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After decades of quiescence, the therapeutic landscape of hairy cell leukemia is undergoing rapid evolution.
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy that accounts for 2% of all leukemias, translating to approximately 1000 new cases reported each year in the United States.1 In HCL, the bone marrow, spleen, and liver are infiltrated by mature B cells, characterized by ample cytoplasm with thin surface projections (giving rise to the descriptive name “hairy” cell leukemia)2 and a specific surface immunophenotype (coexpression of CD103, CD25, CD123, and CD11c).3,4
Although HCL is considered incurable in most patients,5 effective treatments are available. For the past 3 decades, purine nucleoside analogues (PNAs), including pentostatin and cladribine, have been the mainstay for first-line treatment for patients with HCL.1 PNAs revolutionized HCL treatment,6 with retrospective studies showing that PNAs induce complete remission (CR) rates of 70% to 90%, with treatment-free intervals of more than 10 years.2,6,7 In an analysis of 121 patients treated with PNA, interferon α, or splenectomy, progressively lower CR rates were observed with each successive line of treatment, ranging from a 77% CR rate with first-line treatment to 50% with fifth-line treatments.8
Despite broadly high CR rates with the use of PNA-based therapy, relapse does occur in a significant proportion of patients.5,6 For instance, in a long-term follow-up study in which cladribine was used as first-line treatment, the relapse rate in initial responders was 37%, with a median time to relapse of 42 months.9,10 Another long-term follow-up study of 233 patients with HCL, treated initially with pentostatin or cladribine, reported that 42% and 38% of patients who received pentostatin or cladribine as first-line treatments relapsed, respectively.2 Overall, roughly half of the patients in this study relapsed within 16 years and required additional therapy.2 It has been found that the time to relapse from CR is also shorter in younger patients.11,12 Additionally, PNAs are associated with severe infection risk13,14 and with increased risk of cumulative toxicity with each additional round of treatment.15
Retreatment with a PNA, especially with an analogue that was not used in first-line treatment, is an option for subsequent lines of treatment for relapsed/refractory (R/R) disease.5 However, progressively shorter durations of remission with additional lines of treatment and myelosuppression risk with PNAs have generated an unmet clinical need in patients with R/R disease.15 Recent efforts have focused on targeted or immunotherapy agents for treating HCL, including agents for relapsed HCL and HCL refractory to treatment with PNAs.5,6 The remainder of this article reviews advances in the treatment of R/R HCL.
BRAF and MEK Inhibitors
Although the specific clinicopathological features of HCL, including the characteristic morphology of the leukemic cells, were first described more than 50 years ago, genetic profiles of HCL cells and the distinguished genetic and molecular alterations have been outlined more recently.16 Most HCL cases (80%-90%) are characterized by somatic hypermutation in the immunoglobulin heavy chain variable region (IGHV) gene, with the frequency of unmutated IGHV being much lower in classic HCL compared with variant HCL (HCLv).17
Mutations in BRAF, a kinase-encoding proto-oncogene, have been considered disease-defining genetic lesions in HCL, being clonally and somatically present at diagnosis in almost all patients across the entire clinical spectrum of the disease.16 A single somatic, clonal point mutation in BRAF was first identified via whole-exome analysis of an index patient with HCL.18 This mutation results in the production of the BRAF-V600E mutant protein,16 leading to downstream phosphorylation and activation of the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway.18-20 Sequencing studies have confirmed the prevalence of the BRAF-V600E mutation in HCL to be nearly 100%.21-23
The incidence of BRAF-V600E, along with the availability of BRAF-V600E—directed kinase inhibitors, provide a rationale for therapeutic targeting of this omnipresent mutation in HCL. Inhibitors that target the BRAF/MEK/ERK pathway have shown promise for patients with BRAF-V600E–mutated cancers.20 Following the drugs’ regulatory approval, the clinical utilization of the BRAF inhibitors vemurafenib and dabrafenib and the MEK inhibitor trametinib has greatly improved outcomes in patients with BRAF-mutated metastatic melanoma.24 Inhibition of the BRAF/MEK/ERK pathway with vemurafenib, dabrafenib, or trametinib was shown to induce molecular and morphological changes in HCL cells, ultimately inducing apoptosis by disrupting the MEK/ERK pathway.25
