For patients >age 60 years, 3-7 days of prednisone 100mg/day pre-R-CHOP as well as G-CSF prophylaxis are recommended to decrease toxicity.Limited-stage DLBCL is associated with favorable outcomes with long-term survival rates up to 80%, although a persistent pattern of late relapses has been described in up to 20-30% of patients. The stage-modified IPI score risk stratifies patients according to the following factors: age >60, stage II, elevated LDH, ECOG >1. In the pre-rituximab era, the phase III SWOG S8736 trial reported superior PFS and OS with CHOP3 plus RT versus CHOP8; 53 however, due to the occurrence of late relapses and treatment complications, there was no difference in PFS or OS between the two strategies with long-term follow-up. 54 In the rituximab era, the MInT trial established R-CHOP x6 as the standard of care for most patients with limited-stage DLBCL. 55 Given the favorable outcomes of limited-stage DLBCL, recent studies have assessed the role for treatment de-escalation to minimize toxicity while preserving efficacy. The LYSA/GOELAMS 02-03 trial of 334 patients with stage I-II nonbulky (<7cm) DLBCL demonstrated that R-CHOP alone is non-inferior to R-CHOP + RT if CR is achieved on interim PET after cycle 4; in addition, 4 cycles of R-CHOP was found to be sufficient for interim PET-negative patients with 0 sm-IPI risk factors (Blood 2018;131(2):174). The phase III FLYER trial found that 4 cycles of R-CHOP has reduced toxicity and non-inferior efficacy compared to 6 cycles for patients with stage I-II non-bulky (<7.5cm) DLBCL with no other sm-IPI risk factors. 56  In addition, the phase II SWOG S1001 trial and real-world data from BC Cancer demonstrated excellent PFS rates with 4 cycles of R-CHOP if CR is achieved after cycle 3, even in patients with up to 2 sm-IPI risk factors (# Table of Contents
Lymphomas encompass a group of lymphoproliferative malignant diseases that originate from T-and B-cells in the lymphatic system. Traditionally, lymphomas have been subcategorized into two groups: Hodgkin lymphoma and non-Hodgkin lymphoma. It is now known however, that Hodgkin lymphoma is simply one of the numerous varieties of lymphoma, and that non-Hodgkin lymphoma is a fairly meaningless term, representing all of the other subtypes of this disease.
Non-Hodgkin lymphoma involves a heterogeneous group of over 40 lymphoproliferative malignancies with diverse patterns of behaviours and responses to treatments. Non-Hodgkin lymphoma is much less predictable than Hodgkin lymphoma and prognosis depends on the histologic type, stage, and treatment. In Canadian males and females, the incidence rates for non-Hodgkin lymphoma showed a marked increase by approximately 50% between 1978 and the late 1990s, but have since stabilized 1. Mortality rates have followed a similar pattern. The clearest risk factor for the disease is immunosuppression associated with HIV infection, or medications used to prevent rejection in organ transplantation. Other factors that increase risk of non-Hodgkin lymphoma are poorly understood but may include occupational exposures to pesticides, herbicides, and dioxins, as well as chronic immune stimulation associated with autoimmune disorders (e.g. thyroiditis, Sjogren's Syndrome, SLE) or infections (e.g. Helicobacter pylori gastritis, hepatitis C virus) 2. In 2015, it is estimated that 8200 new cases of non-Hodgkin lymphoma will be diagnosed in Canada, and 2650 deaths will occur, making non-Hodgkin lymphoma the sixth most common cause of cancer-related death in Canada 3.
Hodgkin lymphoma is a malignancy characterized histopathologically by the presence of Reed-Sternberg cells in the appropriate cellular background. Although rare, Hodgkin lymphoma is one of the best-characterized malignancies of the lymphatic system and one of the most readily curable forms of malignant disease. 2 The incidence rate has remained fairly steady over time, it is estimated that approximately 1000 new cases of Hodgkin lymphoma are diagnosed in Canada each year 3. It is important to note that lymphoma also represents the most commonly diagnosed non-epithelial cancers in adolescents and young adults in Canada. Between 1992 and 2005, 5577 new cases of Hodgkin and non-Hodgkin lymphoma were diagnosed in Canadians aged 15-29 years 1. The following guidelines do not address lymphoma in the pediatric or adolescent populations.

# Guideline Questions
- What are the diagnostic criteria for the most common lymphomas?
- What are the staging and re-staging procedures for Hodgkin and non-Hodgkin lymphomas?
- What are the recommended treatment and management options for Hodgkin and non-Hodgkin lymphomas?
- What are the recommended follow-up procedures for patients with malignant Hodgkin and non-Hodgkin lymphoma?

# Search Strategy
Medical journal articles were searched using Medline (1950 to October Week 1, 2015), EMBASE (1980 to October Week 1, 2015), Cochrane Database of Systematic Reviews (3 rd Quarter, 2015), and PubMed electronic databases. An updated review of the relevant existing practice guidelines for lymphoma was also conducted by accessing the websites of the National Comprehensive Cancer Network (NCCN), Cancer Care Ontario (CCO), the British Columbia Cancer Agency (BCCA), the European Society for Medical Oncology (ESMO), and the British Committee for Standards in Haematology.

# Target Population
The following guidelines apply to adults over 18 years of age. Different principles may apply to pediatric and adolescent patients.
I. Diagnosis and Pathologic Classification  An excisional lymph node biopsy of the largest regionally involved lymph node is the optimal specimen for initial diagnostic assessment. Similarly, a sizable biopsy from the organ of origin in extranodal lymphomas is also suitable. Compelling clinical contraindications to an open biopsy should be present before considering any other options. A careful clinical examination or radiological investigations for more accessible or palpable pathologic adenopathy could be useful in decision making prior to opting for a lesser diagnostic specimen. Fine needle aspirate biopsies are inadequate for the initial diagnosis of lymphoma. These latter specimens may provide adequate material for evaluating possible relapse, clarification of staging at questionable sites and as a source of additional specimen where required for further special testing or research. Occasionally, a generous core needle biopsy comprising many core samples with sufficient material to perform the appropriate ancillary techniques required for diagnostic assessment (immunohistochemistry, flow cytometry, PCR for IgH and TCR gene rearrangements, and FISH for major translocations) may supply adequate tissue, in cases when a lymph node is not easily accessible for excisional or incisional biopsy. A reference lymphoma pathologist should confirm lymphoma diagnoses in each and every case. This is particularly important in cases when only a core needle biopsy is available, and whenever requested by the treating clinician.
Table 1 describes the histologic subclassification of the malignant lymphomas, and is an adaptation of the most recent WHO classification 6. This classification is based on the light microscopic interpretation complemented by special stains, immunophenotyping, cytogenetics and other ancillary information as available. The specific lymphomas are divided into three major groups, according to the degree of clinical aggressiveness, for treatment planning. All B-cell lymphomas should be immuno-phenotyped to determine if they are CD20 positive.

# Required Immunohistochemical and Ancillary Testing for Lymphoma
In general, guidelines for using the various ancillary methods, includingimmunohistochemical and fluorescence in situ hybridization (FISH) testing as outlined in the most recent version of the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues should be followed so as to confirm a specific diagnosis and provide necessary prognostic and/or predictive information 6. In addition, the following are recommended by the Alberta Provincial Hematology Tumour Team 7,8 :
- Classical Hodgkin Lymphoma: The immunohistochemical panel may include CD45/CD3/CD20/CD30/CD15/ PAX5/MUM1 and should be selected on a case by case basis at the discretion of the hematopathologist. EBV studies by in situ hybridization (EBER) may be considered if difficulty exists diagnostically, as most cases of the mixed-cellularity subtype of classical Hodgkin lymphoma are EBER positive.

# Diffuse Large B-Cell Lymphoma (DLBCL):
- Immunohistochemical (IHC) panels to distinguish between Activated B Cell (ABC) type and Germinal Centre B-cell (GCB) cell of origin (COO) types have limitations (regardless of which algorithm is employed)when compared to gene expression profiling 8,9. However, GCB vs non-GCB COO by IHC does correlate with survival rates following RCHOP chemotherapy, and therefore adds prognostic information when managing DLBCL. The Alberta hematopathologists currently use a simple algorithm published by Hans et al, requiring IHC stains for CD10, BCL6 and MUM1, in which CD10+ or BCL6+/ MUM1-cases are designated as GCB COO, whereas cases negative for negative/BCL6+/MUM1+ phenotype are considered to have a non-GCB COO.
- EBER and CD5 expression confer worse prognosis, and may be used to identify various clinicalpathological entities with distinct implications. Determining CD5 expression should be considered on all DLBCL cases. EBER should be performed in patients with immune suppression related lymphomas, or those who possibly have EBV-related DLBCL (consider past the age of 50) 10.
- Rearrangments of the C-MYC gene as determined by FISH, especially in association with BCL2 and/or BCL6 (so called "double hit" or "triple hit" disease) are associated with very poor outcomes following R-CHOP therapy, as well as high rates of central nervous system relapse.
Patients with a double-hit or triple-hit lymphoma under age 70 years should receive more aggressive therapy and possibly stem cell transplantation. Though it represents approximately only 5-10% of DLBCL cases 11 it is very important to recognize these patients, and therefore, MYC rearrangement testing by FISH is to be performed on all patients younger than 70 y.o. with the appropriate lymphoma histology, i.e. DLBCL or lymphoma that are so called "unclassifiable" with intermediate morphological features between DLBCL and Burkitt. If MYC is rearranged, the case should also undergo BCL2 and BCL6 rearrangement testing by FISH. MYC and BCL2 test results are required within 2 weeks of diagnoses for all new patients within the appropriate diagnostic category and age group. FISH testing may also be performed in select instances at the discretion of the reporting hematopathologist if such studies are deemed diagnostically useful.
- Immunohistochemical studies cannot be used as a surrogate for MYC rearrangement.
- However, the detection of MYC and BCL2 concurrent overexpression by IHC in so-called "dual expressor" DLBCL, identifies a numerically significant subset of the DLBCL with potentially similar aggressive behavior compared to double-hit lymphoma cases, but representing a distinct group of patients (more often an ABC subtype as opposed to double hit DLBCL which are usually GCB). This group is also associated with a high rate of CNS relapse 11. Therefore, provided adequate benchmarks and interpretation standards can be established for reproducibility, IHC for MYC and BCL2 expression should also be strongly considered on all DLBCL cases 9,12.
- Follicular Lymphoma: must document grade (1-2, 3a or 3b), because all grade 3b should receive R-CHOP rather than other chemotherapy regimens. Also, if a diffuse pattern is present, this should be specified and a relative proportion noted, as outlined in the WHO Classification. 4. Peripheral T-Cell Lymphoma: cytotoxic T-cell markers (CD8/CD57/Granzyme B) correlate with poor prognosis and should be considered. Notably, however, peripheral T cell lymphomas are not classified on the basis of these phenotypic markers. EBV studies by in situ hybridization (EBER) should be performed in cases where angioimmunoblastic T cell lymphoma (AITL) and extranodal T/NK cell lymphoma, nasal type enter in the differential diagnosis. 5. Mantle Cell Lymphoma: Evidence of CyclinD1 deregulation confirmed by IHC (positive staining for CyclinD1) and/or FISH (positive for t (11;14)) is needed to confirm the diagnosis, provided other morphophenotypic findings are consistent with the diagnosis. Poor prognostic features must be mentioned in the report, including blastoid and pleomorphic morphologic variants. The proliferation index as measured by Ki67 or Mib-1 (used to calculate MIPI score) is to be reported. In cases where it is difficult to differentiate MCL from CLL, flow cytometry for CD200 and IHC for SOX11 may be performed 13. For patients who are deemed transplant-eligible (i.e. age <65 and fit for intensive therapy), TP53 mutational testing should be performed at time of diagnosis to identify high-risk patients more appropriate for allogeneic stem cell transplantation 14.
II. Staging  Mandatory Staging Procedures
- Pathology review whenever possible (essential for core needle biopsies)
- Complete history and physical examination stating ECOG Performance Score, B symptoms
- CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium
- Hepatitis B Surface Antigen (HBsAg), Hepatitis B Surface Antibody (anti-HBs), and Hepatitis B Core Antibody (total anti-HBc) must be done prior to initiating chemo/immunotherapy. Patients who are HBsAg positive are either acutely or chronically infected and require consultation with Hepatology. Patients who are HBsAg negative/anti-HBc positive (regardless of anti-HBs titre levels) and are going to be treated with B-cell depleting therapy (e.g. rituximab) should receive prophylactic therapy with entecavir or tenofovir. Those who are HBsAg negative/anti-HBc positive and fall under low or moderate risk as per Table 1 do not require prophylaxis and should undergo serial HBV DNA testing q6-12 months and serial ALT testing q3 months while on immunosuppressive therapy (see Figure 1). Hepatitis B prophylactic therapy should be continued for at least 6 months following the completion of immunosuppressive therapy, except for those treated with anti-CD20 agents who should continue for at least 12-18 months due to the lag in B-cell function recovery.   Adapted from Coffin, Carla S., et al. 13 Anti-HBc = antibody to HBV core; anti-HBs = antibody to HBsAg; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; TNF = tumour necrosing factor.
- ESR (for early stage Hodgkin lymphoma)
- Serum protein electrophoresis and quantitative IgG, IgA, and IgM for indolent B-cell lymphomas
- Pregnancy test: if at risk
- Bone marrow aspiration and 2cm biopsy (BMasp/bx) with flow cytometry for patients with indolent B-cell and a marrow biopsy (without flow cytometry) for aggressive T-cell non-Hodgkin lymphomas. BMasp/bx is not required for Hodgkin lymphoma or DLBCL if a staging PET/CT is performed.
- FDG-PET and Diagnostic CT NeckChestAbdomenPelvis for FDG-avid, nodal lymphomas, which includes all histologies except chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, mycosis fungoides, and marginal zone NHLs (unless there is a suspicion of aggressive transformation). Nodal lymphomas that are not FDG avid should have a staging diagnostic CT scan of NCAP. PET-CT is especially important for patients who otherwise have non-bulky, stage I-IIA lymphoma, and are being considered for involved field radiation (IFRT) following abbreviated (or no) chemotherapy. PET/CT is not necessarily required for Follicular Lymphoma if the results will not change management, particularly for a patient who will likely undergo watchful waiting.
- The following are to be performed prior to each chemotherapy treatment:
- Clinical parameters: brief history and physical examination, toxicity notation, ECOG status - Bloodwork: o CBC/differential/platelet o also consider EP/creatinine and LFTs 2. Requirements for CT scanning of chest/ abdomen/ pelvis:
- Routine CT scanning: o after 3 months (4 cycles) of therapy and again after completion of all therapy for Non-Hodgkin Lymphomas o if a residual mass is seen on the CT after completion of all therapy, then repeat a PET/CT for aggressive lymphoma to determine partial or complete remission. o a repeat CT scan should be considered 6-12 months post-treatment; otherwise, no further routine CT scans are required o Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines.
- Other requirements for CT scanning: o as indicated to investigate clinical signs or symptoms, or abnormal laboratory tests 3. Bone marrow aspirate & biopsy (with sample sent for flow cytometry):
- Repeat for transplant-eligible patients with aggressive histology lymphomas who otherwise are in complete remission after completion of chemotherapy, if marrow was positive at diagnosis 4. PET/CT Imaging:
- Assessment of residual radiographic or clinical abnormalities of uncertain significance at the time of re-staging following completion of therapy.
- Hodgkin lymphoma patients should undergo a PET/CT after 2 cycles ABVD (rather than CT after 4 cycles) as outlined below in the Hodgkin Lymphoma treatment guidelines. For DLBCL, factors associated with high risk (>10%) for relapse in the central nervous system include 4-6 of the following factors: 1) Age >60 years, 2) elevated LDH, 3) ECOG=2-4, 4) Stage 3-4, 5) >1 extranodal site of involvement, and 6) kidney or adrenal involvement. Other high risk situations include double hit lymphoma (MYC + BCL2 and/or BCL6 translocations) and testicular lymphoma. Prophylactic intrathecal chemotherapy does not penetrate the brain parenchyma and has not been proven to decrease meningeal or parenchymal brain relapse of lymphoma in well-designed studies.
Due to the lack of proven benefit, intrathecal chemotherapy cannot be recommended even in highrisk situations where the risk of CNS relapse is 10% or higher.
For patients at high-risk of CNS involvement, we previously recommended CNS prophylaxis with high dose intravenous methotrexate (HD-MTX) 3.5g/m2 x 3 doses mid-cycle of R-CHOP following cycles 2, 4, 6. We recently reviewed our outcomes for patients who were treated according to our guidelines with a recommendation for incorporating intravenous HD-MTX for all patients with CNS-IPI score 4-6, double-hit lymphoma or testicular lymphoma. 67 Among 906 patients treated for DLBCL, with a median follow-up of 35.3 months, CNS relapse risk was similar with and without intravenous MTX (11.2% vs 12.2%, p=0.82), with rates in high-risk patients comparable to previous reports in patients who did not receive CNS prophylaxis (10-12%). However, the risk of CNS relapse trended lower in patients who received consolidative ASCT or intensified chemo-immunotherapy versus R-CHOP (6.0% vs 14.6%, p=0.09). The ineffectiveness of prophylactic HD-MTX has been confirmed in several other multiinstitutional retrospective studies, 68,69 71 CAR T-cell therapy is an established treatment for adult patients with relapsed/refractory large B-cell lymphoma after two or more lines of therapy, with two immune effector cellular therapies approved in Canada, namely axicabtagene ciloleucel (axi-cel, Yescarta) and tisagenlecleucel (Kyrmiah). In the pivotal phase I/2 Zuma-1 study, 110/111 enrolled patients with refractory DLBCL, primary mediastinal B-lymphoma, or transformed follicular lymphoma received a single infusion of axi-cel, with CR rate of 52% and ongoing CR of 40% at 15.4 months of follow-up, and OS of 52% at 18 months. 72 At 38.1 months median follow-up, the OS rate was 47% with median of 25.8 months. 73,74 In the phase 2 Juliet trial 93 patients with relapsed/refractory DLBCL or transformed follicular lymphoma received a single infusion of tisagenlecleucel, with CR of 40% and relapse-free survival of 65% at 12 months (79% in those who achieved CR). 75 Lisocabtagene maraleucel (Liso-cel) is a third immune effector cell therapy being studied, and the TRANSCEND NHL001 study presented at ASH 2019 demonstrated similar efficacy data, with CR rate of 53%, and OS 57.9% at 1 year (85/% in patients with CR). 76 The main toxicities of these therapies are cytokine release syndrome, neurotoxicity, cytopenias, and B-cell aplasia/hypogammaglobulinemia and as such this therapy is be administered only at centers approved for cellular therapy treatments.
Phase III trials with axi-cel and liso-cel as second line therapy compared to the standard salvage chemotherapy approach in patients with poor prognosis relapsed/refractory DLBCL 50% of these patients subsequently proceeded with CAR T therapy in 3 rd line, with inferior outcomes. Review of 125 southern Alberta patients between 2015 and 2019 with relapsed/refractory DLBCL after RCHOP chemotherapy demonstrated that of the 50 patients that were intended for salvage and HDT-ASCT, only 28 underwent a stem cell transplant, with long-term cure in only 9 of these patients. 78 These data suggest that while the current standard of care results in poor outcomes for most patients with relapsed/refractory DLBCL, the use of CAR T therapy second line could substantially increase the proportion of patients able to receive curative treatment at first progression.

