Successful Salvage with High-Dose Sequential Chemotherapy Coupled with In Vivo Purging and Autologous Stem Cell Transplantation in 2 Patients with Primary Refractory Mantle Cell Lymphoma Presenting in the Leukemic Phase

We report the results of an aggressive salvage regimen in 2 patients with advanced-stage leukemic-phase mantle cell lymphoma who were refractory to previous conventional therapies. We combined multiple phases of a cytoreductive regimen including rituximab and sequential high-dose treatment with autologous stem cell transplantation (ASCT). The regimen consisted of a debulking phase with fludarabine, idarubicin, high-dose cytarabine, and high-dose methotrexate; a mobilization and in vivo purging phase with rituximab, cyclophosphamide, and granulocyte colony-stimulating factor; high-dose sequential chemotherapy with etoposide, mitoxantrone, and melphalan followed by ASCT; and, finally, posttransplantation consolidation with rituximab for treatment of minimal residual disease. With this regimen, these 2 refractory patients with multiple poor prognostic factors are in complete remission at 41 and 42 months following transplantation. Although the fact that these 2 patients are still in remission beyond 3 years after ASCT is encouraging, we need a longer follow-up to comment on their long-term survival.     

Autologous stem cell transplantation in follicular non-Hodgkin's lymphoma

The failure of conventional chemotherapy to improve overall survival rates in follicular non-Hodgkin's lymphoma (NHL) has led to the development of alternative treatment regimens. One such regimen is high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT). In ASCT stem cells, harvested predominantly from peripheral blood, are used to repopulate the haemopoietic system after high-dose chemotherapy. Comparison of failure-free survival rates following ASCT, with those previously obtained with conventional chemotherapy, suggests a benefit for ASCT in patients who have previously responded to chemotherapy. Other factors that adversely influence the outcome of ASCT include large tumour burden and bcl-2 overexpression. Although ASCT in follicular NHL can prolong the period of remission, relapse is still common and can be caused either by contamination of the stem cell harvest with tumour cells, or regrowth of residual malignant cells not eradicated by the high-dose chemotherapy. Several strategies have been developed to reduce the rate of relapse, including in vitro purging of the stem cell product to remove tumour cells and using allogenic stem cells from HLA-matched donors with no history of malignant disease. While both these methods may have some benefit, they also have limitations. In vitro purging is labour intensive, costly and, as yet, the effect on relapse is unclear. Allogenic stem cell transplants have been associated with a reduced risk of relapse, but this is offset by increased transplant-related mortality. The most promising strategy to reduce the rate of relapse following ASCT is in vivo purging using rituximab, a monoclonal antibody to CD20. Rituximab mobilises mechanisms to kill lymphoma cells, and causes a rapid depletion of B cells from peripheral blood. Rituximab has demonstrated good efficacy as monotherapy in patients with both aggressive and indolent lymphoma and has shown very high response rates (>95%) when used in combination with HDT.     

Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen)

Mantle cell lymphoma (MCL) is rarely cured with standard-dose chemotherapy. From January 1997 to February 2000, 28 previously untreated advanced-stage MCL patients younger than 61 years of age were treated at 9 Italian hematologic departments with 3 cycles of standard-dose debulking chemotherapy followed by a high-dose rituximab-supplemented sequence (R-HDS) including intravenous administration of high-dose cyclophosphamide, high-dose cytarabine, high-dose melphalan, and high-dose mitoxantrone plus melphalan. Study end points included toxicity, clinical and molecular response rates, long-term event-free survival (EFS), and overall survival (OS) rates, as well as the ability to harvest tumor-free peripheral blood stem cells. Optimal amounts of polymerase chain reaction-negative (PCR-negative) CD34+ cells were collected from all 20 informative patients. One patient died of toxicity. All 27 patients assessable for response achieved a complete response (CR), of which 24 remain in continuous complete remission (CCR) after a median follow-up of 35 months. Three patients had transient evidence of PCR-detectable disease in the bone marrow. The OS and EFS rates at 54 months were 89% and 79%, respectively. These results compare with the 42% OS rate and the 18% EFS rate observed in 35 age-matched historic controls treated with standard-dose chemotherapy at the participating centers. The use of rituximab in combination with high-dose chemotherapy represents a very effective in vivo purging method. The R-HDS regimen can be safely applied in a multicenter hematology setting and leads to long-term EFS and OS in the majority of patients with an otherwise incurable disease.     

Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion

Elimination of tumor cells ("purging") from hematopoietic stem cell products is a major goal of bone marrow-supported high-dose cancer chemotherapy. We developed an in vivo purging method capable of providing tumor-free stem cell products from most patients with mantle cell or follicular lymphoma and bone marrow involvement. In a prospective study, 15 patients with CD20(+) mantle cell or follicular lymphoma, bone marrow involvement, and polymerase chain reaction (PCR)-detectable molecular rearrangement received 2 cycles of intensive chemotherapy, each of which was followed by infusion of a growth factor and 2 doses of the anti-CD20 monoclonal antibody rituximab. The role of rituximab was established by comparison with 10 control patients prospectively treated with an identical chemotherapy regimen but no rituximab. The CD34(+) cells harvested from the patients who received both chemotherapy and rituximab were PCR-negative in 93% of cases (versus 40% of controls; P =.007). Aside from providing PCR-negative harvests, the chemoimmunotherapy treatment produced complete clinical and molecular remission in all 14 evaluable patients, including all 6 with mantle cell lymphoma (versus 70% of controls). In vivo purging of hematopoietic progenitor cells can be successfully accomplished in most patients with CD20(+) lymphoma, including mantle cell lymphoma. The results depended on the activity of both chemotherapy and rituximab infusion and provide the proof of principle that in vivo purging is feasible and possibly superior to currently available ex vivo techniques. The high short-term complete-response rate observed suggests the presence of a more-than-additive antilymphoma effect of the chemoimmunotherapy combination used.     

Safety and feasibility of CHOP/rituximab induction treatment followed by high-dose chemo/radiotherapy and autologous PBSC-transplantation in patients with previously untreated mantle cell or indolent B-cell-non-Hodgkin's lymphoma

Patients with no prior chemotherapy and with advanced and progressive follicular lymphoma (FCL) or mantle cell lymphoma (MCL) were enrolled into a treatment protocol combining CHOP/rituximab-CHOP therapy with subsequent consolidation high-dose therapy (HDT) to evaluate the safety and feasibility of this treatment. Overall, 15 patients were enrolled and 13 patients completed the entire treatment protocol without major toxicities or increased infectious complications. One patient withdrew consent after achieving complete remission (CR) prior to HDT. One patient was taken off study with signs of disease progression after induction treatment. All patients showed stable engraftment after HDT. Response rates appear to be favorable, indicating an additional effect of rituximab and HDT. Overall, 12 of 13 patients achieved CR/CRu and one patient partial remission. Follow-up of immune reconstitution displayed transient severe combined immunodeficiency with slow normalization of the cellular and humoral compartments without a significant increase of infectious complications. Taken together, high-dose chemotherapy can be safely given following treatment with CHOP+rituximab. Efficacy in this small cohort of patients was encouraging with sustained remissions in both FCL and MCL patients. Upfront HDT should be considered as a therapeutic option especially in young and/or high-risk patients.     

Role of hematopoietic stem cell transplantation for advanced-stage diffuse large cell B-cell lymphoma-B

The prognosis of patients with relapsed or refractory diffuse large cell B-cell lymphoma-B (DLCL-B) is poor with conventional salvage chemotherapy; therefore, high-dose therapy (HDT) combined with autologous stem cell transplant (ASCT) has become the treatment of choice for these patients. The outcomes of transplant are better in patients with chemosensitive relapse: those with a longer duration of first remission (>12 month) and those with an age-adjusted low-risk International Prognostic Index (IPI) at relapse. Several high-dose regimens with or without total body irradiation (TBI) have been used with similar outcomes. Relapse remains the most common cause of treatment failure, and thus the use of radioimmunotherapy (RIT) in the high-dose regimens and incorporation of rituximab in the transplant setting have been explored. Several studies have shown that RIT both at conventional dose and at high dose can be given in combination with high-dose chemotherapy regimens without additional toxicity or delay in hematopoietic recovery after ASCT. Additional studies using RIT in combination with high-dose chemotherapy and ASCT are ongoing, and preliminary results suggest that these approaches may be superior to conventional high-dose regimens. Since rituximab is an effective therapy for B-cell non-Hodgkin's lymphoma and given its limited toxicity, rituximab has been incorporated into HDT and ASCT for DLCL-B as in vivo purging, as part of high-dose regimens, and as maintenance therapy to prevent relapse. Preliminary results suggested that rituximab during ASCT and as maintenance therapy post-transplant reduces the risk of relapse and improves survival; however, these results need to be confirmed in phase III randomized trials. The role of ASCT during first remission as consolidative therapy in patients with DLCL-B remains controversial and should not be performed outside of the clinical trial setting. Allogeneic stem cell transplant (allo-SCT) for patients with relapsed DLCL-B is associated with significant toxicity and should be reserved for patients who relapse after ASCT or those with persistent marrow involvement. Innovative approaches are needed for primary refractory and chemoresistant relapsed DLCL-B since these patients have very poor outcomes after ASCT.     

Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL

The purpose of this study was to evaluate feasibility and efficacy of Rituximab included into a sequential salvage protocol for CD20(+) B-NHL in relapse or induction failure. Twenty-seven patients with CD20(+) B-NHL in relapse or induction failure received Rituximab combined with DexaBEAM (R-DexaBEAM) for stem cell mobilization. Additional ex vivo selection of CD34-positive cells was performed using the CliniMacs device. Two doses of Rituximab were included in the high-dose therapy regimen (HDT). R-DexaBEAM was well tolerated and 26 of 27 patients mobilized sufficient numbers of CD34(+) blood stem cells. Application of R-DexaBEAM resulted in significant depletion of peripheral B cells. No treatment-related deaths occurred after HDT and all patients showed stable engraftment of hematopoesis. Combined immunodeficiency was observed post HDT and eight patients developed CMV antigenemia. Remission rate post HDT was 96% (CR, 24/26; PR, 1/26). Overall and progression-free survival (PFS) at 16 months post HDT (range 6-27) is 95% and 77%, respectively. With regard to histology, PFS was 71% in aggressive lymphoma (n = 11), 74% in indolent FCL (n = 10) and 100% in MCL (n = 5). The treatment protocol has proven feasible, with high purging efficiency and encouraging remission rates.     

High-dose therapy supported with immunomagnetic purged autologous bone marrow in high-grade B cell non-Hodgkin's lymphoma.

From August 1987 to March 1995, 25 patients with high-grade B cell non-Hodgkin's lymphoma (NHL) were treated with high-dose therapy (HDT) followed by bone marrow purged with immunomagnetic beads. At the time of transplantation, 20 patients were in sensitive relapse and five in first complete or partial remission. Ten patients had secondary high-grade NHL transformed from low-grade NHL. The HDT consisted of TBI followed by high-dose cyclophosphamide. All patients engrafted, except for two patients with early treatment-related death. Eleven patients relapsed, of whom nine died of lymphoma, and two are alive in new CR. The estimated event-free and overall survivals at 5 years were 40% and 48%, respectively, with a median follow-up of 48 months (range 1-123). Eight of the tumours contained the translocation t(14;18) at the major breakpoint region (MBR) of BCL-2. In these patients the presence of tumour cells in the bone marrow graft before and after purging were assessed by PCR. Four of five patients infused with non-detectable minimal residual disease in their autografts are in complete remission, while two of three patients reinfused with t(14;18) positive cells after purging, experienced a fast and aggressive relapse. As found by others, our data suggest that reinfusion of tumour-free autografts obtained by efficient in vivo purging using chemotherapy before harvesting, and/or by in vitropurging of the stem cell products, influence the patients remission status after HDT.     

Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group

Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.     

Rituximab retherapy in patients with relapsed aggressive B cell and mantle cell lymphoma

Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pre-treated patients with relapsing aggressive lymphoma. We report here a single-centre retrospective outcome analysis of second-line immunochemotherapy with rituximab. In 28 patients with relapsed or refractory diffuse large B cell lymphomas, first-line immunochemotherapy had induced objective responses in 18 patients. Nine of 28 patients responded to rituximab containing salvage therapy, leading to a median overall survival of 243 days after start of second immunochemotherapy. Long-term disease free survivors (1,260 and 949 days) were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy. In 21 patients with relapsed mantle cell lymphomas (MCL), 19 patients had reached remissions with first-line therapy. Of those, 16 patients experienced responses to salvage therapy with a median overall survival of 226 days. Noteworthy, none of patients with initial non-responding disease reached a remission with second immunochemotherapy. Seven patients with MCL stayed free from progression after high-dose therapy with autologous or allogeneic stem cell transplantation in two and five cases, respectively. In summary, responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma, respectively, but not in primarily refractory disease. Lasting remissions were achieved only by high-dose chemotherapy with stem cell transplantation.     

