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Recurrent Clostridium difficile infection (CDI) is a consequence of intestinal dysbiosis and is particularly common following hematopoietic stem cell transplantation (HSCT). Fecal microbiota transplantation (FMT) is an effective method of treating CDI by correcting intestinal dysbiosis by passive transfer of healthy donor microflora. FMT has not been widely used in immunocompromised patients, including HSCT recipients, owing to concern for donor-derived infection. Here, we describe initial results of an FMT program for CDI at a US HSCT center. Seven HSCT recipients underwent FMT between February 2015 and February 2016. Mean time post HSCT was 635 days (25-75 interquartile range [IQR] 38-791). Five of the patients (71.4%) were on immunosuppressive therapy at FMT; 4 had required long-term suppressive oral vancomycin therapy because of immediate recurrence after antibiotic cessation. Stool donors underwent comprehensive health and behavioral screening and laboratory testing of serum and stool for 32 potential pathogens. FMT was administered via the naso-jejunal route in 6 of the 7 patients. Mean follow-up was 265 days (IQR 51-288). Minor post-FMT adverse effects included self-limited bloating and urgency. One patient was suspected of having post-FMT small intestinal bacterial overgrowth. No serious adverse events were noted and all-cause mortality was 0%. Six of 7 (85.7%) patients had no recurrence; 1 patient recurred at day 156 post FMT after taking an oral antibiotic and required repeat FMT, after which no recurrence has occurred. Diarrhea was improved in all patients and 1 patient with gastrointestinal graft-versus-host disease was able to taper off systemic immunosuppression after FMT. With careful donor selection and laboratory screening, FMT appears to be a safe and effective therapy for CDI in HSCT patients and may confer additional benefits. Larger studies are necessary to confirm safety and efficacy and explore other possible effects.

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate ( > 80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation., FM was supported by educational grants from the 'Association for Training, Education and Research in Hematology, Immunology and Transplantation' (ATERHIT, Nantes, France)

Background Although several studies have documented adverse outcomes for vancomycin-resistant Enterococcus (VRE) colonization and infection in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, data are inadequate for patients undergoing autologous (auto-)HSCT. Methods We conducted a retrospective cohort study of 300 consecutive patients receiving an auto-HSCT between 2006 and 2014. Patients had stool cultures for VRE on admission and weekly during hospitalization. Results Thirty-six percent of patients had VRE gastrointestinal (GI) colonization and 3% developed a VRE bloodstream infection (BSI), all of whom were colonized. VRE strain typing of BSI isolates showed that some patients shared identical patterns. Rates of colonization and BSI in colonized patients were similar to simultaneous patients undergoing allo-HSCT, except that the latter had a higher rate of colonization at admission. A diagnosis of lymphoma was associated with an increased risk of colonization. VRE BSI was associated with longer lengths of stay and possibly higher costs, but no decrease in overall survival, and colonized patients had no VRE infections during the year following discharge. Repeat stool cultures in patients subsequently undergoing allo-HSCT suggested that most, if not all, VRE-positive auto-HSCT patients lose their detectable GI colonization within a few months of discharge. Conclusion VRE colonization is frequent but carries a low risk for infection in patients undergoing auto-HSCT. However, these patients can serve as reservoirs for transmission to higher risk patients. Moreover, patients may remain colonized if proceeding to an allo-HSCT shortly after auto-HSCT, potentially increasing the risk of the allogeneic procedure.

Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.

The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m2 fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P

Purpose We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

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.

Rationale Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis (MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. Patients Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. Results The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (±7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by ≥ 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (±12)% at 3 years being 66 (±23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (±13)%; p = 0.59. The probability of confirmed disease progression was 20 (±11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. Conclusion Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

In this multicenter, randomized study, cytomegalovirus (CMV)-seropositive patients who received an allogeneic bone marrow transplant were provided high-dose intravenous acyclovir (500 mg/m(2) q8h) from the day of transplantation until engraftment. The patients were then randomly assigned to receive either oral valacyclovir, 2 g q.i.d. (n=83), or intravenous ganciclovir, 5 mg/kg q12h for 1 week, then 6 mg/kg once daily for 5 days per week (n=85), until day 100 after transplantation. CMV infection occurred in 12% of the patients who received valacyclovir and in 19% of the patients who received ganciclovir (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.391-2.778; P=.934). CMV disease developed in only 2 patients who received valacyclovir and in 1 patient who received ganciclovir (HR, 1.943; 95% CI, 0.176-21.44; P=.588). Oral valacyclovir can be an effective alternative to intravenous ganciclovir for prophylaxis of CMV disease after bone marrow transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

The purpose of this investigation was to define the maximum tolerated dose (MTD) of unshielded total body irradiation (TBI) delivered from dual {sup 60}C sources at an exposure rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy in patients with advanced lymphoid malignancies. Forty-four patients with a median age of 28 (range 6-48) years were entered into a Phase I/II study. All patients received cyclophosphamide (Cy), 120 mg/kg administered over 2 days before TBI. Marrow from human leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not exceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRTs) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. None of the four patients at the dose level of 13.2 Gy developed Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additional 32 patients were evaluated at the 14.4 Gy level to confirm these initial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) developed Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dose limiting toxicity wasmore » Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia syndrome occurred in 5% of patients. The actuarial probabilities of event-free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TBI. The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in patients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximum set as the goal of this study, suggesting that 13.2 Gy is a more appropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children. 36 refs., 1 fig., 3 tabs.« less

PURPOSE To evaluate a high-dose chemotherapy regimen without total-body irradiation (TBI) followed by allogeneic (allo) bone marrow transplantation (BMT) in patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. PATIENTS AND METHODS Fifty-six patients with non-Hodgkin's lymphoma (NHL, n = 26), Hodgkin's disease (HD, n = 17), or acute lymphoblastic leukemia (ALL, n = 13) with a history of previous radiation therapy were treated with cyclophosphamide (7.2 g/m2), carmustine (300 mg/m2 or 600 mg/m2), and etoposide (2,400 mg/m2; CBV) followed by allo BMT. RESULTS Nine of 56 patients are alive and disease-free a median of 1,091 (range, 512 to 1,784) days post-transplant. The probabilities of transplant-related mortality, relapse, and event-free survival at 2 years for the entire group of 56 patients were .62, .59, and .17, respectively. Patients who received 600 mg/m2 of carmustine had a higher incidence of grade 3 or 4 regimen-related toxicities (RRTs) (14 of 22) than did patients who received 300 mg/m2 (12 of 33; P < .04), whereas there was no difference in relapse (.34 and .53, respectively, P = .73). Fourteen of 16 patients who received allo BMT for advanced disease (n = 12) or less-advanced disease (n = 4) but who were also eligible for auto BMT relapsed (n = 4) or died of transplant-related complications (n = 10). CONCLUSIONS Allo BMT following a high-dose CBV regimen resulted in long-term disease-free survival in 17% of patients with lymphoid malignancies who had received prior dose-limiting radiotherapy. A high incidence of transplant-related complications, especially fatal idiopathic pneumonia syndrome (IPS) and a high relapse rate limited success. Morbidity and mortality associated with carmustine 600 mg/m2 were high and were not associated with a decrease in relapse. The number of patients in this study eligible for either allo or auto BMT was limited and precluded meaningful analysis of relative effectiveness.