# Patients unfit for intensive therapy:
The prognosis of patients with relapsed/refractory DLBCL who are not candidates for cellular therapy is extremely poor, with median survival rates of less than 6 months, thus palliation is the main goal of any chosen therapy. Palliative-intent regimens including R-GemOx, polatuzumab vedotin with bendamustine/rituximab, and tafasitamab with lenalidomide have been studied in phase II trials of patients with r/r DLBCL who are unfit for intensive therapy:

# Recommendations for treatment:
- R-GemOx is the preferred second-line treatment because it is a well-established outpatient platinum-based regimen that is better tolerated in older patients than other regimens such as GDP, DHAP, or ICE, although it is associated with significant myelosuppression.
Polatuzumab, bendamustine, and rituximab can be considered for second or later relapses, and for patients who are unfit for, or intolerant of, R-GemOx. Patients should have reasonable performance status (ECOG 0-2) and adequate hematologic function to be expected to benefit from and tolerate polatuzumab with BR. Tafasitamab-lenalidomide is also approved but is not yet funded in Alberta. Bendamustine and tafasitamab should be avoided in patients potentially eligible for CAR-T cell therapy due to the respective risks of lymphodepletion and CD19 downregulation.
Some palliative patients at or beyond second relapse may have symptomatic benefit from prednisone alone, or low dose daily oral chemotherapy with chlorambucil 0.1mg/kg/day or etoposide 50mg/day, or combination oral therapy such as PEPC.
Involved field radiotherapy (IFRT) to symptomatic sites or localized relapses may also benefit these palliative patients.
Addressing goals of care and ensuring timely integration of palliative care should be a priority for all patients with r/r DLBCL who are unfit for intensive therapy.

# Secondary CNS Lymphoma 79-82
Selected patients with CNS relapse/progression may be candidates for intensive therapy as outlined in Appendix A, subheading VIII. Favorable outcomes were reported in an Alberta study of 62 SCNSL patients with median age 58 years (range 20-75) intended for transplant, with ASCT rates of 84%, 5year PFS 53% and OS 65% for all patients, and 5-year PFS 62% and OS 73% for those undergoing R-TBuM conditioning and ASCT. One of 3 induction regimens is recommended for transplant-eligible patients and one of two options for transplant ineligible patients, based on presentation:
1) Isolated CNS lymphoma: HDMTX-based induction then RDHAP for stem cell mobilization and collection, then R-TBuM/ASCT for transplant eligible (

# High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements by FISH:
High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double hit lymphoma or DHL) is associated with a poor prognosis, with a large multicenter retrospective analysis of 311 patients reporting an OS rate <50% if IPI=2-5 vs 65% for IPI=0-1 (Blood 2014;124(15):2354). The optimal treatment of DHL is unknown, but intensive induction regimens such as da-EPOCH-R or R-CODOX-M/R-IVAC are commonly used and have demonstrated PFS benefit over R-CHOP in some retrospective studies (Blood 2014;124(15):2354) but not others (Am J Hematol 2021; 96(3):302). In

# CAR T-cell Therapy
addition, the use of consolidative HDT/ASCT has been associated with superior outcomes among patients achieving CR after R-CHOP induction but not after intensive induction regimens. 83 This suggests that DHL patients treated with R-CHOP can be considered for ASCT consolidation, especially if IPI=2-5 at diagnosis, however other patients who achieve CR after an intensive induction regimen probably should not receive ASCT consolidation. A retrospective analysis of 99 patients with DHL in Alberta found relatively favorable outcomes with 4-year PFS 59% and OS 66%, with no significant difference in PFS or OS between patients treated with intensive induction regimens vs intention-to-transplant following R-CHOP induction. Among the 48 patients intended for ASCT, outcomes were excellent for the 75% of patients undergoing upfront ASCT with 4-year PFS 80-90%, whereas there were no survivors among the 25% of patients with primary refractory disease. This suggests that upfront ASCT can achieve durable remissions in the majority of DHL patients with chemosensitive disease, whereas alternative strategies such as CAR-T cell therapy should be strongly considered for patients with chemorefractory disease.

# Alberta recommendations for high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements:
- IPI=0-1: R-CHOP x 6 cycles or da-EPOCH-R x 6 cycles - IPI=2-5: Options include:
- A. R-CHOP x 2-3

# Primary Mediastinal B-Cell Lymphoma
Primary mediastinal B-cell lymphoma (PMBCL) of thymic origin represents 6-10% of all DLBCLs, and most commonly affects young adults (median age ~35), women more than men. 84 It is frequently associated with a bulky mediastinal mass that directly extends into extranodal thoracic tissues such as pleura, pericardium and chest wall. Patients with distant lymphadenopathy or extranodal involvement outside the thorax should likely be diagnosed and treated as systemic DLBCL with secondary mediastinal involvement, rather than as PMBCL. 85 Overall, PMBCL is associated with a better prognosis than other DLBCLs, including GCB DLBCLs. The IPI score tends not to work well for PMBCL because most patients are young with fairly well-preserved performance status, and have elevated LDH. Therefore, limited vs advanced stage, and number extranodal sites (esp pleural effusions) tend to be the only factors that subdivide patients into excellent vs good prognosis. Likewise, because most patients have a very good prognosis, interim restaging PET imaging is associated with very high negative predictive value, but relatively low positive predictive value. 86 These findings were confirmed in 20 patients treated with R-CHOP in Alberta, where the PPV of a positive interim PET scan was only 20% for disease progression/relapse whereas a negative interim PET had NPV 100%. Therefore, a positive interim PET scan should probably not be used alone to guide further therapy.  87 There is no phase III evidence that RT after R-CHOP improves survival rates relative to R-CHOP alone, but this is being studied in the ongoing IELSG-37 clinical trial. Real-world data from the BCCA demonstrates that omitting RT for PETnegative patients at the end of R-CHOP therapy achieves similar TTP (80%) and OS (89%) as historical cohorts treated routinely with RT, with a reduction in RT use from 78% in the historical cohort to 28% in the PET-directed era. 88 Similarly, retrospective data for 91 consecutive patients in Alberta treated with R-CHOP from 2004-2020 found a 5-year overall survival rate of 86%, with similar outcomes for patients with advanced versus limited stage (86% vs 92%, p=0.31) or bulky versus nonbulky disease (83% vs 96%, p=0.12). For patients responding to R-CHOP, the 5-year OS rate was 93% with RT versus 100% without RT (p=0.17). Among 40 patients with a PET-defined complete metabolic response after R-CHOP, 5-year OS was 100% for all patients treated with (n=9) or without (n=31) RT.
Management of patients with partial metabolic response after R-CHOP is uncertain. Prospective data show that the majority of Deauville 4 end-of-treatment (EOT) PET scans after DA-EPOCH-R are false-positives which can be monitored with surveillance PET without RT, with progressive disease occurring in only 1/16 patients with Deauville. 89 Among the 34 patients in BC and Alberta with Deauville 4 EOT PET after R-CHOP (the majority of whom received RT), survival outcomes were excellent and similar to EOT PET-negative patients. It is likely that many cases of partial metabolic response after R-CHOP are false positives as well; indeed, 5 patients in Alberta and BC with Deauville 4 after R-CHOP were observed without RT and none relapsed. Extrapolating from this data, it has been proposed that surveillance imaging without radiation may be reasonable for young patients with Deauville 4 EOT PET after R-CHOP given the likely low risk of progression and long-term risks of toxicity from RT. 90 In conclusion, available evidence supports the use of R-CHOP for patients with PMBCL, with less toxicity but similar excellent outcomes as DA-EPOCH-R. End of treatment PET should be done 6-8 weeks after day 1 of the final cycle of chemoimmunotherapy to allow time for the post-treatment inflammatory response to resolve. 91 In view of the long-term risk of secondary malignancy and premature heart disease from RT in young patients, RT can probably be safely omitted for patients with PET-negative disease after R-CHOP. Omitting RT in favour of surveillance imaging in 6-8 weeks (CT is the preferred modality in Alberta) may be reasonable for patients <60 years old with Deauville 4 on EOT PET after R-CHOP, while older patients and those with Deauville 5 should receive RT. For the 10-20% of patients with suspected relapsed/refractory PMBCL, the diagnosis of progressive disease should be confirmed with biopsy or clear progression on CT, and not based on FDG uptake on PET alone. Treatment options at relapse include radiation for localized disease, salvage chemotherapy and autotransplant, radiation therapy, axicabtagene ciloleucel (funded only after 2 prior lines of therapy), and pembrolizumab. Follicular Lymphoma  Throughout the following suggested treatment approach, three over-riding principles should be considered: 1. These are guidelines only. This disease often carries a long, incurable, remitting/relapsing natural history and, therefore, several treatment approaches are reasonable. 2. The mere presence of disease does not alone imply the need for treatment. 3. If therapy is required for predominantly localized disease, IFRT should be considered in lieu of systemic pharmacological treatment as long as the radiotherapy can be done with minimal early or delayed side-effects (e.g., xerostomia, severe nausea/vomiting) and without eliminating future treatment options (e.g., should not radiate 25% bone marrow). Figure 2 outlines the treatment algorithm for follicular lymphoma.  For patients who do not have any of the above indications for therapy, the recommended approach is to observe with (or arrange) follow-up clinical assessments every 3-6 months ("watchful waiting"), and a CT CAP 1 year after diagnosis. For patients not meeting treatment criteria 1 year after diagnosis, another CT 2 years after diagnosis could be considered. Patients who have progressive disease on www.ahs.ca/guru follow-up should generally be treated, even if they do not fulfill any of the other indications for therapy.
A retrospective study of 238 Alberta follicular lymphoma patients managed with watchful waiting found that 24% developed transformed disease or significant organ dysfunction (at a median of 30months) prior to initiating initial therapy, and these patients had inferior survival rates compared to other patients requiring therapy who were initially managed with watchful waiting (10 yr OS 67.9% vs 85.7%, HR 3.000 (95%CI 1.696-7.126), p=0.0007). These watchful waiting patients did not undergo routine follow-up CT scans at 1 or 2 years to identify progression. It is possible that these adverse outcomes might have been avoided with closer monitoring by CT imaging and earlier initiation of chemoimmunotherapy 138.
For grades 1,2,3a follicular lymphoma who have an indication for therapy, the recommended therapy involves 6 cycles of B-R (bendamustine-rituximab) chemotherapy, followed in responding patients by 2 years of maintenance rituximab (every 3 months for total of eight doses). In patients with previously untreated indolent lymphoma, B-R can be considered as a prefered first-line treatment approach to R-CHOP because of increased progression-free survival and fewer side-effects. Patients who have limited life-expectancy from serious co-morbid illness, or who do not want intravenous therapy, may be treated with oral chlorambucil or fludarabine monotherapy.
The GALLIUM clinical trial investigated the value of obinutuzumab in combination with chemotherapy followed by maintenance therapy compared to standard therapy with rituximab chemoimmunotherapy plus maintenance in the firstline treatment of follicular lymphoma. The study demonstrated superiority of obinutuzumab over rituximab in terms of PFS (3-year PFS was 81.9% (95%CI: 77.9-85.2%) vs. 77.9% (95%CI: 73.8-81.4%), with acceptable increased toxicity.. As no OS advantage has yet been demonstrated, obinutuzumab is not funded in Canada for this indication and we continue to recommend rituximab. 139.
Grade 3b follicular lymphoma should be treated as DLBCL with, R-CHOP. Rituximab maintenance has not been proven effective following R-CHOP therapy for large B-cell lymphoma, and therefore is not recommended.
Therapy of relapsed disease: Therapeutic recommendations for recurrent follicular lymphoma need to be individualized, and no one recommendation is suitable for all patients. Numerous factors need to be taken into consideration before recommending therapy for recurrent follicular lymphoma, including:
- Patient Factors: Age, co-morbidity, symptoms, short vs. long-term goals, preservation of future options, reimbursement/ability to pay for expensive treatments, acceptance of risks/toxicities of treatment option relative to potential benefit (RR, PFS, OS).
- Disease Factors: Stage, sites of involvement, grade, transformation, prior therapy, time from prior therapy (disease-free interval).
For example, previously healthy patients younger than 70 years who relapse within 2 years of initial chemotherapy have a median life expectancy of <5 years, and are best managed with HDCT/ autologous SCT. HDCT/SCT maximizes the length of disease control for all patients less than 70 years, regardless of length of initial remission, and as such is a reasonable treatment option for those who accept potential risks/toxicities. Therefore, patients younger than 70 years without serious comorbid disease, and who respond to salvage therapy should be considered for high dose chemotherapy and autologous (relapse 1-2) or allogeneic stem cell transplantation (relapse 3). A large retrospective study of consecutively treated relapsed follicular lymphoma patients in Alberta and BC reported 5 year overall survival rates following relapse of ~90% for those who received ASCT vs ~60% for those who did not receive ASCT. This marked difference in survival retained significance in multivariate as well as instrumental variable analyses 140. While the study used bendamustine as a chemotherapy backbone, few patients on the study had received bendamustine as their frontline therapy. Given current practice ofBR for the frontline treatment of FL and the fact that there is no biological reason that the same clinical benefit of obinutuzumab would not be seen in combination with other chemotherapies, alternate NHL chemotherapy backbones can be considered for patients deemed inappropriate for bendamustine retreatment. Relatively frequent infections were noted so prophylactic antibiotics and antivirals should be considered, especially when obinutuzumab is combined with bendamustine.
Another option to consider for rituximab-refractory relapsed FL is radioimmunotherapy with 90Yibritumomab tiuxetan (Zevalin). This optionrequires Director's Privilege approval, and is not currently listed on the Alberta Cancer Drug Benefit List for funding. In a small study of 57 patients with rituximab-refractory FL (median 4 prior therapies), the overall response rate to 90Y-ibritumomab tiuxetan was 74% (CR 15%) and median duration of response of 8.7months. There may be small subset of patients (10-15%) who achieve long-term PFS following 90Y-ibritumomab tiuxetan 118,141.
Idelalisib, a PI3K inhibitor has also shown efficacy in a Phase 2 study of double-refractory FL patients (patients with lack of response or progression within 6 months of both rituximab and an alkylator). Idelalisib can lead to durable remissions in a minority of patients and is currently not funded in Canada but is available through a compassionate access program. Infectious complications and immune toxicities are frequent and prophylactic antibiotics and anti-virals are required to reduce the risk of serious infections. 142 Palliative, symptomatic care (possibly including palliative IFRT 4Gy/2 fractions) is usually the best option for patients who were refractory to their 2 most recent treatment regimens, those with CNS involvement, or those with an ECOG score of 3-4.

