Ralph Naumann

Use of Positron Emission Tomography for Response Assessment of Lymphoma: Consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma

PURPOSE To develop guidelines for performing and interpreting positron emission tomography (PET) imaging for treatment assessment in patients with lymphoma both in clinical practice and in clinical trials. METHODS An International Harmonization Project (IHP) was convened to discuss standardization of clinical trial parameters in lymphoma. An imaging subcommittee developed consensus recommendations based on published PET literature and the collective expertise of its members in the use of PET in lymphoma. Only recommendations subsequently endorsed by all IHP subcommittees were adopted. RECOMMENDATIONS PET after completion of therapy should be performed at least 3 weeks, and preferably at 6 to 8 weeks, after chemotherapy or chemoimmunotherapy, and 8 to 12 weeks after radiation or chemoradiotherapy. Visual assessment alone is adequate for interpreting PET findings as positive or negative when assessing response after completion of therapy. Mediastinal blood pool activity is recommended as the reference background activity to define PET positivity for a residual mass > or = 2 cm in greatest transverse diameter, regardless of its location. A smaller residual mass or a normal sized lymph node (ie, < or = 1 x 1 cm in diameter) should be considered positive if its activity is above that of the surrounding background. Specific criteria for defining PET positivity in the liver, spleen, lung, and bone marrow are also proposed. Use of attenuation-corrected PET is strongly encouraged. Use of PET for treatment monitoring during a course of therapy should only be done in a clinical trial or as part of a prospective registry.

Rituximab Added to First-Line Mitoxantrone, Chlorambucil, and Prednisolone Chemotherapy Followed by Interferon Maintenance Prolongs Survival in Patients With Advanced Follicular Lymphoma: An East German Study Group Hematology and Oncology Study

PURPOSE Rituximab has been shown to be active in follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. We conducted a randomized trial comparing mitoxantrone, chlorambucil, and prednisolone (MCP) chemotherapy plus rituximab with MCP alone. PATIENTS AND METHODS Previously untreated patients with stage III or IV CD20+ indolent or mantle cell lymphoma were randomly assigned to either eight 28-day cycles of MCP plus rituximab (R-MCP; n = 181) or eight cycles of MCP alone (n = 177). All patients who achieved a complete or partial remission were treated with interferon maintenance until relapse. Herein, we report the results from the primary analysis population of patients with FL, who constituted the majority of patients (56%) recruited to the trial (n = 201; R-MCP, n = 105; MCP, n = 96). RESULTS Rates of overall and complete response were significantly higher in the R-MCP arm than the MCP arm (overall response, 92% v 75%, respectively; P = .0009; complete response, 50% v 25%, respectively; P = .004). With a median follow-up time of 47 months, median event-free survival (EFS) and progression-free survival (PFS) times were significantly prolonged with R-MCP compared with MCP (EFS, not reached v 26 months, respectively; P < .0001; PFS, not reached v 28.8 months, respectively; P < .0001), and overall survival (OS) was significantly improved with R-MCP compared with MCP (4-year OS rate, 87% v 74%, respectively; P = .0096). CONCLUSION The R-MCP regimen significantly improves complete and overall response rates, EFS, PFS, and OS in patients with previously untreated advanced FL, without a clinically significant increase in toxicity.

A systematic review of phase‐II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised‐controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase‐II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty‐two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400–600 mg/d in 10 and 200 mg/d in one trial. The intention‐to‐treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29·4% (95%‐confidence interval, 27–32%). The rates for minor responses or stable disease were 13·8% (12–16%) and 11·0% (9–13%). Progressive disease was reported in 9·9% (8–11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III–IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo‐embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29·4% of patients with relapsed or refractory multiple myeloma.