Vemurafenib is currently the only BRAF inhibitor recommended for treatment of R/R HCL in the National Comprehensive Cancer Network (NCCN) 2019 guidelines.26 NCCN recommends vemurafenib for progressive disease following second-line therapy. Vemurafenib is a highly specific BRAF-V600E kinase inhibitor that has demonstrated low toxicity and a rapid clinical response in clinical trials of advanced melanoma patients harboring the BRAF-V600E mutation.27 In addition to the rationale for clinical utilization of BRAF inhibitors in HCL outlined above, the lack of significant myelotoxicity with vemurafenib is proposed to be an additional advantage in HCL management, especially in salvage treatment for HCL patients who have relapsed with pancytopenia and low marrow reserve due to previous chemotherapies.28 In the context of R/R HCL, vemurafenib offers this distinct advantage over PNAs, which are known to cause profound myelosuppression with enduring immunosuppression, with febrile neutropenia occurring in 30% to 50% of patients who undergo PNA induction therapy.13
Two phase II, multicenter clinical trials in Italy and the United States have evaluated the efficacy and safety of vemurafenib in patients with R/R HCL.28 In both studies, all patients had received prior PNA therapy (median, 3 lines); the overall response rate (ORR) in the Italian and US studies was 96% and 100%, respectively.28 The median relapse-free survival (RFS) in the Italian cohort was 9 months, with a significantly longer median RFS in patients who achieved CR than in those with partial response (PR).28 In the US trial, the progression-free survival (PFS) was 73% and the overall survival rate was 91% at 1 year.28 Updated analyses of the data from the completed US trial showed that 50% of the patients relapsed with a median follow-up of 24 months, and retreatment with vemurafenib yielded an ORR of 85%, with 1 patient developing acquired resistance to vemurafenib, associated with a KRAS mutation.29
Dabrafenib is selective type 1 BRAF inhibitor with clinical activity and class-defined toxicity similar to that of vemurafenib.30 Vemurafenib and dabrafenib are also less potent toward wild-type RAF proteins.31 Although both inhibitors have demonstrated comparable clinical efficacy, they have shown different effects in RAF kinase inhibition, toxicity profile, and prospective evidence for activity in non—BRAF-V600E melanoma and brain metastases.30 In a recent case report, a patient with malignant melanoma and HCL, both harboring the BRAF-V600E mutation, was successfully treated with dabrafenib.32 Thus, dabrafenib, which was approved by the FDA for the treatment of BRAF-V600E—positive non–small cell lung cancer in combination with trametinib,33 may be of clinical utility in BRAF-V600E—positive HCL as well. However, it is not currently included in the NCCN treatment guidelines.
BRAF-resistant disease is an emerging concern in HCL.5 Currently, the mechanisms of vemurafenib resistance in HCL are not completely understood.34 Mutations reported in vemurafenib-resistant HCL include alteration in IRS1, NF1, and NF2, in addition to KRAS mutations.29,35 Based on the role of MEK in the BRAF pathway and vemurafenib resistance, the use of MEK inhibitors has been proposed as a therapeutic strategy in patients who have aberrantly reactivated ERK signaling.34,36 An international multicenter trial of dabrafenib and trametinib is currently underway in diseases with BRAF-V600E—positive histology, including BRAF-V600E—positive HCL.37
Bruton tyrosine kinase (BTK) is a member of the Tec kinase family and plays a central role in B-cell receptor (BCR) signaling; BTK is also involved in chemokine receptor and adhesion molecule signaling in normal and malignant B cells.38,39 The visualization of the role BTK plays in the BCR signaling pathway can be seen in Figure 1.39 Moreover, C-X-C chemokine receptor type 4 and BCR-interacting proteins, such as BTK, have been shown to be essential for the survival and expansion of HCL cells.40 BTK is uniformly expressed in HCL cells, and the BTK inhibitor ibrutinib has been shown to inhibit HCL cell proliferation and cell cycle progression.38 BTK inhibition, as a downstream kinase in the BCR pathway, leads to resistance of BCR-mediated activation of signaling events that promote B cell growth, proliferation, and survival, serving as a therapeutic strategy in HCL.6,38,39
