John D. Shepherd

Admission of bone marrow transplant recipients to the intensive care unit: outcome, survival and prognostic factors.

The role of ICU support in BMT patients is controversial. In an era of constrained resources, the use of prognostic factors predicting outcome may be helpful in identifying patients who are most likely (or unlikely) to benefit from this intervention. We attempted to define the survival of patients admitted to ICU following autologous or allogeneic BMT and to identify those factors important in determining patient outcome. A retrospective study of all adult BMT recipients admitted to intensive care over a 6 year study period was performed to determine overall and prognostic indicators of poor outcome. Pre-treatment, pre-ICU admission and ICU admission data were analyzed to identify factors predicting long-term survival. 116 patients were admitted to ICU on 135 separate occasions with the primary reasons for admission being respiratory failure (66%), sepsis associated with hypotension (10%), and cardiorespiratory failure (8%). No pre-ICU characteristics were predictive of survival. Univariate analysis identified the number of support measures required, the need for ventilation or hemodynamic support, the APACHE II score, the year of ICU admission and the serum bilirubin as significant predictors of post-discharge survival. On multivariate analysis the year of ICU admission, the need for hemodynamic support and the serum bilirubin remained significant. The APACHE II score significantly underestimated survival in the 46% of patients with scores less than 35, and could only be used to predict 100% mortality when it exceeded 45. Twenty-three percent of all BMT patients admitted to the ICU and 17% of ventilated patients survived to hospital discharge. Of the 27 patients surviving to leave hospital, 16 remain alive with a median follow-up of 4.2 years and a mean Karnofsky performance status of 90. Although mortality in BMT recipients admitted to ICU is high our results indicate that intensive care support can be lifesaving and that the outcome in patients requiring ventilation and ICU support may not be as poor as has been previously reported. No single variable was identified which could be used to predict futility but patients requiring both hemodynamic support and mechanical ventilation, and those with an APACHE II score greater than 45 have a very poor prognosis and are unlikely to benefit from lengthy ICU support.

Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation.

Hemorrhagic cystitis is a major complication of high-dose cyclophosphamide therapy used in preparation for allogeneic or autologous bone marrow transplantation. Although previous reports had suggested that the sulfhydryl-containing compound mesna might be superior to forced diuresis in preventing hemorrhagic cystitis, there were concerns about the effect of mesna on engraftment in these studies. To address these concerns, 100 patients were randomized to receive mesna or forced saline diuresis while undergoing bone marrow transplant conditioning with regimens that included high-dose cyclophosphamide. To try to minimize the likelihood of graft rejection, patients who were being transplanted with cyclophosphamide as a sole agent were excluded from the study. After randomization and administration of therapy, patients were monitored by microscopic and dip-stick urinalyses; they were also followed for effects of therapy on engraftment. The incidence of consistent or severe hematuria was 33% in the mesna arm and 20% in the hyperhydration arm (P = .31). Severe bleeding occurred in 12.5% of mesna patients and 7.5% of hyperhydration patients (P = .71). No unexpected toxicities were encountered, and engraftment times did not differ. Based on this randomized trial of 100 patients, we conclude that mesna and hyperhydration are equally effective in preventing cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation patients.

Lymphoproliferative disorders following allogeneic bone marrow transplantation : the Vancouver experience

