C. Ippoliti

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.

PURPOSE To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. PATIENTS AND METHODS Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richters transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. RESULTS Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). CONCLUSION These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richters, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.

Respiratory syncytial virus upper respiratory tract illnesses in adult blood and marrow transplant recipients: combination therapy with aerosolized ribavirin and intravenous immunoglobulin.

Respiratory syncytial virus (RSV) is an important cause of serious respiratory illness in blood and marrow transplant (BMT) recipients. In some subsets of these immunocompromised patients, RSV upper respiratory illnesses frequently progress to fatal viral pneumonia. The frequency of progression to pneumonia is higher during the pre-engraftment than during the post-engraftment period. Once pneumonia develops, the overall mortality is 60–80%, regardless of the treatment strategy. We performed a pilot trial of therapy of RSV upper respiratory illnesses using aerosolized ribavirin and IVIG (500 mg/kg every other day), with the goal of preventing progression to pneumonia and death. Two dosages of ribavirin were used: a conventional regimen (6 g/day at 20 mg/ml for 18 h/day) and a high-dose short-duration regimen (6 g/day at 60 mg/ml for 2 h every 8 h). Fourteen patients were treated for a mean of 13 days (range: 7–23 days). In 10 (71%) patients, the upper respiratory illness resolved. The other four (29%) patients, three of whom were in the pre-engraftment period, developed pneumonia, which was fatal in two. The most common adverse effect was psychological distress at being isolated within a scavenging tent. In conclusion, prompt therapy of RSV upper respiratory illnesses in BMT recipients with a combination of aerosolized ribavirin and IVIG was a safe and promising approach to prevent progression to pneumonia and death. Bone Marrow Transplantation (2000) 25, 751–755.

Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease.

Chronic graft‐versus‐host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid‐resistant cGVHD. Thirty‐five patients who developed GVHD after day 100 post‐transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count ≥100 × 109/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD‐free survival are warranted.

Late Cytomegalovirus Pneumonia in Adult Allogeneic Blood and Marrow Transplant Recipients

To assess the impact of antiviral prophylaxis during the first 3 months after transplantation on the frequency, timing, and outcome of cytomegalovirus (CMV) pneumonia during the first year, 541 adult allogeneic blood and marrow transplant recipients were evaluated. Thirty-four patients (6.3%) developed 35 episodes of CMV pneumonia at a mean of 188 days after transplantation, with an associated mortality rate of 76%. Twenty-six episodes (74%) occurred late (after day 100). Of the patients with late CMV pneumonia almost all (92%) had chronic graft vs. host disease or had received T cell-depleted transplants. Fourteen late CMV pneumonias (54%) were associated with serious concurrent infections, and 100% of these episodes were fatal. In conclusion, although the frequency of CMV pneumonia in the early posttransplantation period may be substantially reduced by prophylaxis, CMV continues to be a major cause of morbidity and mortality in the late period. Some subsets of patients need more prolonged surveillance and prophylaxis and/or preemptive therapy.

Reduced-intensity allogeneic stem cell transplantation in relapsed and refractory Hodgkin's disease: low transplant-related mortality and impact of intensity of conditioning regimen

Summary:A total of 40 patients with relapsed/refractory Hodgkins disease (HD) underwent reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) from an HLA-identical sibling (n=20) or a matched unrelated donor (n=20). The median age was 31 years (range 18–58). Disease status at allo-SCT was refractory relapse (n=14) or sensitive relapse (n=26). The conditioning regimens were fludarabine-cyclophosphamide±antithymocyte globulin (n=14), a less intensive regimen, and fludarabine-melphalan (FM) (n=26), a more intensive one. The two groups had similar prognostic factors. The median time to neutrophil recovery (ie absolute neutrophil count ⩾500/μl) was 12 days (range 10–24). The median time to platelet recovery (ie platelet count ⩾20 000/μl) was 17 days (range 7–132). Day 100 and cumulative (18-month) transplant-related mortalities (TRMs) were 5 and 22%. Twenty-four patients (60%) are alive (14 in complete remission or complete remission, unconfirmed/uncertain) with a median follow-up of 13 months (4–78). In all, 16 patients expired (TRM n=8, disease progression n=8). FM patients had better overall survival (73 vs 39% at 18 months; P=0.03), and a trend towards better progression-free survival (37 vs 21% at 18 months; P=0.2). RIC allo-SCT is feasible in relapsed/refractory HD patients with a low TRM. The intensity of the preparative regimen affects survival.

Tacrolimus-associated posterior reversible encephalopathy syndrome after allogeneic haematopoietic stem cell transplantation

Summary. Neurotoxicity is a significant complication of the use of tacrolimus. From April 1998 to December 2001, we identified 10 patients (six women, four men) who developed 11 episodes of tacrolimus‐associated posterior reversible encephalopathy syndrome (PRES) after allogeneic haematopoietic stem cell transplantation for haematological malignancies. The diagnosis was made by characteristic clinical findings (mental status changes, seizures, neurological deficits) with the exclusion of other causes and characteristic imaging findings. The median age was 35·5 years (range 19–57 years). Seven patients received a matched‐unrelated donor transplant and three received a cord blood transplant. The overall incidence of PRES was 1·6%, while the incidence in matched‐unrelated, mismatched‐related and cord blood transplants was 3·5%, 4·9% and 7·1% respectively. Mental status changes, cognitive deficits, seizures and lethargy were the most common clinical findings. Eight of 10 patients had characteristic findings of hyperintensity of the white matter on T2‐weighted images and FLAIR (fluid‐attenuated inversion recovery) sequence on magnetic resonance imaging of the brain. Serum tacrolimus levels were within the therapeutic range in most patients. Tacrolimus treatment was continued (n = 4) or temporarily withheld (n = 7) for 1–14 d. One patient was changed to cyclosporine. In most patients, subsequent treatment with tacrolimus was well tolerated without recurrence of neurotoxicity.