Ibrutinib is approved for the treatment of chronic lymphocytic lymphoma and mantle cell lymphoma, and it has been evaluated in patients with HCL.41 Early data from an ongoing multicenter trial of ibrutinib monotherapy in relapsed HCL and HCLv were promising; the ORR in the 28 patients who were evaluable for response in the 2 dosing cohorts (420 mg/d and 840 mg/d ibrutinib) was 46%, including 4 CRs and 9 PRs.41 Relapsed patients in this study had received a median of 4 prior therapies (range, 1-11), including PNAs, rituximab, and vemurafenib.41 The estimated 24-month PFS was 79%; median PFS had not been reached at the time of analysis.41 Notably, this study included 10 patients with relapsed HCLv. In a recent case report, a patient with multiply relapsed HCLv treated with ibrutinib derived clinical benefit from this regimen.6 NCCN lists ibrutinib along with vemurafenib as appropriate for progressive disease following
Rituximab-Based Combination Regimens
Rituximab is a human/murine chimeric anti-CD20 monoclonal antibody indicated for various CD20-expressing B-cell malignancies, including non-Hodgkin lymphoma (NHL) and HCL.42 Rituximab is thought to eliminate CD20-positive cells using various mechanisms, including by promoting apoptosis of CD20-positive cells and by mediating complement-dependent cytotoxicity and/or antibody-dependent cell-mediated cytotoxicity.42 In addition to evaluating combinations of rituximab with PNAs, recent trials have sought to combine rituximab with other agents, including vemurafenib and bendamustine, for the treatment of HCL.9,43 The 2019 NCCN guidelines recommend rituximab—PNA–vemurafenib combinations for patients with R/R HCL.26
Bendamustine is approved for use in chronic lymphocytic leukemia (CLL) and relapsed B-cell NHL44; it has both alkylating and antimetabolite properties.45 Preclinical studies provide support for a synergistic effect of rituximab and bendamustine using lymphoma cell lines and ex vivo cells from patients with CLL and leukemic B-cell lymphomas.46 In a case report of a patient with multiply relapsed HCL and transfusion-dependent disease, bendamustine monotherapy induced a temporary PR, suggesting the potential utility of bendamustine in this setting.47 A subsequent randomized trial (NCT01059786) in patients with multiply R/R HCL sought to compare the utility of concurrent administration of rituximab/bendamustine with rituximab/pentostatin.48 CRs were observed in 4 of the 6 patients who received bendamustine at 90 mg/m2 versus 3 of the 6 patients who received bendamustine at 70 mg/m2, with 5 other patients achieving PRs.48 The rates of minimal residual disease (MRD)-negative CR (67% in the 90 mg group vs 33% in the 70 mg group) as well as the duration of CR (111 vs 223 days) indicated that the higher dose of bendamustine provided more favorable outcomes.48 Based on these data, another trial is currently randomizing patients either to rituximab/pentostatin or to rituximab with a higher dose of bendamustine.6
Moxetumomab Pasudox: A Novel Treatment for Relapsed/Refractory HCL
The HCL immunophenotypic profile is characterized by the expression of CD11c, CD25, and CD103 markers, in addition to the B-cell antigens CD20 and CD22.3 For HCL and other B-cell malignancies, CD22, a single-spanning membrane glycoprotein of 140 kDa, is expressed at a higher density than CD25.49 CD22 plays an important role in establishing signaling thresholds for B-cell activity through its role as an inhibitory coreceptor of the BCR.50 CD22-mediated BCR signaling modulation, along with expression of CD22 on malignant HCL and HCLv cells, form the rationale for targeting CD22 in HCL and other B-cell neoplasms.51
Several therapeutic approaches, including CD22-directed small molecules, monoclonal antibodies, antibody—drug conjugates, and recombinant immunotoxins, have been or are being developed to induce B-cell depletion in B-cell neoplasms. Among these CD22-targeting strategies, recombinant bacterial immunotoxin–antibody conjugates have been shown to be highly cytotoxic to HCL cells.6 The recombinant immunotoxin—antibody conjugates have 2 main components: a plant or bacterial protein toxin, which is a highly potent catalytic agent that exhibits cytotoxicity with a single molecule reaching the cytosol that has been engineered such that it lacks the toxin domain binding to normal animal cells; and a recombinant toxin, which is fused to a recombinant variable fragment (Fv) of a monoclonal antibody.49
In 2018, the FDA approved moxetumomab pasudotox (MPT), a CD22-directed bacterial toxin—based immunoconjugate, for the treatment of adult patients with R/R HCL who have received 2 or more prior lines of therapy, including treatment with a PNA.52 The approval of MPT was granted under FDA priority review and fast track designation.52 The availability of a targeted agent to the HCL paradigm provides a long-needed nonchemotherapy option for treating patients whose disease has progressed or become refractory to first-line therapies.53,54 In 2019, the role of MPT within the HCL therapeutic spectrum became more established, with its addition to the NCCN guidelines as a category 2a recommendation.26
