Relapsed Hairy Cell Leukemia Research Articles

A Single Arm Phase II Pilot Study of Low Dose Vemurafenib Plus Rituximab in the Front-Line and Relapsed/Refractory Treatment of Hairy Cell Leukemia

Introduction: Hairy Cell Leukemia (HCL) is a rare, low-grade B-cell malignancy that is characterized by cytopenias, infections and splenomegaly. Given the chronic and incurable nature of this disorder, limiting therapy-related toxicity is of paramount importance. Though purine nucleoside analogs have an established track record of durable efficacy, they are associated with significant myelosuppression and immunosuppression as well as late secondary malignancies. Mechanistic exploitation of aberrant BRAF V600E activation with vemurafenib in combination with CD20 targeting with rituximab has provided an effective means of eradicating leukemic cells without significant myelosuppression or immunosuppression. However, vemurafenib at the standard dose of 960 mg twice daily is often poorly tolerated and frequently requires dose reduction. We conducted a pilot study of rituximab and low-dose vemurafenib (240 mg twice daily) in patients with untreated or relapsed HCL, with a focus on providing a non-cytotoxic regimen that minimizes toxicity with potentially comparable treatment outcomes. Methods: This phase 2, open-label, single-arm, investigator-initiated pilot trial was designed, conducted, and managed at Scripps Clinic in La Jolla, California. We enrolled adult patients with HCL and mutated BRAF V600E who met standard treatment initiation criteria defined by an ANC ≤1.0, Hgb ≤ 10.0 or PLT ≤100K. The treatment plan consisted of eight weeks of oral vemurafenib 240 mg twice daily and eight intravenous rituximab infusions at 375 mg per square meter of body-surface area administered every two weeks. The primary outcome was complete hematologic response. Secondary endpoints included time to complete hematologic response, clearance of minimal residual disease determined by BRAF V600E allele frequency in the bone marrow, safety and progression-free, relapse-free and MRD-free survival. Results: From March 2022 to July 2023, a total of six patients were enrolled in the study. Three patients had previously received a purine analog and three patients were previously untreated. The median age of patients was 61 years, and all were male. At the interim efficacy analysis, all five (5/5) evaluable patients had demonstrated a complete hematologic response with resolution of cytopenias and splenomegaly. 6-month bone marrow biopsy data were available for 3 patients. In 2 of these patients, MRD assessment by allele-specific PCR for BRAF V600E was absent in the bone marrow. In the third patient, though residual disease was present by MRD assessment, he had a hematologic response and requires no subsequent treatment to date. At a median follow-up time of 303 days, the relapse-free survival rate was 100%. There were no adverse grade 3 or 4 adverse events and no vemurafenib dose limiting toxicity was observed. Conclusions: Interim results to-date suggest that rituximab and low-dose vemurafenib (240 mg twice daily) have efficacy and good tolerability in patients with untreated or relapsed HCL. With accruing patient data and further enrollment on study, more information will guide the durability, efficacy and tolerability of this treatment approach.

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.

Treatment outcomes with purine nucleoside analog alone or with rituximab for hairy cell leukemia at first relapse.

Frontline treatment of hairy cell leukemia (HCL) with a single course of the purine nucleoside analog (PNA) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, although treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R), practice patterns vary and data supporting each approach are limited. We conducted a multisite outcomes analysis of patients treated for HCL between 1995 and 2018 at six US medical centers. All patients were treated with frontline PNA and subsequently required treatment with a PNA alone (PNA) or with R (+R). Of the 88 patients analyzed, 56 (63.6%) received second-line PNA and 22 (36.4%) received a PNA+R. Baseline characteristics of both groups were similar. There was no difference in median PFS [67months (95% CI 43.8 non-reached (NR)) vs. 65months (95% CI 60-NR)] or 5-year OS [98% (95% CI 0.94-1) vs. 94% (95% CI 0.83-1), p=.104] in the PNA versus PNA+R cohorts, respectively. To our knowledge, this is the largest study evaluating the role of R in treatment of relapsed HCL and suggests that there is no advantage to the addition of R to PNA therapy at the time of first re-treatment.

Phase 1 trial of anti-CD22 recombinant immunotoxin moxetumomab pasudotox combined with rituximab for relapsed/refractory hairy cell leukemia.

