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You Make the Call: How would you treat a patient with cold agglutinin disease and pathology consistent with MCL?

January 20, 2023

February 2023

Ariela Noy, MD
Ariela Noy, MD
Attending Physician and Member
Memorial Sloan Kettering Cancer Center
New York, NY



I have a 66-year-old male patient with a history of cold agglutinin disease, atrial fibrillation, dyslipidemia, depression, and anxiety. He has an Eastern Cooperative Oncology Group (ECOG) performance status score of 1. He presented with left testicular swelling and had an orchiectomy. Pathology is consistent with mantle cell lymphoma (MCL):

  • CD20: Diffusely positive
  • Cyclin D1: Positive
  • BCL2: Positive
  • MUM1: Variably, weakly positive
  • Ki-67: Increased, approximately 70-80%
  • BCL6: Negative
  • TdT: Negative

A post-orchiectomy PET scan showed no evidence of metastatic disease. I was originally planning to treat the patient with either four cycles of R-DHAX (rituximab, dexamethasone, cytarabine, and oxaliplatin) plus autologous hematopoietic cell transplantation (AHCT) or the Nordic regimen (rituximab with dose-intensified cyclophosphamide, doxorubicin, vincristine, prednisone alternating with high-dose cytarabine, followed by AHCT). However, his PET scan came back negative, so I am wondering if this is too aggressive of an approach? Would you recommend rituximab plus bendamustine with cytarabine +/- intrathecal methotrexate instead?


This is certainly a unique and interesting question: MCL presenting in a sanctuary site, now status post-orchiectomy.

First, I would start by checking for sites of disease outside of the removed testis. Borrowing from the predilection for diffuse large B-cell lymphoma (DLBCL) of the testis to involve central nervous system sites and other extranodal sites, I would also evaluate the cerebrospinal fluid (CSF) with flow cytometry in addition to the peripheral blood and bone marrow. The CSF multiparameter flow needs to be run irrespective of cell count and processed on the same day. I would also get an MRI of the brain with and without gadolinium. Because MCL involves the gastrointestinal track in nearly 90% of cases, I would also consider upper and lower endoscopy.

Now, on to the treatment of this patient. In the case of stage I disease, I would err on the side of avoiding AHCT; for example, one would not pursue that for stage I DLBCL of the testis. For nodal stage I MCL, I would defer AHCT. I do agree that a DHAX-based regimen, which covers the blood-brain barrier, contralateral testicular radiation, and intrathecal therapy, appears to be a rational choice. As an aside, it is increasingly unclear if AHCT in front-line therapy adds to outcome now that we have Bruton tyrosine kinase (BTK) inhibitors. At least in younger patients, it is beginning to look like adding BTK inhibitors to chemoimmunotherapy up front in advanced-stage disease might obviate the need for AHCT.1


Dreyling M, Doorduijn JK, Gine E, et al. Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized triangle trial by the European MCL Network. Abstract #1. Presented at the 2022 American Society of Hematology Annual Meeting; December 11, 2022; New Orleans, Louisiana.

Editor’s note: Click here to check out our on-site coverage of the presentation by Dreyling et al.


For patients with hemochromatosis, UpToDate recommends phlebotomy when ferritin levels are greater than 1,000 ng/mL, while the American Society of Hematology Self-Assessment Program (ASH-SAP) recommends it when ferritin levels are greater than 300 ng/mL in male patients and greater than 200 ng/mL in non-pregnant female patients. Both publications indicate phenotypic manifestations are only 1% to 25% even if they are homozygotes, so my question is, when do we start phlebotomy for asymptomatic patients with hemochromatosis – at a ferritin level of 300 ng/mL or 1,000 ng/mL? Based on UpToDate, it looks like iron overload in the liver and cirrhosis can happen only when ferritin levels are greater than 1,000 ng/mL, so for patients with levels above 500 ng/mL, does a liver MRI need to be done? If there is no evidence of transaminase elevation or congestive heart failure and the patient is asymptomatic, when should a phlebotomy be done – at a ferritin level of 1,000, 500, or 300 ng/mL? Is there a difference in when to do a phlebotomy for heterozygotes versus homozygotes, and is that guideline the same for ferritin levels above 500 ng/mL or 1,000 ng/mL?

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Disclaimer: ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.


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