It's Time to Tackle the Evidence Gap in Lymphoid Cancers

Publication
Article
Oncology Live®May 2015
Volume 16
Issue 5

In Partnership With:

Although CLL is the most common chronic leukemia, there remains no single agreed-upon standard of care for first-line treatment.

Ahmad Halwani, MD

Assistant Professor,

Division of Hematology

and Hematologic Malignancies

Huntsman Cancer Institute

University of Utah Healthcare

Case Study: Mrs Smith

You’re in clinic and your next patient is Mrs Smith. She is a 66-year-old woman who was diagnosed with chronic lymphocytic leukemia (CLL) four years ago. Lately she has developed gradually worsening anemia and enlarging lymph nodes. She does not have deletion 17p by conventional karyotype analysis or FISH. You need to recommend a treatment option for her now symptomatic CLL.

Best Treatment Option Unclear

Although CLL is the most common chronic leukemia, there remains no single agreed-upon standard of care for first-line treatment. In Mrs Smith’s case, it would be quite reasonable to attempt to apply evidence from the recently reported German CLL Study Group randomized con- trolled trial (RCT) of fludarabine, cyclophosphamide, and rituximab (FCR) versus bendamustine rituximab (BR) for first-line treatment of CLL.1 At first glance, FCR seems like the better option, as it is associated with a longer progression-free survival (PFS).

However, FCR is more toxic with almost twice the rate of severe infections. In an unplanned subgroup analysis, there was no benefit in patients who were older than 65 years, or in those with multiple and/or moderate comorbidities. The trial excluded patients with impaired kidney function. Despite being quite active, Mrs Smith was diagnosed with diabetes more than 7 years ago, and has diabetic nephropathy. Her renal function is borderline normal. On account of her comorbidities and renal function, it’s quite likely that she would not have been eligible for this trial.

This case illustrates a common context in hematological malignancies. Despite having the results of a phase III RCT, the best treatment option for many patients who are older or who have comorbidities remains unclear.

Efficacy Established in Carefully Selected Populations

Treatment options for lymphoid malignancies have greatly increased over the past decade thanks to advances in cancer biology and therapeutics. For example, a clinician treating lymphoma or CLL can draw upon more than a dozen agents from a handful of modalities: chemoimmunotherapy,2 antibody-drug conjugates,3 checkpoint inhibitors,4 immunomodulators,5,6 and tyrosine kinase inhibitors.7—9

As a result, some patients with advanced-stage indolent lymphoma or CLL can live for decades, and a significant proportion of patients with aggressive lymphomas can be definitively cured of their disease.

Clinical research in oncology has typically relied on prospective, often randomized, clinical trials as the gold standard methodology to generate evidence of the benefits and risks of novel treatments. Prospective clinical trials rely on a number of elements to achieve a high level of internal validity: strict eligibility criteria, consistent treatment delivery, predefined endpoints, and a priori statistical power considerations to accept or reject the null hypothesis.10 Randomization ensures the exchangeability of patients in different treatment arms and allows causal inference.

The resulting high internal validity of prospective clinical trials is often achieved at the expense of external validity, or applicability of evidence to patients in real world settings. Stringent eligibility criteria often lead to exclusion of patients with comorbidities. As a result, trials often accrue patients who are younger and healthier than patients in actual clinical practice.11,12 Patients who belong to ethnic minorities are also underrepresented in clinical trials.13 The technical and regulatory challenges involved in the conduct of clinical trials often lead to a predominance of patients treated in academic settings as opposed to community settings.

The average patient enrolled in pivotal prospective trials in CLL over the last decade is typically in their early 60s, predominantly white, and has normal organ function and limited number and severity of comorbidities.14—16 At diagnosis, the average patient with CLL in real world settings is almost a decade older.17,18 About 15% of patients with CLL in the United States are nonwhite (including 7% black and 5% Hispanic.)19 Black and Hispanic patients have a worse overall survival compared with white patients with CLL.13,19,20 At the time of diagnosis, patients with CLL have a median of two comorbidities and take two prescription medications per day.21

Patients with CLL with two or more comorbidities who still qualify for participation in clinical trials have a worse PFS and overall survival compared with patients with a lower comorbidity burden.22 It is estimated that one in four patients with CLL is not eligible to participate in clinical trials on account of organ function per National Cancer Institute-Working Group 1996 guidelines.21

Evaluating Therapies in Real World Scenarios

As a result of these differences, the need to complement our understanding of the efficacy of cancer treatments as studied in RCTs with evidence of effectiveness in a real world setting is increasingly recognized.23 This type of research is typically referred to as comparative effective- ness research (CER), population research, or outcomes re- search. While not as common as explanatory RCTs, and at times lagging behind RCTs addressing the same question, CER studies are now starting to address the evidence gap.