# Indolent Lymphomas (Excluding Follicular Histology) 1, 143-151
Indolent lymphomas should generally be treated similarly to follicular grade 1-2 lymphomas. - majority should receive B-R, then rituximab maintenance - alternatives in special situations include IFRT, fludarabine, or chlorambucil

# Splenic Marginal Zone Lymphoma
Splenic marginal zone lymphoma is an uncommon type of non-Hodgkin lymphoma characterized by splenomegaly, cytopenias, lymphocytosis, and less commonly lymphadenopathy. Revised diagnostic criteria now specify the typical blood and bone marrow findings of SMZL and splenic biopsy is not usually required to establish the diagnosis 152. It is still reasonable, however, to proceed with splenectomy if the cause of splenomegaly is not determined following peripheral blood and bone marrow evaluation.
The disease course is indolent and many patients can be managed expectantly until symptomatic splenomegaly or pronounced cytopenias develop. SMZL prognostic scoring systems have been described, with low hemoglobin, low platelets, elevated lactate dehydrogenase and extra-hilar lymphadenopathy as adverse markers 153.
In rare cases, SMZL has been associated with hepatitis C infection (HCV), so all patients should be screened at diagnosis. Those who are HCV+ should first be offered HCV-directed therapy, as the lymphoma may regress avoiding the immediate need for further therapy 154,155. Splenectomy has previously been the standard approach to treat SMZL for over two decades 156. The role of splenectomy as frontline treatment of SMZL is now controversial 157, 158 159 160. Risks posed by splenectomy include operative morbidity and mortality, particularly in the elderly, or those with multiple comorbidities. However, surgical outcomes are improving at experienced centres. The risk of infection with encapsulated organisms is a serious concern, but may be mitigated with timely vaccination and long-term antibiotic prophylaxis 161.
Monotherapy with rituximab has recently emerged as a non-operative alternative  with reports suggesting survival outcomes similar to historical patients treated with splenectomy. Chemoimmunotherapy such as rituximab-bendamustine (BR) is also a rational approach for SMZL given the recent favourable results of a large scale RCT of iNHL, including marginal zone histology 136.
Although existing evidence is inadequate to conclude which treatment approach is superior, we propose the following strategy for managing SMZL:
- Rituximab monotherapy is recommended as frontline therapy for most patients. A standard regimen is rituximab weekly for 4 weeks, followed by a response assessment 4-6 weeks later. a. Those achieving at least a partial response, defined by conventional response criteria 152 should subsequently receive maintenance rituximab as per other iNHL subtypes. b. Non-responders or those with progressive disease should proceed with either: i. Splenectomy if the spleen is the major site of disease or ii. BR for those with additional nodal disease, extensive bone marrow involvement, or non-operative candidates, then followed by maintenance rituximab in responding patients.
- Select patients who require a splenectomy to establish the diagnosis and have no bone marrow, peripheral blood, or nodal involvement, do not require maintenance rituximab and may simply be observed.

# Lymphoplasmacytic Lymphoma (LPL)
Diagnostic criteria for Waldenstrom macroglobulinemia (WM):
- IgM monoclonal gammopathy of any concentration - Bone marrow infiltration by small lymphocytes showing plasmacytoid/plasma cell differentiation, usually with intertrabecular pattern of bone marrow infiltration predominantly lymphocytic to lymphoplasmacytic to overt plasma cells. 5. CT of the abdomen and pelvis: to detect organomegaly and lymphadenopathy (skeletal surveys and bone scans are not necessary in absence of symptoms). 6. Blood or plasma viscosity: if signs and symptoms of hyperviscosity syndrome (HVS) or IgM> 50 g/L. 7. Direct antiglobulin test and cold agglutinin titre if positive. 8. Cryoglobulins. 151. Serum IgM monoclonal protein should be measured by serum protein electrophoresis. The use of nephelometry to determine total serum IgM should be discouraged because this method is unreliable, especially when the levels of monoclonal protein are high. The presence of cryoglobulin or cold agglutinin may affect determination of IgM; therefore, testing of cryoglobulin and cold agglutinin at baseline should be considered, and if present, serum samples should be reevaluated at 37C to ensure accurate and consistent determination of the monoclonal protein levels.
- LPL immunophenotype: o surface IgM+ CD5-CD10-CD19+ CD20+ CD22+ CD23-CD25+ CD27+ FMC7+ CD103-CD138- - Recent

# IgM monoclonal protein response assessment in WM

# Hyperviscosity syndrome (HVS) in LPL
Symptoms and signs of hyperviscosity include spontaneous bleeding, neurological symptoms and retinopathy. Patients with HVS have an expanded plasma volume and cardiac failure may also occur. There are several published reports demonstrating the efficacy of plasmapheresis in HVS although randomised data are lacking. There is not, however, a simple linear relationship between paraprotein concentration and either plasma viscosity, whole blood viscosity or symptoms. An increase in IgM concentration from 20 to 30 g/L results in an increase in plasma viscosity of <2 centipoise (cP) but an increase from 40 to 50 g/L increases the plasma viscosity by around 5 cP. Indeed, a 1-volume plasma exchange results in a 35-40% decrease in IgM concentration but in up to a 60% reduction in plasma viscosity. In patients with WM the actual plasma volume may exceed that calculated and, given the data above, a 1-1.5 volume exchange is therefore advisable.

# General treatment guidelines for LPL/WM 151.
The usual indications for starting patients with LPL/WM on active therapy consist of clinical evidence of adverse effects of the paraprotein (HVS with neurological or ocular disturbance, peripheral neuropathy, amyloidosis, symptomatic cryoglobulinemia), symptomatic anemia (Hb<100g/L beware of pseudo-anemia from hemodilution), platelets <100, progression to high-grade lymphoma, significant adenopathy or organomegaly, or constitutional symptoms.
- Plasmapheresis: 1-2 procedures, exchanging 1-1.5 calculated plasma volumes, are advised for the treatment of HVS in WM, followed by chemotherapy to prevent paraprotein re-accumulation. In patients who are drug-resistant, plasmapheresis may be indicated for long-term management.
Although there are few studies that consider the role of plasma exchange in the treatment of cryoglobulinemia, there is a clear rationale for its use. The treatment room should be warm and blood warmers used in the cell separator circuit to prevent precipitation during the procedure.
- Chemotherapy: The most common initial chemotherapy for LPL is B-R (Bendamustine-Rituximab) followed by rituximab maintenance, similar to other indolent B-cell lymphomas. For patients who do not tolerate B-R, CDR (Cyclophosphamide, Decadron, Rituximab) or Bortezomib-based therapy (eg. R-Bortezomib, R-CyBorD) should be considered. Rituximab is active in the treatment of WM but associated with the risk of transient exacerbation of disease-related complications and should be used with caution in patients with symptoms of hyperviscosity and/or IgM levels >40 g/L. In patient with hyperviscosity and/or IgM levels >40 g/L, it is advised to hold rituximab for cycle 1, and start rituximab with cycle 2 chemotherapy. In retrospective studies, purine analogue therapy is associated with higher rates of prolonged cytopenias, infections, secondary MDS/AML, and transformation to large cell lymphoma when compared to therapy with alkylating agents.
- New data supports the use of ibrutinib in LPL (both first line and for relapsed/refractory disease).
Given the tolerability and durable responses to ibrutinib monotherapy, this is the preferred second line therapy for most patients. 163,164 - Many second-line therapy options exist. Patients who have obtained lengthy first remissions can be re-treated with chemo-immunotherapy with or without the addition of bortezomib (eg. R-Bortezomib, R-CyBorD). Purine analogues (Fludarabine) are usually reserved for multiply relapsed disease.

# Hairy Cell Leukemia
Hairy cell leukemia (HCL) and HCL variant (HCL-V) are mature lymphoid B-cell disorders, characterized by the identification of hairy cells and a specific genetic profile. Diagnosis of HCL is based on morphological evidence of hairy cells, immunophenotypic positivity for CD11C, CD103, CD123, and CD25 expression and the presence of BRAF V600E somatic mutation. BRAF-V600E has not been identified in other B-cell chronic lymphoproliferative disorders except very rarely so the mutation is now considered as the molecular hallmark of the disease. Absence of the BRAF gene mutation is reported in approximately 10% of patients with HCL and appears to constitute a subgroup with a poor prognosis 165.
Patients with asymptomatic HCL may be managed with active observation (watch & wait strategy). Symptomatic patients should be treated with symptoms commonly derived from cytopenias or splenomegaly. Most guidelines agree that even asymptomatic patients with marked cytopenias should be treated including at least one of the following: hemoglobin < 110 mg/dL, platelet count <100 000/L, or an absolute neutrophil count <1000/L.
In the first-line setting, purine analogs (cladribine or pentostatin) have been demonstrated to result in long overall survival. No randomized trials have been performed in HCL with no studies to suggest superiority of either drug but cladribine is available in Canada and is the most frequently used drug worldwide for HCL. Early studies used continuous intravenous dosing over 7 days 166 but more recent studies (non-comparative) have investigated subcutaneous dosing over 5 days and demonstrate excellent responses 167. The recommended dose of cladribine is 0.1-0.14mg/kg daily for 5-7 days. We recommend sc dosing for convenience and reduced infusion times. Infection prophylaxis is recommended as with other purine analogues (PJP and viral prophylaxis for 6-12 months) and patients with active infections should have control of infection prior to therapy initiation if possible.
For relapsed HCL, cladribine can result in a second durable remission however, synergy has been demonstrated with rituximab such that we recommend combination therapy with rituximab and cladribine for relapsed disease 168. Studies of rituximab have used a weekly schedule x 8 weeks, concurrent with cladribine. Careful attention for and prophylaxis against infection is recommended.
A recent study investigated the addition of rituximab to cladribine in the frontline setting. HCL patients treated with concurrent cladribine and 8 weekly doses of rituximab had higher MRD-free complete remission rates than patients treated without rituximab or with delayed rituximab. (JCO 2020; 38:1527) As improved responses are predicted to lead to longer remissions and given the proven benefit of rituximab in combination with chemotherapy frontline for other indolent NHLs, we recommend consideration of cladribine + rituximab for frontline HCL treatment. Infectious risks and lack of survival data should be considered with cladribine monotherapy favoured for frailer patients and those at high risk of infection.
Given the importance of BRAF V600E in this disease, BRAF inhibitors have been investigated in relapsed patients with high response rates. Low dose vemurafenib at 240mg twice daily was reported to result in complete remissions in 40% of patients. Unfortunately, results do not appear durable after drug discontinuation and retreatment or chronic treatment may be required 169. We recommend BRAF inhibition for patients who are refractory to cladribine (relapse < 24 months) or relapse after cladribine + rituximab 170. Vemurafenib has also been used successfully in previously untreated patients with active infections as a bridge to cladribine therapy during treatment of the infection.
Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin, which has also proven efficacy in highly refractory HCL patients. This agent is associated with severe adverse reactions including hemolytic-uremic syndrome (7.5%) and capillary leak syndrome (5%). (leukemia 2018; 32: 1768) Moxetumumab is not currently funded in Canada but could be considered in relapsed HCL patients who have exhausted all other therapeutic options.

# Special Lymphomas
Mantle cell lymphoma 136, 137, 171-186 : Characteristics of mantle cell lymphoma include: male predominance, median age approximately 65 years, advanced stage with multiple extranodal sites (marrow, blood, and intestinal tract), relative chemoresistance, no evidence for curability following R-CHOP chemotherapy, median time to relapse after initial chemotherapy of 12-18 months and median survival following RCHOP induction of 3-5 years. Significant improvements in PFS over RCHOP alone have been demonstrated with the addition of high dose cytarabine to RCHOP-like regimen induction followed by high dose therapy and ASCT for transplant eligible patients, and for B-R induction for transplant ineligible patients, as well as for prolonged rituximab maintenance after completing initial chemotherapy.

