Robert Haake

Positive effect of prophylactic total parenteral nutrition on long-term outcome of bone marrow transplantation.

In a randomized trial we studied the impact of providing total parenteral nutrition (TPN) to bone marrow transplant (BMT) patients during their cytoreductive therapy, and for 4 weeks following BMT, on 8 parameters of outcome. A total of 137 patients over 1 year of age and with normal nutritional status were randomized either to receive TPN starting one week prior to transplant or to receive hydration with a 5% dextrose solution containing electrolytes, minerals, trace elements, and vitamins. TPN was ultimately required by 40 of the 66 control patients when nutritional depletion was documented. Average total calorie and protein intake was significantly higher for the TPN group than for the control group. Minimum follow-up was 1 year and median was 2 years. Overall survival, time to relapse, and disease-free survival were significantly improved in the TPN group. Engraftment, duration of hospitalization, and incidences of acute and chronic graft-vs.-host disease and bacteremia were not different. Thus TPN during BMT had a positive effect on long-term outcome. Prophylactic nutritional therapy appears to be indicated even for well-nourished individuals during cytoreduction and BMT.

Non-Candida fungal infections after bone marrow transplantation: Risk factors and outcome

PURPOSE To determine the incidence, risk factors, and outcome of non-Candida fungal infections in a bone marrow transplant population. PATIENTS AND METHODS A consecutive series of 1,186 patients who underwent bone marrow transplant at the University of Minnesota Hospital between 1974 and 1989 were analyzed for the occurrence of a post-transplant non-Candida fungal infection. The risk factors were analyzed with regard to clinical characteristics such as age, sex, primary disease process, type of transplant, recipient cytomegalovirus serostatus, time to engraftment, and the presence of graft-versus-host disease. RESULTS In this population, 123 of 1,186 patients (10%) developed a non-Candida fungal infection within 180 days of transplant. The majority of infections (85%) occurred in allogeneic recipients, and 58% of infections were prior to white blood cell engraftment. The most common isolates were Aspergillus species (70%), Fusarium species (8%), and Alternaria species (5%). Although 47% of infections involved a single organ or site, 44% were disseminated and 9% were isolated fungemias. Only 17% of patients survived. Sixty-eight percent of deaths were related to the fungal infection. In univariate analysis, allogeneic transplant, positive recipient cytomegalovirus serostatus, delayed engraftment, and recipient age of greater than or equal to 18 years were identified as risk factors for non-Candida fungal infection. All of these factors except for recipient age were independently significant in multivariate analysis. In allogeneic recipients, positive cytomegalovirus serostatus, delayed engraftment, and age of greater than or equal to 18 years were each significantly associated with a greater risk of fungal infection; none of these factors were independently significant in the autologous recipients. CONCLUSION Fungal infections remain a major cause of morbidity and mortality in patients undergoing bone marrow transplant. More effective antifungal prophylaxis and therapy, earlier diagnosis, and transplant regimens incurring a brief period of neutropenia may substantially reduce the incidence and clinical impact of these infections.

Cytomegalovirus pneumonia after bone marrow transplantation. Risk factors and response to therapy.

Cytomegalovirus pneumonia complicated bone marrow transplantation in 75 (63 allogeneic and 12 autologous) of 1136 recipients (Kaplan-Meier incidence 8.8%). CMV pneumonia occurred more frequently in allogeneic (12.4%) than autologous recipients (3.3%). Increased risk for CMV pneumonia was observed in allogeneic recipients who were seropositive (relative risk = 2.9), older age (RR = 1.4 per decade), those conditioned with total-body irradiation (RR = 2.7), who received antithymocyte globulin (RR = 2.9) or T cell-depleted marrow (RR = 2.7) or who had CMV viruria (RR = 4.0) or viremia (RR = 5.9). Autologous recipients were also at increased risk if they were seropositive (RR = 6.1), or developed viruria (RR = 7.0) or viremia (RR = 15.4). Thirteen of 14 untreated patients died without improvement. Prognosis was poor in patients who were ventilator-dependent at initiation of therapy (median survival 17 days), with only 1 long-term survivor. In contrast, patients ventilator-independent at initiation of therapy with ganciclovir and immunoglobulin (n = 22) had a median survival of > 274 days, with 9 long-term survivors. Ganciclovir alone or acyclovir with immunoglobulin in ventilator-independent patients was less effective (median survivals 80 and 10 days, respectively). Overall, 10 of 75 patients were surviving 10-73 months (median 47) from diagnosis; 9 of these were ventilator-independent at initiation of therapy and received ganciclovir with immunoglobulin. CMV pneumonia was less common, but was severe in autologous recipients, with only 2 of 12 surviving. CMV pneumonia remains a prominent cause of death following BMT. Early therapy with ganciclovir and immunoglobulin before respiratory failure supervenes may improve survival.