In vivo purging and relapse prevention following ASCT

The combination of high-dose chemotherapy and autologous stem cell transplantation (ASCT) is a potentially curative therapy for patients with relapsed chemosensitive non-Hodgkin's lymphoma (NHL) and is increasingly being considered as a first-line treatment for NHL patients with poor prognosis or poor outcomes from chemotherapy. However, there is a degree of relapse following the latter which is associated with high levels of tumour cell contamination of the stem cells and/or the presence of residual malignant cells in the host following chemotherapy. Reducing the rate of relapse can be achieved by pre-transplant purging of the stem cell graft followed by post-transplant maintenance to minimise residual disease. Various methods of in vitro purging have been shown to reduce, but not eliminate, the level of stem cell contamination and invariably result in a reduced harvest. To date, this has been reflected in disappointing outcomes for the patient. In contrast, in vivo purging with rituximab during the process of stem cell mobilisation and collection does not adversely affect the yield or function of stem cells and shows a significant improvement in the level of tumour cell contamination as measured by bcl-2 clearance. The relapse potential from residual malignant cells in the host can be addressed by a programme of post-transplant rituximab maintenance therapy. In one study 17 patients with follicular lymphoma who underwent ASCT with in vivo rituximab-purged stem cells, followed by rituximab maintenance, have all remained in complete response at a median follow-up of 12.4 months. The optimum in vivo rituximab purging protocol and the precise effect in terms of overall and disease-free survival are currently being evaluated but appear to present an attractive first-line alternative for NHL patients with poor prognosis or poor outcomes following chemotherapy.     

High dose chemotherapy with autologous stem cell support for patients with histologically transformed B-cell non-Hodgkin lymphomas. A Norwegian multi centre phase II study

We present a prospective phase II study of patients with relapse after chemotherapy showing transformation of follicular lymphoma to diffuse large B-cell lymphoma, performed before rituximab was included in standard treatment. Patients in complete (CR) or partial remission (PR) after salvage chemotherapy were eligible for high-dose chemotherapy with autologous stem cell support (HDT). Forty-seven patients from five Norwegian centres were included, of whom 30 (63%) received HDT. Eighteen (60%) achieved CR, seven (23%) PR and five (10%) had progressive disease following HDT. Median follow-up for the surviving patients was 75 months; median progression-free (PFS) and overall survival (OS) were 26 and 47 months, respectively. Median OS for all patients was 43 months, compared to only 10 months for patients not eligible for HDT. Patients receiving CD34(+) enriched/B-cell depleted grafts had inferior PFS and a trend for inferior OS compared to patients receiving non-purged grafts (Log Rank 0·025 and 0·151, respectively). In conclusion, two thirds of patients with transformation of follicular lymphoma were eligible for HDT. The majority of patients achieved CR and a considerable number had prolonged OS. The use of in vitro purged grafts did not result in a survival benefit compared to that of non-purged grafts.     

Primary treatment with autologous stem cell transplantation in mantle cell lymphoma: outcome related to remission pretransplant

OBJECTIVES: The aim of the first Nordic mantle cell lymphoma (MCL) protocol was to study the clinical significance of an augmented CHOP induction chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT) and to examine the prognostic significance of stem cell contamination rates in newly diagnosed patients with MCL. PATIENTS AND METHODS: Forty-one newly diagnosed patients below 66 yr were enrolled and given three series of an augmented CHOP regimen. Responders underwent stem cell mobilization with a fourth course of CHOP, stem cell harvest and ASCT. Stem cell purging was optional in the protocol and followed the routine of each participating centre. The number of tumour cells in the reinfused autografts was estimated by flow cytometry or quantitative PCR. RESULTS: Induction therapy led to complete remission (CR) in 11 of 41 patients (27%), partial remission (PR) in 20 of 41 patients (49%) and no response in nine patients (22%), whereas one patient was not evaluable. Twenty-seven of the 31 responders underwent ASCT and 24 achieved or maintained a CR. The overall and failure-free 4-yr survival on intention-to-treat basis were 51% and 15%, respectively. Among the transplanted patients, a significantly increased failure-free (P<0.03) and overall survival (P=0.03) was noted among patients transplanted in CR compared with PR, respectively. By contrast, reinfusion of highly variable numbers of tumour cells with the autografts (range 0.71-80 x 10(6) tumour cells), did not affect outcome. CONCLUSION: In MCL, an important strategy to improve the outcome will be to intensify the induction chemotherapy.     

