The relationship of TP53 R72P polymorphism to disease outcome and TP53 mutation in myelodysplastic syndromes.

Nonsynonymous TP53 exon 4 single-nucleotide polymorphism (SNP), R72P, is linked to cancer and mutagen susceptibility. R72P associations with specific cancer risk, particularly hematological malignancies, have been conflicting. Myelodysplastic syndrome (MDS) with chromosome 5q deletion is characterized by erythroid hypoplasia arising from lineage-specific p53 accumulation resulting from ribosomal insufficiency. We hypothesized that apoptotically diminished R72P C-allele may influence predisposition to del(5q) MDS. Bone marrow and blood DNA was sequenced from 705 MDS cases (333 del(5q), 372 non-del(5q)) and 157 controls. Genotype distribution did not significantly differ between del(5q) cases (12.6% CC, 38.1% CG, 49.2% GG), non-del(5q) cases (9.7% CC, 44.6% CG, 45.7% GG) and controls (7.6% CC, 37.6% CG, 54.8% GG) (P=0.13). Allele frequency did not differ between non-del(5q) and del(5q) cases (P=0.91) but trended towards increased C-allele frequency comparing non-del(5q) (P=0.08) and del(5q) (P=0.10) cases with controls. Median lenalidomide response duration increased proportionate to C-allele dosage in del(5q) patients (2.2 (CC), 1.3 (CG) and 0.89 years (GG)). Furthermore, C-allele homozygosity in del(5q) was associated with prolonged overall and progression-free survival and non-terminal interstitial deletions that excluded 5q34, whereas G-allele homozygozity was associated with inferior outcome and terminal deletions involving 5q34 (P=0.05). These findings comprise the largest MDS R72P SNP analysis.

Long-term follow-up of patients undergoing auto-SCT for advanced germ cell tumour: a multicentre cohort study.

Failure of cisplatin-based chemotherapy in advanced germ cell tumour (GCT) is associated with a poor outcome. High-dose chemotherapy and auto-SCT is one therapeutic option, although the long-term outcome after this procedure is unclear. We conducted a multicentre cohort study of consecutive patients undergoing a single auto-SCT for GCT between January 1986 and December 2004. Of 71 subjects, median follow-up is 10.1 years. OS at 5 years is 44.7% (95% confidence interval (CI) 32.9-56.5%) and EFS is 43.5% (95% CI 31.4-55.1%). There were seven (10%) treatment-related deaths within 100 days of auto-SCT. Three (4.2%) patients developed secondary malignancies. Of 33 relapses, 31 occurred within 2 years of auto-SCT. Two very late relapses were noted 13 and 11 years after auto-SCT. In multivariate analysis, favourable outcome was associated with IGCCC (International Germ Cell Consensus Classification) good prognosis disease at diagnosis, primary gonadal disease and response to salvage chemotherapy. We conclude that auto-SCT results in successful outcome for a relatively large subgroup of patients with high-risk GCT. Late relapses may occur, a finding not previously reported.

Long-term outcome after allo-SCT: close follow-up on a large cohort treated with myeloablative regimens.

We analyzed the late outcomes of 429 long-term survivors post allogeneic hematopoietic SCT (allo-HSCT) who received transplant in our center between 1981 and 2002, and were free of their primary disease for > or =2 years after allo-HSCT. Late recurrent primary malignancy was found in 58 (13.5%) patients and was the primary cause of late death. A total of 37 (8.6%) patients died of non-relapse causes at a median of 5.5 years (range, 2-15.6 years) post allo-HSCT. The major non-relapse causes of death were chronic GVHD (cGVHD), secondary malignancy and infection. The probabilities of OS and EFS were 85% (95% cumulative incidence (CI) (81-89%)) and 79% (95% CI (74-83%)) at 10 years, respectively. Long-term allo-HSCT survivors were evaluated for late complications (median follow-up, 8.6 years (range, 2.3-22.8 years)). cGVHD was diagnosed in 196 (53.1%) survivors. The endocrine and metabolic complications were hypogonadism in 134 (36.3%) patients, osteopenia/osteoporosis in 90 (24.4%), dyslipidemia in 33 (8.9%), hypothyroidism in 28 (7.6%) and diabetes in 28 (7.6%). Hypertension was diagnosed in 79 (21.4%), renal impairment in 70 (19.0%), depression in 40 (10.8%) and sexual dysfunction in 33 (8.9%) survivors. We conclude that in patients who receive allo-HSCT as treatment for hematological malignancy and who are free of their original disease 2 years post transplant, mortality is low and the probability of durable remission is high. Lifelong surveillance is recommended.

