90Y-ibritumomab tiuxetan consists of a murine monoclonal antibody covalently attached to a metal chelator, which stably chelates 111In for imaging and 90Y for therapy. It is often used for other than first line of treatment for lymphoma.

A recent guideline states experts’ consensus: “It is the opinion of the Hematology Disease Site Group that the benefit of 90Y-ibritumomab tiuxetan radioimmunotherapy may be generalizable to other relapsed or refractory indolent non-Hodgkin’s lymphomas previously treated with rituximab….but not CLL.

F. Morschhauser, T. Illidge, D. Huglo et al., “Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation,” Blood, vol. 110, no. 1, pp. 54–58, 2007.

Leung M, Haynes AE, Stevens A, Meyer RM, Imrie K, Hematology Disease Site Group. Ibritumomab tiuxetan in lymphoma: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2006 Jul 17. 42 p. (Evidence-based series; no. 6-17). [44 references]

Giulia Motta, Michele Cea, Eva Moran, Federico Carbone, Valeria Augusti, Franco Patrone, and Alessio Nencioni Monoclonal Antibodies for Non-Hodgkin’s Lymphoma: State of the Art and Perspectives Clinical and Developmental ImmunologyVolume 2010 (2010),

Yang DH, Kim WS, Kim SJ, Kim JS, Kwak JY, Chung JS, Oh SY, Suh C, Lee JJ. Pilot trial of yttrium-90 ibritumomab tiuxetan consolidation following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy in patients with limited-stage, bulky diffuse large B-cell lymphoma. Leuk Lymphoma. 2012 May;53(5):807-11.

For Lay version see here

Freudenberg LS, Antoch G, Schutt P, et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging. 2004;31:325–329

Yuliya S. Jhanwar and David J. Straus The Role of PET in Lymphoma Journal of Nuclear Medicine Vol. 47 No. 8 1326-1334, 2006

Bruce D. Cheson MD, Non-Hodgkin’s Lymphomas: New Insights and Therapeutic Strategies
Staging and Evaluation of the Patient with Lymphoma
Hematology/Oncology Clinics of North America
Volume 22, Issue 5, October 2008, Pages 825-837

Patients with low-grade non-Hodgkin’s lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A ‘watch-and-wait’ strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.

In addition to the R-CVP regimen,  NCCN 201 on p. FOLL_B, 1 cites R-CHOP, FR(fludarabine/rituximab), radioimmunotherapy, RFNDP, bendamustine/rituximab, rituximab alone.

The impact of maintenance treatment with rituximab on overall survival is one of the most important open questions for patients with indolent non-Hodgkin lymphoma. Recent randomized trials performed by the German Low Grade Lymphoma Study Group (GLSG) and by the EORTC demonstrated the superiority of rituximab maintenance after immunochemotherapy and after chemotherapy compared with observation alone.

Clinical trials have demonstrated prolongation of progression-free survival and, in some cases, increased survival when “maintenance” rituximab is given following rituximab induction, chemotherapy induction, or rituximab/chemotherapy (relapsed setting).

A recent guideline says this about maintenance rituximab for low grade lymphoma: “For previously treated patients with follicular or other indolent B-cell-histology lymphoma (such as mantle cell lymphoma, marginal zone lymphoma, and lymphoplasmacytoid lymphoma), excluding small lymphocytic lymphoma (SLL):
However, a Canadian guideline does recommend this approach and it is becoming the predominant approach in clinical practice.NCCN also lists it as category 1 recommendation on p. FOLL-B. First line extended therapy – If initially treated with single-agent Rituxan, consolidation with Rituximab 375mg/m2 one dose q 12 weeks is supported. FDA approved Rituxan as a maintenance therapy for patients with advanced follicular lymphoma in January of 2011. Farthermore, NCCN marginal lymphoma guideliens take one to the follicular lymphoma pages, where maintenance is recommended

On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published. The schedule is not NCCN prescribed and various schedules have been reported. NCCN recommends up to 2 years of maintenance therapy on FOll-B, 1

For large cell lymphoma, NCCN does NOT recommend maintenance Rituxan. Rituxan after CHOP, but not after R-CHOP, significantly prolongs TTF, but fails to prolong OS, possibly due to a delayed pattern of relapse and/or the efficacy of rituximab in the salvage setting(An Intergroup E4494/C9793 update). NCCN on p. BCEL specifically states that and does not recommend it.

