Cost of implementing CAR-T activity and managing CAR-T patients: an exploratory study.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T) represent an innovation but raise issues for healthcare payers because of the uncertainty on impact at market launch, high cost and important organisational impact. The literature has focused on their assessment, appraisal and market access solutions. No evidence on the costs sustained to implement CAR-T is available and a few studies reported the cost of the CAR-T clinical pathway, including the activities that are remunerated through inpatient or outpatient fee-for-service/episode. This paper aims at filling the information gap, assessing the cost of implementing CAR-T activity and the full cost of managing the CAR-T clinical pathway. METHODS: Cost analysis relied on the Activity Based Costing approach, which was applied to two Italian healthcare organisations, both CAR-T Centres authorized by the regional governments with a minimum of 20 patients treated with the first two CAR-T therapies launched on the market. RESULTS: The cost of implementing CAR-T was estimated at €1.31 million (calculated for one of the organizations with complete data). Most of these costs (77%) were generated by quality assurance activity. The mean cost per patient entering the CAR-T pathway (59 and 27) and surviving at follow-up (21 and 5) ranges from €48K to €57K and from €96K to €106K, respectively. Fees for hospitalization and infusion of gene therapy accounts for more than 70% of these costs. The actual hospitalisation cost varies greatly across patients and is in general lower than the fee-for-episode paid by the region to the hospital. CONCLUSIONS: Despite its limitations (exploratory nature; the time spent by staff on activities which are not remunerated through fees was estimated through interviews with the CAR-T coordinators; cost items are not fully comparable), this research highlighted the relevant organisational and economic impact of CAR-T and provided important insights for policy makers and healthcare managers: the necessity to invest resources in CAR-T implementation; the need for assessing activities which are not remunerated through fees for service / episode; the opportunity to shift from fee-for-episode / service to bundled payments for CAR-T clinical pathway.

Outcome of early treatment of SARS-CoV-2 infection in patients with haematological disorders.

Outcome of early treatment of COVID-19 with antivirals or anti-spike monoclonal antibodies (MABs) in patients with haematological malignancies (HM) is unknown. A retrospective study of HM patients treated for mild/moderate COVID-19 between March 2021 and July 2022 was performed. The main composite end-point was treatment failure (severe COVID-19 or COVID-19-related death). We included 328 consecutive patients who received MABs (n = 120, 37%; sotrovimab, n = 73) or antivirals (n = 208, 63%; nirmatrelvir/ritonavir, n = 116) over a median of two days after symptoms started; 111 (33.8%) had non-Hodgkin lymphoma (NHL); 89 (27%) were transplant/CAR-T (chimaeric antigen receptor T-cell therapy) recipients. Most infections (n = 309, 94%) occurred during the Omicron period. Failure developed in 31 patients (9.5%). Its independent predictors were older age, fewer vaccine doses, and treatment with MABs. Rate of failure was lower in the Omicron versus the pre-Omicron period (7.8% versus 36.8%, p < 0.001). During the Omicron period, predictors of failure were age, fewer vaccine doses and diagnosis of acute myeloid leukaemia/myelodysplastic syndrome (AML/MDS). Independent predictors of longer viral shedding were age, comorbidities, hospital admission at diagnosis, NHL/CLL, treatment with MABs. COVID-19-associated mortality was 3.4% (n = 11). The mortality in those who developed severe COVID-19 after early treatment was 26% in the Omicron period. Patients with HM had a significant risk of failure of early treatment, even during the Omicron period, with high mortality rate.

Dual combined antiviral treatment with remdesivir and nirmatrelvir/ritonavir in patients with impaired humoral immunity and persistent SARS-CoV-2 infection.

