Addressing Immune Compromise in CLL: Risk-Mitigation Strategies

Amy Goodrich

Our patients with chronic lymphocytic leukemia [CLL] experience early-onset immune dysregulation, which poses increased risks of infection, autoimmune complications, and even second malignancies. Targeted therapies with small-molecule agents such as inhibitors of Bruton's tyrosine kinase [BTK], PI3 [phosphoinositide 3] kinase, and BCL-2 [B-cell leukemia/lymphoma-2] have improved therapeutic outcomes. The benefits are due to the potency of these drugs, the high response rates, and overall better tolerability than chemotherapy. However, chronic immune deficiency in CLL is still a significant problem.

Carmen Nobre

Yes, and a comprehensive multidisciplinary approach is required to manage the myriad of complications and health setbacks associated with immune compromise in CLL. Patient management needs to be multipronged, encompassing preventative care, active monitoring, early diagnosis and treatment, and patient education. As always, clinical research is essential so we can deepen our understanding of CLL-related immune defects and identify the best tools and approaches for optimal patient outcomes and quality of life.

Amy Goodrich

Right, Carmen, and those immune complications in CLL are an important clinical consideration. With some of the targeted therapy regimens improving progression-free and overall survival, CLL is now more of a chronic disease than it ever has been. To start our discussion, why don't we talk about the immune suppression underlying the biology of CLL?

Carmen Nobre

Sure. Early in the course of CLL, there's an apparent dysfunction in both the adaptive and innate immune responses. The mechanism by which this occurs isn't well understood. However, the T-cell dysfunction observed includes an increased TH1:TH2 ratio, and an abnormal CD4:CD8 ratio, as well as altered helper T-cell profiles that suggest T-cell exhaustion.

Amy Goodrich

We also see humoral immune defects such as altered memory B and plasma cells that are associated with hypogammaglobulinemia, which is a characteristic condition in CLL that can worsen with disease progression and treatment. Other changes that we see in the innate immune system include monocyte and macrophage immunophenotype alterations together with increased levels of circulating immunosuppressive cells. In addition, neutrophil function is dysregulated and serum complement levels are decreased.

Carmen Nobre

Besides those immune-function changes related to the disease itself, broadly speaking, the treatment of CLL has its own impact on the immune system.

Amy Goodrich

That’s very true. Patients receiving immunochemotherapy may have worsening immunosuppression followed by recovery. Purine analogs such as fludarabine and bendamustine are also associated with profound depletion of lymphocytes, particularly impacting the recovery of CD4-positive lymphocytes, which may take months or years to recover.¹ In that regard, targeted therapy is associated with less acute and long-term worsening in immunosuppression, though it is certainly not without risk.

So let's close the loop on the hypogammaglobulinemia angle in CLL. Immunoglobulin abnormalities really should be considered frequently, with levels monitored intermittently. Certainly evaluation of IgG levels is appropriate whenever recurrent or severe infections are noted—and if IgG levels drop to below 500 mg/dL together with a pattern of infections, which are typically sinus or pulmonary infections. If these infections require IV antibiotics or hospitalization, then monthly subcutaneous or intravenous immunoglobulin at a dose of 0.3 g/kg or 0.5 g/kg should be initiated. The dose and/or the interval should be adjusted to maintain a nadir level of around 500 mg/dL.²

This therapy is open-ended once it's started, with the goal being to prevent severe and even fatal infections. In clinical practice, Carmen, as you know, IgG therapy typically really dramatically alters a patient's pattern of infections and improves quality of life. Often when patients develop infections, there’s a negative impact on their wellbeing and strength. The use of intravenous immunoglobulin reduces or eliminates these infection-related setbacks.

Now let's focus on a few key immune effects that we encounter in CLL: infections, autoimmune complications, and second malignancies. Infections are a major cause of morbidity and mortality in CLL. Studies have shown that infections account for about one third to one half of all deaths. As therapies for CLL have changed, we have also seen changes in the spectrum of infectious complications. Carmen, can you highlight some of the more common infections seen in our patients with CLL?  

