High-dose BEAM Chemotherapy Research Articles

Yttrium-90 Ibritumomab Tiuxetan Doses Calculated to Deliver up to 15 Gy to Critical Organs May Be Safely Combined With High-Dose BEAM and Autologous Transplantation in Relapsed or Refractory B-Cell Non-Hodgkin's Lymphoma

To determine the maximum-tolerated radiation-absorbed dose (RAD) to critical organs delivered by yttrium-90 ((90)Y) ibritumomab tiuxetan in combination with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy with autologous transplantation. Eligible patients had relapsed or refractory CD20+ non-Hodgkin's lymphoma (NHL). Individualized (90)Y activities were based on dosimetry and were calculated to deliver cohort-defined RAD (1 to 17 Gy) to critical organs with three to six patients per cohort. The therapeutic dose of (90)Y ibritumomab tiuxetan was followed by high-dose BEAM and autologous transplantation. Forty-four patients were treated. Thirty percent of patients had achieved less than a partial remission to their most recent therapy and would not have been eligible for autologous transplantation at most centers. The toxicity profile was similar to that associated with high-dose BEAM chemotherapy. Two dose-limiting toxicities occurred at the 17 Gy dose level, which made 15 Gy the recommended maximum-tolerated RAD. Although eight patients received at least twice the conventional dose of 0.4 mCi/kg, a weight-based strategy at 0.8 mCi/kg would have resulted in a wide range of RAD; nearly 25% of patient cases would have received 17 Gy or more, and many would have received less than 10 Gy. With a median follow-up of 33 months for all patients, the estimated 3-year progression-free and overall survivals were 43% and 60%, respectively. Dose-escalated (90)Y ibritumomab tiuxetan may be safely combined with high-dose BEAM with autologous transplantation and has the potential to be more effective than standard-dose radioimmunotherapy. Careful dosimetry is required to avoid toxicity and undertreatment.

Late Effects after Autologous Hematopoietic Cell Transplantation

Over 30,000 autologous hematopoietic cell transplants (HCT) have been performed yearly during the past decade. With improvement in supportive care, few patients succumb to early treatment complications; hence, more attention is being paid to causes of late complications and death. However, interpretation of the data that exist is difficult as the definition of ‘‘late’’ varies by study, as does the patient population, underlying diseases, HCT mobilization and conditioning regimens, stem cell sources, and duration of follow-up (Table 1). Most importantly, the methods used to estimate the incidence of late complications over time are different or are not explained in sufficient detail. Some studies report relative risk or standardized mortality compared with the general population. Other studies report an acturial estimate (which ignores competing risks and thus may overestimate the incidence), whereas others report cumulative incidence calculations.

A phase 2 pilot study of pegfilgrastim and filgrastim for mobilizing peripheral blood progenitor cells in patients with non-Hodgkin's lymphoma receiving chemotherapy

Growth factors are frequently used to aid peripheral blood progenitor cell mobilization from bone marrow. This phase 2 study examined the efficacy and safety of pegfilgrastim for mobilizing peripheral blood progenitors cells for autologous transplantation. Patients with non-Hodgkin's lymphoma received one cycle of mobilizing chemotherapy (ifosfamide, carboplatin and etoposide, ICE). Twenty-four hours later they were randomized, double-blind, to receive a single dose of pegfilgrastim 6 mg or 12 mg, or filgrastim 5 mug/kg/day (until the end of leukapheresis). Following leukapheresis (collection phase), patients rested or received one or two 'salvage' cycles of ICE. High-dose BEAM chemotherapy was then given before peripheral blood progenitor cell transplantation. The primary end-point was the patients' mean yield of CD34(+) cells/kg during the collection phase. Ninety patients were randomized and received a study drug; 63% completed the collection phase. The patients' mean (95% CI) CD34(+) cell harvest per leukapheresis was 0.8 (0.5-1.4), 0.8 (0.5-1.6) and 1.2 (0.7-2.0)x10(6) cells/kg for the pegfilgrastim 6 mg, pegfilgrastim 12 mg and filgrastim groups, respectively. Twenty (69%), 17 (59%) and 23 (72%) patients in these three groups achieved the targeted minimum harvest (>/=2 x 10(6) cells/kg). The mean total harvests were 1.7, 1.4 and 2.2 x 10(6) cells/kg, respectively. Post-transplantation, the median days to absolute neutrophil count recovery (>/=0.5 x 10(9)/L) were 12, 11, and 11, respectively. Pegfilgrastim and filgrastim were generally well tolerated. Pegfilgrastim (6 or 12 mg) was effective for mobilizing peripheral blood progenitors cells in patients with non-Hodgkin's lymphoma. These data may aid the design of studies to clarify optimal dosing and leukapheresis with pegfilgrastim.