Despite global vaccination efforts, immunocompromized patients remain at high risk for COVID-19-associated morbidity. In particular, patients with impaired humoral immunity have shown a high risk of persistent infection. We report a case series of adult patients with B cell malignancies and/or undergoing B cell targeting therapies with persisting SARS-CoV-2 infection and treated with a combination antiviral therapy of remdesivir and nirmatrelvir/ritonavir, in three Italian tertiary academic hospitals. A total of 14 patients with impaired adaptive humoral immunity and prolonged SARS-CoV-2 infection were treated with the dual antiviral therapy. The median age was 60 (IQR 56-68) years, and 11 were male. Twelve patients had B cell lymphoma, one patient had chronic lymphocytic leukemia and one patient had multiple sclerosis. Thirteen out of 14 patients had received prior B cell-targeting therapies, consisting of anti-CD20 monoclonal antibodies in 11 patients, and chimeric antigen receptor T therapy in 2 patients. The median time between diagnosis and therapy start was 42.0 (IQR 35-46) days. Seven patients had mild, 6 moderate and one severe disease. Nine patients had signs of interstitial pneumonitis on chest computed tomography scans before treatment. The median duration of nirmatrelvir/ritonavir and remdesivir combination therapy was 10 days. All patients showed resolution of COVID-19-related symptoms after a median of 6 (IQR 4-11) days and viral clearance after 9 (IQR 5-11) days. Combination therapy with remdesivir and nirmatrelvir/ritonavir is a promising treatment option for persistent COVID-19 in immunocompromized patients with humoral immunity impairment, worthy of prospective comparative trials.

The classic prognostic factors in advanced Hodgkin's lymphoma patients are losing their meaning at the time of Pet-guided treatments.

The International Prognostic Score (IPS) is the most commonly used risk stratification tool for patients with advanced Hodgkin lymphoma (HL). It incorporates seven clinical parameters independently associated with a poorer outcome: male sex, age, stage IV, hemoglobin level, white blood cell and lymphocyte counts, and albumin level. Since the development of the IPS, there have been significant advances in therapy and supportive care. Recent studies suggest that the IPS is less discriminating due to improved outcomes with ABVD therapy. The aim of the present study was to asses if classic prognostic factors maintain their prognostic meaning at the time of response-adapted treatment based on interim PET scans. We evaluated the prognostic significance of IPS in the 520 advanced stage HL patients enrolled in the PET-guided, HD0801 trial in which PET2-positive patients underwent a more intense treatment with an early stem-cell transplantation after 2 cycles of ABVD. We observed that in these patients, the IPS completely loses its prognostic value together with all the single parameters that contribute to the IPS. Furthermore, neutrophils, monocytes, lymphocytes, and the ratio among them also no longer had any predictive value. We believe that the substantial improvement in survival outcomes in PET2-positive patients treated with early autologous transplantation could explain the complete disappearance of the residual prognostic significance of the IPS.

Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial.

BACKGROUND: Up to 40% of elderly patients with untreated diffuse large B-cell lymphoma (DLBCL) given a regimen of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone every 21 days (R-CHOP21) relapse or develop refractory disease. Lenalidomide has high activity in relapsed or refractory aggressive B-cell lymphomas. In phase 2 of the REAL07 trial, we aimed to establish the safety and efficacy of the combination of lenalidomide and R-CHOP21 in elderly patients with untreated DLBCL. METHODS: REAL07 was an open-label, multicentre trial that was done in 13 centres in Italy and one in Germany. Eligible patients were aged 60-80 years; had newly diagnosed, untreated, CD20-positive, Ann Arbor stage II-IV DLBCL or grade 3b follicular lymphoma; had an Eastern Cooperative Oncology Group performance status of 0-2; had an International Prognostic Index (IPI) risk of low-intermediate, intermediate-high, or high; and were fit according to comprehensive geriatric assessment. Participants were to receive 15 mg oral lenalidomide on days 1-14 of six 21-day cycles, and standard doses of R-CHOP21 chemotherapy (375 mg/m(2) intravenous rituximab, 750 mg/m(2) intravenous cyclophosphamide, 50 mg/m(2) intravenous doxorubicin, and 1·4 mg/m(2) intravenous vincristine on day 1, and 40 mg/m(2) oral prednisone on days 1-5). The primary endpoint was frequency of overall response (complete response [CR] and partial response [PR]), which was assessed by (18)F-fluorodeoxyglucose ((18)F-FDG) PET at the end of the treatment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00907348. FINDINGS: 49 patients were included in phase 2: nine had been enrolled into phase 1 between Oct 23, 2008, and June 4, 2009, and had received the maximum tolerated dose of 15 mg lenalidomide; and 40 were enrolled into phase 2 between April 28, 2010, and June 3, 2011. 45 patients (92%, 95% CI 81-97) achieved a response (42 [86%] CR; three [6%] PR). Three patients (6%) did not respond and one (2%) died for reasons unrelated to treatment or disease. 277 (94%) of 294 planned cycles of lenalidomide and R-CHOP21 were completed. Grade 3-4 neutropenia was reported in 87 cycles (31%), grade 3-4 leukopenia in 77 (28%), and grade 3-4 thrombocytopenia in 35 (13%). No grade 4 non-haematological adverse events were reported. No patients died during the study as a result of toxic effects. INTERPRETATION: Lenalidomide with R-CHOP21 is effective and safe in elderly patients with untreated DLBCL. FUNDING: Fondazione Italiana Linfomi and Celgene.