The spectrum of Non-Candida fungal infections following bone marrow transplantation

We evaluated a consecutive series of patients who underwent bone marrow transplantation (BMT) at a single institution between 1974 and 1989 for the occurrence of a non-Candida fungal infection in the first 180 days after BMT. Of the 1186 patients, 129 (11%) patients developed a total of 138 significant non-Candida fungal infections in this period. Eight patients had multiple distinct infections. The most common isolate was Aspergillus spp. (n = 97), followed by Fusarium (n = 10), and Alternaria (n = 6). The 4 clinical subtypes of infections were minor skin or soft-tissue infections (n = 7), infections of a single organ or site (n = 61), disseminated fungal infection (n = 58), and isolated fungemia (n = 12). The respiratory tract was involved in 95% of single organ or site infections, and 84% of disseminated infections. Outcome was poor, with only 18% of patients surviving. The cause of death was directly related to the non-Candida fungal infection in 66% of patients who died. Mortality rates were significantly higher in patients with either single-organ or site infections (41%) or disseminated infections (83%). The cause-specific mortality rate was greatest following infections with Aspergillus, Chrysosporium, Fusarium, Mucor, or Scopulariopsis, in which there was a high potential for invasive disease and disseminated infection. In contrast, the cause-specific mortality rate was lowest in infections which were either isolated fungemia or were localized and amenable to surgical debridement, most often seen with those infections caused by Acremonium, Alternaria, Penicillium, and Saccharomyces. The spectrum of clinical infections caused by these uncommon non-Candida fungal isolates both in our series and in the literature is reviewed. These unusual opportunistic fungal isolates are now gaining recognition in immunosuppressed patients such as the BMT population, and have a significant impact on patient outcome. Effective therapy of non-Candida fungal infections remains difficult. Early aggressive surgical debridement appears to be important in control of localized invasive infections. Prolonged therapy with amphotericin B is the standard of care, although the role of the newer antifungal agents is not yet well-defined. Ancillary roles may also be provided by granulocyte transfusions and the colony-stimulating factors.

Avascular necrosis of bone: A common serious complication of allogeneic bone marrow transplantation

PURPOSE To describe the incidence, presentation, clinical course, and management of avascular necrosis of bone following bone marrow transplantation, and to identify risk factors related to its development and outcome. PATIENTS AND METHODS All patients developing avascular necrosis after transplantation between March 1974 and May 1988 were identified by means of the Minnesota Bone Marrow Transplant Database and hospital records and included in analysis. Of 902 consecutive patients undergoing bone marrow transplantation, 28 developed avascular necrosis of bone. RESULTS Twenty-eight of 642 allogeneic transplant recipients (10.4% by product limit estimate) developed avascular necrosis compared to zero of 260 autologous transplant recipients. Symptoms developed 1 to 62 months (median 12 months) after transplantation. In the 28 patients a total of 91 joints were affected (mean 3.3 per patient, range one to eight joints). The hip joint was most often involved (64% of patients), followed by knee (61%), ankle (29%), shoulder (21%), and elbow (7%). Initial standard radiographs were negative in 13 patients, while in nine patients, technetium-99 scans and/or magnetic resonance imaging demonstrated changes of osteonecrosis before changes on routine radiographs. Almost all patients had received steroid prophylaxis and therapy for graft-versus-host disease (GVHD). We observed a significant correlation between the total cumulative dose of steroids and number of joints involved (p less than 0.01). A multivariate analysis (allogeneic transplant patients only) identified acute or chronic GVHD requiring steroid therapy (p = 0.003), and increasing age (p = 0.002) as significant and independent risk factors. Fourteen patients required surgery, including joint replacement in 11 patients. In six of six patients, hip core decompression failed to halt disease progression, and total hip arthroplasty was subsequently required. CONCLUSION Avascular necrosis of bone is a frequent late complication of bone marrow transplantation, causing significant morbidity and often requiring surgery; diagnosis using conventional imaging techniques may be difficult and treatment remains inadequate.

