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Cladribine is a nucleoside analog that is phosphorylated in its target cells (B and T-lymphocytes) to its active triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad

Cladribine is a nucleoside analog that is phosphorylated in its target cells (B- and T-lymphocytes) to its active adenosine triphosphate form (2-chlorodeoxyadenosine triphosphate). Cladribine tablets 10 mg (Mavenclad®) administered for up to 10 days per year in 2 consecutive years (3.5-mg/kg cumulative dose over 2 years) are used to treat patients with relapsing multiple sclerosis. The ATP-binding cassette, solute carrier, and nucleoside transporter substrate, inhibitor, and inducer characteristics of cladribine are reviewed in this article. Available evidence suggests that the distribution of cladribine across biological membranes is facilitated by a number of uptake and efflux transporters. Among the key ATP-binding cassette efflux transporters, only breast cancer resistance protein has been shown to be an efficient transporter of cladribine, while P-glycoprotein does not transport cladribine well. Intestinal absorption, distribution throughout the body, and intracellular uptake of cladribine appear to be exclusively mediated by equilibrative and concentrative nucleoside transporters, specifically by ENT1, ENT2, ENT4, CNT2 (low affinity), and CNT3. Renal excretion of cladribine appears to be most likely driven by breast cancer resistance protein, ENT1, and P-glycoprotein. The latter may play a role despite its poor cladribine transport efficiency in view of the renal abundance of P-glycoprotein. There is no evidence that solute carrier uptake transporters such as organic anion transporting polypeptides, organic anion transporters, and organic cation transporters are involved in the transport of cladribine. Available in vitro studies examining the inhibitor characteristics of cladribine for a total of 13 major ATP-binding cassette, solute carrier, and CNT transporters indicate that in vivo inhibition of any of these transporters by cladribine is unlikely.

Background: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study of patients with relapsing-remitting multiple sclerosis, treatment with cladribine tablets 3.5 mg/kg (CladT) significantly reduced the annualised relapse rate (ARR) versus placebo; this effect was sustained in CLARITY Extension, without further treatment. Objective: To assess the frequency and severity of relapses in patients treated with CladT versus placebo in CLARITY over 2 years and evaluate the durability of effect in patients who received no further treatment for 2 years in CLARITY Extension. Methods: In this post hoc analysis, ARRs were calculated for qualifying and all relapses, and qualifying and all severe relapses (i.e. requiring steroid treatment or leading to hospitalisation) in patients treated with CladT ( n = 433) and placebo ( n = 437) in CLARITY, and those from the CladT group who received placebo in CLARITY Extension ( n = 98). Results: At Month 6, Year 1 and Year 2, patients receiving CladT had a significantly lower risk of qualifying or all relapses (all p Conclusion: The results show durable efficacy of cladribine tablets 3.5 mg/kg for reducing frequency and severity of relapses in patients with relapsing-remitting multiple sclerosis. CLARITY: NCT00213135; CLARITY Extension: NCT00641537

What is this summary about? This is a summary of an article originally published in the Multiple Sclerosis Journal. The article presents the results from the CLARITY and CLARITY Extension studies, which looked at how well cladribine tablets work in treating people with multiple sclerosis (shortened to MS). Cladribine tablets are a medication approved for treating relapsing forms of MS. This study looked at how treatment with cladribine tablets affects the frequency and severity of relapses in people with MS. A relapse is when new symptoms develop or old symptoms return or get worse after a period of stability or improvement. What happened in the studies? In the CLARITY study, 870 people received either cladribine tablets (3.5 mg/kg, the approved dose) or placebo (a dummy pill). After the CLARITY study ended, some participants who received cladribine tablets chose to take part in a second study called the CLARITY Extension study. Of these participants, 98 were given placebo for 2 more years following an interval period of up to 10 months between participating in each study. What were the results? People with MS who were treated with cladribine tablets for 2 years in the CLARITY study had lower risks of any relapse compared with those given placebo. Participants taking placebo (after cladribine tablets) in the CLARITY Extension study experienced these same benefits, which continued for up to 3 more years after having received cladribine tablets in the CLARITY study. What do the results mean? Researchers concluded the recommended 2-year dosing of cladribine tablets may reduce the number and severity of relapses in people with MS for up to 5 years. Clinical Trial Registration: NCT00213135 ( ClinicalTrials.gov ) Clinical Trial Registration: NCT00641537 ( ClinicalTrials.gov )

Relapsing–remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine tab...