PURPOSE To analyze results of 127 patients undergoing myeloablative therapy followed by marrow transplantation for relapsed or refractory Hodgkin's disease. PATIENTS AND METHODS Twenty-three patients had primary refractory disease, 34 were in early first relapse or second complete remission (CR), and 70 had refractory first relapse or disease beyond second CR. Preparative regimens included total-body irradiation (TBI) and chemotherapy (n = 61) or chemotherapy only (n = 66). Sixty-eight patients received autologous marrow, six syngeneic marrow, and 53 allogeneic marrow. RESULTS The 5-year actuarial probabilities of survival, event-free survival (EFS), relapse, and nonrelapse mortality for the entire group were 21%, 18%, 65%, and 49%, respectively. HLA-identical allogeneic marrow recipients had a statistically lower relapse rate compared with recipients of autologous marrow, but survival, EFS, and nonrelapse mortality rates were not significantly different. In the multivariate analysis, higher performance status and absence of bulky disease predicted for improved EFS and lower relapse rates, while fewer prior treatment regimens predicted for improved EFS and lower nonrelapse mortality rates. Additionally, the univariate analysis showed that patients who underwent transplantation with disease refractory to chemotherapy or beyond second CR had a worse outcome compared with those who had less advanced disease. CONCLUSION Outcome with transplantation for patients with Hodgkin's disease is improved if transplantation is performed early after relapse when disease burden is less, tumor chemosensitivity is greater, and the patient is likely to have a better performance status. The use of HLA-matched sibling marrow results in a lower relapse rate and, thus, for some individuals, may be preferable to the use of autologous marrow.

PURPOSE This study compares outcomes of autologous bone marrow transplantation (ABMT) in patients with acute myeloid leukemia (AML) in untreated first relapse (REL1) or in second complete remission (REM2). PATIENTS AND METHODS Forty-seven patients with AML in REL1 (n = 21) or in REM2 (n = 26) were treated with busulfan (BU) and cyclophosphamide (CY) with or without total-body irradiation (TBI) followed by ABMT. All REL1 patients and four REM2 patients had marrow stored during first remission (REM1). Twenty-seven had marrow stored with and 20 without treatment in vitro with 4-hydroperoxycyclophosphamide (4-HC). Eighteen patients received BU and CY and 29 received BU, CY, and TBI. REL1 patients relapsed within a median of 9 months (range, 2 to 26) after marrow harvest and were transplanted a median of 30 days (range, 9 to 87) from detection of relapse. RESULTS With a median follow-up of 2.1 years (range, 0.4 to 5.3), 19 patients survive in remission (10 of 21 in REL1; nine of 26 in REM2). The actuarial probabilities of relapse-free survival at 2 years for patients transplanted in REL1 and REM2 were 45% +/- 22% and 32% +/- 18%, respectively (P = .33). The corresponding probabilities of relapse were 30% +/- 26% and 44% +/- 23%, respectively (P = .45). No conclusions could be drawn about the benefits of adding TBI to BU plus CY. There were no significant differences in neutrophil or platelet recovery or in posttransplant probabilities of relapse and nonrelapse mortality between patients who received marrow treated or not treated with 4-HC. CONCLUSION These results suggest that ABMT may produce long-term leukemia-free survival in approximately one third of patients with AML in REL1 or in REM2. There is no apparent clinical advantage in attempting to obtain second remissions in relapsed patients before ABMT if marrow has been cryopreserved during REM1. Although a strategy of transplantation in REL1 has advantages for the patient, such an approach involves the storage of marrow, which may not be used, and is impractical without the coordinated support of the treating physician, the patient, and the marrow transplant center.

Purpose Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients. Patients and Methods Two hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression. Results With a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk. Conclusion Allogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML.

PURPOSE To study the toxicity and potential efficacy of busulfan (BU) and cyclophosphamide (CY) as a conditioning regimen before allogeneic bone marrow transplantation (ABMT) in patients with multiple myeloma (MM). PATIENTS AND METHODS Twenty patients with MM underwent conditioning, which was followed by ABMT from 16 HLA-identical donors, three one-antigen-mismatched donors, and one HLA A, B, D-identical unrelated donor. Four levels of BU plus CY were evaluated. RESULTS Severe regimen-related toxicity occurred in two of five patients who received BU 16 mg/kg and CY 120 mg/kg, in none of the four patients who received BU 14 mg/kg and CY 120 mg/kg, in one of eight patients who received BU 14 mg/kg and CY 147 mg/kg, and in two of three patients who received BU 14 mg/kg and CY 174 mg/kg. Twelve of 15 (80%) assessable patients achieved a complete remission with the disappearance of M-protein and the return of normal marrow morphology. Ten patients died of complications related to the ABMT, and two patients died of progressive or relapsed MM. Overall, eight of 20 patients were alive; seven (35%) were in complete remission 190 to 1,271 days after ABMT. CONCLUSIONS The maximum-tolerable dose given in this setting was BU 14 mg/kg and CY 147 kg/mg. These results suggest that this regimen may have significant antimyeloma activity. Further phase II studies are warranted.

Respiratory failure was measured as the institution of assisted mechanical ventilation for hypoxemic (oxygenation) or hypercarbic (ventilatory) failure after marrow transplantation. There were 348 (23%) marrow recipients who required mechanical ventilation for an average of 8 days (median, 5; range, 1 to 45). The average onset of mechanical ventilation was 39 days (median, 22; range, 0 to 172) after transplantation. Factors previously found to be associated with mechanical ventilation were tested in a Cox proportional hazards model. Older age, active malignancy at time of transplantation, and donor-recipient marrow HLA-non-identity were independent risks for assisted mechanical ventilation after marrow transplantation. Twenty-one percent (n = 72) of the marrow recipients receiving assisted mechanical ventilation for respiratory failure were extubated. Four percent (n = 15) were discharged from the hospital, and 3% (n = 10) survived 6 months after transplantation. All of these survivors were physically functional. Three had mild chronic respiratory symptoms and restrictive or obstructive airflow defects 1 yr after transplantation. Respiratory failure requiring assisted mechanical ventilatory support occurs in 23% of marrow recipients and is associated with functional survival at 6 months in 3%. Older age, active malignancy at time of transplantation, and donor-recipient marrow HLA-non-identity are risk factors for subsequent respiratory failure. In view of the poor prognosis associated with respiratory failure, these factors should be considered when counseling patients and families regarding this mode of treatment.

We report the case of a 6.5-year-old male who received an unrelated orthotopic liver transplant for hepatic failure and encephalopathy following non-A-non-B hepatitis and subsequently developed severe aplastic anemia. For treatment of his aplastic anemia, he received a successful marrow transplant from his 9-year-old genotypically HLA- identical sister following conditioning with cyclophosphamide 200 mg/kg and anti-thymocyte globulin 90 mg/kg. Significant veno-occlusive disease of the liver and graft-versus-host disease did not occur. The patient remains alive without clinical chronic active hepatitis or need for blood product therapy. His hematocrit is 36%, white blood cell count 9.7 x 10(3)/mm3, and platelet count 1.7 x 10(5)/mm3 almost 2 years after marrow transplantation.

