Ak Stewart

High treatment-related mortality in cardiac amyloid patients undergoing autologous stem cell transplant.

Dose-intensive chemotherapy with PBSC support was recently reported to be feasible in cardiac amyloidosis with some patients achieving post-transplant improvement in performance status. At our center, 11 patients with symptomatic primary systemic amyloidosis and predominant cardiac involvement confirmed by biopsy or increased wall thickness on echocardiogram were evaluated for high-dose therapy. The average time from diagnosis to referral was 11 months (4–26 months). Of the 11 patients, two were not candidates for high-dose therapy, based on poor performance status. The remaining nine patients proceeded to PBSC collection. Three patients died during the mobilization period: two of rapid atrial fibrillation, and the third secondary to progressive heart failure. Six patients proceeded to transplantation. However, one died of sudden cardiac arrest the day of melphalan administration, one following hypotension related to stem cell infusion, and one of hypotensive shock the day following stem cell infusion. Three patients recovered and left the hospital, but one died of a cardiorespiratory event at home within 6 weeks of discharge. Both surviving patients demonstrate objective improvement. A decision to use high-dose therapy and stem cell support in cardiac amyloidosis must balance the substantial morbidity of the procedure with the potential benefits. Transplant regimens should avoid cardiotoxic agents such as cyclophosphamide and DMSO and patients should receive anti-arrythmic therapy.

Ovarian function after autologous bone marrow transplantation.

PURPOSEnTo determine the frequency of return of ovarian function after autologous bone marrow transplantation (ABMT), and the major factors that predict recovery.nnnPATIENTS AND METHODSnRecords of 200 consecutive women who underwent ABMT at the University of Toronto Autologous Blood and Marrow Program (Toronto, Canada) were reviewed. Seventeen patients met the inclusion criteria, which were (1) alive at the time of evaluation, (2) disease-free at least 18 months after transplantation, (3) age younger than 50 years at transplantation, and (4) premenopausal before transplantation. Recovery of ovarian function was determined by pregnancy or regular menses, with no menopausal symptoms and an estradiol level greater than 20 pmol/L off hormonal therapy.nnnRESULTSnAll 17 patients became menopausal immediately after ABMT. Five patients (29%) recovered ovarian function a median of 24 months post-ABMT (range, 6 to 48 months). The median age at transplantation of women with restored ovarian function was 19 years (range, 19 to 28 years) versus 30 years (range, 22 to 48 years) for those who did not regain function. Younger age at transplantation predicted ovarian recovery (P = .03) by means of a log-rank test. Only one of five women who regained ovarian function received total-body irradiation (TBI) compared with five of 12 women who did not. Univariate analysis suggested a trend for TBI to predict a sustained loss of ovarian function (P = .067). The number of regimens of induction or salvage chemotherapy that contained an alkylating agent ranged from none to five and was not predictive (P = .45).nnnCONCLUSIONnAll women became menopausal after ABMT but 29% recovered ovarian function. Younger age at transplantation predicted return of ovarian function, whereas TBI may have had a negative effect.

Genetic risk identifies multiple myeloma patients who do not benefit from autologous stem cell transplantation

Summary:Genetic aberrations have emerged as major prognostic factors for patients with multiple myeloma (MM). We evaluated 126 MM patients for t(4;14) or t(11;14), 13q or p53 deletions and correlated the number of genetic aberrations with patients clinical outcome following undergoing autologous stem cell transplantation. We demonstrate the significance of genetic-based risk classification that clearly segregate patients into low (no genetic abnormalities or only t(11;14)), intermediate (any one of the genetic abnormalities other than t(11;14)) and high-risk groups (any two or more of the genetic abnormalities other than t(11;14)). High-risk patients do not benefit from stem cell transplant and should be offered alternative therapies.