7036 Background: Anti-CD22 recombinant immunotoxin moxetumomab pasudotox (Moxe) is FDA-approved for hairy cell leukemia (HCL) patients who have received at least two prior systemic therapies including a purine nucleoside analog. In phase 3 testing the complete remission (CR) rate was 41%, and response was higher in patients with lower tumor burden and lower titers of antidrug antibodies (ADA). Phase 1 testing indicated that most CRs were without minimal residual disease (MRD) and eradication of MRD was associated with prolonged CR duration. Monoclonal antibody (Mab) rituximab binds to CD20 on HCL cells and induces apoptosis or immune-mediated killing, but as a single-agent achieved only 13% CRs in relapsed HCL requiring therapy. In a phase 1 trial to determine safety, rituximab was combined with Moxe, with the goal to help reduce tumor burden and to prevent or delay ADA by killing normal B-cells. Methods: To allow rituximab sufficient time to accomplish both goals, it was infused 3 days before day 1 of cycle 1 at 375 mg/m2, and Moxe was given by 30-minute infusion on days 1, 3 and 5. On repeat cycles of Moxe days 1, 3 and 5, rituximab was given on day 1. Cycles were generally spaced 4 weeks apart. Moxe was begun at a lower dose, 30 rather than the 40 mcg/kg dose used in phase 3 in case the rituximab would increase its toxicity. Bone marrow aspirate flow cytometry, which can detect 0.002% HCL cells, was the most sensitive test used for MRD detection, much more sensitive than BRAF V600E digital droplet PCR (ddPCR) or bone marrow biopsy immunohistochemistry (IHC). Patients could receive 4 cycles past MRD-free CR, but not more than 8 cycles. Results: Three patients received Moxe at 30 mcg/Kg/dose and 6 received 40 mcg/Kg/dose, all without dose limiting toxicity (DLT). There was no evidence of hemolytic uremic syndrome or capillary leak syndrome. To prevent intravascular hypovolemia due to expected third spacing, patients were encouraged to drink one cup per hour of water or other fluid from days 1 to 8 and take dexamethasone 4 mg orally if headache or nausea prevented good oral hydration. Of the 9 patients, 7 (78%) achieved CR after 2 (n = 6) or 3 (n = 1) cycles, and achieved MRD-free CR after 2 (n = 3), 4 (n = 3) or 6 (n = 1) cycles. No patients became infected with COVID-19. Conclusions: This phase 1 trial met its primary endpoint of determining whether rituximab could be safely combined with Moxe and will enroll 4 additional patients to further access clinical activity. Further testing will determine whether addition of a CD20 Mab to Moxe significantly improves clinical outcome compared to Moxe alone, particularly long-term MRD-free CR rate. Clinical trial information: NCT03805932.

IBCL-324: Hairy Cell Leukemia in the Era of Targeted Therapy: A Case Presentation

Context: Hairy cell Leukemia (HCL), a chronic B-cell neoplasm, accounts for 2% of all leukemias, mainly of males in their 50s. Diagnosis relies on morphology, flow cytometry, and immunohistochemistry. Purine analogues are first-line therapy since more than 20 years ago. Strategies such as combined chemoimmunotherapy, targeted therapy, and minimal residual disease (MRD) are taking over the landscape of HCL. Patient: A 47-year-old man presents with weakness, respiratory infections, pancytopenia, and a 19-cm spleen. Peripheral blood revealed mononuclear cells with hairlike projections, monocytopenia, and thrombocytopenia. Misdiagnosis of splenic lymphoma 2 years earlier had been managed with bendamustin and rituximab in a different center, having resulted in normalization of counts. At our assessment, his immunophenotype showed CD103/CD123/CD25/CD11c in 63% of cells, diagnostic of relapsed HCL. Interventions: Cladribine was initiated at 0.14 mg/kg/d, 2 h infusion for 5 days, and supportive measures. At 3 months, MRD was negative; 28 months later, he remains in remission. Results: Molecular identification of somatic BRAFV600 mutation is diagnostic, as well as an effective therapeutic target. MRD is thought to predict late relapse in HCL and select patients to benefit from additional or further treatment. Monoclonal antibodies anti-CD20 and anti-CD22 Moxetumomab have proven safe and efficacious in treating HCL. Conclusions: Hairy cell Leukemia is a rare hematologic malignancy that can be confused with other indolent lymphoid malignancies. Current treatment is effective, but clinical trials are needed to develop best practices to offer patients with HCL a normal life expectancy.

