Treatment Of Indolent Lymphoma Research Articles

Treatment of indolent lymphoma.

Treatment of indolent lymphoma has improved significantly in recent decades since the advent of rituximab (anti-CD20 monoclonal antibody). Although, some patients with limited disease can be cured with radiation therapy alone, most patients experience disease progression and recurrence during follow-up despite early initiation of treatment. Thus, watch-and-wait is still regarded the standard for asymptomatic patients. Patients with indolent lymphoma have a significant heterogeneity in terms of tumor burden, symptoms (according to anatomical sites) and the need for instant therapy. Therefore, the initiation of treatment and treatment option should be decided with a clear goal in each patient according to the need for therapy and clinical benefits with the chosen treatment. In this review, we cover the current treatment of follicular lymphoma and marginal zone lymphoma.

Metabolic Tumor Volume and Total Lesion Glycolysis Can Predict Response to Very Low Dose Radiotherapy (4 Gy) in Indolent B-Cell Lymphomas

Numerous studies have established the role of very low dose radiotherapy (VLDRT), only 4 Gy in 2 fractions, in the management of indolent non-Hodgkin's lymphoma (NHL). While objective response rates to VLDRT are excellent, there are no widely accepted biomarkers of the depth and the durability of response after VLDRT. Radiosensitivity to VLDRT is not clearly linked to clinical features, such as tumor grade, histology, prior treatments or [18F]-FDG-PET standardized uptake values (SUV). Our group has recently demonstrated that pre-treatment tumor size greater than 6 cm may predict suboptimal response to VLDRT; however, this remains an imperfect predictor, and the majority of patients selected for VLDRT have lesions smaller than 6 cm. [18F]-FDG-PET metrics like baseline metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are shown to stratify patient response to chemotherapy for some NHLs, but neither has been shown to predict radiotherapy response to VLDRT. Therefore, we aimed to determine if these features could predict response to VLDRT in indolent B-cell NHLs.Between 2005 and 2018, 250 patients with follicular or marginal zone lymphoma were locally irradiated to 299 sites using 2 Gy x2. Response was assessed within 1.5-6 months of VLDRT (n=231), and local failure (LF) was assessed over a median follow-up of 29 months. Out of the 299 treated sites, 254 (85%) had a corresponding [18F]-FDG-PET/CT scan performed prior to radiotherapy. PET scans were imported into MIM, a radiotherapy contouring and planning software program, and pre-radiotherapy disease was manually defined. A uniform expansion of 0.5 cm was performed to define a larger region of interest containing the contoured lesion but accounting for technical variability in defining the tumor edges. Of the 254 lesions, 207 (81%) had a maximum SUV (SUVmax) greater than 2.5 and were considered for further analysis. PET parameters were obtained using an SUV of 2.5 as a cutoff for MTV (MTV2.5) and TLG (TLG2.5), which capture lesion bulk, and using 41% of the SUVmax as a cutoff for MTV (MTV41%) and TLG (TLG41%), which capture the most metabolically active parts of a lesion. Maximum lesion size was analyzed using 4 cm and 6 cm as predetermined cutoffs. Lesion response was analyzed using multivariate logistic LASSO regression to account for predictor multicollinearity, and receiver operating characteristic curve analysis to obtain estimates of the area under the curve (AUC). To analyze time to LF, we performed Cox proportional hazards multivariate regression using stepwise selection. PET parameters were divided in quartiles to aid in interpretability. Estimates are shown with 95% confidence intervals.A complete response (CR) was seen in 156 (68%) lesions and LF was seen in 81 (27%) lesions after VLDRT. Using size alone had similar predictive value for response (AUC: 0.57(0.49-0.65) compared to MTV2.5 (AUC:0.66 (0.57-0.74)), MTV41% (AUC:0.64 (0.56-0.73)), TLG2.5 (AUC:0.64 (0.54-0.74)), and TLG41% (AUC:0.64 (0.54,0.75)). Through LASSO logistic regression, we determined that only MTV41% > 75 th percentile was associated with lower odds of CR (odds ratio (OR):0.21 (0.08-0.53)) versus size ≥4 (OR: 0.94 (0.32, 2.73) ) with no interaction noted. Likewise, in a multivariate model of LF, TLG2.5> 75 th percentile was shown to be a better predictor of worse LF (HR: 2.44 (1.32, 4.52)) than size when considering lesions < 6 cm.In stratifying response and local control for patients receiving VLDRT for indolent lymphomas, MTV and TLG may aid in patient selection, especially for lesions smaller than 6 cm. As PET-based radiotherapy planning is routinely performed in the treatment of indolent lymphomas, these parameters are easily attained after contouring and may have immediate clinical utility. These findings may also be applicable to radiotherapy response with higher doses, and the incorporation of [18F]-FDG-PET metrics into treatment decisions is an area of active research. It remains to be seen in ongoing work whether higher-order PET radiomic features (which for instance capture heterogeneity of tumor glucose metabolism) can further improve the accuracy of [18F]-FDG-PET-based radiotherapy outcome prediction. DisclosuresMayerhoefer: Siemens: Other: Speaker Honoraria; General Electric: Other: Speaker Honoraria; Bristol Myers Squibb: Other: Speaker Honoraria.

