A randomized study of melphalan 200 mg/m(2) vs 280 mg/m(2) as a preparative regimen for patients with multiple myeloma undergoing auto-SCT.

We aimed to examine whether doses of melphalan higher than 200 mg/m(2) improve response rates when used as conditioning before autologous transplant (ASCT) in multiple myeloma (MM) patients. Patients with MM, n=131, were randomized to 200 mg/m(2) (mel200) vs 280 mg/m(2) (mel280) using amifostine pretreatment. The primary end point was the proportion of patients achieving near complete response (⩾nCR). No treatment-related deaths occurred in this study. Responses following ASCT were for mel200 vs mel280, respectively, ⩾nCR 22 vs 39%, P=0.03, ⩾PR 57 vs 74%, P=0.04. The hazard of mortality was not statistically significantly different between groups (mel200 vs mel280; hazard ratio (HR)=1.15 (95% confidence interval (CI), 0.62-2.13, P=0.66)) nor was the rate of progression/mortality (HR=0.81 (0.52-1.27, P=0.36)). The estimated PFS at 1 and 3 years were 83 and 46%, respectively, for mel200 and 78 and 54%, respectively, for mel280. Amifostine and mel280 were well tolerated, with no grade 4 regimen-related toxicities and only one grade 3 mucositis (none with mel200) and three grade 3 gastrointestinal (GI) toxicities (two in mel200). Hospitalization rates were more frequent in the mel280 group (59 vs 43%, P=0.08). Mel280 resulted in a higher major response rate (CR+nCR) and should be evaluated in larger studies.

Maintenance rituximab after autologous stem cell transplantation in patients with mantle cell lymphoma.

BACKGROUND: High-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes for patients with mantle cell lymphoma (MCL), but relapse ultimately occurs in most patients. Recently presented interim results from a phase III prospective trial suggest maintenance rituximab (MR) after ASCT for MCL improves progression-free survival (PFS). The maturation of these data and any benefit of MR on overall survival (OS) remain to be defined. PATIENTS AND METHODS: In this retrospective study, we examined a cohort of consecutive patients with MCL that underwent ASCT for MCL at our center and evaluated their outcomes according to whether they received MR after ASCT (n = 50) or did not (n = 107). MR was treated as a time-dependent covariate to account for variation in timing of its initiation. RESULTS: MR was associated with an improved PFS [hazard ratio (HR) 0.44; confidence interval (CI) (0.24-0.80), P = 0.007] and overall survival (OS; HR 0.46; CI 0.23-0.93, P = 0.03) following a multivariate adjustment for confounding factors with a median follow-up of ∼5 years. Grade 4 neutropenia was increased (34% versus 18%, P = 0.04) in the MR group, but no effect on the rate of mortality unrelated to relapse was observed. CONCLUSIONS: These data support that MR after ASCT for MCL confers a benefit in PFS and additionally suggest it may improve OS. General application of this strategy will require confirmation of benefit in prospective randomized trials.

Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis.

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16mg/ kg (targeted to 800-900 ng/ml), and cyclophosphamide 120 mg/ kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P<0.001), more frequently had progressed to tAML (53 vs 31%, P=0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P=0.004), had higher transplant specific comorbidity indices (68 vs 42%, P=0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P=0.56)), progression-free survival (28%/4 44%, (P=0.60)), and nonrelapse mortality (41%/34%, (P=0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR=0.9, P=0.84) and progression-free survivals (HR=1, P=0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.

Hematopoietic cell transplantation from HLA-identical sibling donors after low-dose radiation-based conditioning for treatment of CML.

A total of 24 patients (median age 58; range, 27-71 years) with chronic myeloid leukemia (CML) in first chronic (CP1) (n=14), second chronic (n=4), or accelerated phase (n=6) who were not candidates for conventional hematopoietic cell transplantation (HCT), received nonmyeloablative HCT from HLA-matched siblings a median of 28.5 (range, 11-271) months after diagnosis. They were conditioned with 2 Gy total body irradiation (TBI) alone (n=8) or combined with fludarabine, 90 mg/m(2) (n=16). Postgrafting immunosuppression included cyclosporine and mycophenolate mofetil. All patients initially engrafted. However, 4 of 8 patients not given fludarabine experienced nonfatal rejection while all others had sustained engraftment. With a median follow-up of 36 (range, 4-49) months, 13 of 24 patients (54%) were alive and in complete remission. There were five (21%) deaths from nonrelapse mortality, one (4%) during the first 100 days after transplant. The proportions of grade II, III, and IV acute GVHD were 38, 4, and 8%, respectively. The 2-year estimate of chronic GVHD was 32%. The 2-year survival estimates for patients in CP1 (n=14) and beyond CP1 (n=10) were 70 and 56%, respectively. This study shows encouraging remission rates for patients with CML not eligible for conventional allografting.