MPT is composed of an Fv of a recombinant murine anti-CD22 monoclonal antibody that is fused to PE38, a 38-kDa fragment of Pseudomonas exotoxin A, thus inhibiting protein synthesis.55,56 MPT has an affinity for CD22 that is 14-fold improved over that of BL22, due to a lower off-rate; this is mediated by engineering random mutations within localized “hot spots” the CDR3 domain of VH using phage selection.57
Initial phase I data indicated that MPT induced a 46% CR rate in patients with R/R HCL with 2 or more prior therapies and abnormal blood counts.58 A subsequent analysis of long-term follow-up data showed that 71% of patients in the extension cohort receiving 50 μg/kg MPT achieved a CR, and the ORR was 91%. In the combined cohort, 64% of patients achieved CR and the ORR was 88%.59 The median duration of the CR in the 21 patients who achieved it was 42.4 months, and of the 20 patients who achieved CR who were evaluated for MRD, 55% were MRD negative. Ten patients persisted in CR at the study’s end.59
The approval of MPT for R/R HCL was based on data from a pivotal, single-arm, open-label phase III study (NCT01829711) that included 80 patients (79% male; median age, 60 years) across 32 centers in 14 countries with R/R histologically confirmed HCL with 2 or more prior systemic therapies, including at least 1 PNA.15,60 The MPT-induced durable CR rate was 30%, with a CR rate of 41.3% and an ORR of 75%. Additionally, 80% achieved hematologic remission.15 Among those who achieved CR, 85% achieved MRD negativity by immunohistochemistry.15 The most frequent adverse events (AEs) were peripheral edema (38.8%), nausea (35%), fatigue (33.8%), and headache (32.5%).15 A total of 50 patients completed a full 6 cycles of treatment (62.5%), with patients most commonly discontinuing due to achieving CR with MRD negativity (15%).15
HUS occurred in 7% of patients in this combined database; 44% and 11% of these were grade 3 and 4, respectively.55 MPT should not be used in patients with a history of severe thrombotic microangiopathy or HUS. Prophylactic IV fluids should also be administered before and after MPT infusions. Monitoring blood chemistry and completing blood counts prior to each dose and on day 8 of each treatment cycle is essential. As with CLS, events of HUS are potentially life-threatening if treatment is delayed.55 Patients should also be monitored for renal function, serum electrolytes, and infusion-related reactions.
The recommended dosage of MPT is .04 mg/kg IV on days 1, 3, and 5 of each 28-day cycle (Figure 2).55 Infusions last about 30 minutes and patients should be well hydrated for 1 day following treatment. MPT is supplied as a sterile, preservative-free, white to off-white lyophilized cake or powder in a single-dose vial for reconstitution and dilution prior to infusion.55
After decades of quiescence, the therapeutic landscape of HCL is undergoing rapid evolution. The addition of the FDA-approved immunotoxin MPT in 2018, coupled with other targeted agents currently being investigated in monotherapy and combination regimens, including BRAF and BTK inhibitors, signal a new era in HCL management. These new agents collectively represent a positive development in the HCL spectrum, particularly for patients who are ineligible to receive PNAs or those with disease that is refractory to or relapsed following treatment with PNAs. Moreover, the inclusion of these novel agents and combinations in the updated 2019 NCCN guidelines for HCL management brings promise for this rare malignancy, as new discoveries shed more light on the genetic and molecular underpinnings of HCL.
MPT carries a boxed warning for 2 serious treatment-related AEs: capillary leak syndrome (CLS) and hemolytic uremic syndrome (HUS).55 In a combined database of patients with HCL treated with MPT, CLS occurred in 34%. Of this population, 68% were grade 2, 4.5% were grade 3, and 6.8% were grade 4. Most cases were reported within the first 8 days of a treatment cycle, and the median time to resolution was 12 days. Patients who develop CLS are clinically indicated to be hospitalized and may be treated with concomitant oral or intravenous (IV) corticosteroids. CLS is potentially fatal if treatment is delayed, so patients must be counseled to seek medical attention if any symptom indicative of possible CLS occurs, including weight gain, hypotension, shortness of breath, cough, peripheral edema, pulmonary edema, and serosal effusions. Patients receiving MPT should be monitored for weight and blood pressure prior to each infusion.55