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

Hairy cell leukemia: present and future directions

Hairy cell leukemia (HCL) is an indolent B-cell malignancy, with long-term responses to purine analogs, but with decreasing efficacy and increasing toxicity with repeated courses. Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCLv, lacking CD25, Anxa1, TRAP, and BRAF V600E, is more aggressive and less purine analog-sensitive. A molecularly defined IGHV4-34+ variant is also resistant whether HCL or HCLv immunophenotypically. Traces of HCL cells, termed minimal residual disease (MRD), accompany most with complete remission (CR) and may cause relapse. Rituximab has limited single-agent activity, but frequent CR without MRD when combined with purine analog, albeit with chemotherapy toxicities. The anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox can achieve MRD-negative CR in multiply relapsed HCL without chemotherapy toxicities and was FDA approved in 2018 as Lumoxiti. Investigational oral non-chemotherapy options also include Vemurafenib or Dabrafenib/Trametinib targeting BRAF V600E ± MEK, and Ibrutinib targeting Bruton’s tyrosine kinase.

Abstract 4595: Moxetumomab pasudotox spares CD4 and CD8 lymphocytes in multiply relapsed hairy cell leukemia patients, while prospective trials of first, second, and later lines of purine analogs show increasing toxicity

Abstract The purine nucleoside analogs cladribine and pentostatin damage DNA and cause long-term suppression of CD4 and CD8 lymphocytes in patients with hairy cell leukemia (HCL). There is increasing concern that these reductions, particularly in CD4+ T-cells, may be associated with opportunistic infections and secondary malignancies. The anti-CD22 recombinant immunotoxin moxetumomab pasudotox targets HCL without damaging DNA, and spares T-cells. In a phase 1 trial, 20 patients treated with 50 ug/Kg every other day for 3 doses for 2-8 (median 4) cycles were evaluated for T-cell subsets. CD4 cells increased -56% to 152% (median 46%) after end of treatment, decreasing in only 1 of the 20 patients. Because there is very little prospective data on the effect of purine analogs on T-cells, we analyzed data from 80 consecutively enrolled patients receiving cladribine in first line, 40 receiving cladribine in second line, and 52 receiving either pentostatin or bendamustine in third or later lines. The latter group was most appropriate to compare with moxetumomab pasudotox, which was also used in third or later-line treatment of HCL. CD4 counts after moxetumomab pasudotox were 85-600 (median 424), compared to 22-618 (median 73) after third or later line purine analog (p<0.0001). These CD4 counts after moxetumomab pasudotox were even higher than those after first line (86-954, median 259, p=0.0037) or second line (53-724, median 185, p<0.0001) cladribine. CD4 counts after first line cladribine were higher than those after second line cladribine (p=0004), which in turn were higher than those after third or later line purine analogs (p<0.0001). Even after 2 years, CD4 counts after third or later line purine analogs, 41-1004 (median 264), n=43, remained suppressed compared to 1st line cladribine, 191-1044 (median 392, n=68, p=0.0013). The percent decreases in CD4 counts after first line cladribine were significantly greater compared to those after moxetumomab pasudotox (median 63% decrease vs 46% increase, p<0.0001). CD8 counts were also preserved after moxetumomab pasudotox, increasing by -32% to 198% (median 46%). Similar differences between moxetumomab pasudotox and purine analog groups were observed with respect to CD8-cell suppression. Opportunistic infections, neutropenic fevers, and other infectious complications were much more common after purine analogs than after moxetumomab pasudotox, particularly in later lines of therapy. These data provide a rationale for avoiding repeated cycles of purine analog for relapsed HCL, and support the use of non-chemotherapy approaches like moxetumomab pasudotox before repeated courses of purine analog are tried. (Supported in part by MedImmune and NCI, Intramural Program). Citation Format: Robert J. Kreitman, Maryalice Stetler-Stevenson, Evgeny Arons, Ira Pastan. Moxetumomab pasudotox spares CD4 and CD8 lymphocytes in multiply relapsed hairy cell leukemia patients, while prospective trials of first, second, and later lines of purine analogs show increasing toxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4595. doi:10.1158/1538-7445.AM2017-4595