Predictors of outcome following myeloablative allo-SCT for therapy-related myelodysplastic syndrome and AML.

Administration of alkylating agents (Alk), topoisomerase II inhibitors (Topo II) and radiotherapy (RT) can result in therapy-related myelodysplastic syndrome or acute myelogenous leukaemia (t-MDS/t-AML), the optimal treatment for which is allo-SCT. A retrospective review was performed of 24 patients who underwent related- or unrelated-donor SCT for t-MDS/t-AML at our institution. Eight patients remain alive and in continuous remission (median follow-up 54 months (range, 12-161)) with estimated 5-year EFS being 30% (95% confidence intervals 16-58%). Corresponding actuarial risks of relapse and non-relapse mortality (NRM) are 39% (19-60%) and 30% (13-50%), respectively. EFS was 40% in Alk/RT-related t-MDS/t-AML and 11% in Topo II-related t-MDS/t-AML (P=0.05), with an increased risk of relapse in the latter (56 vs 29%, respectively (P=0.05)). In multivariate analysis, development of acute GVHD (P=0.009) and Topo II-related t-MDS/t-AML (P=0.018) were associated with inferior EFS. Patients with acute GVHD had an increased risk of NRM (P=0.03) whereas risk of relapse was higher for patients of advanced age (P=0.046) and for patients who underwent bone marrow (vs blood) SCT (P=0.032). Allo-SCT can result in long-term survival for individuals with t-MDS/t-AML although outcome in Topo II-related t-MDS/t-AML patients remains suboptimal.

Allogeneic SCT for relapsed composite and transformed lymphoma using related and unrelated donors: long-term results.

Outcome is poor with conventional therapy for relapsed transformed non-Hodgkin's lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n=25) and unrelated donors (n=15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n=14) or treatment-related complications (transplant-related mortality, TRM; n=15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2- and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.

Positive impact of selective outpatient management of high-risk acute myelogenous leukemia on the incidence of septicemia.

BACKGROUND: Curative intent chemotherapy for acute myelogenous leukemia (AML) leads to prolonged severe neutropenia, during which patients are highly susceptible to infection. Traditionally these high-risk patients were treated as inpatients. Our center recently implemented a selective ambulatory management policy for AML patients undergoing chemotherapy. MATERIALS AND METHODS: A retrospective analysis was conducted to assess the occurrence of septicemia in AML patients treated over a 5 years period with curative intent chemotherapy. This review encompasses a change in policy from primarily inpatient care to selective outpatient management coupled with prophylactic antibiotic therapy. RESULTS: A total of 294 patients, receiving 623 cycles of chemotherapy were identified. A significant decrease in septicemia was observed from the inpatient to outpatient cohort (22% to 13% P < 0.05), which correlated with the shift towards outpatient treatment of consolidation cycles. A shift from Gram-negative to Gram-positive organisms as the cause of septicemia was also detected in the outpatient cohort, likely due to the introduction of ciprofloxacin prophylaxis. No significant emerging resistance and no septicemia-related mortality were noted in the outpatient cohort. CONCLUSION: The observed decrease in the incidence of septicemia in the ambulatory cohort adds supportive evidence to the feasibility of selective outpatient management of AML patients with respect to infectious complications.

Primary therapy for adults with T-cell lymphoblastic lymphoma with hematopoietic stem-cell transplantation results in favorable outcomes.

BACKGROUND: Controversy exists regarding the role of high-dose therapy followed by stem-cell transplant (SCT) in the treatment of T-cell lymphoblastic lymphoma (T-LBL). We conducted an intention-to-treat analysis of the strategy of SCT as definitive treatment of T-LBL. PATIENTS AND METHODS: From July 1987 to March 2005, 34 adults with T-LBL were diagnosed and treated in British Columbia. Treatment, before planned SCT, consisted of a non-Hodgkin's lymphoma (NHL)/acute lymphoblastic leukemia hybrid chemotherapy protocol (28 patients) or a standard NHL chemotherapy regimen (six patients). RESULTS: Median follow-up of the 23 surviving patients is 51 months (range 13-142 months). Twenty-nine proceeded to SCT (four allogeneic, 25 autologous). For all 34 patients, 4-year overall survival (OS) and event-free survival (EFS) are 72% and 68%, respectively. For patients proceeding to SCT, the 4-year OS and EFS are 79% and 73%, respectively. All patients who received allografts are alive without disease at 38-141 months since diagnosis. For patients who received autografts, the 4-year EFS is 69%. Bone marrow involvement was a significant prognostic factor predicting for a worse survival (P = 0.02). CONCLUSION: A treatment strategy for adults with chemosensitive T-LBL that includes planned consolidation with SCT in first response produces favorable long-term outcome.