Chemotherapy free treatment of indolent lymphoma.

Chemotherapy free treatment of indolent lymphoma.

Treating Indolent Lymphoma in Older Adults: What Is the Right Way?

Introduction: The treatment of hematological malignancies in older adults is an emerging and important issue due to the aging population trend as well as drug-related toxicities in pts (pts) with comorbidities. Indolent lymphomas constitute a subgroup of incurable non-Hodgkin lymphomas characterized by multiple relapses. Anthracycline containing chemo-immunotherapy regimens (ACR) such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) are very active in indolent lymphomas, resulting in a long progression-free survival (PFS). Due to their high rate of associated toxicities, such regimens are less likely to be given to the elderly population. Currently, there is no consensus regarding the treatment of indolent lymphomas in older adults. The present study assessed overall survival (OS), time to next treatment (TNT) and treatment-associated toxicity in this distinctive subpopulation of pts with indolent lymphoma, aiming to develop an optimal approach to the management of such pts.Methods: This retrospective cohort analysis included pts with indolent lymphoma (histology diagnosis of follicular lymphoma, marginal zone lymphoma, Waldenstrom's macroglobulinaemia and indolent lymphoma not otherwise specified) aged ≥60 at therapy initiation (1st line) treated with either an ACR or a non-ACR at the Rambam Department of Hematology and Bone Marrow Transplantation between the years 2000 and 2012. All regimens included rituximab. OS, TNT and treatment-related toxicity (neutropenic fever and hospital admission due to noninfectious causes during the treatment period) were assessed.Results: Forty three pts treated with an ACR and 55 pts receiving a non-ACR were included in the analysis. Clinical characteristics, response to therapy and treatment modification data are presented in table 1. The median age was 67 years in the ACR group and 73 years in the non-ACR group; median duration of the follow-up was 4.3 years (range 0.1-11.9 years). No difference in terms of high risk co-morbidity score, defined as modified Charlson co-morbidity score ≥5 (Charlson et al, 1987), was found between the ACR group and the non-ACR group. Significantly more pts with follicular lymphoma were treated with ACR compared to non-follicular indolent lymphomas. There was no difference in CR rate between the ACR and non-ACR groups. In a univariate analysis, OS was found to be significantly higher in the ACR group, but in the multivariate analysis, OS appeared to be influenced only by age. The cause of death was disease-related in 8 pts (100% of deaths) in the ACR group and in 7 pts (64%) in the non-ACR group (data on the cause of death were available for 11 out of 18 pts from the non-ACR group). The median TNT was longer in the ACR cohort, but the difference did not reach statistical significance. No difference was found between the ACR and non-ACR groups in terms of major treatment-related toxicities assessed by the number of hospital admissions because of infection or other causes. Dose adjustments and treatment delays were far more frequent in the ACR cohort. This study is limited by its retrospective nature, the small number of patients and a significantly higher number of pts with follicular lymphoma treated in the ACR group.Conclusions: The present analysis of a cohort of older adults with indolent lymphoma treated with chemo-immunotherapy regimens in routine clinical practice has demonstrated that ACR was safe and efficacious. When approaching older adults suffering from indolent lymphoma, the considerations of quality of life (time without the need of further treatment, the minimal number of hospital admissions and minimal number of infections requiring hospitalization) should play a major role in treatment decision-making. In the current study, ACR was not inferior to non-ACR in terms of toxicity. A trend to an improved OS and longer TNT was demonstrated in the ACR group. The patient age should not deter physicians from using ACR in older adults.Table 1ParametersACR N=43Non-ACR N=55P valueAge, median67730.05Pts with modified Charlson comorbidity score ≥5 (%)7 (17)10 (19)0.55Pts with follicular lymphoma (%)33 (77)27 (49)0.007CR rate (%)30 (70)33 (60)0.44-year OS, %8167<0.04Median time to next treatment, months90550.2Dose adjustments65370.008Treatment delays57370.06 DisclosuresNo relevant conflicts of interest to declare.

