Refractory Hairy Cell Leukemia Research Articles

Efficacy and Safety of Obinutuzumab in Relapsed or Refractory Hairy Cell Leukemia (R/R HCL): An Italian Multicenter Phase-2 Academic Trial (HCL-PG04)

INTRODUCTION About 50% of HCL patients (pts) relapse after chemotherapy with purine analogs (PA). After identifying the BRAF-V600E mutation as the genetic cause of HCL (Tiacci et al. NEJM 2011), we documented a high efficacy of the BRAF inhibitor vemurafenib in R/R pts (Tiacci, Park et al. NEJM 2015), especially when added to rituximab (Tiacci et al. NEJM 2021). HCL expresses bright CD20 and obinutuzumab (OBI) is a more effective anti-CD20 agent than rituximab (RTX) in other indolent B-cell neoplasms such as chronic lymphocytic leukemia and follicular lymphoma. RTX produces ~20% complete remissions (CR) in R/R HCL (Kreitman, ASH Educ Program 2012), while OBI activity in this setting is unknown. METHODS In the ongoing academic, phase-2, multi-center trial HCL-PG04, R/R HCL pts needing treatment due to cytopenia(s) received OBI 1000 mg intravenously on days 1-8-15 of cycle 1 and on day 1 of cycles 2-6 (1 cycle = 28 days). CR required resolution of cytopenias (platelets ≥ 100,000/mmc; neutrophils ≥ 1500/mmc; hemoglobin ≥ 11 g/dl), no palpable splenomegaly and no leukemic cells on morphologic analysis of the bone marrow biopsy, as assessed one month after the last OBI dose. Minimal residual disease (MRD) was analyzed by BRAF-V600E specific PCR in the bone marrow aspirate (sensitivity: 0.05% mutant alleles). RESULTS We enrolled 26 pts (M/F 24/2; median age 62 years, range 39-80) with a median of 2 prior therapies (range 1-7), including 7 refractory to PA (26%) and 2 to RTX (8%). Median values of disease burden parameters at baseline were: 70% BM HCL infiltration, 830 neutrophils/mmc, 62000 platelets/mmc, 14 g/dl hemoglobin, and 16 cm of longest spleen diameter (in 16/26 splenomegalic patients; 1 pts. had been splenectomized and 9 were not splenomegalic at baseline). Toxicity was as expected, largely of grade (G) 1-2, always reversible and mainly consisting in: infusion reactions (G1-2 92%; G3 4%, in a single pt allergic to previous RTX who discontinued OBI); asymptomatic increase of liver enzymes (G1-2 19%; G3 GGT 15%; G3 ALT 4%); transient worsening of baseline G1-G3 thrombocytopenia to G3 (23%) or G4 (35%), with only 1 minor bleeding (4%, G1 epistaxis); transient neutropenia (G2 4%; G3 15%; G4 15%); and rare infections (G1-2 herpes labialis 8%; G3 pneumonia 4%). CR was reached in 12/25 evaluable pts (48%), including 2 pts with incomplete platelet recovery (~70000-90000/mmc) and 2 pts with delayed resolution of palpable splenomegaly. Notably, CR was achieved in 5/7 pts refractory to PA and 1/2 pts refractory to RTX. Furthermore, CR was negative for MRD in 9/12 pts (75%, including 3 pts with delayed MRD clearance), something never observed with vemurafenib. However, the kinetics of cytopenia resolution was slower compared to our previous vemurafenib trial, in that in pts obtaining CR with OBI neutrophil recovered to ≥1500/mmc after a median of 7 weeks (vs 4 weeks with vemurafenib) and platelets recovered to ≥100000/mmc after a median of 8 weeks (vs 2 weeks with vemurafenib). Prior exposure to RTX (n=12 pts) did not compromise OBI efficacy (5 CR, all MRD-negative, in 11 evaluable pts). In pts achieving CR with OBI, progression-free and MRD-free survival were both 100% at 56 months (range 20-66) and 48 months (range 6.5-60) of median follow-up, respectively (Fig.1). The 13 non-CR pts (minor response 7; no response 3; progression 3) were effectively salvaged with another course of OBI combined with vemurafenib, which will be presented at the meeting. CONCLUSIONS OBI frequently produced deep and durable responses in R/R HCL, to an extent apparently greater than RTX, thus qualifying as an active and safe chemotherapy-free strategy in this setting.

Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy

AbstractVemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.

New therapeutic options for hairy cell leukemia

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder characterized by pancytopenia, splenomegaly and increased susceptibility to infections. In 2011, BRAF gene mutation was identified in almost all the patients with the classical type of HCL. The purine analogs cladribine and pentostatin induce long-term remission in the majority of patients, and they remain the standard treatment for this type of leukemia. However, more than half of patients in complete response relapse over the long term, with a quarter of them relapsing within the first five years. Recently, new drugs have been developed and have demonstrated efficacy in refractory or relapsed HCL. The immunotoxin Moxetumomab pasudotox was registered for HCL in 2018. The BRAF kinase inhibitors vemurafenib and dabrafenib, as well as the Bruton kinase inhibitor ibrutinib, are also proven highly effective in clinical trials.

Generation of Single-Domain Antibody-Based Recombinant Immunotoxins.

The discovery of single-domain antibodies has opened new avenues for drug development. Single-domain antibodies, also known as nanobodies, can access buried epitopes that are inaccessible to conventional antibodies. These antigen-binding domains have a high level of solubility and stability, which makes them well suited for therapeutic development. This chapter will discuss the design, production, and testing of single-domain antibody-based recombinant immunotoxins. Recombinant immunotoxins are chimeric proteins that combine the specificity of an antibody with the ribosomal-inhibitory domain of a bacterial toxin. Immunotoxins using the Pseudomonas exotoxin domain have been well studied in clinical trials. Recently, an anti-CD22 immunotoxin was granted marketing approval for use in patients with relapsed or refractory hairy cell leukemia. This supports the idea that treatment with recombinant immunotoxins can be explored for cancers that have not responded to standard therapies.

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

Durable Responses with Vemurafenib plus Rituximab in Hairy-Cell Leukemia.

Of 30 patients with relapsed or refractory hairy-cell leukemia, 87% experienced complete responses.

Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial

Safety and efficacy of the BRAF inhibitor dabrafenib in relapsed or refractory hairy cell leukemia: a pilot phase-2 clinical trial

Pierwsza w Polsce allogeniczna transplantacja komórek macierzystych u chorego z oporną postacią białaczki włochatokomórkowej

Introduction. Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder characterized by distinctive cells present in bone marrow, peripheral blood and spleen. Treatment of relapsed and/or refractory (R/R) HCL remains a challenge. Case report. A 28-year-old male was treated with cladribine +/- rituximab for his newly diagnosed BRAF-V600 mutated HCL. A year later leukemia relapsed and he received interferon alfa with poor response. Subsequently, vemurafenib was continued for 5 months but this treatment also failed. Then, he received bendamustine with rituximab but significant response was not achieved. Finally, he was found eligible for allogeneic stem cell transplantation (Allo-SCT) from a 9/10-matched unrelated donor. He was conditioned with total body irradiation (TBI) and cyclophosphamide. Cyclosporine and methotrexate were used as graft-versus-host prophylaxis (GVHD). He engrafted and achieved full donor chimerism. There were 0.4% of hairy cells in bone marrow sample by flow cytometry at discharge. 3 months after transplantation he developed neurological and psychiatric deficits which remained unexplained despite a detailed work-up. The symptoms partly resolved after steroids implementation. At the last contact, 14 months after transplantation he remained in complete remission and his neurological condition improved substantially. Conclusions. Allo-SCT seems to be a promising treatment option for R/R HCL.

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

Contextualizing the Use of Moxetumomab Pasudotox in the Treatment of Relapsed or Refractory Hairy Cell Leukemia.

