Rituximab combinations in hairy cell leukemia

Introduction

Hairy cell leukemia (HCL) and HCL variant (HCL-V) are very rare mature lymphoid B-cell disorders characterized by characteristic hairy cell morphology and specific immunophenotypic and genetic markers (1). However, the two diseases have different clinical courses and prognoses. In classic HCL, the presence of BRAF V600E somatic mutation is pathognomonic for diagnosis. While various treatment regimens exist for the two conditions, the management protocol for HCL-V is less standardized.

For many years, the PNAs, pentostatin (DCF) and cladribine (CDA), with or without rituximab, have been recommended for first-line treatment of classic HCL (2,3). When used in the first line, these agents induce long-lasting complete response (CR) in more than 70% of patients, with half demonstrating overall survival (OS) above 20 years. CDA and DCF achieve similar results; however, the two have never been directly compared (1,2). However, HCL-V is a more aggressive disease and does not respond well to PNA monotherapy.

This article discusses the role of rituximab in patients with classic HCL and HCL-V, used alone and in combination with PNAs and BRAF inhibitors. An initial search of Google Scholar and PubMed was made for articles in English published from 2000 to May 2026. The references from the chosen articles were reviewed to obtain additional relevant publications. In addition, a manual search was performed of conference proceedings from the last five years of the American Society of Hematology, American Society of Clinical Oncology and the European Hematology Association.

Rationale for rituximab combinations

Rituximab is characterized by rather low efficacy in relapsed HCL when used as a single agent. Nieva et al. report that among 24 HCL patients treated with 375 mg/m² rituximab per week for four weeks, only six (25%) responded, including three (13%) CR and three (13%) partial response (PR) (4). Despite this, rituximab increases sensitivity to PNA, and the two agents have demonstrated synergy ex vivo (5). This synergistic interaction supports the combined use of rituximab with PNAs for anti-CD20-directed therapy in the treatment of classic HCL. In clinical studies, rituximab was demonstrated to increase efficacy of the PNAs, CDA or DCF, in both frontline and relapsed settings, and against classic HCL and HCL-V (6-9). Rituximab has also been investigated in combination with fludarabine and bendamustine in relapsed HCL and HCL-V (10,11).

Rituximab plus PNA combinations

Several clinical studies have found the combination of CDA with rituximab to have high efficacy and an acceptable safety profile in both first-line treatment and relapsed settings. However, until recently, the combination of rituximab with DCF or bendamustine remained poorly investigated.

Rituximab plus DCF or bendamustine

In a recent issue of Blood, Schroeder et al. (12) report the results of a prospective phase 2 study of rituximab with either DCF (DCFR) or bendamustine (BR) in patients with classic HCL or HCL-V, who had multiply relapsed after standard therapies. The primary outcome of the study was overall response rate (ORR). The aim was to establish whether DCFR and BR can achieve an ORR 40% or higher. In total, 56 patients (43 with classic HCL; 13 with HCL-V) were included in the study. Patients were randomized to either DCFR (28 patients) or BR (28 patients) to decrease patient homogeneity. However, those randomized to DCFR at baseline had received fewer previous PNA courses (median 2 vs. 3, P=0.021) and demonstrated lower bone marrow (BM) HCL infiltration than those randomized to the BR group. The 3-month ORR was 89% for DCFR and 54% for BR. CR was 79% for DCFR and 32% for BR. Measurable residual disease (MRD)-free CR rates were 75% (DCFR) and 32% (BR). MRD negativity in peripheral blood (PB) flow cytometry MRD was also higher in the DCFR group (71%) than in the BR group (29%). The ORR difference between DCFR and BR by 6 months was lower than by 3 months (93% vs. 86%, respectively) and CR 79% vs. 71%, respectively. Both arms demonstrated ORR >65% and the study met the primary end point. Median disease-free survival (DFS) was not reached for DCFR but 45 months for BR, and median MRD-free survival was 142 (DCFR) and 25 months (BR). PFS was also longer for DCFR (141 months) than for BR (50 months) (12). The influence of previous lines of PNA therapies on treatment results were also investigated. Patients with ≤2 previous lines of PNAs had longer DFS than patients with ≥3 previous PNAs lines (138 vs. 51 months) longer MRD-free survival (138 vs. 52 months), longer PFS (141 vs. 58 months) and longer time to the next treatment (TTNT) (117 vs. 53 months). However, in both the DCFR and BR arms, similar PFS and DFS were observed. TTNT values were observed for patients with ≤2 previous PNAs and ≥3 previous PNAs (12).

