Your patient has chronic leukemia: Now what?
ABSTRACTAlthough still in their infancy, biologic therapies for hematologic cancers are making rapid strides, diminishing the role of chemotherapy and offering long-term remission. More patients are surviving cancer and therefore are increasingly being seen by primary care physicians, who must be aware of complications of standard and newer treatments and how to manage them.
KEY POINTS
- Chronic myelogenous leukemia (CML) can now be functionally cured with tyrosine kinase inhibitors, which interfere with the product of the oncogene causing the disease.
- Patients diagnosed with CML should begin therapy immediately even if they have no symptoms.
- Tyrosine kinase inhibitors have side effects that increase cardiovascular risk.
- Chronic lymphocytic leukemia (CLL) is an immunologic disease involving clonal proliferation of B cells. Chemotherapy for CLL should begin only when symptoms or indicators of impaired marrow function reach a certain threshold.
- New treatments for CLL increase the risk of atrial fibrillation and autoimmunity.
- Experimental B-cell–targeted therapies have demonstrated encouraging results even when chemotherapy fails in CLL and other B-cell cancers.
Diagnosing CLL
Lymphocytosis can indicate other low-grade lymphoproliferative diseases and malignancies, so further evaluation is critical. To diagnose CLL, the B-cell count by flow cytometry (not the absolute lymphocyte count from the complete blood cell count) must be at least 5 × 109/L. Below that threshold, monoclonal B-cell lymphocytosis is diagnosed unless lymphadenopathy is present, indicating small lymphocytic lymphoma. Unlike in benign lymphoproliferations, CLL lymphocytes coexpress the B-cell marker CD19 and the T-cell marker CD5.17 Bone marrow examination is rarely needed for the diagnosis of CLL.
Two types of CLL can be defined, depending on whether the B cells carry V genes that are mutated or unmutated. B cells expressing ZAP-70 and CD38 tend to carry the unmutated gene, which is associated with a worse prognosis.18 Regardless of which type a patient has, treatments and the indications for treatment are the same.
Increasing immune dysfunction
CLL is staged according to effects on lymph tissue and hematopoiesis. The Rai system for clinical staging of CLL has been used since 1975 with little alteration (Table 2).19
CLL is often an indolent lymphoproliferative malignancy and does not always progress to a fatal end stage. Therefore, treatment may be deferred, with a watch-and-wait approach until symptoms develop or the disease progresses. Approximately half of patients never require treatment.20 Progression involves increasing bone marrow impairment with greater susceptibility to infection (due to intrinsic features of CLL and its therapy) and hypogammaglobulinemia in advanced disease.21,22 Systemic infection is the cause of death for most patients.
Because CLL is a disease of the immune system, the development of autoantibodies is a cardinal feature. Autoimmune complications are almost exclusively limited to blood and can include hemolytic anemia, pure red cell aplasia, immune-mediated thrombocytopenia, and granulocytopenia. Other autoimmune diseases, such as rheumatoid arthritis, thyroiditis, and Addison disease, are uncommon.23,24
Other complications may occur in patients who have been treated with chemotherapy, and these are usually fatal. The Richter transformation (to an aggressive lymphoma) occurs in about 15%. Other less common complications include prolymphocytoid transformation and secondary malignancies, particularly carcinomas of the lung and gastrointestinal tract and acute (myeloid) leukemia.25
Survival rates in CLL have improved substantially over the past decades,26–28 with significant gains following the introduction of antibiotics and, to a lesser extent, transfusions. Median survival is generally between 6 and 9 years, but many patients live for years without requiring therapy.
Chemotherapy: The mainstay of treatment
When to begin therapy remains one of the most challenging issues of patient management. Unlike in CML, there is no advantage to starting at diagnosis when most patients are asymptomatic.29
In 1996, the National Cancer Institute issued guidelines for starting treatment, which were updated in 2008 with very little change (Table 3).30 In general, the onset of symptoms and evidence of impaired marrow function, including an abnormal hemoglobin level and platelet count, are indications. The white blood cell count continuously increases during the disease course but is not usually an important factor for initiating treatment.
The therapeutic goal for most patients who require treatment has historically been palliation of symptoms. Therapy must be individualized to a patient’s age and clinical status, with a heavier reliance on chemotherapeutic agents for patients who can tolerate it and on immunotherapy for others. General strategies are as follows:
- “Go-Go” patients—young, fit, with few comorbidities, good renal function—are the minority. Recommendation: combination chemotherapy with fludarabine, cyclophosphamide, and rituximab (FCR).
- “Slo-Go” patients are reasonably fit and can tolerate chemotherapy but not FCR. Recommendation: combination therapy with either bendamustine and rituximab or chlorambucil and rituximab (for less fit patients). Recent evidence indicates ibrutinib may be useful for such patients.31
- “No-Go” patients are frail with short life expectancy. Recommendation: rituximab or observation (see below)
All CLL treatments are potentially toxic. Chemotherapy damages DNA and often causes blood cell counts to fall. Immunosuppression worsens with almost any treatment, involving a substantial risk of secondary malignancy. Although survival improves with therapy, relapse is universal.
