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.

Effect of antimicrobial prophylaxis on hematopoietic recovery following autologous bone marrow transplantation: ciprofloxacin versus co-trimoxazole.

We evaluated the effect of oral ciprofloxacin on neutrophil recovery in 20 consecutive patients undergoing autologous bone marrow transplantation (BMT) for malignant lymphoma and compared the results with a control group of 20 patients receiving co-trimoxazole and folinic acid. Both groups started the prophylactic antibiotic as well as granulocyte-macrophage colony-stimulating factor (GM-CSF) the day after marrow infusion and continued the former until the onset of febrile neutropenia (median duration of treatment 6 days for co-trimoxazole and 7 days for ciprofloxacin). The time of attain an absolute neutrophil count > or = 0.5 x 10(9)/L was significantly shorter in patients receiving ciprofloxacin (16 days vs 22 days; P = 0.006). There was no difference in time to attain a platelet count > or = 20 x 10(9)/L independent of transfusion or in time to the first febrile episode or incidence of bacteremia. We conclude that antibiotic prophylaxis with ciprofloxacin results in more rapid neutrophil recovery than prophylaxis with co-trimoxazole. This may result from a myelosuppressive effect of co-trimoxazole or an enhancement of neutrophil recovery by ciprofloxacin, or both.

Peripheral neuropathy following high-dose etoposide and autologous bone marrow transplantation.

We investigated the incidence of peripheral neuropathy in 142 consecutive patients receiving high-dose etoposide between August 1988 and December 1991. A retrospective chart review was conducted. Six patients with hematologic malignancies presented with a new sensory polyneuropathy after receiving an intensive therapy regimen consisting of etoposide 60 mg/kg i.v. and melphalan 140-160 mg/m2 i.v. followed by autologous bone marrow transplantation. Neurologic symptoms began 2-8 weeks after transplant, were grade 2-3 in severity and pursued a chronic course with slow improvement over months. Electromyographic studies in three of the patients tested confirmed distal sensory polyneuropathy. All 6 patients had previously received vincristine 1-60 months prior to autotransplant. We conclude that peripheral neuropathy of moderate severity is a potential complication of high-dose etoposide therapy but appears to be self-limited.

New clonal karyotypic abnormalities acquired following autologous bone marrow transplantation for acute myeloid leukemia do not appear to confer an adverse prognosis.

We undertook a retrospective review of all 76 patients with AML transplanted between August 1986 and March 1995 at our center. All patients received melphalan (140-160 mg/m2), etoposide (60 mg/kg) and total body irradiation. All patients had bone marrow cytogenetic analysis at regular intervals following ABMT. The primary study end point was the development of the new cytogenetic abnormalities. Secondary end points were the development of myelodysplasia (MDS) or AML. Sixty-two of 77 patients were alive at least 6 months post transplant. Cytogenetic abnormalities developed in 7/62 patients (11%) following ABMT. No patients demonstrated MDS or AML. At a median of 30 months after development of the cytogenetic abnormality, only one patient developed features suggestive but not diagnostic of MDS. All seven patients remain alive and leukemia-free up to 70 months after detection of the abnormal clone. There was no increased incidence of cytogenetic abnormalities developing in patients receiving a purged autograft. New cytogenetic abnormalities are frequent following ABMT for AML but do not appear to predict development of myelodysplasia or acute myeloid leukemia. These abnormalities may relate to use of total body radiation as part of the high-dose therapy.

Microbial contamination of harvested bone marrow and peripheral blood.

The incidence and clinical consequences of microbiological contamination of autologous bone marrow and peripheral blood progenitor cells are not well documented. We therefore retrospectively analysed our experience with bacterial or fungal contamination of harvested bone marrow and/or peripheral blood. From January 1987 to the end of January 1994, 499 patients were harvested or which 301 were transplanted. A total of 3910 specimens obtained during three stages in the processing were assessed for microbial contamination: (1) in the operating room immediately after harvesting (1662 bags) with 2.1% culture positivity, (2) after processing for cryopreservation (1039 bags) with a further 1.1% cultures positive, and (3) after thawing at the time of reinfusion (1209 bags) of which 2.2% were culture positive. There were no culture positive specimens obtained from any peripheral blood progenitor cell products. The vast majority of the 85 culture positive specimens obtained from marrow were skin flora (89%) and 35% of all positive harvest specimens remained positive following processing and freezing. At least 36% of culture positive specimens were thought to have arisen as a result of exogenous contamination of blood culture bottles. Potentially pathogenic enteric organisms were present in nine (0.2%) specimens and infusion of these organisms occurred in four cases. A further seven patients were reinfused with marrow culture positive for skin organisms. No adverse clinical sequelae were noted following infusion of any contaminated products. However, clinical decision making continues to be influenced by culture results and multistage microbial culture continues to be of value in the management of our marrow recipients.

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.

Fludarabine in alkylator-resistant follicular non-Hodgkin's lymphoma.

Follicular small cell and follicular mixed small and large cell lymphoma (FL) are incurable with conventional chemotherapy, and generally follow a relapsing course, eventually becoming resistant to first-line therapy with alkylating agents. Fludarabine is a novel chemotherapeutic agent that is effective in FL, but its role in alkylator-resistant disease remains unclear. We conducted a retrospective review of all patients with alkylator-resistant FL treated with fludarabine. Patients were identified from pharmacy records and included if they fulfilled criteria for alkylator-resistant FL. Resistance was defined as failure to achieve a partial response, progression while on therapy, or relapse within six months of completing therapy. Seventeen patients met the criteria of alkylator-resistant FL and were included in the analysis. All patients received fludarabine 25 mg/m(2) for five days. A median of 2.5 courses of fludarabine was given. One patient had a complete remission and eight patients had partial remissions, for an overall response rate of 53%. Median progression-free survival was 5.4 months and median overall survival was 15.4 months for all patients. Four patients underwent subsequent autologous stem cell transplantation; all required additional salvage chemotherapy for post-fludarabine relapses. Three patients remain in remission more than 12 months post-transplantation. Fludarabine produces partial responses in patients with advanced refractory FL; however, the duration of the response limits its utility in alkylator-resistant disease.