In the total group, ≤80% baseline BM HCL infiltration was noted in 30 patients, and ≥85% in 26 patients. In addition, patients with lower baseline BM infiltration (≤80%) exhibited better results than those with higher levels (≥85%), including CRs (25% vs. 17%) and MRD-free CRs (22% vs. 16%). Patients with HCL/HCL-V and BM infiltration ≥85% achieved better results in the DCFR group than the BR group, including median MRD-free survival after DCFR (138 months) and BR treatments (18 months). When comparing the ≤2 previous PNAS and ≥3 previous PNAs subgroups, and the ≤80% BM infiltration and ≥85% BM infiltration subgroups [95% confidence intervals of hazard ratios (HRs) above 1 for both comparisons], similar PFS and TTNT were achieved by DCFR and BR. However, each group only included four patients (12).

Post hoc comparisons revealed even more differences between DCFR and BR treatment when the analysis was limited to 41 patients with classic HCL. In this group, among patients with ≤2 previous PNAs MRD-free survival, longer PFS and TTNT were noted in the DCFR arm than the BR arm. The differences were greater in patients with ≤80% BM infiltration. In this study, eight patients in the DCFR group had previously received DCF (n=6) or DCFR (n=2). Median PFS after DCFR given on protocol was 47 months; this value may have been longer that that observed for last DCF(R) before enrollment (18 months; HR, 0.41) due to the addition of rituximab (12).

Per study protocol, patients progressing on DCFR or BR could cross over to the alternate treatment six months or more after the last dose of DCFR or BR, or ≥2 months after disease progression (PD). Crossover treatment was used in eight patients after BR and nine patients after DCFR. Among patients crossing over from BR to DCFR, response was achieved in four patients (50%), all of which were CRs, including three (38%) MRD-free CRs. Nine patients crossed over from DCFR to BR, and seven patients (78%) responded, including six (67%) CR and one PR. MRD-free CR was achieved by three (33%) (12).

As expected, the most frequent hematologic adverse events (AEs) in patients treated with DCFR were leukopenia (57%) and lymphopenia (64%). In contrast, in the BR group, leukopenia was observed in 54% of patients and lymphopenia in 82%. Thrombocytopenia, neutropenia, febrile neutropenia and anemia were more common in the BR group (29–68%) than DCFR (18–39%). Infections occurred in 21% of the DCFR group and 18% of the BR group. Taken together, similar AEs were observed between patients treated with DCFR and those with BR. However, DCFR may have produced deeper and more durable responses than BR, and these results may influence treatment decisions in relapsed HCL/HCL-V. It should also be considered that the outcomes may have been influenced by baseline imbalances between treatment arms, prior PNA exposure and BM infiltration, as well as small subgroup sizes. Therefore, any claims regarding the superiority of either method should be made with caution.

The above study by Schroeder et al. (12) is the first randomized trial to compare two purine analogs (DCF and bendamustine) combined with the CD20 monoclonal antibody rituximab in relapsed patients with classic HCL and HCL-V. Its findings include important randomized data supporting the ongoing role of chemoimmunotherapy, particularly in HCL-V and non-BRAF V600E disease; they also highlight the need for further comparative studies in the evolving era of targeted therapy. These findings were similar to those achieved for both combinations in previous studies (9,11). In a pilot study of 12 HCL/HCL-V patients with ≥2 prior therapies by Burotto et al. (11), BR treatment achieved ORR in 100% and CR in seven (58%) (Table 1).