Less than 40% of the patients who could benefit from marrow transplantation have an HLA-matched relative who can serve as a donor. For this reason, several centers have explored marrow transplantation from other categories of donors. This retrospective study analyzes the results of marrow transplantation for 52 patients receiving grafts from HLA-A,B,DR,Dw-phenotypically matched, MLC-compatible, unrelated volunteer donors compared to a disease, disease-stage, and age-matched cohort of 104 patients transplanted from HLA-genotypically identical sibling donors. The patients transplanted from unrelated donors had an increased incidence of grade II-IV acute graft-versus-host disease compared to patients transplanted from related donors (79% vs. 36%, P much less than 0.001). However, the probability of relapse-free survival appears similar in the two groups (P = 0.39 over all, with estimates of 41% vs. 46% at 1 year). We conclude from this preliminary data that marrow transplantation from HLA-matched unrelated donors should be considered in most, if not all, circumstances where transplantation from an HLA-matched sibling would be indicated if such a donor were available.

The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression. This trial is registered at [www.ClinicalTrials.gov][1] as #[NCT00223925][2]. [1]: http://www.ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00223925&atom=%2Fbloodjournal%2F111%2F11%2F5403.atom

We report the results of 256 patients (median age = 59; range, 5–74 years) with de novo AML in first complete remission (CR1; n=100), beyond CR1 (n=79) and with treatment-related or secondary AML (n=77) who underwent allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related (n=109) or from unrelated donors (n=147). Indications of allogeneic HCT in CR1 were persistent cytogenetic or molecular evidence of disease, poor-risk cytogenetics at diagnosis, treatment-related or secondary AML and age more than 60 years. Younger patients were included if they had comorbid conditions that excluded them from conventional allogeneic HCT. Sixteen patients were mismatched with their donors for ≥ one HLA antigen, while the remainder were matched 10/10 at the antigen level. Conditioning consisted of low-dose total body irradiation (TBI; 2 Gy) on day 0 either alone (n=28) or combined with fludarabine, 30 mg/m2/day on days −4 to −2 (n=228). Calcineurin inhibitors (cyclosporine or tacrolimus) and mycophenolate mofetil were used for postgrafting immunosuppression. Durable engraftment was observed in 94% of patients. With a median follow-up of 35 (range, 3 – 111) months in surviving patients, the estimated progression-free and overall survivals at 5 years were 32% (95% CI: 25–38%) and 32% (95% CI: 25–38%), respectively. The cumulative incidences of relapse/progression and non-relapse mortality at 5 years were 40% (95% CI: 33–46%) and 29% (95% CI: 22–35%), respectively. Estimated 5-year survival rates, progression-free survival, relapse/progression rate, and non-relapse mortality according to disease status are shown in Table 1; Table 2 shows the same indices according to donor type. The cumulative incidences of grades II–IV and III–IV acute graft-versus-host disease (GVHD) in patients with related donors were 40% and 13%, and in those with unrelated donors were 58% and 14%, respectively. The cumulative incidence of chronic extensive GVHD at 5 years was 44% in patients with related donors, and 42% in patients with unrelated donors. Age > 60 years at the time of HCT did not have an impact on the outcome (univariate analysis). Additional analyses regarding the impact of HCT comorbidity scores and minimal residual disease at the time of HCT are in progress. Based on this multicenter analysis, we conclude that allogeneic HCT from related or unrelated donors, utilizing a conditioning regimen of low dose TBI (2 Gy) with fludarabine provides long term remission in elderly and/or medically infirm patients with AML, who were not considered candidates for conventional HCT. Table 1. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to disease status. CR1: 1st remission; >CR1: subsequent remission, induction failure/persistent disease; sAML: treatment-related and secondary AML. Disease Status n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) CR1 100 33 (20–46) 34 (23–46) 36 (26–47) 30 (19–40) >CR1 79 38 (26–49) 35 (23–46) 40 (29–52) 25 (15–35) sAML 77 20 (8–32) 23 (11–35) 45 (32–57) 32 (20–45) Table 2. Estimated 5-year overall survival (OS), progression-free survival (PFS), relapse/progression rate (RR), and non-relapse mortality (NRM) according to donor type. Donor Type n %OS (95% CI) %PFS (95% CI) RR (95% CI) NRM (95% CI) HLA-identical related 109 34 (23–44) 34 (24–45) 47 (37–58) 18 (10–26) HLA-matched unrelated 131 31 (22–40) 30 (21–39) 37 (29–46) 33 (24–72) HLA mismatched unrelated 16 24 (0–50) 24 (0–50) 6 (0–18) 70 (43–97)

A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32, respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against, and had a higher incidence of, acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.

We evaluated the utility of allogeneic HCT using nonmyeloablative conditioning as a potential treatment option for 79 patients (pts) with HL who were ineligible for high dose conventional allogeneic HCT and compared outcome based on donor cell source (MRD n=34, URD n=24, Haplo n=21). Conditioning consisted of 2 Gy TBI alone (n=15, MRD) or combined with either 90 mg/m2 (MRD n=19, all URD) or 150 mg/m2 (all Haplo) fludarabine. All haplo recipients also received cyclophosphamide pre (29 mg/kg) and post (50 or 100 mg/kg) HCT. GVHD prophylaxis consisted of mycophenolate mofetil and a calcineurin inhibitor. Pts were heavily pretreated with a median number of 5 (range, 2–10) prior regimens. Most pts failed prior autologous HCT (91%) and radiation therapy (86%). There were no graft rejections. The incidences of acute grades III–IV and extensive chronic GVHD were 15%/47% (MRD), 8%/60% (URD), and 10%/31% (Haplo). There were no statistically significant differences in the ability to discontinue immunosuppression based on donor cell sources. With a median follow up of 20 (range, 4–91) months for living pts; the 18 month overall survivals (OS), progression free survivals (PFS), and incidences of relapse/progressive disease (PD) were 47%, 20%, and 55% (MRD), 74%, 27%, and 65% (URD), and 71%, 60%, and 35% (Haplo), respectively. Nonrelapse mortalities (NRM) were significantly lower for URD (HR 0.16; p=0.03) and Haplo (HR 0.13; p=0.02) recipients compared to MRD recipients. There were also significantly decreased risks of relapse for Haplo recipients compared to MRD (HR 0.35; p=0.03) and URD (HR 0.36; p=0.02) recipients. These data suggest that salvage allogeneic HCT using nonmyeloablative conditioning provides anti-tumor activity in pts with very advanced disease; however, Rel/PD continue to be major problems regardless of stem cell source. Importantly, alternative donor sources are a viable option particularly for those pts who may have a limited window of opportunity to proceed to HCT. Pt Characteristics MRD (n=34) URD (n=24) Haplo (n=21) Median Age (yrs) 33 28 31 Disease Status at HCT CR 11 (32%) 5 (21%) 5 (24%) PR 16 (47%) 8 (33%) 5 (24%) Rel/Ref 7 (21%) 11 (46%) 11 (52%) Disease Bulk > 5cm 3 (9%) 3 (13%) 3 (14%) HCT-Comorbidity Index >2 21 (62%) 17 (74%) 13 (62%) Regimens > 5 16 (47%) 16 (67%) 12 (57%) Failed Prior Auto HCT 30 (88%) 23 (96%) 19 (90%) Median Time Diagnosis - Allo HCT (months) 33 31 32 Median Time Auto-Allo HCT (months) 16 19 17 Outcomes by donor type MRD (n=34) URD (n=24) Haplo (n=21) Median f/u living pts months (range) 15 (4–91) 26 (8–58) 15 (4–49) Acute GVHD grade II–IV, III–IV 53%, 15% 50%, 8% 43%, 10% 18 month extensive chronic GVHD 47% 60% 31% Day 200 NRM 18% 0% 0% 18 month OS 47% 74% 71% NRM 25% 8% 5% Rel/PD 55% 65% 35% PFS 20% 27% 60%

Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors. Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days −4 to −2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day −3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after related and 42% after unrelated HCT, respectively. With a median follow-up of 44 months (range, 26 to 79 months), 51 patients were alive, of whom 48 were in complete remission (CR). Cumulative nonrelapse mortalities were 10% and 22%, and cumulative mortalities from disease progression were 47% and 33% at 2 years for related and unrelated recipients, respectively. Overall, 2-year survival was 48%, and disease-free survival was 44%. Patients receiving transplantation in CR1 had 2-year overall survivals of 44% after related and 63% after unrelated HCT, respectively. Conclusion We conclude that HCT from related and unrelated donors after low-dose TBI is a promising treatment for elderly patients with AML.

