Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline.

Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm3; (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications.

Prolonged clinical remissions in patients with relapsed or refractory follicular lymphoma treated with autologous stem cell transplantation incorporating rituximab.

Three sequential phase II trials were conducted with different immunotherapy approaches to enhance the outcome of autologous transplant (high-dose therapy and autologous stem cell transplantation (HDT/ASCT)) for recurrent follicular lymphoma. Seventy-three patients were enrolled from 1996 to 2009. Patients received HDT/ASCT combined with (1) interferon-α 3 MU/m(2) subcutaneously (SC) three times per week (TIW) for 2 years post-ASCT, (2) rituximab (R) 375 mg/m(2) for in vivo purging 3-5 days pre-stem cell collection and 2 × 4 weekly R at 2 and 6 months post-ASCT, respectively, or (3) three infusions of R pre-stem cell collection followed by 6× R weekly and interferon-α 3 MU/m(2) SC TIW. Although not statistically significant, progression-free survival (PFS) for patients who received rituximab was 56.4 and 49.1% at 5 and 10 years compared to 36 and 21% in those who did not receive rituximab. Molecular relapse post-HDT/ASCT was the strongest predictor of PFS in a multivariate analysis. Molecular relapse was coincident with or preceded clinical relapses in 84% of patients who relapsed­median of 12 months (range 0-129 months). Adverse events included secondary malignancy, transformation to diffuse large B cell lymphoma, prolonged mostly asymptomatic hypogammaglobulinemia, and pulmonary fibrosis. The long-term toxicity profile must be considered when selecting patients for this treatment.

Bortezomib in multiple myeloma: systematic review and clinical considerations.

We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects. Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016). In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001). In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.

Bortezomib in multiple myeloma: a practice guideline.

AIMS: Bortezomib (Velcade™, PS-341), a first-in-class proteasome inhibitor, has been extensively studied either alone or in combination with other agents for the treatment of multiple myeloma. We created a provincial guideline for the use of bortezomib, in newly diagnosed individuals (both eligible and ineligible for transplant) and in individuals with relapsed or refractory multiple myeloma. MATERIALS AND METHODS: A systematic review was conducted searching MEDLINE, EMBASE, the Cochrane Library and relevant meeting abstracts. Outcomes of interest were survival, disease control, response rate, response duration, quality of life and adverse effects. Members of the Cancer Care Ontario Hematology Disease Site Group (CCO HDSG), comprising physicians with content expertise, epidemiologists and consumers, developed a guideline through a systematic process that involved assessment of the best available evidence, consensus interpretation of the evidence and a validation process involving practitioners across the province. RESULTS: The CCO HDSG recommends the use of bortezomib-based combinations in previously untreated patients with multiple myeloma who are candidates for autologous stem cell transplantation and in individuals who are ineligible for autologous stem cell transplantation. The group further recommends the use of bortezomib, alone or in combination, for patients with relapsed/refractory disease. The evidence did not establish a subgroup of patients with myeloma that should be uniquely targeted for therapy with bortezomib. Qualifying statements by the HDSG address alternative dosing options, the management of cytopenias and the prevention of toxicities, including herpes zoster reactivation. CONCLUSIONS: Bortezomib alone or in combination with other agents can be recommended for both previously untreated or relapsed/refractory patients with multiple myeloma. Guidelines for monitoring and reducing toxicity are provided.

I-Tositumomab in lymphoma.

Radioimmunoconjugates are radioisotope-bound monoclonal antibodies that target radiation specifically to sites of lymphoma involvement. Initial studies of (131)I-tositumomab in non-Hodgkin lymphoma (NHL) have suggested benefit in patients with relapsed or refractory indolent disease. However, the routine adoption of this agent is tempered by concerns about associated toxicities and unclear long-term benefit. Based on a comprehensive search for studies on (131)I-tositumomab use in lymphoma, this systematic review summarizes and evaluates the evidence on the benefits and risks of this novel therapy,the predictors for response and toxicity, and the role of dosimetry and imaging studies before treatment.We identified 18 trials investigating the use of (131)I-tositumomab for the treatment of adult patients with nhl. In trials of patients with relapsed or refractory indolent nhl, overall response rates ranged from 67% to 83%. In patients with follicular nhl refractory to the monoclonal antibody rituximab, response rates remained high (65%-72%). However, in rituximab-naïve patients with relapsed or refractory indolent or transformed nhl, improvements in time to progression or survival have not been clearly established. (131)I-Tositumomab is an active agent in relapsed and refractory non-Hodgkin lymphoma that should be considered in selected patients.

Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma.

We enrolled 23 patients with relapsed follicular lymphoma (FL) in a prospective single-arm study of auto-SCT combined with in vivo rituximab graft purging and post transplant rituximab maintenance. Minimal residual disease was monitored with quantitative PCR testing. With a median follow-up of 74.2 months, neither median overall survival (OS) nor PFS has been reached. Here, 5-year OS and 5-year PFS are 78% (95% confidence interval (CI) 61-95%) and 59% (95% CI 38-80%), respectively. Time to progression (TTP) with the experimental regimen was significantly improved compared with TTP with the last prior treatment (P<0.001). Durable molecular remissions occurred in 11 of 13 assessable patients. PFS was significantly longer in patients who achieved a molecular remission by 3 months post-auto-SCT (P=0.001). Prolonged hypogammaglobulinemia occurred in most patients; however, no increase in major infections was observed.

Alemtuzumab in chronic lymphocytic leukemia.

QUESTIONS: With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (cll)?What toxicities are associated with the use of alemtuzumab?Which patients are more likely-or less likely-to benefit from treatment with alemtuzumab? PERSPECTIVES: Evidence was selected and reviewed by one member of the Hematology Disease Site Group (dsg) of Cancer Care Ontario's Program in Evidence-Based Care (pebc) and by methodologists. The practice guideline report was reviewed and approved by the Hema-tology dsg, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario. OUTCOMES: Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates. METHODOLOGY: A systematic review of the medline, embase, HealthStar, cinahl, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the pebc. RESULTS: The literature review found no published randomized controlled trials (rcts) that evaluated alem-tuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory cll. One rct evaluated alemtuzumab administered to consolidate a complete or partial response to first-line fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients receiving alemtuzumab experienced significantly improved progression-free survival as compared with patients undergoing observation. Six single-arm studies evaluated disease response with administration of alemtuzumab as a single agent in the treatment of patients with relapsed or refractory cll post-fludarabine. The pooled overall response rate was 38% (complete response: 6%; partial response: 32%). Adverse events associated with the use of alemtuzumab were commonly reported and included serious infusion-related, hematologic, and infection-related toxicities. RECOMMENDATION: This evidence-based recommendation applies to adult patients with B-cell cll. Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic cll that is refractory to both alkylator-based and fludarabine-based regimens. QUALIFYING STATEMENTS: The evidence supporting treatment with alemtuzumab comes principally from case series that evaluated disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and currently remain speculative. Treatment with alemtuzumab is associated with significant and potentially serious treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice. Given the potential toxicities associated with alemtuzumab, and given the limited nature of the agent's testing in clinical trials in broad populations of patients with cll, the use of alemtuzumab in patients with important comorbidities may be associated with excessive risks.

Bortezomib in multiple myeloma and lymphoma: a systematic review and clinical practice guideline.

