Treatment Of Hairy Cell Leukemia Research Articles

Successful Treatment of Hairy Cell Leukemia with 2ʼ-Deoxycoformycin After Failure of Interferons Alpha or Beta

Two patients with hairy cell leukemia (HCL) who failed alpha-2a-interferon and one who failed beta-ser-interferon were treated with 2'-deoxycoformycin (DCF), 4 mg/m2, by intravenous bolus infusion every 2 weeks. All three patients achieved a complete response, continuing for 9+, 14+, and 15+ months. Treatment was discontinued when complete remission was diagnosed. DCF-induced remission has not been previously reported after beta-ser-interferon failure. These patients, as well as 12 others in the literature reviewed herein, demonstrate the efficacy of DCF in HCL patients unresponsive to alpha, beta, and gamma interferon.

Treatment of hairy cell leukaemia

Treatment of hairy cell leukaemia

Duration of response after interferon treatment of hairy cell leukemia [letter; comment

Duration of response after interferon treatment of hairy cell leukemia [letter; comment

DURATION OF RESPONSE AFTER INTERFERON TREATMENT OF HAIRY CELL LEUKEMIA

DURATION OF RESPONSE AFTER INTERFERON TREATMENT OF HAIRY CELL LEUKEMIA

Successful treatment of hairy cell leukemia with β‐ser interferon

Twelve patients with hairy cell leukemia underwent treatment with beta-ser interferon, a type I interferon with potent antiproliferative activity. Ten of the 12 patients had had prior therapy and the median time from diagnosis to initiation of treatment was 8.5 months (range 1 month to 18 years). Bone marrow involvement ranged from 90-100% hairy cells. Beta-ser interferon was administered as an intravenous injection of 90 million units per dose, three times weekly. Dose reductions were by dose and by frequency in individual patients. Ten of 12 patients (83%) responded, including 7 complete (CR) and 3 partial (PR) responses. The median time to at least PR was 6 months and the median time to CR was 12 months. The median duration of overall response (PR + CR or PR) is 31+ months (range 26(+)-40+ months). Of the 6 patients who underwent dose reductions due to toxicity or poor tolerance, 4 CR patients reverted to PR, and 2 PR patients have increased the number of hairy cells in the marrow, while maintaining normal peripheral blood counts. One each of these has regained CR and PR status after an increase in dose.

Durable complete remissions after 2′‐deoxycoformycin treatment in patients with hairy cell leukemia resistant to interferon alpha

The efficacy of interferon alpha in treatment of hairy cell leukemia is well established. Our experience with low doses of 2'-deoxycoformycin, a competitive inhibitor of adenosine deaminase, showed that it was also effective against hairy cell leukemia in 10 of 11 patients studied whose disease was resistant to interferon alpha. Ten patients entered complete remission after five to 12 doses of 2'-deoxycoformycin (4 mg/m2 every other week), and one patient did not respond. No relapses were observed after median follow-up of 18.5 months; unmaintained complete remissions lasted from more than 10 to more than 30 months. The study demonstrated that 2'-deoxycoformycin induces a high rate of durable, unmaintained complete remissions in patients with hairy cell leukemia resistant to interferon alpha.

Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study.

Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end of treatment (14 months), and at 6-month intervals during follow-up. Before treatment, all patients had hypercellular marrows with hairy cels replacing normal marrow elements; all showed at least a 95% clearing of their hairy cell infiltrate by 6 months of therapy. However, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral samples in all patients. All patients have completed treatment with a median duration of follow-up off therapy of 27 months (range, 15 to 31 months). To date, all peripheral counts and serum soluble interleukin-2 receptor (sIL2R) levels remain stable, and no patient has had progression of the hairy cell infiltrate in the bone marrow. Although no patient achieved a pathologic complete response, alternating monthly cycles of dCF and rIFN-alpha 2a produced durable partial remissions (PRs) in all patients. Continued follow-up is required to determine the length of such remissions.