Changes in the diagnosis and treatment of patients with low grade lymphoma in Germany: years 2006–2009

Today's treatment options for indolent lymphoma and chronic lymphocytic leukemia (CLL) range from watch & wait, immunochemotherapy up to allogeneic transplantation. We describe changes in the diagnosis and treatment of indolent lymphoma and CLL in Germany between 2006 and 2009. Two nation-wide surveys in the fourth quarter of 2006 and 2009 included patients with indolent lymphoma and CLL. Data from 576 patients from 46 centers in Q4/2006 were compared with data from 521 patients from 57 centers in Q4/2009. The subpopulation of patients ≥ 70 years of age and the number of patients with comorbidities increased from 39% to 55% and 47% to 55%, respectively. Both in indolent lymphoma and CLL, Rituximab and R-based immunochemotherapy (50.6% vs. 64.4%) as well as bendamustine (4.8 % vs. 24%) were much more frequently applied. In contrast, high dose chemotherapy consolidation was almost abandoned in first line treatment. Supportive care is given more frequently, with exception of erythropoietin and immunoglobulins. Our national survey confirmed that scientific results were rapidly transferred into clinical care of indolent lymphoma.

Management of secondary immune deficiencies

Management of secondary immune deficiencies

Diagnosis and Treatment of Follicular Lymphoma: Where do we Stand?

SUMMARY The treatment of follicular lymphoma (FL) has advanced in the past decade. The routine use of monoclonal antibodies, arrival of bendamustine and application of radioimmunotherapy have ushered in major improvement in response rates for patients with indolent lymphoma. Studies have documented an improvement in progression-free survival and overall survival with chemoimmunotherapy followed by maintenance rituximab. The purpose of this review is to share an overview of recent advances in clinical care and research underway that will be incorporated into clinical practice in the foreseeable future. We will restrict our review to FL because the wide variety of types of indolent lymphoma makes it impossible to cover all of them in a brief review. FL is the most common indolent lymphoma and the general approach to diagnosis and treatment of this disease is often utilized as a foundation for the diagnosis and treatment of indolent lymphomas in general.

Maintenance therapy in follicular lymphoma

This article reviews the potential benefit of maintenance therapy for patients with follicular lymphoma. Follicular lymphoma, despite substantial improvements in survival, is usually incurable. Several randomized studies have shown that the combination of anti-CD20 and chemotherapy can improve overall survival for these patients. Recently, the old concept of maintenance treatment developed for acute leukemias was reintroduced in the treatment of indolent lymphomas. On the basis of its favorable toxicity profile, single agent rituximab remains a valuable option when given in a prolonged schedule to obtain durable remissions. A first remission is easily obtained but relapses appear unavoidable. Patients achieving a partial response have poorer outcomes compared with those achieving complete remission. Furthermore, it has been demonstrated that among patients with follicular lymphoma who reach complete remission, those obtaining negative minimal residual disease, as assessed by molecular biology, have a better outcome compared with those remaining with residual disease. There is, therefore, a rationale to give additional treatment in an attempt to eradicate or to control the lymphoma cells responsible for relapse. An ideal maintenance regimen would have limited toxicity and should be easy to administer. Results of the International Primary Rituximab and Maintenance study show that 2 years of rituximab maintenance prolongs progression free survival, delays the time to next antilymphoma treatment and improves the quality of response in patients with previously untreated follicular lymphoma. Rituximab maintenance was well tolerated with a limited number of adverse events.

ASH update 2010: Chronic lymphocytic leukaemia

The annual meeting of the American Society of Hematology 2010 offered a wealth of interesting pilot studies in CLL rather than large practice changing trials. Although these new compounds are mostly in a very early phase of drug development, the results are impressive. Concerning clinical practice, new or updated results of trials exploring alemtuzumab in CLL underscore the clinical value of this drug, in particular for high-risk CLL patients. And finally, preliminary data indicate that rituximab maintenance strategies as applied for the treatment of indolent lymphoma may also have a role in CLL.

