Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.

BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

Incidence of graft rejection in small bowel transplanted pigs after immunosuppression withdrawal.

As intestinal grafts require heavy immunosuppression, there are no reports of immunosuppression withdrawal after clinical small bowel transplantation. In this large-animal study, we investigated the occurrence of graft rejection in intestinal-transplanted pigs after withdrawal. Large-White unrelated piglets were transplanted and divided in three groups: group 1 (n = 5), intestinal transplantation (ITx) with no immunosuppression; group 2 (n = 7), Itx and 60 days of treatment with tacrolimus and mycophenolate mofetil; group 3 (n = 5), Itx and donor bone marrow infusion (DBMi) and 60 days of treatment with tacrolimus and mycophenolate mofetil. Follow-up time after withdrawal was 120 days. Group 1 pigs died of graft acute cellular rejection (ACR) after a median of 11 days. In group 2, two pigs died of ACR-related infection and another two of ACR within 90 days. The remaining three animals (43%) were sacrificed at day 180, and their grafts showed no signs of ACR. In group 3, two pigs died of ACR-related infection and one of graft versus host disease within 80 days; at day 180 the two surviving animals showed signs of chronic rejection in the allograft. This study demonstrates that total withdrawal after ITx is followed by sudden and lethal ACR (or ACR-related infection) in more than 50% of the recipients. When a tolerance-inducing strategy as DBMi is applied, lethal graft versus host disease may also occur. In group 3, the intestinal allograft, to which the recipients were partially tolerant, developed chronic rejection that was probably associated with a decline with time of donor-leukocytes chimerism, as recently demonstrated in rats.

Efficacy, toxicity and feasibility of a shorter schedule of DCEP regimen for stem cell mobilization in multiple myeloma.

From 2000 to 2004, 152 patients with multiple myeloma aged or=4 x 10(6) cells/kg. The proportion of patients in whom mobilization failed was similar in the two groups. The incidence of WHO grade III neutropenia was higher in group II, although the difference was not statistically significant; the percentage of patients requiring hospitalization for severe infections was similar in the two groups. The incidence of WHO grade IV thrombocytopenia did not differ between the two groups. The response rate was 72% in group I and 80% in group II with similar percentages of patients achieving good responses. DCEP-short is a good mobilizing regimen, sharing the same characteristics as infusional-DCEP: high mobilizing efficacy, low toxicity and good antitumor activity. This new schedule of DCEP does, however, allow complete outpatient management and so could be advantageously included in any high-dose therapy program.

Peripheral arterial vascular function at altitude: sea-level natives versus Himalayan high-altitude natives.

OBJECTIVES: Regulation of the vascular system may limit physical performance and contribute to adaptation to high altitude. We evaluated vascular function in 10 Himalayan high-altitude natives and 10 recently acclimatized sea-level natives at an altitude of 5,050 m. METHODS: We registered electrocardiogram, blood flow velocity in the common femoral artery, and blood pressure in the radial artery using non-invasive methods under baseline conditions, and during maximal vasodilation after 2 min leg occlusion. Vascular mechanics were characterized by estimating pulse wave velocity and input impedance. RESULTS: Pulse wave velocity and parameters of input impedance did not differ between groups under baseline conditions. In the post-ischemic period, the ratio between maximal hyperemic and baseline blood flow velocity was significantly higher in the high-altitude than in the sea-level natives (5.7 +/- 2.5 versus 3.8 +/- 1.2, P < 0.05). The leg vascular resistance decreased in the post-occlusive period without differences between groups. Characteristic impedance decreased in the post-ischemic period by about one third of the baseline level without differences between groups. The post-ischemic decrease of input impedance modulus was more marked in the high-altitude than in the sea-level natives at low frequencies (28 +/- 12 versus 6.4 +/- 20% at 2 Hz, P < 0.01). CONCLUSIONS: Our results demonstrate a superior ability to increase blood flow velocity as a response to muscular ischemia in high-altitude natives compared to sea-level natives. This phenomenon may be associated with a more effective coupling between blood pressure and blood flow which is probably caused by differences in conduit vessel function.

Intensive chemotherapy followed by donor PBSC in ANLL relapsed after allogeneic BMT.

We describe a 42-year-old man with ANLL-M4 in relapse after allogeneic BMT, in whom a new CR was obtained by conventional chemotherapy followed by the infusion of his female donor PBSC. At the time of BMT he was in CR. Six months later a full hematological relapse occurred an a three drug 5-day regimen was started. Two days after the end of chemotherapy he received donor PBSC collected by two leukaphereses after mobilization with G-CSF, given subcutaneously at 5 micrograms/kg/day for 7 days. The mononuclear PBSC were 4.2 x 10(8)/kg; the CD34 positive cells were 8.2 x 10(6)/kg and the CFU-GM were 14 x 10(4)/kg. Two days after PBSC infusion the patient received G-CSF at a dose of 5 micrograms/kg/day. Hemopoietic recovery occurred promptly on day + 13 and Y-FISH revealed 14% of Y-spot positive cells in the marrow. On day +20 hematological and cytogenetic remission was documented. The percentage of recipient cells decreased from day +36 onwards following the occurrence of a grade II GVHD, from which the patient recovered 1 week later with oral cyclosporin A and intravenous high-dose steroids. At present (day +200 from relapse) the patient is still in CR with 3% of Y-spot positive cells.

Chemotherapy and donor peripheral blood progenitor cells for acute leukemia in early relapse after allogeneic bone marrow transplantation.