We evaluated the results of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with diffuse aggressive non-Hodgkin lymphoma (NHL) in first relapse (Rel 1) or second complete remission (CR 2). Data were evaluated from the Autologous Blood and Marrow Transplant Registry on 429 patients with diffuse aggressive NHL who underwent transplantation in Rel 1 or CR 2. Transplantations were performed between 1989 and 1996 and were reported to the Autologous Blood and Marrow Transplant Registry by 93 centers in North and South America. The probability of 3-year survival was 44% (95% confidence interval [CI], 33%–55%). The probability at 3 years of progression-free survival was 31% (95% CI, 27%–36%). Patients who underwent transplantation in CR 2 had a 3-year probability of progression-free survival of 38% (95% CI, 30%–46%) compared with 28% (95% CI, 22%–33%) for those who were not in remission at the time of transplantation (P < .001). In multivariate analysis, chemotherapy resistance, increased lactic dehydrogenase at diagnosis, an interval of

The invasion and colonization of oral cavity mucosal tissues by microflora may contribute to the pathophysiology of ulcerative oral mucositis (UOM). Iseganan is an analog of protegrin-1, a naturally occurring peptide with broad-spectrum microbicidal activity. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of iseganan in preventing UOM after stomatotoxic therapy. Patients received an oral rinse, consisting of iseganan 9mg or placebo, to be swished/swallowed six times daily, starting with stomatotoxic therapy and continuing up to 21 days. Patients were assessed for stomatitis and UOM, and administered a questionnaire evaluating mouth pain and difficulty swallowing thrice weekly. The primary study efficacy endpoint was the proportion of patients who did not have peak stomatitis NCI-CTC grade >or=2. Between November 2001 and June 2002, 502 patients were randomized to receive iseganan (251) or placebo (251). Equivalent numbers of patients in both cohorts received bone marrow or peripheral blood allogeneic or autologous stem cell transplantation (SCT). Forty-three percent and 37% of iseganan and placebo patients, respectively, did not have peak stomatitis grade =2 (P = 0.182). There was no significant difference between the cohorts in stomatitis severity, incidence of UOM, peak mouth pain, peak difficulty swallowing, amount of opiate analgesics used, or adverse event type or incidence. A major impact of Iseganan on reducing stomatitis, UOM, or its clinical sequelae in patients receiving stomatotoxic therapy was not detected on this study.

BACKGROUND : Accurately predicting the outcomes of peripheral blood stem cell harvests is important because unproductive collections are expensive and subject the donor to unnecessary toxicity. STUDY DESIGN AND METHODS : Predictive factors for stem cell mobilization and collection by a retrospective review of 104 consecutive donors were evaluated. RESULTS : Of several previously suggested measures, the peripheral CD34+ cell concentration on the day of harvest (pCD34 DH ) correlated best with total numbers of CD34+ collected (r = 0.88). This was followed by the pCD34 on the day before harvest (pCD34 Day –1 ) (r = 0.74). The peripheral WBC count on the day of harvest (pWBC) was inferior (r = 0.39). When ratios of potential predictive factors divided by the previous day's value were examined, pWBC ratio was found to be a significant independent predictive factor for cells collected (r = 0.45). Furthermore, the predictive value of both the pCD34 Day –1 and the pWBC can be improved by combining with the pWBC ratio. To examine whether the chosen collection starting days were optimal, serial pCD34 obtained daily during the harvest procedures was examined. Poorly mobilizing donors, who required several days of collection, did not reach maximal harvest yields until the fourth collection day. CONCLUSIONS : pCD34 DH is the optimal predictive factor for harvest yields. If pCD34 DH is not available, pCD34 Day –1 or pWBC combined with the pWBC ratio may offer the best prediction of harvest outcomes. The best harvest yields on poorly mobilizing donors occur 3 to 4 days after the usual collection starting times.

Background While delayed or failed engraftment following reduced intensity conditioning (RIC) umbilical cord blood transplant (UCBT) now occurs less frequently than initially reported, it continues to be higher than in the conventional donor setting. It has been shown that patients who have had a prior autologous transplant or who have received chemotherapy within 4 months of UCBT have an increased incidence of sustained donor engraftment compared with those without this prior therapy (98% vs 64%) (Barker et al ASH abstract 2003). The standard measure of engraftment following UCBT is neutrophil recovery to > 500 x 3 days. However, there has recently been established a possible correlation between time to neutrophil engraftment and early full donor chimerism after UCBT (Avery S et al BMT 2012). Herein, we conducted an RIC UCBT trial in which patients were assigned to one of two treatment regimens based on their risk of graft failure. In addition to evaluating sustained donor engraftment characterized by time to neutrophil recovery, we also sought to assess the achievement of full donor chimerism at Day +28 post-transplant in patients pre-determined to be high versus low risk of graft failure. Methods Forty-eight patients median age 59 years (range 25 - 73) and comorbidity index = 3 (range 0 - 8) with high risk hematologic malignancies received an RIC regimen containing cyclophosphamide 50mg/kg on Day -6, fludarabine 40mg/m2 Day -6 to -2 (dose reduced to 35mg/m2 for creatinine clearance < 70), and either 200 cGy TBI (Arm 1 = low risk of graft failure) or 300 cGy TBI (Arm 2 = high risk of graft failure) on Day -1. High risk for graft failure was defined as “receiving < 2 cycles of multiagent chemotherapy or no multiagent chemotherapy within the 3 months prior to UCBT.” Low risk for graft failure was defined as “having received a prior autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months prior to UCBT.” Patients on both arms received GVHD prophylaxis with cyclosporine from Day -1 to Day +180 and mycopheolate mofeteil 1 gram every 8 hours until Day +40. Forty-seven of 48 patients received 2 UCB units (one patient received a single UCB) with a median TNC/kg of 4.05 x 107 and a post-thaw median CD34+cells/kg of 1.75 x 105. UCB grafts (98%) were 1-2 HLA antigen mismatched with the recipient. Twenty-six patients were assigned to Arm 1 and 22 patients were assigned to Arm 2. Bone marrow and peripheral blood chimerism assessment were performed at approximately Day +28 and Day +80. The blood was flow sorted in the clinical hematopathology lab into defined lineage subsets. Wilcoxon rank-sum test was used to compare the 2 groups. Results All evaluable patients engrafted (n = 46). Patients on Arm 1 achieved neutrophil recovery (ANC > 500 x 3 days) at a median of 12 days (range 6 - 38) versus 23 days (range 7- 46) in patients on Arm 2 (p = 0.01). Day +28 chimerism values were evaluable for 23 patients on Arm 1 and 20 patients on Arm 2. Median chimerism in the CD3+ compartment was 100% (57 - 100) and 100% (0 - 100) on Arm 1 and Arm 2 respectively (p = 0.58). Median chimerism in the CD33+compartment was 98% (15 - 100) and 100% (44-100) on Arm 1 and Arm 2 respectively (p =0.26). Median chimerism in the bone marrow was 98% (15 - 100) and 100% (4 - 100) on Arm 1 and Arm 2 respectively (p = 0.84). This was maintained at Day +80. Acute graft versus host disease (GVHD) grades II - IV was seen in 84% (n = 21) and 68% (n = 15) of patients on Arm 1 and 2 respectively with 5% and 12% grade III-IV GVHD in the respective arms. Chronic GVHD was seen in 40% of patients on Arm 1 (8 mild, 2 moderate) and 23% on Arm 2 (3 mild, 1 moderate, 1 severe). Overall survival at 1 year in Arm 1 was 43% (95% CI: 22-62%) and Arm 2 was 46% (95% CI: 20-69%). Conclusions The goal of this RIC UCBT study was to assess engraftment rates by neutrophil recovery and Day +28 chimerism in patients at low versus high risk of graft rejection. Although time to neutrophil recovery was significantly faster in patients with low risk of graft failure, patients at high risk of rejection achieved a similar incidence of full donor chimerism at Day +28 as those with low risk of graft rejection. Using Day +28 chimerism as a measure of engraftment, patients deemed high risk of graft failure achieved early engraftment with UCBT following an RIC conditioning regimen containing 300cGy TBI. Disclosures: No relevant conflicts of interest to declare.