Biology and treatment of indolent lymphomas: follicular lymphoma and marginal zone B-cell lymphoma

Biology and treatment of indolent lymphomas: follicular lymphoma and marginal zone B-cell lymphoma

IXB.1 Treatment of indolent lymphoma in medically non-fit patients

The majority of patients with early-stage (IA–IIA) Hodgkin's disease (HD) can at present be cured by current available therapeutic options. Actually the “gold standard” for patients with early-stage HD is a combined approach consisting of a short-duration chemotherapy (e.g., two to four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine; ABVD) and low-dose (20–30 Gy) involved-field irradiation (IF-RT).The treatment of choice for advanced-stage HD is still represented by chemotherapy alone or followed by RT. At present, it is internationally accepted that ABVD should be the standard regimen.High-dose chemotherapy (HDC) with peripheral-blood stem-cell support (PBSCs) represents the treatment of choice for patients relapsing after chemotherapy, but, nevertheless, about 50% of transplanted patients relapse or progress after HDC.Regarding low- and high-grade non-Hodgkin's lymphomas, Rituximab associated or not to chemotherapy, is much more extensively used. In advanced low-grade lymphomas the role of immunochemotherapy has been definitively demonstrated in a phase III study, comparing eight courses of rituximab plus chemotherapy (CVP regimen) versus CVP alone at diagnosis. Three courses of CHOP plus Rituximab associated to involved fields radiotherapy (RT) is considered to be the standard treatment in localized high-grade lymphoma. In advanced disease patients, intensified CHOP-like regimen and new therapeutic agents have been tried to improve the clinical results in newly diagnosed patients with encouraging results. Finally, several studies confirmed the usefulness of prognostic scores as IPI for high-grade lymphoma and FLIPI for follicular lymphoma, and the usefulness of PET in the staging of lymphomas.

Overcoming Rituximab Resistance: The US Clinical Experience With Bendamustine

Despite the wide usage, mild side effect profile, and commendable efficacy of rituximab in frontline treatment of indolent lymphoma, resistance to this agent commonly develops, ultimately limiting patient treatment options. The mechanisms of rituximab resistance have not yet been fully elucidated, although both tumor- and host-associated resistance mechanisms have been proposed. Several strategies for overcoming rituximab resistance are currently being evaluated, including manipulation of the immune system, as well as second-generation engineered anti-CD20 antibodies. Ultimately, the use of novel agents with alternative mechanisms of action may represent the best solution for overcoming rituximab resistance. The cytotoxic chemotherapeutic agent bendamustine, which has both alkylating agent and other cell-killing properties, has been used successfully in phase II clinical trials to treat rituximab-refractory disease. Ongoing pivotal studies are currently evaluating the use of bendamustine in this difficult-to-treat lymphoma patient population.

Treatment of indolent lymphomas from watch and wait to high dose therapy

Indolent B-cell non-Hodgkin’s lymphomas (IBCNHL) represent a heterogenous group of chronic diseases [1]. Follicular lymphomas grades 1 and 2 (FL1/2) are by far the most common, accounting for approximately 20% of all NHL worldwide. Indolent IBC-NHL also include small lymphocytic lymphoma (SLL), which is the tissue counterpart of B-chronic lymphocytic leukemia (B-CLL); [2], lymphoplasmacytic lymphoma (LPL; 1%), mantle cell lymphoma (MCL; 6%), and marginal zone lymphomas, either splenic (SMZL; 1%), nodal (NMZL, 2%) or extranodal MALT (8%). Various treatment strategies ranging from ‘‘watch and wait’’ policies or oral alkylating agent monotherapy to more aggressive combination chemotherapy (CT), chemoimmunotherapy or even CT followed by high dose therapy and autologous stem cell transplantation (ASCT) have been used in previously untreated patients with IBC-NHL. However there is no clear evidence for the superiority of any particular approach in terms of overall survival (OS), because: (i) The natural history of IBC-NHL is generally prolonged and many of these approaches are ultimately integrated in the overall treatment strategy, thus minimizing OS differences, despite significant differences in progression free survival (PFS); (ii) With the exception of FL, the rarity of these disorders raises further difficulties in the design of randomized trials. We will review here current treatment approaches for FL1/2, MCL, SLL, LPL including Waldenstrom’s macroglobulinemia and NMZL, SMZL and extranodal MZ lymphomas of MALT type (EMZL), focusing mainly on first-line therapies.

