The efficacy of ibrutinib in the treatment of Richter syndrome

To the editor:

Richter syndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL).¹ Traditional anthracycline- or platinum-based chemotherapy is associated with complete response (CR) rates of <20%, and median survival after transformation is <12 months.² Although stem cell transplantation has been shown to improve outcomes in RS,³ fewer than 15% of patients are able to proceed to transplantation because of primary refractory disease.⁴

Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has shown remarkable efficacy in relapsed/refractory CLL.⁵ In a pivotal phase 1B/2 study of ibrutinib in 85 pretreated CLL patients, the overall response rate (ORR) was 71%. Despite this remarkable activity, 7 patients experienced RS at the time of progression.⁵ A subsequent phase 3 study (n = 391) comparing ibrutinib to ofatumumab in relapsed/refractory CLL found no difference in the rate of transformation to RS between treatment arms.⁶ Although some have interpreted these results to imply that ibrutinib has no activity in RS, we describe here the successful use of ibrutinib in patients with RS. The Mayo Clinic Institutional Review Board approved this study.

Table 1 shows the characteristics of 4 CLL patients who developed biopsy-proven DLBCL. The median time to transformation from CLL was 4.3 years (range, 3.1 to 11.4 years). In the only patient with available testing to determine clonality (patient 3), the DLBCL was clonally related to the underlying CLL. At the time of transformation, 3 patients were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a suboptimal response. Subsequent regimens in these 3 patients included rituximab, ifosfamide, carboplatin, and etoposide (R-ICE; n = 2); rituximab, cytarabine, cisplatin, and dexamethasone (R-DHAP; n = 1); and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (R-EPOCH; n = 1) with no response. Because of a lack of efficacious standard treatment options for refractory RS, ibrutinib was initiated in these 3 patients. The fourth patient, with heavily pretreated CLL harboring a 17p deletion, was felt to be a poor candidate for anthracycline-based therapy and began treatment with ibrutinib at the time of RS diagnosis.

Table 1.

Clinical characteristics of CLL patients diagnosed with RS

Patient	1	2	3	4
At the time of CLL diagnosis
Age, y	51	69	65	71
Sex	Female	Male	Male	Female
WBC ×109/L	57	4.9	28.4	9.6
Hemoglobin, g/dL	14	13.4	12.5	12
Platelet count ×109/L	370	197	155	218
β2 microglobulin, mg/dL	1.72	1.91	N/A	N/A
Rai stage	I	I	0	I
IGHV mutation status	Unmutated	Unmutated	Unmutated	Unmutated
IGHV4-39 gene usage	No	No	Yes	No
ZAP-70 expression ≥20%	Yes	Yes	Yes	Yes
CD49d expression ≥30%	No	No	No	Yes
CD38 expression ≥30%	No	No	N/A	No
FISH	del13q	Normal	Normal	del17p
CLL therapy	1. Rituximab, alemtuzumab, and β-glucan 2. Pentostatin, cyclophosphamide, and rituximab 3. Everolimus and alemtuzumab	1. Bendamustine and rituximab	1. Pentostatin, cyclophosphamide, and rituximab	1. Bendamustine and rituximab 2. Everolimus and alemtuzumab 3. Methylprednisolone and ofatumumab 4. Methylprednisolone and alemtuzumab
Time from last CLL therapy to RS diagnosis (months)	8	2	24	<1
At the time of DLBCL diagnosis
Age, y	62	74	68	74
WBC ×109/L	131.6	80.3	6.3	2.6
Hemoglobin, g/dL	10.8	9.2	14.5	9.8
Platelet count ×109/L	116	111	149	169
LDH, U/L (normal:111-222 U/L)	810	236	204	466
RS prognosis score4	1 (low)	2 (low-intermediate)	0 (low)	3 (high-intermediate)
Type of biopsy specimen	Bone marrow aspirate and biopsy	Core biopsy of T7 bone	Left neck excisional biopsy	Bone marrow aspirate and biopsy
Subtype (GCB vs ABC)	ABC	ABC	ABC	ABC
MYC rearrangement by FISH	Negative	Not done	Not done	Negative
EBV status	N/A	N/A	N/A	Negative
Initial therapy for RS	1. R-CHOP (2 cycles, PR) 2. R-ICE (1 cycle, PD) 3. Palliative therapy with methylprednisolone (twice per wk for 6 wks, SD)	1. R-CHOP (2 cycles, PD) 2. R-EPOCH (2 cycles, PD)	1. R-CHOP (2 cycles, PD) 2. R-ICE (3 cycles, PR) 3. R-DHAP (2 cycles, PD)	None
Ibrutinib dose, mg per day	420	140	420	420
Concomitant therapy with ibrutinib	Methylprednisolone 1000 mg Intravenously (twice per wk for 1 mo, once per wk for 1 mo, and once every 2 wks for 1 mo)	Methylprednisolone 1000 mg Intravenously (twice per wk for 2 mo)	None	None
Duration of ibrutinib therapy, months	8.5	3.7	2.8	10.8
Best response achieved	PR	Clinical benefit*	CR	PR
Status at most recent follow-up	Progressive DLBCL	Death	Ongoing complete remission	Progressive CLL

