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We identified 19 persons with B-cell chronic lymphocytic leukemia (CLL) who received genetically identical twin blood cell or bone marrow transplants after high-dose conditioning. Ten are alive (eight disease-free) with a median follow-up of 89 months (range, 31-171 months); 5-year relapse rate was 50% (95% confidence interval (CI), 26-73%). Estimated 5-year survival and disease-free survival were 61% (95% CI, 37-82%) and 45% (95% CI, 23-68%). In two of four patients tested at 12 and 21 months by polymerase chain reaction no evidence of residual CLL was detected post-transplant. In one recipient who relapsed at 6 years, molecular studies showed a different CLL clone from that detected pretransplant. This clone was subsequently identified in the donor suggesting transfer of occult leukemia at the time of transplant. Genetically identical twin transplants can result in long-term disease-free survival and molecular remissions, these data suggest the potential for CLL control in the absence of allogeneic graft-versus-leukemia effect. The case of leukemia transfer indicates the need for careful evaluation of donors prior to graft collection.

Allogeneic progenitor cell transplantation is the only curative therapy for patients with refractory acute myelogenous leukemia or myelodysplastic syndromes. To identify prognostic factors in these patients, we performed a retrospective analysis of transplantation outcomes. Patients were selected if they had undergone an allogeneic transplantation between January 1988 and January 2002 and were not in remission or first untreated relapse at the time of transplantation. A total of 135 patients were identified. The median age was 49.5 years (range, 19-75 years). At the time of transplantation, 39.3% of patients had not responded to induction therapy, 37% had not responded to first salvage therapy, and 23.7% were beyond first salvage. Forty-one patients (30%) received unrelated donor progenitor cells. Eighty patients (59%) received either a reduced-intensity or a nonmyeloablative regimen. A total of 104 (77%) of 135 patients died, with a median survival time of 4.9 months (95% confidence interval, 3.9-6.6 months). The median progression-free survival was 2.9 months (95% confidence interval, 2.5-4.2 months). A Cox regression analysis showed that Karnofsky performance status, peripheral blood blasts, and tacrolimus exposure during the first 11 days after transplantation were predictive of survival. These data support the use of allogeneic transplantation for patients with relapsed or refractory acute myelogenous leukemia/myelodysplastic syndromes and suggest that optimal immune suppression early after transplantation is essential for long-term survival even in patients with refractory myeloid leukemias.

Despite posttransplantation immunosuppressive therapy, acute graft-versus-host disease (GVHD) remains a major cause of sickness and death. Tumor necrosis factor-alpha (TNF-alpha) is implicated in the pathophysiology of GVHD at several steps in the process. Infliximab is a genetically constructed immunoglobulin G1 (IgG1) murine-human chimeric monoclonal antibody that binds the soluble subunit and the membrane-bound precursor of TNF-alpha, blocking its interaction with receptors and causing lysis of cells that produce TNF-alpha. In this study we retrospectively evaluated 134 patients who had steroid-refractory acute GVHD. Of these, 21 who received infliximab as a single agent were analyzed. The overall response rate was 67% (n = 14), and 13 patients (62%) experienced complete response (CR). Five patients (24%) did not respond, and 2 (10%) had progressive GVHD. None had a toxic reaction to infliximab. Ten patients (48%) had 18 fungal infections, including Aspergillus species in 7 and Candida species in 10. Seventeen patients (81%) had bacterial infections, including 32 gram-positive and 8 gram-negative infections. Viral infections, primarily cytomegalovirus reactivation, occurred in 14 patients (67%). The Kaplan-Meier estimate of overall survival was 38%. In conclusion, infliximab was well tolerated and active for the treatment of steroid-resistant acute GVHD, particularly with gastrointestinal tract involvement. Survival after steroid-resistant acute GVHD continues to be problematic. The possibility of excessive fungal and other infections must be explored further.

A 31-year-old man with a diffuse large-cell lymphoma in first refractory relapse received a bone marrow transplant (BMT) from a matched unrelated donor using CAMPATH-1H, carmustine, etoposide, cytarabine and melphalan as conditioning regimen, and methotrexate and tacrolimus for graft-versus-host disease (GVHD) prophylaxis. The transplant was complicated by grade II skin acute GVHD. Lymphoma relapse occurred 4 months post-transplant. Immunosuppression withdrawal plus rituximab induced a complete response. He remains in complete remission (CR) 11 months post-immunosuppression withdrawal and 15 months post-transplant.

We conducted a retrospective analysis of all allogeneic stem cell transplantation (ASCT) patients started on extracorporeal photopheresis (ECP) for the management of steroid-dependent (SD) or steroid-refractory (SR) cutaneous chronic graft-versus-host disease (cGVHD) following ASCT during a 36-month period (9/98-8/01). Only SD or SR patients who were treated by ECP after day 100 and who received at least 4 weeks of ECP were considered evaluable for this analysis. Out of 64 ASCT patients reviewed, 32 patients met the inclusion criteria. All 32 patients had been previously treated with systemic corticosteroids with 11 (34%) being SR and 21 (66%) SD. Cutaneous cGVHD was extensive in 28 patients (88%) and was accompanied by visceral (hepatic, gastrointestinal) cGVHD in 23 patients (72%). The 32 evaluated patients had received a median of three prior therapies before ECP, most commonly systemic corticosteroids, tacrolimus, and mycophenolate mofetil. Patients received a median of 36 ECP sessions (range 12-98) over a median of 5.3 months (range 1-28), with a median of six sessions per month. The complete response (CR) rate was 22% (n=7) and the partial response rate was 34% (n=11). In all, 28 patients were on systemic corticosteroid therapy at ECP initiation and 18 patients achieved 50% dose reduction while on ECP, yielding a 64% steroid-sparing response rate. Of seven CRs, five are ongoing. A total of 11 (34%) patients have died after ECP, with all cases due to visceral cGVHD or cGVHD-related infectious complications. All 21 surviving patients remain on at least some immunosuppressive cGVHD therapy (including ECP in eight). Overall, ECP displays a substantial response rate and, in particular, steroid-sparing activity in SR/SD extensive cutaneous cGVHD. However, most patients continue to require at least some chronic therapy and cGVHD-related morbidity and mortality remain high.

High-dose myeloablative therapy with allogeneic hematopoietic transplantation is an effective treatment for hematologic malignancies, but this approach is associated with a high risk of complications. The use of relatively nontoxic, nonmyeloablative, or reduced-intensity preparative regimens still allows engraftment and the generation of graft-vs-malignancy effects, is potentially curative for susceptible malignancies, and reduces the risk of treatment-related morbidity. Two general strategies along these lines have emerged, based on the use of (1) immunosuppressive chemotherapeutic drugs, usually a purine analog in combination with an alkylating agent, and (2) low-dose total body irradiation, alone or in combination with fludarabine (Fludara).