Leukocyte count as a predictor of death during remission induction in acute myeloid leukemia.

Acute myeloid leukemia (AML) presenting with a high leukocyte count has been associated with an increase in induction mortality and poor results in a number of other survival measures. However, the level at which an elevated leukocyte count has prognostic significance in AML remains unclear. In this report on a series of 375 adult (non-M3) AML patients undergoing induction chemotherapy at a single institution, leukocyte count analyzed as a continuous variable is shown to be a better predictor of induction death (ID) and overall survival (OS) than a leukocyte count of > or = 100 x 10(9)/L, a value characteristically associated with "hyperleukocytosis" (HL). In this patient cohort, a presenting leukocyte count of > or = 30 x 10(9)/L had high sensitivity and specificity for predicting ID, and both performance status (PS) and leukocyte count more accurately predicted for ID than age. Considering these parameters in newly-diagnosed AML patients may facilitate the development of strategies for reducing induction mortality.

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

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.

Characteristics and outcome of patients developing endocarditis following hematopoietic stem cell transplantation.

Endocarditis is an uncommon complication of hematopoietic stem cell transplantation (HSCT). A retrospective review of 1547 patients who underwent HSCT in Vancouver between January 1986 and December 2001 was performed. In all, 20 cases of endocarditis were identified (1.3% of all patients) with nine patients having received cryopreserved autologous stem cells, six stem cells from a histocompatible sibling and five patients stem cells from an unrelated donor. Five patients had endocarditis diagnosed while alive, a median of 6 months post-HSCT, by transthoracic (four patients) or transesophageal (one patient) echocardiography. The remaining 15 cases of endocarditis were only identified post mortem. The mitral valve was the most frequently involved (10 patients) followed by the aortic valve (six patients); multivalvular disease was noted in five patients. Of the 11 affected allogeneic HSCT patients, 10 had previously developed acute graft-versus-host disease (GVHD). Causative organisms were identified in 11 patients, while nine additional cases were felt to be thrombotic in origin. Of the 20 patients, 19 died with the sole survivor alive 10 years following an aortic valve replacement. Endocarditis is an uncommon complication of HSCT usually involving the cardiac valves on the left side of the heart and is associated with a high mortality rate.

Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis.

To establish incidence and risk factors for development of second malignant neoplasms after high-dose chemo/radiotherapy (HDT) and autologous hematopoietic stem cell transplantation (AHSCT), the case files of 800 consecutive patients who underwent AHSCT at our institution between June 1982 and December 2000 were reviewed. In all, 26 patients developed 29 second malignancies (nine myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML), 16 solid tumors and four lymphoproliferative disorders (LPDs)) for a 15-year cumulative incidence of 11% (95% confidence interval (CI), 5-18%). These second tumors occurred at a median of 68 (range 1.5-177) months following AHSCT. The relative risk (RR) compared to the general population of developing a second malignancy following AHSCT was 3.3 (CI 2.2-4.7) P<0.001. The RR of developing MDS/AML, LPD and a solid tumor was 47.2 (CI 21.5-89.5) P<0.001, 8.1 (2.2-20.7) P=0.002 and 1.98 (1.1-3.2) P=0.009, respectively. In multivariate analysis, age >or=35 years at the time of AHSCT (P=0.001) and an interval from diagnosis to AHSCT >or=36 months (P=0.03) were associated with a greater risk of developing a second malignancy. Patients who have undergone HDT and AHSCT are at significant risk for developing a second malignancy and should receive indefinite follow-up.

Acute myelogenous leukemia complicated by acute necrotizing ulcerative gingivitis due to Aspergillus terreus.