Targeting CLL pathways
The new paradigm for cancer therapy is to identify a cellular pathway that drives oncogenesis or proliferation and interfere with it. The B-cell receptor pathway is enormously complex with numerous complex factors, making it difficult to discern the critical mutation that drives the proliferation of lymphocytes.
Bruton tyrosine kinase (Btk) is one factor that is critical for CLL proliferation. Patients with congenitally mutated or dysfunctional Btk have lymphopenia and agammaglobulinemia, making it a promising target for patients with B-cell disorders. Other experimental therapies are based on other such identified factors.
In 2014, the FDA approved two drugs for CLL—ibrutinib, a Btk inhibitor, and idelalisib, an inhibitor of phosphoinositide 3-kinase—after they were shown in clinical trials to dramatically improve outcomes in patients with relapsed CLL.32,33 Trials with these drugs are ongoing. These drugs also inhibit tyrosine kinase and so have vascular side effects in addition to their own idiosyncratic effects.
Ibrutinib has anticoagulant effects and should be stopped before surgery. It also can cause or exacerbate atrial fibrillation, making management of CLL difficult. It is associated with hypogammaglobulinemia, often requiring ongoing immunoglobulin replacement.
Idelalisib tends to cause systemic autoimmune phenomena such as pneumonitis and colitis.
Using T cells as therapy
It has long been observed that patients who undergo bone marrow transplant for leukemia have lower relapse rates if the transplant is allogeneic rather than from a twin. Further, if T cells are removed from the donor graft, graft-vs-host disease may be prevented but the risk of relapses increases. Finally, the presence of graft-vs-host disease tends to reduce the risk of relapse.34 Therefore, T cells clearly are key ingredients for success in the setting of bone marrow transplant. In fact, merely providing T cells for a relapse after allogeneic transplant can induce remission. However, because donor T cells are not targeted, acute and chronic graft-vs-host disease often can ensue.
‘Designer’ monoclonal antibodies
The B lymphocyte has multiple potential targets for new therapies for CLL as well as other cancers involving B cells. CD20 was identified on the surface of B cells in 1988 and is the target protein of the monoclonal antibody drug rituximab. Monoclonal antibodies can be modified to target other surface antigens, to link radioisotopes to deliver radiation therapy, and to deliver drugs that would otherwise be too toxic to be given systemically.35 Monoclonal antibodies can also be modified to enhance function.
Antibodies alone, however, must often rely on the host T cells for cytotoxicity and they are often compromised by either the underlying disease or treatment. Adapting the targeting function of antibodies to enhance or genetically alter T cells to recognize cancer-specific antigens is now being explored for leukemias.36
In 2014, the FDA approved blinatumomab for the treatment of relapsed or refractory acute lymphoblastic leukemia. This biopharmaceutical agent recruits T cells with one antibody-like moiety and targets the CD19 receptor of B cells with another. Given as a single intravenous treatment without chemotherapy, it has an almost 50% response rate, and those who respond tend to stay in remission. Other similar drugs are being developed, and using them earlier in treatment and for other B-cell leukemias is being explored.
New B-cell targeted therapy with CAR-Ts
Newer treatments are being developed based on chimeric antigen receptor T (CAR-T) cells. These engineered T cells express an anti-CD19 moiety that targets B cells, but also activate upon binding to them.37 CAR-T technology is being refined and shows great promise for cancer treatment.
Multiple clinical trials are currently under way in which the investigators collect autologous T cells by leukopheresis from a patient with a relapsed or refractory B-cell malignancy, transduce the T cells with retroviral vectors into anti-CD19 CAR-T cells, and then reinfuse them into the patient following modest chemotherapy.38
Study results from a small number of patients with relapsing or refractory CLL showed that some patients achieved long-term, progression-free survival.39 The most success with this therapy, however, has been in acute lymphoblastic leukemia.40 Possibly, this treatment could be applied to other lymphoid malignancies that also express CD19.
More advances
CAR-T cell therapy has drawbacks. The cells attack only the target antigen, which currently limits their use mostly to hematologic malignancies. In addition, autologous T cells are not robust. Also, the use of allogeneic T cells is restricted by their major histocompatibility complex, and the cells will be rejected by the recipient if not matched.
An attempt to overcome some of these drawbacks is to develop T cells redirected for universal cytokine killing. CAR-T cells are modified with a gene that causes them to excrete interleukin 12, which attracts macrophages and natural killer cells to the environment to better fight the tumor.41
Other modifications include editing out certain genes including the major histocompatibility complex, which avoids the problem of rejection. Another modification is to insert a “suicide gene” that allows the engineered T cells to be killed with an antidote if they do not work as planned.
Such gene-editing techniques hold great promise for curing cancers without chemotherapy in the not so distant future.