Gene therapy for cancer

INTRODUCTION RAPID advances in recombinant DNA technology make it likely that genetic manipulation and somatic gene therapy will become part of medical practice in this decade. In the case of the human cancers several possibilities arise for diagnosis, monitoring and treatment. Some have been shown to be effective whilst others are more speculative. One example of the successful uses is that of y-interferon recombinant gene products in the treatment of hairy cell leukaemia. Trials of other products such as interleukin 2 (IL2), interleukin 4 (IL4) and tumour necrosis factor (TNF), alone or in combination, in the treatment of several different cancers await completion. Recombinant products such as granulocyte colony stimulating factor and granulocyte/monocyte colony stimulating factor have been shown to ameliorate the granulocytopenia induced by the myelosuppressive chemotherapy regimens used for leukaemia, lymphoma and autologous transplantation for many solid tumours [ 11. Where a disease susceptibility gene has been cloned, such as that for retinoblastoma [2, 31, or mapped, such as in colorectal carcinoma in the familial form of polyposis coli [4, 51, it may be possible to predict whether an individual has that genetic susceptibility by use of restriction fragment length polymorphism analysis. Tumour infiltrating lymphocytes (TIL) may be expanded in vitro and, before reinfusion into the patient, labelled with a genetic marker (such as the neomycin resistance gene) to study their tumour homing and killing properties. The first investigation in man in which that gene was inserted into TIL cells with a retroviral construct has been completed [6]. Since TIL cells might recognize tumours and thus ‘home’ to sites of malignancy, their tumoricidal properties could be enhanced. Gene insertion that would either enhance local cytokine production (i.e. TNF, y-interferon, IL2 or IL4) or deliver a therapeutic gene product such as a toxin (e.g. Pseudomonas exotoxin) is a promising area of research. Theoretically, it should be possible to insert antisense genes (sequences that are complementary to the gene coding

Treatment of Hairy Cell Leukaemia with 2'-Deoxycoformycin.

The adenosine deaminase inhibitor 2'-deoxycoformycin (DCF) has been used to treat 40 patients with hairy cell leukaemia (HCL) who have been followed up for a minimum of 6 months. 21 patients had previously undergone splenectomy. 33 had received treatment with alpha-interferon (IFN), half of whom had relapsed and the remainder had either been partially treated due to intolerance or had an incomplete response. Deoxycoformycin was administered by slow intravenous injection at a dose of 4 mg/m(2) weekly for 4 consecutive weeks and then 2-weekly for 4 doses followed by 4-weekly injections until a complete remission was achieved. No maintenance therapy was given. The overall response rate was 97yi, with 82% complete remission (CR) and 15% partial remission (PR). CR have lasted from 3+ to 30+ months (median 12 +) with no relapses recorded so far. Only one evaluable patient, suffering from a variant form of HCL, failed to respond to DCF, whilst two other HCL-variant cases who had been resistant to alpha-IFN have achieved a PR and are still on treatment. DCF was generally well tolerated, the major toxicity being related to cytopenia and associated infection. Four patients developed severe infections, one of whom died of septicaemia before it was possible to evaluate the response to DCF. A group of 12 patients who had received alpha-IFN immediately prior to treatment with DCF and had obtained clinical and haematological benefit had fewer infections with DCF than the group who had either not received IFN immediately before or who had failed to respond to it. In view of the infections associated with DCF, we would now recommend initial therapy for HCL patients with alpha-IFN for 2-4 months to obtain clinical and haematological improvement, followed by DCF given 2-weekly, to eradicate residual disease. This approach may achieve a higher proportion of sustained CR with a short treatment time and minimal toxicity.

The Treatment of Hairy Cell Leukemia: A Review.

