Treatment Of Hairy Cell Leukemia Research Articles

In SituEvaluation of Fludarabine-DNA Interaction Using a DNA-Electrochemical Biosensor

Fludarabine, 9-β-D-arabinosyl-2-fluoroadenine, the nucleoside analog, represents a highly effective treatment for hairy cell leukemia. The electrochemical behaviour of fludarabine is an irreversible diffusion controlled oxidation mechanism and was investigated at a glassy carbon electrode in different supporting electrolytes using cyclic, differential pulse, and square wave voltammetry. The diffusion coefficient of fludarabine was calculated to beDFLU=1.71×10−6 cm2s-1in pH 7.0 0.1 M phosphate buffer. The oxidation mechanism of fludarabine occurs with the transfer of one proton and one electron and the formation of a hydroxylated species. The interaction of fludarabine with DNA was investigated, by differential pulse voltammetry, in incubated solutions and using dsDNA- and polyhomonucleotides-, poly[G] and poly[A], electrochemical biosensors. The results showed that fludarabine interacts with DNA causing changes in the DNA structure.

Hairy cell leukemia treatment: where we are now?

Hairy cell leukemia (HCL) is a very rare type of leukemia, in which abnormal B lymphocytes, present in the bone marrow, spleen, and peripheral blood stream, get worse slowly or do not get worse at all. HCL is the disease where patients have pancytopenia with splenomegalia over 90% percent, palpable lymphadenopathy occur in 35% of patients, some form of serious infection eventually developed in over 50% of patients and was the most common cause of death in patients. HCL is dominantly a male disease, with the male-female ratio, ranging from 4:1 to 7:1. Treatment and prognosis of HCL depends on: the number of HC in the peripheral blood or bone marrow, if the spleen is enlarged and on the existence of the visible leukemia infection symptoms. Prognostic factors are similar to the above mentioned and also if the basic disease HCL is aggressive or the number of HC grow slowly and there is no need for treatment. Starting from September 1985 till September 2010, we observed a group with total number of 28 patients (22 males and 6 females) at the age of 30-76 (median range 46 years), all with HCL disease. From the total number of participants, 20 patients (71,43%) received hemotherapy, Cladribine and 8 patients (28,57%) received different type of therapy, such as immunomodulator therapy, surgery or combination of both, without Cladribine. Most effective therapy for HCL, from all of the above mentioned was definitely Cladribine which is dominant with a resulting response rates of 80-100%, where 70-90% of patients were achieving a complete remission, as defined by a complete disappearance of hairy cells in the bone marrow.

Hairy cell leukemia: current therapies and future directions

Evaluation of: Zinzani PL, Pellegrini C, Stefoni V et al. Hairy cell leukemia: evaluation of the long-term outcome in 121 patients. Cancer 116(20), 4788–4792 (2010).Hairy cell leukemia is a rare disease for which there are multiple treatment options. Purine nucleoside analogs (cladribine and pentostatin) are generally used for front-line treatment. Other active agents include interferon, rituximab and, although rarely, splenectomy. In the series published by Zinzani et al. in Cancer, the authors conclude that initial treatment for hairy cell leukemia should be maximized since these patients generally enjoy the highest complete response rates and the longest remission durations, and subsequent lines of therapy have lower response rates and more frequent relapses. However, evolving immunohistochemical and molecular diagnostic techniques, as well as criteria for evaluating response to therapy and clinical trials investigating chemoimmunotherapy, may result in clinicians re-evaluating how patients are treated in the front-line and when treatment should be initiated for relapsed patients.

Abstract 3717: Randomized phase II trial of cladribine with or without immediate rituximab for newly diagnosed or previously treated hairy cell leukemia to eliminate minimal residual disease: Interim report

