Initial Evaluation of Young Patients With Chronic Lymphocytic Leukemia

Only 10% of patients diagnosed with CLL are younger than 50 years of age, and these patients often present a diagnostic and therapeutic dilemma to hematologists initially evaluating them. The great majority of patients diagnosed before the age of 50 years will have early-stage CLL with a slightly higher predisposition to a prior first-generation relative with this disease. Additionally, these patients are generally of a higher economic status or have chronic fatigue or medical illnesses for which they have been undergoing routine blood testing, leading to diagnosis of CLL. When the diagnosis of CLL is made, these younger patients have a more challenging time understanding how the disease will impact them. For patients with no symptoms referable to CLL, we generally discuss complications of the disease during the first visit and have a detailed discussion regarding assessment of genetic risk factors predisposing to early disease progression, including select interphase chromosomal abnormalities [del(17p13.1) and del(11q22.3)] and IgV_H mutational status (unmutated). During this time, it is important to counsel patients that identification of high-risk genomic features can actually increase anxiety because no treatment intervention is indicated in the absence of symptoms, regardless of genomic profile, outside of a clinical trial. In our experience, the great majority of patients desire this testing. Despite the potential benefit of allogeneic SCT in younger patients with CLL, we generally mention this only as one treatment option used in this disease and do not pursue consultation or tissue typing of patients or siblings until patients are truly symptomatic from their disease. We provide considerable discussion about the promising new kinase inhibitors coming forward in the treatment of CLL, analogous to how imatinib impacted treatment of CML. During the second visit 4 to 6 weeks later, we review the results of these prognostic factors and answer additional questions that have arisen. Ultimately, the majority of patients have low-risk disease, and knowing this allows patients to take partial control of their disease and move on with their lives. Serial assessment of the psychological well-being of patients with CLL during this first year is incredibly important. At no place during the evaluation do we refer to CLL as being a good or favorable leukemia. In our experience, the most common reason for dissatisfaction toward the initial hematology evaluation is lack of explanation of the disease process or the minimization of CLL as a “good leukemia to have.”

For young patients presenting with other chronic medical problems who are asymptomatic from their CLL, we follow the approach outlined above. More commonly, these patients have fatigue, mild anemia, or other symptoms that could be referable to the CLL. Additionally, this group is more commonly overweight or obese. In either setting, it is important to first think like an internist and pursue other causes for symptoms potentially referable to CLL. In particular, encouragement of both weight loss and a fixed exercise plan should be encouraged for fatigue and often improve quality of life and in other medical comorbidities. It is very important to note that younger patients with CLL can often go a decade or more without therapy, and early treatment of this patient group in the absence of symptoms still offers no proven long-term advantage. For this reason, our group remains very conservative on starting therapy for young patients with CLL.

Figure 32-1 CHRONIC LYMPHOCYTIC LEUKEMIA (CLL).

The peripheral blood smear (A) typically shows lymphocytosis and increased smudge cells as a result of the fragility of the CLL cells (see also smudge cell in C, right side). These can be avoided by making a preparation of blood and bovine serum albumin (22%) at a ratio of 11 drops of blood and 1 drop of albumin before preparing the slide (B). Cytologic features of CLL cells differ. Classic cells have a small nucleus with a “soccer ball” chromatin pattern (C). Some cases have increased large cells, or prolymphocytes, with more open chromatin and prominent “punched-out” nucleoli (D; prolymphocyte, right side). Other cases, sometimes referred to as “atypical,” have clefted cells and large cells (E). The bone marrow can show nodular infiltrates of CLL cells (F), an interstitial infiltrate, or a diffuse infiltrate (G).

Table 32-2 Evaluation of Chronic Lymphocytic Leukemia Patients at Diagnosis

BM, Bone marrow; CBC, complete blood count; CLL, chronic lymphocytic leukemia; CT, computed tomography; DAT, direct antiglobulin test; LDH, lactate dehydrogenase; LFT, liver function test; PET, positron emission tomography.

When Do We Consider a Transplant Evaluation in Chronic Lymphocytic Leukemia?