In the example of chemo-immunotherapy for first-line treatment of CLL, three groups have so far examined the effectiveness of FCR in real world settings.18,24,25 Their findings are similar and point to frequent dose reductions, which lead to a lower PFS. In a study of 106 patients with CLL who were treated with FCR in the Oncomip healthcare network in France from 2005—2011, Bouvet el al reported that one in two patients had a dose reduction of more than 20%.24 About 60% of patients had grade 3-4 neutropenia, 16% had neutropenic fever, and 19% were hospitalized due to sepsis. Dose reductions were associated with a lower PFS.

Herishanu et al recently reported outcomes on 128 young patients treated in 10 Israeli medical centers, with similar results.25 About 50% of patients had dose reductions. Patients who received less than two-thirds the recommended dose had a fourfold increase in hazard of progression.

Knauf et al recently reported the characteristics of 806 patients with CLL treated by office-based hematologists in Germany.18 The group’s first report suggests that two regimens had comparable effectiveness; a more detailed report on the cohort’s survival outcomes is yet to be published.

Other groups have used Surveillance, Epidemiology, and End Results (SEER) data or SEER and Medicare databases to examine the impact of patient factors such as age, race, and ethnicity on outcomes of treatment as well as treatment practices in elderly patients with CLL in the United States.19,26

The Road Ahead

Going forward, various methodologies have been proposed to extend and validate the results of clinical trials in actual clinical practice settings. These include pragmatic trials, observational cohort studies, systematic reviews and meta-analyses.27 Widespread adoption of electronic health records offers the promise of observational effectiveness research using clinical information that was requested, recorded, and/or used by treating physicians at the point of care. This is a richer dataset than claims-based data, and provides greater longitudinal follow-up than registry-based data. The causal inference framework,28 applied to observational effectiveness research, offers the potential of explicitly specifying the assumptions made in the analysis, and minimizing and/or quantifying the biases inherent to the observational nature of the study.29

While prospective clinical trials will remain integral to our understanding of the efficacy of novel cancer treatments, there is a mostly unmet need for research that aims to further our understanding of the comparative effectiveness of cancer treatments in real world settings. Novel approaches in comparative effectiveness research, including cohort studies that leverage robust data from electronic medical records, have the potential to address these knowledge gaps.

