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About Lymphoma > Prognostic Indicators
Last update: 10/30/2013
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TOPICS
Prognostic Indicators & Biomarkers
IPI | FLIPI / FLIPI-2 | MIPI | CLL/SLL
Indications of Need-to-Treat indolent lymphomas: GELF / NCCN | Specific Biomarkers
TOPIC SEARCH ASCO.org | ASH | Medscape | PubMed
"Because most of the prognostic studies are based on a retrospective analysis of historical data, they must be interpreted with caution at a time when treatment modalities are changing." herkules.oul
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Prognostic Indicators
TOPIC SEARCH microenvironment AND prognosis PubMed
Related Topics:
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NOTABLE QUOTE ON LIMITATIONS OF PROGNOSTIC MARKERS:
"What is really the most important for people to remember is that prognostic markers only tell you which curve you are on, they do not tell you where you are on the curve.
[For CLL] nothing is more helpful than the pace of your disease. If your WBC is rising slowly, hemoglobin and platelets stable, lymphadenopathy and spleen size stable, then you are behaving in a very indolent manner. This means that the CLL is progressing very slowly and, by and large, will continue to do so for future."
~ Rick Furman, MD
Question: I have been diagnosed with Lymphoma Stage 4. Do you have any statistics as to the survival rate of patients with this diagnosis?
Prognosis is a case-based guess - specific to your age, lymphoma type, the variable clinical behavior even within specific subtypes (follicular, MALT, MCL ...) secondary conditions, general health, etc. - answering the question of a patient: "What's my prognosis, doctor?"
Median survival is the result of arithmetic to find the middle point ... done on a large group - answering the question of researchers: "Are we making progress overall?"
So if your doctor gives you the median survival when you ask how long you've got ... he's not using the terminology correctly. And providing a prognosis would also be a guess .. a poor guess at that for follicular lymphoma (as an example), because of the variable behavior of this condition.
Survival of lymphoma varies also by cell type ... and there are about 30 types of lymphoma. Some types of lymphoma can be cured. Other cell types can be managed very well, like a chronic disease.
Statistics cannot predict what will happen to you or a loved one. Each patient and case is unique, and treatment outcomes can vary from one person to another. Indeed, not even your doctor can tell you for sure what will happen.
The term '5 year survival' is used often. It relates to the proportion of people in research studies who were still alive 5 years after diagnosis. However, importantly, patients who live 6, 10, or 30 years after diagnosis are also in this group.
Therefore "5 year survival" statistics do not mean you have five years to live.
Survival expectations increase for those who have survived beyond 1, 2, 3, or 4 years. For example, 8 year survival might be the average for a given type of lymphoma, but for patients who have already survived five years, the average survival could be well beyond the average survival at diagnosis. (Similarly, a higher percentage of Marathon runners who reach the 10 mile mark will complete the race, compared to all that have started it.)
Furthermore, Overall Survival (OS) is calculated based on death from any cause, and is strongly influenced by the average age at diagnosis. For follicular lymphomas, a median OS of 8 to 10 years is often cited and the average age at diagnosis is about 65 years. However, a recent report from Stanford, based on patients with a median age of 49, the median (average) OS was 18 years.
It's worth considering that OS measures time to death from *any* cause. Ask yourself: What is the median OS if you are 65 years old and have no lymphoma? 14 years? 8 years?
Factors that influence, but do not predict, the survival for patients with lymphoma include:
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the cell type,
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the grade (a good percentage of pts with aggressive NHL can be cured, and pts with indolent NHL can live well and long with the disease)
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the stage of the disease (almost everyone is diagnosed with stage 4),
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the age and performance level of the patient,
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tumor burden,
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LDH levels,
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number of extranodal sites (tumors outside the lymph organs).
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hemoglobin level (< 12 g/dL vs. >/= 12 g/dL),
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response to initial treatment, and duration of the response;
"Response to treatment is one of the most important prognostic indicators, particularly in patients with aggressive NHL." ncbi.nlm.nih.gov
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genetic characterizations, including the microenvironment which are now being explored with advanced testing.
