7.4. Treatment in the elderly

Conventionally, very elderly patients are not considered candidates for aggressive therapy for various reasons. This population is not represented well in the clinical trials that form the basis for standard treatment. To address this issue GELA study group undertook a phase II study where 149 patients age 80 years and above were administered reduced dose CHOP with conventional dose rituximab (so-called R-mini-CHOP). The extended follow up from this study revealed 4-year OS and PFS rates of 49 and 41% with neutropenia being most frequent


high grade toxicity [73]. Comprehensive geriatric assessment may help in identifying patients

Table 4. Summary of updated recommendations for the initial evaluation, staging, response assessment and follow up

• In Waldeyer's ring uptake may be more than mediastinum with complete response but

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263 57

• Every 3 months for first 2 years, then every 6 months for 3 years followed by annually

• Physical assessment and lab investigations including CBC, metabolic panel and LDH

should not be higher than the uptake in surrounding normal tissues.

Supportive care is imperative to mitigate the toxic effects of the chemotherapy. Care must be taken during initial cycles of chemotherapy and patients should have prophylactic allopurinol to prevent tumor lysis syndrome with highly effective regimens used currently. Patients should be screened for and appropriately treated for underlying hepatitis B infection if

Assessment of response to therapy is accomplished by PET scans. Interim PET scans after 2 cycles may have prognostic significance. In a study 2-year PFS and OS were shown to be significantly better for the patients with PET negative disease after 2 cycles of therapy than those with positive scans [69]. Interpretation of PET scans should be done according to 5-point scoring system—Deauville criteria [76]. As per Deauville criteria score of 1, 2 or 3 with or without residual mass is considered a complete response, while a score of 4 or 5 with reduced uptake from baseline, represents responding disease when PET-CT is performed in the interim or residual disease if the PET-CT is performed at the end of the treatment. A score of 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment is regarded as no response or stable disease. New lesions or a score of 4 and 5 with increase in intensity of uptake from baseline at interim or end of treatment, signify disease progression [77]. There is not enough evidence that this can be used to change the therapy when performed in the interim. Re-biopsy should be performed if contemplating change of therapy due to positive scans, since false positive scans may be encountered [78]. Additional imaging with MRI or

biopsy is also recommended when bone marrow only findings are evident on PET-CT.

Routine imaging in patients after complete remission (CR) without any symptoms can safely be deterred, in a study by Guppy et al. only 6% relapses were noted in asymptomatic patients as

suitable for chemotherapy [74].

afterwards.

should be checked.

evaluation of patients with DLBCL as suggested in Lugano classification.

• No role of imaging and it should be discouraged.

rituximab use is contemplated [75].

7.7. Surveillance and follow up

7.6. Assessment of therapeutic response

7.5. Supportive care

Follow up evaluation

• In Waldeyer's ring uptake may be more than mediastinum with complete response but should not be higher than the uptake in surrounding normal tissues.

Follow up evaluation

Initial evaluation

Staging

Bone marrow involvement

Response assessment

History • Demographics including age and gender

56 Hematology - Latest Research and Clinical Advances

cases.

stage.

studies in the rituximab era.

or solitary mass.

negative PET

not required.

accurate for organomegaly.

6 months) of unknown etiology and swelling.

Physical examination • Specifically assessment of nodal regions and size of spleen and liver. CT imaging is more

Diagnosis • FNAC is inadequate for initial diagnosis. Incisional and excisional biopsy is the standard if

astinal or central vessels and for planning of radiation.

• Clinical including fever (>38.3C or 101F), night sweats, significant weight loss (>10% in

• Assessment of comorbidities which could affect the lymphoma management and outcome.

• PET-CT is the preferred imaging modality over CT scan wherever available. Chest X-ray is

• CECT should be included in selected cases for more precise measurement of lymph nodes, to distinguish bowel from lymph nodes, in cases with compression or thrombosis of medi-

• If CT is used for imaging, up to 6 of the largest lymph node masses or other lesions should be measured (largest diameter LDi] and smallest diameter) as marker of disease burden. It should include mediastinal and retroperitoneal regions, if affected. Significant lesions are

• Instead of classical, modified Ann Arbor staging is used in which bulky stage II is a separate

12 cm has been used in various studies. Current recommendations are >13 cm. • Normal size does not rule out lymphomatous involvement. PET-CT is the best modality which could show homogenous splenomegaly, diffuse infiltration, miliary lesions, nodular

uptake, with/without focal or disseminated nodules support involvement.

• Involvement of BM on DLBCL is sufficient to label advanced stage disease. In patients with

• CT, BM may be required to r/o simultaneous presence of other histologies or when malig-

• 5-point scale should be used both for interim analysis (for early treatment response) and end

• Score of 3 (uptake > mediastinum but < liver) = good response in real practice but in clinical

• Score of 4 (uptake moderately > liver) and 5 (uptake markedly > liver) = in interim analysis, if uptake is decreased from baseline, is considered as chemosensitive disease. However, if it persists till end of treatment, it is considered as treatment failure. New foci of lymphoma at

• Score of 1 (no uptake) and 2 (uptake < mediastinum) = complete metabolic response at

feasible core needle biopsy is acceptable if excisional biopsy cannot be done. • Morphology, IHC and flow cytometry in most of the cases and molecular studies in selected

• Additional tissue or cell suspension should be preserved for future research.

lymph node with LDi > 1.5 cm and extranodal masses with LDi >1 cm

Bulky disease • Exact size for bulky tumor is not clear for DLBCL. 6–10 cm is reported as bulky in various

Splenic involvement- • The exact cut off is affected by ethnicity, body size and height. No consensus. More than 10–

Hepatic involvement • Size is not a reliable marker of lymphomatous involvement. Presence of focal or diffuse

• Routine bone marrow biopsy is not required in DLBCL.

nant transformation is suspected.

interim or end of treatment

• Should be done with PET-CT wherever available.

of treatment assessment (to establish the remission).

trials should be considered as inadequate response.

any time is also considered treatment failure.