Abstract Purine analogs including cladribine can induce complete remission (CR) in a high percentage of patients with previously untreated hairy cell leukemia (HCL), but late relapses are common and disease-free survival curves show no convincing evidence of cure. Many patients in CR after cladribine have minimal residual disease (MRD) which strongly expresses CD20, and the anti-CD20 Mab rituximab, particularly with a purine analog, can eliminate MRD to undetectable levels. To determine the potential benefit of adding rituximab to cladribine for initial or 2nd-line treatment of HCL, a randomized trial was begun in 150 HCL patients with 0-1 prior courses of cladribine requiring therapy. Patients receive cladribine 0.15 mg/Kg by 5 daily 2-hr i.v. infusions, and 8 weekly i.v. infusions of rituximab 375 mg/m2. Rituximab in half the patients is begun with the 1st dose of cladribine, and in the other half is delayed at least 6 months when MRD is detectable in blood. Endpoints include determining whether MRD rates are lower at 6 months with immediate rituximab, and whether blood MRD-free survival is longer when rituximab is delayed at least 6 months or begun with cladribine. HCL variant (HCLv) patients, known to respond poorly to initial cladribine alone, are not randomized and receive rituximab with cladribine. Bone marrow and blood are assessed for MRD by immunohistochemistry, PCR and flow cytometry at 1 and 6 months after cladribine. At this time 14 patients are enrolled, including 6 untreated and 8 with 1 prior course of cladribine, the latter group including 1 with HCLv. So far, the overall response rate is 100% with 10 (83%) CRs in 12 evaluable patients at 61-243 (median 202) days of follow-up. By 1 month, 0 of 5 patients after cladribine alone vs 5 (71%) of 7 after cladribine with immediate rituximab were MRD-free (p=0.028), including the patient with HCLv. Neutropenic fever was more frequent in patients receiving immediate rituximab, and was associated with both infusional reactions and reversible infections. We conclude that rituximab with cladribine can result in early clearing of MRD which is frequently present after cladribine alone. Additional accrual and follow-up is needed to determine whether simultaneous cladribine and rituximab can reduce MRD rates at 6 months, whether MRD-free survival might be longer or shorter with delayed rituximab, and whether rituximab added to cladribine for 1st or 2nd line treatment of HCL can prevent or delay clinical relapse. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3717.

Antiproliferative Properties of Type I and Type II Interferon.

The clinical possibilities of interferon (IFN) became apparent with early studies demonstrating that it was capable of inhibiting tumor cells in culture and in vivo using animal models. IFN gained the distinction of being the first recombinant cytokine to be licensed in the USA for the treatment of a malignancy in 1986, with the approval of IFN-α2a (Hoffman-La Roche) and IFN-α2b (Schering-Plough) for the treatment of Hairy Cell Leukemia. In addition to this application, other approved antitumor applications for IFN-α2a are AIDS-related Kaposi’s Sarcoma and Chronic Myelogenous Leukemia (CML) and other approved antitumor applications for IFN-α2b are Malignant Melanoma, Follicular Lymphoma, and AIDS-related Kapoisi’s Sarcoma. In the ensuing years, a considerable number of studies have been conducted to establish the mechanisms of the induction and action of IFN’s anti-tumor activity. These include identifying the role of Interferon Regulatory Factor 9 (IRF9) as a key factor in eliciting the antiproliferative effects of IFN-α as well as identifying genes induced by IFN that are involved in recognition of tumor cells. Recent studies also show that IFN-activated human monocytes can be used to achieve >95% eradication of select tumor cells. The signaling pathways by which IFN induces apoptosis can vary. IFN treatment induces the tumor suppressor gene p53, which plays a role in apoptosis for some tumors, but it is not essential for the apoptotic response. IFN-α also activates phosphatidylinositol 3-kinase (PI3K), which is associated with cell survival. Downstream of PI3K is the mammalian target of rapamycin (mTOR) which, in conjunction with PI3K, may act in signaling induced by growth factors after IFN treatment. This paper will explore the mechanisms by which IFN acts to elicit its antiproliferative effects and more closely examine the clinical applications for the anti-tumor potential of IFN.