Salvage chemotherapy with mini-BEAM for relapsed or refractory non-Hodgkin's lymphoma prior to autologous bone marrow transplantation

BACKGROUNDnThe role of intensive chemotherapy with autologous blood and marrow transplantation (ABMT) for patients with relapsed or refractory intermediate grade non-Hodgkins lymphoma has recently been established. However, conventional dose salvage chemotherapy is frequently used to determine chemotherapy sensitivity and reduce tumor bulk prior to intensive therapy. Different salvage regimens have been proposed but none appears significantly superior. The purpose of this study was to determine the efficacy of mini-BEAM salvage chemotherapy in patients referred for AMBT and to define prognostic factors of response.nnnPATIENTS AND METHODSnOne hundred four patients referred for consideration of AMBT after failure of primary anthracycline-based chemotherapy received BCNU 60 mg/m2 day 1, etoposide 75 mg/m2 day 2-5, ara-C 100 mg/m2 q12 h day 2-5, melphalan 30 mg/m2 day 6 (mini-BEAM) until maximum tumor reduction. Median age was 52 (range 18-65), 57% had failed to achieve a complete response (CR) to doxorubicin-based chemotherapy at diagnosis and only 13% had a previous CR lasting > 12 months. Seventy-six received mini-BEAM as first salvage chemotherapy.nnnRESULTSnThe overall response rate (RR) was 37% (95% confidence interval (CI) 28-46%) with 12 patients achieving CR and 25 achieving PR. The response rate among patients treated as first salvage was 43% compared to 20% for patients who had failed to respond to a previous salvage regimen. Only 15% of patients who failed to respond to mini-BEAM responded to another conventional dose salvage regimen. Thirty-eight of 104 patients ultimately demonstrated sufficient response to proceed to ABMT. Actuarial survival at four years is 22% for all 104 patients, and 36% for those who went on to AMBT. For those who were not transplanted, four-year survival was 18%. B symptoms and tumor burden at relapse were significant predictors of response to mini-BEAM in multivariate analysis, and identified a poor prognosis group of patients unlikely to be cured by the approach.nnnCONCLUSIONSnMini-BEAM does not appear to be a superior salvage regimen in this high-risk group of relapsed or refractory NHL patients for whom ABMT was the ultimate treatment intention. Only one-third of patients referred for ABMT ultimately proceed to transplant; alternative treatment strategies should be developed for those with a low likelihood of cure by this approach.

Radiation-associated pneumonitis following autologous stem cell transplantation: predictive factors, disease characteristics and treatment outcomes.

High-dose therapy followed by autologous stem cell transplantation (ASCT) prolongs survival in patients with multiple myeloma and is relatively safe with treatment-related mortality rates of only 1–5%. Interstitial pneumonitis (IP) is normally an infrequent complication of ASCT with a reported incidence of 0–16%. Between 1992 and 1998, 94 myeloma patients at our center underwent ASCT using a high-dose regimen of etoposide (60u2009mg/kg), melphalan (160u2009mg/m2) and fractionated TBI 12u2009Gy. An unusually high incidence of IP (29/94 (31%)) was noted. Mortality in the IP patients was high at 45%. Patients developing IP were more frequently anemic than those who did not have pulmonary complications (hemoglobin <100u2009g/l) prior to transplant (Pu2009=u20090.03) but no other pre-transplant factors were predictive (ie age, gender, smoking history, CMV status, pulmonary function, creatinine, β2-microglobulin or C-reactive protein, prior cumulative chemotherapy or chest irradiation). A significantly lower IP rate was noted in 32 contemporaneous myeloma control patients conditioned with BU-CY without TBI at our center (3/32 (9%); Pu2009=u20090.03) and in 32 lymphoma control patients conditioned with the same melphalan and etoposide regimen minus the TBI (2/32 (6%); Pu2009=u20090.003). In contrast, when using the same TBI-containing regimen in 32 concurrently treated lymphoma patients, an increase in IP similar to that seen in our myeloma cohort (7/32 (22%); Pu2009=u20090.3) was noted. This strongly suggests that TBI is the predominant factor contributing to lung toxicity. We conclude that radiation-associated pneumonitis cannot be easily predicted by pre-transplant variables. Therefore surveillance, early recognition and prompt therapy are recommended. Bone Marrow Transplantation (2001) 27, 177–182.