Chylous ascites secondary to B-cell non Hodgkin's lymphoma in a patient with the acquired immune deficiency syndrome (AIDS)

In the present article we describe a patient with AIDS and chylous ascites secondary to B-cell non Hodgkin's lymphoma. A 43 years old homosexual HIV-positive man. Complained of abdominal fullness, diarrhea and a rapidly increase in abdominal girth of 1 week duration. A diagnostic paracentesis was performed and revealed a milky fluid with high triglyceride levels. All blood tests and analysis of the peritoneal fluid with polymerase chain reaction for DNA sequence of broad-range bacterial Post Voiding Residual volume, Mycobacterium tuberculosis, Kaposi Sarcoma associated Herpes virus and Epstein Barr Virus were negative. CT scan did not demonstrate any evidence for cancer. An exploratory laparotomy was thus performed. A mass spreading along the mesenteric route to the omentum was found and a debulking resection was performed. The final pathology report was of diffuse, CD20-positive, CD3-negative, Epstein Barr Virus-negative, large B-Cell non Hodgkin's lymphoma. Subsequently, he underwent five cycles of CHOP (cyclofosfamide, doxorubicin, vincristin, prednison) chemotherapy with further partial regression of the abdominal tumour. Five months after the initial diagnosis of lymphoma, the patient relapsed and was treated with high-dose BEAM (carmustine, etoposide, cytosine, arabinoside, melphalan) chemotherapy followed by CD34 stem-cell transplantations salvage therapy. This notwithstanding, the patient died due to intestinal secondary to tumor relapse 2 months later.

BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: comparative analysis of efficacy and toxicity

The treatment of choice for relapsed/refractory non-Hodgkin's lymphoma (NHL) consists of high-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT). Little is known, however, regarding the comparative toxicity and efficacy of various HDC regimens applied in NHL. We have retrospectively evaluated the clinical aspects of the BCNU, etoposide, cytarabine, and cyclophosphamide (BEAC) and BCNU, etoposide, cytarabine, and melphalan (BEAM) regimens for ASCT. Between April 1994 and February 2005, 97 NHL patients underwent HDC with BEAC (N = 69) or BEAM (N = 28), followed by ASCT, at the Asan Medical Center. We matched each BEAM patient with two BEAC patients having the same International Prognostic Index. Thus, 84 patients (56 BEAC and 28 BEAM) were analyzed. Median age was 40.5 years, and baseline characteristics were well balanced between the two groups. The median time to neutrophil engraftment (>500/mm(3)) was significantly longer with BEAC than with BEAM (12 vs 11 days, P = 0.001), as was the total amount of red blood cell transfusion (6.5 vs 3.7U, P = 0.037), but the median time to platelet engraftment (>20,000/mm(3)) and the total amount of platelet transfusion did not differ between the two groups. BEAM patients had significantly more frequent World Health Organization grade greater than or equal to 2 diarrhea than BEAC patients (46.4 vs 19.6%, P = 0.010), but the incidence of mucositis, nausea/vomiting, and bleeding and the number of episodes of febrile neutropenia and septicemia did not differ between the two groups. Median follow-up for survivors was 33 months in the BEAM group and 89 months in the BEAC group. Median overall survival and median event-free survival were not reached in the BEAM group and were 7.9 (95% confidence interval [CI], 1-14.8 months, P = 0.003) and 3.7 months (95% CI, 0.1-7.2 months, P = 0.001), respectively, in the BEAC group. BEAM appeared to be superior to BEAC for survival. Regimen-related toxicities were similar, except that BEAM was associated with more frequent but acceptable diarrhea.

Yttrium-90–ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma

To determine the safety and outcome following standard-dose ibritumomab tiuxetan followed by BEAM high-dose chemotherapy and autologous stem cell transplantation (ASCT) in patients with chemo-refractory aggressive non-Hodgkin's lymphoma. The study included 23 patients, median age 55 years (range, 35-66) with chemo-refractory lymphoma, either primary refractory (n = 11) or in refractory relapse (n = 12). Rituximab 250 mg/m(2) followed by ibritumomab tiuxetan 0.4 mCi/kg were given on day -14 and high-dose BEAM chemotherapy started on day -6. All patients engrafted. Twenty-one patients are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy (overall CR rate 76%). With a median follow-up of 17 months (range, 4-27) 16 patients are alive and 12 are progression-free. The estimated 2-year overall and progression-free survival are 67% (95% CI, 46-87%) and 52% (95% CI, 31-72%), respectively. The day-100 rate of treatment-related mortality was 9% (95% CI, 2-33%) and the 2-year cumulative incidence of relapse was 31% (95% CI, 17-57%). Extensive prior therapy (>3 lines), high LDH and IPI score at ASCT, bulky disease, and progression during last chemotherapy were risk factors for reduced survival. Ibritumomab tiuxetan-BEAM and ASCT is relatively safe and may improve outcome in patients with refractory lymphoma. Although excess nonrelapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved outcome. Standard-risk patients with chemo-sensitive disease may also benefit from ibritumomab tiuxetan-BEAM and ASCT. This hypothesis merits further study in larger-scale prospective randomized studies.