Between June 1988 and May 1996, 428 patients underwent allogeneic BMT (288 related donor (RD) and 140 unrelated donor (UD)) at the Vancouver General Hospital. Eight patients (UD six and RD two) developed a post-transplant lymphoproliferative disorder (PTLD). Median age at BMT was 38 years (range 22–51). Five of the six UD allografts were T cell depleted. Cyclosporine ± methotrexate was used for GVHD prophylaxis. All eight patients developed GVHD; in six this was refractory to treatment with corticosteroids. Rabbit antithymocyte globulin (ATG) or an anti-CD5-ricin A chain immunotoxin (Xomazyme) was used as second-line therapy for GVHD. Presentation with PTLD occurred at median day 90.5 (range 34–282) post BMT. Five of the eight patients had a rapidly progres- sive course characterized by fever, lymphadenopathy, lung and liver involvement and died within 3–8 days. PTLD was an incidental finding at post mortem examination in two patients. The remaining patient had localized disease and recovered. Pathological analysis revealed two morphological patterns; diffuse large B cell lymphoma (DLBC lymphoma, five patients) and polymorphous B cell hyperplasia (PBCH, three patients). EBV expression was positive in all eight cases and monoclonality was demonstrated in seven cases. In multivariate analysis, T cell depletion of the allograft (P = 0.0001, relative risk (RR) = 30.5), anti-T cell therapy for GVHD (P = 0.006, RR = 12.7) and acute GVHD grades 3–4 (P = 0.04, RR = 7.7) were the significant factors for development of PTLD. In conclusion, we have identified two forms of PTLD after BMT: one is characterized by disseminated disease with a rapidly progres- sive and often fulminant course and the other by localized, relatively indolent disease. Morphology, EBV positivity and clonality do not appear to correlate with the clinical course. The major risk factors for development of PTLD after BMT are ex vivo T cell depletion of the allograft and in vivo anti-T cell therapy for GVHD.

Allogeneic bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia

Twenty-six patients with low-grade lymphoma (LGL) (n = 18) or chronic lymphocytic leukemia (CLL) (n = 8) received allogeneic BMTs between 1985 and 1998. Median age was 42 years, median interval from diagnosis to transplant 22 months and median number of prior treatments three. Twenty (77%) had stage IV disease; 22 (85%) had never achieved CR. Donor source was HLA matched sibling (n = 19, 73%), matched unrelated (n = 6, 23%) or syngeneic (n = 1). Conditioning therapy included total body irradiation in 23 patients and busulphan in three. Twenty-five received GVHD prophylaxis with cyclosporine A; + methotrexate (n = 19), + methylprednisolone (n = 2) or + T cell depletion of allograft ± methotrexate (n = 4). Sixteen patients are alive, a median of 2.4 years post BMT. Death occurred due to transplant complications (n = 7) or underlying disease (n = 3). Eighteen (12 LGL, six CLL) of 22 evaluable patients (82%) achieved CR post BMT. Cumulative incidence of refractory/recurrent disease was 18% (95% confidence interval (CI) 7–42%). Overall and event-free survivals were 58% (95% CI 35–75%) and 54% (95% CI 32–72%), respectively. Allogeneic BMT for young patients with advanced LGL or CLL is feasible and can result in long-term disease-free survival. Bone Marrow Transplantation (2000) 25, 605–612.

Myeloablative allografting for chronic lymphocytic leukemia : evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease

Summary:In all, 30 patients with CLL proceeded to myeloablative allogeneic BMT using related (n=20, 67%) or unrelated (n=10) donors, at the Princess Margaret Hospital (Toronto) (n=20) or the Leukemia/BMT Program of BC (Vancouver) (n=10), from 1989 to 2001. Median (range) interval from diagnosis to BMT was 4.8 (0.3–13) years, median number of prior therapies was three and median age 48 years. The preparative regimen included total body irradiation in 15 (50%). In all, 14 of 30 patients (47%) are alive, with median (range) follow up of 4.3 (2.4–10.5) years. All are in complete remission, two following therapy for post-BMT progression. Actuarial overall (OS) and event-free survival (EFS) at 5 years is 39% (OS 48% for related donor and 20% for unrelated donor BMT); cumulative incidence of nonrelapse mortality (NRM) and relapse is 47 and 19%, respectively. Both acute (RR=0.008, P=0.01) and chronic (RR=0.006, P=0.02) Graft-versus-host disease (GVHD) were associated with markedly decreased risk of relapse. Patients receiving grafts from unrelated donors had increased NRM (RR=3.6, P=0.02) and decreased OS (RR of death=3.4, P=0.002). Allogeneic BMT has resulted in long-term EFS in approximately 40% of patients with CLL. There is evidence for a strong graft-versus-leukemia effect associated with acute and chronic GVHD, resulting in near complete protection from relapse.