Cladribine is a purine nucleoside analog initially developed in the 1970s as a treatment for various blood cancers. Due to the molecule’s ability to preferentially reduce T and B lymphocytes, it has been developed into an oral formulation for the treatment of multiple sclerosis (MS). The unique proposed mechanism of action of cladribine allows for the therapy to be delivered orally over two treatment-week cycles per year, one cycle at the beginning of the first month and one cycle at the beginning of the second month of years 1 and 2, with the potential for no further cladribine treatment required in years 3 and 4. This review summarizes the clinical development program for cladribine tablets in patients with MS, including the efficacy endpoints and results from the 2-year phase III CLARITY study in patients with relapsing–remitting MS (RRMS), the 2-year CLARITY EXTENSION study, and the phase III ORACLE-MS study in patients with a first clinical demyelinating event at risk for developing MS. Efficacy results from the phase II ONWARD study, in which cladribine tablets were administered as an add-on to interferon-β therapy in patients with RRMS, are also summarized. A review of all safety data, including lymphopenia, infections, and malignancies, is provided based on data from all trials in patients with MS, including the initial parenteral formulation studies. Based on these data, cladribine tablets administered at 3.5 mg/kg over 2 years have been approved across the globe for various forms of relapsing MS. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review (MP4 279143 kb) Enhanced Digital Features To view enhanced digital features for this article, go to 10.1007/s40265-020-01422-9

Background We previously summarized outcomes for 46 cladribine tablets (CladT)-treated patients with multiple sclerosis (MS) and confirmed or suspected COVID-19, as reported to the Merck KGaA Global Patient Safety Database. This report updates on these findings, to 15 January 2021, for a total of 272 reported cases of COVID-19 among CladT recipients. Methods Case definitions: confirmed (COVID-19 diagnostic test was positive); suspected (no confirmatory test performed/reported). Cases fulfilling the criteria of hospitalized, medically significant, or fatal were designated as serious and outcomes were classified per usual pharmacovigilance practice. Results The evaluable cohort comprised 261 patients (confirmed COVID-19, n=160; suspected, n=101); an additional 11 patients had symptoms compatible with COVID-19 but were not evaluated further given their negative diagnostic tests. Median time to onset of COVID-19 from the most recent preceding CladT treatment course was 162 days (n=139). Outcomes were: recovered/recovering, n=133 (51%); not recovered/not resolved, n=19 (7%); died, n=1 (0.4%); and not reported/missing/pending, n=108 (41%). Of the total cohort, 40 (15%) experienced serious COVID-19. Conclusion Our results suggest that CladT-treated patients with MS are generally not at greater risk of serious disease and/or a severe outcome with COVID-19 compared with the general population and other patients with MS who acquired COVID-19.

Relapsing-remitting multiple sclerosis (RRMS) patients with high disease activity (HDA) experience more severe disease than those without HDA. This analysis describes the efficacy of cladribine tablets 3.5 mg/kg in HDA patient subgroups that were either treated with disease-modifying drugs (DMDs) prior to study entry or were treatment naïve.The DMD-naïve cohort (