For mantle cell lymphoma, NCCN also does not recommend maintenance. On June 13, 2011, at the 16th Congress of the European Hematology Association in London, there was presented a study of maintenance rituximab after responding to initial therapy. It was restricted to elderly patients and showed that maintenance doubled the duration of remission doubled. Overall survival at 4 years also improved with rituximab maintenance, and experts suggest it should become the new standard of care. At 4 years, 57% of the patients treated with rituximab were still in in remission, compared with 26% of those treated with interferon (P = .0117). ” This study has not yet been published.

NCCN recommends it for marginal zone lymphoma

NCCN, MZA-A, 2 2017

NCCN.ORG, NHLm follicular 2017

NCCN, MANT-4 2017

Revised 2/4/2012

Imrie K, Stevens A, Meyer R, Hematology Disease Site Group. Rituximab in lymphoma and chronic lymphocytic leukemia: a clinical practice guideline. Toronto (ON): Cancer Care Ontario (CCO); 2005 Dec 22. 46 p. (Evidence-based series; no. 6-8). [65 references]

S. J. Horning
Optimizing Rituximab in B-Cell Lymphoma
J. Clin. Oncol., February 20, 2005; 23(6): 1056 – 1058.

John D. Hainsworth, Sharlene Litchy, Don W. Shaffer, Van L. Lackey, Manuel Grimaldi, F. Anthony Greco, Maximizing Therapeutic Benefit of Rituximab: Maintenance Therapy Versus Re-Treatment at Progression in Patients With Indolent Non-Hodgkin’s Lymphoma—A Randomized Phase II Trial of the Minnie Pearl Cancer Research Network
Journal of Clinical Oncology, Vol 23, No 6 (February 20), 2005: pp. 1088-1095

Habermann TM, Weller EA, Morrison VA, et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol 2006;24:3121–3127.

Revlimid is an orally administered derivative of thalidomide, which is a very active agent for the treatment of multiple myeloma but has serious side effects, especially thromboembolism. Revlimid is reported to have less toxicity than thalidomide but retains antimyeloma effects. Revlimid has recently been approved by the FDA for review of treatment of myelodysplastic syndromes (MDS) wih a 5q- mutation and for first line treatment of multiple myeloma in conjunction with dexamethasone. Revlimid is in clinical trials for the evaluation of treatment for other hematologic cancers including CLL.

There are many studies supporting effectiveness of Revlimid, although most of them are small and presented in the abstract form.

Researchers from the Roswell Park Cancer Center and the Toronto Sunnybrook Regional Cancer Center have reported that Revlimid has significant activity in CLL. This study was also presented at the 2005 meeting of the American Society of Hematology in December 2005. Thalidomide has also demonstrated activity when combined with Fludara for initial treatment of CLL. This was a small study involving only 16 patients, but the complete response rate was over 50%.

The study presented at ASH 2005 and ASCO 2006 involved 29 patients with relapsed or refractory CLL. More than 50% has failed Rituxan combinations and more than 50% had failed fludarabine combinations. The complete response rate was 15%, the partial response rate was 53% and an additional 15% had stable disease. Two patients had complete molecular responses. The most common side effects reported were fatigue, neutropenia and thrombocytopenia. Approximately 60% had “flare reaction”—described as tender swelling of lymph nodes and rash—which was successfully treated with steroids. In-vitro studies showed an increased number of natural killer cells but no increase in apoptosis.

In 2008, Celgene reported two REVLIMID (lenalidomide) Phase II studies at the 50th American Society of Hematology Meeting. Both demonstrated high response rates and manageable side effects in patients previously untreated with symptomatic chronic lymphocytic leukemia (CLL). The studies demonstrated greater than 90 percent disease control across all evaluable patients. In 2009, at ASH, there was presented a phase II study of Rituxan. Revlimid combination conducted at MD Anderson Cancer Center demonstrated a 64 percent overall response after 12 cycles, including the observation of complete responses. In 2008, at ASH, there was presented a phase II study of Rituxan. Revlimid combination conducted at MD Anderson Cancer Center demonstrated a 64 percent overall response after 12 cyces, including the observation of complete responses.

