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Richter’s transformation

A 75-year-old woman with a 7-year history of chronic lymphocytic leukemia (CLL), previously treated with fludarabine and cyclophosphamide, was admitted with weight loss, night sweats, and fevers. She had widespread low-volume lymphadenopathy and a palpable spleen but no new large nodal mass. The complete blood count showed hemoglobin 112 g/L, white blood cell count 11.92 × 109/L, lymphocytes 10.73 × 109/L, and platelets 67 × 109/L. Two weeks later, her white cell count had risen to 92 × 109/L, and platelet count had fallen to 22 × 109/L. Her LDH was 3859 U/L. She died shortly thereafter. | Richter transformation can occur in up to 10% of patients with CLL. It is heralded by a sudden clinical deterioration characterized by a rapid increase in lymphadenopathy, extranodal involvement, splenomegaly, worsening “B” symptoms, and rapid rise in LDH. The prognosis is very poor and therapeutic options are limited. | Richter transformation in peripheral blood. (2010). Blood, 115(22), 4330–4330. https://doi.org/10.1182/BLOOD-2009-06-192153

Richter’s syndrome (RS), aka Richter’s transformation, is a rapid transformation of B cell chronic lymphocytic leukaemia (CLL) or hairy cell leukaemia into a histologically proven aggressive lymphoma.

  • 5% of CLL cases
  • Transformation rate: 0.5–1%/year
  • Median time from diagnosis to RT: 2-4 years

Types of lymphoma due to RT:

  • Diffuse large B-cell lymphoma (M/C)
    • Variety of non-Hodgkin lymphoma refractory to treatment with bad prognosis
  • Hodgkin’s variant
  • Composite lymphoma
  • Interdigitating dendritic cell sarcoma (very rare)

History

The development of lymphoma in CLL was originally reported by Maurice N. Richter in 1928, and the term “Richter’s syndrome” was coined in 1964 by Lortholary et al to describe the development of malignant reticulopathy in 14 patients with CLL.

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Maurice N. Richter (1959): New York University. College of Medicine. New York City

Aetiology

Risk factors:

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Germline genetic characteristics, clinical characteristics, biologic and genetic features of the CLL B-cell clone, and therapy for progressive CLL influence the risk of RS (data on the role of CLL therapy are controversial, with some studies suggesting they are contributory to the development of RS in CLL patients, and other studies suggesting not. ZAP-70, ζ-associated protein-70) | Parikh, S. A., Kay, N. E., & Shanafelt, T. D. (2014). How we treat Richter syndrome. Blood, 123(11), 1647–1657. https://doi.org/10.1182/blood-2013-11-516229

Pathophysiology

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Pathways of Development of Richter’s Transformation in Chronic Lymphocytic Leukemia (CLL) | Rossi Et Al. (2019) Richter’s Transformation in Chronic Lymphocytic Leukemia: Page 2 of 3 | Cancer Network. Retrieved May 07, 2019, from https://www.cancernetwork.com/chronic-lymphocytic-leukemia/richters-transformation-chronic-lymphocytic-leukemia/page/0/1

Clinical features

Can appear suddenly, even in patients who were in remission.

  • Fever (without infection)
  • Lymphadenopathy (rapidly progressing/enlarging)
  • Hepatosplenomegaly

Diagnosis

  • ↑ Serum lactate dehydrogenase (LDH)
    • 8% CLL cases have elevated LDH levels while >50% of CLL patients with Richter’s transformation will have elevated LDH levels.

Imaging

PET-CT:

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a PET scan showing extensive lymphadenopathy in the pelvis and abdomen consistent with the diagnosis of RT. b PET scan after 3 cycles of combination chemotherapy with rituximab-ifosfamide/carboplatin/etoposide (R-ICE). c PET scan showing excellent metabolic response with virtual complete interval resolution of the previously noted extensive FDG avid lymphadenopathy with ibrutinib therapy. | Master, S., Leary, C., Takalkar, A., Coltelingam, J., Mansour, R., Mills, G. M., & Koshy, N. (2017). Successful Treatment of Richter Transformation with Ibrutinib in a Patient with Chronic Lymphocytic Leukemia following Allogeneic Hematopoietic Stem Cell Transplant. Case Reports in Oncology, 10(2), 534–541. https://doi.org/10.1159/000477338

Histopathology

Bone marrow biopsy:

Combined morphologic-FISH analysis:

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Combined morphologic-FISH analysis shows MYC rearrangement in small mature chronic lymphocytic leukemia cells and large prolymphocytes: (a, b): Wright-Giemsa stain of bone marrow aspirate smear; (c, d): FISH analysis with MYC break-apart probe on the same slides as (a) and (b). Arrow head: granulocyte and myelocyte; arrow: prolymphocytes; others are small CLL cells. | The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia. Li Y, Hu S, Wang SA, et al. Mod Pathol. 2016;29:444–451.