Series of Hairy Cell Leukemia Patients with Co-Existent Plasma Cell Disorders

Despite a reported increased incidence of secondary hematologic malignancies and plasma cell disorders in the literature, the specific co-existence of hairy cell leukemia (HCL) and monoclonal gammopathies of unknown significance (MGUS) or plasma cell multiple myeloma (MM) has been based on a few case reports. In the following report, we compile clinico-pathologic data on a series of hairy cell leukemia patients with myeloma precursor diseases using immunohistochemistry, molecular polymerase chain reaction (PCR) and multi-parametric flow cytometry (MFC) techniques with an aim to deep sequence these parallel lymphoid processes in the future.Between 2004 and 2014, 6 HCL patients followed at the National Institutes of Health were identified with associated plasma cell disorders, based on presence of increased clonal plasmacytosis in bone marrow and abnormal serum and/or urine protein electrophoresis/immunofixation. Immunohistochemical (IHC) staining for CD20, TRAP, CD138, cyclin D1, kappa and lambda light chains was performed on bone marrow biopsies. MFC using a panel of B-cell antibodies and PCR clonality studies targeting immunoglobulin heavy and light chain loci were performed prior to treatment to confirm the presence of malignant lymphoid clonal processes.Among the 6 hairy cell leukemia patients with associated plasma cell disorders, there were 5 males and one female. Median age was 67 (range, 47-74). Patients prior to treatment showed bone marrow involvement by HCL with 5-90% infiltration. Hairy cells in all patients tested were TRAP positive, Cyclin D1 was positive in 5, and BRAF V600E was detected in 5 of 5 patients tested. All patients were diagnosed as classic HCL, although 1 patient had an additional population consistent with HCL variant. In addition, 3/6 patients (50%) showed mild increase in marrow plasma cells (5-10%) and the other 3 patients (50%) had over 10% of plasma cells in the core biopsy. The mean plasma cell percentage was 10% (3-25%), mean monoclonal protein concentration was 1.3 g/dL, and isotypes included: 4 IgG, 1 IgA, and 1 free kappa only. 3 patients were classified as MGUS and 3 as smoldering MM (SMM). Interestingly, three out of 6 (50%) patients had positive cyclin D1 expression by IHC in both plasma cells and hairy cells. Several patients had evidence of multiple clonal rearrangements by PCR studies. In addition, two patients demonstrated evidence of monoclonal B-cell lymphocytosis (MBL) on MFC. So far, 3 patients achieved complete remission without minimal residual disease (MRD) using moxetumomab pasudotox in one multiply relapsed case, and first line cladribine plus rituximab in 2 newly diagnosed HCL cases, without significant progression to MM. No patients demonstrated end organ damage due to MGUS/SMM after a median follow-up of 4.6 (range 0.9-10.1) years.By using serum studies, IHC staining, PCR and MFC tools, we identified a group of HCL patients with evidence of additional precursor malignant lymphoid disease states, including MGUS/SMM and MBL. Underlying mechanisms of these parallel malignant processes may include global lymphoid dysregulation through common lymphocyte ancestry pathways; or, it could be due to post-immune HCL therapy exposure, or a combination. Currently, we are conducting deep sequencing of these samples with the aim to uncover mechanisms of pathogenesis. Treatments capable of eliminating HCL MRD, including addition of rituximab to first-line cladribine, or single-agent moxetumomab pasudotox for multiply relapsed HCL, might be advantageous for patients who may need treatment for MM in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Improved Survival in Hairy Cell Leukemia Over Three Decades: A SEER Database Analysis of Prognostic Factors.