QUESTIONS: In patients with multiple myeloma, Waldenström macroglobulinemia, or lymphoma, what is the efficacy of bortezomib alone or in combination as measured by survival, quality of life, disease control (for example, time to progression), response duration, or response rate?What is the toxicity associated with the use of bortezomib?Which patients are more or less likely to benefit from treatment with bortezomib? PERSPECTIVES: Evidence was selected and reviewed by two members of the Hematology Disease Site Group and by methodologists from the Program in Evidence-based Care (pebc) at Cancer Care Ontario. The practice guideline report was reviewed and approved by the Hematology Disease Site Group, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to practitioners throughout Ontario to obtain their feedback. OUTCOMES: Outcomes of interest were overall survival, quality of life, response rates and duration, and rates of adverse events. METHODOLOGY: A systematic search was conducted of the medline, embase, HealthStar, cinahl, and Cochrane Library databases for primary articles and practice guidelines. The resulting evidence informed the development of clinical practice recommendations. Those recommendations were appraised by a sample of practitioners in Ontario and modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body w theithin pebc. RESULTS: The literature review found one randomized controlled trial (rct)-the only published rct of bortezomib in relapsed myeloma. A number of phase ii studies were also retrieved, including a randomized phase ii study. No randomized trials were retrieved for lymphoma. The rct found bortezomib to be superior to high-dose dexamethasone for median time to progression and 1-year survival in patients with relapsed myeloma, although grade 3 adverse events were more common in the bortezomib arm. Bortezomib is recommended as the preferred treatment option in patients with myeloma relapsing within 1 year of the conclusion of initial treatment; it may also be a reasonable option in patients relapsing at least 1 year after autologous stem-cell transplantation. PRACTICE GUIDELINE: This evidence-based series applies to adult patients with myeloma, Waldenström macroglobulinemia, or lymphoma of any type, stage, histology, or performance status. RECOMMENDATIONS: Based on the results of a large well-conducted rct, which represents the only published randomized study in relapsed myeloma, the Hematology Disease Site Group (dsg) offers the following recommendations: For patients with myeloma refractory to or relapsing within 1 year of the conclusion of initial or subsequent treatment or treatments, including autologous stem-cell transplantation, and who are candidates for further chemotherapy, bortezomib is recommended as the preferred treatment option.Bortezomib is also a reasonable option for patients relapsing at least 1 year after autologous stem-cell transplantation. The dsg is aware that thalidomide, alkylating agents, or repeat transplantation may also be options for these patients. However, evaluation of these other options is beyond the scope of this practice guideline.For patients with myeloma relapsing at least 1 year after the conclusion of alkylating agent-based chemotherapy who are candidates for further chemotherapy, further treatment with alkylating agent-based chemotherapy is recommended.Evidence is insufficient to support the use of bortezomib in patients with non-Hodgkin lymphoma or Waldenström macroglobulinemia outside of clinical trials. QUALIFYING STATEMENTS: Limited evidence supports the appropriateness of a specific time-to-relapse period as being indicative of treatment-insensitive disease. The 1-year threshold provided in the foregoing recommendations is based on the opinion of the Hematology dsg. For specific details related to the administration of bortezomib therapy, the dsg suggests that clinicians refer to the protocols used in major trials. Some of those details are provided here for informational purposes. DOSAGE: Bortezomib 1.3,g/m(2) is given as a rapid intravenous bolus over 3-5 seconds on days 1, 4, 8, and 11 of a 21-day cycle; a minimum of 72 hours between doses is required to allow for recovery of normal proteasome function. Vital signs should be checked before and after each dose. A complete blood count is recommended before each dose, with blood chemistries (including electrolyte and creatinine levels) monitored at a minimum on days 1 and 8 of each cycle. The dose of bortezomib should be reduced or held immediately upon development of painful neuropathy, as described in the product monograph; dose modification may also be required for peripheral sensory neuropathy without pain or for other toxicities. Most toxicities are reversible if dose modification guidelines are followed. RESPONSE TO TREATMENT: Responses are usually apparent by 6 weeks (2 cycles). For patients achieving complete remission (determined by negative electrophoresis and immunofixation), bortezomib should be given for 2 additional cycles beyond the date of confirmed complete remission. In patients with progressive disease after 2 cycles or stable disease after 4 cycles, dexamethasone added to the bortezomib regimen (20 mg by mouth the day of and the day after each bortezomib dose) may produce an objective response. Bortezomib (with or without dexamethasone) should be continued in patients showing benefit from therapy (excluding those in complete remission) unless disease progression or significant toxicity is observed. Therapy should be discontinued in patients who do not respond to bortezomib alone if disease progression is seen within 2 cycles of the addition of dexamethasone. The Hematology dsg recognizes that thalidomide is an active agent in multiple myeloma patients who have relapsed after autologous stem-cell transplantation or who are refractory to alkylating agent-based chemotherapy. To date, no reported rcts have evaluated thalidomide in this role, and specifically, no trials have compared thalidomide with bortezomib. Given these limitations, the members of the Hematology dsg regard thalidomide or bortezomib as therapy alternatives to dexamethasone.

Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle-cell lymphoma: a matched pair analysis.

BACKGROUND: The outcome of 20 patients with newly diagnosed mantle-cell lymphoma (MCL) treated on a prospective trial of autologous stem-cell transplantation (ASCT) and rituximab immunotherapy was compared with the outcome of 40 matched historical control patients treated with standard combination chemotherapy. PATIENTS AND METHODS: Control patients with MCL were identified from a lymphoma database, and pairs were matched with patients receiving ASCT-rituximab for stage of disease, gender and age (+/-5 years). Only patients treated with an anthracycline- or cyclophosphamide-fludarabine-based regimen were included. RESULTS: Seventeen of 20 patients who received ASCT-rituximab remain alive in remission at a median of 30 months from diagnosis; one patient relapsed 2 years post-ASCT, and two died at 7 and 11 months post-ASCT without evidence of lymphoma. Of 40 patients treated with conventional chemotherapy, with a median follow-up of 80 months, 33 have relapsed or progressed and 29 have died. Overall (OS) and progression-free (PFS) survival were superior in patients treated with ASCT-rituximab compared with those treated with conventional chemotherapy (PFS at 3 years, 89% versus 29%, P <0.00001; OS at 3 years, 88% versus 65%, P = 0.052). CONCLUSIONS: This matched-pair analysis suggests that patients with advanced-stage MCL treated with ASCT-rituximab had statistically significantly better PFS and a trend toward better OS than patients treated with conventional chemotherapy. Longer follow-up will determine response duration and the true impact of this treatment strategy on PFS and OS.

Gemcitabine, dexamethasone and cisplatin is an active and non-toxic chemotherapy regimen in relapsed or refractory Hodgkin's disease: a phase II study by the National Cancer Institute of Canada Clinical Trials Group.

BACKGROUND: Gemcitabine (difluorodeoxycytidine) is active as a single agent in Hodgkin's disease and has been used successfully in combination with cisplatin to treat a variety of solid tumors. PATIENTS AND METHODS: We evaluated the combination of gemcitabine/dexamethasone/cisplatin (GDP) as salvage chemotherapy in 23 patients with relapsed or refractory Hodgkin's disease (median age 36 years, range 19-57). Treatment consisted of gemcitabine 1000 mg/m(2) intravenously on days 1 and 8, dexamethasone 40 mg orally days 1-4 and cisplatin 75 mg/m(2) on day 1, every 21 days as an outpatient. Response was assessed following two cycles of treatment. RESULTS: There were four complete responses and 12 partial responses for a response rate of 69.5% (95% confidence interval 52% to 87%); the remaining seven patients had stable disease and no patient progressed on treatment. All patients had successful stem cell mobilization and underwent transplantation with a median 10.6 x 10(6) CD34+ cells/kg. Hematological toxicity from GDP was mild (grade 3 neutropenia 8.6%, grade 3 thrombocytopenia 13%). CONCLUSIONS: In summary, GDP is an active regimen for patients with relapsed or refractory Hodgkin's disease. The response rate is similar to the rates of other current salvage regimens, it can be given to outpatients with tolerable toxicity and it does not inhibit the mobilization of autologous stem cells.

Follow-up of patients with Hodgkin's disease following curative treatment: the routine CT scan is of little value.

