Approximately 20% of all Hodgkin lymphoma (HL) patients are older than 60 years and have a poor prognosis, mainly because of increased treatmentrelated toxicity resulting in reduced overall dose intensity and more treatmentrelated mortality. To possibly improve the treatment of elderly HL patients, the German Hodgkin Study Group developed a new regimen, PVAG (prednisone, vinblastine, doxorubicin, and gemcitabine). In this multicenter phase 2 study, elderly HL patients in early unfavorable and advanced stages received 6 to 8 cycles of PVAG and additional radiotherapy if they were not in complete remission (CR) after chemotherapy. Endpoints included feasibility, acute toxicity, and response rate. Fifty-nine patients 60 to 75 years of age (median, 68 years) were eligible for analysis; 93% had advanced stage disease. WHO grade 3/4 toxicities were documented in 43 patients; 46 patients responded with CR/CR uncertain (78%). Within 37 months median observation time, 15 progressions or relapses and 17 deaths were observed, of which 8 were related to HL and 1 was the result of treatment-related toxicity. The 3-year estimates for overall survival and progression-free survival were 66% (95% CI, 50%-78%) and 58% (95% CI, 43%-71%), respectively. We conclude that PVAG is safe and feasible in elderly HL patients. This trial was registered at www.clinicaltrials.gov as #NCT00147875. (Blood. 2011;118(24): 6292-6298)

Secretory processes have been implicated in the mechanism of target-cell lysis by cytotoxic T-lymphocytes (CTL) (refs 1, 2). Both CTL and cytotoxic large granular lymphocytes have cytolytic granules, containing the cytolytic molecules 'perforin' and 'cytolysin'; perforin and cytotoxic lymphocytes can damage target cells through the membrane assembly of pores. The description of proteases which are cytotoxic cell-associated and granule-located has supported the granule exocytosis model of cytotoxicity mediated by cytotoxic lymphocytes, and has emphasized the similarities between cell-mediated and complement-mediated cytotoxicity. But recent experiments have challenged the importance of lytic granules and perforin in CTL activity. Here we report that CTL can be triggered to deliver a lethal hit to target cells even when exocytosis of lytic granules has been abolished by removal of extracellular calcium. This dissociation of exocytosis of granules and delivery of the lethal hit suggests that cytolytic granules may not be involved in target-cell lysis by CTL.

Summary:We studied the immunomodulating effect of withdrawal of immunosuppression with cyclosporin A (CsA) in 42 patients with leukemic relapse of chronic myelogenous leukemia (CML) (n ‫؍‬ 24), acute myeloid leukemia (AML) (n ‫؍‬ 13) and acute lymphoblastic leukemia (ALL) (n ‫؍‬ 5) after allogeneic unmanipulated bone marrow (BMT) or peripheral blood stem cell transplantation (PBSCT). Response to CsA withdrawal was monitored molecularly by the polymerase chain reaction for elimination of CML cells containing the bcr-abl messenger RNA (mRNA) transcript (n ‫؍‬ 24), or mll-af4 mRNA transcript characteristic of leukemic cells with a 11q23 chromosomal abnormality (n ‫؍‬ 1). Rapid tapering of CsA resulted in subsequent achievement of cytogenetic remission in 11 of 14 CML patients (79%) who relapsed in early disease phase (n ‫؍‬ 9 cytogenetic relapse, n ‫؍‬ 2 hematological relapse) after a median of 57 days. Three of 13 AML patients and one of five ALL patients achieved complete remission. CsA withdrawal was accompanied by the development of acute graft-versushost disease (GVHD) grade II in most of the 24 patients with CML. Two patients who achieved remission of AML or ALL died from severe GVHD grade III-IV. We calculated a probability of 84% for achieving and remaining in remission with early relapse of CML 4 years after relapse post BMT, whereas patients with AML have only a probability of about 10% of achieving and remaining in remission after 3 years. Patients with advanced CML and ALL had no chance of achieving and remaining in remission in the same time period.

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