Carmen Nobre

Treatment-naive patients are at higher risk for bacterial infections, which typically are caused by common pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and H. influenzae or even E. coli. About one quarter of viral infections in CLL are due to the herpes simplex virus [HSV] and influenza, and most viral infections occur in the lower respiratory tract, the skin, or the urogenital tract. Reactivation of HSV infection can also occur in our treatment-naive CLL patients. Traditional agents that have been used in CLL treatment for decades—for example, alkylating agents such as chlorambucil—are also mainly associated with bacterial infections. And purine analogs such as fludarabine are associated with severe and atypical infections as well as a higher incidence of viral infections, due to prolonged suppression of CD4 T cells.³

With anti-CD20 monoclonal antibodies like rituximab or obinutuzumab, the first infectious complication that I think about is hepatitis B reactivation, and the risk for fulminant hepatic failure and even death. Screening is recommended prior to starting anti-CD20 therapy, with testing for hepatitis B surface antigen and hepatitis B core antibody. If these are positive, there should be additional workup with determination of viral load by quantitative PCR. Initiation of entecavir or another appropriate anti-HBV [hepatitis B virus] agent may be recommended for these patients. Patients’ hepatitis B viral load should be monitored monthly during treatment and every 3 months following treatment completion. If the viral load remains low or undetectable, entecavir is considered prophylactic and should continue to be administered throughout treatment and for 12 months after the end of treatment. However, if the viral load fails to decrease after treatment with entecavir or becomes positive after previously being undetectable, then the anti-CD20 therapy should be held and a hepatology consult obtained.

If screening is negative, rescreening for the core antibodies is recommended for patients with new or worsening liver function abnormalities. Both rituximab and obinutuzumab carry warnings for progressive multifocal leukoencephalopathy, or PML. In addition, patients may experience fatal bacterial infections; viral infections, both new and reactivated; and even fungal infections. New or reactivated viral infections that have been reported include CMV [cytomegalovirus], HSV, parvovirus B19, varicella zoster, West Nile virus, and hepatitis B and C. In monotherapy with rituximab, a 5% serious infection rate is noted, and that rate is 32% with obinutuzumab. And of course, infection rates vary when these agents are used in combination regimens.^2,4,5

Amy Goodrich

Yes, Carmen, since targeted treatment with BTK and BCL-2 inhibitors is moving to the forefront of CLL therapy, let's talk about infections encountered with these agents, starting with BTK inhibitors.

Carmen Nobre

Infectious complications seen with BTK inhibitors are similar across all of these targeted agents. Bacterial; viral; and, rarely, fungal infections have been seen with ibrutinib and acalabrutinib in CLL, as well as with zanubrutinib use in its currently approved indication of mantle cell lymphoma. Other less common infections are hepatitis B reactivation and PML. In general, grade three or higher infections are seen in about 20% to 30% of patients receiving BTK inhibitors. All the agents’ prescribing information recommends considerations for prophylactic anti-infectives in patients at high risk for opportunistic infections. This could be a heavily pretreated patient or a patient on chronic low-dose steroids, whether it be for asthma and immune disorder or another comorbidity. In general, while many patients will not require prophylaxis, all are at risk for infection and diligent monitoring is important for early identification and intervention. Patient education is also critical to promote early identification of symptoms of infection and prompt reporting to the healthcare team.^6-8

Amy Goodrich

Right. In comparison, our BCL-2 inhibitors have been shown to be associated with slightly lower infection rates. When you look at venetoclax as monotherapy in the relapsed/refractory setting, treated patients have about an 11% incidence of grade three or higher upper and lower respiratory tract infections and pneumonia. With venetoclax used in combination for initial therapy with obinutuzumab, grade three or higher pulmonary infections occur at an incidence of about 1%, while with rituximab in the relapsed/refractory setting, there's about an 11% incidence of grade three or higher pulmonary infections. And there are no prophylaxis requirements for venetoclax given in any of these three settings—that is, alone or with obinutuzumab or rituximab, although all patients with CLL who are at high risk for opportunistic infections should always be evaluated for anti-infective prophylaxis.⁹ And then Carmen, there are unique considerations for infections when using our PI3K inhibitors, which are reserved for patients with multiply relapsed/refractory CLL.