A total of 10-40% of patients with Hodgkin's disease relapse following initial curative therapy. Intensive follow-up is resource intensive and may identify false relapses. We performed a retrospective review of all patients with Hodgkin's disease treated at our centre between 1990 and 1999 to evaluate the utility of the components of follow-up. A total of 107 patients met the inclusion and exclusion criteria. The median age was 33 years and the median duration of follow-up 38 months. The total number of follow-up visits was 1209 and total number of CT scans 283. There were 109 suspected relapses of which 22 proved to be true relapses. Of the latter, 14 were identified clinically, six radiologically and two via lab testing. The routine CT scan detected only two relapses (9%), yet accounted for 29% of the total follow-up costs. Based on data from our centre, the cost per true relapse was $6000 US, 49% incurred by radiological tests. The majority of the cost of follow-up was incurred by routine follow-up (84%) as opposed to the investigation of suspected relapses (16%). We conclude that most true relapses are clinically symptomatic and that the routine CT is an expensive and inefficient mode of routine follow-up.

Spontaneous regression of Hodgkin's disease: two case reports and a review of the literature.

We present two cases of patients with Hodgkin's lymphoma who experienced spontaneous regressions of their disease. The first case was a 31-year-old man diagnosed with stage IIIA lymphocyte predominant Hodgkin's disease in 1994, who elected to be followed without any treatment. Over the subsequent 3 years, he experienced significant regression in his lymphadenopathy, and still remains asymptomatic of his disease 70 months after diagnosis. The second case was a 47-year-old man with a bulky anterior mediastinal mass found on a thoracic CT scan, ultimately diagnosed with stage IIB Nodular Sclerosing Hodgkin's Lymphoma. Repeat imaging of the chest performed two months later, just prior to initiating treatment, revealed that the mass had spontaneously decreased by >75% of its original size. Spontaneous regressions of Hodgkin's lymphoma are exceedingly rare. A review of the literature regarding spontaneous regressions of lymphoma and cancer in general is discussed.

Pharmacokinetic study of patients with follicular or mantle cell lymphoma treated with rituximab as 'in vivo purge' and consolidative immunotherapy following autologous stem cell transplantation.

BACKGROUND: Little is known about the pharmacokinetics of rituximab in an autologous stem cell transplant (ASCT) setting. PATIENTS AND METHODS: We evaluated serum rituximab levels in 26 patients with follicular or mantle cell lymphoma treated with a combination of ASCT and immunotherapy. Patients received nine infusions of rituximab (375 mg/m(2)): one dose as an 'in vivo purge' prior to stem cell collection, and two 4-week cycles at 8 and 24 weeks following ASCT. Pre- and post-infusion serum rituximab levels were measured during the purging dose, with doses 1 and 4 of both sets of maintenance rituximab cycles, and 12 weeks and 24 weeks following treatment. RESULTS: Rituximab levels were detectable after the first infusion, and peaked at a mean concentration of 463.8 micro g/ml after the final dose. Levels remained detectable 24 weeks after completion of treatment. There was a trend toward higher rituximab levels in patients with follicular lymphoma. Serum concentrations achieved during the maintenance cycles were similar to levels observed in patients with measurable lymphoma treated during 'the pivotal trial'. No correlation was observed between serum rituximab levels achieved in the minimal disease state and the risk of later clinical relapse, nor with the ability to achieve a molecular remission following ASCT. CONCLUSIONS: The finding that patients treated in minimal disease states and at the time of active disease both achieve similar final serum rituximab concentrations after four infusions suggests that the pharmacokinetics are complex, and may not necessarily correlate with disease burden. The precise factors influencing rituximab clearance in patients with lymphoma are unresolved, and this remains an area of active research.

The development of marked elevation in white blood cell count does not predict inferior outcome in chronic lymphocytic leukemia.