Prognostic value of positron emission tomography in the evaluation of post‐treatment residual mass in patients with Hodgkin's disease and non‐Hodgkin's lymphoma

The prognostic value of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) in the assessment of post‐treatment residual masses in patients with Hodgkins disease (HD) or non‐Hodgkins lymphomas (NHL) was evaluated. We prospectively studied 58 patients with HD (n = 43) or NHL (n = 15) who had post‐therapeutic complete remission with residual masses (CRu) indicated by computerized tomography. Analysis of 62 residual locations by FDG‐PET was performed separately for HD and NHL. Patients with a PET‐positive residual mass [standardized uptake value (SUV) > 3] had a recurrence rate of 62·5% (5/8 patients), whereas patients with PET‐negative residual mass (SUV ≤ 3·0) showed a recurrence rate of 4% (2/50 patients, P = 0·004). A positive FDG‐PET study correlated with a significantly poorer progression‐free survival (P < 0·00001). No recurrence occurred in any of the 39 HD patients with a negative PET scan (negative predictive value, 100%). Four out of four NHL patients with a positive PET study relapsed (positive predictive value, 100%). In conclusion, FDG‐PET is a suitable non‐invasive method with a high degree of accuracy in the prediction of early recurrence in lymphoma patients with CRu.

High Rates of Durable Responses With Anti-CD22 Fractionated Radioimmunotherapy: Results of a Multicenter, Phase I/II Study in Non-Hodgkin's Lymphoma

PURPOSE Fractionated radioimmunotherapy targeting CD22 may substantially improve responses and outcome in non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS A multicenter trial evaluated two or three weekly infusions of yttrium-90 ((90)Y) epratuzumab tetraxetan (humanized anti-CD22 antibody) in 64 patients with relapsed/refractory NHL, including 17 patients who underwent prior autologous stem-cell transplantation (ASCT). Objective (OR) and complete responses (CR/complete response unconfirmed [CRu]), as well as progression-free survival (PFS), were determined. RESULTS At the maximum total (90)Y dose of 45 mCi/m(2) (1,665 MBq/m(2)), grade 3 to 4 hematologic toxicities were reversible to grade 1 in patients with less than 25% bone marrow involvement. The overall OR rate and median PFS for all 61 evaluable patients was 62% (CR/CRu, 48%) and 9.5 months, respectively. Patients without prior ASCT obtained high OR rates of 71% (CR/CRu, 55%) across all NHL subtypes and (90)Y doses, even in poor-risk categories (refractory to last anti-CD20-containing regimen, 73% [CR/CRu, 60%]; bulky disease: 71% [CR/CRu, 43%]). Patients with prior ASCT received lower doses, but achieved an OR rate of 41% (CR/CRu, 29%). For patients with follicular lymphoma (FL), OR rates and median PFS increased with total (90)Y-dose, reaching 100% (CR/CRu, 92%) and 24.6 months, respectively, at the highest dose levels (> 30 mCi/m(2) total (90)Y-dose [1,110 MBq/m(2)]). Further, patients with FL refractory to prior anti-CD20-containing regimens achieved 90% (nine of 10 patients) OR and CR/CRu rates and a median PFS of 21.5 months. CONCLUSION Fractionated anti-CD22 radioimmunotherapy provides high total doses of (90)Y, yielding high rates of durable CR/CRus in relapsed/refractory NHL, resulting in 20 mCi/m(2) x 2 weeks as the recommended dose for future studies.

A systematic review of phase II trials of thalidomide/dexamethasone combination therapy in patients with relapsed or refractory multiple myeloma

Thalidomide monotherapy in relapsed/refractory multiple myeloma (MM) has a response rate of 30%. The combination of thalidomide with dexamethasone (Thal/Dex) is expected to improve responses, but it is unknown if the combination increases the rate of adverse events. Here, we conducted a systematic review of studies evaluating Thal/Dex in relapsed/refractory MM. Twelve studies were included, comprising 451 patients. The response rate (CR and PR) was 46% (95% CI 42–51%). Therapy‐related toxicity was comparable to thalidomide monotherapy and included somnolence (26%, 95% CI 22–31%), constipation (37%, 95% CI 32–42%) and peripheral neuropathy (27%, 95% CI 23–32%). Only venous thromboembolism appeared to occur more often with Thal/Dex (5%, 95% CI 3–8%). Thus, using Thal/Dex results in an improved response rate in relapsed/refractory MM, with a toxicity rate comparable to thalidomide monotherapy.