The role of surgery for haematologic neoplasms of bone.

We report on 205 patients with haematologic neoplasms of bone treated from 1985 to 2009. There were 77 patients with primary bone lymphoma, 77 with myeloma and 51 with plasmacytoma. All patients had medical treatments; 43 patients had wide and 162 intralesional surgery. Mean follow-up was 5 years (median, 3.5 years); 11 patients were lost to followup. At the latest examination, 99 patients were alive without disease, 20 were alive with disease and 75 were dead of disease; 13 patients (6.7%) had local recurrence; 12 patients (24%) with plasmacytoma developed myeloma. Survival to death was significantly higher after wide resection for lymphoma and plasmacytoma, but not for myeloma. Survival to local recurrence was not statistically different between wide and intralesional surgery for any haematologic neoplasm. Surgical complications including aseptic loosening, infection, neurological deficits and breakage of implants occurred in 21 patients (11%).

CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group.

BACKGROUND: The MInT study was the first to show improved 3-year outcomes with the addition of rituximab to a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimen in young patients with good-prognosis diffuse large-B-cell lymphoma. Extended follow-up was needed to establish long-term effects. METHODS: In the randomised open-label MInT study, patients from 18 countries (aged 18-60 years with none or one risk factor according to the age-adjusted International Prognostic Index [IPI], stage II-IV disease or stage I disease with bulk) were randomly assigned to receive six cycles of a CHOP-like chemotherapy with or without rituximab. Bulky and extranodal sites received additional radiotherapy. Randomisation was done centrally with a computer-based tool and was stratified by centre, bulky disease, age-adjusted IPI, and chemotherapy regimen by use of a modified minimisation algorithm that incorporated a stochastic component. Patients and investigators were not masked to treatment allocation. The primary endpoint was event-free survival. Analyses were by intention to treat. This observational study is a follow-up of the MInT trial, which was stopped in 2003, and is registered at ClinicalTrials.gov, number NCT00400907. FINDINGS: The intention-to-treat population included 410 patients assigned to chemotherapy alone and 413 assigned to chemotherapy plus rituximab. After a median follow-up of 72 months (range 0·03-119), 6-year event-free survival was 55·8% (95% CI 50·4-60·9; 166 events) for patients assigned to chemotherapy alone and 74·3% (69·3-78·6; 98 events) for those assigned to chemotherapy plus rituximab (difference between groups 18·5%, 11·5-25·4, log-rank p<0·0001). Multivariable analyses showed that event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI and that overall survival was affected by treatment group and presence of bulky disease only. After chemotherapy and rituximab, a favourable subgroup (IPI=0, no bulk) could be defined from a less favourable subgroup (IPI=1 or bulk, or both; event-free survival 84·3% [95% CI 74·2-90·7] vs 71·0% [65·1-76·1], log-rank p=0·005). 18 (4·4%, 95% CI 2·6-6·9) second malignancies occurred in the chemotherapy-alone group and 16 (3·9%, 2·2-6·2) in the chemotherapy and rituximab group (Fisher's exact p=0·730). INTERPRETATION: Rituximab added to six cycles of CHOP-like chemotherapy improved long-term outcomes for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows a more refined therapeutic approach to these patients than does assessment by IPI alone. FUNDING: Hoffmann-La Roche.

Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity.

Chimeric antigen receptor (CAR) T-cell therapy is an emerging highly effective treatment for refractory haematological malignancies. Unfortunately, its therapeutic benefit may be hampered by treatment-related toxicities, including neurotoxicity. Early aggressive treatment is paramount to prevent neurological sequelae, yet it potentially interferes with the anti-cancer action of CAR T-cells. We describe four CAR T-cells infused patients who presented with reiterative writing behaviours, namely paligraphia, as an early manifestation of neurotoxicity, and eventually developed frontal predominant encephalopathy (one mild, three severe). Paligraphia may represent an early, specific, and easily detectable clinical finding of CAR T-cell therapy-related neurotoxicity, potentially informing its management.

Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study.