References

  1. Eichhorst B, Fink AM, Busch R, et al. Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with Advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 Study). Presented at: 2014 ASH Annual Meeting; December 6-9, 2014; San Francisco, CA. Abstract 642.
  2. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia [published online March 14, 2005]. J Clin Oncol. 2005;23(18):4079-4088.
  3. Gopal AK, Chen R, Smith SE, et al. Durable remissions in a pivotal phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma [published online December 22, 2014]. Blood. 2015;125(8):1236-1243.
  4. Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma [published online December 6, 2014]. N Engl J Med. 2015;372(4)311-319.
  5. Tuscano JM, Dutia M, Chee K, et al. Lenalidomide plus rituximab can produce durable clinical responses in patients with relapsed or refractory, indolent non-Hodgkin lymphoma [published online March 7, 2014]. Br J Haematol. 2014;165(3):375-381.
  6. Chen CI, Bergsagel PL, Paul H, et al. Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia [published online December 28, 2010]. J Clin Oncol. 2011:29(9):1175-1181.
  7. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with Ibrutinib in relapsed chronic lymphocytic leukemia [published correction appears in N Engl J Med. 2014;370(8):786]. N Engl J Med. 2013;369(1):32-42.
  8. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia [published online May 31, 2104]. N Engl J Med. 2014;371(3):213-223.
  9. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia [published online January 22, 2014]. N Engl J Med. 2014;370(11):997-1007.
  10. Sargent D. What constitutes reasonable evidence of efficacy and effectiveness to guide oncology treatment decisions? Oncologist. 2010;15(suppl 1):19-23.
  11. Tadmor T, Polliack A. Optimal management of older patients with chronic lymphocytic leukemia: some facts and principles guiding therapeutic choices [published online September 28, 2011]. Blood Rev. 2012;26(1):15-23.
  12. Molica S, Brugiatelli M, Morabito F, et al. Treatment of elderly patients with chronic lymphocytic leukemia: an unmet cinical need. Expert Rev. Hematol. 2013;6(4):441-449.
  13. Coombs CC, Falchi L, Weinberg JB, et al. Chronic lymphocytic leukemia in African Americans [published online July 9, 2012]. Leuk Lymphoma. 2012;53(11):2326-2329.
  14. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lance. 2010;376(9747):1164-1174.
  15. Knauf WU, Lissichkov T, Aldaoud A, et al. Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia [published online August 3, 2009]. J Clin Oncol. 2009;27(26):4378-4384.
  16. Fischer K, Cramer P, Busch R, et al. Bendamustine in combination with rituximab for previously untreated patients with chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group [published online August 6, 2012]. J Clin. Oncol. 2012;30(26):3209-3216.
  17. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network [published online November 1, 2011]. Br J Cancer. 2011;105(11):1684-1692.
  18. Knauf W, Abenhardt W, Dörfel S, et al. Routine treatment of patients with chronic lymphocytic leukaemia by office-based haematologists in Germany—data from the Prospective Tumour Registry Lymphatic Neoplasms [published online April 15, 2014]. Hematol Oncol. 2015;33(1):15-22.
  19. Nabhan C, Aschebrook-Kilfoy B, Chiu BC, et al. The impact of race, ethnicity, age and sex on clinical outcome in chronic lymphocytic leukemia: a comprehensive Surveillance, Epidemiology, and End Results analysis in the modern era [published online April 3, 2014]. Leuk Lymphoma. 2014;55(12):2778-2884.
  20. Falchi L, Keating MJ, Wang X, et al. Clinical characteristics, response to therapy, and survival of African American patients diagnosed with chronic lymphocytic leukemia: joint experience of the MD Anderson Cancer Center and Duke University Medical Center [published online July 8, 2013]. Cancer. 2013;119(17):3177-3185.
  21. Thurmes P, Call T, Slager S, et al. Comorbid conditions and survival in unselected, newly diagnosed patients with chronic lymphocytic leukemia. Leuk Lymphoma. 2008;49(1):49-56.
  22. Goede V, Cramer P, Busch R, et al. Interactions between comorbidity and treatment of chronic lymphocytic leukemia: results of German Chronic Lymphocytic Leukemia Study Group trials [published online February 28, 2014]. Haematologica. 2014;99(6):1095-1100.
  23. Sox HC, Goodman SN. The methods of comparative effectiveness research [published online January 3, 2012]. Annu Rev Public Health. 2012;33:425—445.
  24. Bouvet, E. et al. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia. Haematologica 98, 65—70 (2013).
  25. Herishanu Y, Goldschmidt N, Bairey O, et al. Efficacy and safety of frontline therapy with "FCR" regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli chronic lymphocytic leukemia study group experiencene. [published online February 6, 2015]. Haematologica. pii:haematol.2014.115808.
  26. Satram-Hoang S, Reyes C, Hoang KQ, et al. Treatment practice in the elderly patient with chronic lymphocytic leukemia—analysis of the combined SEER and Medicare database [published March 18, 2014]. Ann Hematol. 2014;93(8):1335-1344.
  27. Lyman GH, Levine M. Comparative effectiveness research in oncology: an overview [published online October 15, 2012]. J Clin Oncol. 2012;30(34):4181-4184.
  28. Pearl J. An introduction to causal inference. Int J Biostat. 2010;6(2):Article 7. doi:10.2202/1557-4679.1203.
  29. Armstrong K. Methods in comparative effectiveness research [published online October 15, 2012]. J Clin Oncol. 2012;30(34):4208-4214.

Related Videos
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
A panel of 4 experts on bladder cancer
Muhamad Alhaj Moustafa, M.D., M.S. of Mayo Clinic
A panel of 4 experts on bladder cancer
Matthew Milowsky, MD, FASCO, an expert on bladder cancer
A panel of 4 experts on bladder cancer