well tolerated, decreased the incidence of hemorrhagic cystitis and may be useful in bone marrow transplant patients.

Phialophora verrucosa infection in a BMT patient

Phialophora is a dematiaceous fungus isolated from soil and wood. Human infections including chromoblastomycosis, mycotic keratitis, cutaneous infections, and prosthetic valve endocarditis have been reported. We report a case of fatal hemorrhage due to Phialophora verrucosa in a patient with prolonged neutropenia undergoing autologous bone marrow transplant (BMT) for acute myelogenous leukemia (AML). Bacterial infections complicated induction and consolidation chemotherapies. Liposomal amphotericin B (LAMB) was given from day +33 to day +72 for febrile neutropenia. Death occurred on day +74 due to tracheal hemorrhage. Autopsy revealed granulation tissue on the posterior wall of the trachea with fungal hyphae on histopathology; the tissue grew Phialophora verrucosa. In vitro susceptibility studies revealed a minimum inhibitory concentration to AmB of 0.1 μ g/ml. This represents the first reported case of invasive P. verrucosa in a BMT patient leading to fatal hemorrhage, despite large cumulative doses of LAMB to which the organism remained susceptible.

Thiotepa and Cyclophosphamide with Stem Cell Rescue for Consolidation Therapy for Children with High-risk Neuroblastoma: A Phase I/ii Study of the Pediatric Blood and Marrow Transplant Consortium

Purpose: We report the results of a phase I/II stem cell rescue trial for patients with high risk neuroblastoma. Patients and Methods: Fifty-one patients with a median age of 2.3 years (range 1 to 20) who were in their first complete remission (CR) (n = 8), very good partial remission (VGPR) (n = 23), partial remission (PR) (n = 5), or subsequent CR/PR (n = 7) after receiving a platinum-based induction regimen were consolidated with high dose chemotherapy and stem cell rescue. They received an ablative regimen of thiotepa (300 mg/m2/day for 3 days) and cyclophosphamide (1500 mg/m2/day for 4 days) followed by either purged marrow (n = 16), unpurged bone marrow (BM) (n = 23), or peripheral blood stem cell (PBSC) rescue (n = 13). The median nucleated cell doses administered were 2.7×108/kg for unpurged marrow (range 1.1 to 13), 1.7×108/kg for purged marrow (range 0.8 to 6.4), and 2.1×108/kg for the PBSC (range 1.1 to 13). Results: Engraftment was achieved for all patients. The time to achieve an absolute neutrophil count (ANC) >500×109/1 was 19 days for patients who received purged BM (range 13 to 18), 17.5 days for patients who received unpurged BM (range 9 to 38), and 13 days for patients who received PBSC (range 9 to 25). An unsustained platelet count >20×109/1 was attained in 33.5 days by patients who received purged BM (range 13 to 100), 35 days for patients who received unpurged BM (range 14 to 128), and 20 days for patients who received PBSC (range 11 to 64). There was one infectious death in the unpurged marrow group caused by aspergillosis pneumonia, but none in the other two groups. Progressive disease (PD) developed in 21 patients at a median of 271 days (range 31 to 1230). The remaining 29 patients are progression-free at a median follow-up of 1190 days (range 530 to 2383). Conclusion: We conclude that this regimen is well tolerated, and that progression-free survival (PFS) with this chemotherapy-only regimen compares favorably with regimens containing total body irradiation (TBI).

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.

Transplantation in patients with multiple myeloma: A multicenter comparative analysis of peripheral blood stem cell and allogeneic transplant

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Treatment of familial erythrophagocytic lymphohistiocytosis with cyclosporine A

Familial erythrophagocytic lymphocytosis (FEL) is a rare, nonmalignant class II histiocytosis characterized by fever, irritability, hepatosplenomegaly, pancytopenia, and hemophagocytosis. Various chemotherapeutic regimens have had mixed success, with the only curative therapy being bone marrow transplantation. We report our experience with two children whose therapy with etoposide and steroids failed. They were successfully treated and had durable remissions with cyclosporine A (CSA). We propose that in FEL there may exist abnormal interactions between antigen-presenting cells and T-lymphocyte subsets, and that CSA may down-modulate this aberrant response. The use of a low-dose CSA regimen may represent a treatment option that should be further explored.

CLINICAL COURSE AND OUTCOME OF PATIENTS WITH HODGKIN'S DISEASE WHO PROGRESS AFTER AUTOLOGOUS TRANSPLANTATION

Twenty-six of fifty-eight patients undergoing autologous bone marrow transplantation (autoBMT) or peripheral stem cell transplantation (PSCT) for Hodgkins disease had progression of lymphoma (Hodgkins or non-Hodgkins) during the course of their follow-up. The majority of progressions, 81% (21/26), occurred within the first year of transplant; 12% (3/26) occurred at three years or more. Three patients developed a non-Hodgkins lymphoma; all B-cell tumors primarily involving the gastrointestinal tract. The majority of patients (23/26) received at least one therapy after progression and 65% (17/26) of patients received multiple therapies. One patient who received a second BMT is alive without evidence of disease at 49 months following the second autologous BMT. The median survival for the entire group is 11 months. Forty-six percent (12/26) of patients survived more than one year and twenty-three percent (6/26) survived more than two years after disease progression. Post-progression survival is significantly related to time to progression.