# Recommendation regarding Watchful Waiting for MCL
Although most patients with MCL have relatively aggressive disease, and even those asymptomatic patients initially managed with watchful waiting have median times to first systemic therapy of 11-12 months, a small proprotion of patients can be manged expectantly for over 5 years 187,188. Features suggestive of indolent MCL include leukemic non-nodal presentations, predominantly hypermutated immunoglobulin heavy chain variable regions, non complex karyotypes and absence of SOX11 expression by immunohistochemistry 189. Occasionally, nodal MCL can also follow an indolent course 187,188. Prognostic indices such as the MIPI have not been shown to identify indolent MCL 187.
Poor prognostic features associated with shorter survivals and response durations, for which expectant management is not appropriate, include high burden nodal disease, Ki-67 positivity >20-30%, blastoid histology, p53 or Notch1 mutation, gene expression profiling and altered microRNA signature 190. No prospective randomized trials, or properly designed retrospective comparative effectiveness research studies have compared immediate treatment versus watch-and-wait for MCL patients without clear indications for therapy. Poorly designed retrospective studies suggest similar survival outcomes to immediate therapy, however these studies were biased because patients were selected for watchful waiting based upon better prognostic factors (eg. younger age, better performance status) and did not routinely administer immediate aggressive therapy according to current standards to all patients in the control groups 187,188. Prospective randomized trials have demonstrated that more aggressive therapy improves PFS and OS rates relative to less aggressive therapy for MCL. Extrapolating these data to the hypothetical question of aggressive therapy vs no immediate therapy leads to the logical conclusion that immediate therapy is likely the superior approach for most MCL patients.
Given the lack of high quality evidence from properly conducted comparative studies to prove the W&W is non-inferior to immediate therapy, W&W should only be considered for patients who present with all of the following features:
1) Non-nodal disease such as CLL-like presentation (lymphocytosis without associated cytopenias) or stage IAE marginal zone-like presentation. Patients presenting with nodal disease should generally receive immediate chemo-immunotherapy as indicated in treatment sections below unless they have significant co-morbidity that will limit life-expectancy, low tumor burden, and meet other criteria listed in this section below. 2) No disease-related symptoms 3) No adverse pathology features such as blastoid variant, Ki67>20% of cells, or complex cytogenetic changes. Other adverse features include SOX11 expression and complex cytogenetic changes, however, SOX11 immunohistochemistry is not routinely available in Alberta. 4) Patient consent to forgo immediate therapy despite knowledge of demonstrated survival benefits of aggressive vs less aggressive therapy. Patient agreement to surveillance disease monitoring.

# Treatment -Transplant Eligible Patients (Age <65yrs)
The accepted standard of care for newly diagnosed MCL patients <65 years of age without major comorbidities involves chemoimmunotherapy followed by high dose therapy with ASCT and then 3 years of rituximab maintenance administered every 2 months. Progression free and overall survival benefit has been established in a prospective randomized trial for patients treated with myeloablative radiochemotherapy followed by autologous stem cell transplant in first remission as consolidation after CHOP-like chemotherapy 183,184. This strategy was compared to interferon alpha maintenance and demonstrated a 22mo improvement in progression free survival and 20.5mo improvement in overall survival with ASCT. These benefits of ASCT were seen in patients who had low risk MIPI, and who attained CR after RCHOP induction. The addition of high dose cytarabine with rituximab (RC) to RCHOP-like regimens is associated with improved rates of CR, PFS, and OS relative to RCHOP alone. This is supported by studies from the GELA and the European MCL Network with R-CHOP/R-DHAP induction prior to ASCT (RCHOP-21 x 3 followed by R-DHAP x3 or alternating RCHOP/RDHAP x 6 cycles) 185 as well as the Nordic regimen published as a phase II trial involving RCHOP-21 alternating with Ara-C for a total of 6 cycles, then ASCT 191. Given the superiority of BR over RCHOP in terms of efficacy and tolerability in patients with MCL, a phase 2 study of BR and RC induction for transplant-eligible patients was conducted and demonstrated a favorable safety profile as well as efficacy (with CR 96% and 93% MRD negativity after ASCT) 192. A pooled analysis of 89 patients who received BR/RC induction chemotherapy prior to ASCT demonstrated a high transplant rate (89%), and durable remissions (5-yr PFS 80% and OS 85%) thus confirming that BR/RC is an excellent choice for induction therapy in MCL 193.
TP53 mutation is an uncommon (11%) but significant poor prognostic finding in patients with MCL, highly associated with blastoid morphology, Ki-67 >30%, and high risk MIPI 194. Unfortunately, intensified standard-of-care regimens for younger patients with MCL do not overcome the deleterious effects of TP53 mutations, with a median OS of 1.8 years, compared to 12.7 years for TP53unmutated (p,0.0001) 194. Response to ibrutinib is also less favorable in patients with mutated versus wild-type TP53, with median PFS of only 4 months 195. As such, all patients who are transplant-eligible should undergo TP53 mutational testing, with allogeneic SCT preferred over autologous SCT for patients with available donors. Allogeneic SCT should also be considered in patients with relapsed disease or with high risk MIPI scores at diagnosis and significant blood/marrow involvement, especially with blastoid morphology.
Although maintenance rituximab has been shown to improve PFS and OS (4 year OS 87% vs. 63%) in the elderly population (age > 60) after induction with R-CHOP 196 the role of rituximab maintenance after ASCT for younger patients was uncertain until results of the phase III trial (LyMa) were reported 182. In the LyMa trial, 299 patients <66years of age with mantle cell lymphoma received 4 courses of R-DHAP followed by R-BEAM/ASCT (patients who did not achieve at least PR after R-DHAP could receive 4 additional courses of R-CHOP to facilitate ASCT) and 240 responders were then randomly assigned to receive 3 years of rituximab maintenance therapy (375 mg/m 2 one injection every two months) or watch and wait. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Progression-free survival at 4 years was improved at 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001)and overall survival was improved at 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). In support of the LyMa trial, a retrospective review of 72 patients previously enrolled in a phase II trial showed a progression free survival benefit in patients who received maintenance Rituximab vs those who did not (2 year PFS 90% vs. 65%) 197.

# Treatment -Transplant Ineligible Patients (Age >60-65yrs)
For patients with mantle cell lymphoma over 60-65 years of age, B-R induction x6 cycles is our standard of care. Results from a recently published open-label, multicentre, randomized, phase 3 non-inferiority trial found a significant benefit for progression-free survival in patients with mantle cell lymphoma treated with B-R versus R-CHOP (HR 0.61, 95%CI 0.42-0.87, p=0.0072) 136. In addition the trial confirmed the improved toxicity profile of BR over RCHOP.
Regarding rituximab maintenance, there is no published trial examining its benefit following BR induction. The European Mantle Cell Lymphoma Elderly trial confirmed a benefit of rituximab q2 months until progression (vs. interferon- 2a or 2b) following RCHOP induction. After a median follow-up of 30 months, rituximab maintenance was associated with a significantly longer remission duration compared to interferon maintenance (51 vs. 24 months; HR=0.56, 95% CI 0.36-0.88; p=0.0117). While there was no difference in overall survival between the two groups, a subcohort of patients treated with R-CHOP appeared to show an advantage in 3-year overall survival with rituximab versus interferon maintenance (85% vs. 70%, p=0.0375). The StiL group investigated the value of R maintenance following BR and reported a lack of benefit in terms of PFS or OS. 198 However, the study was underpowered to detect a difference. Further, a multicentre retrospective study reported superior outcomes of patients given R maintenance (vs. observation) after achieving CR or PR with BR, with an OS advantage for those who achieved PR only. 199 We favour following BR x 6 cycles with R maintenance but with a maximum duration of 4 years of rituximab maintenance given the balance between efficacy, toxicity and cost. Given the lack of strong data to support this approach, R maintenance could be omitted or truncated in patients for whom the benefits of extending a remission do not outweigh the inconvenience of maintenance therapy.
The rare patient who has stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.

# Summary Initial Treatment Recommendations for Mantle Cell Lymphoma:
Immediate chemoimmunotherapy is recommended for most patients. See Recommendation regarding Watchful Waiting for MCL for details on the minority of patients for whom watchful waiting is recommended.
Treatment -Transplant Eligible Patients (Age 60 ml/min, and no pre-existing neurotoxicity ii. 1.5 g/m 2 BID for age>60, or CrCl 46-60 ml/min, or pre-existing neurotoxicity iii. 1 g/m 2 BID for CrCl 31-45 ml/min 2) Autologous blood stem cell collection with high dose cytarabine and G-CSF mobilization 3) Consolidation: High dose therapy and ASCT 4) Maintenance rituximab 375mg/m2 IV or 1400mg sc (preferred) every 2 months x 3 years post ASCT
For patients with TP53-mutated MCL and/or blastoid variant, consolidation with an allogeneic SCT is recommended over autologous SCT.
Treatment -Transplant Ineligible Patients (Age >60-65yrs). 1) Induction: Bendamustine-Rituximab x6 cycles 2) Rituximab maintenance q2mo until progression or for maximum 4 years
The rare patient with stage I-IIA, non-bulky mantle cell lymphoma could be considered for B-R + IFRT, or even IFRT alone if they are older than 70 years of age or have significant co-morbidities.

# Treatment Relapsed Mantle Cell Lymphoma.
There is no standard treatment for relapsed MCL but there are many options, including chemotherapy and novel agents 200. In general, treatment choice should take into consideration the duration of response to previous treatment.
The Bruton's tyrosine kinase (BTK) inhibitors have shown the most promise as therapeutic agents for relapsed MCL and are the preferred secondline therapy. A phase 3 trial that randomized relapsed or refractory MCL patients who previously received at least one rituximab-containing regimen showed superior PFS using ibrutinib over temsirolimus (mPFS 14.6 vs. 6.2 months, p<0.0001) but no significant advantage in OS 201. Acalabrutinib has also been investigated in relapsed/refractory MCL in a Phase 2 study with 12 month PFS and OS of 67% and 87% respectively. 202 Similarly, in a phase 1/2 trial with zanubrutinib the median PFS was 21.1 months and median DOR was 18.5 months. 203 Patients who achieved 12-24 months PFS with previous chemotherapy may do well with a different noncross-resistant chemotherapy regimen (R-bendamustine or R-BAC if previous (R) CHOP, or vice versa 200,204,205. Other treatment options include bortezomib combined with rituximab +/chemotherapy 206,207. Maintenance rituximab prolongs PFS and OS in relapsed MCL 208 but has not been studied in patients that received it after first-line therapy.
Lenalidomide also has efficacy in this setting, particularly in combination with rituximab +/chemotherapy 207,209.
Brexucabtagene autoleucel (brexu-cel) is a CAR T therapy that is Health Canada approved for patients with relapsed or refractory mantle cell lymphoma who have received treatment with a BTKi.
In the ZUMA-2 phase 2 trial, the estimated PFS was 61% and OS 83% at 12 months. 210 This will be an option in the future for patients who are progressing on BTKi who are fit for intensive therapy.
Allogeneic stem cell transplant has the potential to cure MCL, as is evident from a plateau in the survival curves that is often seen post transplant. Because most patients present over the age of 60 and with multiple comorbidities, allogeneic stem cell transplant is not often offered. It is suggested in relapsed or refractory disease for those patients who are young and fit, even after autologous stem cell transplant.
Several retrospective reviews have looked at the outcomes of allogeneic stem cell transplant in the relapsed/refractory setting. Le Gouill et al. have shown a 2 year EFS of 50%, 2 year OS of 53% and 1-and 2-year transplant related mortality of 22% and 32% respectively 211. Longer term follow up has demonstrated 6 year PFS and OS rates of 46% and 53%, respectively confirming the plateau in response that is often seen to allogeneic stem cell transplantation 212. Response to chemotherapy has consistently been shown to predict both success of allogeneic stem cell transplant and transplant related mortality, with the best outcomes in those who have achieved a CR or CRu. Chronic GVHD has been shown in retrospective reviews to reduce the risk of relapse and DLI has been shown to salvage some patient who relapse or progress post allogeneic stem cell transplant, suggesting a graft-versus-tumour effect in MCL. Reduced intensity Allo SCT in the MCL setting has also been looked at retrospectively with 5 year PFS and OS rates of 14% and 37% respectively, and 1 year non relapse mortality of 18% 213. Ibrutinib bridging prior to allogeneic SCT has recently been shown to improve transplant outcomes, with 2 year PFS 76% and 2-year OS 86% in one published series 214.
The Calgary experience suggests no difference in OS or PFS when allogeneic vs. autologous stem cell transplantation are used in front-line therapy however, in the relapsed/refractory setting, allogeneic stem cell transplantation appears to offer superior OS and PFS.  iii. If responding to therapy (PR/CR), fit and eligible for allogeneic SCT, particularly if high risk disease (e.g. TP53+), refer for opinion regarding allogeneic SCT iv. If not responding to therapy, OR progressing on BTKi, refer for CAR T therapy (once available)  . Patients could also be considered for initial ISRT in addition to H. pylori therapy if the tumour is associated with t (11;18). Rituximab or chemoimmunotherapy may be considered for patients ineligible for or relapsing after RT .
2) Localized (stage I-II1) H. pylori negative gastric MALT lymphoma: For the minority of patients whose gastric biopsies are negative for H. pylori, non-invasive testing (e.g. stool antigen test, urea breath test, and/or serology) should be performed to confirm H. pylori status. H. pylori-negative gastric MALT lymphoma is more likely to be associated with t(11;18) 243,244. A trial of H. pylori eradication may still be considered as up to 38% of cases of H. pylori negative gastric MALT lymphoma can respond to antibiotics 245 presumably due to false negative testing or infection with other helicobacter species 246 ; these patients should receive ISRT if there is no evidence of lymphoma regression after 3-6 months on repeat endoscopy. Alternatively, initial treatment with ISRT can be considered since the majority will not respond to H. pylori eradication, whereas ISRT achieves complete responses in >95% of patients with long-term event-free survival rates of 80-90% 228,.
Repeat endoscopy should be done 3-6 months after ISRT to confirm response. The decision to treat with initial ISRT versus a trial of H. pylori eradication should be individualized and made in conjunction with patient wishes.
3) Advanced (stage II2, IIE or IV) gastric MALT lymphoma: These patients should be managed as advanced stage indolent B-cell lymphoma with active surveillance if asymptomatic or chemoimmunotherapy if symptomatic disease. These patients should also receive H. pylori eradication therapy.
Testicular lymphoma  :
In contrast to other patients with localized large B-cell lymphoma, patients with stage IAE or IIAE testicular lymphoma are cured less than 50% of the time using brief chemotherapy and irradiation. Thus, the recommended treatment for all stages of testicular lymphoma is a full course of chemotherapy (R-CHOP x 6 cycles). An additional problem often seen in these patients is relapse in the opposite testicle. This can be prevented by scrotal irradiation (25-30Gy/10-15 fractions). Finally, these patients are at high risk for CNS relapse. Although some experts recommend prophylactic intrathecal chemotherapy, especially for stage 3-4 disease, this has not been proven effective. Unfortunately, many of the CNS relapses occur within the brain parenchyma, and are not prevented by intrathecal chemotherapy. For this reason, CNS prophylaxis should involve high dose intravenous methotrexate 3.5g/m 2 every 14-28 days x 2-3 doses after completion of all 6 cycles of R-CHOP.  255.
Whole brain radiotherapy (WBRT) has fallen out of favour for PCNSL, based in part upon high rates of severe neurotoxcity following high-dose methotrexate, and in part due to the results of the G-PCNSL-SG1 randomized controlled trial, in which 551 immunocompetent PCNSL patients (median age 63 years) were randomized to chemotherapy followed by WBRT (arms A1, B1) or chemotherapy alone (arms A2, B2) 267. 411 patients entered the post-high dose methotrexate phase, and 318 of these patients were treated per protocol. For this per protocol population, there were no differences in median OS (32.4 vs. 37.1 months, p=0.8) or median PFS (18.3 vs. 12 months, p=0.13) between the chemotherapy plus WBRT arms (A1+B1, n=154) or chemotherapy alone arms (A2+B2, n=164), respectively 267. A recent study suggests neurotoxicity can be reduced by decreasing WBRT dose to 23.4Gy after CR to induction HDMTX-based chemotherapy. The 2-year PFS was 78% in these patients 266.
Although patients with refractory or relapsed PCNSL typically have dismal outcomes, autologous stem cell transplantation (ASCT) has shown promising results in this setting. Soussain et al. (2001) have reported a 3-year event-free survival (EFS) rate of 53% for patients with relapsed/refractory PCNSL undergoing ASCT following high dose thiotepa, busulfan and cyclophosphamide (TBC) conditioning 265.
Small studies have demonstrated durable remissions with ASCT for PCNSL, however, the optimal conditioning regimen remains undefined . With the knowledge of our initial encouraging experience with TBC/ASCT 268 and the lack of any widely accepted standard treatment for PCNSL, TBC/ASCT consolidation was considered an acceptable option to treat consenting PCNSL patients at our centre. Review of our data proved the efficacy of this therapy (PFS 52% at 5 years post TBC/ASCT) but with significant toxicity (5 treatment-related deaths, all occurring in patients over 60 yrs). To reduce the TRM, we modified our protocol to omit cyclophosphamide starting in 2011. We recently completed a retrospective review of the outcomes of this protocol for patients treated between Nov 2011 and Dec 2017.  272.Based on these data, we recommend TBu/ASCT consolidation therapy for all eligible PCNSL patients. 273,274 The role of Rituximab in treating PCNSL was evaluated in the International Extranodal Lymphoma Study Group (IELSG) 32 study 275 which randomized patients with histologically-proven primary CNS lymphoma to receive a maximum of four 3-week cycles of methotrexate at 3.5 g/m2 on day 1 and cytarabine at 2 g/m2 twice daily on days 2 and 3, either alone (arm A; n = 75), in combination with 375 mg/m2 of rituximab on day -5 and 0 (arm B; n = 69), or combined with rituximab at the same dose plus 30 mg/m2 of thiotepa on day 4 (MATRIX arm; n = 75). The study was conducted at 52 locations across five countries. The median patient age was 58 years (range, 18-70) and all patients were HIVnegative. Overall, patients had an ECOG PS 3, with patients aged 66 to 70 years having an ECOG PS 2. Patient characteristics were well balanced among the study arms. Autologous stem cells were successfully collected after the second treatment course in 152 patients (94%). In the MATRIX arm C, the overall response rate was 87% (95% CI, 80-94) compared with 74% (95% CI, 64-84), and 53% (95% CI, 42-64) in arms B and A, respectively (P =.00001 for A vs C) 275. As reported by Dr. Andres Ferreri at the ASH 2016 conference (abstr 511), at a median follow-up of 40 months, the PFS rate was approximately 55% in the MATRIX arm C, 39% in arm B, and 29% in arm A, with OS rates of 63%, 46%, and 31%, respectively. Of the 219 enrolled patients, 118 (54%) patients without progressive disease (n=52) or excessive toxicity/poor mobilization/refusal (n=49) underwent a second randomization comparing consolidation with whole-brain irradiation (n=59) or ASCT (n=59). The CR rate similarly improved from 54% after induction up to 94% after either consolidation therapy, suggesting a very important role for consolidation therapy. There were no statistically significant differences in PFS after the two consolidation treatments (3yr PFS approximately 60-70%), however, neurotoxicity rates were higher in the WBRT arm.
The potential benefit of rituximab with induction chemotherapy was not confirmed in different phase III trial by HOVON 105/ALLG NHL 24 276 in which 119 patients in Netherlands, Australia and New Zealand were randomized to 2 cycles of induction (MTX, BCNU, teniposide, prednisone) with or without rituximab, then followed by consolidation with cytarabine and WBRT 30Gy (+10Gy boost) if <60yrs of age. This study reported non-significantly different 1 year EFS rates of 49% and 52% for rituximab vs no rituximab (ORR 87% and CR 67%).
The Alberta Lymphoma Group established a provincial PCNSL Treatment Protocol in November 2011. The rationale behind the 2011 protocol included:
1) Induction chemotherapy: a. First 2 cycles: HDMTX 3.5g/m2 d1,15 with procarbazine 100mg/m2 po d1-7. This treatment had been shown to induce response and is tolerable for patients who may be debilitated at the time of initial diagnosis of PCNSL. Cytarabine was not added to first cycle HDMTX because patients may not tolerate intensive therapy well until performance status improves. b. Stem Cell Mobilization and Apheresis: to be done with first dose of Cytarabine because stem cells may not mobilize well after multiple cycles Cytarabine/G-CSF. Rituximab will be used in addition to Cytarabine due to reports that lymphoma cells can circulate in blood and marrow in patients with PCNSL 277 and Rituximab may decrease risk of collecting contaminated autograft as has been shown for other B-cell lymphomas. c. Final 2 Cycles will combine Cytarabine with HDMTX as done in a prior IELSG study to improve response rates and decrease frequency of primary progressive disease 255.
d. Rituximab was added in 2016 for a total of 6 doses during induction to improve response 2) High Dose Chemotherapy (patients 60% after induction therapy, and PCNSL not secondary to immune suppression): a. Thiotepa 300mg/m2 x2d and Busulfan 3.2mg/kg x3d without cyclophosphamide. Because cyclophosphamide does not penetrate the blood brain barrier particularly well, its omission may decrease treatment-related mortality without decreasing cure rates compared to the previous TBC regimen. 3) Ifosfamide consolidation (transplant refusal or ineligible patients):
a. Ifosfamide crosses BBB approximately 30%, and gives some exposure of PCNSL to alkylating agent therapy 278,279.

