Skip the Bone Marrow Biopsy in Follicular Lymphoma?  

Alexander M. Castellino, PhD

August 02, 2017

Clinical trials in patients with follicular lymphoma (FL) mandate that patients undergo bone marrow biopsies (BMBs) at baseline and at subsequent points following treatment in order to monitor response. But how necessary are they?

The biopsies are unnecessary in most patients, argue researchers reporting results from a  retrospective analysis of 99 patients with FL enrolled across 32 clinical trials at Weill Cornell Medical College. The study found that the  mandatory BMBs resulted in response assessment change in at most 1% of patients and so concluded that they were not needed.

"In our patient-centered approach to care, we find that these biopsies are painful and anxiety-provoking. The procedures take time, add to healthcare costs, and are a hindrance for patients to participate in clinical trials," corresponding author, Sarah Rutherford, MD, medical oncologist at Weill Cornell Medicine and New-York Presbyterian, New York City, told Medscape Medical News.

"In routine clinical practice, we do not often do bone marrow biopsies in follicular lymphoma patients. Removal of this barrier can contribute significantly to increasing patient interest in clinical trials, which can provide them access to novel and promising therapies," she added.

The study was published in the British Journal of Haematology.

Value of BMBs in FL

"This study basically confirms what we know about BMB in follicular lymphoma  in most scenarios," commented lymphoma expert Nadia Khan, MD, assistant professor in the Department of Hematology-Oncology at the Fox Chase Cancer Center, Philadelphia, Pennsylvania.

"In the era of PET/CT [positron emission tomography/computed tomography] scans and also in the setting of advanced-stage vs early-stage disease, BMBs may not provide information that is likely to change clinical management," she told Medscape Medical News .

Dr Khan, who is not associated with the study, is also on the Lymphoma Panel of the National Comprehensive Cancer Network.

She acknowledged that "in the context of a clinical trial, it is important to know if patients with stage I or II disease who have to undergo treatment have bone marrow involvement, and  PET/CT is not sufficient to determine that."

However, she also pointed out that patients with FL who have Ann Arbor stage I disease rarely have bone marrow involvement and a BMB is likely to be negative.

"In any event, most Ann Arbor stage I or II patients are managed with watchful waiting or surveillance," Dr Khan said.

At the same time, she cautioned that it may not be possible to do away with the requirement for BMBs altogether. In patients with very advanced disease there is concern about transformation, and BMBs provide important information for clinical management, she explained.

Dr Rutherford noted that response criteria used in clinical trials for FL were developed by physicians who treat patients with lymphoma and by radiologists. In addition to imaging tests, BMBs are required at baseline to determine extent of disease. At a certain timepoint after treatment (eg, 6 weeks), patients undergo follow-up imaging. If the results are negative, response criteria mandate that patients undergo BMBs to confirm imaging results. This is the method recommended by the 2007 International Working Group revised criteria and the 2014 Lugano Classification.

The 2014 Lugano Classification does not require BMBs at initial assessment for Hodgkin's lymphoma, a disease in which bone marrow involvement is rare. FL is more frequently found in the bone marrow, and the requirement still exists for this condition, Dr Rutherford said.

That is because FL is a gray area, Dr Khan added. "PET/CT is not sensitive to rule out bone marrow involvement," she said.

Dr Rutherford clarified that physicians should still be vigilant to do BMBs in certain scenarios, such as when patients have prolonged low blood counts. "Clinical discretion will dictate when clinicians may require their patients to undergo BMBs," she said.

Dr Khan concurred. "A BMB is recommended when there is a clinical suggestion of marrow infiltration," she said. "If patients have cytopenias, it is important to determine if there is marrow involvement, and in a patient with prolonged cytopenias who shows partial remission in response to treatment, one needs to understand if the marrow has cleared," she said.

"We advocate that if the PET/CT is negative and bone marrow recovery is observed, then a BMB does not provide any useful additional information,"  Dr Khan said.

"It is unnecessary and problematic to expose a clinical trial patient to testing [with BMB] if it is unlikely to provide any useful information," Dr Rutherford said.