Background: Total body irradiation (TBI) is commonly used with autologous bone marrow transplantation (BMT) for treatment of hematologic malignancies. Pulmonary complications of TBI can cause long-term morbidity and mortality. The authors have compared the pulmonary toxicity and efficacy of two different TBI fractionation regimens in otherwise identical autologous BMT protocols., Methods: Between 1990 and 1997 patients younger than 60 years of age with low-grade lymphoma at high risk of treatment failure were enrolled on one of two sequential protocols for autologous BMT differing only in their TBI regimens. The preoperative chemotherapy regimens were identical and consisted of intravenous etoposide (1500 mg/m(2)) for 1 day, intravenous cyclophosphamide (60 mg/kg) for 2 days, and mesna (10 mg/kg). The TBI used in protocol A consisted of twice-daily fractions of 1.7 grays (Gy) for 3 days to a total of 10.2 Gy through lateral fields, with no lung shielding. In protocol B, the TBI consisted of 3 Gy once daily for 4 days to a total of 12 Gy through anteroposterior fields, with lung shielding (5 half-value layers) during the third dose. Fifty-eight patients were treated on protocol A and 24 on protocol B. The groups were equivalent with regard to age, performance status (PS) and gender. Lung function was assessed objectively by pulmonary function tests (PFTs) before and at intervals after TBI. The pulmonary function parameters assessed included forced vital capacity (FVC), forced expiratory volume in 1 second (FEV(1)), forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)), diffusing capacity for carbon monoxide (DL(CO)), and total lung capacity (TLC). Each patient's post-TBI PFTs were normalized to the corresponding pre-TBI values and analyzed using a random effects model. Clinical pulmonary function status was scored according to Radiation Therapy Oncology Group criteria for acute and late lung toxicity. All clinical pulmonary toxicities such as pneumonitis, pneumonia, and diffuse alveolar hemorrhage, whether specifically related to TBI or not, were scored. Toxicity was classified as either acute (i.e., occurring within 90 days of TBI) or late (i.e., occurring more than 90 days after TBI). The endpoints of analysis were overall survival (OS), freedom from progression, and chronic pulmonary toxicity. Survival, progression, and complication free survival were computed using the method of Kaplan and Meier., Results: Three-year actuarial OS rates were 66% and 67% for protocols A and B, respectively. Patients 50 years of age or older had a hazard ratio of death 3.5 times higher than younger patients. Freedom from progression was significantly different for the 2 TBI regimens (P < 0.001; log-rank test): 31% at 3 years in the protocol A group compared with 82% in protocol B group. Patients on protocol A had a rate of progression 4.7 times higher than patients on protocol B. The TBI protocols did not differ significantly in their effects on FVC, FEV(1), FEF(25-75), DL(CO), and TLC. Patients 45 years of age or older had lower average posttransplant values of FEV(1), FVC, and DL(CO) than younger patients. There was no significant difference in acute or late toxicity rates between patients on the two protocols. Seven of the 57 patients in the twice-daily TBI (protocol A) group had acute pulmonary events (Grade 3 or greater), compared with 6 of the 24 patients in the once-daily (protocol B) group (P = 0.19). The 3-year freedom from late complications rate was 80% in the protocol A group and 70% in the protocol B group (P = 0.45). Patients with a PS of 1 had a hazard ratio of late complications 3.2 times greater than patients with a PS of 0 (P < 0.001)., Conclusions: It is possible to intensify TBI from a total dose of 10.2 Gy delivered in 6 twice-daily fractions to 12 Gy delivered in 4 once-daily fractions without significantly increasing the risk of pulmonary toxicity. The increased dose may contribute to a decrease in the recurrence rate in these patients. (c) 2001 American Cancer Society.

Patients with acute leukemias relapsing within 1 year of an allogeneic BMT have a poor prognosis. We studied the use of melphalan 180 mg/m2 followed by allogeneic peripheral blood stem cells (PBSC) as salvage treatment for patients relapsing after related (n = 7) or matched unrelated transplants (n = 3). Diagnoses were AML (n = 4), ALL (n = 3), biphenotypic acute leukemia (n = 2) and CML in blast crisis (n = 1). Eight patients were beyond first relapse and none were in remission. The median time from previous transplant to relapse was 146 days (range 66-206). The melphalan dose was 90 mg/m2 intravenously on days -4 and -3 with PBSC infusion on day 0. GVHD prophylaxis consisted of cyclosporine and methylprednisolone. The median time to an absolute neutrophil count >0.5 x 10(9)/l and to a platelet count >20 x 10(9)/l was 11 and 13 days, respectively. All engrafting patients (n = 8) had 100% donor cells. Two patients died before day 30, but no other grade 3 or 4 toxicity occurred. Acute GVHD grades II-III occurred in two subjects, and chronic GVHD in four. Seven patients achieved CR, but relapsed at a median of 116 days (range 56-614). Leukemia was the cause of death in eight patients. Median survival was 149 days (range 6-614). This treatment produced responses in the majority of this poor prognosis group. However, durable remissions were not observed, and new treatments to consolidate the responses achieved in this setting are needed. This regimen could be considered for short-term disease control to facilitate donor lymphocyte infusion-based immunotherapy or other measures to prevent disease recurrence.

Purpose: Standard G-band cytogenetic analysis (CG) provides information on approximately 25 metaphases for monitoring the presence of Philadelphia chromosome positive (Ph+) cells in chronic myelogenous leukemia (CML) patients, making the detection of a low frequency of Ph+ cells problematic. The purpose of this study was to improve the detection of a low frequency of Ph+ cells., Patients and Methods: We combined fluorescence in situ hybridization (FISH) with long-term colcemid exposure, capturing several hundred metaphases in bone marrow cultures (hypermetaphase FISH [HMF]). Using probes that identify Ph+ cells, HMF was compared with CG analysis in the follow-up evaluations of 51 patients with CML at various time points after allogeneic bone marrow transplant (BMT)., Results: Thirty-five patients never showed the presence of Ph+ cells by either method. In four patients, high frequencies of Ph+ cells were detected by both methods. In the remaining 12 patients, Ph+ cells were detected by HMF at time points after BMT when they were not detected by CG. In seven of the 12 patients, low but statistically significant frequencies of Ph+ cells (0.37% to 5.20%) were detected 3 months or later after BMT, and when no intervention was initiated, all seven patients later relapsed. Based on those data, an eighth patient with mixed chimerism and a similar HMF-detected Ph+ frequency (1.8% at 27 months after BMT) was reinfused with donor lymphocytes and achieved remission with 0% Ph+ cells studied by HMF (up to 50 months after BMT). Ph+ cells detected by HMF but not by CG less than 3 months after BMT disappeared on later examination in two of four patients. After detection of Ph+ cells by HMF only, the median time to cytogenetic progression (detection of Ph+ cells by CG) was 101 days., Conclusion: The results demonstrate the ability of HMF to detect low but clinically relevant levels of leukemic cells not detected by CG in transplant patients. The data indicate that HMF can detect low levels of Ph+ cells before standard cytogenetics at a time that may be useful in monitoring disease status and planning clinical interventions.