Lenalidomide in patients with refractory or multiple relapsed Hodgkin lymphoma

Most Hodgkin Lymphoma (HL) patients can be cured with chemotherapy, radiotherapy or combined modality treatment. However, current treatment is associated with toxicities, such as infertility, cardiovascular damage and secondary malignancies (Fuchs et al, 2006). Moreover, about 10% of all HL patients have refractory disease despite high dose chemotherapy and autologous or allogeneic stem cell transplantation (Cashen & Bartlett, 2008; Laport, 2008; Sureda et al, 2008). Lenalidomide (Revlimid), a thalidomide-derivate, belongs to a novel class of immunomodulatory drugs (IMIDs) approved for the treatment of Multiple Myeloma and Myelodysplastic Syndrome with deletion (-q5) (ChananKhan & Cheson, 2008). Lenalidomide has multiple modes of action, including direct induction of apoptosis in tumour cells, antiangiogenic effects and the activation of immune cells, such as Natural Killer cells and T-cells (Marriott et al, 2001; Bartlett et al, 2004). Apoptosis resistance, increased neoangiogenesis and impaired immunity critically contribute to HL (Re et al, 2005; Enblad et al, 2007). We therefore hypothesized that single agent lenalidomide might be active in HL patients who have failed conventional chemotherapy. Lenalidomide was provided by Celgene (Munich, Germany) for each individual patient within a named patient program. Between February 2007 and November 2008, 12 patients with relapsed or refractory HL were included in this program in four German centres (Table I). Participants gave written informed consent, had no curative treatment options, an Eastern Cooperative Oncology Group performance status £2 and normal organ functions including peripheral blood counts within the normal range. Patients received oral Lenalidomide 25 mg/d for 21 d of a 28-day cycle. Patients were staged and restaged with computed tomography (CT) of the initially involved sites; the use of PET was optional. Response was defined according to the National Cancer institute Sponsored International Working Group criteria (Cheson et al, 1999) and evaluated after two cycles and every other cycle thereafter. Treatment was continued until disease progression or intolerable toxicity occurred. Concomitant anti-thrombotic prophylaxis with oral acetylsalicylic acid 100 mg/d was mandatory. Patients with a history of thrombosis or thrombembolic events received low molecular heparin. All patients were informed regarding the teratogenic risks of lenalidomide and agreed to use effective contraception at least during treatment and 4 weeks afterwards. Toxicities were assessed at each study visit according to National Cancer Institute Common Terminology Criteria (CTC) for Adverse Events version 3.0 (http://ctep.cancer.gov/protocolDevelopment/electronic_ applications/docs/ctcaev3.pdf). Twelve adult patients (median age 34Æ5 years, range 20– 64 years) with relapsed (Patients 4 and 8) or refractory HL (all other patients) were treated with single-agent lenalidomide. Two patients had lymphocyte predominant HL, all other patients had classical HL; nodular sclerosis was the most frequent histological subtype. All patients had relapsed after at least four chemotherapies (mean 6, range 4–9 previous therapies) and 10 of the 12 patients had advanced-stage disease. All but two patients had previously undergone highdose chemotherapy and autologous stem cell transplantation; one patient had relapsed after allogeneic stem cell transplantation. Most patients (10 of 12) had not responded to the previous treatment. One patient discontinued lenalidomide because of asymptomatic pulmonary embolism, which was detected on a routine CT scan. One patient withdrew consent after two cycles of lenalidomide. All other patients completed a minimum of four treatment cycles. None of the patients received concomitant medication other than anticoagulation. Four patients continued the treatment after the first four cycles and three patients are currently still on treatment. The mean number of cycles applied to date was 7 (range 2–25). Overall toxicity was very low with no toxicity occurring with a CTC grade above 2. Non-haematological toxicities observed were one CTC grade-2 pulmonary embolism in a patient who discontinued the treatment and CTC grade-1 constipation and CTC grade-1 dyspnea in two other patients. One patient experienced an episode of CTC grade-2 diarrhoea with positive testing for Norovirus-RNA, and another patient developed a non-squamous, spontaneously resolving CTC grade-2 rash. Haematological toxicity included CTC grade-2 leucopenia in two patients and CTC grade-2 thrombocytopenia in another patient. All patients continued on the same dose level and recovered without further intervention. For two patients (No 7 and 9) the dose of lenalidomide was increased to 25 mg/d continuously after the sixth cycle due to the decision of the treating physician. None of the 12 patients showed radiological evidence of progression after two cycles of lenalidomide. Overall, six of correspondence