Hemorrhagic cystitis after bone marrow transplantation. Risk factors and complications.

Hemorrhagic cystitis (HC) is a major cause of morbidity after BMT; we have analyzed its incidence, risk factors, and complications in 977 patients undergoing BMT between 1974 and 1988. Despite vigorous hydration and frequent voiding in all patients receiving cyclophosphamide, 135/977 (15% by Kaplan-Meier projection) developed HC (micro- or gross hematuria, dysuria, bladder pain) between −11 and +100 days (median +22) after BMT. Of these, 60 had severe HC, including major urinary obstruction (4/60), renal failure (13/60), or need for surgical or chemical bladder cauterization (16/60). By univariate analysis, allogeneic BMT recipients had more frequent HC than autologous patients (17% vs. 9%, P = 0.002). In addition, allogeneic patients with adenoviruria were at increased risk for the development of HC. Patients with aplastic anemia conditioned with high dose cyclophosphamide and total lymphoid irradiation had the highest rate of HC (22%) versus those with hematologic malignancies (15%, P = 0.03). A Cox proportional hazards regression model was used to further identify those factors independently associated with HC. In all regression models, the factor most highly associated with the development of HC was the finding of adenovirus in the urine preceding the onset of hematuria. HC-related morbidity, and its associated increased hospitalization costs, frequently complicates BMT. Improved prophylactic measures, perhaps including the use of 2-mercaptoethane sulfonate, are needed, at least for allogeneic BMT patients with their attendant risk of adenovirus infection.

Pretransplantation Burden of Leukemic Progenitor Cells as a Predictor of Relapse after Bone Marrow Transplantation for Acute Lymphoblastic Leukemia

BACKGROUND We developed a test to discern small numbers of residual leukemic progenitor cells in the bone marrow of patients with acute lymphoblastic leukemia (ALL) in remission. Preliminary studies revealed that before undergoing bone marrow transplantation such patients differed in their burden of leukemic progenitor cells. These observations suggested that the burden of these cells might influence the risk of relapse after transplantation. METHODS The number of residual leukemic progenitor cells before bone marrow transplantation was determined for 83 patients with high-risk ALL. We combined multiparameter flow cytometry and cell sorting with assays for leukemic progenitor cells in a quantitative method for the detection of minimal residual disease. RESULTS The count of leukemic progenitor cells in bone marrow specimens from patients in remission varied markedly between patients, ranging from 0 to 12,546 cells per million mononuclear cells, or from 0 to 1.255 percent (median, 51 leukemic progenitor cells per million mononuclear cells, or 0.005 percent). Patients whose count of leukemic progenitor cells exceeded the median value had a higher likelihood of relapse than did patients with values below the median (relapse rate at one year, 100 percent vs. 41 percent; P < 0.001). There was a statistically significant inverse relation between the leukemic progenitor-cell content of bone marrow before transplantation and the duration of remission after transplantation (P < 0.001). The estimated risk of relapse for patients with > or = 51 leukemic progenitor cells per million mononuclear cells was more than 3.5 times the risk for patients with lower counts, after adjustment for the effects of other covariates (P = 0.005). CONCLUSIONS The count of residual leukemic progenitor cells is a powerful predictor of relapse after autologous bone marrow transplantation, particularly among male patients. Its measurement may be useful for analyzing and improving the treatment of patients with high-risk ALL in remission.

Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission.