# Recommendations: PCNSL Transplant-Eligible (Usually <70 years old)
The above evidence suggests that transplant-eligible patients are best treated with HDMTX/AraCbased induction followed by TBu/ASCT consolidation. There also is a potentially important role for the addition of rituximab to induction chemotherapy when ASCT consolidation is used. However, the optimal number of induction chemotherapy cycles is unknown, and perhaps as soon as a patient achieves a response and is physically well, they should proceed directly to ASCT before the disease starts to progress, or cumulative toxicity from further induction therapy prevents ASCT consolidation.
As such, the 2018 PCNSL guidelines have been modified to decrease the length of induction therapy prior to ASCT. We have not incorporated MATRIX induction, because the use of MATRIX may decrease the ability of patients to proceed to ASCT due to toxicity, increased likelihood of patient refusal due to treatment-fatigue, or due to poor stem cell mobilization. We believe the use of ASCT is more important than the use of MATRIX. Our real world outcomes using non-MATRIX induction and TBu/ASCT are numerically superior to those reported in the MATRIX study. We also increased the age limit for the transplant eligible protocol to 75 years, however, patients over age 70 years must be extremely healthy with no comorbidities and must also be highly motivated to receive TBu/ASCT. For a detailed description of recommended PCNSL treatment regimens, please refer to Appendix A, subheading VII, sections A and B.
For palliative therapy, doses of cranial radiotherapy should be 30Gy in 10-20 fractions.

# Eye lymphoma
Orbital or peri-orbital lymphoma 251,280 : Peri-orbital lymphoma of the bony orbit or the soft tissues in and around the orbit but outside of the globe and optic nerve should be managed as indicated in the earlier sections on aggressive lymphomas, marginal zone lymphomas or follicular lymphoma, as appropriate for the type and stage of the lymphoma. Approximately 40% of such patients have advanced disease discovered when carefully staged. In general, 25-30Gy/20 fractions radiotherapy to whole orbit/periorbital tissue is recommended for indolent peri-orbital lymphomas.
Conjunctival lymphoma 251,280 : Lymphoma involving the conjunctiva but not the structures within the globe or the optic nerve is usually of low grade and should be treated with 25-30Gy/20 fractions of radiotherapy. Doses, fields, and shielding specifically modified for treatment of the eye are necessary to minimize long-term complications such as xerophthalmia or cataract formation.
Intra-ocular and optic nerve lymphoma 251,281 :
- Lymphoma involving the vitreous, retina or other structures within the optic nerve or globe is usually of large cell type and is equivalent to PCNSL. Bilateral involvement is common. Evaluation and management should be the same as for PCNSL. Acceptable treatment involves induction chemotherapy with high dose methotrexate and high dose cytarabine as described for PCNSL in Appendix A.
- Lymphoma involving the uveal structures (choroid) is a rare presentation of lymphoma, and is usually of indolent type. This disease is best managed with treatment appropriate for stage and local extent of disease.

# Aggressive T-Cell Lymphomas:
NK/T-cell lymphoma, nasal type  Natural killer (NK)/T-cell lymphoma, nasal type is a rare and aggressive extranodal neoplasm that almost exclusively affects Asian and South American adults in the fifth decade of life, with a male:female ratio of approximately 3:1. It typically arises in the nasal cavity or surrounding structures, such as the sinuses, palate, nasopharynx, tonsils, hypopharynx, and larynx. While the pathogenesis of NK/T-cell lymphoma, nasal type is not well understood, the Epstein-Barr virus (EBV) is implicated in almost all cases. Approximately 25% of cases show a p53 mutation; in addition, p21 overexpression is also frequent in nasal NK/T-cell lymphoma, and seems to be independent of p53 gene status 285.
Hematopathological evaluation of a biopsy specimen from the site of involvement is the basis for diagnosis of nasal NK/T-cell lymphoma. The recommended immunohistochemistry panel includes 283,291 :
- B-cell: CD20
- T-lineage antigens: CD2, CD7, CD8, CD4, CD5, CD3
- NK lineage markers: CD56
- Cytotoxic granules (granzyme B and/or TIA-1)
In situ hybridization for EBV-encoded RNA (EBER)
For patients with early-stage nasal NK/T-cell lymphoma (ENKTCL), early or upfront radiotherapy (intensive regimens such as a total dose  50 Gy) plays an essential role in therapy, and has been associated with higher overall survival and complete response rates compared to chemotherapy alone 286. However, radiotherapy alone is also associated with high relapse rates. Combined modality therapy is recommended with sequential and concurrent chemo-radiotherapy regimens having relatively equivalent outcomes. No standard of care therapy exists for ENKTCL with our guidelines previously recommending VIPD consolidation after concurrent single agent cisplatin and radiotherapy. Local outcomes were poor with this approach and most novel regimens incorporate Lasparaginase into treatment due to high single agent activity. 292 Given the recent discontinuation of Lasparaginase, we favour the combination of peg-asparaginase with gemcitabine and oxaliplatin (P-GEMOX) for patients with limited stage disease. With this approach, treatment is initiated with 2 cycles of P-GEMOX, followed by radiotherapy (48-56 Gy) followed by 2 further cycles of P-GEMOX restarted 1 week after completion of radiotherapy. With this approach, in 33 patients, the ORR was 94% and 2 year PFS and OS were 77% and 83% respectively. Notably, Grade 3-4 toxicities were rare.
For patients with stage III-IV disease, complete remission rates are less than 15%, and the median overall survival is approximately 4 months 290. The recommended options for therapy include either enrollment in a clinical trial or treatment with an L-asparaginase-based combination chemotherapy regimen. The most well-studied regimen is the SMILE regimen with several small series of patients reported . While the SMILE regimen was first reported to have excellent response rates (overall, and complete in 79% and 45%, respectively) in relapsed/refractory patients, an updated study of the use of the SMILE regimen as frontline therapy for advanced stage patients reported a short median OS (12.2 months; 1-year OS was 45%) with a high rate of TRM (5 of 87 patients died of sepsis) 293.
While the GOLD regimen has less reported patients, the toxicity is significantly less (Grade 3-4 neutropenia of 16% compared to SMILE of 92% 294 with serious infections in 4% and 31-45% 293,294 of patients treated, respectively). For this reason, patients of advanced age or with comorbidities or a history of infections should be considered for therapy with GOLD for 2-4 cycles followed by SCT if possible while younger, fit patients can be treated with SMILE x 2 cycles with a goal of proceeding to SCT as consolidation. The role of allogeneic or autologous SCT is not yet well defined because of limited data; but it is suggested when possible for advanced stage or relapsed/refractory patients.
Peripheral T-cell lymphomas (PTCL) .
With the exception of ALK-positive anaplastic large cell lymphoma, CHOP chemotherapy cures less than 30% of patients with PTCL. Options that may be associated with higher cure rates include CHOP x 4-6 cycles followed by HDCT/ASCT in responding patients or brentuximab-vedotin + CHP or intensification of CHOP with etoposide (CHOEP). 305 The ECHELON-2 study was a Phase 3 of CD30+ ( 10% by immunohistochemistry) PTCL with IPI  2 comparing CHOP with BV-CHP. The median PFS was improved with BV-CHP at 48.2 months compared to 20.8 months with CHOP. Overall survival was also numerically superior in the BV-CHP arm. Important toxicities were comparable between the arms. Unfortunately, the study was not powered to detect differences between the different subtypes of PTCL and the study was biased to include a majority of patients with ALCL (70%). Patients with ALK+ ALCL were 22% of the population and had the largest noted benefit from the addition of BV-CHP. The subgroup of AITL patients appeared to do slightly worse with BV-CHP compared to CHOP but patient numbers were small. Given the lack of single agent efficacy in non-anaplastic subtypes, it remains unclear if there is any benefit to BV-CHF in non-anaplastic subtypes of PTCL such that it can not be recommended that BV be routinely implemented for those patients at this time.  297.
Retrospective and prospective phase II trials support the use of SCT as part of upfront therapy for PTCL. Sieniawski and colleagues reported 5-year PFS rates of 60% for 26 patients with enteropathy associated T-cell lymphoma treated with IVE-methotrexate induction therapy followed by autologous SCT, compared to only 22% for 54 patients treated with CHOP-like therapy alone 297. Two prospective trials have also been reported. In the first, Reimer and colleagues reported results of CHOP x 4-6 cycles followed by dexabeam or ESHAP followed by CyTBI/ASCT for 83 patients (including 32 with PTCL-not otherwise specified, and 27 with angioimmunoblastic T-cell lymphoma) 299. Fifty-five of the 83 patients received transplantation. In an intent-to-treat analysis, with a median follow-up time of 33 months, the estimated 3-year OS, DFS, and PFS rate were 48%, 53%, and 36%, respectively 307. In the second prospective trial, Rodriguez and colleagues from the Spanish Lymphoma and Autologous Transplantation Cooperative Group reported the results of 74 patients transplanted in the first complete response (65% had 2-3 aaIPI risk factors) 300. With a median follow-up of 67 months from diagnosis, the 5-year OS and PFS rates were 68% and 63%, respectively.
For PTCL patients who relapse following CHOP-type induction and respond to salvage therapy, ASCT should be recommended, as several studies report similar ASCT outcomes to those seen with relapsed DLBCL. Brentuximab vedotin may be considered for those patients with CD30+ anaplastic large cell lymphoma who have had failure of initial chemotherapy 308.
For patients who are ineligible for ASCT or who have failed ASCT, PFS and OS is extremely short and end of life care and planning should be implemented. Palliative therapy options include chemotherapy (with limited expectation of response or benefit), romidepsin and/or pralatrexate.
Alberta has funded only 1 of romidepsin or pralatrexate despite these agents have non-overlapping mechanisms of action for reasons of cost (due to unavailability of published data for responses to either drug in patients who failed the alternate). No quality evidence exists to direct the decision between romidepsin and pralatrexate however, durables responses to romidepsin have been most commonly seen in patients with AITL, favouring romidepsin in that group.
An open-label, single arm, phase II study of romidepsin in relapsed or refractory peripheral T-cell lymphoma (N=130) with a median two (range: 1-8) prior systemic therapies found an objective response rate of 25%, including 15% with CR/CRu. 309 An evaluation of longer term follow-up found median duration of response was 28 months (range: 1 to >48 months). 310 Patients who achieved CR/CRu had a median PFS of 29 months. The most common grade 3 AEs were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Another phase II study of romidepsin in cutaneous and peripheral T-cell lymphoma (N=45; median 3 prior therapies) found complete response in n=8 and partial response in n=9 for an overall response rate of 38% (95%CI: 24-53%).
Median duration of overall response was 8.9 months (range: 2-74). Of note, 6 of the 18 responses were among patients with prior stem-cell transplant. 311 The prospective PROPEL trial evaluated the effectiveness of pralatrexate in patients with relapsed or refractory peripheral T-cell lymphoma. N=111 patients received pralatrexate after a median 3 prior therapies (range: 1-12). The overall response rate was 29% with 11% achieving complete response.
The median duration of response was 10.1 months. Median PFS and OS were 3.5 months and 14.5 months, respectively. The most common grade 3 AEs were thrombocytopenia (32%), mucositis (22%), and anemia (18%). 312 Summary of treatment recommendations for PTCL. - recommendation for stage I-II NK/T cell lymphoma: P-GEMOX x 2 cycles (then IFRT (48-56 Gy) then 1 week later, 2 further cycles P-GEMOX (total 4 cycles) 313 AIDS-related lymphomas:  In general, the treatment of AIDS-related lymphoma should be the same as for non-AIDS related lymphoma if the AIDS does not otherwise compromise the patient's performance status and he/she is free of coincident serious opportunistic infection. HAART should be given with CHOP chemotherapy.
Treatment should be planned in conjunction with the patient's HIV physician and an antiviral regimen without overlapping toxicity should be chosen. R-CHOP results in the highest rates of disease-free survival, but may also increase the risk of infectious complications and treatment-related mortality in patients with CD4 counts below 50.