One hundred patients of median age 34 years (range, 14-53) received bone marrow transplants from unrelated donors serologically matched for human leukocyte antigen HLA-A, HLA-B, and HLA-DR using tacrolimus and minimethotrexate for prevention of acute graft-versus-host disease (GVHD). Sixty-eight patient-donor pairs had allelic matches at HLA-DRB1 and HLA-DQB1, 20 pairs had a single mismatch at HLA-DRB1 or HLA-DQB1, and 12 were mismatched at both HLA-DRB1 and HLA-DQB1. Minimum follow-up time was 6 months. Grades 2 to 4 GVHD occurred in 43% of patients with matched donors, 69% with single allele-mismatched donors, and 71% with double allele-mismatched donors; grades 3 to 4 GVHD occurred in 22%, 43%, and 64%, respectively. On multivariate analysis, the relative risk of grades 2 to 4 GVHD was 2.2 (95% CI, 1.1-4.5; P = .03) with a single allele mismatch and 2.7 (95% CI, 1.2-6.0; P = .02) with a double allele mismatch. The relative risks of grades 3 to 4 GVHD were 3.0 (95% CI, 1.2-7.6; P = .02) and 5.0 (95% CI, 1.9-12.6; P = .001), respectively. Day 100 treatment-related mortality was also adversely affected by allelic mismatching, occurring in 21% of those with matched donors, 50% with single allele-mismatched donors, and 42% with double allele-mismatched donors (P = .02), but overall survival at day 180 did not differ significantly among the 3 groups. Tacrolimus does not abrogate the adverse impact of allele mismatching at HLA-DRB1 and HLA-DQB1 on the risk of moderate-to-severe acute GVHD.

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.

The therapeutic benefit of allogeneic hematopoietic transplantation is due largely to an immune graft-vs-malignancy effect. Most of the evidence for such an effect has come from studies of allogeneic transplantation in leukemia. In patients with susceptible malignancies who relapse following an allogeneic transplant, infusion of donor lymphocytes can induce durable remissions. Use of less toxic, nonmyeloablative preparative regimens permits engraftment and generation of graft-vs-malignancy effects. This strategy permits allogeneic transplantation to be used in older patients and those with comorbidities who cannot tolerate conventional high-dose preparative regimens. The long-term efficacy of nonmyeloablative preparative regimens and induction of graft-vs-malignancy effects remains to be determined. Also, further clinical trials are required to address various unresolved issues and to compare this strategy with standard, myeloablative transplantation regimens.

Thirty-six adults with chronic myelogenous leukemia (CML) in second or greater chronic phase, accelerated phase, or blast crisis underwent marrow or blood stem cell transplantation from an HLA-matched sibling using high-dose thiotepa, busulfan and cyclophosphamide (TBC) as the preparative regimen. All evaluable patients engrafted and had complete donor chimerism. One patient failed to clear meningeal leukemia, and one patient had one of 30 metaphases positive for the Philadelphia chromosome at 2 months post transplant. The remainder of the patients studied had eradication of CML documented by cytogenetics and/or Southern blot for BCR gene rearrangement, and 13 of 15 patients studied became negative for the BCR gene rearrangement by polymerase chain reaction. Three-year relapse rate is 42% (95% CI, 19-64%). The relapse rate was significantly lower for patients transplanted without blast crisis (9% vs 100%, P < 0.001). Eight (22%, 95% CI, 10-39%) patients had severe or fatal veno-occlusive disease (VOD). Elevated liver enzymes within 1 month prior to transplantation and transplantation using marrow were significantly associated with the occurrence of VOD. Three-year survival is 28% (95% CI, 13-43%). Survival was significantly higher for patients transplanted without blast crisis (45% vs 0%, P = 0.01). TBC is an effective preparative regimen for CML in accelerated phase but not refractory blast crisis, and it should be used with caution in patients with prior hepatopathy who have an increased risk of severe VOD.

Bone marrow transplantation was initially developed as a means to deliver supralethal doses of chemotherapy and radiation for treatment of malignancies. Myelosuppression is the dose-limiting toxicity for many chemotherapy drugs and whole-body radiation. Many malignancies exhibit a steep dose-response relationship to chemotherapy or radiotherapy. Bone marrow transplantation allows escalation of doses beyond those levels which produce severe bone marrow toxicity. Doses of many agents, particularly alkylating agents and whole body radiation, can be increased three- to fivefold above their conventional maximally tolerated dose. Marrow transplantation was considered a supportive care modality to restore hematopoiesis. It has become clear, however, that the high dose therapy does not eradicate the malignancy in many patients, and that the therapeutic benefit of allogeneic marrow transplantation is largely related to an associated immune-mediated graft-versus-malignancy effect.

Purpose: This study was performed to evaluate the outcome of high-dose chemotherapy and autologous transplantation in patients with diffuse B-cell large-cell lymphoma, and, specifically, to evaluate the impact of primary mediastinal localization on the outcome of high-dose chemotherapy., Patients and Methods: A retrospective review was performed of all patients with diffuse large B-cell lymphoma who underwent autologous marrow or peripheral-blood stem-cell transplantation at our institution between January 1 986 and December 1995., Results: Ninety patients were identified, of whom 31 (34%) had a primary mediastinal B-cell large-cell lymphoma (PML). Cumulative probabilities of disease-free survival, overall survival, and disease progression are 40% (95% confidence interval [CI], 29 to 51), 42% (95% CI, 31 to 53), and 52% (95% CI, 40 to 64), respectively. By univariate analysis, low lactate dehydrogenase (LDH) level and low Ann Arbor stage at transplant were associated with improved survival and disease-free survival. There was a trend for improved disease-free survival and survival for patients with PML. Multivariate stepwise Cox regression analysis showed that LDH level, Ann Arbor stage, and primary mediastinal localization were independent favorable prognostic factors for disease-free survival and survival. LDH level and Ann Arbor stage were also predictive for the risk of disease progression., Conclusion: Our results indicate that patients with PML may display an increased susceptibility to high-dose chemotherapy compared with other types of B-cell large-cell lymphoma. These findings, if confirmed, may have implications for the initial management of patients with PML.