A retrospective analysis by Else et al. (13) analyzed eight patients who received DCF or CDA combined with rituximab concurrently (six patients) or sequentially (two patients). All patients responded, including seven (87.5%) with CR, all of whom were MRD-negative. This CR rate was significantly higher than that achieved by these patients after first-line treatment with a single-agent PNA (P=0.02). Treatment was well tolerated, with only one AE (asymptomatic eosinophilia), which resolved spontaneously after discontinuation of rituximab. Additional follow-up studies may help to determine whether DCFR or BR should be considered as first-line treatment, particularly in HCL-V.

Rituximab in combination with CDA

CDA is used in both TN and R/R HCL/HCL-V patients, and even more frequently than DCF or bendamustine. Its influence on malignant cells is further sensitized by rituximab, indicating that the combination might improve response in HCL and HCL-V. Indeed, several studies have found the combination of CDA with rituximab to be more effective than CDA alone or rituximab alone (Table 1) (7,14-16).

Furthermore, in a first-line setting, CDA combined with concurrent rituximab (CDAR) is more effective than delayed rituximab administration. Chihara et al. (7) describe a randomized study in TN HCL patients. One group was treated with first-line CDA (0.15 mg/kg days 1–5) with concurrent rituximab (CDAR) for eight weekly doses of 375 mg/m², begun either day 1. The other group received CDA monotherapy with delayed rituximab, i.e., starting six months or later after detection of MRD in PB. Negative MRD at four weeks was observed in 62% of patients treated with CDAR and 9% of patients treated with CDA alone (P<0.0001). At six-month follow-up, the CR rates was 100% (CDAR) and 88% (CDA; P=0.11). The respective MRD-free CR rates were 97% vs. 24% (P<0.0001) in BM and 100% vs. 50% (P<0.0001) in PB. At 96 months median follow-up, MRD negativity was noted in 94% (CDAR) and 12% (CDA and delayed rituximab). However, 12 patients in the delayed rituximab arm were MRD-free after a median 78 months from the last delayed rituximab treatment. Hence, concurrent CDAR appears superior to CDA and delayed rituximab in eradicating MRD. CDAR was more toxic to platelets than CDA alone as the prevalence of grade 3/4 thrombocytopenia was 59% (CDAR) compared to 9% (CDA; P<0.0001), and platelet transfusions without bleeding was noted in 35% (CDAR) compared to 0% (CDA; P=0.0002).

While patients with HCL-V respond poorly to PNA monotherapy compared to classic HCL, CDAR improves response rates and long-term results in this group. Chihara et al. (16) treated 20 HCL-V patients with CDAR, including 12 previously treated with 0 to 1 prior courses of CDA and/or rituximab and eight TN patients (16). The CR rate from CDAR was 95% and 16 patients (80%) were MRD negative. The median duration of MRD-negative CR was 70.1 months. In another phase 2 trial, CDA plus immediate rituximab was evaluated in 10 patients with HCL-V, nine with TN and one with R/R disease (8). CDA was given at a dose of 0.15 mg/kg daily for five days and rituximab at a dose 375 mg/m² weekly for eight weeks. Nine (90%) patients had achieved CR by six months, and eight remain free of MRD at 12 to 48-month follow-up. Treatment was well tolerated with no dose-limiting toxicities, but most patients received short-term steroids to prevent and treat rituximab infusion reactions. The combination of CDA with rituximab is the standard of care for initial treatment of progressive HCL-V (2). In patients with a severe performance status or active uncontrolled infection, PNA-free options with BRAF inhibitors, rituximab, obinutuzumab, or interferonα are recommended (2). Interferon-α and rituximab are also recommended in HCL patients who require treatment during pregnancy (17).

BRAF inhibitors ± rituximab combinations

Following the recent discovery of the BRAF V600E mutation in classic HCL, studies have evaluated the therapeutic potential of the BRAF inhibitors vemurafenib and dabrafenib, with and without anti-CD20 monoclonal antibodies, particularly in R/R patients (Table 2) (18-25). It was found that the combination of BRAF inhibitors with rituximab is effective in HCL patients, even those heavily pretreated with PNAs and moxetumomab pasudotox (20). Vemurafenib alone led to a response in 91% of patients, with 35% of patients exhibiting a CR (18). However, the median relapse-free survival was only nine months after the end of treatment (Table 2).