It is also listed by the Drugdex compendium for CLL. The most recent noteworthy paper was in Blood 2011. Sixty patients with CLL age 65 years and older received treatment with lenalidomide orally 5 mg daily for 56 days, then titrated up to 25 mg per day as tolerated. Treatment was continued until disease progression. At a median follow-up of 29 months, 53 patients (88%) are alive and 32 patients (53%) remain on therapy. Estimated 2-year progression-free survival is 60%. The overall response rate to lenalidomide therapy is 65% including 10% complete response, 5% complete response with residual cytopenia, 7% nodular partial response, and 43% partial response. These are very good results for the limited reported toxicity in the ederly population.

Miller K, Czuczman MS, Dimicli L, et al. Lenalidomide (L) induces high response rates with molecular remission in patients (pts) with relapsed (rel) refractory (ref) chronic lymphocytic leukemia (CLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. 2006. Abstract # 6605.

Chanan-Khan AA, Miller KC, DiMicheli L, et al. Results of a phase II study of lenalidomide (L) (Revlimid) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Blood 2005;135a, abstract # 447.

Chanan-Khan A, Miller KC, Takeshita K, et al. Results of a phase 1 clinical trial of thalidomide in combination with fludarabine as initial therapy for patients with treatment-requiring chronic lymphocytic leukemia (CLL). Blood. 2005;106:3348-3352.

Chanan-Khan A, Miller KC, Musial L, et al. Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. Journal of Clinical Oncology. 2006;24:5343-5349.

Chen C, Paul H, Xu W, et al. A phase II study of lenalidomide in previously untreated, symptomatic chronic lymphocytic leukemia (CLL). Blood. 2008;112:23, abstract number 44.

Kornblau SM, Burger JA, Ferrajoli A.et al, Lenalidomide (REVLIMID) as initial therapy of elderly patients with chronic lymphocytic leukemia.Blood. 2011 Jul 1.

Takvorian and colleagues (1987) studied 49 patients with either high-grade (n = 29), intermediate-grade (n =14) or low-grade (n = 6) lymphoma. All patients were considered to have a poor prognosis either due to relapse (n = 41) or poor prognostic factors (n = 8). These latter 8 patients were in at least partial remission but were considered to be at high-risk for relapse due to a bulky tumor mass, or multiple sites of extranodal involvement. All patients had a good performance status. The common feature of all these patients was that they were responsive to conventional induction therapy such that at the time of HDC, all patients had a minimal disease burden. In fact, 23 patients were considered to be in complete remission. A total of 34 of the 49 patients remained in complete remission for 2 to 52 months post-HDC, which translated into a 65 % probability that patients would remain disease free for greater than 11 months. Two patients died from treatment-related toxicity and relapse occurred in 13 others. All relapses occurred before 11 months. Other earlier studies of HDC had included all patients relapsing from disease, regardless of their performance status or whether the lymphoma was chemo-resistant. In these studies the mortality rate ranged from 20 to 40 % and long-term disease survival was seen in only 20 % of patients. Considering their improved results, the authors suggested that HDC should be a treatment option for patients with relapsing disease but with a minimal tumor burden that is still responsive to chemotherapy.

Schouten et al (1994) reported their findings of 92 patients with low-grade NHL treated with HDC and ASCT. At the time of ASCT, the majority of patients had chemosensitive disease in first or subsequent remission (37 %) or disease with a good response to chemotherapy (49 %). At a median follow-up of 19 months, the progression free survival is 52 %. Patients with complete remission or responding relapse at the time of ASCT had a significantly better progression-free survival compared to patients with refractory disease. Patients with transformed low-grade NHL at ASCT had a very poor outcome. Despite the relatively short follow-up of this study, the data suggested that chemosensitive disease responded better to HDC followed by stem cell transplant than refractory disease at the time of ASCT.