AbstractAbstract 2891 Introduction:Hairy cell leukemia (HCL) is a rare B cell malignancy with a variable clinical course. Therapies have changed dramatically in the last 3 decades. Specifically, approval of recombinant alpha interferon (IFN-α) in 1984, followed by the development of purine nucleoside analogues (pentostatin in 1986 and cladribine in 1990), represent significant therapeutic advances, affording high response rates and (using the latter agents) disease control lasting years. Monoclonal antibodies including rituximab -first approved in 1999- have also shown promise, to date mainly in relapsed HCL. However, given the rarity of HCL, large population analyses of survival of affected patients, and survival trends over time, are lacking. Therefore, using the Surveillance Epidemiology and End Results (SEER-17) database, we evaluated overall survival, and factors associated with mortality trends, in HCL patients in the general US population over the past 35 years. Methods:The SEER-17 database was interrogated for HCL patients presenting over the last 35 years, from 1973–2008. 3904 patients were identified; after excluding patients whose survival status was unavailable, 3480 were analyzed. Available demographic information, including age, gender, race, and year of diagnosis, were analyzed. Age was analyzed as a continuous variable. We utilized Cox proportional hazards models to assess prognostic factors. Additional models were formed to evaluate a possible step change in survival in the years following key therapeutic advances (1984, 1990, and 1999). Specifically, the population was separated into four cohorts (pre-1984, 1984–1990, 1991–1999, and 2000–2008) and the entire cohort was included as an additional predictor in the model. Kaplan Meier curves were constructed to estimate overall survival and statistically significant differences between the curves was estimated using the 2 tailed log rank test. The survival curves for the 3 groups post 1984 were plotted along with patients from 1973–1983 and are shown below in Figure 1. The three predictors associated with survival were identified as age, race and year of diagnosis. Results:The mean age was 56 years (95% CI 33–86) for the entire study population. There was no difference in the mean age before 1984 (56.5 yrs.) compared to the three cohorts after 1984 (mean ages 58 yrs., 57 yrs. and 57 years respectively). The risk of death increased by 5.8% (95% CI 5.14– 6.55) per year with older age at diagnosis. However, after adjusting for age, survival has improved over the study period, as the risk of death in an unselected patient of the same age with HCL in the US has decreased by 90.5%. African-American patients were noted to have a significantly higher mortality than Caucasians (OR 1.942, 95% CI 1.254–3.008). Survival of patients appears to have improved over the years with the risk of mortality decreasing by 6.5% per year (95% CI 5.6%-7.4%) with a later year of diagnosis. With additional models, the risk of death for an individual of a given age decreased by 5.3 % every year with a further reduction of 27.5% occurring in 1984 (p=0.04), consistent with a dramatic reduction in mortality after 1984. Models derived using other landmark years did not show any further step wise reduction in mortality (1990 p=0.441; 1999 p=0.535) at these specific time points. However, the reduction in mortality conferred by diagnosis at a later year has resulted in significantly improved survival being different for all groups before and after 1984 (Figure 1). [Display omitted] Conclusions:Survival of modern cohorts of patients with HCL in the US has improved significantly. While the diagnosis of HCL has employed classic morphologic, cytochemical, and (more recently) immunohistologic features, effective antineoplastic therapy has evolved significantly in recent decades. Thus, modern therapies may have played a significant role in the survival improvements of modern HCL patients. African- American ethnicity is associated with higher mortality, a disparity requiring further analysis in the context of patient factors and an improving understanding of HCL pathobiology. Disclosures:No relevant conflicts of interest to declare.

Bendamustine and Rituximab for the Treatment of Multiply Relapsed Hairy Cell Leukemia,