Bendamustine and rituximab act synergistically in vitro and are effective in the treatment of relapsed or refractory indolent and mantle cell lymphomas

6565 Bendamustine combines a purine-like benzimidazol and bifunctionally alkylating nitrogen mustard group. The drug is active in a variety of lymphoproliferative disorders without crossresistance to cyclophosphamide. We investigated simultaneous combination of rituximab with bendamustine and found synergistic effects of apoptosis in vitro on lymphoma cell lines (DOHH-2, WSU-NHL) as well as on ex vivo cells of pat. with CLL. Apoptosis was determined by Annexin V and JC-1. The synergistic effects of rituximab in combination with bendamustine were evenly strong when rituximab was applied at a dose, at which half of the CD20 molecules per cell were saturated. Based on our in vitro results we initiated a phase-II study to examine efficacy and toxicity of bendamustine combined with rituximab (BR) as therapy of 1st, 2nd or 3rd relapse. Treatment schedule: 6 x Rituximab 375 mg/qm day 1 combined with 4 x Bendamustine 90 mg/qm day 2+3, every 4 weeks. Included entities: 17 immunocytomas, 16 mantle cell (MCL), 24 follicular, 6 marginal zone lymphomas. 63 pat. entered the study. Results: 57 pat. responded to therapy yielding to an ORR of 90% with a CR-rate of 60%. In MCL an ORR of 75% was achieved with an CR-rate of 50%. All pat. with immunocytome achieved a remission with a CR-rate of 53%. The median duration of remission was 25 months. BR induced considerable low hematological toxicity with only 16% granulocytopenias grade 3 and 4. We conclude that BR seems to be very effective in the treatment of relapsed indolent and mantle cell lymphomas reaching an overall response rate of 90% and a CR rate of 60%. Based upon the encouraging results obtained with BR in this study we initiated two Phase III trials that compare BR to established chemo-immunotherapy regimens. One trial compares BR versus R-CHOP in pat. with previously indolent lymphomas to demonstrate a non-inferiority of BR in comparison to R-CHOP with respect to efficacy but to show a more favorable toxicity profile. The second trial compares BR to fludarabine/rituximab in pat. with relapsed indolent lymphomas. These studies should provide considerable guidance for the appropriate role of bendamustine in the treatment of indolent lymphomas. No significant financial relationships to disclose.

The Role of Mitoxantrone in the Treatment of Indolent Lymphomas

With the introduction of newer therapeutic approaches, survival in indolent non-Hodgkin's lymphoma (NHL) appears to be improving. Mitoxantrone (Novantrone; Serono, Inc.; Rockland, MA, http://www.seronousa.com), an anthracenedione with low cardiotoxic potential, has demonstrated activity in indolent NHL in combination with fludarabine (Fludara; Berlex Laboratories; Wayne, NJ, http://www.berlex.com) and other agents. In a Southwest Oncology Group trial (SWOG 9501), treatment with fludarabine and mitoxantrone (FM) induced a complete remission (CR) rate of 44% and a partial remission (PR) rate of 50% in untreated patients. The estimated 4-year progression-free survival (PFS) rate was 38%. In a multicenter Italian trial comparing the efficacy of FM with that of cyclophosphamide, doxorubicin (Adriamycin; Bedford Laboratories; Bedford, OH, http://www.bedfordlabs.com), vincristine (Oncovin; Eli Lilly and Company; Indianapolis, IN, http://www.lilly.com), and prednisone (Deltasone; Pfizer Pharmaceuticals; New York, NY, http://www.pfizer.com), CHOP, followed by rituximab (Rituxan; Genentech, Inc.; South San Francisco, CA, http://www.gene.com) for patients with incomplete clinical or molecular responses, the CR and molecular response rates were significantly higher in the FM arm, but the PFS and overall survival (OS) rates did not differ between the two arms. However, FM was also significantly less toxic than CHOP. The administration of rituximab following chemotherapy resulted in higher clinical and molecular response rates in both arms. In a separate trial, FM plus dexamethasone (Decadron; Merck and Co., Inc.; Whitehouse Station, NJ, http://www.merck.com), FND, plus concurrent rituximab produced a CR rate of 92%. In a randomized German study, patients with indolent lymphomas received FM plus cyclophosphamide (FCM) or FCM with rituximab. PFS and OS times were significantly better for patients who received combined chemoimmunotherapy. Mitoxantrone-based regimens are highly active and well tolerated in patients with both relapsed and previously untreated indolent lymphomas. The addition of rituximab appears to increase the activity of the FM, FND, and FCM regimens. Although the results of the Italian multicenter study support the superiority of FM over CHOP in terms of clinical and molecular responses and tolerability, additional studies using rituximab in combination with both of these regimens should be attempted to determine the possible further benefit of both in the management of indolent lymphoma. Because cure remains elusive in patients with indolent lymphoma, maximum prolongation of PFS with minimal toxicity and maximum preservation of quality of life should remain central goals of treatment.