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Resources:
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Expert background: Optimal Use of Prognostic Factors in NHL asheducationbook. 2006 pdf
The management of non-Hodgkin lymphoma is complicated by wide heterogeneity within recognized subtypes. Patients with supposedly similar diagnoses can have remarkably varied clinical presentations, molecular profiles and clinical outcomes. Reliable prognostic markers could allow the identification of patient subsets that may benefit from alternate approaches.
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Survival after progression in patients with follicular lymphoma: analysis of prognostic factors annonc.oxfordjournals.org
In patients with FL, Response Duration (RD) along with performance status at progression are features that predict Survival Following Progression. These variables could thus be useful to select candidates for experimental treatments.
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cFLIP expression correlates with tumour progression and patient outcome in non-Hodgkin lymphomas of low grade of malignancy. Br J Haematol. 2006 Mar;132(5):560-70. PMID: 16445828
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nih.gov
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Ann Arbor Stages of Non-Hodgkin's Lymphoma Grade
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Biologic Prognostic Features in Non-Hodgkin’s Lymphoma and Their Implications, Bertrand Coiffier PDF | PDF-Help
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Bone marrow involvement and survival for low grade NHL? PubMed | Related articles
"Conclusion. The presence of bone marrow infiltration at diagnosis did not significantly affect the prognosis of LGNHL."
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Liver involvement and survival? PMID: 10561315 PubMed
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Transformation PAL
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What if I'm BCL2 negative? BCL2 Negative
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Research News
CLL/SLL
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CLL Aggressiveness May Be Predicted By New Biomarker medicalnewstoday.com
They found that high levels of a particular enzyme PDE7B) in the blood are an indicator that chronic lymphocytic leukemia (CLL) - the most common form of adult leukemia - will be aggressive and in need of immediate treatment.
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Diffuse Large Cell Lymphoma:
TOPIC SEARCH prognostic markers PubMed
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Low absolute lymphocyte count is a poor prognostic factor in diffuse-large-B-cell-lymphoma.
Leuk Lymphoma. 2008 Sep;49(9):1745-51. PMID: 18798109
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A redox signature score identifies diffuse large B-cell lymphoma patients with a poor prognosis.Blood. 2005 Aug 4; PMID: 16081686 | Related articles
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Follicular lymphoma:
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Gene-Expression and Immunohistochemical Study of Specific T-Cell Subsets and Accessory Cell Types in the Transformation and Prognosis of Follicular Lymphoma. J Clin Oncol. 2007 Jan 2; PMID: 17200149 | Related articles
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Overexpression of SOCS3 is associated with decreased survival in a cohort of patients with de novo follicular lymphoma. Br J Haematol. 2006 Aug 24; PMID: 16939500
OCS3-positive FL patients had a median OS of 10 years compared with 22 years in
SOCS3-negative patients (P = 0.001, log rank test).
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Immunohistochemical analysis of the antiapoptotic Mcl-1 and Bcl-2 proteins in follicular lymphoma. Br J Haematol. 2006 Mar;132(6):743-6. PMID: 16487175
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Molecular pathogenesis of follicular lymphoma: a cross talk of genetic and immunologic factors. J Clin Oncol. 2005 Sep 10;23(26):6358-63. Review. PMID: 16155020
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Increased Vascularization Predicts Favorable Outcome in Follicular Lymphoma 2005 aacrjournals.org | full text
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Predicting Cancer Patient Survival with Gene Expression Data
DOI: 10.1371/journal.pbio.0020118 - full text plosbiology.org
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[2266] Follicular Lymphoma: Design of a Protein-Based Survival Predictor Using Tissue-Microarrays (TMA). Session Type: Poster Session 479-II ASH 2004
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High expression of cyclin B1 predicts a favorable outcome of patients with follicular lymphoma. Blood. 2004 Dec 2; PMID: 15576476
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Bone marrow histological patterns can predict survival of patients with grade 1 or 2 follicular lymphoma: a study from the Groupe d'Etude des Lymphomes Folliculaires.
Br J Haematol. 2004 Aug;126(3):364-71. PMID: 15257708
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Follicular lymphoma international prognostic index.