Hairy cell leukemia is a chronic lymphoproliferative malignancy first described by Bouroncle et al. over 30 years ago(1). Representing less than 2% of adult leukemias, hairy cell leukemia has become the focus of intense interest over the past few years as a result of therapeutic advances. The malignant cell has characteristic irregular cytoplasmic projections visible on the peripheral blood smear and cytoplasmic vesicles staining positive for tartrate-resistant acid phosphatase. The origin of the hairy cell appears to be a preplasma cell B lymphocyte based on immunoglobulin gene rearrangements and B-cell-specific antigens, although very rare T-cell variants have been reported. While the diagnosis may be suspected from the clinical manifestations and examination of the peripheral smear, a bone-marrow biopsy is frequently necessary for definitive diagnosis. The typical patient is a middle-aged man with complaints of fatigue or weakness; symptoms of splenic pain, bleeding or bruising, or recurrent infections are less common at presentation(2). Splenomegaly without peripheral adenopathy occurs in 70-80 % of newly diagnosed patients(2). Pancytopenia is present in approximately two-thirds of patients, although 10% of patients present with a leukocytosis resulting from a high circulating hairy cell count.

Chemical stability of pentostatin (NSC-218321), a cytotoxic and immunosuppressant agent.

Pentostatin, an unusual nucleoside of natural origin, has been used for the treatment of hairy cell leukemia, as an immunosuppressant agent, and as an inhibitor of adenosine deaminase. The studies of the physicochemical properties and solution stability of pentostatin are important to the development of a parenteral formulation for extensive preclinical and clinical testing. Pentostatin displayed apparent pKa values at 25 +/- 0.1 degree C and ionic strength of 0.15 M of 2.03 +/- 0.03 and 5.57 +/- 0.14 (spectrophotometric) and 5.50 +/- 0.02 (potentiometric) for N1 and the amidine nitrogen in the seven-membered ring, respectively, which are the most likely protonation sites. The rates of degradation of pentostatin were determined as a function of pH, buffer concentration, and temperature. In the pH range 1.0-4.0, pentostatin undergoes acid-catalyzed glycosidic cleavage leading to the formation of the base compound, and 2-deoxyribose. A carbonium ion mechanism in which C-N bond cleavage was the rate-determining step was consistent with the data. In the pH range 6.5-10.5, the imine bond at C5 position in pentostatin is hydrolyzed to form the corresponding formamide. Pentostatin hydrolysis in this pH range was independent of pH. At pH greater than 11, pentostatin decomposes to nonchromophoric products probably through multiple-step base-catalyzed hydrolytic mechanisms. Pentostatin appears to be quite stable after reconstitution of a lyophilized experimental dosage form. Care must be taken if pentostatin is extensively diluted with 5% dextrose in water, as pentostatin stability is compromised at pH values less than 5.

Low-dose interferon alfa-2b in the treatment of hairy cell leukemia.

Twenty-two patients with hairy cell leukemia were treated with low-dose interferon alfa-2b (0.2 X 10(6) U/m2 given three times weekly) for 6-12 months. The overall response rate was 54%, with only 18% complete plus partial responses. The therapy had to be terminated early in five of these patients because their progressive disease led to severe cytopenia. Although the toxic effects with this regimen were minimal, the significantly lower response rate and the poorer quality of the responses prohibit its use as initial therapy in hairy cell leukemia.

Very low dose alpha-2b interferon for the treatment of hairy cell leukemia [see comments

Alpha-2b interferon (alpha-2b IFN), administered at 2 x 10(6) U/m2 three times per week is highly effective in the treatment of progressive hairy cell leukemia (HCL) and in the retreatment of patients who have relapsed after previous IFN therapy. To determine if a lower interferon dose would induce a comparable antileukemic effect with less toxicity, a-2b IFN was administered at 2 x 10(5) U/m2 subcutaneously three times per week to 17 patients with progressive HCL. Thirteen patients had HCL in relapse after a previous response to alpha-2b IFN; four patients were previously untreated. The median duration of treatment was 9 months. Toxicity consisted only of transient, mild flu-like symptoms in two patients. Of the 13 previously IFN-treated patients, four had a minimal response, one had no response, and eight had progressive disease. Of four previously untreated patients, one had a partial response, two had a minimal response, and one had no response. In seven of eight patients whose disease progressed on low-dose IFN, the dose was escalated to 2 x 10(6) U/m2 three times per week, and all seven patients demonstrated hematologic response within 3 months to the dose escalation. We conclude that alpha-2b IFN at 2 x 10(5) U/m2 three times per week is relatively ineffective for the treatment of relapse after previous IFN therapy.