purpose: To evaluate the efficacy of prophylactic low-dose amphotericin B (0.1 mg/kg per day) (LDA) in preventing fungal infections in patients who have had a bone marrow transplant (BMT). materials and methods: Double-blind, randomized, controlled trial in which patients undergoing bone marrow transplantation received intravenous LDA or similar-appearing placebo from the onset of neutropenia until the absolute neutrophil count remained >0.5 × 10 9 /L, or until high-dose amphotericin B was initiated. Weekly surveillance cultures were obtained from all patients. results: Five of 18 patients (28%) randomized to placebo developed documented systemic fungal infections within the first 30 days after transplantation, compared to none of 17 patients who received LDA ( P = 0.045). LDA recipients received fewer days of high-dose amphotericin B ( P = 0.04) and fewer days of antibiotics ( P = 0.008). There were trends towards fewer days of hospitalization ( P = 0.14) and improved survival ( P = 0.08); these differences were statistically significant among recipients of allogeneic BMT. No adverse effects occurred with LDA therapy. conclusions: LDA appears to be safe and to reduce early systemic fungal infections in BMT recipients. Improved survival was observed among LDA recipients, but this was not directly attributable to the prevention of fungal infection.

PURPOSE To evaluate a high-dose treatment regimen of fractionated total-body irradiation (TBI), etoposide, and cyclophosphamide (Cy) followed by autologous stem-cell transplantation (ASCT) in patients with malignant lymphoma. PATIENTS AND METHODS Fifty-three patients with non-Hodgkin's lymphoma (NHL; n = 43) or Hodgkin's disease (HD; n = 10) received 12.0 Gy of fractionated TBI, etoposide 60 mg/kg, and Cy 100 mg/kg followed by infusion of autologous hematopoietic stem cells. RESULTS Thirty-one of 53 patients are alive a median of 643 (range, 177 to 1,144) days after transplant. The 2 year Kaplan-Meier (K-M) estimates of survival, event-free survival (EFS), and relapse for all 53 patients were 54%, 45%, and 43%, respectively. Sixteen of 24 patients with less advanced disease and 10 of 29 patients with more advanced disease survive free of disease for K-M estimates of EFS of 61% and 31%, respectively (P = .006). The K-M estimates of relapse were 34% for patients with less advanced disease and 53% (P = .05) for patients with more advanced disease. The K-M estimates of dying from causes other than relapse were 8% in patients with less versus 25% in patients with more advanced disease (P = .09). CONCLUSION These data indicate that approximately 60% of patients transplanted early after failure of initial therapy for malignant lymphoma are projected to be disease-free more than 2 years after treatment with fractionated TBI, etoposide, and Cy and infusion of autologous hematopoietic stem cells. The transplant-related mortality rate is low and relapse is the main cause of treatment failure in patients with less advanced disease. For patients with more advanced disease, the K-M estimates of both transplant-related deaths (25%) and relapse (53%) remain major problems.

Context A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. Objective To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. Design, Setting, and Participants From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m 2 , before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. Main Outcome Measures Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. Results Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P Conclusion Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.

PURPOSE The impact of a second marrow transplant on long-term disease-free survival (DFS) was evaluated for 77 consecutive patients aged 2 to 51 years who relapsed subsequent to allogeneic marrow transplantation after high-dose chemotherapy and total-body irradiation (TBI). PATIENTS AND METHODS Patients received a second transplant for recurrent chronic myelogenous leukemia (CML) (n = 28), acute myelogenous leukemia (AML) (n = 32), and acute lymphoblastic leukemia (ALL) (n = 15) or lymphoma (n = 2) that used the same marrow donor as the initial transplant. High-dose chemotherapy of busulfan (BU) and cyclophosphamide (CY), or CY, carmustine (BCNU), and etoposide (VP-16), was used as a preparative regimen for the second transplant. Graft-versus-host disease (GVHD) prophylaxis consisted of the following: no prophylaxis (n = 8), T-cell depletion (n = 36), methotrexate (MTX) only (n = 21), cyclosporine (CSP) only (n = 1), MTX and CSP (n = 9), or anti-thymocyte globulin (ATG) and prednisone (n = 2). RESULTS Engraftment occurred in the 74 assessable patients. Severe veno-occlusive disease (VOD) was the most frequent cause of grades 3 and 4 regimen-related toxicity (RRT); it occurred in 20 patients. The probability of death before day 100 from nonleukemic causes was 36%. The probability of relapse after second transplant was 70%, and the DFS rate was 14% (median DFS, 36 months; range, 22 to 87). The DFS rates for ALL, AML, and CML were 8%, 10%, and 25%, respectively. Multivariate analysis showed that the risk of relapse was inversely associated with acute GVHD (relative risk [RR] of relapse = 0.2; P = .0009). No other factor was associated with relapse. DFS was associated with the presence of acute GVHD (RR of treatment failure = 0.5; P = .0085), and a reduction of DFS was associated with severe VOD (RR = 10.6; P = .0001) and those patients older than 10 years (RR = 2.5; P = .0337). CONCLUSION These data show that some patients may benefit from a second marrow transplant for recurrent leukemia after an initial marrow transplant. Younger patients and patients with CML especially should be considered as potential candidates for a second transplant.