With the introduction of nonmyeloablative stem cell transplantation, the morbidity and mortality associated with this therapy in CLL has decreased, and this option thereby has been extended to young and older patients alike. Additionally, extended follow-up in several transplant series has suggested that prolonged remissions can occur with this treatment approach, potentially providing the only curative therapeutic option for this disease. In general, we do not consider detailed discussion of transplant or referral for asymptomatic patients. When patients become symptomatic and require therapy for their CLL, we also consider if they would qualify for transplant. Approximately 50% of patients with CLL are 75 years of age or younger, have acceptable end-organ function, and lack comorbidities when symptomatic disease develops. It is this CLL patient group who may benefit from an allogeneic transplant consultation. Autologous transplant in CLL offers no opportunity for cure and is associated with treatment-related MDS/AML. For patients without del(17p13.1) attaining a complete remission to initial combination chemotherapy, we would never consider a consolidative SCT. However, for patients having only a partial response to combination therapy and who are likely to have only a short remission duration, consolidation transplant in the first partial remission should be strongly considered. Consolidation transplant after induction is generally pursued for patients with del(17p13.1) given the extreme poor outcome associated with this genetic group. For all patients relapsing after first therapy, we strongly recommend transplant evaluation and pursuit of this option after second treatment unless a complete remission is obtained again. For patients attaining a complete remission both to initial therapy and therapy at first relapse, remission duration can be prolonged and the allogeneic transplant can be delayed, particularly in the absence of high-risk genomic features. At the time of writing this chapter, introduction of kinase inhibitors appears to be altering the natural history of relapsed CLL similar to how imatinib influenced decisions of pursuing transplantation of CML in the 1990s. It is possible that the indication(s) for transplantation in CLL will change dramatically if these kinase inhibitors are eventually approved and alter long-term outcomes in CLL.

How Should Staging and Biomarkers Be Used for Treatment Decisions in Chronic Lymphocytic Leukemia Patients?

Our understanding of the biology of CLL has improved dramatically, and many relevant biomarkers are now becoming useful for predicting when CLL will clinically progress. However, no study to date has demonstrated that earlier treatment will alter the natural history of the patient in even the higher risk groups with high progression rates. Therefore, at the present time, the use of staging and predictive biomarkers should be used only to provide patients with information relative to the expected course of their disease. Outside of a clinical trial, these results should never be used to initiate therapy in patients with asymptomatic disease and no indication for treatment. Before performing predictive tests, a detailed discussion of how these tests will be used with the patient should occur and the option of not performing them should be provided. In a subset of patients, significant anxiety can be produced by identifying high-risk features for which observation, without therapeutic intervention, remains the standard of care. Table 32-2 provides an example of the initial evaluation provided by our group when seeing a newly diagnosed patient. Because lymphocyte-doubling time is a prognostic feature in the progression of CLL, our approach is to follow patients every 3 months during the first year; if little change in clinical or laboratory parameters occurs at this point, we extend this time period to every 6 months in the absence of new complaints.

Table 32-3 Modified Indications for Treatment of Chronic Lymphocytic Leukemia

AIHA, Autoimmune hemolytic anemia; CLL, chronic lymphocytic leukemia; ITP, idiopathic thrombocytopenic purpura; WBC, white blood cell.

What Is the Role of Rituximab in Chronic Lymphocytic Leukemia?

Studies of rituximab to this point have demonstrated modest single-agent clinical activity in both previously untreated CLL patients using the weekly dosing schedule and in the relapsed state using more intensive dosing regimens. Rituximab does not have activity against CLL with del(17p13.1). For this reason, rituximab monotherapy is generally used in either of these settings only if more definitive therapy cannot be administered because of other comorbid conditions. Rituximab’s greatest contribution is to combination therapy both in symptomatic, previously untreated CLL patients and relapsed patients receiving the FR or FCR regimen, particularly in younger patients. Phase III studies have demonstrated the clear benefit of chemoimmunotherapy over traditional chemotherapy alone and, combined with multiple retrospective analyses, established chemoimmunotherapy as the standard of care in CLL. Several phase II studies have combined rituximab with other therapies such as bendamustine, chlorambucil, and pentostatin–cyclophosphamide that might be more tolerable to the more common older patients. Phase III studies with several of these agents are ongoing at this time. Inclusion of rituximab in alternative chemoimmunotherapy regimens for patients not appropriate for fludarabine-containing regimens is reasonable and our current practice approach. Although several phase II studies of maintenance rituximab have been published after completion of chemoimmunotherapy, the benefit of this is uncertain. Until ongoing phase III results are available justifying maintenance rituximab in CLL, it should not be used outside of the context of a clinical trial.