Blood. 2004 May 4 [Epub ahead of print] PMID: 15126323
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Prognostic indicator: Expression of bcl-6 and CD10 protein is associated with longer overall survival and time to treatment failure in follicular lymphoma. Am J Clin Pathol. 2004 Jan;121(1):34-42. PMID: 14750238 | Related articles
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Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood. 2000 Feb 1;95(3):783-9 full text | Related abstracts
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Survival in young patients (less than 40 years) with follicular lymphoma: a population based study by the Scotland and Newcastle Lymphoma Group. Leuk Lymphoma. 2004 Jun;45(6):1149-57. PMID: 15359994
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Survival after progression in patients with follicular lymphoma: analysis of prognostic factors. Ann Oncol. 2002 Apr;13(4):523-30. PMID: 12056701 | Related articles
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Serum CA 125 as a prognostic factor in non-Hodgkin's lymphoma.
Leuk Lymphoma. 2003 Oct;44(10):1733-8. PMID: 14692526 | Related articles
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High serum interleukin-6 levels correlate with a shorter failure-free survival in indolent lymphoma. Leuk Lymphoma. 1998 Aug;30(5-6):563-71. PMID: 9711918 | Related articles
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Increased serum levels of interleukin-9 correlate to negative prognostic factors in Hodgkin's lymphoma. Leukemia. 2003 Oct 9 [Epub ahead of print] PMID: 14562126 | Related articles
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Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2003 Jun 15;21(12):2335-41. PMID: 12805335 | Related articles
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Tumor load in patients with follicular lymphoma post stem cell transplantation may correlate with clinical course. Bone Marrow Transplant. 2003 Aug;32(3):287-291. PMID: 12858200 PubMed
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Low-grade stage III-IV follicular lymphoma: multivariate analysis of prognostic factors in 484 patients--a study of the groupe d'Etude des lymphomes de l'Adulte.
J Clin Oncol. 1999 Aug;17(8):2499-505. PMID: 10561315 PubMed
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Clinicopathologic correlations of genomic gains and losses in follicular lymphoma.
J Clin Oncol. 2002 Dec 1;20(23):4523-30. PMID: 12454108 PubMed
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A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytological subtypes do not predict survival. Blood. 2002 Nov 7 PMID: 12424193 PubMed
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Assessment of prognostic factors in follicular lymphoma patients.
Int J Hematol. 2001 Apr;73(3):363-8. PMID: 11345204 PubMed
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Pregnancy in the patient with lymphoma does not predict an adverse prognosis Year: 2002 Abstract No: 1141
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Prognosis of follicular lymphoma: a predictive model based on a retrospective analysis of 987 cases. Intergruppo Italiano Linfomi. Blood. 2000 Feb 1;95(3):783-9. PMID: 10648386 PubMed
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Prognostic significance of Ki-67 nuclear proliferative antigen, bcl-2 protein, and p53 expression in follicular and diffuse large B-cell lymphoma. Med Oncol. 2001;18(1):15-22. PMID: 11778965 PubMed
"Prognostic factors for overall survival in the multivariate analysis were age (p = 0.02) and LDH (p = 0.003). Time to progression was worse among follicular lymphoma with high p53 expression than with mild/moderate p53 expression (p = 0.009)."
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Cutaneous b-cell lymphoma
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Prognostic Factors in Primary Cutaneous B-Cell Lymphoma: The Italian Study Group for Cutaneous Lymphomas. J Clin Oncol. 2006 Feb 21; PMID: 16492713
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Hodgkins Lymphoma
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NEW: Better Prognosis for Patients with Lymphocyte-predominant Hodgkin’s Lymphoma patient.cancerconsultants.com
"In order to better understand characteristics of LPHL [Lymphocyte-predominant HL], researchers from Germany conducted an analysis of 8,298 HL patients treated within a German medical trial to compare patient characteristics and treatment outcomes among cHL [classical HL) patients and others diagnosed with LPHD . "
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NEW: Prognostic impact of bone involvement in Hodgkin lymphoma.