Hairy cell leukemia (HCL) is an indolent B-cell malignancy characterized by high initial sensitivity to purine analog chemotherapy, minimal residual disease (MRD) frequently accompanying complete remission (CR), and relapses requiring additional treatment. Repeat chemotherapy shows decreasing efficacy and increasing toxicity with each course. Newer therapies targeting BRAF/MEK or Bruton's tyrosine kinase are effective but generally leave MRD. Rituximab has modest activity as a single agent and can achieve MRD-negative CR in combination with purine analogs, but there is significant toxicity from the chemotherapy. Moxetumomab pasudotox-tdfk (Moxe) is a biologic containing an antibody fragment (Fv) binding to CD22, attached to a portion of Pseudomonas exotoxin A. Binding to CD22 enables the toxin to enter and kill cells. Moxe is administered by 30-minute infusions on days 1, 3, and 5 of up to six cycles spaced 4 weeks apart. In phase I testing, 64% of 33 patients at the highest dose level achieved CR, most without MRD. Lack of MRD correlated with prolonged CR duration; of 11 MRD-negative CRs, 10 were still in CR after a median of 42 months of observation. In pivotal testing, 75% of 80 patients had a hematologic response, 41% with CR; 82% (27/33) of CRs were MRD-negative, and only 4 of the 27 MRD-negative patients relapsed during the follow-up period. Hemolytic uremic syndrome and capillary leak syndrome were each observed in 9% of patients, all reversible. In September 2018, the U.S. Food and Drug Administration approved Moxe for the treatment of relapsed/refractory HCL after ≥2 prior therapies. Moxe is undergoing further development in combination with rituximab. IMPLICATIONS FOR PRACTICE: Hairy cell leukemia (HCL) has effective treatments including purine analogs with and without rituximab, and oral inhibitors of BRAF, MEK and Bruton's tyrosine kinase (BTK). Despite these therapies, relapse occurs, and moxetumomab pasudotox has an important role in relapsed and refractory HCL because of its ability to achieve high rates of complete remissions (CRs) without chemotherapy; most of these CRs are without minimal residual disease (MRD). CR duration is enhanced in patients who achieve eradication of MRD. To improve the efficacy of this recombinant immunotoxin, a phase I trial is underway in combination with rituximab to reduce tumor burden and decrease immunogenicity.

Moxetumomab pasudotox for the treatment of relapsed and/or refractory hairy cell leukemia

ABSTRACTIntroduction: Hairy cell leukemia is a rare indolent B-cell malignancy, characterized by pancytopenia, recurrent infections, and splenomegaly. After initial therapy with purine nucleoside analogs, up to 50% of patients relapse after several years of remission. The number of relapsed patients is increasing and, until recently, there was no approved therapy with durable responses for hairy cell leukemia patients in the relapsed setting, thus the need for new non-chemotherapy approach with significant efficacy and less myelosuppression.Areas covered: Moxetumomab pasudotox is a recombinant immunotoxin containing a Fv fragment of an anti-CD22 monoclonal antibody and truncated Pseudomonas exotoxin (PE38). The authors reviewed pre-clinical and clinical studies that led to the FDA approval of the drug in patients with relapsed and/or refractory hairy cell leukemia, who received at least two prior therapies, including at least one purine nucleoside analog.Expert opinion: Moxetumomab pasudotox demonstrated a durable complete remission rate of 30% in heavily pretreated patients with hairy cell leukemia, and MRD eradication in 85% of responding patients. Moxetumomab pasudotox got a global FDA approval in September 2018. The US prescribing information carries boxed warnings regarding the risk of capillary leak syndrome and hemolytic uremic syndrome. Long-term follow-up of the pivotal study is ongoing (NCT01829711).

Moxetumomab pasudotox: A first-in-class treatment for hairy cell leukemia.