EBV, Epstein-Barr virus; FISH, fluorescence in-situ hybridization; IGHV, immunoglobulin heavy chain genes; LDH, lactate dehydrogenase; N/A, not available; PD, progressive disease; PR, partial response; SD, stable disease; WBC, white blood cell count; ZAP-70, zeta-chain–associated protein kinase 70.

^*Documentation of reduction in lymphadenopathy by physical examination. The patient died of pulmonary mucormycosis (diagnosed prior to ibrutinib initiation) after 15 weeks of therapy and prior to repeat imaging to allow for response assessment.

The median duration of ibrutinib therapy for these patients was 6.1 months (range, 2.8 to 10.8 months). All patients experienced an improvement in constitutional symptoms. According to the 2007 revised response criteria for malignant lymphoma,⁷ 1 patient had a CR and 2 patients had a partial response. The fourth patient was started on low-dose ibrutinib (140 mg per day) because of concomitant voriconazole use (metabolized through the CYP3A4 pathway); he subsequently died of pulmonary mucormycosis (diagnosed prior to ibrutinib initiation) after 15 weeks of therapy and prior to repeat imaging to allow for response assessment. The patient who achieved a CR is currently receiving ibrutinib (duration of therapy, 2.8 months). Of the 2 patients who achieved a partial response, 1 experienced progression of CLL after 11 months and the other experienced progression of DLBCL after 8 months of ibrutinib therapy. Ibrutinib was well-tolerated; no patient required discontinuation as a result of adverse events.

On the basis of gene expression profiling in de novo DLBCL, patients can be stratified according to the cell of origin of the tumor cells—germinal center B-cell (GCB) and activated B-cell (ABC) subtype.⁸ When treated with R-CHOP, de novo DLBCL patients with ABC subtype have a worse prognosis compared with those who have a GCB subtype. Constitutive activation of nuclear factor κB is observed in ABC DLBCL; this is in part related to chronic BCR signaling.⁹ A phase 2 study of ibrutinib in relapsed/refractory de novo DLBCL (n = 79) found an ORR of 23%. On subgroup analysis, the ORR was significantly higher in patients with the ABC subtype compared with those who had the GCB subtype (41% vs 5%, respectively; P = .007).⁹ A subsequent study of 23 de novo DLBCL patients treated with ibrutinib and R-CHOP showed a higher CR rate for patients with the ABC subtype compared with those who had the GCB subtype (100% vs 71%, respectively).¹⁰ Although the DLBCL tissue of >90% of patients with RS had the ABC subtype, the genetic profile of RS differs from de novo DLBCL,¹ and the potential mechanisms of response to ibrutinib observed in our patients are unknown.

Although the progression-free survival in these 4 patients was relatively short, it was nonetheless encouraging for a condition with a median survival of <12 months.² Our experience with these patients suggests that ibrutinib has potential as a novel therapeutic approach for patients with RS, and future trials investigating its use, either as monotherapy or in combination, appear warranted.

Authorship

Acknowledgments: This work was supported by National Institutes of Health, National Cancer Institute grants K23CA160345 (W.D.) and CA95241 (N.E.K.). S.A.P. is a recipient of the Mayo Clinic Department of Medicine Career Development Grant for Scholarly Clinicians. T.D.S. is a scholar of the Leukemia and Lymphoma Society.

Contribution: M.T., T.D.S., and S.A.P. designed the research, collected, analyzed, and interpreted data, and wrote the manuscript; T.G.C., W.D., D.B., and M.C. cared for the patients, analyzed data, and critically reviewed the manuscript; A.C.-K., J.F.L., G.S.N., and N.E.K. analyzed data and critically reviewed the manuscript; S.M.S. collected data for statistical analysis; S.L.S. analyzed data, conducted statistical analyses, and critically reviewed the manuscript; C.A.H. performed pathology review and critically reviewed the manuscript; and all authors approved the manuscript in its final format.

Conflict-of-interest disclosure: T.D.S. has received research funding from Genentech, GlaxoSmithKline, Cephalon, Hospira, Celgene, Jannsen, and Polyphenon E International. The remaining authors declare no competing financial interests.

Correspondence: Sameer A. Parikh, Division of Hematology, Department of Medicine, Mayo Clinic, 200 First St SW, Rochester, MN, 55905; e-mail: parikh.sameer@mayo.edu.