The role of fludarabine in the treatment of follicular and mantle cell lymphoma.

Advanced-stage follicular lymphoma (FL) and mantle cell lymphoma (MCL) cannot be cured using conventional chemotherapy. Fludarabine, the most widely used purine analog, exhibits a particularly high level of activity against small lymphocytic lymphoma and chronic lymphocytic leukemia (CLL). Numerous studies have investigated the efficacy of fludarabine as a single agent or in combination with other cytostatic compounds in the treatment of FL and MCL. Hematologic toxicity is the most commonly observed adverse event in patients treated with fludarabine, but serious infectious complications are relatively rare. Fludarabine monotherapy has proven to be particularly effective in the treatment of FL; however, complete responses (CRs) are observed in only approximately 20-40% of all cases. In contrast, combinations containing fludarabine and anthracyclines or alkylating agents have yielded superior response rates and longer periods of progression-free survival (PFS), and the addition of the anti-CD20 antibody rituximab appears to yield even better results. In a randomized trial, an immunochemotherapy regimen consisting of a fludarabine-containing combination and rituximab resulted in superior remission and survival rates compared with the fludarabine-containing combination alone. In summary, fludarabine has proven to be a safe and effective agent in the treatment of indolent lymphoma. In particular, combinations containing fludarabine, anthracyclines and/or alkylating agents, and rituximab have yielded remarkable CR and PFS rates. Consequently, current research efforts have focused on the use of fludarabine-containing combinations in the first-line treatment of FL and MCL.

Bexxar: novel radioimmunotherapy for the treatment of low-grade and transformed low-grade non-Hodgkin's lymphoma.

Immunotherapy using monoclonal antibodies to specifically target B cells has provided new hope to many patients with indolent lymphomas, particularly those with chemotherapy-refractory disease. Lymphomas are extremely sensitive to radiation, and significant progress has been made over the last decade in the development of radioimmunotherapy with anti-CD20 antibodies. Herein we review clinical experience with tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corporation; South San Francisco, CA; and GlaxoSmithKline; Philadelphia, PA) in patients with non-Hodgkin's lymphoma. Therapy with Bexxar has demonstrated high response rates and long durations of response compared with unconjugated anti-CD20 antibodies in patients with relapsed low-grade and transformed low-grade non-Hodgkin's lymphomas. Iodine-131 (I-131) has a long history of clinical experience, an excellent safety record, and favorable nuclear and pharmacologic properties. Importantly, the gamma emissions of iodine-131 facilitate accurate dosimetry to calculate the appropriate patient-specific therapeutic activity to deliver a predetermined total-body dose of radiation, thereby minimizing hematologic toxicity. In clinical trials of Bexxar, objective response rates ranged from 54%-71% in heavily pretreated patients. In the pivotal trial, the number of patients with a longer duration of response after treatment with Bexxar was significantly greater than the number of patients with a longer duration of response after their last qualifying chemotherapy regimen. In 76 newly diagnosed patients, the objective response rate was 97%, and 63% of patients achieved complete responses. These data suggest that Bexxar will become an important new option in the treatment of indolent lymphoma.

Progress and promise in the treatment of indolent lymphomas.