Early recognition of hereditary motor and sensory neuropathy type 1 can avoid life-threatening vincristine neurotoxicity

Hereditary motor and sensory neuropathy type 1 (HMSN‐1) is an autosomal dominant disorder, which is usually not associated with neoplastic diseases. The disease predisposes to severe vincristine neurotoxicity. We report a 31‐year‐old women with recurrent Hodgkins lymphoma and unrecognized HMSN‐1 who developed severe motor neuropathy 3 weeks after the first cycle of treatment including 2 mg of vincristine. HMSN is diagnosed in most cases retrospectively, usually suggested by the observation of foot abnormalities or family history. Recognizing early signs of HMSN, such as areflexia and pes cavus deformity, can prevent severe neurotoxicity of polychemotherapy by avoiding vincristine.

Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation

This study was undertaken to evaluate the toxicity and pharmacokinetics of a dimethyl sulphoxide (DMSO)‐based intravenous formulation of busulphan in the conditioning of 45 patients undergoing allogeneic or autologous stem cell transplantation (SCT). Busulphan was given as a single daily dose. In 15 patients a single dose of intravenous busulphan, given over 3 h in 1 d, was combined with additional oral (single daily) doses. Thirty patients received all four daily doses intravenously. Busulphan plasma levels were analysed using high performance liquid chromatography. There was no major acute toxicity with daily intravenous doses of 2·8–3·1 mg/kg infused over 3 h. No veno‐occlusive disease (VOD) was seen in 30 patients receiving busulphan as an intravenous formulation over 4 d. In the group of 15 patients receiving three oral doses and one intravenous single daily dose, one patient experienced mild VOD. Pharmacokinetic samples were taken over at least 2 d of treatment in 44 patients. The area under the concentration time curve (AUC) values normalized for a dose of 1 mg/kg were 7000 ng/ml × h on d 1 and 5890 ng/ml × h on d 4, thus showing a moderate decrease over time. This was accompanied by a moderate increase of the clearance from 2·6 to 3·0 ml/min/kg. Administration of busulphan as a DMSO‐based intravenous formulation was well tolerated. The total dose of busulphan can be given in four (rather than the typical 16) doses. With such a regimen, the intravenous administration becomes feasible on an outpatient basis.

Relapsed Hodgkin Lymphoma in Older Patients: A Comprehensive Analysis From the German Hodgkin Study Group

PURPOSE Progression or relapse of Hodgkin lymphoma (HL) is common among older patients. However, prognosis and effects of second-line treatment are thus far unknown. PATIENTS AND METHODS We investigated second-line treatment and survival in older patients with progressive or relapsed HL. Patients treated within German Hodgkin Study Group first-line studies between 1993 and 2007 were screened for refractory disease or relapse (RR-HL). Patients with RR-HL age ≥ 60 years at first-line treatment were included in this analysis. RESULTS We identified 105 patients (median age, 66 years); 28%, 31%, and 41% had progressive disease, early relapse, or late relapse, respectively. Second-line treatment strategies included intensified salvage regimens (22%), conventional polychemotherapy and/or salvage-radiotherapy with curative intent (42%), and palliative approaches (31%). Median overall survival (OS) for the entire cohort was 12 months; OS at 3 years was 31% (95% CI, 22% to 40%). A prognostic score with risk factors (RFs) of early relapse, clinical stage III/IV, and anemia identified patients with favorable and unfavorable prognosis (≤ one RF: 3-year OS, 59%; 95% CI, 44% to 74%; ≥ two RFs: 3-year OS, 9%; 95% CI, 1% to 18%). In low-risk patients, the impact of therapy on survival was significant in favor of the conventional polychemotherapy/salvage radiotherapy approach. In high-risk patients, OS was low overall and did not differ significantly among treatment strategies. CONCLUSION OS in older patients with RR-HL can be predicted using a simple prognostic score. Poor outcome in high-risk patients cannot be overcome by any of the applied treatment strategies. Our results might help to guide treatment decisions and evaluate new compounds in these patients.