BACKGROUND: The definition and role of bulky disease in young patients (ie, aged 18-60 years) with good-prognosis diffuse large-B-cell lymphoma (DLBCL), who have been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-like chemotherapy with or without rituximab, remain controversial. We aimed to assess the effect of maximum tumour diameter (MTD) in these patients. METHODS: Patients from the MInT (Mabthera International Trial Group) study were eligible. We analysed event-free (EFS) and overall survival (OS) after CHOP-like chemotherapy with or without rituximab, according to MTD, by Martingale residual analyses and Cox regression models. Radiotherapy was given to sites of primary bulky disease according to national standards, and to primary extranodal disease at physician discretion. The primary endpoint was EFS and the secondary endpoint was OS. Analyses were by intention to treat. FINDINGS: Of the 824 patients enrolled in the MInT study, the informed-consent form of one patient was missing, leaving 823 patients evaluable for intention-to-treat analysis. Data on MTD of involved sites were available for 802 patients. Martingale residual analysis showed an adverse prognostic effect of MTD on EFS and OS, which increased linearly. In a multivariable analysis with MTD as a linear regression variable, the effect of MTD was significant after CHOP-like treatment alone for EFS (hazard ratio 1.090 [95% CI 1.051-1.130], p < 0.0001) and OS (1.119 [1.057-1.184], p = 0.0001), and after CHOP-like treatment and rituximab for OS (1.089 [1.003-1.183], p = 0.043), but not for EFS (1.044 [0.991-1.099], p=0.103). For CHOP-like treatment alone, 3-year EFS ranged from 78.2% (MTD < 5.0 cm, 95% CI 68.3-85.4) to 41.3% (MTD > or = 10.0 cm, 31.8-50.4). For CHOP-like treatment and rituximab, 3-year EFS ranged from 83.2% (MTD < 5.0 cm, 72.8-89.9) to 72.7% (MTD > or = 10.0 cm, 63.8-79.7). With CHOP-like treatment alone, 3-year OS decreased from 92.9% (MTD < 5.0 cm, 84.9-96.8) to 73.5% (MTD > or = 10.0 cm, 63.9-81.0); for CHOP-like treatment and rituximab, 3-year OS decreased from 98.0% (MTD < 5.0 cm, 92.2-99.5) to 85.2% (MTD > or = 10.0 cm, 77.0-90.6). For CHOP-like treatment, any cut-off point between 5.0 cm and 10.0 cm separated two populations with a significant EFS difference (p < 0.0001 for all log-rank tests) and OS difference (p < or = 0.003 for all log-rank tests). For CHOP-like treatment and rituximab, only a cut-off point of 10.0 cm separated two populations with a significant EFS difference (log-rank p = 0.047), but any cut-off point of 6.0 cm or more separated two populations with a significant OS difference (log-rank p values 0.0009-0.037). INTERPRETATION: Rituximab decreased, but did not eliminate the adverse prognostic effect of MTD in young patients with good-prognosis DLBCL. Due to the linear prognostic effect of MTD on outcome, arbitrary cut-off points for bulky disease can be set between 5.0 cm and 10.0 cm, depending on clinical considerations. Based on this study, a cut-off point of 10.0 cm might be a suitable margin in the rituximab era to delineate those patients with bulky disease.

Diagnostic role of 18F-FDG PET in gastric MALT lymphoma.

BACKGROUND: The aim of the study was to evaluate the usefulness of 18F-FDG-PET in patients with gastric lymphoma, in particular those affected by mucosa-associated lymphoid tissue (MALT) type and aggressive gastric non-Hodgkin's lymphoma (NHL). MATERIAL AND METHODS: The study group consists of 15 patients with a previous diagnosis of gastric NHL referred to our PET centres in Bologna Hospital and Rovigo Hospital, Italy, in the period 2003-2004. In 9/15 patients the subsequent histological evaluation was consistent with a gastric MALT lymphoma, while aggressive gastric NHL was diagnosed in the other 6/15. PET scan was carried out in patients with known active disease in order to stage or re-stage disease prior to treatment or in patients in complete clinical remission to monitor disease during follow up. Patients were considered in complete clinical remission if free from disease for at least 8 months after chemotherapy or surgery.18F-FDG PET was performed following standard procedures. RESULTS: Overall 18F-FDG-PET was true positive in all cases of gastric MALT and non-MALT aggressive NHL with known active disease, while no pathological 18F-FDG uptake was evident in the subjects who were in complete clinical remission. The degree of 18F-FDG uptake (mean SUVmax values) in MALT lymphoma was much less intense in comparison to aggressive gastric NHL, suggesting a prognostic role of SUV calculation in gastric lymphomas. CONCLUSION: Our data demonstrate the significant accuracy of 18F-FDG-PET in detecting active disease in gastric lymphoma of both MALT and non-MALT NHL type. A higher SUV value appears to be related to a more aggressive disease.