Interferon as an alternative to purine analogues in the treatment of hairy cell leukaemia

We read with interest the recent article regarding the long-term follow-up of 233 patients with hairy cell leukaemia (HCL) treated initially with pentostatin or cladribine (Else et al, 2009). The authors presented a 97% overall response rate after treatment with either drug with a median relapse-free survival of 16 years. The results look encouraging; however, they offer some difficulties in interpretation. Considering the list of centres participating in the study, the number of included patients seems rather small. Were some patients given alternative treatments, such as Interferon or splenectomy, and if so what was the authors’ decision algorithm for choosing alternative treatments? What was the outcome of patients not included in the study treated with pentostatin or cladribine in the observed time period? The analysis by Else et al (2009) did not show an increased risk for secondary malignancies after treatment with purine analogues, but this point remains a matter of debate in HCL patients. Several studies on purine analogues in HCL (Cheson et al, 1998; Saven et al, 1998; Chadha et al, 2005) and the largest study focusing primarily on secondary cancer in HCL (Hisada et al, 2007) have shown a higher rate of secondary malignancies in HCL patients. Regarding the data of Hisada et al (2007), the rate seems to increase in parallel to the introduction of purine analogues. Given that patients with HCL have an almost normal life expectancy and the peak incidence of diagnosis is around 55 years, these patients are at long-term risk for secondary malignancies. In particular, patients with early relapses after initial treatment with several cycles of purine analogues may be at increased risk for later malignancies. In fact, as in other series, one third of patients had to be retreated 5 years after the initial treatment (Goodman et al, 2003; Jehn et al, 2004) and the disease-free survival tended to be shorter after each cycle of purine analogues in the previous studies. We therefore believe that purine analogues should be cautiously reused in non-responders and younger patients with early relapses. We and others showed very good long-time survival rates with relatively few side effects in HCL patients treated with low-dose interferon-α during induction and maintenance (Damasio et al, 2000; Benz et al, 2009). In our opinion, because of the lack of available alternative treatments, interferon-α should still be considered in non-responders and patients with early relapses to diminish the risk of secondary cancers which might occur even decades after therapy. Although interferon-α treatment cannot cure HCL, it may be less harmful than purine analogues in this extremely long-term disease. None. None.

Interferon as an alternative to purine analogues in the treatment of hairy cell leukaemia - response to Benzet al

Interferon as an alternative to purine analogues in the treatment of hairy cell leukaemia - response to Benz<i>et al</i>

Cladribine: not just another purine analogue?

Cladribine was synthesized as a purine analogue drug that inhibited adenosine deaminase. It received FDA approval in the 1980s for treatment of hairy cell leukemia. Given its toxicity towards lymphocytes and its corresponding immunosuppressive effects, it has been studied and found efficacious in a variety of hematologic malignancies and autoimmune conditions, most recently multiple sclerosis. This review highlights pharmacological, toxicological and clinical data for the use of cladribine. It also discusses existing and new mechanisms that may contribute to its unique clinical activity. Emerging data show that in addition to its known purine nucleoside analogue activity, cladribine possesses epigenetic properties, inhibiting S-adenosylhomocysteine hydrolase and DNA methylation. This may contribute to its efficacy and highlights the importance of studying combination therapy with other epigenetic or targeted agents. Clinical trials are underway in a variety of malignant and nonmalignant conditions.

Long‐term follow‐up of interferon‐alpha induction and low‐dose maintenance therapy in hairy cell leukemia

Interferon-alpha (IFNalpha) was the first effective pharmacologic treatment of hairy cell leukemia (HCL). Since 1990 purine analogs replaced IFNalpha because of higher rates of complete remission and an invariable disease recurrence after cessation of IFNalpha. However, there are only limited data about long-term maintenance treatment with IFNalpha and none about dose finding in this phase. Fifty-two consecutive patients treated at our institution for HCL are included in this retrospective analysis. Forty (77%) patients received IFNalpha and 35 patients continue on long-term IFNalpha maintenance therapy. The initial dose of IFNalpha was 3 Mio IU three times per week and was tapered 6 months after initiation to doses as low as 3 Mio IU/12 wk. Dose adaptation was performed by repeated measurement of soluble Interleukin 2 receptor (sIL2R) together with peripheral blood values. The median follow-up of patients in the long-term IFNalpha group was 13.6 +/- 7.5 yr. Long-term IFNalpha was in general well tolerated and only in six (17%) patients the treatment had to be changed to purine analogs in the long-term IFNalpha group because of side effects. There are no deaths directly related to HCL. IFNalpha is still an effective and well tolerated therapeutic option. By repeated measurements of sIL2R together with the peripheral blood values, IFNalpha doses can be tapered to the minimal effective dose. The advantages and disadvantage of IFNalpha in regards to the standard treatment in HCL patients are discussed.