Abstract 3909 Background:Hairy cell leukemia (HCL) is highly sensitive to purine analogs cladribine (CdA) and pentostatin (DCF), but patients who relapse have decreasing remission rates with each course and can eventually become purine analog-refractory. Bendamustine and rituximab (BR) have been reported as effective with acceptable toxicity in several B-cell malignancies, particularly B-cell lymphomas and chronic lymphocytic leukemia. The structure of bendamustine contains an alkylating group and also part of cladribine, suggesting it might be useful in HCL. In one case report, bendamustine achieved a transient partial response in a patient with relapsed/refractory HCL, but its activity in other patients with this disease is not reported. The combination of DCF and rituximab (DCFR) is reported to achieve high complete remission (CR) rates in HCL in retrospective series, but prospective phase II trials of this combination have not been reported. Methods:To determine the activity of BR relative to DCFR in HCL, a randomized trial was undertaken in multiply relapsed HCL comparing the 2 regimens in which each arm could constitute a prospective phase II trial, with 2-way crossover for lack of response to or relapse from the originally assigned regimen. The primary endpoint is an overall response rate of 65% for each arm and the 2 arms will be compared with respect to response and other secondary endpoints including toxicity, response duration, and eradication of minimal residual disease (MRD). Patients received 6 cycles at 4-week intervals of rituximab 375 mg/m2 days 1 and 15 with either pentostatin at 4 mg/m2 days 1 and 15, or bendamustine days 1 and 2. To test the tolerability of bendamustine prior to randomizing 56 patients between the 2 arms, 12 non-randomized patients received BR using 70 (n=6) or 90 (n=6) mg/m2/dose of bendamustine. Doses of all agents could be delayed but not reduced. Results:A total of 20 patients are so far enrolled and the 12 patients receiving the 2 dose levels of BR are evaluable for response and toxicity. Patients had 1–6 (median 3) prior courses of purine analog and 8 (67%) had prior rituximab. All toxicity was reversible and only 1 patient at 90 mg/m2 required >2-week delay due to prolonged neutropenia and thrombocytopenia. However, this delay was only between cycles 1 and 2 and not between subsequent cycles after responding to BR. Of the 36 cycles of BR administered to each group of 6 patients on the 2 dose levels of bendamustine, 90 vs 70 mg/m2/dose, common grade 3–4 toxicities included lymphopenia (28 vs 22%), leukopenia (19 vs 17%), and thrombocytopenia (14 vs 17%). Febrile neutropenia requiring hospitalization occurred just once in 3 patients at 90 vs 0 patients at 70 mg/m2/dose. Major response was achieved in 10 (83%) of 12 patients. CR was achieved in 3 (50%) of 6 patients at each dose level, while 2 (33%) at 70 and 3 (50%) at 90 mg/m2 achieved clearance of MRD at all sites including bone marrow aspirate by flow cytometry. No patient in CR has relapsed after 8–14 (median 11) months of follow-up. Of 4 patients evaluable by clone-specific real-time PCR, previously reported sensitive to 1 HCL cell in 106 normal, 3 patients at 90 mg/m2/dose were negative. Conclusions:BR can achieve responses including CRs in multiply relapsed HCL, and its safety profile permits comparison of BR with DCFR using the more common dose level of bendamustine, 90 mg/m2 days 1 and 2. Additional patients and follow-up will be required to access durability of response and long-term eradication of MRD, and to compare BR with DCFR (Supported in part by NCI, intramural research program, NIH, Genentech, Inc, and Cephalon, Inc). Disclosures:Kreitman:Cephalon: Research Funding; Genentech: Research Funding. Off Label Use: Use of bendamustine and rituximab for HCL. Arons:Genentech: Research Funding.

Recombinant immunotoxins and other therapies for relapsed/refractory hairy cell leukemia

Standard treatment for hairy cell leukemia (HCL) is markedly effective, but the constant decrease in disease-free survival, together with the presence of minimal residual disease (MRD), suggests that few if any are cured. HCL cells in MRD are always strongly CD20 + and CD22 + , and also CD25 + unless the patient has the poor-prognosis variant HCLv. To target relapsed/refractory HCL, immunotherapy has been developed using anti-CD25 and anti-CD22 recombinant immunotoxins, or the anti-CD20 monoclonal antibody (mAb) rituximab alone or combined with purine analogs. The recombinant immunotoxins contain an Fv fragment of a mAb fused to a truncated form of Pseudomonas exotoxin called PE38. BL22 targeting CD22, in phase I and II testing of relapsed/refractory HCL, achieved 47–61% complete remissions (CRs), several of them ongoing after 9–10 years. A completely reversible form of hemolytic uremic syndrome (HUS) was observed in 12% of patients, several of whom could later achieve a partial remission (PR) or CR with LMB-2 targeting CD25. A higher-affinity version of BL22, termed HA22, CAT-8015, or moxetumomab pasudotox, developed to more effectively treat other hematologic malignancies, also achieves CRs in HCL, and with only non-dose-limiting HUS. In separate randomized trials, rituximab is undergoing phase II testing with cladribine for early HCL and with bendamustine or pentostatin for multiply relapsed HCL.