In the Phase 3, 96-week ORACLE-MS study, cladribine 10 mg tablets (3.5 mg/kg or 5.25 mg/kg cumulative dose over 2 years) significantly reduced the rate of conversion to clinically definite multiple sclerosis (CDMS) per the Poser criteria (henceforth referred to as CDMS), multiple sclerosis (MS) per the 2005 McDonald criteria, and the number of new or persisting T1 gadolinium-enhancing (Gd+), new or enlarging T2, and combined unique active (CUA) lesions versus placebo in participants with a first clinical demyelinating event (FCDE). Patient demographic and disease characteristics may be predictors of disease progression. The current study analyzed the effect of cladribine tablets in subgroups of participants in the ORACLE-MS study by baseline demographics and disease characteristics.This analysis retrospectively examined data collected from 616 participants enrolled in the ORACLE-MS study (placebo, n=206; cladribine tablets 3.5 mg/kg, n=206; cladribine tablets 5.25 mg/kg, n=204). Five subgroups were predetermined by baseline demographics, including sex, age (30 or ≥30 years), classification of FCDE, and lesion characteristics, including absence or presence of T1 Gd+ lesions and number of T2 lesions (9 or ≥9). Selected endpoints of the ORACLE-MS study were re-analyzed for these subgroups. The primary and main secondary endpoints were time to conversion to CDMS and MS (2005 McDonald criteria), respectively. Secondary magnetic resonance imaging (MRI) endpoints included cumulative T1 Gd+ and new or enlarging T2 lesions. Cox proportional hazards models were used to evaluate time to conversion to CDMS and MS (2005 McDonald criteria). This analysis focused primarily on the results for the cladribine tablets 3.5 mg/kg group because this dosage is approved for relapsing forms of MS.In the overall intent-to-treat (ITT) population, cladribine tablets 3.5 mg/kg significantly reduced the risk of conversion to CDMS (hazard ratio [HR]=0.326; P0.0001) and MS (2005 McDonald criteria; HR=0.485; P0.0001) versus placebo. Similar effects of cladribine tablets on risk of conversion were observed in post hoc analyses of subgroups defined by various baseline characteristics. In both the ITT population and across subgroups, cladribine tablets 3.5 mg/kg reduced the numbers of cumulative T1 Gd+ (range of rate ratios: 0.106-0.399), new or enlarging T2 (range of rate ratios: 0.178-0.485), and CUA (range of rate ratios: 0.154-0.384) lesions versus placebo (all nominal P0.03). Multivariate Cox proportional hazards models revealed that age (HR=0.577, nominal P0.0001), FCDE classification (HR=0.738, nominal P=0.0043), presence of T1 Gd+ lesions (HR=0.554, nominal P0.0001), and number of T2 lesions (HR=0.417, nominal P0.0001) at baseline were factors associated with risk of conversion to MS (2005 McDonald criteria), whereas no baseline factors examined were associated with risk of conversion to CDMS.In this post hoc analysis of the ORACLE-MS study, cladribine tablets reduced the risk of conversion to multiple sclerosis and lesion burden in participants with an FCDE in the overall ITT population and multiple subgroups defined by baseline demographics and lesion characteristics.

Background The COVID-19 pandemic is a concern for people with multiple sclerosis (pwMS), especially those receiving disease-modifying therapies. Methods We previously summarized outcomes for 46 pwMS treated with cladribine tablets (CladT) and confirmed or suspected COVID-19, as reported to the Merck KGaA Global Patient Safety Database (Jack et al., 2020). Here, we report an update to January 15, 2021 for 272 reported cases of COVID-19 among CladT-treated pwMS. Case definitions: confirmed = COVID-19 diagnostic test reported as positive; suspected = no confirmatory test performed/reported. Cases fulfilling the criteria of hospitalized, medically significant or fatal were designated as serious, while outcomes were classified per usual pharmacovigilance practice. Results Evaluable cohort: 261 pwMS, median age 41 (range: 18–73) years, 70% female. Confirmed COVID-19, n=160; suspected, n=101 (an additional 11 pwMS with compatible COVID-19 symptoms were not evaluated further given negative PCR tests). Median time to COVID-19 since last CladT treatment course was 162 (range: 0–643) days (n=139). Outcomes: recovered/recovering, n=133 (51%); not recovered/not resolved, n=19 (7%); died, n=1 (0.5%); not reported/missing/pending, n=108 (41%). Of the evaluable cohort, 40 (15%) experienced serious COVID-19; demographics and outcomes were comparable among all patients. A single fatal case was reported of a woman aged 60 years with suspected COVID-19 who initiated CladT treatment in July 2019. No COVID-19 test result was reported. The patient died in December 2020. Conclusion CladT-treated pwMS do not appear to be at greater risk of serious disease and/or a severe outcome with COVID-19 versus the general and MS populations.

