Accurate pretreatment evaluation and response assessment are critical to the optimal management of patients with lymphoproliferative disorders. CLL is a heterogeneous lymphoproliferative disease with a wide range of dificult to evaluate presentations and may have the molecular potential for transformation to rapidly progressive disease which affects mortality and morbidity. Standardization of imaging charters for clinical trials as well as tumor interpretation will lead to improved diagnosis and therapies for patients with malignant lymphoma.

Introduction

Lymphoid malignancies are a diverse and complex group of disorders derived from B-cells, T-cells, and NK cells. Traditional classifications have distinguished between “lymphomas” – neoplasms that typically present with an obvious tumor or mass of lymph nodes – and “leukemia”– neoplasms that typically involve the bone marrow and peripheral blood, without tumor masses. However, it is now known that many lymphoid malignancies may have both tissue masses and circulating cells.

There are an estimated 327,520 people currently living with, or in remission from, leukemia in the US. In 2014, the American Cancer Society projected that 52,380 people per year would be diagnosed with leukemia in the United States, with 15,720 of those being chronic lymphocytic leukemia (CLL). From 2004-2010, the five-year relative survival rate for CLL overall was reported to be 83.5%. As is the case for most malignancies, the exact root cause of CLL is uncertain, although particular phenotypes and genotypes have been identified.

CLL and the mature B cell neoplasm small lymphocytic lymphoma (SLL) are now considered synonymous. The term CLL is used when the disease manifests primarily in the bone marrow and blood, while the term SLL is used when involvement is primarily nodal. Up to half of patients can be asymptomatic when the disease is incidentally discovered by routine blood work up. Patients may present with hepatomegaly, splenomegaly or both and/or a hemolytic anemia.

Diagnosis

While CLL is usually indolent, disease related symptoms or evidence of “active disease” dictate necessary treatment and surveillance. Aside from allogeneic hematopoietic cell transplantation (HCT), treatment options for CLL are not curative. In as many as 5-10% of patients the disease may undergo a Richter’s transformation into a much more aggressive lymphoid malignancy, with lower overall survival. Additionally, the occurrence of a second malignancy may complicate the disease.

The Rai and the Binet staging systems are routinely used for CLL.

The Rai staging system categorizes patients into low, intermediate, and high-risk groups:

• Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population).
• Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of patients).
• High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 10 9/L) (25% patients).

The Binet staging system categorizes patients according to the number of lymph node groups involved:

• Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 10 9/L, and fewer than 3 lymph node areas involved.
• Stage B – Hemoglobin and platelet levels as in stage A and three or more lymph node areas involved.
• Stage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 10 9/L, or both.

Treatment

The evolution of treatment for lymphoid malignancies has advanced due to the ability to perform molecular profiling. CLL B-lymphocytes typically show B-cell surface antigens, as demonstrated by CD19, CD20, CD21, and CD23 monoclonal antibodies. The detection of these surface antigens leads to the identification of several prognostic indicators of CLL. There are several high-risk genetic and molecular features for progressive disease including unmutated immunoglobulin heavy chain variable genes (IGHV), 17P deletion, CD38, and zeta chain associated protein kinase 70 (ZAP-70) expression.

In 1997, rituximab became the first anti-CD20 monoclonal antibody to be approved for the treatment of hematologic malignancies and has become a major weapon against CLL. Immunomodulators likewise play an important role in the treatment of CLL. Multiple new molecular target agents are now being developed and will play a vital role in the future management of CLL. It is most likely that a combination of molecular agents will achieve optimal response and improve overall survival, particularly for CLL patients with relapsed or refractory disease and with high-risk clinical and genetic markers. The best treatment for an individual patient is enrollment in a well-conducted clinical trial.

Imaging

CT and PET/CT

Biopsy of the involved tissue is considered a key component of the workup for aggressive or transformed lymphoproliferative diseases. Therefore, the selection of an optimal biopsy site is critical, particularly if transformation or second malignancy is highly suspected clinically.

For most lymphoid malignancies, computed tomography (CT) scanning is the mainstay of imaging due to its availability, ease of scanning and reproducibility. CT scans are mandatory for initial staging as well as for the evaluation of response and detection of relapse during follow-up. For CLL however, the role of CT scanning has not yet been clearly defined, particularly for indolent disease.

Positron Emission Tomography/Computed Tomography (FDG PET/CT) is increasingly used for tumor staging and re-staging as well as for the assessment of therapy response in the lymphoproliferative diseases. Most types of lymphomas are FDG-avid, with aggressive lymphomas typically showing higher uptake than more indolent lymphomas and CLL. FDG PET/CT leads to a change in stage and management in 10 to 30% of patients with lymphoma, more often leading to upstaging.