Management

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Schematic approach to a patient with suspected RS: Signs and symptoms suspicious for transformation include: B-type symptoms (weight loss, night sweats, and fever), rapid enlargement of lymph nodes or spleen, hypercalcemia, and increased lactate dehydrogenase. ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine. | Parikh, S. A., Kay, N. E., & Shanafelt, T. D. (2014). How we treat Richter syndrome. Blood, 123(11), 1647–1657. https://doi.org/10.1182/blood-2013-11-516229
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Management of CLL patients with Richter transformation to diffuse large B-cell lymphoma in which no clinical trial is available: The simplest way to determine clonality is to compare the κ and λ light chain restriction between the CLL and the DLBCL. For patients in whom they are different (eg, κ light chain–restricted CLL and λ light chain–restricted DLBCL), DLBCL is clonally unrelated to the CLL. In those patients in whom the light chain restriction is the same, clonality is determined either by sequencing the IGHV V-D-J genes or by comparing immunoglobulin gene rearrangements between the CLL and DLBCL tissue samples. Consider a platinum-containing regimen for patients with prior anthracycline exposure. We generally administer pegfilgrastim to all patients undergoing intensive chemotherapy for RS. Age, functional status, comorbidities, and chemosensitive disease determine if patient is a suitable candidate for stem cell transplantation. Both autologous and allogeneic SCT may play a role in improving durability of remission. Factors that influence whether autologous or allogeneic is preferred strategy include patient age/fitness, availability of a suitable donor, the presence or absence of del(17p13.1)/TP53 mutation, and whether the patient’s underlying CLL is purine analog refractory. An allogeneic stem cell transplantation is preferred in patients with clonally related RS as well as those with clonally unrelated DLBCL whose underlying CLL is purine analog–refractory or harbors the del(17p13.1)/TP53 mutation. §§Autologous SCT is our preferred approach for patients with clonally unrelated DLBCL whose CLL does not harbor the del(17p13.1)/TP53 mutation. An autologous SCT may be considered in select patients with clonally related RS who do not have a suitable donor or who are not candidates for allogenic SCT based on age/comorbidity. The primary intent of autologous SCT in such cases is to eradicate the DLBCL component rather than simultaneously treat the underlying CLL. At this time, outside of a clinical trial, there are no specific recommendations for a postremission strategy among patients with clonally related RS who demonstrate a response to induction chemotherapy and are not considered candidates for SCT. | Parikh, S. A., Kay, N. E., & Shanafelt, T. D. (2014). How we treat Richter syndrome. Blood, 123(11), 1647–1657. https://doi.org/10.1182/blood-2013-11-516229

Intensive chemotherapy regimens and chemo-immunotherapy regimens

Have improved response rates but have not clearly affected long-term outcomes.

  • R-HyperCVAD [rituximab + hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone]
  • OFAR [oxaliplatin (Eloxatin), fludarabine, and ara-C])

Allogeneic stem-cell transplantation:

As postremission therapy and/or salvage therapy. Unfortunately, most patients with RS do not achieve adequate response to induction to proceed to transplant. 

Prognosis

Generally poor, with a median survival of about 10 months.

  • Hodgkin’s lymphoma variant of Richter’s carries a better prognosis than the predominant diffuse large B-cell lymphoma type, but a worse prognosis than a de novo case of Hodgkin’s.

RS prognosis score (based on 5 characteristics):

  1. Eastern Cooperative Group (ECOG) performance status (>1)
  2. Serum LDH  (≥1.5 × normal)
  3. Platelets (<100 × 109/L)
  4. Tumour size (>5 cm)
  5. Number of prior therapies for CLL (>1)

Patients assigned 1 point for each adverse feature and then grouped into 1 of 4 risk categories based on their total score:

  • Low risk (score 0-1, median survival: 1.1 years)
  • Low-intermediate risk (score 2, median survival: 0.9 years)
  • High-intermediate risk (score 3, median survival: 0.3 years)
  • High risk (score 4-5, median survival: 0.1 years)

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