The role of allogeneic marrow transplantation as treatment of myeloproliferative disorders other than chronic myelogenous leukemia is not yet determined. At our center, 1 patient with primary myelofibrosis, 1 with mastocytosis, and 4 with myeloid metaplasia have been transplanted using HLA-identical sibling donors. All patients engrafted with full donor chimerism, and morphologic and cytogenetic manifestations of disease in the marrow resolved posttransplant. Three patients died; two with relapse and one from infection. The other three patients are alive in remission at 24+, 28+, and 32+ months posttransplant. Including these cases, a total of 40 patients transplanted for myeloproliferative disorders have been reported. The most common indications for transplantation were cytopenias, increasing blasts in marrow or blood, uncontrolled counts on conventional therapy, poor prognosis cytogenetics, organ dysfunction, and consolidation after induction therapy for blast transformation. Using the outcome data published for these patients, the actuarial estimate of 3-year survival is 55% (95% C.I., 44-76%) with a median reported follow-up of survivors of 21 months (range, 4-158 months). For patients with myeloproliferative disorders and evidence of accelerated disease, HLA-identical marrow transplantation is well tolerated and can result in an extended disease-free survival.

Purpose: Diarrhea associated with acute gastrointestinal (GI) graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) can result in severe morbidity and mortality. A pilot study was conducted to evaluate the efficacy and toxicity of octreotide in the management of diarrhea in patients with GVHD after allogeneic BMT., Patients and Methods: Twenty-one patients entered the study. Patients received either peripheral-blood stem cells (n = 13) or bone marrow (n = 8). Seven patients had grade 4, 13 grade 3, and one grade 2 GVHD. Intravenous (I.V.) octreotide 500 microg every 8 hours for 7 days was administered. Octreotide treatment was discontinued if no response was observed after 7 days or for grade 4 toxicity., Results: Fifteen (71%) of 21 treated patients had a complete response within 7 days of the initiation of octreotide; three (14%) had a partial response and three (14%) failed to respond to treatment. Toxicities were minimal; hyperglycemia was seen in four patients and one patient developed a partial ileus. Octreotide was discontinued and the ileus resolved within 48 hours., Conclusion: If initiated early in the course of GI GVHD, octreotide appears to be an effective, well-tolerated agent in reducing severe voluminous diarrhea. Octreotide should be discontinued within 24 hours after the resolution of diarrhea to avoid the development of ileus. Because no additional reduction in the volume of diarrhea occurred after 7 days of therapy, continuation of the drug beyond this time is not cost effective.

Cytomegalovirus (CMV) disease can be prevented by administration of ganciclovir prophylactically post-transplant. However, up to 30% of patients discontinue use of ganciclovir as a result of profound neutropenia and may subsequently develop CMV infections while unprotected. To prevent reactivation of CMV, we administered foscarnet to 39 adults unable to receive ganciclovir due to delayed engraftment or ganciclovir-induced neutropenia. Twenty-four (62%) of the patients had received T cell-depleted marrow transplants. Foscarnet sodium 60 mg/kg i.v. daily was continued until the neutropenia resolved, at which time ganciclovir was resumed. CMV prophylaxis commenced at a median of 28 days following transplantation. Median time to initiation of foscarnet was day 60 post-transplant, and the median duration of treatment was 22 days. Foscarnet was well-tolerated. Six (15%) patients had CMV detected while receiving prophylaxis, and CMV-related mortality was 5%. Foscarnet is a safe and effective agent for prevention of CMV disease in allogeneic transplant recipients unable to receive ganciclovir.

We report the outcomes of 44 consecutive patients with non-Hodgkin's lymphoma (NHL) who participated in prospective studies of allogeneic transplantation after conditioning with thiotepa, busulfan and cyclophosphamide. Within a range of 27-57 years, the median age was 37. Of the 44 patients, 12 (27.2%) had high-grade lymphomas, 27 (61.4%) had intermediate-grade lymphomas, and five (11.3%) had low-grade lymphomas. Twenty-eight (63.6%) patients had chemotherapy refractory disease. Thirty (68.2%) patients had stage IV disease at the time of transplantation, involving the bone marrow in 19 (43.2%). Eight (18.1%) patients had undergone previous transplantation, and 13 (29.5%) patients had received high-dose CVP as induction within 2 months prior to transplantation. Thirty-eight (86.3%) patients had an HLA-identical donor, and 6 (13.6%) had a one-antigen mismatched related donor. Twenty (45.4%) patients received bone marrow and 24 (54.6%) received granulocyte colony-stimulating factor (G-CSF) mobilized stem cells. The graft-versus-host disease (GVHD) prophylaxis contained cyclosporine or tacrolimus in combination with either methylprednisolone in 32 (72.7%) patients or with methotrexate in 12 (27.2%) patients. The actuarial probability of disease-free survival at 2 years is 23% (95% CI 13%-40%). Donor stem cell use was associated with a significantly decreased risk of treatment-related toxicity (p < 0.001), but with an increased risk for GVHD and delayed fungal and viral infections. These infections are linked not only to the use of donor-stem cells, but also to the methylprednisolone in the GVHD prophylaxis regimen. Improvements in the outcome of patients with advanced NHL and undergoing allogeneic transplantation will depend on the development of effective and non-toxic regimens for conditioning, GVHD prophylaxis, and opportunistic infections prophylaxis.

Unrelated donor bone marrow transplants have been associated with relatively high rates of acute graft-vs.-host disease and treatment-related mortality. These complications reflect histo-incompatibility between donor and recipient. Molecular technology has recently been applied to HLA typing to identify alleles not distinguishable with serologic typing techniques. We report results in 92 unrelated marrow transplant recipients who were HLA seroidentical with donor HLA-A, -B, and -DR antigens and assess the effect of DR beta 1 and DQ beta compatibility using sequence specific oligonucleotide primers. Forty-eight patients received T-cell depleted marrow grafts, and 44 received unmodified grafts. Among recipients of unmodified marrow grafts, matching for both DR beta 1 and DQ beta reduced the rate of grade 3-4 acute graft-vs.-host disease to 38 +/- 20% vs. 73 +/- 20% among recipients mismatched for either allele (p = 0.02). This difference was not observed in recipients of T-cell depleted marrow grafts. Multivariate analysis confirmed matching for both DR beta 1 and DQ beta loci (p = 0.015), and receiving a T-cell depleted graft (p = 0.008) independently predicted for reduced risk of grade 3-4 acute graft-vs.-host disease. In conclusion, both DR beta 1 and DQ beta appear biologically important for development of acute graft-vs.-host disease in patients receiving unmanipulated marrow grafts for unrelated donor transplant.