Hairy cell leukemia is a rare indolent B-cell lymphoid malignancy. Durable remission can be obtained with purine analogues, but relapse is inevitable, and effective treatment options may be limited. Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin that has recently been approved by the United States Food and Drug Administration for the treatment of relapsed or refractory hairy cell leukemia. Approval was based on a pivotal phase III study in this unique patient population. Rationale for use, clinical trial data, and current treatment recommendations are detailed. Common adverse effects are reviewed, and management strategies for select adverse effects are suggested. Implications for contemporary practitioners are also provided, as use of this novel agent is likely to increase as follow-up studies are reported.

Acquired Resistance to BRAF Inhibition in Hcl Is Rare and Retreatment with Vemurafenib at Relapse Can Induce High Response Rates: Final Results of a Phase II Trial of Vemurafenib in Relapsed Hcl

Acquired Resistance to BRAF Inhibition in Hcl Is Rare and Retreatment with Vemurafenib at Relapse Can Induce High Response Rates: Final Results of a Phase II Trial of Vemurafenib in Relapsed Hcl

Pharmacokinetics (PK), pharmacodynamics (PD) and immunogenicity of moxetumomab pasudotox (Moxe), an immunotoxin targeting CD22, in adult patients (Pts) with relapsed or refractory hairy cell leukemia (HCL).

7061Background: Moxe is a recombinant immunotoxin that specifically binds to CD22 on the B cell surface and internalizes leading to cell death. The PK, PD, and immunogenicity of moxe were evaluated...

Immunogenicity of therapeutic recombinant immunotoxins.

Recombinant immunotoxins (RITs) are chimeric proteins designed to treat cancer. They are made up of an Fv or Fab that targets an antigen on a cancer cell fused to a 38-kDa portion of Pseudomonas exotoxin A (PE38). Because PE38 is a bacterial protein, it is highly immunogenic in patients with solid tumors that have normal immune systems, but much less immunogenic in patients with hematologic malignancies where the immune system is suppressed. RITs have shown efficacy in refractory hairy cell leukemia and in some children with acute lymphoblastic leukemia, but have been much less effective in solid tumors, because neutralizing antibodies develop and prevent additional treatment cycles. In this paper we will (i) review data from clinical trials describing the immunogenicity of PE38 in different patient populations; (ii) review results from clinical trials using different immunosuppressive drugs; and (iii) describe our efforts to make new less-immunogenic RITs by identifying and removing T- and B-cell epitopes to hide the RIT from the immune system.

Vemurafenib Shows Activity in Hairy-Cell Leukemia

Abstract Short-term vemurafenib is effective in patients with relapsed or refractory hairy-cell leukemia.

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia

BackgroundBRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues.MethodsWe conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily) — one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial.ResultsThe overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK–positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism.ConclusionsA short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.)

Authentic caring occasions for patients in hairy cell leukemia clinical trials.

Rare diseases present challenges for patients, healthcare providers, and researchers. Rare disease communities exist for collaboration, dissemination of information, and to promote support for all community members. Patients with a rare disease desire to be supported through a rare disease community. Hairy cell leukemia (HCL) is a rare adult B-cell lymphocytic cancer that currently has no cure. Patients with relapsed or refractory HCL may need to consider participation in a clinical trial. The research nurse can initiate a planned caring occasion based on Watson's Theory of Human Caring. The purpose of the planned caring occasion for patients with HCL in clinical trials is to establish authentic intentional caring encounters between the research nurse and patients and meaningful caring encounters between patients. Relapsed or refractory patients enrolled in an HCL clinical trial identify the trial as a microcommunity and the research nurse as an advocate and liaison. Patients seek support, empowerment, and the opportunity to connect with other patients with HCL. The planned caring occasion has the potential to provide a healing environment and facilitate shared experiences of living with HCL. The potential outcome for patients is strengthened holistic wellness.

Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that accounts for 2% of all leukemia. Recent identification of the recurrent V600E BRAF mutation in a majority of HCL patients has led some teams to evaluate the clinical potential of vemurafenib, a BRAF V600 specific inhibitor in a limited number of refractory HCL patients. Recently, we published the case of an HCL patient successfully treated with a low dose of vemurafenib. Eight months after the ending of treatment this patient relapsed. We present here the successful retreatment of this patient with a second line of vemurafenib. Our data suggest for the first time that vemurafenib at the dose of 240 mg once a day could be sufficient to maintain a complete hematological remission after an initial induction treatment with low-dose vemurafenib (2 × 240 mg) daily without inducing major toxicity.

Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia

Background: Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a 30-40% relapse rate. For these patients (pts) and those intolerant to purine analogs, novel therapies are needed. The major finding that BRAFV600E mutations occur in 98% of HCL suggests BRAF as a promising therapeutic target. We therefore designed a phase II trial to (1) determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed/ refractory HCL and (2) identify biologic determinants of response and resistance to vemurafenib in HCL. Patients and Methods: Pts with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible pts received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Pts with partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional months. The primary endpoint of the study was overall response rate (ORR: CR + PR). Using a Simon’s mini-max two-stage design, if at least 4 of the 19 pts (≥20%) achieve ORR in the first stage, an additional 17 patients will be accrued to the second stage. If 11 or more pts achieve ORR out of the 36 pts, the study would be considered worthy of further investigation. Serial peripheral blood and/or BM samples were collected during the study for quantitative BRAF mutant allele burden, serum cytokine, multiparameter flow cytometry, and targeted next-generation sequencing analysis of a 350-gene panel to detect potential predictors of resistance and identify genes collaborating with BRAF mutations in HCL. Results: 22 pts have been enrolled and 20 pts received treatment. The median age was 61 years (range 44-77), and the median number of prior treatments was 3.5 (range 1-7). 20 pts are evaluable for toxicity and 17 patients for disease response with a median follow up of 10 months (range 2-19). The most common adverse events were rash (40%, Gr1-2), arthralgia (30%, Gr1-2), photosensitivity (20%, Gr1), and pruritis (15%, Gr1). Three pts developed squamous cell carcinoma (SCC), all of whom had previous history of SCC. All patients were able to complete the intended treatment (3 cycles: 11 pts, >3 cycles: 6 pts). All 17 evaluable pts achieved complete hematologic recovery with an overall response rate (ORR) of 100%. 6 pts achieved CR (4 MRD- and 2 MRD+) and 11 pts achieved PR with very minimal disease (Figure 1). Responses were rapid with reduction of circulating hairy cells within 24 hours and normalization of sCD25 within 2-3 weeks (Figure 2). This correlated with dephosphorylation of ERK at 1 month. Several additional inflammatory cytokines correlated with the leukemic cell burden identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R.Genetic analysis identified a median of 3 (range 0-5) somatic mutations co-existing with the BRAFV600E mutation in HCL including recurrent mutations in MLL2 and CREBBP (Figure 2). Several of these alterations were present as minor clones identifying a clonal architecture in HCL which was not previously appreciated.One pt was found to have de novo resistance to vemurafenib. Genetic analysis identified that this pt’s pretreatment HCL cells harbored a previously undescribed missense mutation in IRS1 (IRS1P1201S) in addition to BRAFV600E mutation. Given prior knowledge that IRS1 (Insulin Receptor Substrate 1) activates both MAP kinase and PI3K-AKT signaling, we compared the effects of expression of wildtype and mutant IRS1 cDNAs on signaling. This revealed robust activation of PI3K-AKT signaling induced by IRS1P1201S-mutant cells relative to wildtype.Conclusions: While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL. These data confirm the MAP kinase pathway as a rational promising therapeutic target in HCL and identify activation of signaling pathways parallel to the MAP kinase pathway as a first mechanism of RAF inhibitor resistance in a hematological malignancy. Subsequent studies will be required to prove that inhibition of B-raf may be the best initial therapy in HCL pts who require treatment. [Display omitted] [Display omitted] DisclosuresPark:Genentech: Research Funding. Off Label Use: Vemurafenib in hairy cell leukemia. Rosen:Novartis: Consultancy.