Neoplasma. 2008;55(2):96-100. PMID: 18237246
... bone involvement is a relatively common finding in HL and is not an independent adverse prognostic factor. Key words: Hodgkin lymphoma - bone involvement - prognostic factors.
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MAL [a gene also expressed in mediastinal (thymic) large B-cell lymphoma] is expressed in a subset of Hodgkin lymphoma and identifies a population of patients with poor prognosis. Am J Clin Pathol. 2006 May;125(5):776-82. PMID: 16707382 | Related articles
"Expression correlated with nodular sclerosis subtype, and within this subtype, with grade 2 histology."
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Marginal Zone/MALT
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Splenic marginal zone lymphoma: a prognostic model for clinical use.
Blood. 2006 Feb 21; PMID: 16493005
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T-cell
TOPIC SEARCH - PubMed
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Marker Expression in Peripheral T-Cell Lymphoma: A Proposed Clinical-Pathologic Prognostic Score. J Clin Oncol. 2006 Apr 24; PMID: 16636342
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Immunophenotypic and molecular features, clinical outcomes, treatments, and prognostic factors associated with subcutaneous panniculitis-like T-cell lymphoma: a systematic analysis of 156 patients reported in the literature. Cancer. 2004 Sep 15;101(6):1404-13. PMID: 15368328
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Prognostic Indexes
IPI and FLIPI
"Because most of the prognostic studies are based on a retrospective analysis of historical data, they must be interpreted with caution at a time when treatment modalities are changing." - herkules.oul
FLIPI DISCUSSION
(Clinical Implications):
"The FLIPI may be used for selecting treatment in individual patients. In patients with a good prognosis (0-1 adverse factor), the 10-year overall survival is 71%. This indicates that optimal treatment in these patients has to avoid toxicity and to preserve quality of life. Involved-field radiation therapy for patients with limited disease and an initial "no treatment policy," for patients with disseminated disease may be recommended outside clinical trials. In contrast, patients with high-risk FL have a median survival around 5 years. Innovative approaches such as the combination of CVP (cyclophosphamide, vincristine, prednisone) or CHOP (CVP plus doxorubicin) and anti-CD20 monoclonal antibody,32 purine analog-based regimens,33 and autologous stem cell transplantation30 followed by vaccine therapies34 may be studied in this subgroup. All these approaches have been so far evaluated in phase 2 studies. The size of the high-risk group (27% of patients in the sample used for creating this index and 28% in the sample used for validation) could allow the design of multicenter randomized trials."
Full Text - Blood
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When considering prognostic indexes we should bear in mind that: "Prognostic factors reflect the outcome of very specific treatments, and as treatment changes, prognostic factors change.
When you include patients who did not receive uniform therapy, prognostic factor analysis and the impact on PFS may not be accurate." ~ Dr. Younes. journals.lww.com/oncology
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Diffuse Large B-cell Lymphoma Prognostic Index
* Lymphoma Hub 2013:
International Prognostic Index, age-adjusted and revised IPI http://bit.ly/1g9qbxJ
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International Prognostic Index (IPI)
Designed to further clarify lymphoma staging. The IPI [roughly] predicts the risk of disease recurrence and overall survival:
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Age over 60 years
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Late-stage disease (Stages 3 and 4)
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More than one extranodal site
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High LDH
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Poor general health or performance
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Source: oncologychannel.com
Calculate your FLIPI qxmd.com
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Follicular Lymphoma International
Prognostic Index (FLIPI)
*Also see Lymphoma Hub 2013:
Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 for follicular lymphoma http://bit.ly/1968ef0
Full Text - Blood
Our impression is that the main purpose of FLIPI is to characterize participants in clinical trials so that the results can be compared better across studies ... (as in FLIPI scores were balanced in each arm of the study, or in this study compared to that).
It appears the physicians may sometimes use FLIPI to guide treatment selection and possibly timing of treatment, but FLIPI is not predictive of outcomes in individual cases - or predictive of outcomes with specific therapies.
