Implementing Individualized Approaches to Management of Different Subtypes of Patients With CLL

Course Director

William G. Wierda, MD, PhD

William G. Wierda, MD, PhD
Professor, Department of Leukemia
Division of Cancer Medicine
The University of Texas MD Anderson Cancer Center
Houston, Texas


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Part 2 of a 2-part series

Dr. Wierda provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

Chronic lymphocytic leukemia (CLL) is a very heterogeneous disease, and while not all patients require treatment at the time of diagnosis, therapy is indicated for patients with advanced stage disease, high tumor burden, severe disease-related symptoms, or repeat infections. Prior to the initiation of active therapy for patients with symptomatic disease, a pre-treatment evaluation should be carried out to determine the extent of disease, patient performance status, and comorbidities that may impact treatment selection.


Disclosures

This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

Course Director
William G. Wierda, MD, PhD, has a financial interest/relationship or affiliation in the form of:
Consultant for AbbVie Inc.; Genentech, Inc./Hoffmann-La Roche Inc.; Gilead; GlaxoSmithKline; Merck & Co., Inc.; and Pharmacyclics, Inc.
Medical Director
Kadrin Wilfong, MD
Answers in CME, Inc.
Kadrin Wilfong, MD, currently has no financial interests/relationships or affiliations in relation to this activity.

Answers in CME staff who may potentially review content for this activity have disclosed no relevant financial relationships.

Penn State College of Medicine staff and faculty involved in the development and review of this activity have disclosed no relevant financial relationships.

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What is the optimal front-line treatment for a 67-year-old patient with symptomatic chronic lymphocytic leukemia?

Dr. Wierda: When you're considering treatment for patients with CLL, there are a couple of features that need to be highlighted with this disease specifically. That is, that most of the patients are elderly. These patients don't tolerate the myelosuppressive regimens as well as their younger counterparts, so purine analogs are challenging to give them. Alkylating agents are also challenging to give them.

They tend to have more toxicity. And I think there's an underappreciated renal insufficiency in the elderly population. You don't get a good idea about [it] by just looking at their creatinine. Fludarabine is renally cleared, and I think we most likely will overdose patients with fludarabine-based regimens who are elderly because we aren't appreciating their renal insufficiency that is a function of their age.

In terms of thinking about age and comorbidities, in the US, we generally use age as sort of a surrogate marker of how they'll be able to tolerate treatment and as a correlate with their comorbidities.

My general rule of thumb is that I use 70 [years] as a cutoff for identifying patients who are more or less likely to be able to tolerate myelosuppression, rather than using 65 [years]. So a patient who's 67 [years old] would be a patient that I would be considering a chemoimmunotherapy regimen such as FCR [fludarabine-cyclophosphamide-rituximab] as their front-line therapy.1-7

If a patient is over 70 [years], then I'm less likely to be considering an FCR-based regimen, unless I feel that they have very aggressive disease. So I will consider an FCR or chemoimmunotherapy-based regimen as a front-line therapy even in the older population, but I will always dose-reduce so that I don't run into problems with myelosuppression and infection and complications.

For people between 65 and 70 [years], I might dose-reduce them, depending on what their blood counts are before I start treatment. But, certainly, for individuals younger than 70, FCR would be my front-line therapy.

Narrator: Purine-analog–based chemotherapy plus rituximab, such as FCR, FR [fludarabine-rituximab], or PCR [pentostatin-cyclophosphamide-rituximab], is preferred for younger patients and for those older patients who are able to tolerate or who require more aggressive therapy. However, other options are recommended for patients aged 70 or older—or younger patients with significant comorbidities. These include chlorambucil with or without rituximab, bendamustine with or without rituximab, fludarabine with or without rituximab, alemtuzumab or rituximab as single agents, lenalidomide, or cladribine.8

Dr. Wierda: There is some suggestion that bendamustine may be a bit better tolerated, including in terms of myelosuppression, that in the elderly.9 So that would be another combination—bendamustine and rituximab—that one could consider for first-line therapy.

Narrator: Recently, the US Food and Drug Administration approved obinutuzumab for use in combination with chlorambucil to treat patients with previously untreated CLL.10 The approval was based on findings from CLL11, a phase 3, randomized, open-label, multicenter trial that compared obinutuzumab in combination with chlorambucil versus chlorambucil alone in patients with previously untreated CLL. Study participants receiving the combination therapy demonstrated a significant improvement in progression-free survival—an average of 23 months versus 11.1 months with chlorambucil alone. The most common grade 3/4 toxicities within the obinutuzumab arm were infusion-related reactions, neutropenia, and thrombocytopenia.

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What would be the next best treatment for a 55-year-old male patient with 17p-deletion CLL, Binet C, who has had no response to 2 cycles of FCR?

Dr. Wierda: 17p deletion can be an acquired feature, so if a patient is getting their front-line therapy, they need to have FISH evaluated to determine if 17p [deletion] is present.

Also, when their disease is relapsing and you're considering new treatment, then FISH should be rechecked to determine whether or not individuals have acquired a 17p deletion. It occurs about in 8% of the patients receiving initial therapy and can be 30[%] to 40% of the patients who are receiving salvage therapy.11-12 So it's more prevalent in the relapsed and refractory population.