In another study, 21 HCL patients were treated with vemurafenib with different dosing regimens (240 to 1,920 mg/day) and a median treatment duration of 90 days (Table 2) (19). CR was observed in 6 of 15 (40%) evaluable patients and median event-free survival (EFS) was 17 months. Importantly, in six patients, retreatment with vemurafenib induced a similar response. In addition, doses 480 mg/day completely abrogated extracellular signal-regulated kinase phosphorylation.

Adding rituximab to vemurafenib (VR) significantly improved treatment results in heavily-pretreated classic HCL (Table 2) (20,21,25). In 30 patients with HCL, with a median of three previous lines of treatment, this combination obtained CR in 26 (87%) patients including ten refractory to chemotherapy, five refractory to rituximab and seven previously treated with single-agent vemurafenib (18). Among this group, 17 (65%) patients were MRD negative, PFS was 78% at a median follow-up of 37 months and relapse-free survival was 85% at a median follow-up of 34 months (20).

Real-life data has recently been published from other studies using VR in patients relapsed after CDA or DCF (Table 2) (22-24). An Italian study examined 54 HCL patients with BRAF V600E mutation (52 R/R and two TN) were treated with VR. The number of prior treatments ranged from 0 to 11 (median two treatments). CDA was used in 47 (87%) cases, previously treated with DCF in 17 (31%), interferon in 15 (28%), rituximab in 16 (30%), and BRAF inhibitor-based therapy in five. Similar to the prospective study, a high CR rate (86%) was observed, including an MRD-negativity rate of 62% and 24-month PFS of 90%. The toxicity was mostly low grade, manageable and reversible. Most common AEs were infusion reactions related to rituximab, cutaneous rash, arthralgia, asymptomatic liver and pancreatic laboratory abnormalities.

A retrospective study in 11 French centers by Tauveron-Jalenques et al. (23) examined 27 HCL patients who received BRAF inhibitors combined with rituximab (Table 2). Twenty-two (81.5%) patients were R/R and five (18.5%) were TN. The R/R patients had received a median of two prior therapies; of these, 22 (81.5%) had received PNAs, 10 (37%) rituximab, four (14.8%) with moxetumomab pasudotox and four vemurafenib as a single agent. Twenty-two (81.5%) patients received vemurafenib and rituximab and five (18.5%) received dabrafenib plus rituximab. The ORR was 100%, including 7/11 (63.6%) CR and 4/11 (36.3%) PR. Hematologic CR was confirmed in 14 of 16 patients (87.5%) who only received PB evaluation. Among the seven BM-confirmed CRs with available BM MRD data, undetectable MRD was confirmed in four patients. Median follow-up from treatment initiation was 18 months. Eighteen-month PFS was 82.1% and OS 94.1%.

A Turkish retrospective study evaluated nine patients with R/R HCL (24). Patients were treated with vemurafenib alone or vemurafenib with rituximab. They had previously been treated with rituximab monotherapy, splenectomy, CDA monotherapy, DCF, rituximab plus CDA, ibrutinib, pegylated interferon or interferon-α. Seven patients achieved a CR and two PR.

The same combination was used in four patients which had relapsed after several lines of therapy, including CDA with or without rituximab and moxetumomab pasudotox (21). Vemurafenib was used mostly at the low dose of 240 mg twice daily for 16 weeks; this was administered concurrently with rituximab at standard doses. Two patients obtained MRD-negative CR with hematologic responses lasting longer than 38 months from the end of treatment for one patient, and 13 months for the other. A third patient achieved PB normalization but was lost from observation after 18 months. The fourth patient died directly after treatment with vemurafenib and rituximab due to infection and multi-organ failure; in this case, it was too early to verify the response to vemurafenib. These results indicate that combining vemurafenib with rituximab improves the prognosis of heavily-pretreated HCL patients. The treatment does not induce myelotoxicity and may be safe in immunosuppressed and deeply-neutropenic patients.

