Stephen H. Nantel

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.

Cytogenetic and molecular responses to standard-dose imatinib in chronic myeloid leukemia are correlated with Sokal risk scores and duration of therapy but not trough imatinib plasma levels.

Cytogenetic and molecular responses to standard-dose imatinib (IM) were correlated with trough IM plasma levels for 78 patients with chronic myeloid leukemia (CML) after a minimum of 12 months of IM therapy. The mean trough IM plasma level was 1065 ng/ml (range, 203-2910). There was no correlation of mean plasma trough IM levels and complete cytogenetic response (CCR) at 1 year (CCR 1010 ng/ml vs no CCR 1175 ng/ml P=.29) or major molecular response (MMR) (MMR1067 ng/ml vs no MMR 1063 ng/ml P=.74) after a median of 1298 days of IM therapy. CCR and MMR did correlate with Sokal risk scores with the odds of achieving CCR or MMR for a low risk vs high risk score of 10.8 (95% CI 2.2-53.5) and 6.4 (95% CI 1.4-29.4), respectively. Furthermore, a longer duration of IM therapy also was associated with a greater likelihood of achieving MMR (P=.02).

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.

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 ≥100×109/L, a value characteristically associated with “hyperleukocytosis” (HL). In this patient cohort, a presenting leukocyte count of ≥30×109/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.

Oral candidiasis in hematopoietic cell transplantation patients: an outcome-based analysis

OBJECTIVES Despite aggressive antifungal prophylaxis, the increased risk for systemic fungal infection in recipients of hematopoietic cell transplants (HCT) continues to be a significant concern because Candida infection can cause morbidity and mortality in these patients. The objectives of this study were to examine the relationship of oral colonization by Candida species to systemic infection, mortality, and the impact of antifungal treatment on a population of recipients of HCT. STUDY DESIGN One hundred and fifteen consecutive patients undergoing hematopoietic cell transplantation were evaluated. Oral examinations and cultures for Candida were completed before transplantation and on a weekly basis until discharge. The oral complications were assessed, and the level of mucositis was scored by using the National Cancer Institute grade. Systemic antifungal prophylaxis was provided to all patients. Chlorhexidine oral rinses were also routinely provided. RESULTS Colonization by Candida species was identified in 31% of patients. Fifty-six percent of patients with colonization had clinical evidence of oral candidiasis. Significantly decreased Candida colonization was seen in patients using chlorhexidine alone compared with those using chlorhexidine and nystatin together (P <.046). Twenty-five patients died in the immediate posttransplantation period, 17 of whom were Candida-positive. The length of hospital stay ranged from 15 to 153 days; increased stay was also associated with Candida colonization (P =.04). Seventy-four percent of all patients developed ulcerative mucositis. More severe mucositis was seen in patients undergoing chemotherapy and radiation therapy. There was no significant difference between Candida colonization and the presence or severity of mucositis. CONCLUSIONS Despite systemic and topical antifungal prophylaxis, oropharyngeal colonization by Candida species was common in patients who had received HCT. Candidiasis was commonly present in those who did not survive the early transplant period. Of the 25 patients who died early after the transplantation, 92% had ulcerative mucositis in comparison with 70% of those who survived, reflecting the association of oral mucositis with the toxicity of HCT. There was a significant relationship among allogeneic and autologous HCT, length of stay, and colonization of Candida. In patients undergoing systemic antifungal prophylaxis, chlorhexidine rinse was statistically more effective in reducing colonization by Candida than chlorhexidine and nystatin combined (P =.046).

High-Dose Therapy and Autologous Hematopoietic Stem-Cell Transplantation Does Not Increase the Risk of Second Neoplasms for Patients With Hodgkin's Lymphoma: A Comparison of Conventional Therapy Alone Versus Conventional Therapy Followed by Autologous Hematopoietic Stem-Cell Transplantation

PURPOSE To determine the incidence of second malignancies among patients with Hodgkins lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence. PATIENTS AND METHODS We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT. RESULTS The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04). CONCLUSION Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.