Severity, Frequency, and Risk Factors for Oral Mucositis after BEAM High-Dose Chemotherapy and Autologous Peripheral Blood Stem Cell Transplantation and Preliminary Results with Palifermin Versus Best Supportive Care.

Mucositis being an adverse effect of high-dose chemotherapy (hd CTx) may compromise results of peripheral blood stem cell transplantation (PBSCT). Keratinocyte growth factor can effectively decrease its severity and frequency. Here, the mucositis rate after BEAM hd CTx followed by auto-PBSCT was analyzed. A total of 50 patients (median age: 55 years, range; 19–70) with high-risk, refractory or relapsed lymphoma were included in a prospective analysis at our center, and mucositis was graded according to WHO. After BEAM-hd CTx, WHO grade 2 mucositis developed in 30%, grade 3 in 10% and grade 4 in 4%. Odds ratios (OR) for mucositis grade 2 or higher were increased to 2.1 (95% CI 0.6–6.7) for female sex, to 1.9 (CI 0.5–6.7) for higher pretreatment (>8 CTx-cycles), and 3.1 (CI 0.9–10.5) with previous mucositis. We found no association for older age, lymphoma type (indolent vs. high-grade NHL/Hodgkin's disease), previous radiotherapy, Karnofsky index, oral hygiene or leukopenia prior to auto-PBSCT. The OR for mucositis with parental nutrition was estimated with 2.2 (CI 0.6–7.7) and for opioid use with 8.7 (CI 2.2–33.7) (p=0.0025), both being directly influenced by the extend and severity of oral mucositis. As expected, myelosuppression was the main toxicity of hd-BEAM: WBC >1.000/ml were reached after a median of 10 days (range 7–15), platelets >20.000/ml after 11 days (range 7–45). The median numbers of red blood cell and platelet units transfused were 5 (range 1–21) and 4 (range 1–35), respectively. The event free survival at 6, 12 and 24 months was 81.9% (CI 71.2–92.6%), 70.5% (CI 57.3–83.6%), and 66% (CI 51.2–80.9%), and the overall survival 83.9% (CI 73.7–94.1%), 79.2% (CI 67.7–90.8%) and 79.2% (CI 67.7–90.8%), respectively. Subsequently, 10 lymphoma patients have been accrued in the follow-up study comparing palifermin to best supportive care (BSC) after hd-BEAM conditioning. All 5 patients receiving palifermin showed only WHO grad 1 mucositis, whereas in the control group one patient each had grade 1, 2 and 3 mucositis and 2 patients are still being treated. In conclusion, we found females, extensive pretreatment and previous mucositis as potential risk factors for the development of mucositis, the latter greatly influencing parental nutrition and opioid use. Although the incidence of grade 2–4 mucositis varies with different CTx-schedules and -intensity, it severely affects supportive measures. Decrease in its severity and duration will substantially reduce side-effects of PBSCT further.

Ibritumomab Tiuxetan (Zevalin) Followed by High-Dose Chemotherapy and Autologous Stem-Cell Transplantation Results in Improved Survival of Patients with Chemo-Refractory Non-Hodgkin's Lymphoma Expected To Have Poor Outcome with Standard Pre-Transplant Conditioning.