Abstract 3450 Objective: Allogeneic hematopoietic cell transplantation (HCT) following a variety of reduced-intensity conditioning regimens has been reported to produce encouraging results in patients with AML. In these studies disease relapse was the main cause of treatment failure, with 2–4 year relapse rates ranging between 32–61% resulting in overall survivals of 28–45% at 2–4 years. Our goal here was to examine whether pre-HCT variables could identify patients at high risk for relapse following nonmyeloablative allogeneic HCT, who thus would become candidates for additional interventions to reduce the risk of AML relapse. Methods: The data were derived from 274 consecutive Seattle Consortium patients (median age: 60 years) with de novo or secondary AML who underwent allogeneic HCT from related or unrelated donors after conditioning with 2 Gy total body irradiation (TBI) with or without fludarabine (90 mg/m2) as recently reported (Gyurkocza et al., JCO 2010 Jun 10;28(17):2859–2867). Cox regression was used to perform multivariate analysis of risk factors for relapse in a subset of 231 patients in morphologic leukemia-free state (defined as less than 5% marrow blasts) with (n=134) or without (n=97) peripheral blood cell count recovery (defined as platelets > 100,000/ml and neutrophils > 1,000/ml) at the time of HCT. In this multivariate model, AML beyond 1st complete remission (CR1), unfavorable cytogenetics (according to SWOG criteria), incomplete peripheral blood cell count recovery before HCT, and shorter time between diagnosis and HCT were associated with statistically significantly higher risk of relapse (Table 1). From this multivariate model we developed a relapse risk score that summarizes the contribution of multiple risk factors by assigning weights based on the relative magnitude of the log hazard ratios associated with the principal risk factors. From a starting score of 0, points were added or subtracted based on the following factors: 2nd CR: +1 point; 3rd or later CR: +2 points; unfavorable cytogenetics: +1 point; absence of pre-HCT peripheral blood cell count recovery: +0.5 points; time from diagnosis to HCT > 18 months, -2 points (Table 2). Patients were then stratified into 2 relapse risk groups according to whether the total risk score was ≤0 (low-risk) or >0 (high-risk). Results: Stratification of patients according to the proposed Relapse Risk Score resulted in a clear separation of the two risk groups, with 5-year relapse rates of 50% and 17% in the high- and low-risk groups, respectively (Figure 1A). Five-year overall survival rates were 26% and 50% in the high- and low-risk groups, respectively (Figure 1B). Conclusion: Our Relapse Risk Score may be a useful tool to identify patients with AML at high risk for relapse, who could potentially benefit from additional interventions to reduce the risk of relapse following allogeneic HCT. We are currently attempting validation in an independent cohort of patients with AML to make this Risk Score more generalizable. Relapse/Progression (A) and Overall Survival (B) rates stratified by Relapse Risk Score. Disclosures: Off Label Use: Off label usage of fludarabine, cyclosporine, tacrolimus and mycophenolate mofetil is discussed.

PURPOSE The purpose of this report was to review the Seattle experience in bone marrow transplantation (BMT) for acute myeloid leukemia (AML) during untreated first relapse. PATIENTS AND METHODS Through 1990, 126 patients were transplanted during untreated first relapse of AML. Several preparative regimens were used, two of which involved more than 20 patients. Regimen 1 (29 patients) consisted of cyclophosphamide (CY) 120 mg/kg and 15.75 Gy of fractionated total-body irradiation (TBI) with methotrexate (MTX) given intermittently during a 102-day period to prevent graft-versus-host disease (GVHD). Regimen 2 (22 patients) consisted of the same CY and TBI treatment and a combination of MTX and cyclosporine (CSP) for GVHD prophylaxis. The remaining 75 patients were treated with 17 other transplant regimens. Outcome was compared for patients who were treated with regimen 1, regimen 2, and any other regimen. RESULTS The 5-year probabilities of relapse-free survival (RFS), relapse, and nonrelapse mortality for 126 patients were .23, .57, and .44, respectively. With regimen 1, relapse (.26) was significantly less than for regimen 2 (.70; P = .004) or any other regimen (.76; P = .004). Regimen 1 patients developed more acute GVHD (.67) than regimen 2 patients (.26; P = .02) or patients on other regimens (.41; P = .02), and had increased nonrelapse mortality. Nevertheless, regimen 1 patients had a significantly higher 3-year RFS (.38) than those treated with regimen 2 (.18; P = .04) or any other regimen (.20; P = .05). CONCLUSIONS For patients who received 120 mg/kg CY and 15.75 Gy TBI, relapse incidence was less and survival was better after GVHD prophylaxis with MTX alone than after a combination of MTX and CSP, despite a significantly higher incidence of acute GVHD. The results of treatment with regimen 1 justify future studies of the optimal timing of allogeneic BMT in the treatment of patients with AML.

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

Median ages of pts with most hematological malignancies are beyond 60 years. The advent of nonmyeloablative conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p=0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p=0.06); both predicted worse OS (p=0.005 and p=0.0009, respectively) and PFS (p=0.01 and p=0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Age groups, years (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) Median Interval from Dx to HCT, months 19 15 8 Median (range) # of prior regimens 3 (0–14) 3 (0–13) 2 (0–10) Median CD34+ cell number x 106/kg 6.7 6.7 6.5 Median CD3+ cell number x 108/kg 2.9 3.1 3.4 % Prior radiotherapy 18 11 13 Prior HCT Failed 19 12 4 Planned 8 6 4 Positive patient CMV sero-status 58 65 79 HLA-matched related 54 53 83 Donor HLA-matched unrelated 41 44 17 HLA-mismatched unrelated 5 3 0 Conditioning 2 Gy TBI 12 13 21 2 Gy TBI + FLU 88 87 79 HCT-CI scores 0 27 27 15 1–2 30 39 25 3–4 30 17 40 ≥5 13 17 20 Diagnoses Acute leukemia 35 47 62 Chronic leukemia 15 13 13 Lymphoma/myeloma 21 23 8 Myelodysplastic/myeloproliferative 16 16 17 Others 3 1 0 Disease status at HCT CR 46 41 38 PR 15 30 21 Refractory 28 21 33 Relapse 11 8 8 Relapse risk Low 19 17 8 Standard 48 51 38 High 33 32 54 Table 2: Outcomes per age groups HCT Outcomes Age groups, years P* (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) FUO indicates fever of unknown origin *Test for trend μBased on hazard ratio analysis Bacterial 1.4 2.3 1.7 .0004 Rates of Infection episodes per person Viral 0.7 1.1 0.7 NS within 100 days FUO 0.3 0.4 0.1 NS Fungal 0.3 0.2 0.3 NS Median (range) days of hospitalization 1 (0–60) 4.5 (0–179) 0.5 (0–47) NS % Acute GVHD Grades II–IV 52 49 54 NSμ Grades III–IV 16 12 13 NSμ Chronic extensive GVHD 39 45 54 0.05μ NCI-CTC criteria grades III–IV non-hematological toxicities 42 57 50 NSμ Pts with Full donor chimerism at 1-year CD3/CD33/BM 68/ 84/ 80 66/ 83/ 77 67/ 79/ 71 NSμ CR at 2-years 40 47 63 NSμ 5-years Relapse/progression 38 46 46 NSμ 5-years NRM 28 22 29 NSμ 5-years OS 37 36 23 NSμ 5-years PFS 34 31 25 NSμ Patients alive and off all immunosuppression 24 25 5 NSμ

Between October 1979 and January 1988, 101 patients with malignant lymphoma who failed initial induction treatment or relapsed received high-dose combination chemotherapy or chemoradiotherapy followed by infusion of autologous bone marrow. Twenty-eight of the 101 patients survive, 18 of whom are disease-free for a median of 26 (range, 12 to 66) months. The 5-year actuarial probabilities of survival, event-free survival (EFS), and relapse from transplantation were 20%, 11%, and 84%, respectively. Multivariate analysis showed that the likelihood of EFS was decreased among patients transplanted with a Karnofsky score of less than 80%. Recurrent lymphoma after transplant was the most important cause of treatment failure with 36 of 62 relapses occurring within 100 days from marrow infusion. Early, but not late relapse, was more frequent in patients transplanted for advanced lymphoma, and both early and late relapses were increased among patients with impaired pretransplant clinical performance or high-grade histology of lymphoma. Ten patients who relapsed post-transplant are alive, seven in remission. Further improvement of these results will require earlier transplantation, improved preparative regimens, or early posttransplant therapy.