Mills and colleagues (1995) reported the main prognostic factors in 107 patients with relapsed or resistant intermediate- or high-grade NHL who underwent HDC with ASCT. All patients had failed to achieve a complete remission to conventional chemotherapy or had subsequently relapsed. Additionally, there was no bone marrow involvement in any of the patients. Forty-two patients (40 %) had chemoresistant disease at the time of HDC, 55 (51 %) had chemosensitive disease, and 10 (9 %) had untested relapse. At 3 months, 44 patients (41 %) were assessed to be in complete remission, 34 (32 %) were in partial remission and 22 (21 %) showed no response or had progressive disease. There were 7 early procedure-related deaths. Overall survival rate at 5 years is 41 % and progression free survival rate is 35 %. None of the patients who were unresponsive to HDC survived beyond 18 months, whereas at a median follow-up of 34 months, 50 % of the partial responders were alive. Patients with chemosensitive disease, small masses, and ASCT after one line of chemotherapy had the best outcome.

In a randomized clinical trial (The European CUP trial), Schouten, et al. (2003) examined if high-dose therapy (HDT) followed by ASCT is more effective than standard treatment with regard to progression-free survival (PFS) and overall survival (OS) in patients with relapsed follicular NHL; and evaluated the additional value of B-cell purging of the stem-cell graft with regards to PFS and OS. Patients received three cycles of chemotherapy. Responding patients with limited bone marrow infiltration were eligible for random assignment to three further cycles of chemotherapy (C), unpurged HDT (U), or purged HDT (P). A total of 140 patients were registered from 36 centers internationally, and 89 were randomly assigned. Reasons for not randomizing included patient refusal, early progression, or death on induction therapy. With a 69-month median follow-up, the log-rank P value for PFS and OS were 0.0037 and 0.079, respectively. The authors concluded that HDT significantly improves PFS and OS in patients under age of 60 years with recurrent chemosensitive disease. Furthermore, there is no clear evidence of benefit through purging. This is in agreement with the observations of Alvarnas and Forman (2004) who stated that data to justify routine use of hematopoietic stem cell graft purging are insufficient.

In a recent review on stem cell transplantation in follicular lymphoma, Tse, et al. (2004) stated that ASCT or allogeneic stem cell transplantation in first remission remains an investigational procedure.

A 2011 review concludes: “Stem cell transplantation (SCT) including both autologous and allogeneic SCT or experimental agent therapy is considered for recurrent disease.”

Freedman A. Follicular lymphoma: 2011 update on diagnosis and management.Am J Hematol. 2011 Sep;86(9):768-75.

HC Schouten, PJ Bierman, WP Vaughan, A Kessinger, JM Vose, DD Weisenburger, and JO Armitage
Autologous bone marrow transplantation in follicular non-Hodgkin’s lymphoma before and after histologic transformation
Blood 74: 2579-2584.

Arnold S. Freedman Biology and Management of Histologic Transformation of Indolent Lymphoma Hematology 2005 © 2005 The American Society of Hematology

Despite nearly identical eligibility criteria and the use of an anthracycline-based induction treatment in all studies, the results are quite different. The previous studies found a significant advantage to autologous stem cell transplantation (ASCT). The German Lymphoma Study Group (GLSG) reported that patients randomized to transplantation had a 64.7% progression-free survival (PFS) rate at 5 years versus 33% with conventional chemotherapy. The Groupe Ouest-Est d’Etude des Leucémies aigues et autres Maladies du Sang (GOELAMS) group reported 60% PFS for those randomized to autologous transplantation versus 48% with conventional chemotherapy. By contrast, the Groupe d’Etude des Lymphomes de l’Adulte ( GELA) study does not show a significant PFS advantage for autologous transplantation.

The overall role of ASCT in follicular lymphoma continues to be debated. It is an excellent treatment option for the management of younger patients with recurrent disease. In advanced newly diagnosed lymphoma, a survival advantage has yet to be shown; with more prolonged follow-up it may still emerge in the GLSG study. An increased risk for therapy-related acute myeloid leukemia (t-AML) was observed in the GLSG and GOELAMS studies, but this risk may be minimized by modulation of induction and mobilization therapy preceding transplantation. Despite spectacular advances since the introduction of rituximab, many patients with advanced disease and a high Follicular Lymphoma International Prognostic Index (FLIPI) score have disease recurrences. For such patients, the continued study of autologous transplantation, possibly in combination with rituximab for in vivo purging, remains an important area of investigation.