Infections caused by Aspergillus terreus are rare but have been associated with a poor outcome in immunocompromised patients due to frequent resistance to conventional antifungal therapy. This report describes a case of a woman who developed acute necrotizing ulcerative gingivitis (ANUG) due to A. terreus during induction chemotherapy for acute myelogenous leukemia. She initially failed to respond to treatment with amphotericin B but the infection resolved following the introduction of oral itraconazole. Opportunistic infections caused by A. terreus are an emerging problem and can be associated with a high mortality rate. Early microbiological diagnosis is critical since resistance to amphotericin B is likely and itraconazole appears to be an effective treatment for this infection.

Fulminant tumour lysis syndrome in acute myelogenous leukaemia with inv(16)(p13;q22).

Tumour lysis syndrome (TLS) is caused by rapid breakdown of malignant cells resulting in electrolyte disturbances and acute renal failure. TLS has rarely been described in patients with acute myelogenous leukaemia (AML). Between November 1997 and July 2001, 114 consecutive adult AML patients aged <60 yr received induction chemotherapy consisting of cytosine arabinoside 1.5 g m(-2) q 12 h x 12 doses and daunorubicin 45 mg m(-2) d(-1) x 3 doses. During induction chemotherapy (CT), seven patients (6.1%, 95% CI 2.5-12.2) developed fulminant TLS, resulting in acute renal failure; five of these seven patients had inversion of chromosome 16 [inv(16)(p13;q22)], and one patient had a biological equivalent [t(16,16)(p13;q22)]. Four of the TLS patients underwent leukapheresis for a presenting white blood cell (WBC) count > 100 x 10(9) L(-1) prior to commencing chemotherapy, and six patients subsequently required haemodialysis for a median of 2 (range 1-8) wk. One TLS patient died of intracerebral hemorrhage on day 10 and another patient of multiorgan failure on day 17. Of the other five patients, all entered a complete remission (CR) and recovered normal renal function. Four patients remain in continuous CR [median follow-up 20 (range 12-25) months]. One patient relapsed at 12 months and again developed TLS on re-induction. In univariate analysis, TLS patients were more likely to have an elevated presentation and pre-chemotherapy WBC counts, elevated serum creatinine, and uric acid levels at presentation, as well as an inv(16). In multivariate analysis, only serum creatinine and inv(16) remained statistically significant (P < 0.001 for each). Patients with an inv(16) are a unique AML subgroup at high risk for fulminant TLS.

Allogeneic hematopoietic stem cell transplantation for progressive follicular lymphoma.

Between 1993 and 2000, 24 patients with follicular lymphoma underwent high-dose chemo/radiotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Median age was 44 years, median interval from diagnosis to HSCT was 24 months and the median number of prior lines of treatment was three. Donor source was HLA matched sibling (23) or matched unrelated donor (one). Conditioning therapy was busulfan based in 22 patients and included total body irradiation in two. All patients received i.v. cyclosporine A and short-course methotrexate for GVHD prophylaxis. Nineteen patients are alive, a median of 2.3 years post HSCT. Death occurred due to transplant complications in four patients and one patient died of a stroke 10 months post HSCT. No patients have relapsed. The overall and progression-free survival was 78% (95% CI 63-97). Allogeneic HSCT for patients with progressive follicular lymphoma is feasible and may result in prolonged disease-free survival.

Myelodysplastic syndrome and a nonrandom chromosomal abnormality t(1;19): an indolent pathologic entity.

The chromosomal abnormality t(1;19) is an infrequent finding in adult hematopoietic malignancies. This is only the second report of t(1;19) in association with myelodysplastic syndrome in which there was an apparent excellent response to oral cyclosporin A and a very indolent clinical course.

Effect of gastrointestinal inflammation and age on the pharmacokinetics of oral microemulsion cyclosporin A in the first month after bone marrow transplantation.