Background In the Phase 3, 96-week ORACLE-MS study, cladribine tablets 10 mg (3.5 or 5.25 mg/kg cumulative dosage over two years) significantly reduced lesions associated with multiple sclerosis versus placebo in participants following a first clinical demyelinating event (FCDE). Objective To determine the timing of effects of cladribine tablets on lesion activity assessed by magnetic resonance imaging (MRI). Methods This post hoc analysis assessed the effect of cladribine tablets versus placebo in ORACLE-MS on secondary MRI endpoints including T1 gadolinium-enhancing (Gd+), new or enlarging T2 lesions, and combined unique active lesions assessed on MRI scans performed at screening and every 3 months thereafter. Results Compared to placebo, cladribine tablets 3.5 mg/kg treatment appeared to lead to a trend of reductions in the mean number of T1 Gd+ lesions by Week 13 (first post-baseline scan: 0.37 vs. 1.00), new or enlarging T2 (0.20 vs. 1.01) and combined unique active (0.29 vs. 1.91) lesions by Week 24. Low lesion counts were maintained with cladribine tablets throughout 96 weeks. Similar results were observed with the 5.25 mg/kg dosage. Conclusion In participants with an FCDE, cladribine tablets appeared to reduce lesion numbers within 13 weeks (time of first evaluation).

Purpose: We applied Multi-Criteria Decision Analysis (MCDA) methods in a structured benefit–risk assessment of cladribine and newer approved disease-modifying drugs (DMDs) for patients with relapsing-remitting multiple sclerosis (RRMS). Methods: Decision conferencing with clinical neurologists as decision makers was used to create an MCDA model that incorporated available evidence on DMDs for RRMS and clinical judgments about the relevance of the evidence. Benefit–risk assessments were conducted for DMDs in both patients with RRMS and patients with RRMS with high disease activity (HDA; defined as ≥2 relapses in the previous year). Treatment options included cladribine and recently approved DMDs available in European Union countries at the time of assessment (December 2015): alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, and teriflunomide. To account for the relative importance of DMD effects, scores for the MCDA model were weighted to ensure that the most clinically important attributes carried more weight in the final benefit–risk calculation. The neurologists weighted different efficacy and safety profile attributes without any reference to individual DMDs to disassociate the assessment of weights with any specific DMD. The neurologists did not do direct comparisons between DMDs. Findings: The highest overall weighted preference value for the RRMS model was for dimethyl fumarate (63) followed closely by cladribine (62). For patients with RRMS and HDA, cladribine had the highest overall weighted preference value (76), followed by alemtuzumab (62) and natalizumab (61). The benefit–risk balance of cladribine in patients with RRMS and specifically patients with RRMS who exhibited HDA characterized by high relapse activity (≥2 relapses in the previous year) was more favorable than the other DMDs included in the model. Implications: The balance of high efficacy and the safety profile makes cladribine an important treatment option to consider, both in patients with RRMS and patients with HDA. Regular, single-country meetings could be organized to explore how differences in cultural values (scores and weights) and updated input data might affect the usefulness of MCDA in different, real-world, dynamic clinical settings.

Background: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19 + B cells and T cells, followed by reconstitution of adaptive immune function. Objective: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). Methods: Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD ® ; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. Results: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19 + B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4 + T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8 + cell counts never dropped below the threshold value. Conclusion: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.

IntroductionAn independent meta-analysis; Pakpoor et al. Neurol Neuroimmunol Neuroinflamm 2015;2:e158) in Phase III trials (with a 2 year duration) of disease modifying drugs (DMDs) in patients with relapsing multiple sclerosis found no increased rate of malignancy with cladribine tablets (CT) versus other DMD treatments. Data from additional trials involving CT 3.5 mg/kg (CT3.5) and a safety registry (up to 8 years’ follow-up) allow further insights into malignancy risk. Objective is to assess malignancy risk with CT3.5 monotherapy and placebo (PBO) in data from 3 Phase III trials and a registry, and compare the incidence rate with a global database.MethodsThe CT 3.5 population comprised 923 patients (3433 patient-years’ [PY] total exposure time) and the PBO group comprised 641 patients (2026 PY). Individual case reports of malignancies were reviewed by independent, blinded adjudication committee. Standardised incidence ratios (SIR) were calculated using the GLOBOCAN reference population (excluding non-melanoma skin cancers [NMSCs]) and a Danish reference population for NMSC rates.ResultsThe incidence per 100 PY of confirmed malignancy was CT3.5 0.293 (95%CI 0.158–0.544) and PBO 0.148 (95%CI 0.048–0.460); the risk difference 95% CI included 0 (−0.166–0.414). The CT 3.5 malignancy SIR was almost identical (0.97, 95% CI 0.44–1.85) to the GLOBOCAN matched reference population. The PBO group SIR was numerically lower (0.48, 95% CI 0.14–1.53). There were no cases of haematological, lymphoproliferative or virus-induced cancers. There was no clustering of specific tumour types, and the incidence of skin cancer was not increased after treatment with CT3.5 versus PBO. The incidence of malignancies with CT3.5 was constant and did not increase over time.ConclusionAnalysis of malignancy rates in a cohort that includes patients with up to 8 years’ follow-up confirms the Conclusion of the earlier meta-analysis; the incidence of malignancies with CT3.5 is similar to a matched reference population.