Although elevation of the white blood cell (WBC) count at diagnosis of chronic lymphocytic leukemia (CLL) appears to predict shortened survival, its significance later in the course of the disease remains unclear. We reviewed all cases of CLL seen in our center between 1980 and 1999 to evaluate the frequency and clinical significance of WBC elevation > 100 x 10(9)/L. CLL was confirmed according to standard diagnostic criteria and data was collected from diagnosis, occurrence of WBC > 100 x 10(9)/L, and last follow-up. 235 consecutive patients with CLL were identified; 94 were excluded. 141 included patients had a median age of 61 years and median WBC 19.7 x 10(9)/L at diagnosis. Median follow-up for all patients was 56 months, and median survival was 104 months. 41 patients (29%) had > or = 1 episode of WBC > 100 x 10(9)1/L, occurring at a median of 38 months from diagnosis. Compared to controls matched for modified Rai stage, development of a WBC > 100 x 10(9)/L did not predict inferior survival (median 107 vs. 101 months, p = 0.72). We conclude that the occurrence of a WBC count > 100 x 10(9)/L in patients with CLL does not shorten the survival, and patients require therapy only if other indications for treatment are present.

Malignant evolution of Schnitzler's syndrome--chronic urticaria and IgM monoclonal gammopathy: report of a new case and review of the literature.

Schnitzler's syndrome, initially described in 1974 is an uncommon condition defined by chronic urticaria and monoclonal IgM gammopathy. Additional features include fever of unknown origin, elevated ESR, bone pain and frequently a benign clinical course. We conducted a literature search of Medline, EMBASE and Cancerlit and found 56 cases of Schnitzler's syndrome reported to date. The absence of lymphoproliferative disease in this condition is typical, but nine patients have progressed to develop lymphoplasmacytic neoplasias, particularly Waldenstrom's macroglobulinemia (WM). Malignant evolution of Schnitzler's syndrome is a rare complication, but emphasizes the importance of long term follow-up and the need for these patients to undergo periodic assessment of the bone marrow and lymph nodes. Treatment of this condition is difficult, with varying response to corticosteroids and largely unsuccessful results with standard chemotherapy used for WM. We describe a case of Schnitzler's syndrome in a 50-year old man with lymphocytic aggregates in the bone marrow after 9 years of chronic urticaria, fever, arthralgias and bone pain. We review the clinical features and treatment, with emphasis on the hematologic aspects of this unusual condition.

Bcl-2 clearance: optimising outcomes in follicular non-Hodgkin's lymphoma.

The long median survival time of patients with follicular non-Hodgkin's lymphoma (NHL), means that the efficacy of new treatments are difficult to assess in the short term. Bcl-2 is an inhibitor of apoptosis and overexpression of the bcl-2 gene in the blood or bone marrow is a feature in up to 85% of patients with follicular NHL. Levels of bcl-2(+) cells in the peripheral blood or bone marrow therefore are a useful measure of disease status in such patients and can be detected by polymerase chain reaction (PCR). Complete bcl-2 clearance from the bone marrow (molecular remission) following autologous stem cell transplant (ASCT) for follicular NHL is considered to be an important prognostic factor for disease-free survival. Tumour cell contamination of the stem cell grafts used in ASCT is commonly associated with relapse. This can be addressed by purging the stem cell harvest prior to transplantation. Various methods of in vitro purging after stem cell collection have been shown to reduce the level of contamination but yield is invariably reduced and grafts remain bcl-2 positive. However, in vivo purging with rituximab during the process of collection has been used to obtain bcl-2-negative stem cell harvests without compromising the yield. Rituximab is a monoclonal antibody licensed for treatment of relapsed and refractory low-grade or follicular NHL. Rituximab targets the CD20 antigen, which is found on cells of the B cell lineage. When used for in vivo purging it depletes the peripheral blood of CD20-positive cells and prevents contamination by lymphoma cells. Molecular remission, as measured by bone-marrow bcl-2 clearance, has been achieved in 7/7 patients with follicular NHL at 1 year after treatment with ASCT using rituximab as an 'in vivopurse', followed by rituximab maintenance. Early clinical outcomes are also encouraging.

Outpatient supportive care following chemotherapy for acute myeloblastic leukemia.