Cost-Benefit Analysis of Interferon Alfa-2b in Treatment of Hairy Cell Leukemia

The clinical benefits as well as the cost benefits of use of recombinant interferon (IFN) alfa-2b instead of conventional chemotherapy (primarily chlorambucil) for progressive hairy cell leukemia were assessed retrospectively on the basis of 12 months of clinical data from 128 patients treated with IFN alfa-2b. Data from 71 matched historical control patients who had received conventional treatment were used for survival analysis. Hematologic response (reversal of cytopenias) was achieved by 18% of the control patients versus 73% of the IFN-treated patients. This response was associated with virtual elimination of the need for transfusions and splenectomy as well as dramatic decreases in the frequency of fatal infections (22.5% vs. 1.6%) and the 12-month mortality rate (28% vs. 3.1%). Direct costs per patient per year for medical care (transfusions, antibiotic treatment, splenectomy, and chemotherapy) of those receiving IFN alfa-2b were 2.8-fold lower than costs for medical care of control patients ($5,027 vs. $14,046). Indirect costs, which reflect the present value of future earnings lost due to premature death, were 13.3-fold lower for IFN-treated patients than for control patients ($4,771 vs. $63,507). Our analysis demonstrates that IFN alfa-2b offers substantial clinical and cost advantages to patients with hairy cell leukemia and that the introduction of this therapy using novel biotechnology furthers the health care community's commitment to cost containment.

Pentostatin in the treatment of advanced hairy cell leukemia.

2'-Deoxycoformycin (pentostatin [dCF]), a potent inhibitor of adenosine deaminase (ADA), was administered in a biweekly low-dose (2 to 4 mg/m2) intravenous (IV) schedule to patients with advanced hairy cell leukemia. Twenty-three patients were treated, including 12 patients previously treated by splenectomy and five patients treated with interferon. Twenty-one of 23 patients had objective responses, including 20 who achieved a complete remission (CR). Responses occurred rapidly, with an average time to CR of 5.4 months. Treatment was not continued once CR was achieved, and 15 of 20 patients remain in remission with an average duration of 12.6 months. CRs were achieved in both patients previously treated with interferon (three of five) and patients with marked splenomegaly (three of three). Relapses, when seen, have occurred in the bone marrow alone and the one patient who required retreatment was reinduced into CR. Toxicity has been mild and reversible, with nausea and vomiting, conjunctivitis, and skin rash as the main complications of treatment. dCF is the most effective single agent in the treatment of hairy cell leukemia, inducing a high percentage of CRs in all subgroups. Two multiinstitutional trials are now underway to compare its effectiveness v alpha interferon.

What is the choice of treatment for hairy cell leukemia?

What is the choice of treatment for hairy cell leukemia?

Alpha-IFN treatment does not induce Ki-ras expression in hairy-cell leukemia patients.

alpha-Interferon (IFN) is effective in the treatment of hairy-cell leukemia (HCL), but the treatment is sometimes over a long period. Biological changes such as the increase of tumorigenicity can occur rapidly in vivo as a result of beginning this treatment; an increase in c-Ki-ras oncogene expression has also been observed. In order to determine whether the findings observed in vitro would be duplicated in an in vivo system, we decided to analyze the Ki-ras RNA and protein levels in the lymphocytes of three HCL patients, compared with these levels in seven normal donors and one non-treated HCL patients. Ki-ras was not activated by IFN, at least not in lymphocytes. Therefore, the data suggest that the drug could be used for long-term therapy with relatively low risk to the patients.