Initial evaluation of early FDG PET/CT scanners using maximum Standardized Uptake Value (SUVmax) of greater than 5 to detect Richter’s transformation of CLL demonstrated promising overall sensitivity, specificity, and positive and negative predictive values. More recently a larger retrospective cohort study confirmed the value of FDG PET/CT imaging in CLL with calculated sensitivity, specificity, and positive and negative predictive values of 88.2%, 71.2%, 51.3% and 94%, respectively.

These findings support the use of FGD PET/CT in prospective trials for evaluation of suspected transformation as well as identifying targeted biopsy sites for the biological/tissue diagnosis of disease transformation versus second malignancy. Moreover, if an FDG PET/CT is positive for marrow involvement during workup and staging, the confirmatory bone marrow biopsy may now safely be omitted for certain types of lymphoma.

With its advantages, FDG PET/CT has become the method most preferred for staging FDG-avid lymphomas, while CT scanning may be more appropriate in other indolent lymphomas and low risk CLL.

MRI

In the imaging evaluation of lymphoproliferative disorders Magnetic Resonance Imaging (MRI) has been shown to be more accurate for evaluation of central nervous system disease involvement and to identify the location and extent of osseous disease. However, there are fewer published studies evaluating the use of MRI for nodal staging in lymphoma. More recently, it has been proposed that the evaluation of patients at initial diagnosis of lymphoma with whole body diffusion weighted (DW) MRI yields accurate assessment
and staging.

In a recent small pilot study it was demonstrated that whole body DW MRI provides results comparable with FDG PET/CT for early chemotherapy response evaluation in patients with DLBCL. Both 1.5T and 3.0T magnets have been used, with 3.0T providing potentially better diagnostic performance. Using a body coil, the patients were positioned head first into the magnet and a DW protocol consisting of a single shot spin echo echo-planar sequence was used with respiratory gating and images acquired in an axial plane from the head through the thighs. However, larger multicenter trials of whole body MRI for staging of lymphoma are needed for verification before implementation into response criteria.

Early Response Criteria

Since the late 20th century, there have been various attempts to define specific criteria for assessment of response to treatment for lymphoma, mainly based on anatomic appearance. The concepts of complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) have evolved since the World Health Organization (WHO) meetings in 1977 and 1979 where initial criteria recommendations were made to enable researchers to compare results from clinical trials. At that time, assessment of response to treatment included radiologic, clinical, biochemical, and surgical criteria with four weeks recommended as the minimum duration of reported response. Anatomic measurement was initially described as the sum of products of the longest diameter (SPD). Eventually CT was incorporated into the criteria and recognized at the Cotswolds meeting in 1989 by Lister et al. The criteria was primarily oriented toward Hodgkin’s Disease (HD).

In 1999 one of the criterion proposed by Cheson et al (named International Workshop Criteria) was reduced size of lymph nodes and/or masses greater than 75% on contrast enhanced CT with a new category for response called “complete response uncertain”, or CRu, incorporating a concept which was initially discussed at the Cotswolds meeting. The category CRu was an early indicator that residual disease is not always reliably defined by anatomic assessment alone. This new criteria was primarily for non-Hodgkin’s Lymphoma (NHL) with less than 1.5 cm in longest transverse diameter to be considered as normal size for lymph nodes after therapy.

Metabolic and molecular information provided by FDG PET/CT was a logical progression toward more accurate evaluation of response. FDG PET/CT guidelines for treatment assessment in solid tumors were introduced in 1999 by the European Organization for Research and Treatment of Cancer (EORTC). By EORTC guidelines, standardized uptake value (SUV) is measured, and treatment response is categorized depending on the percentage change in the SUV from baseline to follow-up:

• CR is defined as complete resolution of uptake.
• PR is defined as a reduction in metabolic activity of 15% or more after one treatment cycle or 25% or more after two or more treatment cycles.
• SD is defined as a decrease in metabolic activity of less than
  15% or an increase in metabolic activity of 25% or less.
• PD is defined as any increase of more than 25% in metabolic
  activity or appearance of new FDG uptake in metastatic lesions.

At the turn of the century, new guidelines called Response Evaluation Criteria In Solid Tumors (RECIST) were proposed for use by the EORTC, and the National Cancer Institutes of the United States and of Canada. Most importantly, lesion measurement changed from bi-dimensional to uni-dimensional, simplifying the imaging process. RECIST was revised in 2009 with respect to number of lesions measured, the size of lymph nodes to be considered normal (less than 10 mm), modifying the definition of PD (5 mm absolute increase required, in addition to 20% increase in sum), and exercising caution when the total sum is very small. FDG PET/CT was considered for the revised RECIST, but ultimately it was determined that absence of standardization and lack of prospective evidence would preclude its use.