High-dose chemotherapy and autologous stem-cell transplantation (autoSCT) have an established therapeutic role in patients (pts) with chemosensitive relapse of aggressive lymphoma. However, autoSCT has only limited success when performed in refractory or progressive stage of the disease and in heavily pretreated or multiply relapsed pts. The expected long-term progression-free survival (PFS) in this setting is less than 20%. This study was designed to explore the safety and outcome following inclusion of Zevalin in the conditioning regimen given prior to autoSCT in pts with refractory lymphoma expected to have poor outcome with standard autoSCT. Pts with aggressive lymphoma were eligible for this study if they did not achieve CR with prior chemotherapy (either as initial treatment or after relapse) and had active disease by PET-CT. Unlike standard treatment with Zevalin, extensive marrow involvement and pancytopenia were not contraindications for therapy. The study uncluded 23 pts, median age 55 years (range, 35–66), a median of 12 months (5–129) from diagnosis. Histology was diffuse large cell (n=15), transformed low grade (n=7) and mantle cell lymphoma (n=1). Disease status was primary refractory disease (n=11) or refractory relapse (n=12). Fourteen pts had bulky disease at autoSCT. The median number of prior therapies was 3 (range, 1–6). Rituximab 250 mg/m2 followed by Zevalin 0.4 mCi/kg were given on day -14 and high-dose BEAM chemotherapy started on day -6. All pts engrafted in a median of 10 days after autoSCT (9–22). Zevalin had no impact on engraftment kinetics although 9 pts became neutropenic on or prior to the day of autoSCT, an uncommon occurrence with standard BEAM. There were no early infusion reactions associated with Zevalin. Two pts died of multi-organ toxicities early after SCT. One died from infection and one died of bronchiolitis obliterans (infection related) 4 and 5 months after SCT, respectively. The day100 rate of non-relapse mortality in these heavily pretreated pts with refractory lymphoma is 9% (95% CI, 2–33) and it seems there was no additional toxicity related to Zevalin. Overall, 21 pts are evaluable for response; 11 achieved CR, 9 achieved PR, 5 of whom converted to CR with additional radiation therapy to residual disease (overall 16 pts achieved CR), 1 pt did not respond. In all, seven pts relapsed or did not respond. The 1-year cumulative incidence of relapse is only 32% (95% CI, 17–60%). As expected in refractory disease, all relapses occurred within 6 months of autoSCT. With a median follow-up of 15 months (range, 4–25), 15 pts are alive. The estimated 1-year overall and progression-free survival were 59% (95% CI, 36–83%) and 49%, respectively, compared with less than 20% expected with standard autoSCT in this setting. In conclusion, inclusion of Zevalin in the conditioning regimen prior to autoSCT is relatively safe and may improve outcome in pts with refractory lymphoma. Although excess non-relapse mortality can not be ruled out, relapse rate was relatively low, resulting in improved PFS. Zevalin in combination with autoSCT merits further study in larger scale randomized studies. Moreover, standard risk pts with chemosensitive disease may also benefit from Zevalin followed by autoSCT combination.

The Addition of Rituximab to Standard High Dose BEAM Chemotherapy for Autologous Stem Cell Transplant in Patients with Lymphoma Does Have a Significant Effect on Engraftment.

The addition of Rituximab to standard combination chemotherapy has significantly improved outcomes in both young and elderly patients with Non-hodgkins lymphoma (NHL). High dose chemotherapy with autologous stem cell transplant is currently the standard of care for patients with relapsed hodgkins lymphoma (HL) and NHL. However the effect of the addition of Rituximab to standard high dose chemotherapy regimen for autologous stem cell transplant on neutrophil and platelet engraftment is unknown. There are however, reported cases of neutropenia developing in patients treated with Rituximab. We performed a retrospect review of all patients with HL and NHL treated in our institution with RBEAM (Rituximab, Carmustine, Etoposide, Cytarabine, Melphalan) chemotherapy between July 2000 and June 2005 and compared it to patients receiving BEAM in the same time period. Rituximab was given at a dose of 375mg/m2 one day prior to beginning standard BEAM high dose chemotherapy. Peripheral blood was the main source of stem cells. The purpose of this study was to determine the effect of the addition of Rituximab on neutrophil and platelet engraftment. A total of 46 patients were treated during this time period. Twelve patients received RBEAM and 34 received BEAM. There was a statistical significant difference in age between the two groups. There was however no difference between the two groups in terms of race, sex and primary diagnosis. Median stem cell dose was not significantly different between the two groups. Characteristic of both groups are shown in Table: 1Characteristics of Both GroupsMedian Age (yrs)RaceDiagnosisMedian Stem Cell Dose(x10^6)AAWhiteHLNHLRBEAM50.539393.9BEAM36132117173.8P-VALUE0.010.490.20.54Neutrophil engraftment was defined as the first day of ANC > 500 on 3 consecutive days. Platelet engraftment was defined as the first day of platelet count > 20,000 with no platelet transfusion in the next seven days. The median time to neutrophil engraftment was 12 day in RBEAM compared to 11 days in BEAM (p=0.09). Platelet engraftment was however significantly delayed in patients receiving RBEAM 18days versus 12 days for BEAM (p= 0.02). Looking at both cohorts together we found that patients with HL had a significant delay in platelet engraftment compared to those with NHL (p=0.04). However there was no difference in neutrophil recovery. Although, stem cell dose affected neutrophil recovery, it had no effect on platelet engraftment. There was no increased toxicity in the early post transplant period associated with the addition of Rituximab. No bleeding complications resulted form the delay in platelet engraftment in the patients who received RBEAM. In a linear regression model the only factor that significantly affected engraftment was conditioning regimen. We conclude that the addition of Rituximab to standard high dose BEAM chemotherapy for autologous stem cell transplant has no effect on neutrophil engraftment; however platelet engraftment may be delayed. The continue use of this regimen despite the small delay in platelet engraftment will depend on whether there is any benefit, in terms of response rate, progression free and overall survival.