Autologous and allogeneic transplantation for multiple myeloma at a single centre

We report the results of a consecutive series of patients who underwent autologous (auto) (40), allogeneic (allo) (22) or syngeneic transplantation (2) for multiple myeloma (MM) at our centre. Median age at diagnosis was 45.5 (auto) and 43 (allo) years. Most patients had stage 2 (27% auto; 27% allo) or stage 3 (62% auto; 50% allo) disease and 73% demonstrated chemosensitivity prior to transplant. Median time from diagnosis to transplant was 18.6 months (auto) and 16.4 months (allo). Standard conditioning regimens were used. Median time to neutrophil engraftment was 11 days (7–18) (auto) and 18 days (13–24) (allo) and median time to platelet engraftment was 11 days (6–60) and 18 days (13–105), respectively. Ninety-day mortality was 5% (auto) and 27% (allo). Median follow-up was 15 months (6–48) (auto) and 42 months (24–52) (allo). Three-year progression-free survival (PFS) was 17u2009±u200910% (auto) and 22u2009±u20099% (allo) and 3-year overall survival (OS) was 74u2009±u200911% (auto) and 32u2009±u200910% (allo). Autologous transplantation for MM is a safe procedure with good OS although disease progression following transplant is frequent. Allogeneic transplantation has a high procedure-related mortality and PFS comparable to autologous transplantation but OS is poor. The early mortality and high OS of autologous transplantation in MM compares favourably with both the results of allogeneic transplantation and published results of standard therapy in this retrospective analysis.

Intensification of the stem cell transplant induction regimen results in increased treatment-related mortality without improved outcome in multiple myeloma.

Randomized trials conducted by the Intergroupe Française du Myelome (IFM) demonstrate that the use of high-dose chemotherapy (HDCT) and stem cell transplantation (SCT) improves event-free (EFS) and overall survival (OS) in younger patients with multiple myeloma (MM). Nevertheless, current HDCT regimens remain inadequate as all patients ultimately relapse following SCT. In an attempt to improve the OS of MM patients post-SCT we used an escalated HDCT regimen incorporating both intensified melphalan (160u2009mg/m2) and fractionated total body irradiation (12u2009Gy) to maximize the dose response of myeloma cells to these agents and included infusional etoposide 60u2009mg/kg in an attempt to eradicate clonal B cells potentially contributing to the myeloma clone. One hundred patients with MM received this intensified SCT regimen. The 100-day treatment-related mortality was 12% predominantly reflecting the development of interstitial pneumonitis (IP) in 28% of patients of whom 7/28 (25%) died. The predicted 5-year OS and EFS following the diagnosis of MM were 60% and 35%, respectively. The median OS from the time of transplant is 41 months and the median EFS is 28 months. More than two prior chemotherapy regimens, previous radiation therapy (RT) and the presence of an abnormal karyotype involving chromosomes 11 or 13 were significantly predictive of poor outcome. Interferon maintenance was not associated with improved outcome. Intensification of the HDCT regimen utilizing etoposide together with escalated melphalan and TBI increases morbidity and mortality without increasing OS beyond that reported with less toxic regimens.

'Relative' chemotherapy sensitivity: The impact of number of salvage regimens prior to autologous stem cell transplant for relapsed and refractory aggressive non-Hodgkin's lymphoma