Stem cell transplantation for myelofibrosis: a report from two Canadian centers.

Summary:We describe the course of 25 patients with myelofibrosis (MF) due to agnogenic myeloid metaplasia (n=19) or essential thrombocytosis (n=6) who underwent allogeneic stem cell transplantation (SCT) at one of two Canadian centers. The median age at transplantation was 48.7 (IQR 45.9–50.4) years and transplantation was carried out at a median of 10.7 (IQR 5.67–26.5) months after diagnosis. Granulocyte engraftment (absolute neutrophil count >0.5 × 109/l) occurred at a median of 20 days after transplantation for splenectomized patients, compared with 27.5 days for nonsplenectomized individuals (P=0.03). Increased risk of grade II–IV acute graft-versus-host disease (P=0.04) was noted in patients transplanted after splenectomy. Patients with MF received 0.264±0.189 U of packed red blood cells per day over the first 180 days after transplantation, and remained dependent on red blood cell transfusions for a median of 123 (IQR 48–205) days. Complete remission of MF was documented in 33% of evaluable patients. The 1 year cumulative nonrelapse mortality was 48.3%. Median survival for this group of patients was 393 (IQR 109–1014+) days, with a projected 2-year overall survival of 41%. We conclude that allogeneic SCT offers a reasonable chance for prolonged survival in patients with advanced MF, but this occurs at the cost of considerable toxicity and nonrelapse mortality.

Allogeneic haematopoietic stem-cell transplantation for relapsed and refractory aggressive histology non-Hodgkin lymphoma*

Forty‐four patients with relapsed or refractory aggressive histology non‐Hodgkin lymphoma (NHL) (diffuse large B cell, n = 23; peripheral T cell, n = 5; transformed B cell, n = 16) proceeded to allogeneic stem cell transplant (allo‐SCT) between 1987 and 2003. Median age at transplant was 40 years (range 19–56 years). At the time of transplant, 35 were chemosensitive and nine were chemorefractory. Thirty‐three patients had matched sibling donors and 11 had unrelated donors. Forty‐two patients (95%) received radiation‐based conditioning regimens. Event‐free survival (EFS) and overall survival (OS) at 5 years was 43% [95% confidence interval (CI): 27–58%] and 48% (95% CI: 32–63%) respectively. Treatment‐related mortality was 25% at 1 year. Grade III–IV acute graft‐versus‐host disease (GVHD) was the only significant variable affecting OS and EFS, and had a negative impact. Chronic GVHD did not influence survival. Lymphoma relapse <12 months after initial therapy predicted for increased risk of relapse post‐transplant (P = 0·02). Patients with chemorefractory lymphoma were not at increased risk of relapse (P = 0·20) with four of nine patients remaining alive without disease 12–103 months post‐transplant. In conclusion, allo‐SCT for relapsed or refractory aggressive histology NHL results in long‐term EFS and OS of 40–50%. Patients with chemorefractory disease can have a durable remission post‐transplant.

Regimen-related toxicity of a busulfan-cyclophosphamide conditioning regimen in 70 patients undergoing allogeneic bone marrow transplantation.