Historical aspects and milestones in the development of effective treatment for hairy cell leukemia

Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder, but is gratifying to treat for both physicians and patients. During the 50 years since its initial description as a clinical entity, hematologists have been fascinated by the bizarre appearance of the malignant cell with its hair-like projections. Therapeutic strategies have evolved from splenectomy to interfere to the purine analogues which have become the treatments of-choice and are very effective. Immunoconjugate Therapy with BLZZ (anti-CDZZ antibody linked to truncated to Pseudomonas exotoxin) represents the newest milestone in the development of effective treatment for hairy cell leukemia.

Cladribine in the treatment of hairy cell leukemia: initial and subsequent results

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder associated with pancytopenia, splenomegaly, and recurrent infections. Although interferon α and pentostatin were initially found to be effective in this disease, cladribine has emerged as the preferred initial therapy. Cladribine given as a single continuous intravenous seven-day infusion is the dosing schedule with the most durable complete remissions and evaluated in the greatest number of patients with HCL. Patients who relapse after purine analogue therapy, whether it be cladribine or pentostatin, can be successfully retreated with cladribine. Patients with HCL may develop complications of recurrent infection and second malignancies. Although both complications are postulated to be related to therapy, they may also be due to the duration and burden of the disease. Minimal residual disease detected on bone marrow biopsy is thought to predict for future relapse. We will review the initial and subsequent results of cladribine in the management of HCL.

Randomized trial of daily versus weekly administration of 2-chlorodeoxyadenosine in patients with hairy cell leukemia: a multicenter phase III trial (SAKK 32/98)

Daily administration of 2-chlorodeoxyadenosine (Cladribine, CDA) is a standard treatment for hairy cell leukemia, but may cause severe neutropenia and neutropenic fever. This trial compared toxicity and efficacy of weekly versus daily CDA administration. One hundred patients were randomized to receive standard (CDA 0.14 mg/kg/day day 1–5 [Arm A]) or experimental treatment (CDA 0.14 mg/kg/day once weekly for 5 weeks [Arm B]). The primary endpoint was average leukocyte count within 6 weeks from randomization. Secondary endpoints included response rates, other acute hematotoxicity, acute infection rate, hospital admission, remission duration, event-free, and overall survival. There was no significant difference in average leukocyte count. Response rate (complete + partial remission) at week 10 was 78% (95% confidence interval (CI) 64–88%) in Arm A and 68% (95% CI 54–80%) in Arm B (p = 0.13). Best response rates during follow-up were identical (86%) in both arms. No significant difference was found in the rate of grade 3+4 leukocytopenia (94%vs. 84%), grade 3+4 neutropenia (90%vs. 80%), acute infection (44%vs. 40%), hospitalization (38%vs. 34%), and erythrocyte support (22%vs. 30%) within 10 weeks. Overall, these findings indicate that there are no apparent advantages in toxicity and efficacy by giving CDA weekly rather than daily.

Underexpression of RhoH in Hairy Cell Leukemia

The cause of hairy cell leukemia (HCL) is unknown. Current treatments seem effective only for a limited period of time. In addition, a significant proportion of patients remain refractive to all treatment options. These considerations indicate the need to develop alternative therapeutic strategies for HCL. Here, we report that HCL is characterized by underexpression of RhoH. In vitro reconstitution of RhoH expression inhibits the aberrant adhesion and transendothelial migration that drives disease pathogenesis. In an in vivo model of HCL, RhoH reconstitution limits malignant progression and protects against mortality. These findings provide the proof of principle that RhoH reconstitution represents a potential new approach to the treatment of HCL.

Hairy Cell Leukemia: Treatment Successes in the Past 25 Years

Hairy Cell Leukemia: Treatment Successes in the Past 25 Years

Cladribine in indolent non-Hodgkin’s lymphoma

Before the advent of rationally designed targeted antineoplastic therapies, cladribine was identified as a lymphocyte-specific cytotoxic agent. Cladribine is a purine nucleoside analogue that is resistant to cellular catabolism. Through diverse mechanisms, cladribine is equally toxic to dividing and nondividing cells, making it highly active in indolent lymphoproliferative diseases. In clinical practice, cladribine is mostly used in the treatment of hairy cell leukemia and Waldenström’s macroglobulinemia. However, its remarkable activity in follicular lymphoma and other indolent non-Hodgkin’s lymphoma subtypes has not been more widely appreciated. Cladribine compares favorably to other standard treatments for these conditions. Future Phase III clinical studies should incorporate cladribine into multiagent chemotherapy programs to more fully evaluate its potential in indolent non-Hodgkin’s lymphoma.