# Post-transplant lymphoproliferative disease (PTLD) after Solid Organ Transplant in Adults:
Epidemiology. Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease with clinical and pathologic manifestations ranging from benign lymphoid hyperplasia (ie. early lesions) to aggressive lymphoma (ie. monomorphic PTLD) 320,321. PTLD and its treatment cause a high rate of mortality and graft loss in patients with solid organ transplants (SOT) 322. The incidence of PTLD is highest in multivisceral (>10%) and lowest in renal transplants (1-5%), attributed to intensity of immunosuppression and amount of lymphoid tissue in the allograft . Epstein-Barr virus (EBV) infection drives the pathogenesis in PTLDs occurring early post-transplant; conversely, PTLDs occurring after prolonged immunosuppression tend to be monomorphic with no detectable EBV genome, calling an infectious etiology into question 326. An epidemiologic shift in PTLD has occurred in the most recent decade: the median latency time from transplant to PTLD has increased from 1 to 3 years 327,328 and the proportion of EBV-positive vs. -negative PTLD has decreased 329 attributed to EBV viral load monitoring in EBV seronegative (ie. high risk) patients.
Diagnosis and staging. Diagnostic tissue must be reviewed by expert pathologists and subtyped according to the WHO 330. Several small case series have confirmed that PET-CT is an effective imaging modality for staging in PTLD . However, some subtypes of PTLD, such as early lesions and T-cell lymphomas, may not be FDG-avid, necessitating CT as an alternate staging modality.
Management. Recommendations for the management of PTLD in SOT are based on few phase II clinical trials, retrospective case series, and expert opinion . The mainstays of therapy for CD20-positive PTLD in SOT include reduction of immune suppression (RIS), rituximab, and chemotherapy; adoptive immunotherapy is promising but considered experimental and is unavailable in Alberta. All patients should undergo RIS to the lowest tolerated levels under the direction of the transplant physician as soon as the diagnosis of PTLD is confirmed 337. A recommended strategy is to discontinue antiproliferative agents and reduce the calcineurin inhibitor by 25-50% while maintaining the steroid 337. Published response rates vary widely (0-73%) and responses are seen within 2 to 4 weeks .
Early lesions, polymorphic and CD20-positive monomorphic PTLD. RIS may serve as definitive treatment of early lesions, but if response is incomplete further treatment with surgery or radiation is favored. In contrast, polymorphic and monomorphic PTLDs require definitive treatment along with RIS, discussed in further detail below  (Figure 3).

# Surgery and radiation.
Patients with localized PTLD, such as isolated skin, GI or renal allograft lesions, can achieve prolonged remissions with surgery or localized radiation 340,343. Some experts consider surgical resection of isolated GI lesions prior to initiating systemic therapy to reduce early mortality from bowel perforation 338. Radiation alone is generally not curative, with exception of plasmacytoma-like PTLD 344 and should not be used as primary treatment 337. Radiation may be used for palliating obstructive or compressive symptoms where systemic therapy fails or is not possible 337.
Chemotherapy. SOT patients do not tolerate chemotherapy well, often developing severe infection or prolonged cytopenias. Estimates of efficacy of chemotherapy in treatment of PTLD in SOT are limited by the almost entirely retrospective nature of publications. Results of retrospective studies of anthracycline-based chemotherapy, mainly CHOP, show ORRs of 65-73% and 5-year OS of 25-78%; however, treatment-related mortality (TRM) is up to 31% .
Rituximab. Several retrospective reviews and phase II clinical trials have confirmed the efficacy of rituximab monotherapy in CD20-positive PTLD post-SOT in patients that fail to respond to RIS. Phase II trials show overall response rates (ORR) of 44% to 71% and CR rates of 26% to 53% after 4 weekly doses with no reported TRM . However, 57% of patients treated with rituximab monotherapy in 2 prospective trials had progressive disease within 12 months; risk factors for survival and need for further treatment included age > 60, ECOG  2, elevated LDH, and lack of CR after rituximab 354. Therefore rituximab causes minimal toxicity but remissions achieved are durable in only a minority of patients.
Sequential therapy. Efficacy of a sequential treatment regimen (4 weekly doses of rituximab followed by 4 cycles of CHOP) was established in a phase II international multicentre trial in adult CD20positive PTLD in SOT (n=70) in an attempt to improve upon the success of rituximab monotherapy and diminish the toxicity of chemotherapy 355. The ORR was 60% after initial rituximab, increasing to 90% after sequential chemotherapy. EBV-positive and -negative PTLDs responded equally. OS was 61% at 3 years and time to progression was 69% at 3 years. There were no TRM events related to rituximab and 11% ascribed to CHOP. In a subsequent analysis, the authors concluded that patients who achieved CR and those in PR with a low-risk IPI score after rituximab monotherapy had a low risk of disease progression 356.
A subsequent phase II trial utilized risk-stratified sequential therapy, in which patients in CR (by CT) after 4 doses of rituximab received 4 further 3-weekly doses of rituximab, and those not in CR after initial rituximab proceeded to RCHOP (4 cycles supported with GCSF). With 152 patients treated, endpoints were superior to sequential therapy (3-year OS 70%, 3-year TTP 73%, TRM 7%), and response to initial rituximab was highly predictive of OS, TTP and PFS (p<0.001) 357,358.
In summary, rituximab monotherapy is effective first-line treatment in most CD20-positive PTLDs with minimal toxicity. Risk-stratified sequential therapy offers the highest survival rates published to date, and allows patients in CR after rituximab monotherapy to avoid chemotherapy. Close follow-up for disease progression is recommended for patients that received rituximab alone. For PTLD that behaves aggressively (ie. IPI 3-5) or progresses during initial treatment with rituximab, proceed directly to RCHOP before completing 4 doses of rituximab (Figure 3). 3b. Primary CNS PTLD. In the largest reported retrospective series of primary CNS PTLD (n=84), patients treated with rituximab and/or cytarabine (most often given after MTX) survived longer, but significant variation in regimens precluded firm conclusions 359. Patients with acceptable renal function and performance status should be offered high-dose methotrexate and rituximab, and others may benefit from palliative radiation 338, 359. 3c. Burkitt Lymphoma PTLD. Several case series cite acceptable outcomes in this rare subtype of PTLD with chemotherapy regimens ranging in intensity . However, no definite recommendations can be made and treatment should be considered individually.
3d. CD20-negative monomorphic PTLDs. Rare subtypes of PTLD that resemble non-transplant lymphomas, such as Hodgkin Lymphoma-like PTLD, T cell monomorphic PTLD, plasmablastic PTLD and plasma cell dyscrasias, require specific chemotherapeutic treatment similar to their nontransplant counterparts (reviewed by 337,338.
The risk of death from NHL is significantly higher in SOT compared to non-transplant patients 363 and PTLD increases the graft failure rate 5-fold 364. Retrospective series of PTLD post-SOT report OS of 30-68% at 5 years, with excess mortality in the first year post-diagnosis 323,328,. Adverse prognostic factors from retrospective studies include monomorphic subtype, monomorphic T-cell, bone marrow or CNS involvement, advanced stage, poor performance status, advanced age, elevated LDH, and hypoalbuminemia 327,328,351,. Risk factors for worsened OS in the PTLD-1 prospective trial include IPI 3-5, thoracic organ transplant and lack of CR after rituximab monotherapy 356. A prognostic score developed from 500 PTLD cases in renal transplant patients is described in Table 8; the score was calculated with the exclusion of patients with monomorphic T-cell and CNS PTLD, both of which carried an adverse prognosis, but the score maintains its ability to discriminate risk groups in the whole population 364.
One or more tumors (=>1-cm diameter)
Confluence of erythema covering =>80% body surface area N (lymph nodes) Abnormal peripheral lymph node indicates any palpable peripheral node that on physical examination is firm, irregular, clustered, fixed or 1.5 cm or larger in diameter. Node groups examined on physical examination include cervical, supraclavicular, epitrochlear, axillary, and inguinal. Central nodes, which are not generally amenable to pathologic assessment, are not currently considered in the nodal classification unless used to establish N3 histopathologically.
No For viscera, spleen and liver may be diagnosed by imaging criteria
No visceral organ involvement
Visceral involvement (must have pathology confirmation and organ involved should be specified)
IIA IIB 1-2 3 1,2 0-2 0 0 0,1 0,189
IIIA IIIB 4 4 0-2 0-2 0 0 0 1 54 48 IVA1 IVA2 IVB 1-4 1-4 1-4 0-2 3 0-3 0 0 1 2 0-2 0-2 41 23 18
response modifiers (IFN-, retinoids) in cases of resistant or progressive skin disease. Local radiotherapy plays a key role in palliation and treating sanctuary sites. Total skin electron beam therapy is highly effective in T2 or T3 disease however its widespread use is limited by the availabilty of this technique. Predictably, chemotherapy leads to short remission durations and therefore should be reserved after other therapies have been tried. Its use should be limited to tumour (T3) or more advanced stages. It may be considered frontline in cases with histologic large-cell transformation and high risk features (see discussion below). Monotherapy (low-dose methotrexate, gemcitabine) is generally preferred over combination chemotherapy (e.g. CHOP) unless the patient has extensive burden of disease (nodal and extra-cutaneous and is fit to tolerate. Targeted therapies have demonstrated activity in MF/SS, and are currently reserved for the relapsed/refractory setting or in clinical trials. The optimal conditions for allogenic bone marrow transplant have not been elucidated, but may play a role in highly selected cases (see discussion below). Extracorporeal photopheresis is a unique treatment modality indicated for the treatment of erythrodermic MF/SS. Consensus recommendations for the treatment of MF/SS have recently been updated and are outlined elsewhere 30. The following table intends to summarize a managment approach.  - T1b: a solitary lesion with diameter >5cm T2
Regional skin involvement (multiple lesions limited to 1 body region or 2 contiguous body regions)
- T2a: skin lesions present in a 15-cm and 30-cm diameter circular area T3 Generalized skin involvement - T3a: multiple lesions involving 2 noncontiguous body regions - T3b: multiple lesions involving 3 or more body regions N N0 No clinical or pathologic lymph node involvement N1
Involvement of 1 peripheral lymph node region that drains an area of current or prior skin involvement N2
Involvement of 2 or more peripheral lymph node regions or involvement of any lymph node region that does not drain an area of current or prior skin involvement N3
Involvement of central lymph nodes M M0 No evidence of organ disease M1
Extracutaneous organ disease

# Staging of other types of non-MF cutaneous lymphomas

# Special topics in CTCL
The role of transplantation in cutaneous lymphoma 8, 9, 14, 40-49 :
Existing studies of allogeneic stem cell transplantation in mycosis fungoides or sezary syndrome are limited to small, retrospective reports or case series. Autologous stem cell transplantation has not been associated with durable remissions and therefore has been largely abandoned for MF/SS. The following recommendations are based on best available outcome data and established consensus guidelines:
- Patients with MF/SS should be risk-stratified using the CTCL International Consortium prognosis score. Patients with high-risk disease (3 or 4 of age>60, elevated LDH, stage IV or LCT) should be considered for allogeneic transplantation as part of second line of therapy.
- Patients with advanced stage 3 or stage 4 MF/SS who progress after more than two lines of systemic therapy should be considered for allogenic transplantation. - Selected patients with stage 2 MF/SS or with large cell transformation may be considered for allogeneic BMT.. - Patients must meet other eligibility criteria for transplant prior to being considered. Issues such as chemosensitivity (CR or PR to last line of therapy), adequate performance status (ECOG 0-2) and preserved organ function apply. - TSEB before transplant may be considered prior to transplantation for improved skin control. - Transplantation in other rare and aggressive CTCL such as CD8+ epidermotropic aggressive T cell lymphoma or primary cutaneous gamma-delta T cell lymphoma is at this time a largely experimental approach - Relapses still occur after allogeneic transplants and may be treated adjustment of immunosuppression, DLI infusion, or further skin-directed treatments. Distinguishing CTCL from transplant associated GVHD requires multidisciplinary expertise.

# Large Cell Transformation in Mycosis Fungoides:
The pathologic definition of large cell transformation in mycosis fungoides (LCT-MF) is the presence of large cells (>= 4 times the size of a small lymphocyte) in 25% of more of the dermal infiltrate or forming microscopic nodules. The cells are often CD30+ by IHC however CD30-variants are also described. It is difficult to discriminate from other subtypes of cutaneous lymphoma, including cutaneous anaplastic large cell lymphoma (cALCL) or lymphomatoid papulosis (LyP), which may also coexist with mycosis fungoides.
The prognosis of LyP and cALCL is considerably more favourable than LCT-MF. Historical estimates for long-term survival with LCT-MF is less than 20%, and most series report a median survival of 2-36 months. However, a subset of patients with limited LCT-MF may follow a more indolent course. One large EORTC cohort analysis reported a median survival of 8.3 years for patients with LCT, and the authors concluded LCT is significant for disease progression but not survival outcome 26.
Currently, there is a lack of prospective research to guide a standardized approach for management of LCT-MF. Most patients are treated with combination chemotherapy however it remains it is unclear which patients benefit from this approach.
Several clinical and pathological characteristics in LCT-MF have been associated with poor prognosis 28,31 including advanced age (> 60 years), elevated LDH at transformation, advanced stage (III/IV), extra-cutaneous transformation, the presence of follicular mucinosis, folliculotropism, and CD30-negativity. Additional pathologic variables have been described but may not be routinely analyzable so have been omitted from these recommendations.
We recommend to consider intensive chemotherapeutic strategies (monotherapy or combination in suitable fit candidates) in patients with any of the following clinical or pathologic variables associated with high risk LCT-MF. In the absence of these, we recommend treatment as per MF guidelines (see Table I).