Phase 1 study of epigenetic priming with decitabine prior to standard induction chemotherapy for patients with AML

We conducted an open-label phase 1 study exploring the feasibility, safety, and biologic activity of epigenetic priming with decitabine before standard induction chemotherapy in patients with less-than-favorable risk of acute myelogenous leukemia (AML). We directly compared the clinical and DNA-hypomethylating activity of decitabine delivered at 20 mg/m² by either a 1-hour infusion (Arm A) or a continuous infusion (Arm B) for 3, 5, or 7 days before a single, standard induction with infusional cytarabine (100 mg/m² for 7 days) and daunorubicin (60 mg/m² × 3 doses). Toxicity was similar to that of standard induction chemotherapy alone. Although we did not identify a maximum tolerated dose, there was more gastro-intestinal toxicity with 7 days of decitabine priming. Decitabine induced DNA hypomethylation at all dose levels and there was a trend toward greater hypomethylation in CD34(+) bone marrow cells when decitabine was delivered by a short pulse (Arm A). Twenty-seven subjects (90%) responded to therapy: 17 with complete remission (57%) and 10 with partial remission (33%). Of the patients with partial remission to protocol treatment, 8 achieved remission to their next therapy, bringing the overall complete remission rate to 83%. We conclude that epigenetic priming of intensive chemotherapy can be safely delivered in an attempt to improve response rates. This trial was registered at www.clinicaltrials.gov as NCT00538876.

Allogeneic blood stem cell transplantation in advanced hematologic cancers

Allogeneic bone marrow transplantation for advanced hematologic cancer is associated with a high risk of early treatment-related morbidity and mortality. To determine the short-term benefits of allogeneic blood stem cell transplants when compared to bone marrow transplants, we reviewed outcomes of 74 adults with advanced hematologic cancer transplanted from HLA-matched related donors after conditioning with thiotepa, busulfan and cyclophosphamide. There were three cohorts: group 1 received bone marrow transplants with cyclosporine (CsA) and methotrexate (MTX) for GVHD prophylaxis; group 2 received bone marrow transplants with CsA and methylprednisolone (MP); and group 3 received blood stem cells with CsA and MP. All patients received filgrastim post-transplant. Median times (range) to neutrophils ⩾0.5 × 109/l were 17 (8–30), 9 (8–16) and 10 (8–13) days post-transplant, and to platelets ⩾20 × 109/l were 28 (14–100+), 19 (13–100+) and 14 (9–86) days post-transplant for groups 1, 2 and 3, respectively (P < 0.05 only for group 1 vs group 3 for both outcomes). Blood stem cell recipients had the least regimen-related toxicity, fewest early deaths and earliest discharge. There was no significant difference in acute GVHD between the three groups. One hundred and eighty-day survivals (95% CI) were 53% (35–72%), 32% (10–53%), and 68% (49–87%) for groups 1, 2 and 3, respectively (P < 0.05 only for group 2 vs group 3). For allogeneic transplantation, use of blood stem cell grafts has substantial advantages over marrow grafts.

Management of Cancer Treatment–Related Diarrhea: Issues and Therapeutic Strategies

The cancer treatment-related diarrhea caused by acute graft-versus-host disease (GVHD) and chemotherapeutic agents, particularly fluoropyrimidines and irinotecan, significantly affects patient morbidity and mortality. The mechanisms causing cancer treatment-related diarrhea are not fully understood, but histopathologic evidence points to a multifactorial process that causes an absorptive and secretory imbalance in the small bowel. Cancer treatment-related diarrhea could be life-threatening, yet assessment and treatment are not currently standardized. Several clinicians participated in a closed roundtable meeting to review the mechanisms of chemotherapy-induced diarrhea (CID) and GVHD-induced diarrhea, management issues in cancer treatment-induced diarrhea, and pharmacologic approaches to treatment. The meeting produced a proposal for new treatment guidelines and an algorithm, which include the use of octreotide for the management of CID- and GVHD-induced diarrhea. The development of diarrhea assessment guidelines that expand on the current National Cancer Institute criteria and allow for better patient management was also proposed.

Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation

Thirty adults with leukemia or lymphoma transplanted with marrow or blood stem cells from 1-antigen mismatched related donors received tacrolimus and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 42 years (range 18–56 years). Twenty-seven patients had advanced disease, and 13 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/day i.v. by continuous infusion from day −2, converted to oral at four times the i.v. dose following engraftment, and continued to day 180 post-transplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6 and 11. Mild nephrotoxicity was common before day 100; 69% of patients had a doubling of creatinine, 56% had a peak creatinine greater than 2 mg/dl, and two patients were dialyzed. Other toxicities prior to day 100 thought to be related to tacrolimus included hypertension (45%), hyperkalemia (17%), hyperglycemia (14%), seizures (13%), headache (3%) and hemolytic uremic syndrome (3%). Grades 2–4 GVHD occurred in 59% (95% CI, 38–70%), and grades 3–4 GVHD in 17% (95% CI, 1–32%). Overall survival at 1 year was 29% (95% CI, 12–45%). We conclude that tacrolimus and minidose methotrexate is active post-transplant immunosuppression for patients with 1-antigen mismatched donors.