Early induction intensification with cladribine, cytarabine, and mitoxantrone (CLAM) in AML patients treated with the DAC induction regimen: a prospective, non-randomized, phase II study of the Polish Adult Leukemia Group (PALG).

We present the results of a prospective, non-randomized phase 2 trial in which 253 AML patients (pts) under 60 years old received DAC (Daunorubicin + AraC + Cladribine) as first induction followed by CLAM (Cladribine + AraC + Mitoxantrone) as early second induction on day 16 based on bone marrow (BM) blasts on day 14 (D14). The CR/CRi rate after a single course of DAC was 83% for pts with D14 BM blasts less than 10%. Forty-six pts had >10% BM blasts on D14, of whom 35 received CLAM with rates of CR/CRi 60% and early death (ED) 23%. The remaining 11 pts were not fit to receive CLAM, with rates of CR/CRi 28%, PR 18%, and ED 18%. Median OS was 7.2 versus 7.5 months, respectively. The overall CR/CRi rate was 77% after the first induction, with final CR/CRi rate 80% after DAC reinduction for pts who achieved PR with initial DAC course. CLAM used as early second induction might improve CR/CRi rates for younger AML pts with poor early response to DAC induction, but may be associated with higher mortality.

Ofatumumab retreatment and maintenance in fludarabine-refractory chronic lymphocytic leukaemia patients.

There are limited data on retreatment with monoclonal antibodies (mAb) in patients with chronic lymphocytic leukaemia (CLL). In a pivotal study, ofatumumab (human anti-CD20 mAb) monotherapy demonstrated a 47% objective response rate (ORR) in fludarabine refractory CLL patients. From this study, a subset of 29 patients who had at least stable disease and then progressed were retreated with eight weekly ofatumumab infusions (induction treatment period), followed by monthly infusions for up to 2 years (maintenance treatment period). The ORR after 8 weeks of induction retreatment was 45% and 24% had continued disease control after maintenance at 52 weeks. Efficacy and safety of the retreated patients were compared with their initial results in the pivotal study. Response duration was 24.1 months vs. 6.8 months; time to next therapy was 14.8 months vs. 12.3 months; and progression-free survival was 7.4 months vs. 7.9 months (medians). Upon retreatment, 72% had infusion reactions, mostly Grade 1-2. Three patients had fatal infections. In summary, ofatumumab retreatment and maintenance therapy was feasible in patients with heavily pretreated CLL and appeared to result in more durable disease control than initial ofatumumab treatment in this subset of patients who may have a more favourable disease profile.

Palifermin does not influence the incidence and severity of GvHD nor long-term survival of patients with hematological diseases undergoing HSCT.

BACKGROUND: Palifermin is known as the effective growth factor to reduce the incidence, duration and severity of oral mucositis (OM) following hematopoietic stem cell transplantation (HSCT). However, additional data on the long-term safety of palifermin and its potential influence on graft versus host disease (GvHD) are needed. MATERIAL/METHODS: In this multi-center, non-randomized, matched-control study we assessed early overall survival (OS), incidence and severity of acute/chronic GvHD (a/cGvHD) and incidence of secondary malignancies in 36 patients with hematological diseases treated with allogeneic HSCT and palifermin. RESULTS: The incidence of aGvHD was 28.2% and 38.4% (p=0.34) and cGvHD 41% and 53.8% (p=0.70) in the palifermin and control groups, respectively. The incidence of aGvHD grade 0-IV was 69.2%, 5.1%, 17.9%, 2.5%, 2.5% in the palifermin group and 61.5%, 12.8%, 12.8%, 10.2%, 5.2% in the control group, respectively (p>0.4 for each). The incidence of limited and extensive cGvHD was 17.9% and 23% in the palifermin versus 25.6% and 28.2% in the control group (p=0.32 and p=0.50, respectively). The estimated 3-year OS did not differ significantly between studied groups. We did not observe any secondary malignancies in these patients. CONCLUSIONS: Administration of palifermin doesn't seem to influence the incidence and severity of aGvHD/cGvHD, secondary malignancies occurrence and early OS in patients undergoing allogeneic HSCT.

Ex vivo measurement of calpain activation in human peripheral blood lymphocytes by detection of immunoreactive products of calpastatin degradation.

Limited proteolysis of multiple intracellular proteins by endogenous Ca-dependent cysteine proteases--calpains--is an important regulatory mechanism for cell proliferation, apoptosis etc. Its importance for cellular functions is stressed by existence of endogenous calpain inhibitors--calpastatins. The calpain-calpastatin system within living cells is in a fragile balance, which depends on both partners. The interdependence of calpain--a protease--and calpastatin--an endogenous inhibitor and at the same time a substrate for this enzyme makes any assessment of actual activity of this enzyme in the cells very difficult. In this work we made an attempt to estimate and compare the activity of calpain in human peripheral blood lymphocytes by assessing the levels of limited proteolysis of calpastatin in these cells by western blot, while at the same time the levels of calpain protein inside these cells was measured by flow cytometry. Our results indicate that it is possible to compare (semi-quantitatively) the activities of calpain in peripheral blood CD4+ and CD19+ lymphocytes from various donors that way. Preliminary results showed that calpain activity is increased in the CD4+ T cells isolated from peripheral blood of rheumatoid arthritis patients as compared to control lymphocytes. Extremely high intrinsic activity of calpain was detected in chronic lymphocytic leukemia (CD19+) cells. All this confirms the detection of immunoreactive products of calpastatin as a good maker of endogenous calpain activity.

Accessory spleens: preoperative diagnostics limitations and operational strategy in laparoscopic approach to splenectomy in idiopathic thrombocytopenic purpura patients.

AIM: The preoperative detection of accessory spleen (AS) is still a very important and serious problem. The aim of the study was to assess the reasons for failure and the long-term results of laparoscopic splenectomy (LS) in patients with idiopathic thrombocytopenic purpura (ITP). METHOD: Fifty-eight ITP patients underwent LS between June 1998 and December 2002. There were 42 women and 16 men. Preoperatively, we performed computed tomography (CT) and sonography to evaluate the size of the spleen and possibly to recognize the presence of the accessory spleens, which were found preoperatively in three cases. RESULTS: Intraoperatively, ASs were found in the course of laparoscopy in six cases overall, three preoperatively false negative. During follow-up (median time 31 months), in three patients the low platelet count was recognized, respectively after 5 months and 1.5 and 1.8 years. In all those cases scintigraphy was performed and in one case the residual accessory spleen, missed both in preoperative examination and during laparoscopy, was revealed. In two other patients, in spite of thrombocytopenia, no residual spleens were found. CONCLUSION: We conclude that the problem of accessory spleens can be managed by careful videoscopic examination of the abdominal cavity during splenectomy, while the use of preoperative imaging techniques in detection of accessory spleens is still limited by the insufficient sensitivity of the examination.