Phase II study of a single pegfilgrastim injection as an adjunct to chemotherapy to mobilize stem cells into the peripheral blood of pretreated lymphoma patients.

BACKGROUND AND OBJECTIVES: The aim of this study was to evaluate the efficacy of pegfilgrastim, in combination with salvage chemotherapy, in mobilizing CD34(+) stem cells into the peripheral blood of pretreated lymphoma patients. DESIGN AND METHODS: This was an open-label phase II study including 25 pretreated patients (Hodgkin's disease=4; aggressive non-Hodgkin's lymphoma=21). The primary end-point of the study was the successful mobilization of a target cell dose of 2x10(6) CD34(+) cells/kg in lymphoma patients receiving ifosfamide, epirubicin and etoposide (IEV) chemotherapy and a fixed dose (6 mg) of pegfilgrastim given as single subcutaneous injection. RESULTS: Following chemotherapy, all patients had grade 4 neutropenia that lasted a median of 1.5 days (1-3). Pegfilgrastim treatment was well tolerated and only 2/25 patients required pain-control medication. CD34+ cells were mobilized in all patients. The median (range) peak value of peripheral blood CD34+ cells after IEV chemotherapy and pegfilgrastim was 141x10(6)/L (12.8-386) and occurred almost invariably on day +14 (13-16). Twenty-three of the 25 patients underwent a single standard volume leukapheresis to collect a median of 8.7x10(6) CD34(+) cells/kg (1.78-17.3). Twenty four/25 patients (96%) reached the target cell dose of 2x10(6) CD34(+) cells/kg. High concentrations of circulating CD34+ cells (> 50x10(6)/L) were observed for several days after the achievement of the peak value. All the study patients were transplanted with their pegfilgrastim-mobilized CD34(+) cells and showed a rapid and sustained engraftment after high-dose chemotherapy. INTERPRETATION AND CONCLUSIONS: Our results show that pegfilgrastim as an adjunct to chemotherapy is a predictable and highly effective mobilization regimen in pretreated lymphoma patients.

Potential pitfalls of 18F-FDG PET in a large series of patients treated for malignant lymphoma: prevalence and scan interpretation.

OBJECTIVE: To evaluate the prevalence and scan interpretation criteria useful in identifying non-tumoural F-FDG focal uptakes (potential pitfalls) in patients who had been previously treated for a malignant lymphoma studied by positron emission tomography (PET). MATERIALS: Nine hundred and ninety-six consecutive PET scans obtained in 706 patients with malignant lymphoma were reviewed. All patients had been previously treated by first-line chemo-radiotherapy, plus surgery when required, and were then studied by FDG PET to investigate suspected recurrence at doubtful or inconclusive conventional radiological imaging (ultrasound, computed tomography, magnetic resonance imaging). PET was obtained with patients in the fasted condition and after i.v. injection of 370 MBq of F-FDG; imaging was acquired 60-90 min later. In patients with focal FDG uptake the final diagnosis was reached on the basis of histological findings or long-term follow-up. RESULTS: Thirty-one of 134 PET scans (23.1%) showing focal FDG uptake were diagnosed as non-tumoural radiotracer uptake, related to the presence of brown fat in seven cases, thymic hyperplasia in five, muscles contraction in four, lymph node unspecific inflammation in four, mediastinal/pulmonary unspecific inflammation in four, gastritis in two, colitis in two, bacterial abscess in one, lactating breast in one, and herpes zoster in one. Each of the above cited situations has been reported in the literature, generally in the form of sporadic reports, as a potential cause of misinterpretation (false positive) in reading a PET scan with the potential for incorrect patient management. An accurate diagnosis in these patients was important for the following therapeutic decision making. CONCLUSIONS: In the whole series of patients with treated malignant lymphoma, the prevalence of non-tumoural FDG focal uptake during follow-up was relatively low (3.1%); conversely, it was relatively high when considering the sub-group of 'positive' PET only (23.1%). The importance of knowing these situations in order to avoid misinterpretation in reading PET scans needs to be emphasized. In this light, an accurate patient's history and a skilful nuclear medicine physician are very important factors. For the same purpose, it is reasonable to think that the use of hybrid PET/CT tomographs could also play an important role in helping to identify non-tumoural FDG focal uptake.