The regimen-related toxicity (RRT) of a busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) conditioning regimen (BuCy) was evaluated in 70 consecutive patients undergoing allogeneic bone marrow transplantation for hematologic malignancies. Patients were given toxicity gradings retrospectively in each of eight organ systems (cardiac, bladder, renal, pulmonary, hepatic, CNS, stomatic, and gastrointestinal) according to a recently developed RRT scale. A set of patient, disease, and treatment parameters (age, sex, diagnosis, Eastern Cooperative Oncology Group [ECOG] score, preconditioning liver function tests [LFT], prior chemotherapy exposure, disease status, graft-versus-host disease [GVHD] prophylaxis, antimicrobial agent use, hematologic recovery, and severity of acute GVHD) was statistically analyzed to determine significant predictors of RRT. The most common significant organ toxicities were stomatic (87% of patients; 63% grades II to IV) and hepatic (83% of patients; 44% grades II to IV). Renal and gastrointestinal toxicities were not uncommon (35% and 27%, respectively) but were rarely serious (9% and 1% grades II to IV, respectively). Twelve patients developed grade III toxicities of the following systems: hepatic (seven), pulmonary (two), bladder (two), and CNS (one). Females had more frequent stomatitis (P = .04) and hepatic RRT (P = .004). Patients receiving methotrexate in their GVHD prophylactic regimen experienced more grade II to IV stomatitis (P = .04) and hepatic RRT (P = .04). The use of amphotericin B (P = .01) or prolonged antibiotic courses (P = .04) was associated with more grades II to IV hepatic RRT. In a multivariate analysis, only amphotericin B administration predicted grades II to IV hepatic RRT (P = .01). The incidence of acute GVHD was 49%, with 31% having grades II to IV GVHD. The estimated 2-year event-free survival (EFS) for the entire study group was 44%. The estimated 2-year EFS was 63% for standard-risk patients (acute leukemia in first remission and chronic myelogenous leukemia [CML] in first stable phase) and 24% for all others (high-risk patients). High-risk patients were at increased risk of disease recurrence and RRT. BuCy is an efficacious bone marrow transplant conditioning regimen for standard-risk patients with leukemia but has significant associated hepatic RRT.

Allogeneic marrow transplantation for refractory Hodgkin's disease.

Eight patients with refractory Hodgkins disease received intensive combination chemotherapy conditioning with cyclophosphamide, carmustine (BCNU), and etoposide (VP 16-213), and allogeneic marrow transplants. All patients achieved complete responses. Three patients relapsed; two died of Hodgkins disease and one of chronic graft-v-host disease (GVHD) and infection. In all, four patients died due to transplant-related toxicity. One patient developed a fatal B-cell lymphoproliferative disorder soon after transplantation, and died without evidence of Hodgkins disease. One patient is alive and free of progression 29 months after transplantation. These data indicate that allogeneic marrow transplantation may be considered as therapy for selected patients with advanced Hodgkins disease and, despite substantial toxicity, will occasionally result in long-term responses. Better patient selection would likely improve results.

Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease with Rabbit Antithymocyte Globulin

Acute graft-versus-host disease (A-GVHD) is a life-threatening complication of allogeneic stem cell transplantation (SCT), and primary therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institutions experience treating steroid-resistant GVHD in 36 adult patients (median age 39 years, range 24-55) with a rabbit antithymocyte globulin product (thymoglobulin). Eleven patients had undergone sibling SCT (10 histocompatible, 1 one-antigen mismatched) and 25 patients had received unrelated donor bone marrow (17 matched, 8 one-antigen mismatched); 32 patients (89%) had grade III or IV A-GVHD. Thymoglobulin was administered in two different regimens; group 1 patients (n = 13) received 2.5 mg/kg/day x 4-6 consecutive days with maintenance of all other immunosuppressives. Group 2 patients (n = 21) were given the same dose of thymoglobulin on days 1, 3, 5, and 7 with discontinuation of cyclosporine for 14 days, during which the corticosteroid dose was held at 2-3 mg/kg/day. Two patients had severe adverse reactions to thymoglobulin (hypoxemia and hypotension) and could not complete treatment, however, in the other patients, aside from transient leukopenia (25%) and and hepatic dysfunction (25%), the antibody preparation was well tolerated. Of the 34 evaluable patients, 13 patients had a complete response (38%) and 7 patients (21%) had a partial response, for an overall response rate of 59%. Response rate was higher in group 1 patients (77%) compared to group 2 patients (48%), (p = 0.15); skin GVHD was more responsive (96% of patients) than gut GVHD (46% of patients) or hepatic GHVD (36% of patients). Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. There were 9 patients (25%) who developed post-SCT lymphoproliferative disorder (PTLD) and 4 patients who had a relapse of underlying primary malignancy; none of these patients survived. Of the 36 patients entered on the study, only 2 patients (6%) survive, at 15+ and 34+ months post-unrelated donor SCT. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily due to the high risk of developing either an opportunistic infection or a PTLD.