FCRL1 on chronic lymphocytic leukemia, hairy cell leukemia, and B-cell non-Hodgkin lymphoma as a target of immunotoxins

FCRL1 (Fc receptor-like 1) is a cell-surface membrane protein belonging to FCRL family and is preferentially expressed on B cells. To evaluate FcRL1 as an immunotherapy target for B-cell malignancies, we prepared anti-FCRL1 mAbs without cross-reactivity to other FCRL family proteins and analyzed FCRL1 protein expression on malignant cells from patients and on B-cell lines. Frequent FCRL1 expression was observed by flow cytometry on 12 B-cell non-Hodgkin lymphoma (B-NHL) cell lines and many patient samples: 12 of 14 chronic lymphocytic leukemia (CLL), 7 of 7 follicular lymphoma (FL), 13 of 17 hairy cell leukemia (HCL), and 2 of 3 mantle cell lymphoma (MCL). Two recombinant immunotoxins, E3(Fv)-PE38 and E9(Fv)-PE38, were constructed. Both immunotoxins bound to FCRL1-positive cells with similar affinities (3.4 and 3.2 nM) and were cytotoxic to cell lines, but E9(Fv)-PE38 was 4- to 20-fold more cytotoxic than E3(Fv)-PE38. The concentrations that inhibited response by 50% (IC(50)s) of E9(Fv)-PE38 on 11 different FCRL1-positive cell lines ranged from 1.0 ng/mL to 90 ng/mL and correlated with the FCRL1 expression levels. Our results suggest that anti-FCRL1 immunotoxin E9(Fv)-PE38 exhibits remarkably specific cytotoxicity and merits further evaluation for the treatment of FCRL1-positive malignancies, including CLL, HCL, FL, MCL, and other B-NHL.

Combined Treatment with Splenectomy and Cladribine in Hairy Cell Leukemia in Taiwan: A Clinicopathologic Study of 5 Cases

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is characterized by the presence of hairy cells in the peripheral blood and bone marrow, pancytopenia and various degrees of splenomegaly. Very few reports have explored the clinicopathologic features and treatment outcome of HCL in Taiwan. Of 33 patients with malignant lymphoma who underwent splenectomy over a 10-year period (1996-2005), 5 cases of HCL were retrospectively studied. All cases presented with various degrees of splenomegaly. Pancytopenia was noted in 3 cases, and lymphadenopathy in 1. Typical hairy cells with positive tartrate-resistant acid phosphatase stain were noted in 2 cases. Only 3 cases could be diagnosed with HCL based solely on bone marrow findings. In contrast, all spleen specimens had characteristic pathologic features. All patients underwent splenectomy uneventfully, and cladribine was given at a median time of 2 months after splenectomy without significant side effects. Complete remission with durable response was documented in 4 patients (80%) with a median follow-up of 29 months (range, 4-96 months). The last patient experienced partial remission but was only followed up for 4 months. For the HCL patients in this study, splenectomy had a role not only in improving cytopenia but in aiding diagnosis. Cladribine is safe and highly effective for Taiwanese patients and should be considered as first-line treatment for HCL.

Rituximab and 2-Chlorodeoxyadenosine in Hairy Cell Leukemia as First Line Treatment: A Faster Way to Remission. Report of Five Cases.