Treatment sequencing

Treatment of HCL is indicated in symptomatic patients, mainly due to splenomegaly, constitutional symptoms and/or significant cytopenia. The PNA CDA and DCF, with or without rituximab, are highly effective in classic HCL and are considered as first-line treatment in most previously-untreated patients (1,2). The addition of rituximab to CDA in frontline treatment improves response in HCL and HCL-V at the expense of an elevated risk of AEs.

In the author’s opinion, in cases of classic HCL, CDA should be used alone in first-line treatment and CDAR in relapsed patients; however, CDAR can be considered in younger and fitter patients with life expectancy longer than 15–20 years (26). Relapsed patients treated with CDAR after CDA monotherapy have demonstrated similar PFS, relapse rates and survival to those of patients treated with front-line CDAR (6). In patients with HCL-V, treatment with PNAs alone is less effective, and it is recommended that CDAR be used as initial therapy. In cases of HCL with active infections or severe cytopenia, treatment can present a challenge because these drugs are both immuno- and myelosuppressive. Instead, it is recommended that they are replaced with low-dose DCF or BRAF inhibitors, with or without rituximab or interferon-α (1,2). Severe neutropenia and infection are common events in HCL, and the use of PNAs, especially CDA, should be delayed or avoided; in these patients, the use of anti-CD20 therapy with a BRAF inhibitor combined with a granulocyte growth factor should be considered.

Classic R/R HCL can be retreated with PNAs, with or without rituximab. Also, BRAF inhibitors, particularly vemurafenib plus rituximab, possess high efficacy in classic HCL. DCFR and BR also remain useful regimens, especially in patients with HCL-V or non-BRAF V600E mutation, who cannot be treated with BRAF inhibitors (27). CDAR, DCFR or BR provide a rapid response and may be better choices than venetoclax or BTK inhibitors used as single agents (6,24). Vemurafenib, as a single drug or in combination with rituximab, appears to be a promising, safe, targeted therapy that may be particularly suitable for long-term use.

Future directions

The use of PNA analogues to treat classic HCL is one of the most spectacular achievements in oncohematology of the last 30–40 years. Despite this, HCL remains incurable, and in many cases, the patient may be refractory to the agents or suffer early relapse, particularly with HCL-V. In HCL-V, it is recommended to use PNA-rituximab combination therapy, as this has been found to be more effective than PNAs alone. Another option in classic HCL, particularly in R/R patients, is the use of the BRAF inhibitors, vemurafenib and dabrafenib.

Due to its rarity, further progress in HCL therapy requires multi-center studies of novel agents, particularly those known to be effective in other B-cell malignancies, such as BTK inhibitors, BCL-2 inhibitors and cellular therapies like chimeric antigen receptor T (CAR-T) and bispecific antibodies (27-30). Furthermore, to support progress in HCL management, further efforts should be made to optimize MRD assessment, and include it in novel drug development and routine clinical practice (31). Most importantly, to improve the chance of developing a curative treatment, it is imperative to gain a better understanding of the biology of HCL.

Conclusions

HCL and HCL-V are distinct, chronic splenic B cell lymphomas with similar clinico-pathological symptoms but different genetic abnormalities, prognoses, and treatments. The introduction of PNAs and CD20 antibodies in first-line treatment has improved the survival and the relapse-free survival of patients with classic HCL, and many now can enjoy near normal life spans. Sequential or concurrent chemoimmunotherapy with PNAs and CD20 antibodies may also be considered in TN classic HCL to achieve longer and deeper response, and is recommended in HCL-V. Treatment with PNA-based regimens can also achieve durable remission in relapsed and refractory HCL, and this can be further enhanced with the use of novel agents and rituximab combinations. Prospective trials, particularly with novel targeted therapies, are needed to further improve outcomes and ultimately enable the cure of patients with these rare diseases.

Acknowledgments

I thank Edward Lowczowski, a native English speaker from the Medical University of Lodz, Poland, for language assistance.

Footnote

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-26-0073/prf

Funding: None.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-26-0073/coif). The author has no conflicts of interest to declare.

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