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.

A phase I study of interleukin-6 after autologous bone marrow transplantation for patients with poor prognosis Hodgkin's disease.

We performed a pilot study of human recombinant IL-6 (SDZ ILs 969) in 6 patients with poor prognosis Hodgkin's disease following autologous bone marrow transplantation (ABMT) to determine its safety and tolerability. IL-6 was administered the day following bone marrow infusion by subcutaneous injection once daily at a dose of 1 micro/kg/day to 3 patients and 2.5 microg/kg/day to 3 patients and was continued for 6 weeks or until platelet engraftment (>50 x 10(9)/L independent of transfusion). No severe or life threatening toxicities were seen at either dose level. A reversible elevation in alkaline phosphatase occurred in 4 patients and all patients complained of headache, myalgias, and fever. Gastrointestinal toxicity was low, grade 3-4 mucositis occured less frequently than in similarly-treated historical controls receiving GM-CSF. Serum concentrations of other cytokines such as IL-3 and G-CSF after ABMT differed from results obtained in transplant recipients given GM-CSF. The median time to an ANC >0.5 x 10(9)/L was 25.5 days and to a platelet count of >20 x 10(9)/L independat of transfusion was 35.5 days. Engraftment was no different from controls. Five patients relapsed at a median of 5 months post-ABMT and four remain alive at a median of 12 months post-ABMT. We conclude that IL-6 administration is safe and well tolerated in patients following ABMT. Further efforts to evaluate its effect on hematopietic recovery as well as relapse following transplantation in a larger patient series are warranted.

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.

HIV-associated lymphoma of the gastrointestinal tract: the University of Toronto AIDS-Lymphoma Study Group experience.

We present a retrospective analysis of 31 (30 male) patients with HIV-associated gastrointestinal lymphoma which was undertaken to determine the natural history and response to therapy. Only seven patients had stage I or II lymphoma and 22 had stage IV. Pathology included diffuse large cell (13), immunoblastic (10), and small cell non-cleaved (7). The median age at presentation was 39 years (range 24-59), and the median CD4 count before treatment was 100/microL (range 4-1150). Eighty-seven percent of patients received systemic chemotherapy and significant response was seen in 84% (CR 38%; PR 46%). Hematologic toxicity was high (febrile neutropenia in 44% and dose reductions were required in 81%) and perforation occurred in five patients. Median survival for all patients was 6 months and death was secondary to lymphoma in 61%, treatment toxicity in 10%, other AIDS-related illnesses in 25% and other causes in 4%. Survival was shorter for patients with bone marrow involvement and for those with poor performance status. HIV-associated GI lymphoma has a poor prognosis despite good initial response to chemotherapy and is associated with a higher perforation rate than in HIV negative patients.

Prolonged ciprofloxacin administration does not accelerate neutrophil recovery after autologous bone marrow transplantation.

STUDY OBJECTIVE: To determine whether prolonged ciprofloxacin administration following autologous bone marrow transplantation (ABMT) accelerates neutrophil recovery. DESIGN: Retrospective analysis of 40 consecutive patients undergoing ABMT. SETTING: Tertiary care bone marrow transplant program. PATIENTS: Two sequential arms of 20 consecutive patients with Hodgkin's disease or non-Hodgkin's lymphoma undergoing ABMT. INTERVENTIONS: The first arm received ciprofloxacin from the day of transplantation until initiation of broad-spectrum antibiotic therapy (median 5 days) while the second arm continued ciprofloxacin until recovery of the neutrophil count (median 15 days). MEASUREMENTS AND MAIN RESULTS: Neutrophil recovery was similar in the two groups (16 vs 14 days; p = 0.41). There were no differences in platelet recovery, bacteremia, or treatment-related mortality. CONCLUSION: Prolonged ciprofloxacin administration does not significantly accelerate neutrophil recovery following ABMT.

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.

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.

Isolated chloroma: the effect of early antileukemic therapy.

OBJECTIVE: To evaluate the effect of antileukemic chemotherapy administered at diagnosis on the survival of patients with isolated chloroma. DESIGN: Retrospective review of locally identified patients and analysis of cases from the medical literature. PATIENTS: The records of all patients with isolated chloroma identified at three teaching hospitals in Toronto between 1980 and 1994 were reviewed. A MEDLINE search was done to identify all cases of isolated chloroma reported in the English-language medical literature. Patients with a previous known hematologic disorder were excluded. MEASUREMENTS: The effect of therapy on 1) the interval between diagnosis of chloroma and diagnosis of acute myeloid leukemia and 2) survival was determined. RESULTS: 7 local patients and 83 published cases were identified, for a total of 90 evaluable patients. For the entire group, the median time to the diagnosis of acute myeloid leukemia was 9 months, and median survival was 22 months. Chemotherapy was administered to 49 patients (54%) at diagnosis of chloroma. Significantly fewer patients treated with chemotherapy subsequently developed acute myeloid leukemia (41% compared with 71%; P = 0.001). Survival was longer in patients treated with chemotherapy (> 50% alive with a median follow-up of 25 months compared with a median survival of 13 months for those initially untreated; P = 0.001). Multivariate analysis showed that neither local radiotherapy nor surgery had an effect on survival. CONCLUSIONS: Administration of antileukemic chemotherapy at diagnosis of chloroma is associated with a significantly lower probability of developing acute myeloid leukemia and with longer survival.