I think it's also important to consider, if it's available, doing mutation analysis for TP53 because the literature indicates 90% to 95% of the patients with 17p deletion also have TP53 deletion. But there are a significant number of patients who have TP53 mutations without 17p deletion, and they are equally high-risk to those patients with 17p deletion.13-20

Patients who have 17p deletion are typically refractory to purine analogs, to alkylating agents; and my opinion is that there isn't a standard front-line or salvage treatment currently for patients with 17p deletion. These are patients who typically, if they need treatment, we like to get them into a remission and have some control of their disease, and we'll quickly, even in first remission, consider moving them to an allogeneic stem cell transplant.

In terms of therapy and chemoimmunotherapies that we have to manage in these patients right now, as I mentioned, chemoimmunotherapy is not very active.21-25 There are data [to show] that high-dose steroids with monoclonal antibody have activity, but those responses are not very durable.26-28 So dexamethasone or high-dose methylprednisolone has been used alone and in combination with CD20 monoclonal antibodies as a debulking and disease-managing strategy—and particularly in efforts to debulk patients to go on to an allogeneic stem cell transplant.

Intensive regimens are not very active and don't give very long, durable remissions—intensive regimens such as hyper-CVAD [cyclophosphamide-vincristine-doxorubicin and dexamethasone alternating with high-dose methotrexate and cytarabine] or CHOP [cyclophosphamide-doxorubicin-vincristine-prednisone] or those types of regimens. 

Narrator: Alemtuzumab, alone or in combination with methylprednisolone, is one agent that has demonstrated activity in cells lacking TP53 function, as seen in patients with chromosome 17p deletion. A retrospective analysis of patients with relapsed or refractory CLL treated with alemtuzumab included 35 patients with 17p deletion. Compared with the entire study population, patients with 17p deletion demonstrated a similar overall response rate and median progression-free survival, but shorter median overall survival.  

Dr. Wierda: I think with these new BTK inhibitor and the BCL-2 inhibitors, we'll see significant advances in management for the patients with 17p deletion.29-31

Narrator: Because no standard treatment exists for patients with 17p deletion—due to poor outcomes with currently available therapies—enrollment in an appropriate clinical trial is recommended for these patients.8

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How would you choose treatment for a heavily pretreated elderly patient with CLL and considerable comorbidities, including coronary artery disease and diabetes mellitus?

Dr. Wierda: In terms of the elderly patients who have comorbidities and who have relapsed disease, I think it's important to consider what your objective is in treating those patients—palliating symptoms, improving blood counts if they have cytopenias—and considering what they'll be able to tolerate.

If they have significant coronary artery disease or diabetes, they're not going to tolerate chemoimmunotherapy regimens very well. And typically, the strategy for managing patients with CLL is that their best opportunity to get into a remission, including a complete remission, is with their first treatment.

And when their disease relapses and if they've had multiple relapses, the disease typically becomes more and more resistant to those agents that it's been exposed to. So we tend to have to increase the intensity of their therapy.

It's a challenge to manage an elderly patient who has comorbidities and who has relapsed disease or who has refractory disease. I think GA101 [obinutuzumab] is something that may be promising in that population.32

Narrator:  The previously mentioned CLL11 trial, which compared chlorambucil plus an anti-CD20 monoclonal antibody—either obinutuzumab or rituximab—with chlorambucil monotherapy in previously untreated patients was the first large, phase 3 study to address treatment for less-fit elderly patients with CLL. The trial cohort had a median age of 73 years, and patients had a range of pre-existing medical conditions, including hypertension, coronary heart disease, heart failure, diabetes, musculoskeletal problems, and renal impairment.

Dr. Wierda: I think these new oral agents will certainly be an advance for those patients and offer the opportunity of longer-term disease control and disease management.

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References

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  8. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Non-Hodgkin’s Lymphomas. Version 2.2013. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf. Accessed December 9, 2013.
  9. Fischer K et al. J Clin Oncol. 2012;30:3209.
  10. US Food and Drug Administration. FDA approves Gazyva for chronic lymphocytic leukemia. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm373209.htm. Accessed December 9, 2013.
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  21. Lozanski G et al. Blood. 2004;103:3278.
  22. Wierda WG. Am Soc Hematol Educ Program. 2006;285.
  23. Stilgenbauer S, Döhner H. N Engl J Med. 2002;347:452.
  24. Grever MR et al. J Clin Oncol. 2007;25:799.
  25. Catovsky D et al. Lancet. 2007;370:230.
  26. Osuji NC et al. Haematologica. 2005;90:1435.
  27. Pettitt AR. Leukemia. 2006;20:1441.
  28. Ravandi F, O'Brien S. Cancer Invest. 2006;24:718.
  29. ClinicalTrials.gov. A study of the efficacy of ABT-199 in subjects with relapsed or refractory chronic lymphocytic leukemia with 17p deletion. Trial NCT01889186. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01889186. Accessed December 9, 2013.
  30. ClinicalTrials.gov. A multicenter phase 2 study of PCI-32765 (ibrutinib) in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma with 17p deletion. Trial NCT01744691. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01744691. Accessed December 9, 2013.
  31. ClinicalTrials.gov. PCI-32765 for special cases of chronic lymphocytic leukemia or small lymphocytic lymphoma. Trial NCT01500733. Available at: http://www.clinicaltrials.gov/ct2/show/NCT01500733. Accessed December 9, 2013.
  32. Goede V et al. J Clin Oncol. 2013;31:(suppl; abstr 7004).

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This activity is supported by an educational grant from Genentech.
Additional support provided by Penn State College of Medicine and Answers in CME.

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Improving Outcomes in Chronic Lymphocytic Leukemia: Expert Perspectives on Current and Emerging Treatment Strategies

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