Phase I trial of recombinant immunotoxin CAT-8015 (HA22) in multiply relapsed hairy cell leukemia.

6523 Background: CAT-8015 (HA22) contains the Fv domains of the anti-CD22 Mab RFB4 and truncated pseudomonas exotoxin, inducing cell death after binding, internalization, and ADP-ribosylation of elongation factor 2. CAT-8015 is a high-affinity mutant of BL22 (CAT-3888), with increased cytotoxicity toward chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL) cells ex vivo. Methods: To determine the clinical activity of CAT-8015, separate phase I trials were initiated in CLL, HCL, and non-Hodgkin lymphoma, and the HCL trial completed accrual. Eligible patients had several prior therapies including purine analogs and needed treatment for cytopenias or symptoms. CAT-8015 was administered over 30 min iv days 1, 3 and 5 (QODx3) at 28-day intervals for up to 10 cycles. Results: 28 HCL patients received CAT-8015: 3 each at 5, 10, 20, and 30 ug/kg QODx3, 4 at 40 and 12 at 50 ug/kg QODx3. Patients had 2-7 (median 3) prior therapies. Patients received 1-9 (median 4) cycles of CAT-8015 each. Dose-limiting toxicity (DLT) was not observed. Two patients, with cycle 3 of 30 and cycle 5 of 50 ug/Kg QOD x3, had a grade 2 reversible hemolytic uremic syndrome (HUS) with peak creatinine of 1.53-1.66 mg/dL and platelet nadir of 111,000-120,000/mm3. Drug-related toxicities in 25-60% of the 28 patients included (in decreasing frequency) grade 1-2 hypoalbuminemia, edema, fever, ALT and AST elevations, headaches, and nausea. Of 25 evaluable patients, 44% made antibodies neutralizing > 75% of the cytotoxicity of 1,000 ng/mL of CAT-8015. Responses were achieved at all dose levels. The overall response rate was 79% including 12 (43%) of 28 HCL patients achieving complete remission (CR). Of the 12 CRs, 11 (92%) are ongoing 7-29 (median 21) months after enrollment. Conclusions: CAT-8015 is active in relapsed/refractory HCL and is without DLT after completion of expansion at the highest dose level (50 ug/Kg x3) to 12 patients. These results justify further treatment of patients at this dose level to further explore efficacy and safety. Dose-escalation will continue in a separate trial to determine if the increased cytotoxic activity of CAT-8015 compared to CAT-3888 will be associated with significant efficacy in CLL and non-Hodgkin lymphoma. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration MedImmune

Treatment of chronic lymphoid leukemias with monoclonal antibodies: current place and perspectives

AbstractOver the past few years, several monoclonal antibodies (MAbs) directed against lymphoid cells have been developed and investigated in preclinical studies and clinical trials. Some of them are highly active in leukemias. At present, the most important clinical value in the patients with chronic lymphocytic leukemia (CLL) has two MAbs. The first is the human mouse antibody, rituximab (IDEC C2B8, Rituxan, Mabthera), which targets CD20 antigen. The second is alemtuzumab (Campath‐1H), a humanized form of a rat antibody active against CD52. Recently, several new MAbs have been explored and have shown promise in treating CLL. Novel MAbs are being evaluated in preclinical studies and in early clinical trials. These treatments include new MAbs targeted CD20 molecule (ofatumumab, GA‐101), lumiliximab, epratuzumab, apolizumab, galiximab, and anti‐CD40 MAbs. Alemtuzumab is also a useful drug in previously treated and untreated patients with T‐cell prolymphocytic leukemia. Rituximab as well as anti‐CD22 and anti‐CD25 immunotoxins have been also investigated in refractory and/or relapsed hairy cell leukemia with high response rate. MAbs provided new opportunities for effective therapies of these disorders. Drug Dev Res 69:373–387, 2008. © 2008 Wiley‐Liss, Inc.

Efficacy of Rituximab in Hairy Cell Leukemia.