Ten patients with acute leukemia (AL) in early relapse after allo-BMT were treated with a modified MEC (mitoxantrone, etoposide and Ara-C) regimen followed by donor PBPC collected after mobilization with G-CSF. Seven patients achieved CR or had normal hemopoietic reconstitution: two had an early relapse at days +53 and +48, two patients died from acute GVHD at days +31 and +96, one died of interstitial pneumonia at day +55, and two patients experienced long-term survival. One patient with refractory disease and nodal involvement who did not respond to the first BMT had overt expansion of the leukemia at day +36; one patient with Ph+ ALL and one with ANLL evolving from MDS, both with skin involvement, had blast cells in peripheral blood at day +27 and +26, respectively. Transient cytopenia occurred in all patients; a normal granulocyte and platelet count was achieved within 3 weeks in all patients but one; acute GVHD occurred in six patients, and four had chronic GVHD. This approach is feasible in patients in early relapse after allo-BMT. It assists prompt re-establishment of normal donor hematopoiesis avoiding the prolonged cytopenia observed after donor lymphocyte infusion in AL patients relapsed after allo-BMT.

A model of in vivo purging with Rituximab and high-dose AraC in follicular and mantle cell lymphoma.

We studied a model of in vivo purging with Rituximab and high-dose (HD) cytarabine in 14 patients with relapsed/refractory follicular lymphoma and two with refractory mantle cell lymphoma enrolled in a program of HD chemotherapy and autotransplant. After two courses of debulking immunochemotherapy with Rituximab, Vincristine and Cyclophosphamide, we used a combination of Rituximab, HD cytarabine and granulocyte colony-stimulating factor for peripheral blood stem cells (PBSC) mobilization. The median number of CD34+ cells collected was 14.69 x 10(6)/kg (range 5.74-73.2). Monitoring of peripheral CD19+ and CD20+ B cells prior to and throughout the purging period showed that a treatment with Rituximab, Vincristine and Cyclophosphamide results in a profound depletion of B cells in peripheral blood. B-cell depletion persists during mobilization with Rituximab and HD cytarabine allowing a collection of PBSC free of B cells (median CD19+ and CD20+ cells counts 0%). Of nine patients PCR positive for bcl-2 or bcl-1 in blood and marrow at the start of immunochemotherapy, all showed PCR-negative PBSC. In conclusion, in patients with indolent lymphoma, the concurrent administration of Rituximab and HD cytarabine is a safe and efficient method to obtain in vivo purged PBSC. Immunochemotherapy prior to mobilization produces B-cell depletion and seems to be a useful preparative step.

Adverse events occurring during bone marrow or peripheral blood progenitor cell infusion: analysis of 126 cases.

Bone marrow (BM) and/or peripheral blood progenitor cells (PBPC) given after high-dose chemo-radiotherapy are commonly cryopreserved. Re-infusion of the thawed product can cause cardiovascular and other complications. We compared two groups of adult patients receiving autologous BM or PBPC transplant to assess the incidence of adverse events occurring during infusion. Fifty-one patients received BM, and 75 PBPC. The two groups were comparable in respect of age, total volume infused, quantity of dimethylsulfoxide (DMSO) and number of polymorphonuclear neutrophils. Patients receiving PBPC had a higher number of nucleated cells per kg of body weight; those in the BM group received a significantly greater quantity of red cells. Non-cardiovascular complications occurred in 19% and 8% of patients rescued by BM and PBPC respectively. The incidence of hypertension was 21% in the BM and 36% in the PBPC group. Asymptomatic hypotension was more frequent in PBPC patients (P<0.001). Bradyarrhythmia was noticed in two of 75 PBPC patients and in 14 of 51 BM patients (P<0.001). In the former group one patient had heart block; he died of renal failure 10 days later. Bradycardia and hemoglobinuria were more common in patients receiving BM where a higher concentration of red cells was present (P<0.001). Since bradyarrhythmias may be a life-threatening complication we advise continuous careful monitoring during infusion of thawed BM. The strong correlation between bradycardia and red blood cell contamination suggests the use of purified products with a very low red cell content.

Growth factors in the therapy of myelodysplasia: biological aspects.

Growth factors (GF) are reported to play an important role in the therapy of myelodisplastic syndromes (MDS). After in vitro administration a consistent group of MDS may respond to GF but the possibility of differentiation, regulation or expansion of myelodisplastic clones following GF therapy is still a question to be answered as their optimum dose and combinations. To validate if in vivo treatment with GF, may promote the regulation or the recovery of myelopoiesis and/or modify the clonality of the responses, we gave G-CSF after intensive chemotherapy in high risk MDS and acute leukemia evolving from MDS patients. According to our data the use of G-CSF after intensive chemotherapy may improve the CR rate without increase of leukemic transformation. However the answer were clonal and the remission duration remained very short so we suggest to utilize this time to perform other therapeutic strategies such as, when possible, the BMT.

Cerebral vasoreactivity in Andeans and headache at sea level.

Headache is common in Cerro de Pasco (CP), Peru (altitude 4338 m) and was present in all patients with chronic mountain sickness (CMS) in CP reported here. Forty-seven percent of inhabitants report headache. Twenty-four percent of men have migraine with aura, with an average of 65 attacks a year. We assessed vasoreactivity of the cerebral vessels to CO2 by rebreathing and to NO by the administration of isosorbite dinitrate (IDN), a nitric oxide (NO) donor, using transcranial Doppler ultrasound in the middle cerebral artery (MCA) in natives of CP, some of whom suffered from CMS. We repeated the measurements in Lima (altitude 150 m) in the same subjects within 24 h of arrival. Vasodilatation in the middle cerebral artery supply territory in response to CO2 and NO, both physiologic vasodilators, is defective in Andean natives at altitude and in the same subjects at sea level. Incapacitating migraine can occur with impaired cerebral vasoreactivity to physiologic vasodilators. We propose that susceptibility to migraine might depend in part on gene expression with consequent alterations of endothelial function.