High-dose Ara-C and beam with autograft rescue in R-CHOP responsive mantle cell lymphoma patients

Mantle cell lymphoma (MCL) has a dismal outcome when treated with conventional chemotherapy. This single arm phase 2 study evaluated intensive consolidation treatment of patients with newly diagnosed MCL up to the age of 65 years, responsive to R-CHOP (rituximab, cyclophosphamide, oncovin, adriamycin, prednisolone). Endpoints for evaluation were toxicity, failure-free survival (FFS) and overall survival (OS). Eighty-seven patients were treated with three cycles of R–CHOP. Sixty-six patients responded to R-CHOP with at least a partial response, 62 continued protocol treatment with high-dose cytarabine (Ara-C; 2000 mg/m², bid. over 4 d) and 61 patients received rituximab and stem cell harvest, followed by BEAM (carmustine, etoposide, Ara-C, melphalan) and autologous stem cell rescue. Non-haematological toxicity, grades III and IV, was seen in 8% of the patients after R-CHOP, in 22% after high-dose Ara-C and in 55% after BEAM. The overall response rate was 70% (complete response rate 64%, partial response rate 6%), FFS and OS at 4 years were 36 ± 7% and 66 ± 6%, respectively. The FFS and OS at 4 years from the evaluation after BEAM in the 61 R-CHOP responsive patients was 46 ± 9% and 79 ± 7%, respectively. In conclusion, high-dose Ara-C and BEAM with stem cell rescue in newly diagnosed MCL patients responsive to R-CHOP is a manageable treatment with respect to toxicity. This regimen leads to long-term, but probably not durable, remissions.     

Long-term follow up of sequential mobilisation and autologous transplantation with CD34-selected cells in multiple myeloma: a multimodality approach

BACKGROUND: Even after high dose chemotherapy (HDT) and autologous haemopoietic stem cell transplantation, the majority of patients with multiple myeloma eventually relapse. Aim: The aim of the present study was to study the -feasibility and outcome of delivering a regimen including in vivo and in vitro purging and double HDT in patients with multiple myeloma. METHODS: Thirty-four patients with advanced multiple myeloma were enrolled in a program of vincristine, doxorubicin and dexamethasone chemotherapy, high dose cyclophosphamide/granulocyte macrophage colony stimulating factor (GM-CSF) stem cell mobilisation, CD34 selection of harvested stem cells (in vitro purging), double HDT (cyclophosphamide/epirubicin in the first, busulphan/melphalan in the second) rescued by CD34(+)-selected cells, the second rescue using cells harvested following the first HDT (in vivo purging) and interferon maintenance. RESULTS: Forty-four per cent of patients completed the program. Fifty-three per cent of withdrawals were as a result of insufficient stem cells. This correlated to previous chemotherapy. Therapy-related mortality was 6%. CD34(+) selection achieved more than a 2-log reduction of CD38(++) cells; in vivo purging achieved 80%. Although similar numbers of CD34(+) cells were reinfused at both HDT, platelet recovery was slower after the second HDT. Additional complete remissions were achieved after each phase of therapy, 3% at the end of vincristine, doxorubicin and dexamethasone and 33% after completing planned HDT. Factors associated with longer overall survival included age less than 60 years (P = 0.044), serum beta-2-microglobulin below 3 micro gamma/L at entry (P = 0.042) and less than 2 months between the two HDT (P = 0.024). The only factor associated with a longer event-free survival was less than 2 months between HDT on study (P = 0.038). CONCLUSIONS: (i) dose intensification with two HDT delivered within 2 months might be associated with a better patient outcome, (ii) early mobilisation should be incorporated in multiple myeloma HDT programs and (iii) higher CD34(+) doses may be required for tandem transplants.     