Table 4. Summary of updated recommendations for the initial evaluation, staging, response assessment and follow up evaluation of patients with DLBCL as suggested in Lugano classification.

high grade toxicity [73]. Comprehensive geriatric assessment may help in identifying patients suitable for chemotherapy [74].

#### 7.5. Supportive care

Supportive care is imperative to mitigate the toxic effects of the chemotherapy. Care must be taken during initial cycles of chemotherapy and patients should have prophylactic allopurinol to prevent tumor lysis syndrome with highly effective regimens used currently. Patients should be screened for and appropriately treated for underlying hepatitis B infection if rituximab use is contemplated [75].

#### 7.6. Assessment of therapeutic response

Assessment of response to therapy is accomplished by PET scans. Interim PET scans after 2 cycles may have prognostic significance. In a study 2-year PFS and OS were shown to be significantly better for the patients with PET negative disease after 2 cycles of therapy than those with positive scans [69]. Interpretation of PET scans should be done according to 5-point scoring system—Deauville criteria [76]. As per Deauville criteria score of 1, 2 or 3 with or without residual mass is considered a complete response, while a score of 4 or 5 with reduced uptake from baseline, represents responding disease when PET-CT is performed in the interim or residual disease if the PET-CT is performed at the end of the treatment. A score of 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment is regarded as no response or stable disease. New lesions or a score of 4 and 5 with increase in intensity of uptake from baseline at interim or end of treatment, signify disease progression [77]. There is not enough evidence that this can be used to change the therapy when performed in the interim. Re-biopsy should be performed if contemplating change of therapy due to positive scans, since false positive scans may be encountered [78]. Additional imaging with MRI or biopsy is also recommended when bone marrow only findings are evident on PET-CT.

#### 7.7. Surveillance and follow up

Routine imaging in patients after complete remission (CR) without any symptoms can safely be deterred, in a study by Guppy et al. only 6% relapses were noted in asymptomatic patients as against 86% in those who had symptoms [79]. However, imaging can also pick up changes early on when disease recurs. Although imaging can diagnose recurrence earlier, it has not been shown to alter the outcomes. The current work up and follow up recommendations for DLBCL are summarized in Table 4.

Drug MOA (target) Eligibility (and design) Phase Subjects (N) Results

Ist line CHOP-R vs.

Chemotherapy Refractory/relapsed II N = 60 ORR: 95%; (CR/CRu:

Anti-CD 20 Refractory/relapsed I N = 6 CR 100%; neutropenia

Refractory/relapsed II N = 25 stepwise (9–

Previously untreated DLBCL (with R-CHOP)

Consolidation therapy after first line R-CHOP

Heavily pretreated NHL II N = 7 PD in all DLBCL: 100%

n = 2)

28–112 μg/d with weekly dose increases; n = 23) or flat (112 μg/d;

II N = 124 ORR 82% for the CPOP-R

Recent Advances in Diffuse Large B Cell Lymphoma http://dx.doi.org/10.5772/intechopen.74263

> arm vs. 90% for the CHOP-R arm, and median PFS not reached in the CPOP-R arm and was 40 months in the CHOP-R arm; median OS not reached in either arm. OS inferior for CPOP-R (hazard ratio 2.37, p = 0.029), with more deaths occurring in the CPOP-R arm (30% vs. 14%)

59

92%, PR: 3%) 5 years OS 87% and PFS 81%

(grade 3: 50%, grade 4: 33%), thrombocytopenia (grade 3: 17%), and Rash (grade 2: 17%).

ORR 43%, CR 19%. Three patients had late CR in follow up without other

60% post-CHOP to 80% post TST/I-131 TST. At 120.0 months, median DOR was 58.4 months. PFS and time to treatment failure were 63.0 months. OS was not reached. Grade 3/4 hematologic adverse events were decreased absolute neutrophil count (47%), white blood cell count (40%), platelet count (27%), and hemoglobin (20%)

was 75%; grade 3–4

treatment

15 CR rate increased from

II 71 2 year event-free survival

CPOP-R

Chemotherapeutic agents Pixantrone [95] Aza-

Liposomal vincristine [96]

Veltuzumab plus Milatuzumab [98]

Blinatumomab

Antibody drugs conjugates

[99]

I-131 tositumomab [100]

Monoclonal antibodies Obintuzumab Plus Lenalidomide plus CHOP [97]

anthracenedione

Anti-CD20 plus anti-CD74

Single chain bispecific T cell engaging antibody anti-CD19 and anti-CD3 mAb

Anti-CD20 radioimmunotherapy

#### 7.8. CNS prophylaxis

The rate of secondary CNS involvement is 3–5% but it is much higher with certain risk factors. Risk factors for CNS involvement include [80] elevated LDH, >1 extranodal site, involvement of testis, renal, breast, epidural space or adrenal gland, high CNS-IPI or MYC + BCL2/BCL6 gene rearrangement. Patients with 3 or more of these risk factors have a risk of CNS recurrence of as high as 25%. Prognosis is very poor with CNS recurrence and death is inevitable with median overall survival of 2–5 months. Hence patients at high risk of CNS recurrence should be considered for intrathecal chemotherapy with methotrexate or ara-C or high-dose IV methotrexate with leucovorin rescue. The intrathecal chemotherapy can be incorporated once in each cycle; alternatively, IV high-dose methotrexate can be given on Day 15 of 21-day R-CHOP. CNS prophylaxis has been reviewed elsewhere in detail [81].