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 ⩾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.

Multicolor Karyotyping and Clinicopathological Analysis of Three Intravascular Lymphoma Cases

Intravascular lymphoma (IVL) is a rare neoplastic disease characterized by the presence of large malignant lymphoid cells in small vessels. It is often diagnosed at autopsy. Clinical manifestations are typically neurologic and dermatologic. Karyotypic abnormalities have been described in a small number of cases and have revealed complex alterations in the majority of cases. We have identified three cases of IVL with varied clinicopathological findings. Karyotypic analysis was undertaken by standard G-banding and supplemented by multi-colored karyotyping (M-FISH) to decipher the chromosomal content of marker chromosomes and undefined additions. M-FISH clarified the chromosomal abnormalities in two cases and unveiled cryptic translocations der(10)t(10;22), der(17)t(17;22), and balanced t(11;14). Comparison with previously published karyotypes revealed prominent involvement of chromosomes 1, 3, 6, 11, 14, and 18, similar to the pattern of clonal evolution in other B-cell lymphomas. The most frequent alterations seen were −6 or 6q− and +18 or dup(18q), with a minimally deleted region located at 6q21-q23 and a commonly amplified region located at 18q13-q23, respectively. Few differences between the classical and Asian variant of this disease were apparent at the karyotypic level. Cytogenetic analysis of additional cases supplemented by multicolor karyotyping may help identify the full spectrum of genetic alterations associated with IVL and assist in the delineation of the critical mutations associated with initiation and progression of this disease.

Idiopathic immune-mediated acquired von Willebrand's disease in a patient with angiodysplasia : Demonstration of an unusual inhibitor causing a functional defect and rapid clearance of von Willebrand factor

A case of idiopathic immune‐mediated von Willebrands disease (AvWD) associated angiodysplasia and recurrent lower gastrointestinal bleeding is reported. Coagulation parameters at presentation were activated partial thromboplastin time of 41 sec, bleeding time >15 min, factor VIII procoagulant activity, 5%; von Willebrand factor antigen (WF:Ag) 5%, and vWF:ristocetirn cofactor activity 11% sodium dodecyl sulfate‐agarose gel electrophoresis pattern of plasma vWF showed a pattern similar to type II vWD. An in vitro inhibitor against vWF in the immunoglobulin (Ig)G fraction of the patients plasma was demonstrated vWF parameters showed a short‐lived increase after 1‐deamino‐8‐D‐arginine vasopressin (DDAVP) administration. The patients bleeding episodes were initially managed adequately with cryoprecipitate replacement therapy and DDAVP, to which she became refractory. No significant improvement was achieved following the institution of immunosuppressive therapy in the form of high‐dose steroids and cyclophosphamide. She was then treated with intravenous immunoglobulin (IvIg) to which she showed an adequate response in terms of her clinical situation and her hemostatic parameters. The patient is on maintenance treatment with repeated courses of IvIg based on vWF parameter monitoring. To our knowledge, this is the third reported association between idiopathic immune‐mediated AvWD and angiodysplasia. Am. J. Hematol. 60:151–157, 1999.

Myelodysplastic Syndrome with Hypereosinophilia and a Nonrandom Chromosomal Abnormality dic(1;7): Confirmation of Eosinophil Clonal Involvement by Fluorescence In Situ Hybridization

We report a case of de novo myelodysplastic syndrome (MDS) with hypereosinophilia and dic(1;7) in which eosinophil clonal involvement was confirmed by fluorescence in situ hybridization. There have been two previous reports in the literature of eosinophilic MDS with dic(1;7) or t(1;7) in which eosinophil clonality was demonstrated. The specific breakpoints on chromosomes 1 and 7 differ in the three cases, making it difficult to implicate disruption of a single gene as causative; nevertheless, the nonrandom occurrence of t(1;7) or dic(1;7) with malignant eosinophilic proliferations suggests that this chromosomal rearrangement is involved in the etiology of the disease.