Treatment of acute myeloid leukemia (AML) involves aggressive myelosuppressive chemotherapy that is generally administered on an inpatient basis. In our centre, AML therapy has been initiated in hospital and followed by early outpatient supportive care according to guidelines established in 1996. We conducted a review of all patients presenting with AML in our centre between January 1996 and July 1998 to evaluate the safety and feasibility of early outpatient supportive care. Nineteen consecutive patients treated with induction chemotherapy were analyzed. Patients were treated with cytosine arabinoside and an anthracycline as aggressive AML induction therapy with the intent for early discharge. Ten patients (53%) were discharged within 10 days of starting induction chemotherapy (median 4.5 days). Reasons for remaining in hospital included sepsis, serious medical complications, and social and geographic factors. Patients discharged early had a median of 1.5 readmissions (range 0-3), but had 30% fewer in-hospital days than inpatients (p = 0.03), and 57% fewer days of in-hospital antibiotic therapy (p = 0.01). There were no significant differences in transfusion requirements or episodes of febrile neutropenia between the two groups. Thirty-one cycles of consolidation therapy were administered to the 18 patients who survived induction. Early discharge from hospital was achieved for 30 cycles (97%). Nine cycles of consolidation chemotherapy were delivered using outpatient intravenous infusion pumps (29%). This study supports the feasibility and safety of early discharge and outpatient supportive care following chemotherapy for AML.

ALVAC-mediated gene transfer is efficient in lymphoid malignancies of T-and early B-cell origin, but not in tumors arising from mature B-cells.

Natural attenuation of ALVAC virus in mammals makes it an attractive vector for cancer vaccine therapy of immunocompromised hosts, such as patients with lymphoid malignancies. However, the transduction efficiency of ALVAC constructs in lymphoid tumors has not yet been characterized. We studied a wide spectrum of human T- and B-cell leukemia and lymphomas and found significant heterogeneity of the ALVAC-mediated gene product expression in these tumors. While ALVAC-B7.1, ALVAC-B7.2, or ALVAC-luciferase vectors effectively expressed recombinant genes in malignancies arising from T- or early B-cell precursors, negative or low expression of ALVAC recombinant genes occurred in tumors arising from mature B-cells. We showed that ALVAC-encoded B7.1 or B7.2 was continuously expressed on the infected, and subsequently irradiated, leukemia cells, and only cells with ALVAC-mediated expression of costimulatory molecules (but not unmodified leukemia cells or those infected with the ALVAC-parental vector) induced significant proliferation and IFN-gamma production by alloreactive T-cells. These data provide the rationale for clinical studies using the ALVAC vector system for gene transfer into lymphoid tumors of T- and early B-cell origin to render them more immunogenic, while alternative strategies should be considered for immunotherapy of mature B-cell malignancies.

Disseminated intravascular coagulation and PC-SPES: a case report and literature review.

BACKGROUND: PC-SPES is a herbal remedy gaining acceptance amongst prostate cancer patients and health care providers due to credible laboratory and clinical studies. However, PC-SPES has not been assessed in the standard rigorous approval process mandated for conventional agents. OBJECTIVES: To present a case of a patient with prostate cancer who, while using PC-SPES, developed disseminated intravascular coagulation (DIC). A review of the literature was conducted to determine if there is a relationship between PC-SPES and hemorrhagic disorders. METHODS: Searches were conducted in MEDLINE (1966-December 2000) and the Cochrane Collaboration's database. RESULTS: There are 116 clinical and laboratory based studies of PC-SPES published to date. There are no randomized controlled trials. Clinical studies have demonstrated a significant reduction in prostate specific antigen (PSA) levels within 6 weeks. Improved quality-of-life, reduction in the volume of tumor deposits and reduction in analgesic use has been demonstrated in hormone refractory patients. Laboratory studies suggest that the beneficial effects of PC-SPES are unrelated to physiologic estrogens. However, PC-SPES has a side-effect profile similar to diethylstilbestrol. There is data demonstrating a <5% risk of thromboembolic events, but this is the first report of DIC. CONCLUSION: The study of PC-SPES is in its infancy. This case may serve as a cautionary note to health care providers and patients regarding herbal remedies. Those using PC-SPES should have an increased level of surveillance for bleeding disorders.