# Clinical variables for high risk LCT-MF:
- advanced age (> 60 years)
- elevated LDH at transformation - generalized tumours (versus solitary or regional)

# - advanced stage (III/IV) - extra-cutaneous transformation Adverse Pathologic variables in LCT
- absent papillary dermal involvement (assessment may be limited by provided tissues)
- folliculotropism - follicular mucinosis - absence of fibrosis - CD30 expression in less than 50% of neoplastic cells Brentuximab vedotin has activity in LCT-MF. A phase 2 study of brentuximab in a heavily pre-treated CD30+ MF/SS population, the majority of whom had LCT (30/32, 90%) showed a significant response rate of 70%. 35 A subsequent prospective, randomized controlled trial of brentuximab vedotin versus physician's choice (MTX or bexarotene) in CD30+ CTCL demonstrated a significant improvement in objective global response lasting atleast 4 months with brentuximab (56.3% versus 12.5%) 39. The study included both previously treatment CD30+ MF and CD30+ ALCL. Although the histologic characteristics of the CD30+ MF patients were unreported, a proportion may have had transformed MF, as this was not an exclusion criteria. Brentuximab vedotin is indicated for previously treated CD30+ MF, and could be tried for high risk LCT-MF patients as defined above, who are either unsuitable for chemotherapy or refractory/relapsed folllowing chemotherapy.

# V. Hodgkin Lymphoma

# Pathologic Classification
The histological sub-classification of Hodgkin lymphoma is based on the light microscopic H&E interpretation. If problems with differential diagnosis arise, staining for CD15, CD30, T-cell and B-cell panels and EMA may be helpful. For lymphocyte predominant Hodgkin lymphoma, CD20, CD45, +/-CD57 are recommended.
Mandatory staging procedures include 2-8 :
- Pathology review whenever possible (essential for core needle biopsies)
- Complete history and physical examination (B symptoms, Etoh intolerance, pruritis, fatigue, ECOG performance score, examination of nodes, Waldeyer's ring, spleen, liver, skin)
- CBC & differential, creatinine, electrolytes, Alk P, ALT, LDH, bilirubin, total protein, albumin, calcium - ESR (required for limited stage patients)
- If a PET/CT is not done, then perform a bone marrow aspiration and biopsy (2cm core preferable) for patients with stage IIB-IV or cytopenias (note: flow cytometry on the marrow aspirate does not add useful information and should not be done)
- Chest x-ray (PA and lateral)
- CT scan of the neck, chest, abdomen, and pelvis - A PET scan with body CT is preferred as initial staging and after 2 cycles of ABVD .
- Pregnancy test, if at risk (consider fertility and/or psychosocial counseling
- Semen cryopreservation if chemotherapy or pelvic radiotherapy is contemplated - HIV: if HIV risk factors or unusual disease presentations Primary Treatment of Classical Hodgkin Lymphoma  General principles: For treatment planning, supradiaphragmatic clinical stage (CS) I or II without bulk (mass >10cm or >1/3 maximal transthoracic diameter (MTD) on CXR) or significant B symptoms is considered limited stage. Initial treatment options for classical Hodgkin Lymphoma involve the chemotherapy regimens ABVD or escalated BEACOPP as well as involved field radiotherapy (IFRT).
Multiple phase III studies conducted by the German Hodgkin Study Group (GHSG) and other cooperative study groups have demonstrated that optimal cure rates are achieved with: 1) ABVD x2 cycles followed by 20Gy IFRT for favorable risk limited stage disease (5yr PFS >90%); 2) ABVD x4 cycles followed by 30Gy IFRT for unfavorable risk limited stage (> 3 nodal sites, ESR > 50 or >30 with B symptoms, or extranodal disease) (5yr PFS >85%); 3) escalated BEACOPP x 4-6 cycles for young healthy patients with advanced stage disease; and 4) ABVD x6 cycles for patients >60 years or with co-morbidities. Advanced stage patients also receive IFRT following chemotherapy to localized PET+ residual disease >2.5cm, and is considered for sites of prior bulk after ABVD.

# Data supporting escalated BEACOPP for advanced stage disease:
The GHSG HD9 trial conducted in the 1990s demonstrated that 8 cycles of an escalated-dose BEACOPP regimen were superior to 8 cycles of a COPP/ABVD regimen or 8 cycles of a baseline-dose BEACOPP regimen in terms of freedom from treatment failure and overall survival rates in patients with advanced-stage Hodgkin lymphoma 20. Each regimen was followed by consolidative radiation therapy to sites of initial bulky disease greater than 5 cm. At the 10-year analysis, freedom from treatment failure was 64% for the COPP/ABVD group, 70% for the baseline BEACOPP group, and 82% for the escalated BEACOPP group (p<0.001); overall survival rates were 75%, 80%, and 86%, respectively (p<0.001) 21. There were higher rates of hematologic toxicities, grades  25.
In an attempt to reduce severe toxicities associated with escBEACOPP, an open-label, randomized, parallel-group, phase 3 trial investigated the utility of PET after two cycles of standard escBEACOPP to allow for adaptation of treatment intensity 26. The trial included 18-60 year olds with newly diagnosed advanced-stage Hodgkin's lymphoma (N=1945), and assigned patients (1:1) to two parallel treatment groups on the basis of their PET results after cycle 2 of escBEACOPP (PET-2).
Patients with positive PET-2 were randomised to receive six additional cycles of either standard escBEACOPP (8  escBEACOPP in total) or escBEACOPP with rituximab (8  R-eBEACOPP) (rituximab abandoned mid-trial due to lack of efficacy). Patients with negative PET-2 were randomised between standard treatment with 4-6 additional cycles of escBEACOPP (6-8  escBEACOPP... the trial switched from total 8 to total 6 escBEACOPP in the standard arm after the results of HD15) or experimental treatment with two additional cycles only (4  escBEACOPP).
Patients with negative PET-2 randomly assigned to either 6-8  escBEACOPP (n=504) or 4  escBEACOPP (n=501) had 5-year progression-free survival of 908% (95% CI 879-937) and 922% (894-950), respectively (difference 14%, 95% CI -27 to 54). 4  escBEACOPP was associated with fewer severe infections (8% vs 15%) and organ toxicities (8% vs 18%) as compared to patients receiving 6-8  escBEACOPP. The trial supports reducing therapy to 4 escBEACOPP in patients who achieve PET-negative disease after 2 cycles of escBEACOPP.
Due to concerns of toxicity, escalated BEACOPP in Alberta should only be considered for the following patients 2,21,22,27-31 :
- Age  70 (ECOG 0-2)
- HIV negative, no other major co-morbidities - Patients must be made aware of infertility implications, and consent to proceed Although the above-described treatment approaches currently optimize cure rates from initial therapy, they result in: 1) the use of radiotherapy that contributes to late mortality from second cancers and cardiac disease; 2) the use of multiple cycles of Bleomycin that may cause serious lung toxicity; or 3) the use of escalated BEACOPP that increases the risk of serious infections and therapy-related MDS/AML. With the use of a PET-guided approach that minimizes therapy for patients whose lymphoma is highly sensitive to ABVD, we anticipate a reduction in toxicity of therapy and a need to only subject less responsive patients to the toxicities of IFRT or escalated BEACOPP.
arm of the study, patients received ABVD x2 then a PET scan, followed by ABVD x 2 (favorable) or 4 (unfavorable) if PET-, or escBEACOPP x2 cycles +INRT if PET+. Comparing control (INRT) and experimental (no INRT) arms for patients with negative PET after 2 cycles ABVD, the difference in PFS was -11.9% (95%CI -16.9%, -8.2%) for favorable risk (not meeting non-inferiority endpoint) and -2.5% (95%CI -6.6%, 0.5%) for unfavorable risk (not meeting non-inferiority endpoint). There was no difference in overall survival. For patients with PET+ disease after ABVD, the 5y PFS 77% vs 91% (p=0.002) and 5yr OS 89% vs 96% (p=0.06) favouring escBEACOPP compared to ABVD + INRT.
As neither the RAPID nor H10 trials confirmed non-inferiority of the PET-directed radiotherapy omission approach, this would support the use of radiotherapy despite a negative interim PET. However, given the lack of difference in OS and small differences in PFS, a PET-directed approach is recommended, accepting the risk of reduced local control with potential need for salvage chemotherapy and transplantation at relapse, reconciled by an expected late gain in OS due to avoidance of the long term sequelae of radiotherapy such as secondary malignancy and cardiovascular disease.

# Advanced Stage:
The UK RATHL trial treated patients with 2 cycles ABVD then performed a PET scan. 172 patients with PET+ disease (uptake > liver, Deauville 4-5) had therapy intensified to escBEACOPP whereas PET-patients were randomized to ABVD x4 (n=470) or AVD x4 (n=465). For PET-patients, 3yr PFS was 85.7% vs 84.4% for ABVD vs AVD (95%CI crossed 5% difference non-inferiority limit), the respective 3yr OS rates were 97.2% vs 97.6%, and the rate of grade 3-4 pneumonitis was 1% vs 0.2%, respectively. Of interest, a prior phase GHSG III trial found that omitting agents from ABVD x2 prior to IFRT for favorable risk limited stage HL resulted in lower 5 PFS rates (5yr FFTF 93.1% ABVD, 89.2% AVD, 77.1% AV, 81.4% ABV) and did not recommend this strategy. In view of the fact that the RATHL trial failed to meet its non-inferiority endpoint and only demonstrated a small reduction is serious pulmonary toxicity by eliminating bleomycin from the final 4 cycles of ABVD, it seems most reasonable to adopt this strategy only for those patients with risks factors for bleomycin lung toxicity (COPD / PFTs, CrCl 40yr), or those with any clinical or PFT evidence of acquiring bleomycin lung toxicity at any time during therapy. Patients with PET2 positive status whose therapy was intensified to 4 additional cycles of BEACOPP (BEACOPP-14 or escBEACOPP) had a 3 yr PFS of 67.5% and 3 yr OS of 87.8%.
The aforementioned HD18 study by German Hodgkin Study Group confirmed that 4 escBEACOPP was as effective as 6-8 escBEACOPP but less toxic in patients who achieved PET-negative status after 2 cycles of escBEACOPP. 3 yr PFS in this group (PET-2 negative after escBEACOPP) was 95.3% and 3 yr OS was 98.8%.
Based upon the above data, it is reasonable to adopt a PET-guided therapy approach for advanced staged Hodgkin lymphoma. Initiation of escBEACOPP as per the HD18 study results in a higher overall survival and is the preferred approach for young, fit patients for whom the fertility implications are acceptable. For patients who initiate therapy with ABVD, PET-directed therapy will minimize the long-terms risks of cytotoxic chemotherapy and radiotherapy for PET-patients after ABVD x2, while maintaining PFS rates <5% inferior to conventional combined modality treatments. These PET-guided approaches are illustrated in Figure 1-2. For centres where PET scanning is not available, or in situations when patients prefer to prioritize their initial cure rate and avoidance of intensive salvage therapy with autologous SCT rather than prioritize a similar long-term survival while minimizing therapy-related second cancers, cardiovascular mortality or bleomycin lung toxicity, the more traditional therapy approach illustrated in Figure 3 is still very reasonable.   A phase II study of N=102 patients treated with BV (1.8mg/kg, outpatient IV, 30min, every 3 weeks for up to 16 cycles) for relapsed/refractory Hodgkin lymphoma after failed hematopoietic autologous stem cell transplantion reported outcomes after approximately 3-years of follow-up. Median OS and PFS were estimated at 40.5 months and 9.3 months, respectively. The estimated 3-year OS and PFS rates were 73% (95%CI: 57-88%) and 58% (95%CI: 41-76%), respectively. Younger age, good performance status, and lower disease burden at baseline were favorable prognostic factors for OS. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.

# Consolidation with Brentuximab Vedotin after ASCT
The AETHERA clinical trial evaluated a strategy of consolidation with brentuximab vedotin after autologous stem cell transplantation in high risk relapsed Hodgkin lymphoma patients. Patients were eligible for BV if they were either: refractory to frontline treatment, relapsed = 12 months with extranodal involvement. Patients were randomized to receive either BV (1.8mg/kg every 3 weeks for up to 16 cycles) or placebo. 5 year PFS was 59% for BV versus 41% for placebo. Grade 3-4 peripheral motor and sensory neuropathy was observed in 6 and 10% of patients receiving BV consolidation, however, improves or resolves in the majority of patients.

# PD1-inhibitors 56 :
The  For primary prophylaxis of febrile neutropenic infection for similar indications above or co-morbidities that increase risk of infectious complications such as chronic obstructive pulmonary disease, or secondary prevention after a prior episode of febrile neutropenia:
- G-CSF 300 or 480g/day starting 3 days after chemotherapy completed until post-nadir ANC>1.0 (usually 7-10 days) (though most patients require only 2-5 days of G-CSF support)
- Must monitor CBC - The alternative is one dose of pegfilgrastim (Neulasta) 6mg on day 4 (without CBC monitoring, but at a cost of ~$2500/dose)
Erythropoeitin is not recommended because of evidence suggesting increased mortality rates. Consider only for symptomatic anemia patients who cannot receive RBC transfusions (i.e., Jehovah's Witnesses, prior severe transfusion reactions or severe iron overload).