Cyclosporin A (CsA) absorption is highly variable in BMT patients. Neoral, a new microemulsion formulation of CsA, permits increased absorption with less variable pharmacokinetic parameters in non-BMT patients. We evaluated the pharmacokinetics of CsA after BMT in patients received microemulsion CsA. Two oral doses of 3mg/kg were given 48 h apart between 14 and 28 days after allogeneic BMT in 20 adults, and one dose in seven children, while subjects were receiving a continuous i.v. infusion of CsA. Whole blood samples were taken throughout the dosing interval to calculate the incremental CsA exposure using maximum concentration (Cmax), time to Cmax (tmax), concentration at 12 h after the dose (C12), the area under the concentration-time curve (AUC), and to establish inter- and intra-patient pharmacokinetic variability. Drug exposure was substantially lower in children than adults, with an AUC of 861+/-805 vs 2629+/-1487 micromg x h/l (P = 0.001), respectively, and absorption was delayed and diminished in both groups by comparison with solid organ recipients. Intra-patient variability in adults for AUC was high at 0.59+/-0.34, while inter-patient variability, measured as the coefficient of variation (c.v.), was 0.55 for the first and 0.54 for the second dose. In adults, gastrointestinal (GI) inflammation due to either mucositis or GVHD resulted in a higher AUC of 3077+/-1551 microg x h/l compared to 1795+/-973 microg x h/l (P = 0.02), and a similar trend was observed in children. AUC seemed little affected by the CsA formulation (liquid or capsule), or co-administration with liquids or food. Trough (12 h) CsA levels correlated poorly with incremental AUC. Sparse sample modeling of the AUC using two-point predictors taken at 2.5 and 5 h after dosing accurately approximated AUC in adults (r2 = 0.94), while 1.5 and 5 h was superior in children (r2 = 0.98). These data suggest that 12 h postdose trough measurements of CsA may not be the most appropriate way to evaluate CsA blood concentrations in order to establish therapeutic efficacy in BMT patients. Based on this study, the dose of microemulsion CsA should be adjusted based on recipient age, and the presence of GI inflammation secondary to mucositis or GVHD. These data would suggest that sparse sampling at time points earlier than the trough more accurately reflects the AUC and may correlate more closely with therapeutic efficacy early post-BMT.

Development of a biologically distinct EBV-related lymphoproliferative disorder following autologous bone marrow transplantation for an EBV-negative post-renal allograft Burkitt's lymphoma.

Post-transplant lymphoproliferative disorder (PTLD) is a known complication of both solid organ transplantation and allogeneic bone marrow transplantation (BMT) but is rarely seen following autologous BMT. We report the case of a 45 year-old female who developed Burkitt's lymphoma eight years after a renal allograft. This PTLD was found to have lambda light chain restriction, contained del(8)(q24) and add(14)(q32), and was negative for EBV on immunohistochemical and DNA-based PCR analyses. Immunoglobulin heavy chain (IgH) PCR studies revealed a prominent clonal rearrangement. She responded to intravenous cyclophosphamide and proceeded to high-dose chemoradiotherapy and mafosfamide-purged autologous BMT. Thirty-nine days post-BMT she presented with cough and fever and developed hepatic dysfunction; abnormal lymphoplasmacytoid cells were noted in the peripheral blood. Investigations revealed kappa light chain restriction, an oligoclonal IgH rearrangement, a normal karyotype and PCR studies for EBV were positive, consistent with a clinically and biologically distinct PTLD. She initially improved following discontinuation of immunosuppression, but then deteriorated abruptly and died 58 days post-BMT. It is likely that the two separate episodes of PTLD in this patient, one of which was atypical, arose as a result of both the chronic use of cyclosporine and the impairment of cell-mediated immunity associated with autologous BMT. The sequence of events in this patient should contribute to a better understanding of late-onset, EBV-negative PTLD.

Bone marrow necrosis in adult acute leukemia and non-Hodgkin's lymphoma.

Bone marrow necrosis is a rare finding in adult patients diagnosed with acute leukemia or non-Hodgkin's lymphoma. Previous reports have suggested that it is associated with a poor prognosis. It remains unclear however, whether improvements in patient care during the last decade have altered patient outcome. In a retrospective review of 581 bone marrow biopsies performed ante mortum on adult patients with acute leukemia or non-Hodgkin's lymphoma, we identified 10 cases of bone marrow necrosis (5 acute myeloid leukemia, 5 non-Hodgkin's lymphoma). Severe bone pain, elevated serum lactate dehydrogenase levels and leukoerythroblastic peripheral blood smears were common presenting features. Despite treating 8 of the 10 patients with curative intent, only 2 patients remain alive and disease-free. This study confirms that bone marrow necrosis in adults with acute leukemia and non-Hodgkin's lymphoma is a rare ante mortum finding and confers a poor prognosis. Whether these patients would benefit from more intensive therapy such as hematopoietic stem cell transplantation remains to be clarified.

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 institution's 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.

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.