Primary non-Hodgkin's lymphoma of the bone: treatment and analysis of prognostic factors for Stage I and Stage II.

PURPOSE: Primary non-Hodgkin's lymphomas of the bone (PLB) are very rare diseases accounting for 3%-5% of primary bone tumors. The best treatment for PLB has not been found yet. We report on the experience of the Radiation Oncology Department of Bologna University, Italy, relative to the diagnosis and treatment of this disease. METHODS AND MATERIAL: Seventy-seven patients with newly diagnosed PLB were treated from June 1983 to October 2001. Fifty-six were male (72.7%) and 21 were female (27.3%); the median age was 41.8 years, with a range of 16-84 years. The majority of patients had B-cell high-grade histology. The median follow-up was 149 months. Forty-four patients had a solitary bone lesion (Stage I); and in 33 patients, the tumor was spread to locoregional lymphatic area (Stage II). All patients were treated with radiotherapy (RT) with a median dose of 40 Gy (range, 36-54 Gy), and 67 received an additional anthracycline-based regimen of chemotherapy (combined modality therapy [CMT]). RESULTS: After therapy 73 of 77 patients (94.8%) reached a complete remission. At a median time of 23 months, 14 of 77 patients (18.2%) had a disease relapse. Four of them were treated with RT alone (in these cases tumor lesions were <3 cm and located at sites different from mandible); 10 patients were treated with combined RT and CMT. Actuarial disease-free survival (DFS) and overall survival (OS) at 15 years were, respectively, 76.6% and 88.3%. No local failures were seen. Prognostic factors such as age, sex, stage, and bulky lesions were analyzed. Age (<40 vs. >40 years) was the only significant factor for DFS (85.3% vs. 66.6%, p = 0.03). Bulky lesions apparently did not affect OS (90.9% vs. 72.7%). However, the difference has no statistical significance (p = 0.05). Acute and late toxicity related to the treatment was moderate. CONCLUSIONS: In PLB the CMT seems to produce a better outcome than RT alone; that still remains the best treatment for local disease control. Radiation therapy alone should be reserved for mandibular tumors, which are usually very small and earlier diagnosed.

Fludarabine + prednisone +/- alpha-interferon followed or not by alpha-interferon maintenance therapy for previously untreated patients with chronic lymphocytic leukemia: long term results of a randomized study.

BACKGROUND AND OBJECTIVES: Fludarabine is an effective therapy for patients with chronic lymphocytic leukemia (CLL) and interferon-alpha (IFN-alpha) has been reported to have anti-leukemic activity in CLL patients. A randomized study was designed to evaluate whether the addition of IFN-alpha to a first-line treatment with fludarabine and prednisone could increase the response rate in patients with advanced CLL and whether IFN-alpha given as maintenance therapy could improve the duration of response. DESIGN AND METHODS: One hundred and thirty-three patients were randomized to receive fludarabine (25 mg/m2/i.v., days 9-13) and prednisone (20 mg/m2, days 1, 3, 5, 7 and 14 and 40 mg/m2, days 9-13) (arm A: 66 patients) or in addition to the same schedule, IFN-alpha (2 MUI/sc, days 1, 3, 5, 7, 9, 11, 13 and 15) (arm B: 67 patients). Seventy-eight patients responsive to therapy entered the post-remission phase of the study in which 41 patients were randomized to receive IFN-alpha (3 MUI three times a week) and 37 to clinical observation. RESULTS: A similar response rate (complete responses + partial responses) was observed in the 2 arms: 86% for arm A and 84% for arm B (p = 0.4). A longer response duration was observed in patients who achieved a complete response (p = 0.001) and in patients who received maintenance therapy with IFN-alpha (p < 0.05). However, the quality of response was the only significant and independent factor influencing response duration (p < 0.01). No benefits in terms of infection-related mortality and morbidity could be ascribed to IFN-alpha administration. INTERPRETATION AND CONCLUSIONS: In previously untreated CLL patients with advanced disease a high response rate is obtained from first-line fludarabine and prednisone and no benefit is derived from the addition of IFN-alpha to this regimen. The achievement of a good quality response to therapy was the only independent predictor of a prolonged response.