Objective: To compare the efficacy and the safety of recombinant human FSH (hFSH) with urinary hFSH for stimulating follicular development in women undergoing IVF-ET. Design: Multicenter, prospective, randomized, open, parallel group, clinical study. Setting: Eight European academic IVF units and one private IVF unit. Patient(s): Infertile female patients aged 18 to 38 years suffering from tubal disease, mild endometriosis, or unexplained infertility. Intervention(s): Pretreatment with buserelin acetate was followed by recombinant or urinary hFSH treatment started at an initial dose of 225 IU FSH/d. Dose adjustment was allowed after 5 days of FSH. After administration of hCG, a standard IVF-ET procedure was performed. Main Outcome Measure(s): Follicular development, oocyte retrieval, fertilized oocytes, duration and dose of FSH, and pregnancy. The hypothesis formulated before the study was that no difference was expected between the two FSH preparations. Result(s): Sixty patients were treated with recombinant hFSH and 63 with urinary hFSH. The mean number (±SD) of growing follicles (mean diameter >10 mm) was 10.3 ± 4.9 and 11.2 ± 5.2, of follicles (mean diameter >14 mm) was 7.8 ± 3.6 and 9.2 ± 4.5, of retrieved oocytes was 9.3 ± 5.0 and 10.7 ± 5.3, and of fertilized oocytes was 5.6 ± 3.8 and 6.5 ± 4.3, for recombinant and urinary hFSH, respectively. The duration of FSH treatment was 9.9 ± 2.3 and 9.4 ± 1.8 days and the average total dose was 2270 ± 714 and 2095 ± 591 IU of FSH, for recombinant and urinary hFSH, respectively. Thirteen pregnancies were recorded in the recombinant hFSH group and 11 in the urinary hFSH group. Nine patients delivered 13 live infants in the recombinant hFSH group and eight delivered 13 live infants in the urinary hFSH group. In terms of safety, no difference was recorded between the groups and no anti-FSH antibodies were found in any of the patients. Conclusion(s): This clinical study shows that recombinant hFSH is as safe and effective as urinary hFSH in stimulating ovarian follicular development.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) was given concurrently with low-dose cytosine arabinoside for 3 weeks to patients with myelodysplasia. Neutrophil activation as evidenced by increased chemiluminescence and reduced surface expression of CD16 was consistently seen during therapy. An attendant fall in chemotaxis was also observed. These effects occurred even when neutrophil counts did not rise significantly at lower doses of GM-CSF. Although no improvement in anaemia or thrombocytopenia was observed, the neutrophil counts became normal during therapy without significant expansion of marrow cellularity or colony-forming ability. No major toxicities were observed, even at higher dosages of GM-CSF.

Toxicity and clinical effects of a new brand of recombinant interleukin 2 (rIL2, Bioleukin™, Biogen, Geneva) were evaluated by a phase I study in 12 patients with stage III melanoma. Escalating doses from 100 μg/m2 to 800 μg/m2 were administered thrice a day with bolus injections given via a peripheral venous catheter for up to a maximum of 7 days. All patients showed malaise, fever and chills and mild gastrointestinal side effects. A modest electrolyte imbalance (hypocalcemia and hypokalemia) was detected in all 12 patients. Renal toxicity as judged by serum creatinine was not observed, and hepatic toxicity was moderate with the possible exception of one patient who had an unclear previous history of liver dysfunction. Mild, transient leukopenia was found in several patients, whereas thrombocytopenia developed in 4 patients; no anemia was observed. Cutaneous rash was seen in half of the patients treated. Fluid retention was minimal, with a weight gain associated to treatment that never exceeded 10% of pretreatment body weight. Electrocardiographic alterations developed in 2 patients in the form of ventricular and supraventricular extrasystoles. In 2 patients given the highest dose of rIL2, a significant reduction in transfer lung factor for carbon monoxide was seen, indicating alterations in pulmonary functions. Other dose-related toxicities were thrombocytopenia and malaise. All side effects disappeared 2-3 days after the end of rIL2 administration. No major responses were seen in association with the 4-8 days of treatment given in this study.