A Phase Ib Clinical Trial of PV701, a Milk-Derived Protein Extract, for the Prevention and Treatment of Oral Mucositis in Patients Undergoing High-Dose BEAM Chemotherapy

Despite the best available agents to prevent mucositis, most patients receiving high-dose chemoradiotherapy regimens experience severe mucositis, and new therapies are needed. In this study, we evaluated the safety and tolerability of a milk-derived growth factor extract (PV701 mouthwash) intended to prevent oral mucositis (OM) after carmustine, etoposide, cytosine arabinoside, and melphalan (BEAM) chemotherapy. PV701 mouthwash (15 mL × 13.5 mg/mL) was administered 6 times a day for 12 days, from day −6 to day +5, to patients with lymphoma, who were given BEAM on day −6 to day −2, with autologous stem cells infused on day 0. Dose de-escalation of PV701 was planned if dose-limiting toxicities occurred. The severity and duration of OM, the duration of enteral/parenteral feeding, the requirement for intravenous opiates, and admission to intensive care were recorded. Outcomes were also compared with those of historical control patients. Nine patients received PV701 13.5 mg/mL. PV701 was well tolerated, and no dose-limiting toxicities were observed. Compared with 89 historical controls, the 9 PV701-treated patients had significantly less frequent grade 2 or 3 OM ( P = .0006) and had grade ≥3 OM for an estimated 5 fewer days ( P = .0003). There was a reduction in the need for enteral/parenteral feeding ( P = .012), its duration ( P = .010), and its frequency ( P = .022) and in the duration of intravenous opiates ( P = .0006). We conclude that PV701 mouthwash is readily administered with minimal side effects at a dose of 1215 mg/d, and further investigation of this agent is warranted.

Phase I Trial of Iodine-131 Tositumomab With High-Dose Chemotherapy and Autologous Stem-Cell Transplantation for Relapsed Non-Hodgkin's Lymphoma

To determine the maximum outpatient dose of iodine-131 tositumomab (up to 0.75 Gy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem-cell transplantation (ASCT) for the treatment of chemotherapy-resistant relapsed or refractory B-cell non-Hodgkin's lymphoma (NHL). Twenty-three patients with chemotherapy-refractory or multiply-relapsed B-cell NHL were treated in a phase I trial combining iodine-131 tositumomab (ranging from 0.30 to 0.75 Gy total-body dose [TBD]) with high-dose BEAM followed by ASCT. The complete response rate after transplantation was 57%, and the overall response rate was 65%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 38 months (range, 27 to 60 months), the overall survival (OS) rate was 55%, and the event-free survival (EFS) rate was 39%. There were no significant added toxicities apparent with the addition of iodine-131 tositumomab up to a dose of 0.75 Gy TBD to high-dose BEAM chemotherapy followed by ASCT. The EFS and OS were encouraging in this group of chemotherapy-resistant or refractory B-cell NHL patients. A follow-up phase II trial with iodine-131 tositumomab at the dose of 0.75 Gy TBD with BEAM is currently ongoing.