The 2016 NCCN )FOLL-6) recommends autologous transplantation in “second-line” and says that allogeneic transplantation is appropriate in selected cases. ESMO, representing an European approach says: “•Myeloablative consolidation followed by autologous stem cell transplantation prolongs PFS and overall survival but its role has to be redefined in the rituximab era [I, B]. A potentially curative allogeneic stem cell transplantation (optionally with dose-reduced conditioning) may be discussed in relapsed disease.” In 2013, NCCN says(FOLL-B, 1) that for second line consolidation autologous stem cell transplantation can be done, or allogeneic for “highly selected patients”.

Koen van Besien Autologous transplantation for follicular lymphoma? Not too soon! Blood, 15 October 2006, Vol. 108, No. 8, pp. 2496-2497. M. Dreyling on behalf of the ESMO Guidelines Working Group Newly diagnosed and relapsed follicular lymphoma: ESMO Clinical Practice Guidelines for treatment and follow-upAnn Oncol (2010) 21 (suppl 5): v181-v183.

Issa F. Khouri Eight-year experience with allogeneic stem cell transplantation for relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, cyclophosphamide, and rituximab Blood June 15, 2008 vol. 111 no. 12 5530-5536

Ronjon Chakraverty et al, Allogeneic Transplantation for Lymphoma JCO 2011 29:1855-1863

NCCN, Follicular FOLL-6, 2016

PET scan at end of treatment, if available
Minimal radiologic examinations in patients with DLBCL at 6, 12, and 24 months after end of treatment, when indicated by site of disease
In regard to followup, a recent study showed that a negative PET scan after completion of therapy does not exclude the presence of residual microscopic disease and does not indicate complete remission. The majority of studies evaluating FDG-PET in lymphoma include patients with diffuse large B-cell non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease. There are limited data available on the role of PET in other histologies.

A negative PET scan at the end of therapy appears to provide favorable prognostic information. Persistently positive PET scans at the end of therapy, or in follow-up, warrant close follow-up or additional diagnostic procedures, since some of those patients may remain in prolonged remission.

The Imaging Subcommittee of the International Harmonization Project (IHP) in Lymphoma developed guidelines for performing and interpreting positron emission tomography (PET) for treatment assessment in patients with lymphoma. The new recommendations, targeting both clinical practice and clinical trials, are published in the January 22 Early Release issue of the 2007 al of Clinical Oncology. They are based on experts’ consensus and not randomized evidence.

Specific recommendations related to followup are:

After treatment completion, PET should be performed at least 3 weeks, and preferably 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Noncontrast PET/CT can be used instead of contrast-enhanced diagnostic CT to follow-up patients with lymphoma, although patients with hepatic or splenic involvement should continue to receive contrast-enhanced diagnostic CT. Attenuation-corrected PET is much preferred over nonattenuation-corrected scans.

Freudenberg LS, Antoch G, Schutt P, et al. FDG-PET/CT in re-staging of patients with lymphoma. Eur J Nucl Med Mol Imaging. 2004;31:325–329

Yuliya S. Jhanwar and David J. Straus The Role of PET in Lymphoma Journal of Nuclear Medicine Vol. 47 No. 8 1326-1334, 2006

Lavely WC, Delbeke D, Greer JP,

NCCN, NHL, BCEL-4, 2012

J. W. Fletcher, B. Djulbegovic, H. P. Soares, B. A. Siegel, V. J. Lowe, G. H. Lyman, R. E. Coleman, R. Wahl, J. C. Paschold, N. Avril, et al.
Recommendations on the Use of 18F-FDG PET in Oncology
J. Nucl. Med., March 1, 2008; 49(3): 480 – 508.

Zelenetz A, Abramson JS, Advani A, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Hodgkin’s Lymphomas. Version 2, 2011. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf.

Jost L. Newly diagnosed large B-cell non-Hodgkin’s lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2007;18(Suppl 2):ii55–ii56