Between November 1976 and December 1987, 84 patients with newly diagnosed acute non-lymphoblastic leukemia who had achieved complete remission underwent non T-cell depleted allogeneic bone marrow transplantation from Human Leukocyte Antigen-Mixed Lymphocyte Culture (HLA-MLC) matched sibling donors. The first 36 patients (November 1976-June 1983) were prepared with cyclophosphamide, 60 mg/kg/day, IV for 2 days and single fraction total body irradiation with 750 cGy at a dose rate of 26 cGy/minute (Group I). The next 48 patients (July 1983-December 1987) were prepared with similar chemotherapy, but received hyperfractionated total body irradiation with total 1320 cGy, 165 cGy twice a day at a dose rate of 10 cGy/minute (Group II). Patient characteristics between these two groups are similar except for the significantly older age distribution in Group II. Median follow-up of Groups I and II are 8 years and 11 months and 2 years and 3 months, respectively. The Kaplan-Meier relapse-free survival, survival, and relapse rates at 3 years are 56, 58, and 19% in Group I and 69 (p = 0.22), 77 (p = 0.07), and 10% (p = 0.37) in Group II. There is no difference in the incidence of interstitial pneumonitis, viral or idiopathic, engraftment rate, or incidence of graft versus host disease (GVHD) between these two groups. The fractionated total body irradiation treated group had significantly less nausea and vomiting. Multivariate analysis shows that total body irradiation regimen is not a significant factor in regard to relapse rate, relapse-free survival, and survival.

Allogeneic bone marrow transplantation for acute lymphoblastic leukaemia : risk factors and clinical outcome

We report 12 years’experience with histocompatible, related donor marrow transplantation for 123 patients with acute lymphoblastic leukaemia; 104 second remission. Four regimens were studied: cyclophosphamide (Cy)+total body irradiation (TBI) (n= 35); Cy + fractionated TBI (n= 45); TBI + high‐dose cytarabine (n= 15); and hyperfractionated TBI + Cy (n= 28). 45 patients survive (34 ± 9%: 95% confidence interval) between 1 and 12·7 years (median 7·8 years) following BMT and 29 ± 8% survive leukaemia‐free. Significantly improved disease‐free survival was observed in patients with an initial WBC < 50 x 109/l (P= 0·02). Conditioning regimens tested yielded similar outcomes, though TBI/cytarabine led to greater treatment associated mortality. Leukaemia relapse was the most frequent cause of failure in 56 ± 11%; median time of relapse 8 months following BMT, none beyond 2·2 years. Relapse was more frequent with higher WBC, shorter initial remission and previous CNS leukaemia. Acute and/or chronic GVHD was associated with a strong trend (P= 0·06) towards less relapse. Allogeneic BMT may be curative for a substantial fraction of patients with ALL, but additional anti‐leukaemic measures beyond these conditioning modifications tested will be required to prevent post‐transplant leukaemia recurrence.

T cell depletion with anti-cd5 immunotoxin in histocompatible bone marrow transplantation: The correlation between residual CD5 negative T cells and subsequent graft-versus-host disease

Twenty-nine patients with advanced leukemias (median age 34 years) received histocompatible sibling marrow that had been depleted of T cells by ex vivo incubation with anti-CD5 monoclonal antibody-ricin immunotoxin (T101-R) for the purpose of graft-versus-host disease prophylaxis. Donor cell engraftment was documented in 28/29 patients by DNA restriction fragment length polymorphisms. In this pilot study the dose of T101-R incubated with donor marrow was increased in a stepwise manner from 300 ng (10 patients) to 600 ng (5 patients) to 1000 ng immunotoxin (IT)/10(7) bone marrow mononuclear cells (14 patients) in an attempt to achieve more effective GvHD prophylaxis. A statistically significant reduction in acute GvHD was achieved for patients receiving marrow pretreated with 1000 ng of immunotoxin (34%) compared to recipients of BM treated with 300 ng immunotoxin (100%, P = 0.0004). T-depleted marrow samples were evaluated for residual T cell activity using several in vitro assays including proliferation to the purified mitogen PHA (HA-17) and in mixed lymphocyte culture (MLC), T cell cytotoxicity, a limiting dilution assay for detecting precursors of proliferating T cells (LDApPTL), and phenotypic analysis of viable T cells expanded in 16-day culture with interleukin 2. The extent of T cell depletion determined by LDA assay varied widely at each immunotoxin concentration used. Thus, there was no correlation between the dose of T cells infused and subsequent GvHD. Phenotyping of lymphocytes recovered from immunotoxin-treated marrow demonstrated that residual T cells were CD5 negative in all cases tested. The only in vitro parameter that predicted subsequent acute or chronic GvHD was the demonstration of viable CD5 negative lymphocytes with T cell phenotype (CD2, CD3, and/or CD7 positive) after 16-day culture with IL-2 of the T-depleted bone marrow. We observed that such CD5 negative cells expressing other T cell markers have cytotoxic function and speculate that these cells may be capable of mediating GvHD in allogeneic transplantation.