Hematopoiesis

Valentina Baez Sosa, MD
@ValenBaezS
Clinical Fellow, Department of Transfusion Medicine and Center for Cellular Engineering
National Institute of Health Clinical Center
Bethesda, MD
Kamille West-Mitchell, MD
@Kwestmitchell
Chief, Blood Services Section 
National Institute of Health Clinical Center
Bethesda, MD
James Kochenderfer, MD
Tenured Senior Investigator, Surgery Branch
National Institute of Health Clinical Center
Bethesda, MD
May 01
  
2023

A THICK PROBLEM

A 56-year-old man was diagnosed with immunoglobulin A (IgA) k multiple myeloma. Over the past year, he has been treated with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for six cycles, followed by autologous stem cell transplantation complicated by relapse with day +100 marrow showing a significant progression of disease with greater than 90% plasma cells. Now, he presents to the outpatient clinic with a diffuse rash comprising violaceous, reticular patches over bilateral lower extremities but sparing his groin and arms (Figure 1A). He reports a history of similar prior episodes occurring intermittently since his initial diagnosis. The rash is accompanied by blurry vision, headache, dizziness, and somnolence but no epistaxis or gait instability.

 Test  Value  Reference Range
 White blood cell (WBC)  2.06 × 103/µL  3.4 - 11.2 × 103/µL
 Hemoglobin  8.8 g/dL  11.7-5.3 g/dL
 Hematocrit  26.5%  35.0-45.0%
 Platelets  121 × 103/µL  150 - 450 × 103/µL
 Total protein  92 g/dL  81.0-100 g/dL
 M-SPIKE  3.0 g/dL  0.2-0.5 g/dL
 IgG  298 mg/dL  700-1600 mg/dL
 IgA  3331 mg/dL  70-400 mg/dL
 IgM  17 mg/dL  40-230 mg/dL
 Free kappa light chain  10.60 mg/dL  0.33 – 1.94 mg/dL
 Free lambda light chain  0.14 mg/dL  0.57 – 2.63 mg/dL 
 Free kappa/lambda ratio  75.71 mg/dL  0.26 – 1.65 mg/dL 
 Beta-2-microglobulin  4.8 mg/dL  0.9 – 1.7 mg/dL 

What is the best next step?

  1. Check serum viscosity
  2. Draw a serum viscosity and initiate plasma exchange
  3. Anticoagulation
  4. Systemic steroids

Answer: B

Symptomatic hyperviscosity is a medical emergency that requires prompt therapeutic plasma exchange based on the patient's neurologic symptoms and physical findings, such as blurry vision, headache, dizziness, and somnolence. The diagnosis is based on the classical triad of neurological deficits, visual changes, and/or mucosal bleeding rather than on the magnitude of the viscosity measurement. Red blood cell transfusions should be avoided before plasmapheresis since they might further increase serum viscosity.

Hyperviscosity syndrome results from the aggregation of light chains and increased blood viscosity in type I cryoglobulinemia1 and generally manifests when the blood viscosity exceeds 4.0 centipoises (cP). Still, the turnaround time is variable, so we shouldn't wait for the results before starting treatment2.

Anticoagulation is the mainstay of treatment for antiphospholipid syndrome, but it is not indicated for hyperviscosity.

High-dose steroids are often used in conjunction with cytoreductive therapy in the treatment of multiple myeloma1. The use of systemic steroids alone is not recommended in the treatment of type I cryoglobulinemia.

  1. Why so thick?

    2. The serum viscosity in this patient was too high to measure, with a recurrent comment from the lab explaining they were “unable to perform due to serum adhering to glass viscometer.” After the first plasma exchange, the viscosity was reduced to 3.0 cP. The second plasma exchange was performed the following day using one plasma-volume 5% albumin as replacement fluid. Post-procedure viscosity was measured at 1.7 cP with a resolution of the rash after plasma exchange (Figure 1B).

    Serum viscosity should be measured in patients with monoclonal gammopathy and signs or symptoms suggestive of hyperviscosity syndrome, such as blurring or loss of vision requiring a prompt retinal exam, or headache, vertigo, nystagmus, dizziness, tinnitus, sudden deafness, diplopia, or ataxia3 or non-neurologic symptoms such as epistaxis, bleeding gums, heart failure, and respiratory compromise. This is a true emergency that can lead to confusion, dementia, disturbances of consciousness, stroke, or coma4. Hyperviscosity symptoms rarely occur until serum viscosity reaches >4 cP (normal value is 1.5 cP relative to water5). However, it has been shown that serum viscosity and immunoglobulin protein concentration are not always linearly related, but serum viscosity can increase with IgM levels as low as 3g/dL and, more commonly, with IgM levels of 6 g/dL, IgA greater than 6g/dL, or IgG of 10g/dL5, even though serum viscosity measurement does not always correlate with clinical symptoms.

     

    Figure 1.A

    Figure 1. B

     

    Figure 1. A. Violaceous, reticular patches over the bilateral lower extremities. B. Resolution of the rash after plasma exchange. (Photos used with permission of NIH.