Carmen Nobre

There sure are. So the PI3K class of agents carries more significant risk of infection complication compared with the BTK and BCL-2 inhibitor classes we just discussed. Our two PI3K inhibitors include idelalisib, potentially administered with rituximab, and duvelisib given as monotherapy. (The PI3K inhibitor copanlisib is currently approved for follicular lymphoma but not CLL, so it’s not relevant to our discussion today.) The incidence of severe infection in CLL patients treated with idelalisib is 24%, and duvelisib is associated with a 31% incidence of severe infection—so, definitely higher numbers than we've seen with the other small-molecule inhibitors. The majority of infections are pulmonary, including PJP [Pneumocystis jirovecii pneumonia, also known as Pneumocystis carinii pneumonia, or PCP], bacterial sources, and fungal pneumonias. Sepsis has also been seen with both of these agents. In addition, CMV infection and reactivation, as well as PJP, have been noted, so much so that PJP prophylaxis is currently recommended and should continue until the CD4 T-cell count is greater than 200 [cell/µL], and prophylactic antiviral therapy should also be considered in patients receiving these agents.^10,11

Amy Goodrich

What are the best practices for proactively identifying and managing these infections in the setting of CLL, Carmen?

Carmen Nobre

Well, first it's important to identify the patient's infection risk, and then the infection risk associated with the agent or the combination regimen under consideration. Taking these factors into account gives us a more complete picture of how best to approach and tailor prophylaxis and care. So we talked about hepatitis B when we discussed the anti-CD20 monoclonal antibodies. Turning to hepatitis C, there is a growing body of evidence associating hepatitis C infection with B-cell lymphomas. Although there are no specific recommendations in CLL, certainly keeping hepatitis C in mind is important for screening as well as any time liver function abnormalities are noted.²

Amy Goodrich

Interestingly, Carmen, the very first case of fulminant hepatitis I ever saw as a new NP was due to hepatitis C. So that has been long etched into my mind, and I always think of hepatitis C along with hepatitis B. And again, we're always thinking about severe infections and hypogammaglobulinemia, so do you want to highlight some important autoimmune complications in our patients with CLL?

Carmen Nobre

Sure thing. About 10% of CLL patients experience autoimmune cytopenias. This can include autoimmune hemolytic anemia, or AIHA; immune thrombocytopenia, or ITP; pure red blood cell aplasia; and autoimmune neutropenia. While autoimmune cytopenias do not carry the same grave prognostic significance as bone marrow failure, according to the International Workshop on CLL, they can represent a serious and sometimes fatal complication. In CLL, unmutated immunoglobulin heavy chain variable gene, called IGHV, is prognostic of shorter survival time compared with mutated IGHV. This wild-type gene is also associated with a higher risk of ITP.¹² So the autoimmune hemolytic anemia workup includes reticulocyte count, haptoglobulin, and direct antiglobulin test or DAT. Typical results are a high reticulocyte count, which reflects the body's production of large numbers of immature red blood cells to correct anemia; a low haptoglobulin level, since haptoglobulin binds to the hemoglobulin found outside of the red blood cell and so is “mopped up” by the effect of lysis; and a positive DAT, which is due to the presence of antibodies on the surface of red blood cells.

ITP requires bone marrow examination to determine the cause of thrombocytopenia. If platelet precursors are seen in normal or large numbers, that indicates the marrow is making platelets and they are being destroyed, which points to ITP. If platelet precursors are low, other causes need to be evaluated.

CLL-directed therapy is recommended for patients with autoimmune cytopenias and extensive CLL-related bone marrow involvement. Treatment for AIHA and ITP may include IVIG [intravenous immunoglobulin], alkylating drugs, rituximab, splenectomy, and corticosteroids. Eltrombopag and romiplostim are additional options for ITP treatment.