Bone marrow transplantation is a worldwide activity involving more than 250 transplant centers in over 40 countries [5]. Since its clinical introduction almost 20 years ago, the indications for transplantation have increased as the long-term results have improved [33]. Following marrow ablation with supralethal doses of total body irradiation and/or chemotherapy, hematopoietic and immunologic reconstitution is achieved via proliferation of engrafted marrow donor stem cells [36]. The ultimate success of the procedure depends, in large measure, upon supportive care of the transplant recipient. The following report reviews aspects of this special care.

Allogeneic marrow transplantation has been used increasingly to treat patients with various hematological diseases. A survey by the International Bone Marrow Transplantation Registry estimated the number of transplants carried out through the year 1987 to be in the order of 20000 [6]. Most of these transplants (80%) have been for therapy of malignant hematological diseases. The current manuscript will review results of and future treatment strategies in marrow transplantation for acute leukemias in Seattle.

Use of HLA-mismatched unrelated donors after myeloablative conditioning is an effective treatment of blood disorders when HLA-matched donors are not available. However, the feasibility of HLA-mismatched HCT following nonmyeloablative conditioning is not well established. We previously demonstrated in over 1200 patients (pts) that a nonmyeloablative conditioning regimen consisting of 2 Gy TBI and fludarabine (90 mg/m2) followed by post-grafting immunosuppression with MMF/CSP was an effective approach for HCT from 10/10 HLA-matched donors. Here we report the results of a clinical trial aimed at determining whether stable hematopoietic grafts from HLA-class I mismatched donors could be safely established after nonmyeloablative conditioning. Pts were conditioned with fludarabine and 2 Gy TBI, followed by extended immunosuppression with CSP (day −3 to +180; tapered by +365) and MMF (tid days 0 to +100; tapered by +150). 46 pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study through April/07. 36 unrelated and 3 related donor-recipient pairs were mismatched in both the HVG and GVH vectors. 43 unrelated pairs were mismatched for at least one antigen (AG) (15 at HLA-A, 5 at HLA-B, 22 at HLA-C) except one pt who had two allele mismatches (HLA-A and B). All 3 related pairs were mismatched for one HLA-A AG. 13 pts, in addition to the AG mismatch, had an allelic mismatch (3 at HLA-A, 4 at HLA-B, 6 at HLA-C). All pts were matched for HLA-DRB1 and HLA-DQB1 at the allele level. Diagnoses included NHL (n=17), HD (n=5), AML (n=11), ALL (n=5), CLL (n=3), MM (n=4) and MDS/AML (n=1). The median age of pts was 56 (range 13–69) years and median time from diagnosis to HCT was 32 (range 5–205) months. Disease status at time of HCT included CR (n=23), PR (n=11), stable disease (n=2), and refractory relapse (n=10). Before HCT, pts had received a median of 7 (range 2–15) courses of therapy. 43% had failed myeloablative HCT (autologous n=18; allogeneic n=2). All pts received G-CSF mobilized PBSC containing median doses of 7.3 ×106 CD34 and 2.4 × 108 CD3 cells /kg. 12 pts were not evaluable for the graft rejection outcome (3 early death, 7 mismatched in GVH vector only, 2 tandem auto-allo). The remaining pts showed median percentages of donor peripheral blood T cell, granulocyte and marrow chimerism of 100% at all time points (on days 28, 56, and 84). Two pts experienced graft rejection but had a successful 2nd HCT from the same or an alternative donor. 35 of the 46 pts developed acute GVHD (2 grade I, 21 grade II, 5 grade III, 7 grade IV) and 15 developed chronic GVHD. At 2 years, the cumulative probabilities of relapse/progression and non-relapse mortality were 30% and 45%, respectively. The 2 year Kaplan-Meier estimates of OS and PFS were 27% and 25%. This study demonstrates that nonmyeloablative conditioning using fludarabine and low-dose TBI can be successfully used for grafts from pts with HLA- class I mismatched donors.

Cytomegalovirus (CMV) remains a major threat to recipients of allogeneic stem cell transplants (SCT). Potential toxicities of currently available anti-CMV agents complicate their use in this population. Maribavir (MBV) is an oral antiviral drug with a unique mechanism of action against CMV and a promising safety profile in early clinical studies. This randomized, double-blind, multicenter, dose-ranging study enrolled adult CMV-seropositive recipients of allogeneic SCT. After engraftment, patients were randomized to receive CMV prophylaxis with placebo or MBV at one of three doses for up to 12 weeks. CMV surveillance was performed weekly with both CMV pp65 antigenemia and plasma CMV DNA PCR assays. If CMV was detected, study drug was stopped and preemptive anti-CMV therapy started as per standard practice at each center. A total of 111 patients were enrolled (median age 47 years; 70% myeloablative SCT; 53% related donor). Incidence of CMV infection or disease in the first 100 days post-SCT are shown in the table. The safety profile of maribavir was favorable in this patient population; most adverse events occurred at similar rates in placebo and MBV groups. There was no adverse impact of MBV on neutrophil counts or other laboratory or ECG parameters. Consistent with prior clinical studies, the most notable events that appeared to be associated with MBV were mild-moderate taste disturbance, nausea, and diarrhea. In conclusion, maribavir prophylaxis reduced the rate of CMV infection compared to placebo, with a favorable safety profile in this complex patient population. Phase 3 studies of maribavir in stem cell and solid organ transplant recipients are being planned. Placebo MBV 100 mg BID MBV 400 mg QD MBV 400 mg BID N evaluable 28 27 27 26 p values represent comparison to placebo (stratified by myeloablative or nonmyeloablative SCT) CMV infection or disease based on: pp65 antigenemia 11 (39%) 4 (15%) 5 (19%) 4 (15%) p=0.046 p=0.116 p=0.053 plasma CMV DNA PCR 13 (46%) 2 (7%) 3 (11%) 5 (19%) p=0.001 p=0.007 p=0.038 Use of preemptive anti-CMV Rx 16 (57%) 4 (15%) 8 (30%) 4 (15%) p=0.001 p=0.051 p=0.002 CMV disease only 3 (11%) 0 0 0 p=0.089 p=0.084 p=0.091

Background: Eligibility for high dose chemotherapy and autologous stem cell rescue often includes adequate pulmonary function. While high dose melphalan has been noted to cause significant pulmonary toxicity in a small percentage of patients with adequate pulmonary function, there are little published data on risk factors and use in lung impaired patients. We retrospectively reviewed the charts of 50 patients with myeloma who received a fixed dose of melphalan (200 mg/m2) and who had pre-melphalan and at least one post-melphalan spirometry (FVC and FEV1) and diffusing capacity (DLco) measurement. Comparisons were made with Pearson correlations and one-way ANOVA. Patients receiving melphalan showed no significant differences in mean FVC (p=0.40), FEV1 (p=0.48) or hemoglobin corrected DLco (p=0.40) comparing baseline to 3-month and 1-year results with 1-way ANOVA. There was a consistent increase in mean FVC(L), FEV1(L) and DLco (ml CO/min/mmHg) from pre to 3 months post (3m) and to one-year post (1y): FVC: pre=3.89, 3m= 4.02, 1y=4.24; FEV1: pre=2.92, 3m=2.95, 1y=3.14; DLco: pre=24.3, 3m=25.1, 1y=26.5. However, individual changes in DLco showed a wide distribution. Therefore, we examined a number of potential risk factors for change in DLco at 3 months. No detrimental effects were discernable for age, gender, history of prior pulmonary disease including smoking, pre-melphalan lung function, the use of high dose cyclophosphamide in the mobilization regimen, amount of prior chemotherapy or chest radiation, disease stage or response, or renal function. CD34+ cell dose (p=0.017, r = −0.344) and immunoglobulin type (IgA worse than IgG) (p=0.029, r = 0.316) were correlated and were independent factors on regression analysis (p