  2. Explain the rash

    3. Cryoglobulinemic vasculitis is an immune complex-mediated inflammation of blood vessels subclassified into different groups based on the pathogenicity and clinical manifestations (Table 2)7. Cutaneous findings can be present in all the subtypes ranging from livedo reticularis to necrotic ulcerations and may be accompanied by neuropathy, arthralgias, and renal disease. Type I cryoglobulinemia vasculitis can be a life-threatening condition associated with hyperviscosity syndrome and cold-induced acral necrosis8.

    Table 1. The Brouet classification criteria of cryoglobulinemia.

  3. When do we use therapeutic plasma exchange?

    4. Plasmapheresis is recommended as stand-alone or adjunctive first-line therapy (Category 1) for hyperviscosity in monoclonal gammopathies based on the Guidelines on the use of therapeutic apheresis in clinical practice6 (Table 1). Serum viscosity and serum protein electrophoresis (SPEP) should be performed before and after each plasmapheresis session. The serum viscosity should be repeated if there is an increase in serum M protein values, recurrence of symptoms, or signs of hyperviscosity.

    Table 2. Indications for Plasma Exchange based on the Guidelines from the American Society for Apheresis

          

    TTP, Thrombotic Thrombocytopenic Purpura; ANCA, antineutrophil cytoplasmic antibody; HUS, hemolytic-uremic syndrome; SLE, systemic lupus erythematosus

  4. Treat the underlying condition

    5. After the autologous transplantation, the patient received two cycles of carfilzomib, lenalidomide, and dexamethasone, which resulted in a partial remission (PR) lasting two months, followed by B-cell Maturation Antigen (BCMA) CAR T-cell therapy as part of the first in human trial with the resolution of his symptoms, including the rash and hyperviscosity, followed by rapidly progressive MM9. Currently, two FDA-approved anti-BCMA CAR T-cell therapies have demonstrated efficacy after four or more lines of therapy. The first anti-BCMA CAR T-cell was idecabtagene vicleucel (ide-cel), which showed an ORR of 81% and 63% VGPR or better10, and the second was ciltacabtagene autoleucel (cilta-cel), which showed an ORR of 97% with 67% stringent complete response11.

Conclusions

  • Symptomatic hyperviscosity is a medical emergency requiring prompt treatment with plasma exchange.
  • Red blood cell transfusion should be avoided as this might further increase the serum viscosity.
  • Do not wait for the serum viscosity results to initiate plasma exchange
  • Always treat the underlying condition and consider newer therapies in relapse refractory patients.

Acknowledgment: This article was edited by Jennifer Cooperrider, MD, and Pallawi Torka, MD

  1. Thomas C, Dommasch E. Reticular rash on the lower extremities. JAAD Case Rep. 2018;4(6):509-511. doi:10.1016/j.jdcr.2017.12.017
  2. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Seminars in Thrombosis & Hemostasis. 2003;29(5):467-71. doi:10.1055/s-2003-44554
  3. García-Sanz R, Montoto S, Torrequebrada A, et al. Waldenström macroglobulinaemia: presenting features and outcome in a series with 217 cases. British Journal of Haematology. 2001;115(3):575-82. doi:10.1046/j.1365-2141.2001.03144.x
  4. Pavy MD, Murphy PL, Virella G. Paraprotein-induced hyperviscosity. A reversible cause of stroke. Postgrad Med. 1980;68(3):109-12. doi:10.1080/00325481.1980.11715533
  5. Weaver A, Rubinstein S, Cornell, RF. Hyperviscosity syndrome in paraprotein secreting conditions including Waldenstrom Macroglobulinemia. Frontiers in Oncology. 2020;10:815. doi:10.3389/fonc.2020.00815
  6. Padmanabhan A, Connelly-Smith L, Aqui N, et al. Guidelines on the use of therapeutic Apheresis in clinical practice - evidence-based approach from the writing committee of the American Society for Apheresis: The Eighth Special Issue. Journal of Clinical Apheresis. 2019;34(3):171-354. doi:10.1002/jca.21705
  7. Davuluri S, Vaqar S. Cryoglobulinemic Vasculitis. StatPearls. StatPearls Publishing Copyright 2022, StatPearls Publishing LLC.; 2022.
  8. Terrier B, Karras A, Kahn JE, et al. The spectrum of type I cryoglobulinemia vasculitis: new insights based on 64 cases. Medicine (Baltimore). 2013;92(2):61-68. doi:10.1097/MD.0b013e318288925c
  9. Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128(13):1688-700. doi:10.1182/blood-2016-04-711903
  10. Brudno JN, Maric I, Hartman SD, et al. T Cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. Journal of Clinical Oncology. 2018;36(22):2267-2280. doi:10.1200/jco.2018.77.8084
  11. Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet. 2021;398(10297):314-324. doi:10.1016/s0140-6736(21)00933-8

Dr. Baez Sosa and Dr. West-Mitchel indicated no relevant conflicts of interest. Dr. Kochenderfer receives research funding and royalties from Kite (a Gilead Company) and Bristol Myers and royalties from Kyverna.

Citations