The outcome of allogeneic haemopoietic transplants including the rate of immune complications for patients with chronic lymphocytic leukaemia (CLL) refractory to or relapsing after chemotherapy with fludarabine was analysed. Fifteen patients with advanced CLL who received allogeneic transplantation were prospectively analysed. All patients had previously received chemotherapy with fludarabine for 3-15 courses; 12 were refractory. The median number of circulating CD4+ and CD8+ lymphocytes at the time of transplant was 0.49 x 10(9)/l and 0.23 x 10(9)/l, respectively. One patient was transplanted from a one HLA-antigen mismatched unrelated donor. Three others received a one or two antigen mismatched graft and 11 had HLA-identical sibling donors. Patients received cyclosporine or tacrolimus in addition to methotrexate or methylprednisolone for prophylaxis of acute graft-versus-host disease (aGVHD). Fourteen patients engrafted; one patient had graft failure, but recovered after therapy with intravenous immunoglobulin. 13 (87%) achieved complete remission (CR). Nine (53%) remain alive and in CR with a median follow-up of 36 (range 3-60) months. None developed visceral graft-versus-host disease. These data compared favourably to published reports in other leukaemia patients and for patients with CLL who received a comparable immunosuppressive therapy but without prior fludarabine exposure. This data indicates that allogeneic haemopoietic transplantation can induce durable remission in patients with CLL refractory to fludarabine and that it is reasonable to delay transplantation until failure of fludarabine therapy. It also suggests that prior exposure to fludarabine may decrease the incidence of severe aGVHD, possibly through its immunosuppressive effects. Further studies are warranted to evaluate this observation.

Donor lymphocyte infusions, by virtue of a graft-versus-tumor effect, have been shown to induce remissions in leukemia that recurs after allogeneic bone marrow transplantation. Similar effects have been postulated to contribute to the decreased recurrence rate observed after allogeneic transplantation in non-Hodgkin's lymphoma. This lower recurrence rate may be due to a variety of other mechanisms. We aimed to evaluate the role of graft-versus-lymphoma effects in patients in whom lymphomas recur after allogeneic transplantation. At the time of recurrence, immunosuppressive therapy was withheld. Patients with non-responding disease received an infusion of donor lymphocytes. Patients were observed for response and graft-versus-host disease. Disease in four of nine patients responded to withdrawal of immunosuppressive therapy. A minor response was observed in one of three recipients of donor lymphocyte infusions. Responses were observed among two patients with follicular lymphoma, one with large cell lymphoma and one with lymphoblastic lymphoma. A minor response was observed in a patient with prolymphocytic leukemia/lymphoma. We conclude that withdrawal of immunosuppressive therapy and donor lymphocyte infusion can induce durable remissions in patients with recurrent lymphoma after allogeneic transplantation.

We evaluated the response to and toxicity of allogeneic or autologous bone marrow transplantation (BMT) for patients with non-Hodgkin's lymphoma (NHL) who relapsed after autologous BMT. Since 1990, 172 patients have received autologous BMTs in NHL at the MD Anderson Cancer Center and 75 have relapsed. Twelve patients (median age, 42 years), with disease recurrence underwent either allogeneic BMT (eight patients) or a second autologous BMT (four patients). Ten patients received thiotepa, busulfan and cyclophosphamide as conditioning, one patient received cyclophosphamide and total body irradiation and one received BCNU, etoposide, Ara-c and melphalan. The median interval between the first and second transplants was 23.5 months (range 5-80 months). Three patients who underwent allogeneic BMT had refractory relapses, three had a responsive relapse and two were in complete response (CR) at the time of BMT. Five patients received peripheral blood stem cells and three patients, allogeneic bone marrow. Three patients are alive and disease-free at 25, 22 and 7 months after allogeneic BMT. Four patients died of treatment-related causes and one from disease recurrence. All four patients undergoing autologous BMT had responsive relapses. Three patients received peripheral blood stem cells and one patient bone marrow. Two patients are alive and disease-free at 12 and 30 months after autologous transplants. There were no treatment-related deaths; two patients died of disease recurrence. This retrospective study shows that in selected patients, allogeneic or autologous BMT is an effective salvage therapy for NHL which recurs after autologous BMT.

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Purpose: To determine the impact of prior or current CNS disease on the outcome of high-dose chemotherapy for patients with hematologic malignancies., Patients and Methods: In a 54-month period, 373 patients with hematologic malignancies underwent allogeneic or autologous bone marrow transplantation (BMT) or blood stem-cell transplantation using high-dose thiotepa, busulfan, and cyclophosphamide (TBC) as the preparative regimen. Four patients with active CNS disease at BMT and 20 patients with a history of prior CNS disease were identified. The outcomes of those with a history of CNS disease were compared with those of a matched control group., Results: Of four patients with active CNS disease at the time of BMT, two had CNS recurrences and one recurred in the bone marrow. One patient died of treatment-related toxicity. Four of 20 patients with prior CNS involvement currently remain free of disease. At 2 years, the disease-free survival (DFS) rate was 23% +/- 19%, and the DFS rate for the control group 39% +/- 24% (P = .053). An increased rate of treatment-related toxicity and especially grades II to IV CNS toxicity accounted for the poorer outcome of patients who had a history of CNS disease. Recurrence rates were not significantly different between the two groups. Prior radiation to the CNS correlated with CNS complications posttransplant (p = .01)., Conclusion: Consolidation with TBC and BMT can induce prolonged DFS in a proportion of patients with a history of CNS disease. Such patients are at increased risk for CNS complications that lead to an inferior overall outcome when compared with a control group.

We report the case of a patient with chronic lymphocytic leukemia (CLL) with persistent lymphocytosis and lymphadenopathy after allogeneic bone marrow transplantation (BMT). After receiving a donor lymphocyte infusion on day 87 he achieved complete remission upon development of chronic graft-versus-host disease, suggesting that a graft-versus-leukemia effect is operative in this malignancy.

Cytopenias following bone marrow transplantation may be severe and life-threatening. These have been described post-allogeneic Klumpp, 1991: Bone Marrow Transplant 8:159-171. or post-autologous bone marrow transplants Khouri et al., 1994: J Clin Oncol 12:748-758. as well as with peripheral blood stem cell transplantation Klumpp et al., 1992: Am J Hematol 41:215-217. It can be immune mediated, associated on occasions with graft-versus-host disease (GVHD) Anasetti et al., 1989: Blood 4:1054-1058; however, in most cases, the underlying mechanism is uncertain. The treatment of post-transplant cytopenias is not well established, and they are often refractory to immunosuppressive therapy with steroids. Herein we describe two cases of neutropenia after allogeneic bone marrow transplantation that improved after therapy with high-dose intravenous immunoglobulin.