New Directions in Radioimmunotherapy of Non-Hodgkin's Lymphoma

trial, which revealed that partial and complete remission were several times greater in the 90 Y ibritumomab tiuxetan arm (0.4 mCi/kg) than in the rituximab arm (375 mg/m 2 weekly for 4 weeks). Based on the pivotal phase III studies, 90 Y ibritumomab tiuxetan and 131 I tositumomab have been approved for the treatment of patients with relapsed or refractory low-grade follicular, or transformed CD20 + Bcell NHL, including patients with rituximab-refractory follicular NHL. A 90 Y ibritumomab tiuxetan trial in patients with rituximabrefractory disease resulted in a 74% response rate. 2 In an additional study, reduced-dose 90 Y ibritumomab tiuxetan (0.3 mCi/kg) in patients with mild thrombocytopenia had a response rate of 83%. 3 The success of RIT in NHL is due in large part to rapid and efficient binding of the MAb to lymphoma cells. Radiolabeled MAbs are especially attractive because lymphoma cells and lymphocytes are highly radiosensitive. Radiometals like 90 Y ibritumomab tiuxetan have been shown to have residualizing properties, advantageous when the MAb is localized on malignant cells, as reviewed here by DeNardo et al. Because the pivotal phase III trials were conducted in patients with < 25% NHL marrow involvement by biopsy, neither drug is approved for patients having more extensive NHL marrow disease. Monoclonal antibodies have been shown to be effective in the presence of marrow disease when “fractionated” into multiple radionuclide doses given in amounts near or at the maximum tolerated dose (MTD). 4 Training and good judgment make it feasible to use these drugs safely, perhaps even with greater safety than that associated with cancer chemotherapeutics. As reviewed by Borghaei et al, toxicities were primarily hematologic, transient, and reversible. Quality of life scores were compared between the 90 Y ibritumomab tiuxetan arm and the rituximab arm in the randomized trial. Quality of life was significantly better after 90 Y ibritumomab tiuxetan. Radioimmunotherapy does not preclude subsequent NHL treatments. Finally, an open-labeled study provided additional safety data. Emmanouilides et al analyzed the safety and efficacy of 90 Y ibritumomab tiuxetan therapy in patients aged ≥ 65 years. 5 Efficacy was not compromised in the older patients. The 90 Y ibritumomab tiuxetan regimen was not associated with the adverse events that are usually associated with chemotherapy, such as hair loss, severe mucositis, or persistent nausea or emesis. Radioimmunotherapy with hematopoietic transplantation has proven feasible and permitted dose escalation. Press et al pioneered the use of RIT in autologous hematopoietic stem cell transplantation for NHL. 6 As reviewed here by Winter, investigators at Northwestern University and the Mayo Clinic are combining 90 Y ibritumomab tiuxetan and high-dose BEAM (carmustine/etoposide/cytarabine/melphalan) chemotherapy in a phase I study that carefully doses the radioimmunoconjugate according to dosimetry. Toxicities have been similar to those reported with high-dose BEAM alone. Thus far, overall survival for all treated patients at all dose levels is 60% at 3 years, and progression-free survival is 47% at 2 and 3 years. Toxicities included mucositis, fever, and skin rash. There are many ongoing trials of ibritumomab tiuxetan with different dose schedules and dose intensities in combination with chemotherapy and autologous or allogeneic stem cell transplantation in an attempt to improve response rate and duration, and to study its effectiveness in other B-cell lymphomas, including mantle cell lymphoma and diffuse large cell lymphoma. Micallef reviews these studies here. In a phase I study of 2 sequential doses of 90 Y ibritumomab tiuxetan for relapsed low-grade B-cell NHL, MTD without prophylactic growth factor support was 0.4 mCi/kg followed by 0.2 mCi/kg. A recent trial of 90 Y ibritumomab tiuxetan for minimal residual disease in chronic lymphocytic leukemia (CLL) with < 25% bone marrow involvement revealed that 7 of 13 patients had a response. Significant cytopenias were observed. These data suggest that myelosuppression is more frequent in patients with CLL receiving 90 Y ibritumomab tiuxetan, and are similar to data for another radiolabeled MAb in CLL. 7 A recent phase II study of 90 Y ibritumomab tiuxetan for the treatment of relapsed or refractory mantle cell lymphoma by Younes et al has shown that 90 Y ibritumomab tiuxetan had clinical activity. 8 All patients had full hematologic recovery.

High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin's disease is unlikely to be associated with a major increased risk of secondary MDS/AML.

Hodgkin's disease is curable in the majority of patients, although a proportion of patients are resistant to or relapse after initial therapy. High-dose therapy with autologous stem cell support has become the standard salvage therapy for patients failing chemotherapy, but there have been reports of a high incidence of myelodysplasia/acute myeloid leukaemia (MDS/AML) following such treatment. Patients who receive such therapy form a selected group, however, who have already been subjected to other leukaemogenic factors, such as treatment with alkylating agents. In order to ascertain the true risk of MDS/AML, comparison must be made with other patients subjected to the same risks but not undergoing transplantation. We report a retrospective comparative study of 4576 patients with Hodgkin's disease from the BNLI and UCLH Hodgkin's databases, which includes 595 patients who have received a transplant. Statistical analysis including Cox's proportional hazards multivariate regression model with time-dependent covariates was employed. This analysis reveals that the risk of developing MDS/AML was dominated by three factors, namely quantity of prior therapy (relative risk [RR] 2.01, 95% confidence intervals [CI] 1.49–2.71, for each treatment block, P < 0.0001) and whether the patient had been exposed to MOPP (RR 3.61, 95% CI 1.64–7.95, P = 0.0009) or lomustine chemotherapy (RR 4.53, 95% CI 1.96–10.44, P = 0.001). Following adjustment for these factors in the multivariate model the relative risk associated with transplantation was 1.83 (95% CI 0.66–5.11, P = 0.25). This study provides no evidence of a significantly increased risk of MDS/AML associated with BEAM therapy and autologous transplantation in Hodgkin's disease. Concern over MDS/AML should not mitigate against the timely use of this treatment modality. © 1999 Cancer Research Campaign