In the era of conventional alkylating agent-based chemotherapy, advanced stage indolent lymphoma has been considered incurable. The failure of our traditional therapies to cure these patients, coupled with the indolent course of the disease and the elderly population affected, has fostered a nihilistic attitude about the treatment of these diseases. Twenty years ago, in the absence of interesting alternatives to alkylating agents, judicious use and reuse of alkylators was perhaps the best we could do. There are now many reasons for optimism and excitement in the treatment of these diseases, including the availability of promising agents such as interferon-alpha, the nucleoside analogues, and rituximab. Radioimmunotherapy will also likely play a role in future therapy programs. Allogeneic stem cell transplantation is a high-risk approach that is not an option for all patients, but it has the potential to cure patients, even in the setting of relapse. Mini-allogeneic transplantation may permit an approach to allogeneic transplantation that is better tolerated than standard transplant strategies. In addition to these therapy options, biological insights have provided new options for monitoring patients. Molecular monitoring (polymerase chain reaction for bcl-2) is a stringent measure of short-term treatment efficacy, and one that correlates with durability of remission, i.e., it is a surrogate marker by which to judge treatment efficacy. There used to be a limited number of conventional treatment approaches, which consistently failed. The pendulum has swung. There are now many promising new options. It is time to plan and conduct trials that are geared for success.

Managing Indolent Lymphomas in Relapse: Working Our Way Through a Plethora of Options.

The front-line management of stage IV indolent non-Hodgkin's lymphoma has ranged from the watch-and-wait approach to intensive experimental regimens such as high-dose chemotherapy and bone marrow transplant. With this broad spectrum of regimens to choose from the decision has become a challenging exercise for both patients and oncologists. With the recent introduction of new agents such as rituximab, fludarabine, and combinations based on these, the management of relapsed cases can be similarly confusing. More aggressive approaches such as high-dose chemotherapy with autologous bone marrow transplant and more recently allogeneic bone marrow transplant have also been used. Recently the technique of "mini-allo transplants" has been introduced. It utilizes a less myelosuppressive conditioning chemotherapy regimen based on fludarabine which is immunosuppressive enough to allow engraftment of the donor marrow. Since it is less myelotoxic it is better tolerated, and this has allowed us to significantly extend the age cut-off for allogeneic transplants. All these advances provide us with a more extensive armamentarium, but at the same time they confront physicians with new challenges in choosing from a large and continuously growing therapeutic menu. In this review of the alternative therapies a panel of three expert hemato-oncologists each discuss their approach to the management of a 49-year-old patient with a relapsed indolent follicular lymphoma. Dr. Horning discusses the traditional alternatives available for this patient such as standard chemotherapy combinations or the watch-and-wait approach in Section I. In Section II, Dr. Kaminski reviews the different therapeutic monoclonal antibody options such as rituximab, Bexxar (Iodine-labeled anti-CD20) and Ytrium-labeled anti-CD20 antibody. Allogeneic transplants are increasingly more popular for the treatment of indolent lymphomas because they can provide an immune-mediated graft-versus-lymphoma effect. In Section III, Dr. Richard Champlin reviews various transplant options including autologous, allogeneic and mini-allogeneic transplants.

Treatment of indolent lymphoma with fludarabine/mitoxantrone combination: a phase II trial

In an effort to reduce the risk of opportunistic infections, 25 patients with advanced indolent lymphoma (age range: 30–77 years) were treated, using a combination of fludarabine and mitoxantrone, without corticosteroids. Fludarabine was given at 25 mg/m2 for three daily doses, and mitoxantrone at 10 mg/m2. Cycles were repeated every four weeks for up to maximum response, and for no more than six months. Eight patients had follicular lymphoma, and 11 had CLL/SLL. Objective response was observed in 11 of 12 previously untreated patients, including five complete remissions, and in 10 of 13 previously treated patients, including three complete remissions. Only two relapsed patients failed to respond, whereas two patients were not evaluable. Hence, the overall response rate based on the intention-to-treat analysis was 84 per cent (95 per cent CI: 70–98 per cent). The median survival has not been reached after a 22-month follow-up. Median time to progression was 15 months. One patient on corticosteroids developed pneumocystis carinii pneumonia, and an elderly patient succumbed to neutropenic sepsis. Apart from granulocytopenia, the treatment was well tolerated. Omission of corticosteroids reduces the risk of opportunistic infections, while the activity of the combination against indolent lymphoma and CLL is maintained. Copyright © 1998 John Wiley & Sons, Ltd.