Page 218 - Haematologica May 2022

Case Reports
Zanubrutinib, rituximab and lenalidomide induces deep and durable remission in TP53-mutated B-cell prolymphocytic leukemia: a case report and litera- ture review
B-cell prolymphocytic leukemia (B-PLL) is a rare lym- phoid neoplasm accounting for approximately 1% of all cases of lymphocytic leukemia. In this disease, TP53 abnormalities are found in more than half of the cases and about 50% of patients have MYC abnormalities (rearrangement and/or increased copy number). Similar to chronic lymphocytic leukemia (CLL), shortened sur- vival in B-PLL is associated with TP53 mutations. Due to the rarity of this disease, most therapeutic approaches have been executed according to CLL guidelines. Specifically, Bruton’s tyrosine kinase (BTK) inhibitors show significant efficacy in CLL patients with 17p dele- tion/TP53 mutation. However, little is known about the treatment outcome of BTK inhibitors (BTKi) in B-PLL. Here, we report for the first time the efficacy of a next- generation BTKi, zanubrutinib, combined with rituximab and lenalidomide (ZR2), in a B-PLL patient with TP53 and MYC abnormalities.
A 52-year-old man visited our hospital in October 2020 with a 3-year history of high white blood cell (WBC) count and splenomegaly. Physical examination revealed multiple palpable lymphadenopathies (bilateral neck, bilateral supraclavicular, bilateral axillary, and bilateral inguinal regions) and massive splenomegaly (19 cm below left costal margin). Complete blood count showed an elevated WBC count of 31.4×109/L, hemoglobin con- centration of 134 g/L and platelet count of 87×109/L. Peripheral blood (PB) smear revealed 88% of prolympho- cytes. Serum lactate dehydrogenase (313 U/L, normal <250 U/L) and β2-microgloubulin (5.42 mg/L, normal <2.8 mg/L) were elevated. The concentration of serum monoclonal immunoglobulin G (IgG) with λ light chain, detected by immunofixation electrophoresis, was 2.8 g/L. Abdominal ultrasound showed splenomegaly (24.6×8.2 cm, 19 cm below left costal margin). 18F-fluorodeoxyglu- cose (18F-FDG) positron emission tomography/comput- ed tomography (PET/CT) scan showed slightly increased FDG metabolism of lymph nodes in the neck, axilla, mediastinum, retroperitoneum, abdominal cavity, pelvic cavity, and groin (the largest diameter is 1.5 cm, SUVmax 4.3). It also demonstrated increased FDG metabolism of spleen (SUVmax 4.3). A bone marrow (BM) biopsy showed B-PLL representing 75% of the marrow cells. Flow cytometry showed these cells were positive for CD19,
CD79a, FMC7, CD81, CD22, CD20, and restricted mon- oclonal λ light chain, together with weakly positive for CD23, CD25, CD38, CD200, surface immunoglobulin M (sIgM), and negative for CD5, CD10, CD43, CD71, CD123, CD103, CD11c, surface IgD (sIgD) and κ light chain. These cells were stained negative for cyclin D1. Immunoglobulin heavy chain (IGH) somatic hypermuta- tion analysis showed mutated IGH variable region genes. Cytogenetics revealed t(8;14) and fluorescense in situ hybridization (FISH) showed MYC gene rearrangement without CCND1/IgH rearrangement which exclude the diagnosis of mantle cell lymphoma (MCL). Molecular studies showed mutations in both MYC and TP53 genes. Based on cell morphology, histopathology, immunohisto- chemistry, genetic analysis, and clinical features, the patient was diagnosed as B-PLL.
This patient was treated with ZR2 regimen (zanubruti- nib, 160 mg twice daily on day 1-21; lenalidomide, 25 mg once daily on day 1-14; rituximab, 375 mg/m2 on day 1) every 28 days. Following the initiation of ZR2 treatment, the patient experienced resolution of splenomegaly, with the WBC decreasing from 31.4×109/L to 8.43×109/L after one cycle treatment (Table 1). Minimal residual disease (MRD) negative complete remission (CR) (by PB flow cytometry and PET-CT scan) was achieved after four cycles of ZR2 treatment, with monoclonal IgG disappear- ance. The patient refused allogeneic hematopoietic stem cell transplantation (HSCT). After 6 cycles of ZR2 treat- ment, MRD negative CR was further verified by PET-CT and flow cytometric analysis of bone marrow aspirates. Subsequently, the patient received two cycles of ZR (zanubrutinib, 160 mg twice daily on day 1-21; ritux- imab, 375 mg/m2 on day 1) as consolidation therapy. Thereafter, zanubrutinib and lenalidomide (zanubrutinib, 160 mg twice; lenalidomide, 25 mg once daily on day 1- 14; administered every 28 days) were used as mainte- nance therapy. Moreover, the patient has been well and has remained in sustained MRD-negative CR for 12 months by now. The most hematological adverse events were common grade 1-2 neutrophil count decrease, which can be recovered in a few days, and no significant non-hematological adverse events such as nausea and fatigue were noted.
There are an estimated 120 new cases of B-PLL per year in the United States and prospective clinical trials are currently not available. There is neither clear expert con- sensus nor are there guidelines for the treatment of B- PLL, and the treatment according to CLL are frequently recommended as upfront therapy. In patients with TP53 mutation and/or deletion, alemtuzumab was an effective
Table 1. Treatment course. Time point
Response evaluation
Baseline Cycle 1
Cycle 2 Cycle3
Cycle4 Cycle 5
Cycle 6 Cycle7
Cycle8
Spleen,
lymph node 88% 75% N/A N/A N/A
WBC count (x109/L)
31.4 ZR2 8.43
ZR2 4.23 ZR2 3.52
ZR2 3.06 ZR2 3.69
ZR2 3.04 ZR 4.62
ZR 2.41
ALC (x109/L)
27.6 5.10
2.67 1.0
1.0 1.27
1.29 1.59
0.83
LDH (U/L)
313 245
362 255
192 184
196 220
206
PET/CT PB MRD BM MRD
N/A N/A
CR N/A
N/A N/A
N/A
14.26% N/A NEG N/A
NEG N/A NEG N/A
N/A NEG N/A N/A
NEG N/A
WBC: white blood cell count; ALC: absolute lymphocyte count; LDH: lactate dehydrogenase; PB: peripheral blood; BM: bone marrow; MRD: measurable residual disease; N/A: not available; NEG: negative; CR: complete remission; ZR2: zanubrutinib+lenalidomide+rituximab; ZR: zanubrutinib+rituximab.
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