The purpose of the study was to assess the impact of number of salvage regimens needed to demonstrate chemotherapy sensitivity on relapse rates, survival, and toxicity following high-dose therapy and autologous bone marrow transplantation (ABMT) in relapsed or refractory non-Hodgkins lymphoma. We retrospectively reviewed 136 patients with intermediate-grade lymphoma who underwent ABMT. All patients were treated with salvage therapy to maximum tumor reduction. Three quarters (102/136) of the patients received one salvage regimen, while 31 (23%) patients received two or more regimens. When compared to patients requiring ⩾ two regimens, patients requiring only one salvage regimen to demonstrate chemosensitivity were more likely to have a longer previous CR from initial therapy (CR ⩾12 months in 47% vs 26%; Pu2009=u20090.04) and to have attained CR with salvage (54% vs 16%; Pu2009=u20090.001). Both median relapse-free survival (RFS) and overall survival (OS) have not yet been reached in patients receiving one salvage regimen (median follow-up 50.6 months). This is superior to the median RFS of 9.1 months (Pu2009=u20090.004) and OS of 11.1 months in patients requiring ⩾two regimens to demonstrate chemosensitivity (Pu2009=u20090.002). Time to engraftment, toxic deaths and incidence of myelodysplasia were similar in the groups. The survival rate observed in patients requiring ⩾two salvage regimens, although inferior to that of patients receiving a single salvage regimen, are still generally superior to results in the literature for patients treated with chemotherapy alone without ABMT. We conclude that high-dose therapy with ABMT is appropriate for lymphoma patients even when disease reduction requires repeated numbers of salvage regimens.

Human herpesvirus 8 (KSHV) contamination of peripheral blood and autograft products from multiple myeloma patients

Human herpesvirus 8 (HHV-8), also known as Kaposis sarcoma-associated herpesvirus (KSHV), has recently been identified within the bone marrow dendritic cells of multiple myeloma (MM) patients. This virus contains homologues to human cytokines such as IL-6 that could potentially stimulate myeloma cell growth and contribute to disease pathogenesis. Since mobilization chemotherapy may increase circulating dendritic cell numbers, we searched for HHV-8 in peripheral blood mononuclear cells (PBMCs) before and after mobilization chemotherapy given to MM patients. Furthermore, we determined if autograft purging using the CEPRATE SC device would reduce the percentage of HHV-8 infected stem cell products. Only two of the 39 PBMC samples collected prior to mobilization chemotherapy contained PCR detectable virus, yet nine of 37 PBMCs collected on the first day of leukapheresis had detectable HHV-8 (Pu2009=u20090.016). HHV-8 was more frequently identified in autograft products before vs after Ceprate SC selection (40% vs 15%, Pu2009=u20090.016). Although the role HHV-8 plays in myeloma pathogenesis remains unclear, these results imply that mobilization chemotherapy increases the numbers of circulating HHV-8-infected dendritic cells within the peripheral blood. In addition, CD34 selection of autograft products in MM patients may reduce the reintroduction of virally infected cells following high-dose chemotherapy. Bone Marrow Transplantation (2000) 25, 153–160.

Safety of therapeutic anticoagulation in patients with multiple myeloma receiving autologous stem cell transplantation

The use of autologous stem cell transplantation (ASCT) for the treatment of multiple myeloma is increasing. Anticoagulation may be required during ASCT for conditions such as Hickman line thrombosis. The safety of anticoagulation in patients receiving ASCT is unknown. We report a retrospective case-control study of the safety of therapeutic anticoagulation in patients with multiple myeloma receiving ASCT. We identified 10 patients who received therapeutic anticoagulation during ASCT. For each of the 10 cases identified, two matched controls were selected. As a primary endpoint, bleeding complications were assessed. Secondary endpoints included survival, length of hospital stay, transfusion requirements, grade 4 toxicity, and days to platelet engraftment. Bleeding complications were not significantly different between patients receiving anticoagulation and controls (Pu2009=u20090.3). Three of 10 anticoagulated patients and two of 20 controls had a bleeding complication. Mortality during admission was similar (Pu2009=u20091.0); one anticoagulated patient and one control died of sepsis. A trend towards increased median number of platelet transfusions in the heparinized patients was seen (27 vs 12 units, Pu2009=u20090.055), reflecting the higher transfusion threshold chosen for the anticoagulated patients. The other secondary endpoints did not differ between patients and controls. In this case control study, bleeding was not significantly increased in the group receiving anticoagulation during ASCT. This group electively received more units of platelets than controls. Thus, therapeutic anticoagulation can be managed with minimal increased toxicity during ASCT.