Amy, can you tell us a little bit about the risks regarding secondary malignancies in CLL?

Amy Goodrich

Sure, Carmen. Patients with CLL have a significantly higher risk of developing second primary malignancies: 20% higher than the general US population. Solid organ cancers account for about 67% of these second primary malignancies in patients with CLL, and a wide range of solid tumor types is reported. Among the more common solid second primary malignancies, tumors of the lung and bronchus account for about 59% and melanoma represents about 31%. And then the most common hematologic malignancies are other non-Hodgkin lymphomas, Hodgkin lymphoma, and AML at rates of 23%, 7%, and 3%, respectively.¹³

The risk of developing a solid tumor second primary malignancy is highest in non-Caucasian populations. For hematologic malignancies, that rate is highest in people of Asian descent. Non-melanoma skin cancers—squamous cell carcinoma and basal cell carcinoma—are also commonly noted second primary malignancies in CLL, and were seen to recur at 7 and 14 times greater frequency than the general US population in a recently published SEER [Surveillance Epidemiology and End Results] database analysis. Patients with CLL are also more likely to die from squamous cell carcinoma or have metastatic squamous cell carcinoma when compared with patients without CLL. High-risk features appear to be Caucasian race and a history of extensive sun exposure at a young age.¹³

The NCCN guidelines recommend that all patients with CLL have a dermatologic evaluation at least annually.² From a clinical perspective, any finding on exam or imaging with a different pattern or appearance should be worked up to rule out a second primary malignancy. This is really where consistent interdisciplinary teams are in a position to very quickly identify findings that are out of step with a patient's prior history. Carmen, given the concern about infection in regard to our patients with CLL and the current COVID-19 pandemic, what are some important considerations for managing treatment?

Carmen Nobre

Since CLL largely affects the elderly and is associated with underlying immunodeficiency, this may put patients at a higher risk for COVID-19 and its related complications. In deciding on CLL treatment for patients, individual factors such as symptoms, disease burdens, comorbidities, and other factors like potential immunosuppressive effects of treatment or frequency of clinic visits have always been something we've considered. These are even more top-of-mind in our current setting of COVID-19, and we really want to minimize, if we can, the frequency of clinic visits here. Patients who do not meet the International Workshop on CLL treatment indications may benefit from a watch-and-wait approach. If treatment cannot be delayed, then again, choosing a therapy that could be managed in the outpatient setting with fewer clinic visits, along with lab assessment that perhaps could be done closer to home, may be of value. Another consideration is to potentially avoid treatment with monoclonal antibodies, such as rituximab or obinutuzumab, because such treatment could increase the risk of infection through B-cell depletion and potentially decrease the patient’s overall response to the SARS-CoV-2 virus.^14,15

Amy Goodrich

For our CLL patients who are already on therapy, again our priority is to appropriately treat their CLL. However, as you said, Carmen, we still want to minimize the number of visits to the clinic and consider using laboratories closer to home, and certainly telemedicine visits for follow-up. CLL-directed therapies may be continued, with the exception of considering omission of anti-CD20 monoclonal antibodies. If a patient tests positive for SARS-CoV-2, then the person’s severity of symptoms and aggressiveness of CLL combined with history of infections and risk of COVID-19 complications need to be all weighed together. An important consideration for patients on BTK inhibitors is the potential for CLL flare and cytokine release that sometimes can be seen with discontinuation of these agents, and it’s also good to keep in mind that these symptoms from discontinuation can mimic symptoms of COVID-19. Of course, we need to learn more here. The good news is that new information continues to be uncovered about the risk of COVID-19 in CLL patients, and many studies are under way that may help to guide us.

Carmen Nobre

Yes, that’s certainly true, Amy. Well, we’ve covered a lot of ground here today, highlighting the complex nature of both CLL and the immune complications seen in patients with CLL. It is truly a disease that requires a multidisciplinary team to keep patients educated and as healthy as possible, and on track to get the maximum benefit from our ever-growing armamentarium of treatment options.