# Antimicrobial Prophylaxis for Immunosuppressive Regimens 6-8
- For patients receiving fludarabine, high dose cyclophosphamide, >5 days high dose corticosteroids every 21 days, bortezomib, and bendamustine, and for immune-compromised patients (i.e., HIV, post-organ transplant or autoimmune disease patients who develop hematologic cancers) use prophylaxis during and for 12 months post-treatment. CD4 count monitoring can be used to help determine if prophylaxis can be stopped earlier (should not be assessed until 3 or 6 months post-treatment). Patients withCD4 count > 200 / L may have earlier discontinuation of antimicrobial prophylaxis.
Patients should be encouraged to keep all immunizations up to date. The reactivation and/or seroreversion of viruses that patients have been previously vaccinated against, such as hepatitis B, is a major cause of morbidity and mortality in patients with hematologic malignancies treated with cytotoxic chemotherapy. Appendix G outlines the general principles and specific immunization schedules for recipients of blood and marrow transplantations. In addition, separate guidelines outlining influenza and pneumococcal immunization recommendations for all patients with cancer can be found at: www.albertahealthservices.ca/cancerguidelines.asp under the "Supportive Care" heading" Recombinant adjuvant herpes zoster vaccine is commercially available however cancer patients were excluded in the pivotal phase 3 trials (ZOE-50 and ZOE-70). Studies with use in cancer patients are not yet published, but results suggest that vaccination responses are better for patients not on treatment or given prior to chemotherapy, as opposed to during chemotherapy 9. Other hematological malignancy patients had better vaccines responses than Non Hodgkin's Lymphoma and CLL patients for reasons not yet identified 10. The AHS Hematology group consensus is that the recombinant adjuvant herpes zoster vaccine is not contraindicated in hematology patients. Patients may receive the vaccine if they have adequateimmune function to amount a response, and are 6-9 months post Rituximab due to the reduced vaccine responses seen in rituximab-treated patients.
Family members and health care providers in contact with patients who have undergone a transplant should also be strongly encouraged to keep all immunizations up to date.
For patients who have experienced reactivation or seroreversion of hepatitis B virus, prompt administration of nucleoside/nucleotide analogues is essential 11. Entacavir or tenofovir following R-CVP or R-CHOP chemotherapy for lymphoma is recommended for all patients who have a positive hepatitis B surface antigen test.
Last Reviewed: September 2017 VIII. Follow-Up Care in the Treatment of Lymphoma  The following late effects should be considered when patients are reviewed during follow-up:
- Relapse. Careful attention should be directed to lymph node sites, especially if previously involved with disease. Routine surveillance CT scans are not indicated. Most relapses have been demonstrated to occur between scheduled clinics visits and tests, and are detected by patients themselves. Highly anxious patients who wish surveillance tests could be considered for occasional CXR and abdominal/pelvic ultrasounds (if thin), especially in the setting of indolent lymphoma and prior retroperitoneal and mesenteric disease. - Dental caries. Neck or oropharyngeal irradiation may cause decreased salivation. Patients should have careful dental care follow-up and should make their dentist aware of the previous irradiation. - Hypothyroidism. After external beam thyroid irradiation to doses sufficient to cure malignant lymphoma, at least 50% of patients will eventually develop hypothyroidism. All patients whose TSH level becomes elevated should be treated with life-long T4 replacement in doses sufficient to suppress TSH levels to low normal. - Infertility. Multi-agent chemotherapy and direct or scatter radiation to gonadal tissue may cause infertility, amenorrhea, or premature menopause. However, with current chemotherapy regimens and radiation fields used, most patients will not develop these problems. All patients should be advised that they may or may not be fertile after treatment. In general, women who continue menstruating are fertile, but men require semen analysis to provide a specific answer. - Secondary neoplasms. Although quite uncommon, certain neoplasms occur with increased frequency in patients who have been treated for lymphoma. These include AML, thyroid, breast, lung, and upper GI carcinoma, melanoma and cervical carcinoma in situ. It is appropriate to screen for these neoplasms by careful history, physical examination, mammography and Pap smears for the rest of the patient's life because they may have a lengthy induction period. Patients should be counseled about the hazards of smoking and excessive sun exposure, and should be encouraged to perform careful breast and skin examinations on a regular basis.
Table 1 outlines the minimum follow-up tests and examinations that should be performed on all patients after treatment for malignant lymphoma. Visits should be scheduled with an oncologist or family physician educated in post-treatment lymphoma surveillance every 3-4 months for 2 years, then every 6 months for 3 years, then annually. - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well. - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well.
- Cyclophosphamide 750 mg/m 2 IV - Rituximab 375mg/m 2 IV day 1 (premedications: Tylenol, Benadryl, Zantac, hydrocortisone 100mg) then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated well.       - weight (call MD if >2kg above day 1)
- CBC & differential, EP, creatinine, glucose - ALT,AlkP,LDH,bilirubin,Alb,Ca,Mg F) Transplant-ineligible patients (age >65 years, significant co-morbidities, or immune suppression) with late relapse (prior RCHOP x6) with relapsed systemic and CNS lymphoma. This situation is unfortunately associated with extremely poor prognosis, and generally should be treated with palliative intent. Treatments could include IT chemotherapy, radiotherapy, decadron, or best supportive care. Patients who received rituximab-based therapy as part of their initial treatment had a 3-year PFS of 70% and an OS of 73% compared with a 3-year PFS of 21% (p1.5 cm before therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis before treatment must have decreased to <1.0 cm in their short axis after treatment.

# Post-Transplantation Lymphoproliferative Disease (PTLD)
- The spleen and/or liver, if considered enlarged before therapy on the basis of a physical examination or CT scan, should not be palpable on physical examination and should be considered normal size by imaging studies, and nodules related to lymphoma should disappear. However, determination of splenic involvement is not always reliable because a spleen considered normal in size may still contain lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use of hematopoietic growth factors, or causes other than lymphoma.
- If the bone marrow was involved by lymphoma before treatment, the infiltrate must have cleared on repeat bone marrow biopsy. The biopsy sample on which this determination is made must be adequate (with a goal of >20 mm unilateral core). If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. A sample that is negative by immunohistochemistry but that demonstrates a small population of clonal lymphocytes by flow cytometry will be considered a CR until data become available demonstrating a clear difference in patient outcome.

# Partial Response (PR)
The designation of PR requires all of the following:
- At least a 50% decrease in sum of the product of the diameters (SPD) of up to six of the largest dominant nodes or nodal masses. These nodes or masses should be selected according to all of the following: they should be clearly measurable in at least 2 perpendicular dimensions; if possible they should be from disparate regions of the body; and they should include mediastinal and retroperitoneal areas of disease whenever these sites are involved.
- No increase should be observed in the size of other nodes, liver, or spleen.
- Splenic and hepatic nodules must regress by >50% in their SPD or, for single nodules, in the greatest transverse diameter.
- With the exception of splenic and hepatic nodules, involvement of other organs is usually assessable and no measurable disease should be present.
- Bone marrow assessment is irrelevant for determination of a PR if the sample was positive before treatment. However, if positive, the cell type should be specified (e.g., large-cell lymphoma or small neoplastic B cells). Patients who achieve a CR by the above criteria, but who have persistent morphologic bone marrow involvement will be considered partial responders. When the bone marrow was involved before therapy and a clinical CR was achieved, but with no bone marrow assessment after treatment, patients should be considered partial responders.
progressive disease, a lymph node with a diameter of the short axis of less than 1.0 cm must increase by >50% and to a size of 1.5 x 1.5 cm or more than 1.5 cm in the long axis.
- At least a 50% increase in the longest diameter of any single previously identified node more than 1 cm in its short axis.
- Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the lesion was PET positive before therapy unless the lesion is too small to be detected with current PET systems (<1.5 cm in its long axis by CT).
- Measurable extranodal disease should be assessed in a manner similar to that for nodal disease. For these recommendations, the spleen is considered nodal disease. Disease that is only assessable (e.g., pleural effusions, bone lesions) will be recorded as present or absent only, unless, while an abnormality is still noted by imaging studies or physical examination, it is found to be histologically negative.
- In clinical trials where PET is unavailable to the vast majority of participants, or where PET is not deemed necessary or appropriate for use (e.g., a trial in patients with MALT lymphoma), response should be assessed as above, but only using CT scans. However, residual masses should not be assigned CRu status, but should be considered partial responses.
Response and site PET-CT-Based Response CT-Based Response New lesions

# Bone Marrow
New FDG-avid foci consistent with lymphoma rather than another etiology (eg. Infection, inflammation). If uncertain regarding etiology or new lesions, biopsy or interval scan may be considered New or recurrent FDG-avid foci Regrowth of previously resolved lesions A new node > 1.5 cm in any axis A new extranodal site> 1.0cm in any axis; if  mediastinum but  liver; 4, uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to lymphoma.

# Ann Arbor Staging Nodal Sites

# ECOG Performance Status 0
Fully active, able to carry on all pre-disease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature.
Ambulatory, capable of all self-care but unable to carry out any work activities. Up and about >50% waking hours.
Capable of only limited self-care. Confined to bed or chair more than 50% of waking hours.
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. Disclaimer The recommendations contained in this guideline are a consensus of the Alberta Hematology Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care.

# Copyright  (2023) Alberta Health Services
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# Data Supporting Brentuximab vedotin for Primary Therapy of Hodgkin Lymphoma 36
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. Additionally, Health Canada restricted approval to patients with Stage 4 disease, who are thus, the only patients currently eligible to receive this therapy in Canada. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation). BV has not been investigated using a PET-directed approach (the current standard for HL in Alberta), has not been proven superior to escBEACOPP (our recommended treatment for young and fit Stage 4 HL patients) and thus the costs of A-AVD are considered too high to justify a change in practice at this time.
We recommend A-AVD only for patients who are appropriate for intensive, curative HL therapy but refuse escBEACOPP for reasons of fertility preservation or personal choice or are ineligible for escBEACOPP due to age or comorbidities (but still suitable for full dose A-AVD).
Data Supporting a PET-Guided Treatment Approach  :

# Limited Stage:
In the UK Rapid trial, patients with stage I-IIA non-bulky HL received ABVD x3 cycles then underwent a PET scan. If the PET was positive (uptake more than blood pool, Deauville score 3-5) the patients received one more cycle ABVD then IFRT, whereas if the PET was negative patients were randomized to observation or IFRT. The 3yr PFS was 85.9% in the 145 PET+ patients, 94.6% in the PET-patients who received IFRT and 90.8% in PET-patients who were observed. The difference in PFS was -3.8% (95%CI: -8.8%, 1.3%) exceeding -7% non-inferiority margin. Of interest, the perprotocol PFS was 97% vs 90.8% because 26 pts did not get allocated IFRT. The respective 3 year overall survival rates were 97.1% vs 99.0%. In the EORTC/LYSA/FIL H10 trial, stage I-II HL patients were randomized between control arm therapy with ABVD x3 +INRT (favorable risk) or ABVD x4 +INRT (unfavorable risk), with all patients undergoing PET after cycle 2 ABVD. In the experimental Future potential option for patients not eligible for PET-guided approach Brentuximab vedotin 36 :
An open-label, multicenter phase 3 trial of 1334 patients with previously untreated stage III/IV Hodgkin lymphoma, randomized (1:1) patients to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) or ABVD. After a median follow-up of 24.6 months, 2 year modified progression-free survival (primary end point) was 82.1% (95%CI: 78.8-85.0%) for the A+AVD group and 77.2% (95%CI: 73.7-80.4%) in the ABVD group (p=0.04). Neutropenia was higher in the A+AVD group (58% vs 45%), febrile neutropenia occurred in 83 patients (rate: 11% in those receiving prophylactic GCSF and 21% in those without GCSF). Peripheral neuropathy was also higher in the A+AVD group (67% vs. 43%), with resolution at last follow-up in 2/3 of patients. Pulmonary toxicity grade 3 occurred in 1% of A+AVD patients vs. 3% in ABVD. No overall survival difference was observed. While this trial showed an improvement in its primary endpoint (modified PFS), this endpoint included patients who received IFRT after achieving a PR, which many would argue is appropriate curative therapy and should not have qualified as treatment failure. With the current analysis, the number needed to treat is very large (and would be even larger if the patients receiving adjuvant radiotherapy were excluded from the PFS calculation) and thus the costs of A-AVD are considered too high to justify a change in practice at this time. However, this regimen has been demonstrated as an effective and tolerable frontline therapy for advanced stage Hodgkin lymphoma and could become the standard against which future non-PET directed treatments are compared.

# Management of Recurrent Hodgkin Lymphoma 2,37-52 :
Similar to the initial workup, recurrent disease should involve re-staging tests.

# Initial relapse.
- Re-induction chemotherapy with GDP or DICEP then high dose therapy and autologous SCT + IFRT 20-30Gy to prior bulk site at relapse, or PET-positive residual disease post-ASCT
- Brentuximab vedotin consolidation post-ASCT for patients with primary refractory HL, relapse within 12 months or extranodal disease at relapse
- Pembrolizumab iv q3-6 weeks for older/unfit patients who are deemed ineligible for ASCT Second or subsequent relapse.
- IFRT if localized relapse in previously non-irradiated site - A PD1-inhibitor (eg. Nivolumab or Pembrolizumab) after prior failure of chemotherapy (and autologous SCT in transplant eligible patients) [data suggests longer remissions with PD1-inhibitor compared to Brentuximab vedotin making PD1i then BV the preferred sequencing)
- Brentuximab vedotin IV q21d for up to 16 doses if prior failure of initial chemotherapy (ABVD or BEACOPP) and prior autologous SCT (excluding patients who progress on BV consolidation post-ASCT)
- Palliative chemotherapy for symptomatic patients (GDP, COPP, ChlVPP, CEPP, vinblastine)
Reduce by 50% for grade 3 motor or sensory neuropathy For patients who develop  grade 3 ileus, treatment should be delayed until recovery and vincristine introduced at 75% of the normal dose thereafter. If  grade 3 ileus recurs, vincristine should be discontinued

# II. Initial Therapy For Indolent Histology Non-Hodgkin Lymphoma
- Bendamustine 90 mg/m 2 IV day 1, 2
- Rituximab 375 mg/m 2 IV day 1 then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
- Cycles: repeated every 3-4 weeks depending on blood counts (usually administered every 28 days) for a maximum of 6 cycles CVP:
- Cyclophosphamide 800 mg/m 2 IV day 1 (or 400 mg/m 2 /day p.o. days 1-5)
- Vincristine 2mg IV day 1
- Prednisone 100mg/day p.o. days 1-5
- Cycles: every 21 days
- Rituximab 375mg/m 2 IV day 1 (premeds: Tylenol, Benadryl, Zantac, hydrocortisone 100mg), then Rituximab 1400mg sc on day 1 from cycle 2 onwards if initial IV dose tolerated.
- Cyclophosphamide 750 mg/m 2 IV day 1

# Chlorambucil (options):
- 0.1-0.2 mg/kg/day for 4-8 weeks then usually reduce for maintenance - 10-14 mg/m2 for 5 to 7 days each 28 days - 0.5 mg/kg days 1 and 15 q28d cycle Fludarabine:
- 25mg/m 2 IV days 1-5 q28 days (days 1-3 only if frail elderly or renal dysfunction)
- 40mg/m 2 p.o. days 1-5 q28 days (round down to nearest multiple of 10mg) (d1-3 only if frail or renal dysfunction)
- Fludarabine 25mg/m 2

# Methotrexate should be omitted if creat clearance < 50 mL/min or if renal dysfunction with prior cycle Cytarabine should be reduced to q24hr if creat clearance < 50 mL/min or complications of myelosuppression

# VIII. Secondary CNS Lymphoma Protocol
A) Transplant-eligible patients (age <65 years, no significant co-morbidities, no immune suppression) with isolated CNS relapse/progression following complete response of systemic lymphoma to RCHOP.
Step    Step 1
Week 1 2 3 4 5 6 7 8 9 10 11 12 15 or 16 Rituximab 375mg/m2 d0, 4 high-dose methotrexate 3.5 g/m 2 d1 procarbazine 100 mg/m 2 x 7 days d1-7
x x x Rituximab 375mg/m2 d0 high-dose methotrexate 3.5 g/m 2 day 1 cytarabine 1.5-2 g/m 2 bid days 2-3 - role of IMRT/VMAT/TOMO over 3DCRT is at discretion of treating radiation oncologist-this is determined on a case by case basis - the low dose bath is a consideration when using IMRT as it relates to potential long term risk of second malignancies The full analysis set was collected from eight phase 3 trials in France, Germany, the United Kingdom, the United States, and Poland (n=3,472 patients, median age 61 years (27-86 yrs)). 89% of patients had received treatment for CLL and median overall survival (OS) was 95 months. The model was externally validated in a third dataset comprising 845 patients with newly diagnosed CLL from the Mayo Clinic; 39% had received treatment for CLL. The final model of multivariate analysis identified 5 independent predictors for OS: TP53 (17p) mutation (deleted and/or mutated; hazard ratio : 4.2); IGHV mutation status (unmutated, HR: 2.6); B2M (>3.5 mg/L; HR: 2.0); clinical stage (Binet B/C or Rai I-IV, HR: 1.6); and age (>65 years, HR: 1.7). Using weighted grading, a prognostic score from 0 to 10 was derived that separated the patients into four different groups: low risk (score 0-1), intermediate risk (score 2-3), high risk (score 4-6), and very high risk (score 7-10). At 5 years, significantly different rates of OS were observed for the low to the very high risk group, 93%, 79%, 64%, and 23%, respectively (P<0.001; C-statistic c=0.72. The multivariable model was confirmed on the internal validation datasets; in addition, the four risk groups were reproduced with on the Mayo dataset, with 5-year OS rates of 97%, 91%, 68% and 21%, respectively (P<0.001; C-statistic c=0. 79

# Role of PET in