Epic as an Effective, Low Toxicity Salvage Therapy for Patients with Poor Risk Lymphoma Prior to Beam High Dose Chemotherapy and Peripheral Blood Progenitor Cell Transplantation

We treated 33 patients with relapsed or refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD) with a combination of etoposide, prednisolone, ifosfamide and car-boplatin (EPIC). After a median of two courses (range 1–5) complete response was achieved in 7 (22%) patients and partial response in 12 (37%) patients, an overall response rate of 59%. The regimen was well tolerated with myelosuppression being the most common toxicity. There were no toxic deaths. 25 (78%) patients were able to proceed to high dose therapy (BEAM) with peripheral blood progenitor cell transplantation either immediately post EPIC or following further salvage therapy. Most patients mobilised peripheral blood progenitor cells well and 24 out of 25 patients subsequently undergoing autologous transplantation had rapid regeneration of counts. EPIC is an effective salvage therapy in the majority of patients with relapsed or refractory lymphoma and does not appear to be toxic to stem cells. Although severe, myelosuppression is of short duration and the generally low toxicity enables patients lo procccd lo successful peripheral blood stem cell harvest and transplantation.

Eruptive lichen planus predictive of diabetes mellitus

In the present article we describe a patient with AIDS and chylous ascites secondary to B-cell non Hodgkin's lymphoma.A 43 years old homosexual HIV-positive man. Complained of abdominal fullness, diarrhea and a rapidly increase in abdominal girth of 1 week duration.A diagnostic paracentesis was performed and revealed a milky fluid with high triglyceride levels.All blood tests and analysis of the peritoneal fluid with polymerase chain reaction for DNA sequence of broad-range bacterial Post Voiding Residual volume, Mycobacterium tuberculosis, Kaposi Sarcoma associated Herpes virus and Epstein Barr Virus were negative. CT scan did not demonstrate any evidence for cancer.An exploratory laparotomy was thus performed. A mass spreading along the mesenteric route to the omentum was found and a debulking resection was performed. The final pathology report was of diffuse, CD20-positive, CD3-negative, Epstein Barr Virus-negative, large B-Cell non Hodgkin's lymphoma. Subsequently, he underwent five cycles of CHOP (cyclofosfamide, doxorubicin, vincristin, prednison) chemotherapy with further partial regression of the abdominal tumour. Five months after the initial diagnosis of lymphoma, the patient relapsed and was treated with high-dose BEAM (carmustine, etoposide, cytosine, arabinoside, melphalan) chemotherapy followed by CD34 stem-cell transplantations salvage therapy. This notwithstanding, the patient died due to intestinal secondary to tumor relapse 2 months later.

Impact of high-dose salvage therapy (BEAM) on overall survival in younger patients with advanced large-cell lymphomas entered into BNLI trials

The survival of two cohorts of patients with stage III/IV large-cell lymphomas treated by CHOP has been compared. In the first cohort of 88 patients (1974-1982), high-dose therapy with autologous bone marrow transplantation (ABMT) was not available as salvage therapy and in the second cohort of 87 patients (1987-1992), this was the recommended salvage for patients with disease that was still chemosensitive to conventional-dose therapy. The actuarial overall survivals at five years were 40% and 44% in the first and second cohorts, respectively, indicating that the availability of ABMT had made little impact. Of the 62 patients in the second cohort who failed CHOP therapy, 8 died before second-line chemotherapy could be given, 1 refused more therapy, and 8 were considered unsuitable for further combination chemotherapy. Seven patients with localized disease remaining received local radiotherapy. Of the 38 patients given salvage therapy, 14 had chemoresistant disease. Only 9 patients received high-dose BEAM chemotherapy and ABMT, and 7 remain disease-free. ABMT was restricted to a highly select patient group, and as a result more widespread application of this strategy might result in only a modest further improvement.