Pain and Cost Associated With BMBs

From the patient's perspective, the BMB can be a traumatic experience. One of  Dr Rutherford's patients, Liam C, is 1 of the 99 patients described in this study. He met with Dr Rutherford in November 2015, who, after routine blood work and a BMB, enrolled him in a clinical trial evaluating an investigational drug for FL. Although Liam is doing well after about 2 years of therapy, he vividly recalls his BMB experience.

"Although I knew it was a drill going through my bone, it felt like someone was sawing through it," he said. He explained that there was no topical pain (Liam had chosen local anesthesia), but the pressure of the drill was intense, with bouts of excruciating pain, and his whole body shaking. "I was so aware of the unusual invasion. The vibrations from the drilling were felt through the entire body," he told Medscape Medical News. "I was pragmatic knowing that this was necessary, but I was terrified," he recalled.

Indeed, a study of patients with hematologic malignancies found that 70% of patients experienced pain during a bone marrow biopsy, with 32% reporting pain as severe (Acta Anaesthesiol Scand. 2009;53:354-363).

Having performed many BMBs, Dr Khan acknowledges that patients undergoing the procedure experience pain and anxiety, but she also pointed out that the pain experienced with BMBs depends on several factors, including the time taken over the procedure, physician experience, and the pain experienced in a previous procedure. She indicated that in the hands of an experienced operator, the pain and discomfort experienced can be minimized.

Dr Rutherford provided her own insight. "When a bone marrow biopsy is necessary, we make every effort for it to be as comfortable as possible for the patient. However, both patients and physicians would prefer to avoid the procedures when information obtained from them is not considered significant," she told Medscape Medical News.

Liam is self-educated on his disease and knows his protocol well. "If no decisions are made based on a bone marrow biopsy and the results are not conclusive, why are they necessary?" he asked.

A BMB does not come cheap. In a July 2017 updated list of common hospital costs (not accounting for physician and/or other provider fees), Johns Hopkins Hospital lists the average cost of a bone marrow biopsy at $5400.

Details of the Study

The only clinical scenario in which BMBs affect response assessment for FL is in patients with positive BMB results at baseline who have a complete response (CR) on post-treatment imaging but residual lymphoma in their bone marrow, the study authors note. They hypothesized that only a small number of patients would fall into this group.

Most of the 99 patients enrolled in this study had stage IV disease (n = 69); 15 patients had stage III disease, 11 had stage II disease, and only 4 patients had stage I disease.

The researchers found that  45 patients had positive BMB results at baseline; post-treatment imaging showed that 12 of these patients had a CR, 19 had  a partial response, 5 had stable disease, and 9 had progressive disease.

Among the 12 patients with a CR, 11 had a negative BMB finding that confirmed the imaging result. One patient declined to undergo a post-treatment BMB despite having a CR. This patient was the only one whose response assessment may have been affected by the BMB.

The 54 patients who had a negative BMB result at baseline were expected to have negative post-treatment BMB results and were not required to undergo a repeat BMB after treatment based on response criteria. Therefore, their BMBs were irrelevant to response assessment.

"If the disease is in complete remission by imaging, we find that bone marrow disease responds as well — and probably below the threshold of detection on a BMB," Dr Rutherford and her colleagues write in the paper.

"Those developing response criteria for follicular lymphoma can omit bone marrow assessments without any evident loss of rigour," they add.

Dr Rutherford and her colleagues are planning to expand this study to other centers that enrolled patients in similar studies. "If such studies provide corroborating evidence to ours, we hope that those formulating study protocols may be able to eliminate the BMB requirement unless there is another reason that justifies its addition," she told Medscape Medical News.

"Less is more," Dr Khan agreed. "Decreasing the requirements for marrow evaluations in lymphoma clinical trials is rational and advantageous for patients and can impact enrollment favorably," she told Medscape Medical News.

"My hope is that in the future, noninvasive testing will ultimately supplant the bone marrow biopsies as endpoints of response," Dr Khan noted.

The study authors have disclosed no relevant financial relationships. Dr Khan is on the advisory board of AbbVie and Pharmacyclics.

Br J Haematol. Published July 5, 2017. Abstract

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