"FLIPI is recommended In patients with FL at first relapse/progression, the FLIPI, along with the presence of bulky disease and B symptoms, are features that predict Five-year survival from progression (SFP) and thus could be useful to select candidates for experimental treatments." annonc.oxfordjournals.org
Five adverse prognostic factors were selected:
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age (> 60 vs. </= 60),
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Ann Arbor stage (III-IV vs. I-II),
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hemoglobin level (< 12 g/dL vs. >/= 12 g/dL),
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number of nodal areas (> 4 vs. </= 4),
See graphic
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serum LDH level (> normal vs. </= normal).
Three risk groups were defined:
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Low-risk (0-1 adverse factor, 36 % of patients,
10-year survival of 70.7 %),
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Intermediate-risk (2 factors, 37 % of patients,
10-year survival of 51 % and a hazard-ratio of 2.3),
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Poor-risk (>/= 3 adverse factors, 27 % of patients,
10-year survival of 35.5 % and a hazard-ratio of 4.3).
See discussion in sidebar
"One point is given for each factor present at diagnosis. Patients with zero to one factors are classified as low-risk patients and have 5- and 10-year survivals of 90% and 71%, respectively.
Patients with two factors are classified as intermediate risk and they have 5- and 10-year survivals of 78% and 51%, respectively.
High-risk disease patients have three to five factors and 5- and 10-year survivals of 53% and 36%, respectively. The relative frequencies of the three risk categories are 36%, 37%, and 27%, which is a significant improvement over the IPI distribution in follicular lymphoma."
Source: Follicular Lymphoma: Management Options in the Era of Targeted Therapy Christopher G. Peterson, MD Brad S. Kahl, MD* ~ Current Treatment Options in Oncology 2005, 6:297–308
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Evaluating FLIPI-2, the Follicular Lymphoma Prognostic Index
Five adverse prognostic factors predicted Progression Free Survival, which is a controversial measure of overall survival (see Discussion below.)
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age > 60
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Hemoglobin level < 12 g/dL
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serum B2M > ULN
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LoDLIN > 6 cm (The longest diameter of the largest involved node)
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Bone Marrow Involvement
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More on FLIPI-2
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Discussion:
Evaluating FLIPI-2, the New Follicular Lymphoma Prognostic Index http://bit.ly/mR3h3I
snip: …. "prognostic factors reflect the outcome of very specific treatments, and as treatment changes, prognostic factors change. When you include patients who did not receive uniform therapy, prognostic factor analysis and the impact on PFS may not be accurate."
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Mantle Cell Lymphoma International Prognostic Index (MIPI)
* Also see Lymphoma hub 2013:
Mantle Cell Lymphoma International Prognostic Index (MIPI) http://bit.ly/HsWY1L
A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma bloodjournal.hematologylibrary.org
Using data of 455 advanced stage MCL patients treated within 3 clinical trials, we examined the prognostic relevance of IPI and FLIPI and derived a new prognostic index (MCL international prognostic index, MIPI) of overall survival (OS).
According to the MIPI, patients were classified into
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low risk (44% of patients, median OS not reached),
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intermediate risk (35%, 51 months), and
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high risk groups (21%, 29 months),
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based on the 4 independent prognostic factors:
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age,
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performance status,
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lactate dehydrogenase (LDH), and
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leukocyte count.
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Cell proliferation (Ki-67) was exploratively analyzed as an
important biologic marker and showed strong additional
prognostic relevance.
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The MIPI is the first prognostic index particularly suited for MCL patients and may serve as an important tool to facilitate risk-adapted treatment decisions in patients with advanced stage MCL.
See also Simplified MIPI: http://bloodjournal.hematologylibrary.org/
NEED TO TREAT CRITERIA
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GELF Criteria
A guide for determining the need to treat indolent lymphoma
NOTE: This is a general guide. The need to begin treatment in individual cases can vary.
One or more of the following
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Involvement of 3 nodal sites, each with a diameter of 3 cm
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Any nodal or extranodal tumor mass with a diameter of 7 cm
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Splenomegaly (enlarged spleen)
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Cytopenias (leukocytes < 1.0 x 10 /L and
or platelets < 100 x 10 /L)
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Leukemia (> 5.0 x 10 /L malignant cells)
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NCCN Guidelines:
Indications to treat indolent lymphomas
NOTE: This is a general guide. The need to begin treatment in individual cases can vary.