The Place of High-Dose BEAM Therapy and Autologous Bone Marrow Transplantation in Poor-Risk Hodgkin's Disease. A Single-Center Eight-Year Study of 155 Patients

Although high-dose chemotherapy and autologous bone marrow transplantation (ABMT) are increasingly being used for the treatment of relapsed and resistant Hodgkin's disease, there have been few large, single-center studies reported with adequate follow-up to allow full evaluation of this therapeutic modality. We present 155 poor-risk Hodgkin's disease patients who received high-dose BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) chemotherapy and ABMT who have been studied over a period of 8 years. All patients had either not attained a remission on mechlorethamine, vincristine, procarbazine, prednisone-type therapy and had poor prognostic features at presentation, not attained a complete remission or relapsed within 1 year of an initial alternating regimen, or not attained remission with two or more lines of treatment. At the time of ABMT the relapse status of the patients was as follows: 46 patients were primarily refractory to induction therapy, 7 were good partial responders, 52 were in first relapse, 37 in second relapse, and 13 in third relapse. Seventy-eight patients had chemoresistant disease, 33 had chemosensitive disease at the time of ABMT, and 44 were untested for chemosensitivity at latest relapse. The procedure related mortality in the first 90 days post-ABMT of 10% overall. At 3 months 43 patients (28%) were assessed as complete responders, 72 patients had a partial response (46%), and 24 patients (16%) had no response or progression of disease. However, by 6 months, 53 (24%) patients were assessed as complete responders and 51 (33%) patients had nonprogressive disease. Forty-five patients had received radiotherapy post-ABMT to residual masses (41 patients) or to previous sites of bulk disease (4 patients). The actuarial overall and progression-free survival at 5 years was 55% and 50%, respectively. On multivariate analysis patients with bulk (masses > 10 cm), heavily pretreated patients (those receiving three or more lines of treatment) and females had a significantly poorer prognosis. Relapse status was also significant for progression-free survival in that patients in second (60%) and third relapse (70%) had a better prognosis than those in first relapse (44%) or with primary refractory disease (33%). Response to prior chemotherapy did not predict for progression-free survival. These results enable comparisons to be made between high-dose chemotherapy with ABMT and conventional dose salvage therapy. Furthermore, although the results as a whole are highly encouraging, certain groups carry an unfavorable prognosis.

The place of high-dose BEAM therapy and autologous bone marrow transplantation in poor-risk Hodgkin's disease. A single-center eight- year study of 155 patients

Although high-dose chemotherapy and autologous bone marrow transplantation (ABMT) are increasingly being used for the treatment of relapsed and resistant Hodgkin's disease, there have been few large, single-center studies reported with adequate follow-up to allow full evaluation of this therapeutic modality. We present 155 poor-risk Hodgkin's disease patients who received high-dose BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) chemotherapy and ABMT who have been studied over a period of 8 years. All patients had either not attained a remission on mechlorethamine, vincristine, procarbazine, prednisone-type therapy and had poor prognostic features at presentation, not attained a complete remission or relapsed within 1 year of an initial alternating regimen, or not attained remission with two or more lines of treatment. At the time of ABMT the relapse status of the patients was as follows: 46 patients were primarily refractory to induction therapy, 7 were good partial responders, 52 were in first relapse, 37 in second relapse, and 13 in third relapse. Seventy-eight patients had chemoresistant disease, 33 had chemosensitive disease at the time of ABMT, and 44 were untested for chemosensitivity at latest relapse. The procedure related mortality in the first 90 days post-ABMT of 10% overall. At 3 months 43 patients (28%) were assessed as complete responders, 72 patients had a partial response (46%), and 24 patients (16%) had no response or progression of disease. However, by 6 months, 53 (24%) patients were assessed as complete responders and 51 (33%) patients had nonprogressive disease. Forty-five patients had received radiotherapy post-ABMT to residual masses (41 patients) or to previous sites of bulk disease (4 patients). The actuarialoverall and progression-free survival at 5 years was 55% and 50%, respectively. On multivariate analysis patients with bulk (masses &gt;10 cm), heavily pretreated patients (those receiving three or more lines of treatment) and females had a significantly poorer prognosis. Relapse status was also significant for progression-free survival in that patients in second (60%) and third relapse (70%) had a better prognosis than those in first relapse (44%) or with primary refractory disease (33%). Response to prior chemotherapy did not predict for progression-free survival. These results enable comparisons to be made between high-dose chemotherapy with ABMT and conventional dose salvage therapy. Furthermore, although the results as a whole are highly encouraging, certain groups carry an unfavorable prognosis.