Purpose: To evaluate outcomes and identify prognostic factors in allogeneic bone marrow transplantation in patients with end-stage lymphoma., Patients and Methods: Data were retrospectively analyzed of 64 patients (42 men and 22 women) 18 to 48 years of age with recurrent or refractory lymphoma who underwent allogeneic bone marrow transplantation from matched sibling donors (or in 1 case from a one antigen-mismatched relative) between May 1981 and July 1994., Results: Twelve patients survived free of disease. They were 8 of 15 with low-grade lymphoma (disease-free survival at 2 years 59% +/- 13%); 3 of 25 with lymphoblastic lymphoma (disease-free survival 17% +/- 8%); and 1 of 10 with diffuse small non-cleaved cell lymphoma (disease-free (10% +/- 9%). Survival and disease-free survival of patients with low-grade lymphoma were significantly superior compared to any other subgroup of patients (P <0.01). Only 2 patients with low-grade lymphoma had disease progression (9% +/- 9% actuarial risk at 2 years) as opposed to 5 of 15 with intermediate-grade lymphoma (39% +/- 14%), 9 of 25 with lymphoblastic lymphoma (28% +/- 9%), and 8 of 10 (80% +/- 13%) with diffuse small non-cleaved lymphoma. The actuarial risk for disease progression was significantly lower for patients with low-grade lymphoma than for any other histologic subgroup (P <0.02). It was significantly higher for those with diffuse small non-cleaved cell lymphoma than for other histologic subgroups (P < or = 0.003)., Conclusions: Allogeneic bone marrow transplantation is an effective procedure in patients with refractory low-grade lymphoma. It results in long-term remissions and should be considered in younger patients with recurrent disease who have a matched sibling donor. The late recurrence in 1 patient indicates the necessity of continued follow-up. A small fraction of patients with end-stage intermediate- and high-grade lymphoma can obtain prolonged disease-free survival, but recurrence and regimen-related toxicity remain major problems. The results could be improved by the development of conditioning regimens with less toxicity and by the use of bone marrow transplantation earlier in the course of the disease.

Donor lymphocyte infusions can reinduce complete remission in the majority of patients with chronic myelogenous leukemia (CML) who relapse into chronic phase after allogeneic bone marrow transplantation (BMT). Such infusions are associated with a high incidence of graft-versus-host disease (GVHD) and marrow aplasia. BMT using selective depletion of CD8+ lymphocytes from donor cells reduces the incidence of GVHD without an increase in leukemia relapse. We hypothesized that infusion of CD8-depleted donor peripheral blood lymphocytes could also reinduce complete remissions with a lesser potential to produce symptomatic GVHD in patients with CML who relapsed after allogeneic BMT. Ten patients with Ph(+) CML who relapsed a median of 353 days after BMT (range, 82 to 1,096 days) received donor lymphocyte infusions depleted of CD8+ cells. Nine patients received a single infusion and 1 received two infusions. Four patients were treated while in chronic phase with clonal evolution, 2 during accelerated phase, 3 during blast crisis, and 1 in a cytogenetic relapse. A mean of 0.9 +/- 0.3 x 10(8) mononuclear cells/kg were infused, containing 0.6 +/- 0.4 x 10(6) CD3+CD8+ cells/kg. Six patients achieved hematologic and cytogenetic remission at 4, 8, 11, 15, 39, and 54 weeks after lymphocyte infusion. Two patients developed > or = grade II acute GVHD, and 1 patient developed mild chronic GVHD. We conclude that donor lymphocyte infusions depleted of CD8+ cells can induce remissions with a low rate of severe acute GVHD in patients with CML who relapse after allogeneic BMT, supporting the hypothesis that CD8+ lymphocytes are important effectors of GVHD, but may not be essential for the graft-versus-leukemia effect against this disease. Further controlled studies are required to confirm these preliminary observations.

To determine if partial T cell depletion and intensive post-transplant immunosuppression is effective for the prevention of graft-versus-host disease (GVHD) in pediatric recipients of HLA-non-identical marrow transplants, 10 children with leukemia received high-dose thiotepa, cyclophosphamide and total body irradiation followed by transplantation of CD3-depleted marrow from matched unrelated or one-antigen mismatched related adult donors. To maximize the number of stem cells infused, a large volume (1-1.51) of marrow was harvested from the donors. After immunopurging, the marrow infused contained a median of 3.7 x 10(6) CD34+ cells/kg, 1.4 x 10(6) CD3+ cells/kg, and 1.6 x 10(6) CD5+ cells/kg as assessed by flow cytometry. Cyclosporine, methylprednisolone and anti-CD4 ricin A chain immunotoxin (XZ-CD5) were used for prevention of GVHD post-transplant. All patients achieved an ANC > 0.5 x 10(9)/l. No patient developed capillary leak syndrome or renal failure from XZ-CD5. Five developed grade 2-4 acute GVHD, and all responded to treatment with steroids. Five of nine evaluable patients developed chronic GVHD. Two patients relapsed, but the most common cause of death was infection with or without chronic GVHD. Four patients survive 10+ to 27+ months post-transplant. XZ-CD5 is well-tolerated in T cell-depleted marrow transplant recipients. However, partial T cell depletion and intensive post-transplant immunosuppression did not prevent moderate acute GVHD or chronic GVHD. This may have been due to the high number of T cells infused with the marrow.

Objectives: To determine the minimal active dose and extent of activity of intravesicular carboprost for the treatment of hemorrhagic cystitis after marrow transplantation., Methods: Twenty-four adults with grade 3 or 4 hemorrhagic cystitis were treated. All but 2 had failed other local therapy. Treatment was initiated at a median of 32 days post-transplant. Eleven patients received carboprost intravesicularly at 0.2 mg/dL for 60 minutes every 6 hours, and the dose was escalated every 24 hours until a dose of 1.0 mg/dL was reached unless a response was achieved. Thirteen additional patients were treated at an initial dose of 0.8 mg/dL, with escalation to 1.0 mg/dL after four doses in the absence of a response., Results: Overall, 15 of the 24 patients responded. In the dose-escalation setting, 0.8 mg/dL was the minimal active dose. The total response rate was 62% with doses at or above 0.8 mg/dL and 18% at lower doses. All but one response occurred with 7 or fewer days of therapy, and 9 patients relapsed later. Four additional patients were salvaged following cystoscopy with clot evacuation with or without alum or formalin instillation. In all but 1 patient, bladder spasms developed during treatment with carboprost, but were not sufficiently severe to discontinue therapy., Conclusions: Intravesicular carboprost at 1.0 mg/dL every 6 hours for no more than 7 days should be considered for a randomized study for treatment of refractory hemorrhagic cystitis. Cystoscopic examination and evacuation of clots prior to therapy may be required to achieve the full benefit of this treatment.

We collected peripheral blood mononuclear cells and bone marrow cells soon after recovery from conventional-dose chemotherapy-induced myelosuppression and transplanted these cells into advanced chronic myelogenous leukemia (CML) patients after treating these patients with 120 mg/kg cyclophosphamide, 750 mg/m2 VP-16, and 1,020 cGy of total body irradiation (TBI). Of the 10 late chronic-phase patients and the eight accelerated-phase CML patients evaluable posttransplant, 90% and 87%, respectively, remain alive posttransplant, whereas none of the three blast crisis CML patients given this therapy remain alive posttransplant. We measured the percentage of Philadelphia chromosome (Ph)-negative cells in the autologous cells collected after conventional-dose chemotherapy-induced myelosuppression before autologous transplant and in the marrow of these same CML patients after autologous transplantation of these cells into recipients treated with the cyclophosphamide, VP-16, and TBI. A direct correlation (correlation coefficient = 0.91) was observed between the level of Ph+ cells in the transplanted cells and the percentage of Ph+ marrow cells after transplant in 21 patients so transplanted. The data show that the chance of generating cytogenetic remissions post-transplant depends on the percentage of diploid cells in the preparations of autologous cells used for transplant and the stage of disease of the patients at the time of collection of the autologous cells.