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Symptoms (fatigue, pain, fevers...)
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Threatened end-organ function (enlarged node obstructing bowel)
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Cytopenia secondary to lymphoma (low blood counts)
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Bulky disease - according to the GELF criteria: nodal or
extra-nodal
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mass (except spleen) > 7cm in its greater diameter 2
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Steady progression
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Patient preference
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Elevated serum LDH or B2-microglobulin
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involvement of multiple nodal sites
(each with a diameter greater than 3 cm) 2
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symptomatic splenic enlargement 2
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compressive syndrome 2
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pleural/peritoneal effusion 2
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Sources:
nccn.org/ 1
PRIMA study: 2 http://prima. gela.org/
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Biomarkers
Under construction
"Indirect" indicates that increased levels can have other causes besides lymphoma.
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TOPIC SEARCH microenvironment AND prognosis WEB | PubMed
NOTABLE QUOTE ON LIMITATIONS OF PROGNOSTIC MARKERS:
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"What is really the most important for people to remember is that prognostic markers only tell you which curve you are on, they do not tell you where you are on the curve.
[For CLL] nothing is more helpful than the pace of your disease. If your WBC is rising slowly, hemoglobin and platelets stable, lymphadenopathy and spleen size stable, then you are behaving in a very indolent manner. This means that the CLL is progressing very slowly and, by and large, will continue to do so for future."
~ Rick Furman, MD
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Some reports on suspected prognostic factors:
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Prognostic Markers http://www.biooncology.com/research/bcell/types/fnhl/diagnosis/prognostic/index.html
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Tumor-associated Antigen Arrays for the Serological Diagnosis of
Cancer http://bit.ly/9xqoNy
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absolute lymphocyte count at diagnosis
Absolute lymphocyte count predicts overall survival in follicular lymphomas. Br J Haematol. 2006 Sep;134(6):596-601. Epub 2006 Aug 1. PMID: 16889618
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Urinary albumin excretion [post treatment] is a predictor of response to treatment and disease progression in low-grade non-Hodgkin's lymphoma. Leuk Lymphoma. 2004 Mar;45(3):547-51. (Lower is better.) PMID: 15160917 | Related articles
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Beta2-microglobulin is a protein found on the surface of many cells, including white blood cells. (indirect)
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Serum CA125: A Tumor Marker for Monitoring Response to Treatment and Follow-up in Patients with Non-Hodgkin’s Lymphoma theoncologist.alphamedpress.org
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Strong Expression of FOXP1 Identifies a Distinct Subset of Diffuse Large B-Cell Lymphoma Patients with Poor Outcome. Blood. 2004 Jul 6 PMID: 15238418
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Lactate Dehydrogenase (LDH) is an enzyme that is expressed at higher levels when lymphocytes are dividing. (indirect)
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Ki-67 - proliferation index (indirect)
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"Typically, reactive follicles are characterized by absence of bcl-2 expression and a high Ki-67-defined cell proliferation index, in contrast to the typical low grade follicular lymphoma, in which the cells are bcl-2-positive and show a very low Ki67-defined cell proliferation index." phenopath.com
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Diffuse component
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BCL-2 - PAL
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BCL-6
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"Rearrangement of the bcl-6 gene correlated with a favorable clinical outcome in Diffuse Large Cell Lymphoma"
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BLyS: Expression of BLyS and Its Receptors in B-Cell Non-Hodgkin Lymphoma: Correlation With Disease Activity and Patient Outcome. Blood. 2004 Jul 13 PMID: 15251985
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Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004 Nov 18;351(21):2159-69.
PMID: 15548776
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Serologic detection of diffuse large B-cell lymphoma-associated antigens. Int J Cancer. 2004 Jul 1;110(4):563-9. PMID: 15122589 | abstracts
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Immunohistochemical detection of ZAP-70 in 341 cases of non-Hodgkin and Hodgkin lymphoma; May 2004 nature.com
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