An analysis of catheter-related complications in a study group consisting of 83 patients, each of whom arrived at a major marrow transplant center after having had a large bore right atrial catheter (RAC) inserted by the referring institution, was compared to a similar analysis of catheter-related complications in 357 patients who had their RAC inserted at the transplant center just before the transplant procedure was begun (control group). Fourteen (17%) patients in the study group had their original catheter removed for complications (five for septicemia and nine for mechanical complications) compared to 57 (16%) of the patients in the control group. Thirteen (16%) of the 83 catheters in the study group were double lumen and only two of these (15%) were replaced due to complications. Sixteen of 59 patients (27%), 13 years old or older, who arrived with a single lumen RAC already inserted, required an additional catheter during the transplant procedure because of an increased need for intravenous access. From this study, we concluded that patients who arrived for marrow transplantation with a RAC already inserted did not routinely need the catheter replaced. However, it is recommended that double lumen catheters be inserted in adult patients if marrow transplantation is anticipated.

The complications associated with the insertion and use of 95 single lumen and 312 double lumen Hickman right atrial catheters in 357 marrow transplant recipients were retrospectively analyzed. Three-hundred (84%) first inserted catheters were in place for a median of 93 days (range, 16-209) without complications and were removed electively. Thirty-nine (9.6%) of all catheters were removed for infections and 24 (5.9%) for mechanical complications. Ninety-five patients (26.6% ) had 111 episodes of septicemia involving 128 separate organisms and 25 patients had 25 episodes of localized catheter infection with 26 separate organisms. The most frequently isolated organism was coagulase-negative staphylococcus. Twelve of 24 removals due to mechanical complications were caused by accidental pulling of the catheter by the patient. (Journal of Parenteral and Enteral Nutrition10:58-62, 1986)

We report two cases of pulmonary venoocclusive disease (PVOD) in children with acute lymphoblastic leukemia treated by marrow allograft transplantation following conditioning with high-dose 1-3 bis chloroethyl-1 nitrosourea (BCNU), etoposide (VP-16), and cyclophosphamide (Cy). Both patients developed symptomatic pulmonary hypertension documented by right heart catheterization. Open-lung biopsy of one patient demonstrated PVOD evident even on frozen sections stained with hematoxylin and eosin. High-dose methylprednisolone was associated with significant clinical improvement in both patients. Pulmonary symptoms resolved in one patient who subsequently died in leukemic relapse. PVOD resolved in the other patient, only to recur when steroids were discontinued and then again respond to reinstitution of therapy. More aggressive therapy for malignant diseases may increase the incidence of PVOD. Prompt recognition of its subtle clinical and histological manifestations allows early institution of steroid therapy, which may be beneficial.

A new instrument which utilizes a computer controlled freezing platform moving in a constant air temperature gradient generated over liquid nitrogen (LN2) was evaluated for cryopreservation of human marrow. Marrows were placed horizontally on the freezing platform which was suspended over LN2 in a cylindrical freezing chamber. The platform was raised or lowered to maintain a predetermined fixed cooling rate in response to temperature monitored and recorded by the computer from a thermocouple placed at platform level. Separate freezing programs were created for different marrow volumes. The viability of normal marrow was tested in vitro before and after freezing. Recovery of marrow cells after freezing and thawing, as measured by cell counts and CFU-GM assays, were the same for the constant air gradient instrument as for a conventional freezing instrument. Thirteen patients received autologous marrow transplants utilizing marrow cryopreserved in the constant air gradient instrument and engraftment results were indistinguishable from those obtained for marrow cryopreserved with a conventional instrument.

Granulocyte and platelet recovery as well as platelet transfusion requirements following allogeneic marrow transplantation were analyzed in 67 patients with chronic myelogenous leukemia in the chronic phase. Twenty patients had splenectomy prior to transplantation. Forty-seven patients were transplanted without splenectomy, 21 of whom had splenic enlargement by physical examination. There were no differences in the proportion of patients with granulocyte recovery, but the recovery of peripheral granulocytes to levels of 200, 500 and 1,000/mm3 occurred more rapidly in the splenectomy group than in the no-splenectomy group. Patients with splenectomy received platelet transfusions for a mean of 10 (2–36) days as compared to 20 (3–82) days for patients without splenectomy (p < .001). Eighteen (90%) patients with splenectomy became platelet transfusion independent at a median of 16 (2–32) days after transplantation as compared to 40 (85%) patients without splenectomy who became transfusion independent at a median of 28 (15–86) days (p < .001). The proportion of patients achieving platelet levels of 50 and 100 × 103/mm3 did not differ between the two groups (p = .07), but patients in the splenectomy group achieved these levels more rapidly following transplant (p < .001). One of 17 evaluable patients in the splenectomy group and 31 of 46 in the no-splenectomy group became refractory to random platelets (p < .001) and required platelets from family members or unrelated completely or partially HLA matched donors. In the no-splenectomy group, splenic size did not affect the speed of granulocyte or platelet recovery or platelet transfusion requirements. There was no difference in the post-transplant survival of patients with or without splenectomy.

Bone marrow transplantation is associated with significant morbidity and mortality, some of which is due to high-dose chemoradiotherapy. In order to quantitate toxicity that was felt to be due to the preparative regimen (termed regimen-related toxicity [RRT]), a system was developed in which toxicities were graded from 0 (none) to 4 (fatal). One hundred ninety-five patients who underwent marrow transplantation for leukemia were studied retrospectively to determine whether toxicities that were clinically felt to be due to the preparative regimen were influenced by other factors such as disease status, graft-versus-host disease (GVHD) prophylaxis, and allogenicity. All patients developed grade I toxicity in at least one organ, and 30 developed grades III-IV (life-threatening or fatal) RRT. RRT was more common in relapsed patients v remission patients (P = .04), in those receiving 15.75 Gy total body irradiation (TBI) v 12.0 Gy TBI (P = .028), and in those receiving allogeneic marrow v autologous marrow (P = .0029). Autologous marrow recipients did not develop grades III-IV toxicity in this study. A multivariate analysis controlling for autologous marrow grafting showed that the dose of TBI was the only statistically significant predictor of grades III-IV RRT. Those patients who developed grade III RRT were unlikely to survive 100 days from transplant, though not all deaths could be attributed to RRT. Patients who developed grade II toxicity in three or more organs were more likely to die within 100 days than those developing grade II toxicity in two or less organs (P = .0027). This system was generally able to distinguish RRT from other toxicities observed in marrow recipients.

Bone marrow transplant recipients require central venous catheterization for a variety of fluids. They are also particularly susceptible to infection. Here we discuss the use of double lumen catheters to reduce the number of invasions necessary. We make particular reference to infection, neutropenia, prophylactic antibiotics, additional catheters, and presence of graft vs host disease.