We treated 12 patients with leukemia relapse after allogenic bone marrow transplantation with a combination of interferon-alpha (IFN-alpha) ((2.5-5.0) x 10(6) u/m2 subcutaneously three times a week) and interleukin-2 (IL-2) ((1.8-3.6) x 10(6) IU/m2 subcutaneously five times a week) to determine the toxicity and efficacy of combination cytokine therapy in this setting. The median age of the patients was 39 years (range: 16-50). There were nine females and three males. The median time to relapse from BMT was 98 days (range: 0-963). At the time of relapse, six patients had AML, four patients had CML (two in blast crisis and two in chronic phase with clonal evolution), and one patient had lymphoblastic lymphoma. Combination cytokine therapy was started a median of 108 days post BMT (range: 37-2404). Nine patients treated at the higher dose level required a 50% dose reduction because of toxicity or GVHD (three CNS, two GVHD, one high fever, one diarrhoea with hypotension, and one pericarditis). At a lower dose level, 2 of 10 patients had their treatment discontinued because of toxicity or GVHD. Six patients developed clinical findings consistent with acute GVHD while on combination cytokine therapy. Two patients responded to combination cytokine therapy: one with CML and one with AML. Combination cytokine therapy is feasible in the setting of relapse post allogeneic BMT. The combination of IL-2 1.8 x 10(6) IU/m2 five times a week with IFN-2 2.5 x 10(6) U/m2 three times a week seems to be tolerable, and merits further study in this setting.

Purpose: To evaluate the role of allogeneic bone marrow transplantation (BMT) in recurrent low-grade lymphoma., Patients and Methods: Between 1989 and 1994, 10 patients with chemotherapy-refractory and recurrent low-grade lymphoma were treated with myeloablative therapy and allogeneic BMT. All patients had poor prognostic features and had been extensively pretreated., Results: Eight patients achieved a complete remission and none have relapsed at a median follow-up time of 816 days (range, 346 to 1,865). Two patients died of early complications. The actuarial survival and failure-free survival rates are both 80% +/- 12.6%. For surviving patients, the duration of the current remission exceeds that of any previous remission achieved., Conclusion: These results compare favorably with those for autologous BMT. Allogeneic BMT offers considerable promise for the treatment of patients with poor-prognosis low-grade lymphoma. Its role should be further defined in prospective studies.

Forty-eight adult patients with recurrent or refractory intermediate grade or immunoblastic lymphoma received high-dose carmustine (BCNU), etoposide, Ara C and cyclophosphamide (BEAC), followed by autologous bone marrow transplantation (BMT). Median follow-up is 906 days (range 613-2067 days). The complete remission rate was 42% and 22% had a partial response. Actuarial failure-free survival is 30% +/- 6.6%. Twenty one patients relapsed or progressed. Only one relapse occurred > 1 year after autologous BMT. Adverse prognostic factors for failure-free survival include high LDH at the time of autologous BMT, chemotherapy-refractory disease and multiple prior relapses. Patients with chemotherapy responsive first salvage (those achieving first CR only with salvage chemotherapy and those with first relapse, responding to salvage chemotherapy) had a failure-free survival of 52% +/- 10% vs 12% +/- 6% for those with more advanced disease. Of 13 patients who had no adverse factors, only two relapsed. Treatment-related mortality occurred in 23%, including infection (n = 4), cardiac toxicity (n = 4), pulmonary toxicity (n = 2) and hemorrhage (n = 1). Pulmonary toxicity was more common among patients who had received prior radiation-therapy to the chest. BEAC chemotherapy with autologous BMT is an effective but relatively toxic regimen for patients with relapsed or refractory lymphomas. The combination of chemotherapy-responsive disease after failure of one chemotherapy regimen and normal LDH identifies patients with a favorable prognosis. Alternative cytotoxic regimens require evaluation, with the goal of reducing treatment related mortality. More effective cytoreductive therapy is required for patient with poor prognostic features.

Purpose: To determine the efficacy and toxicity of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) as the conditioning regimen for allogeneic bone marrow transplantation (BMT) in patients with hematologic malignancies., Patients and Methods: Seventy-nine patients underwent BMT from a human leukocyte antigen (HLA)-identical sibling using cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis. Thirty-four patients had early leukemia (acute leukemia or lymphoblastic lymphoma in first remission, chronic myelogenous leukemia [CML], or refractory anemia [RA]), and 45 patients had more advanced disease. Patients received etoposide 1,500 mg/m2 on day -8, followed by cyclophosphamide 60 mg/kg/d on days -7 and -6, and 10.2 Gy of TBI administered in six fractions of 1.7 Gy given twice daily for 3 days from day -3 to -1. Donor bone marrow was harvested and infused on day 0., Results: Patients with early leukemia had a disease-free survival rate of 53% +/- 9% and an overall survival rate of 57% +/- 10% at 3 years. Patients with advanced disease had a disease-free survival rate of 15% +/- 5% and overall survival rate of 17% +/- 5%. The actuarial relapse rate for the early-leukemia group is 33% +/- 9% versus 69% +/- 9% for patients with more advanced disease. Severe toxicity was most frequently manifested as pulmonary hemorrhage followed by multiorgan failure and death. The 100-day mortality rate for the early-leukemia group was 10% versus 50% for patients with more advanced disease., Conclusion: The combination of cyclophosphamide, etoposide, and TBI is a relatively safe and effective preparative regimen for patients with early hematologic malignancies. Controlled trials are needed to evaluate critically this combination versus other standard preparative regimens. Greater toxicity was observed in patients with advanced disease, and this program does not appear to offer any advantage over other regimens.