A phase II clinical trial of intensive chemotherapy followed by consolidative stem cell transplant: long-term follow-up in newly diagnosed mantle cell lymphoma

Mantle cell lymphoma (MCL) is associated with high relapse rates and poor survival when treated with conventional chemotherapy, with or without rituximab. We report the long-term follow-up of a phase II clinical trial using a new intensive multiagent chemotherapeutic regimen [cyclophosphamide, teniposide, doxorubicin and prednisone (CTAP) alternating with vincristine and high-dose methotrexate and cytarabine (VMAC)] in newly diagnosed MCL. Following 4–6 cycles of CTAP/VMAC induction, patients aged ≤65 years proceeded to consolidative autologous haematopoietic stem cell transplantation (auto-HSCT), while patients ≤55 years who had a HLA-identical sibling received allogeneic-HSCT (busulfan/cyclophosphamide conditioning for both). Twenty-five untreated MCL patients enrolled on the protocol between 1997 and 2002. Among evaluable patients, overall response rate (ORR) was 74% following induction chemotherapy. Seventeen patients received HSCT (autologous-13/allogeneic-4). On intent-to-treat analysis, ORR for patients who received consolidative HSCT was 100% (complete remission 76%). Therapy was well-tolerated with 4% treatment-related mortality (including HSCT). The 5-year event-free-survival (EFS) and overall survival (OS) for all patients was 35% and 50% respectively. Furthermore, at 66-months median follow-up, the 5-year EFS and OS for patients who received consolidative auto-HSCT was 54% and 75% respectively. Patients who received auto-HSCT had improved outcomes compared to no auto-HSCT (EFS P  = 0·001; OS P  = 0·0002). CTAP/VMAC induction followed by consolidative auto-HSCT for newly diagnosed MCL is associated with high ORR and durable survival.     

Autologous stem cell transplantation in lymphoma

High-dose therapy (HDT) followed by autologous transplantation of hematopoietic stem cells (ASCT) is frequently performed in patients with lymphoma. For many subentities, reliable results from prospective randomized studies are missing. In Hodgkin's disease (HD), HDT/ASCT is a standard indication for patients with chemosensitive first relapse. Patients with indolent or aggressive B-cell lymphoma may benefit from HDT/ASCT if considered as part of first-line therapy or at the time of relapse. However, new randomized studies comparing HDT/ASCT with optimal chemoimmunotherapy are necessary because the introduction of monoclonal antibodies (rituximab) significantly improved the results of conventional chemotherapy. Because data on patients with less frequent entities like mantle cell lymphoma, T-cell lymphoma, Burkitt's lymphoma, or lymphoblastic lymphoma are insufficient, the role of HDT/ASCT needs further study.     

Evolving treatment strategies in mantle cell lymphoma

Mantle cell lymphoma is an incurable, moderately aggressive B cell lymphoma. While a small proportion of patients with indolent disease can be managed expectantly, most patients require treatment. The therapeutic approach is driven by physician recommendation, patient choice, age, fitness and comorbidities. Young, fit patients often receive combination chemoimmunotherapy, including high dose cytarabine, with autologous stem cell transplant. Recent data has indicated benefit from maintenance rituximab following autologous stem cell transplant. Ongoing trials are investigating combinations of chemotherapy and targeted agents as well as the role of minimal residual disease guided therapy. Older, less fit patients often receive bendamustine and rituximab or anthracycline based regimens. Maintenance rituximab is typically administered in older MCL patients after anthracycline based chemotherapy although its use after bendamustine based therapy is not supported by current data. Current trials focus on refining this regimen with the addition of targeted agents. In the relapsed and refractory setting, novel agents have demonstrated activity although durability of responses remains unsatisfactory.     

A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma

The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- s.d.) were 65 +/- 16 and 63 +/- 15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86 +/- 14 and 82 +/- 15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.     

Adjuvant rituximab causes prolonged hypogammaglobulinaemia following autologous stem cell transplant for non-Hodgkin's lymphoma

Rituximab is an anti-CD20 monoclonal antibody that has efficacy in B-cell non-Hodgkin's lymphoma (NHL). Adjuvant immunotherapy with rituximab may reduce relapse rates for high-risk B-cell NHL following high-dose chemotherapy with autologous stem cell transplantation (SCT). However, the potential adverse effects of rituximab on immune reconstitution following SCT are not fully characterized. We performed a retrospective analysis of immunoglobulin (Ig) levels and peripheral blood neutrophil counts in 11 patients who received adjuvant rituximab following autologous SCT for B-cell NHL. Results were compared to a contemporaneous group of 24 patients who received an identical conditioning regimen and autologous SCT for lymphoma, but no adjuvant rituximab. Adjuvant rituximab was associated with a significantly increased incidence of hypogammaglobulinaemia between 12 and 24 months post-SCT, but not neutropenia. Despite suppression of Igs, there were no late or atypical infective complications attributable to rituximab.