Background Hairy-Cell leukaemia (HCL) is an uncommon B-cell chronic lymphoproliferative disorder that accounts for about 2% of all leukaemias. Although the disease is generally indolent in its natural course, the majority of patients requires treatment for life-threatening infections due to pancytopenia or symptomatic splenomegaly. Remarkable progresses have been made in the treatment of HCL. Prior to the advent of nucleoside analogues, which are currently the standard initial treatment, interferon and splenectomy were the most effective therapies. Treatment with purine analogs (PNA) such as 2-chlorodeoxyadenosine (2-CdA) is associated with excellent remission rate and long-term survival. Recently, immunotherapeutic approaches which use monoclonal antibodies, like rituximab, have increased the number of therapeutic options for HCL and offer promising salvage strategies for patients who relapse or who are refractory to treatment with purine analogues. Previously rituximab, used in patients relapsing or refractory to CdA and for elimination of MRD after treatment with PNA, showed hematological CR and good MRD eradication. Patients and treatment We analysed, in a retrospective study, five consecutive patients M/F 4/1, 4 with HCL and one with HCLVariant treated at the diagnosis with one rituximab administration at the dose of 375mg/mq and 2CdA at the dose of 0.14 mg/mq/day s.c. for 5 days. Their median age was 70 years (range 41–71). All patients showed splenomegaly and thrombocytopenia (median platelet count was 65000 with range 49000–88000), four of these presented neutropenia (median count was 435/mmc with range 430–800/mmc) and one patient was severely anemic (Hb < 8 g/dl).Results None of the patients had severe therapy-related side effects. Four patients showed febrile cutaneous rash, although received prophyilaxis with acyclovir. The median time of recovery for neutrophil count >1500/mmc was 20 days (range 15–38) for platlets count> 100000/mmc was 21days (12–21), and hemoglobin level> 8g/dl was 31.5 days(27–36). Our median follow up at today was 264 days(range 40–570). At this time all patients are in hematological and morphologic complete remission.Conclusions The use of Rituximab together with 2CDA in first line therapy is safe and feasible. Moreover when Rituximab is used in such setting, median time of recovery in neutrophils and platelets count is significatively shorter than that obtained after therapy with 2CdA alone (8 and 4 weeks respectively). A longer follow-up is needed to evaluate the long-term results of the treatment.

The role of rituximab in combination with pentostatin or cladribine for the treatment of recurrent/refractory hairy cell leukemia

The purine analogs pentostatin and cladribine have revolutionized the treatment of hairy cell leukemia (HCL) with overall responses in greater than 85% of patients and a median progression-free survival of up to 15 years. They continue to be effective at second- and even third-line therapy; however, alternative treatments are needed for patients who are or have become refractory to these agents or whose remissions are shorter with each course of therapy. The authors conducted a retrospective review of 8 patients who received pentostatin or cladribine combined concurrently (n = 6 patients) or sequentially (n = 2 patients) with rituximab at second-line therapy (n = 3 patients) and at subsequent lines of therapy (n = 5 patients). Results from a previously reported database of 219 patients with HCL (73 patients who received second-line therapy and 20 patients who received third-line therapy) were used as a historic control group against which to measure benefit. All 8 patients responded to therapy, with 7 complete responses (CRs) (87.5%) and minimal toxicity. All patients who had CRs were negative for minimal residual disease (MRD). At a median follow-up of 29 months (range, 5-39 months) 1 patient developed recurrent disease, and the estimated 2-year recurrence rate was 20% (0% after second-line therapy and 25% after subsequent lines of therapy). In the historic control group, the CR rates were 70% after second-line therapy and 45% after third-line therapy, and the recurrence rates at 2 years were 15% and 33%, respectively. The combination of purine analogs with rituximab was safe and effective for patients with recurrent and/or refractory HCL, and the current results suggested an added benefit compared with standard treatment.

The purification and characterization of alpha interferons and related cytokine receptors—A personal account

In 1976–1977, I adapted reversed-phase HPLC (RP-HPLC) to peptide and protein purification, starting with pituitary proteins and continuing with the first successful purification to homogeneity of human leukocyte interferon (IFN-α). Using this technology, I isolated and characterized 6–8 different leukocyte interferon subtypes, which were later identified as products of the IFN-α gene family. Since then, RP-HPLC became a standard procedure for isolation and analysis of proteins. The successful purification of IFN-α led to the development of Roferon-A™, a drug used for the treatment of hairy cell leukemia, hepatitis C and a variety of other diseases. Later studies with my colleagues in Israel and abroad led to isolation and discovery of several cytokine receptors and binding proteins, including those of Type I IFNs, TNF and IL-18. The use of HPLC was indispensable in most of these studies.