Purpose: This study was undertaken to evaluate the feasibility and therapeutic effect of high-dose chemoradiotherapy with autologous or allogeneic bone marrow transplantation (BMT) in patients with advanced chronic lymphocytic leukemia (CLL) who relapse after fludarabine treatment., Patients and Methods: Twenty-two patients with advanced CLL received high-dose cyclophosphamide, total-body irradiation, and BMT. Eleven patients with relapsed CLL received autologous BMT with marrow collected during a prior fludarabine-induced remission; leukemia cells were depleted from the autologous marrow in seven patients using an anti-CD19 monoclonal antibody and immunomagnetic separation. Eleven patients received allogeneic or syngeneic BMT, seven of whom had refractory Rai stage III or IV disease., Results: Six autologous transplant recipients achieved a complete remission (CR), four a nodular CR (nCR), and one a partial remission (PR). Two recurred with CLL, and three developed Richter's transformation. Two patients had recurrence of immune cytopenias while in morphologic remission; one of these patients died of cytomegalovirus pneumonia. Six of 11 patients survive in remission 2 to 29 months following BMT. Of the 11 patients who received allogeneic or syngeneic BMT, seven achieved a CR, two a nCR, and one a PR; 10 survive 2 to 36 months following BMT., Conclusion: These data indicate that high-dose chemotherapy with allogeneic BMT is effective at producing CRs in patients with CLL. Autologous transplantation in CLL is feasible and is capable of producing remissions in patients with advanced CLL. Further studies are warranted to assess the role of BMT in the treatment of CLL.

The prognostic significance of detecting minimal residual disease by polymerase chain reaction (PCR) amplification of bcr/abl mRNA transcripts was investigated in 27 bone marrow samples from 20 patients with Philadelphia chromosome (Ph1) positive chronic myelogenous leukaemia (CML) in complete cytogenetic remission following allogeneic bone marrow transplantation. Sixteen were transplanted in first chronic phase, two were in second chronic phase, one was in accelerated phase and one was in blast crisis. All 20 achieved complete cytogenetic remission post transplant and 15 patients had detectable bcr/abl mRNA by PCR from 2 to 22 months following the procedure. One of these patients had graft failure and one died from graft-versus-host-disease at 7 months. Of the remaining 13 PCR-positive patients, only one (8%) relapsed after 23 months; the other 12 were alive and still in remission after a median follow-up of 16+ months (ranging 5+ to 29+ months). Five patients were PCR negative; all are alive in complete clinical and cytogenetic remission at 10+, 11+, 19+, 25+ and 25+ months post transplant. In this study, detection of subclinical Ph1-positive cells by PCR was not associated with imminent clinical or cytogenetic relapse. Since late recurrence may potentially occur, long-term follow-up is required to definitely determine the prognostic value of the PCR assay.

Pneumocandins have concentration-dependent antifungal activity and higher dose of caspofungin (HD-CAP) in combination with other licensed antifungal therapy (OLAT) may improve response. Thirty-four patients who received HD-CAP were compared with 63 patients who received standard dose (SD)-CAP. There were no differences between the groups in either patient or disease characteristics. Significantly more patients in the HD-CAP arm had extrapulmonary infections (29 vs 8% in SD group; P=0.0053), and non-Aspergillus species infection (21 vs 6%; P=0.05) and had received prior antifungal therapy (71 vs 33%; P=0.0004). No serious adverse reactions were noted in patients receiving HD- or SD-CAP therapy. Twelve weeks after treatment commenced 44% had a complete or partial response compared with 29% in SD-CAP group (P=0.1). Logistic regression analysis showed a significant probability of a favorable outcome at 12 weeks in patients who received HD-CAP (OR 3.066, 95% CI, 1.092–8.61; P=0.033). This may in part reflect higher number of patients in HD group had received granulocyte–macrophage colony-stimulating factor (41 vs 14% in SD group; P=0.04) and/or interferon γ (26 vs 5% in SD group; P=0.003) immune enhancement. Further studies are needed to evaluate efficacy of HD-CAP in severely immunosuppressed cancer patients with invasive fungal infections.Bone Marrow Transplantation (2007) 39, 157–164. doi:10.1038/sj.bmt.1705559 [ABSTRACT FROM AUTHOR]

Summary:A total of 40 patients with relapsed/refractory Hodgkin's 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.Bone Marrow Transplantation (2005) 35, 943-951. doi:10.1038/sj.bmt.1704942 Published online 4 April 2005 [ABSTRACT FROM AUTHOR]

Summary:Nine patients with advanced Hodgkin's lymphoma (HL) who had undergone allogeneic stem cell transplantation (allo-SCT) received donor leukocyte infusions (DLIs) for treatment of persistent or progressive disease (PD). A total of 15 DLIs were performed, with four patients receiving more than one DLI. In four patients, prior salvage chemotherapy was administered. The median CD3+cell dose administered was 77.5×106/kg (range 5-285). GVHD developed in all but one patient. The response rate was 4/9 (44%). Three of these four responders developed GVHD and 3/4 had received chemotherapy. No correlation was observed between CD3+cell dose infused and disease response. At the latest follow-up, three patients are alive and six have expired (PD n=3, nonrelapse mortality n=3). The median response duration was 7 months (range 4-9), with one response currently ongoing. These data suggest that DLIs for immunotherapy of recurrent HL have significant activity, although they frequently leads to GVHD. The small sample size does not allow any conclusion as to whether chemotherapy administration increases the chance of response. The CD3 cell dose infused does not seem to correlate with disease response.Bone Marrow Transplantation (2004) 34, 511-514. doi:10.1038/sj.bmt.1704621 Published online 26 July 2004 [ABSTRACT FROM AUTHOR]

Six patients with advanced Hodgkin’s disease in which multiple conventional treatments (median prior chemotherapy regimens: seven), radiation therapy, and a prior autologous stem cell transplantation (SCT) had failed underwent allogeneic SCT following a fludarabine-based conditioning regimen. Median age was 29 years (22–30). Median time to progression after autologous SCT was 6 months (4–21). Disease status at transplant was refractory relapse (n = 3) and sensitive relapse (n = 3). Cell source was filgrastim-mobilized peripheral blood stem cells from an HLA-identical sibling (n = 4) or matched unrelated donor marrow (n = 2). Conditioning regimens were fludarabine–cyclophosphamide–antithymocyte globulin (n = 4), fludarabine–melphalan (n = 1) and fludarabine–cytarabine–idarubicin (n = 1). Myeloid recovery was prompt, with an absolute neutrophil count 500/μl on day 12 (11–15). Median platelet recovery to 20000/μl was on day 9 (0–60). Chimerism studies on day 30 indicated 100% donor-derived hematopoiesis in 4/5 evaluable patients (4/4 non-progressors). All responders (3/3) have ongoing 100% donor-derived chimerism. Acute graft-versus-host disease (GVHD) was diagnosed in 4/6 evaluable patients. Chronic GVHD was present in 2/4 evaluable patients. There were no regimen-related deaths. Overall day 100 transplant-related mortality was 2/6 (33%). Three patients have expired and three are alive and progression-free with a median follow-up of 9 months (6–26) post transplant. We conclude that allogeneic stem cell transplantation with fludarabine-based preparative regimens is feasible in these high-risk, heavily pretreated HD patients. Bone Marrow Transplantation (2000) 26, 615–620. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor of "Leukemia" journal commenting on the mechanisms of graft failure in human leukocyte antigen (HLA)-matched and HLA-mismatched bone marrow transplant recipients.