BACKGROUND: Hairy Cell Leukemia (HCL) is a rare B-chronic lymphoproliferative disorder (BCLD) with an indolent course. First-line treatment modalities include 2-chlorodeoxyadenosine (2-CDA), 2-deoxycoformycin (2-DCF) and interferon-alpha. The efficacy of anti-CD20-Rituximab (R) in other BCLDs, as well as strong CD20 expression by HCL cells, indicate that R could be an alternative treatment of HCL.AIMS: The experience of a single Hematology Unit in the treatment of relapsed HCL with R.PATIENTS AND METHODS: We retrospectively analyzed all HCL patients (pts) who received R as salvage therapy in 1st or subsequent relapse.RESULTS: 13 patients treated with R were located among 110 patients diagnosed with HCL between 1980 and 2005. 11 were males and their median age before R treatment was 46 years (range: 42–88). 5 pts had splenomegaly with a median spleen size of 7cm below left costal margin (range:5–20cm). 3 pts has an absolute neutrophil count<1.5×109/L, 4 a hemoglobin <10g/dL and 5pts a platelet count<100×109/L. All patients displayed a typical immunophenotype from blood and/or bone marrow (CD20 strongly +, CD19+, CD22+, FMC-7+, CD11c+, CD25+, CD103+). Four of them were CD23+ and two CD10+. 8 pts received Rituximab at 1st relapse. Among them, one had received 2-DCF as first-line treatment, one 2-CDA and 6 interferon-alpha as induction and maintenance. 3 pts had received more than one prior treatments. Two pts received R at diagnosis, due to older age. The median time from diagnosis to R initiation was 61 months (range: 4–275). R was administered at 375mg/m2 weekly for 6 cycles. Overall response rate was 67%, with 4 pts showing a negative immunophenotype. One pt discontinued treatment after the first cycle due to the development of thrombocytopenia that was attributed to the drug. 7/8 responders showed a complete restoration of their cytopenias. No other complications were recorded, except of mild infusion-related symptoms. Among the responding pts, none has relapsed so far with a median follow-up of 14 months (range: 4–40+). Among partial responders, one achieved a complete response including a negative bone marrow and immunophenotype after R retreatment.CONCLUSIONS: R is a highly effective and tolerable treatment for HCL in relapse with a response rate of 67%. Retreatment or maintenance with R may be important, since ongoing responses are seen.

Monoclonal Antibodies in the Treatment of Chronic Lymphoid Leukemias

In recent years preclinical and clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) either alone or coniugated to toxins in patients with several lymphoid malignancies, including chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL) and hairy cell leukemia (HCL). Two MoAbs, directed against CD20 antigen (Rituximab, RIT) and CD52 antigen (Campath-1H, alemtuzumab, ALT) demonstrate significant activity in CLL. The most notable success to data has been achieved with ALT, both in previously treated and untreated patients with CLL. ALT is a humanized rat IgG1 antibody that binds to the cell membrane of virtually all normal as well as malignant lymphocytes. In the vast majority of CLL patients ALT causes constant reduction of abnormal blood lymphocytes, usually in less than 4 weeks, and disappearance of CD5/CD19 co-expression cells from blood. The regression of lymphoid infiltration from other sites is less clear. ALT is also highly active in patients with CLL in progression, even refractory to fludarabine (FA). Hematological toxicity, especially long-lasting lymphocytopenia, was noted in the majority of patients. The most important clinical side effects of ALT treatment were infections, mainly herpes simplex virus and cytomegalovirus reactivation. RIT is also active in CLL in conventional doses. However some studies suggest that higher doses are more effective than standard doses, used routinely in other lymphoid malignancies. The activity of ALT and RIT in CLL patients resistant to FA and their synergistic interactions with cytotoxic drugs suggests that a combination of these agents may lead to further progress in the treatment of this disease. The T-cell variant of PLL has demonstrated impressive responses to ALT in several trials even if the patients were refractory to deoxycoformycin (DCF) and other agents. However, this MoAb is not curative, because all patients eventually relapsed. Consequently, treatment with ALT may need to be associated with stem cell transplantation to consolidate and maintain long-term remissions. Recently anti-CD22 and anti-CD25 immunotoxins have been investigated in purine analogues refractory or relapsed HCL. The presented results indicate that these agents are highly active and well tolerated even if the patients were resistant to 2-CdA or DCF.