The International Harmonization Project (IHP) of 2007 revised the 1999 response criteria proposed by Cheson et al to include FDG PET/CT and eliminated CRu. The new recommendation reflected the subtype of lymphoma (FDG avid vs FDG-not avid) and hybrid FDG PET/CT was encouraged if glycolytic activity was present, versus CT alone for morphologic evaluation of FDG-non avid disease. Two years later Wahl et al established PET Response Criteria In Solid Tumors (PERCIST), with SUV normalized for lead body mass, and measured by a 1 cm3 region of interest (ROI). By PERCIST, a 30% decrease in SUV was the proposed threshold for PR. However, PERCIST criteria, despite being designed for use in HD and NHL, has not been used extensively in the literature and in clinical trials.

Modern Response Criteria

The most current staging and response criteria accepted for lymphoma is from the International Working Group (IWG) Lugano classification, which strongly recommend FDG PET/CT staging, especially in clinical trials. By convention, enhanced CT should also be included for a more accurate measurement of nodal size as required by clinical trial design. While numerical SUV values may be reported for each lesion, the IWG criteria for reviewing FDG PET/CT scans in clinical trials is based on visual interpretation and is primarily intended for evaluation at the conclusion of therapy for lymphoma trials.

The Deauville 5-point scale is recommend for both interim and end-of-treatment assessment in clinical trials involving FDG-avid lymphomas. The scale ranges from 1 to 5, where 1 is the lowest uptake and 5 is the highest uptake of radiotracer. Each FDG-avid (or previously FDG-avid) lesion is rated independently.

1. no uptake or no residual uptake (when used interim)
2. slight uptake, but below blood pool (mediastinum)
3. uptake above mediastinal, but below or equal to uptake in the liver
4. uptake slightly to moderately higher than liver
5. markedly increased uptake or any new lesion (on response evaluation)

Some authors also use X for any lesion not overtly attributable to lymphoma.

For curable lymphomas the risk of relapse diminishes over time. Published studies do not support routine surveillance scans for these patients with CT or FDG PET/CT as the false positive rate has been reported to be as high as 20%. This leads to unnecessary investigations, radiation exposure, and biopsies as well as increased cost and patient anxiety. Instead, follow up scans should be prompted by clinical presentation and findings. In clinical trials the imaging time points are pre-defined for evaluation of therapy. Judicious use of imaging is recommended in indolent lymphomas with residual intra-abdominal or retroperitoneal disease that is not easily evaluated clinically.

Summary

Accurate pretreatment evaluation and response assessment are critical to the optimal management of patients with lymphoproliferative disorders. CLL is a heterogeneous lymphoproliferative disease with a wide range of difficult to evaluate presentations and may have the molecular potential for transformation to rapidly progressive disease which affects mortality and morbidity. Prognosis depends on the disease stage at diagnosis as well as the presence or absence of high-risk markers.

Standardization of imaging charters for clinical trials as well as tumor interpretation will lead to improved diagnosis and therapies for patients with malignant lymphoma in this era of enhanced understanding of the disease molecular mechanisms. Several descriptive response criteria for morphological and metabolic components of the disease have been proposed in order to standardize reports and facilitate interpretation of clinical trials.

References

1. Rozovski, Uri, et al. “Outcomes of patients with chronic lymphocytic leukemia and Richter’s transformation after transplantation failure.” Journal of Clinical Oncology (2015): JCO-2014.
2. Mauro, F. R., et al. “Diagnostic and prognostic role of PET/CT in patients with chronic lymphocytic leukemia and progressive disease.” Leukemia (2015).
3. Police, Rachel L., et al. “Randomized Controlled Trials in Relapsed/Refractory Chronic Lymphocytic Leukemia: A Systematic Review and Meta-Analysis.” Clinical Lymphoma Myeloma and Leukemia 15.4 (2015): 199-207.
4. Bruzzi, John F., et al. “Detection of Richter’s transformation of chronic lymphocytic leukemia by PET/CT.” Journal of Nuclear Medicine 47.8 (2006): 1267-1273.
5. Cheson, Bruce D., et al. “Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification.” Journal of Clinical Oncology 32.27 (2014): 3059-3067.
6. Maffione, Anna M., et al. “Response criteria for malignant
7. lymphoma.” Nuclear medicine communications 36.4 (2015):
8. 398-405.
9. Desai, Anjali Varma, Hassan El-Bakkar, and Maher Abdul-Hay. “Novel agents in the treatment of chronic lymphocytic leukemia: a review about the future.” Clinical Lymphoma Myeloma and Leukemia (2014).
10. Tsuji, Kazunobu, et al. “Evaluation of staging and early response to chemotherapy with whole-body diffusion-weighted MRI in malignant lymphoma patients: A comparison with FDG-PET/CT.” Journal of Magnetic Resonance Imaging 41.6 (2015): 1601-1607.
11. Azzedine, Benaissa, et al. “Whole-body diffusion-weighted MRI for staging lymphoma at 3.0 T: comparative study with MR imaging at 1.5 T.” Clinical imaging 39.1 (2015): 104-109.

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Volume 5, Issue 10: Guidance for Sponsors: Medical Imaging of Chronic Lymphocytic Leukemia

Originally written by legacy Intrinsic Imaging Medical Director

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