Twelve previously untreated patients with small cell lung carcinoma (SCLC) were treated with r-interferon-gamma (Immuneron, Biogen S.A., Geneva, Switzerland). The planned dose was 1 mg (28 X 10(6) mu)/ms daily for 5 days, followed by 0.5 mg/m2 three times a week for 3 weeks or until progression, whichever was first. Eight patients were fully evaluable, and there were no responses. In four of the eight, the disease remained stable for 1 month, and four progressed before this time. Toxic reactions included pyrexia, headache, and malaise, which were mild to moderate. Ten patients subsequently received conventional chemotherapy, which resulted in three complete and four partial responses. The mean duration of response to chemotherapy was 8 months. It is concluded that r-interferon-gamma, at the dose and schedule used, has no significant clinical activity in small cell lung carcinoma.

From January 1987 to February 1988, 15 stage IV melanoma patients were treated with two courses of bolus injection of rIL-2 plus LAK cell infusions at the National Cancer Institute of Milan. The original treatment regimen included a first course of rIL-2 administration (400 μg/m5 bolus injection 3 times a day [TID] for 4 days) and a second course of rIL-2 administration (800 μg/m2 bolus injection TID for 7 days) separated by 4 consecutive daily leukaphereses. Autologous lymphokine activated killer (LAK) cells were reinfused into each patient on three occasions during the second period of rIL-2 administration. Due to the appearance of grade III–IV neurological, hepatic and cardiopulmonary toxicity, 7 patients discontinued dosing before the end of treatment, one patient desired to be withdrawn and one patient died from rapidly progressive disease, although complications of rIL-2 administration may have contributed to her death. Only 6 patients completed the schedule without evidence of major intolerance, even though the planned dose during the second course of rIL-2 was reduced to 400 μg/m2. The complete duration of treatment ranged from 11 to 19 days. The total dose of rIL-2 injected ranged from 12.6 to 30.4 mg. The number of infused LAK cells ranged from 15.5x109 to 60x109/patient. Two of the 14 evaluable patients showed a minor anti-tumor response. In 5 patients new metastases in other sites were documented from 2 to 5 months after completion of dosing. No apparent association was found between progression of the disease (or the appearance of new metastases) and the total dose of rIL-2 injected, the number of LAK cells administered or the number of days of treatment. By December 1988, all patients had died of their disease in a period ranging from 3 to 14 months from the last injection of rIL-2. The lack of significant clinical responses in this study and the high toxicity of this treatment lead us to conclude that at least as far as melanoma patients are concerned, adoptive immunotherapy with rIL-2 plus LAK cells (as described here) is not a justifiable treatment option unless new evidence presents itself.

A phase-I study of the recombinant, non-mutagenized interleukin 2 (rIL2, BioleukinTM) was performed in 12 melanoma patients (Pts). From 100 to 800 micrograms/m2 of rIL2 were administered by i.v. bolus injection, TID for 4-8 days. Side-effects included fever, malaise, low serum K+ and Ca++ values, electrocardiographic abnormalities, leukopenia and thrombocytopenia. No major organ toxicity and no significant fluid retention were observed at the administered doses. Treatment induced a rapid depletion of peripheral blood lymphocytes (PBL) with a rebound (2-6 times the pre-treatment values), 24-48 hr after rIL2 discontinuation. PBL obtained between the 5th treatment day and the 2nd post-treatment day showed: (a) enhanced proliferation (II/12 Pts) with stimulation indexes of 6-52; (b) increased cytotoxicity against autologous tumor cells (2/2 Pts), allogeneic melanomas (5/7 Pts), the Daudi (5/6 Pts) and K562 cell lines (7/12 Pts); and (c) increased expression of IL2 receptors (8/12 Pts) and of DR antigens (6/12 Pts). Lymphocytes collected 1-2 days after treatment and activated in vitro with rIL2 showed a more rapid development of tumor cytotoxicity, with an earlier loss of activity. Spontaneous proliferation, autologous or allogeneic tumor cytotoxicity and expression of IL2 receptors obtained after in vivo treatment with rIL2 were significantly weaker than those induced during in vitro stimulation. No major objective responses were detected in these patients.