Immunological recovery and dose evaluation in IFN-alpha treatment of hairy cell leukemia: analysis of leukocyte differentiation antigens, NK and 2',5'-oligoadenylate synthetase activity.

A low-dose interferon (IFN)-alpha regimen for the treatment of hairy cell leukemia (HCL) was evaluated by following changes in leukocyte differentiation antigens (LDA), natural killer cell (NK) and 2',5'-oligoadenylate (2-5A) synthetase activities. Due to hairy cells' (HC) weak expression of several antigens positive for T cells, B cells, NK cells and monocytes, the use of a double marker specific for hairy cells was needed to distinguish the different subpopulations. Analysis of LDA in peripheral blood (PB) showed a total normalization of the T cell and monocyte numbers within 90 days, the number of NK cells normalized in 90 to 180 d, whereas normalization of B cell number was seen only after 180 to 360 d of treatment. Mean pretreatment 2-5A synthetase activity was normal or low, but upon treatment the levels rose immediately to higher than normal values and remained high throughout the study. Pretreatment NK activity was low, but normalized after between 90 to 360 d, except in 2 patients with severe splenomegaly. In vitro incubation of peripheral blood mononuclear cells (PBMNC) with IFN-alpha induced activation of the NK and 2-5A synthetase activity in untreated patients, but with treatment these effects were gradually abolished, indicating an increasing effect of IFN-alpha in vivo with time. These results shows that the different PBMNC subpopulations and important immunological functions normalize with treatment. This normalization is, however, not seen until at least after 1 year of treatment, indicating that the treatment schedule should be longer. As no exhaustion to the effect of IFN was seen, as measured by the 2-5A synthetase activity, a continuing beneficial effect of treatment is anticipated. The increasing effect of IFN-alpha after the first signs of clinical effect suggests that the doses used in the present study were higher than necessary.

Effect of recombinant interferons on hairy cell leukemia progenitors

The effects of recombinant interferons (rIFNs) on colony formation by progenitor cells from the peripheral blood of patients with hairy cell leukemia (HCL) were examined. Results showed that both rIFN-alpha and -beta inhibited HCL colony formation in a dose-dependent manner, with the inhibitory effect of rIFN-alpha being similar in degree with that of rIFN-beta. The inhibitory effect of rIFN-gamma, however, was not uniform; of four patients, inhibition was observed in cells from two patients, but no effect was found in the cells of the other two. These results indicate that rIFN-alpha and -beta could be effective in the treatment of HCL, whereas rIFN-gamma may be of limited efficacy.

Therapy for Neutropenia in Hairy Cell Leukemia with Recombinant Human Granulocyte Colony-Stimulating Factor

To determine whether recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in increasing neutrophil counts in patients with hairy cell leukemia and neutropenia. Open label, phase I/II study of G-CSF, given by daily subcutaneous injection for up to 7 weeks. Outpatient oncology clinic of a university medical center. A consecutive sample of four patients with hairy cell leukemia complicated by severe neutropenia. Three patients completed the study; one patient was removed after 2 weeks of therapy. Granulocyte colony-stimulating factor was given by daily subcutaneous injection. Each patient began therapy with 1 microgram/kg body weight.d; after 1 week the dose was increased to 3 micrograms/kg.d, and 1 week later to 6 micrograms/kg.d. Therapy was continued for 5 to 6 weeks. Patients were taught self-injection, and administered treatment at home. In three patients, an increase in absolute neutrophil counts from less than 0.9 X 10(9)/L to greater than 4.0 X 10(9)/L was noted within 2 weeks of beginning G-CSF therapy. In two patients, infections resolved during therapy. One patient developed acute neutrophilic dermatosis (the Sweet syndrome) while receiving 3 micrograms/kg.d of G-CSF, and drug therapy was discontinued. Granulocyte colony-stimulating factor may increase neutrophil counts within 2 weeks in patients with hairy cell leukemia and neutropenia. This therapy may be a useful adjunct to definitive treatment of hairy cell leukemia with interferon or pentostatin.