High doses of transplanted CD34+ cells are associated with rapid T-cell engraftment and lessened risk of graft rejection, but not more graft-versus-host disease after nonmyeloablative conditioning and unrelated hematopoietic cell transplantation.

This report examines the impact of graft composition on outcomes in 130 patients with hematological malignancies given unrelated donor granulocyte-colony-stimulating-factor-mobilized peripheral blood mononuclear cells (G-PBMC) (n = 116) or marrow (n = 14) transplantation after nonmyeloablative conditioning with 90 mg/m(2) fludarabine and 2 Gy TBI. The median number of CD34(+) cells transplanted was 6.5 x 10(6)/kg. Higher numbers of grafted CD14(+) (P = 0.0008), CD3(+) (P = 0.0007), CD4(+) (P = 0.001), CD8(+) (P = 0.004), CD3(-)CD56(+) (P = 0.003), and CD34(+) (P = 0.0001) cells were associated with higher levels of day 28 donor T-cell chimerism. Higher numbers of CD14(+) (P = 0.01) and CD34(+) (P = 0.0003) cells were associated with rapid achievement of complete donor T-cell chimerism, while high numbers of CD8(+) (P = 0.005) and CD34(+) (P = 0.01) cells were associated with low probabilities of graft rejection. When analyses were restricted to G-PBMC recipients, higher numbers of grafted CD34(+) cells were associated with higher levels of day 28 donor T-cell chimerism (P = 0.01), rapid achievement of complete donor T-cell chimerism (P = 0.02), and a trend for lower risk for graft rejection (P = 0.14). There were no associations between any cell subsets and acute or chronic GVHD nor relapse/progression. These data suggest more rapid engraftment of donor T cells and reduced rejection rates could be achieved by increasing the doses of CD34(+) cells in unrelated grafts administered after nonmyeloablative conditioning.

Allogeneic peripheral blood stem cell graft composition affects early T-cell chimaerism and later clinical outcomes after non-myeloablative conditioning.

We have studied the influence of cell subsets [CD34, CD3, CD4, CD8, CD14, CD20, natural killer (NK; CD3(-)/CD56(+)), NKT (CD3(+)/CD56(+)), DC1, and DC2 cells] of granulocyte colony-stimulating factor mobilized peripheral blood stem cells (PBSC) on early T-cell chimaerism and later clinical outcomes in 125 patients with haematological malignancies who received human leucocyte antigen (HLA)-matched related grafts after non-myeloablative conditioning. Conditioning consisted of 2 Gy total body irradiation (TBI) alone (n = 28), or 2 Gy TBI preceded by either 90 mg/m(2) fludarabine (n = 62) or planned autologous haematopoietic cell transplantation (HCT) (n = 35). Post-transplant immunosuppression included mycophenolate mofetil and ciclosporin. Multivariate analysis showed that higher numbers of grafted NK cells predicted higher early T-cell chimaerism (P = 0.03), while higher numbers of B cells were associated with better clinical outcomes and a higher risk for chronic graft-versus-host disease (P = 0.05). Higher numbers of CD14(+) cells were associated with worse overall survival (P = 0.03), while higher numbers of CD34(+) cells showed better survival (P = 0.03). The addition of fludarabine or autologous HCT predicted higher early T-cell chimaerism (P = 0.001), while advanced donor age predicted lower chimaerism (P < or = 0.02). Patients with aggressive diseases were at higher risk for relapse/disease progression, and shorter progression-free and overall survival (P < 0.01). These results suggest that the dosing of certain cellular subsets of PBSC products can influence important outcomes post-HCT after non-myeloablative conditioning.

CD34 cell dose in granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell grafts affects engraftment kinetics and development of extensive chronic graft-versus-host disease after human leukocyte antigen-identical sibling transplantation.

A retrospective analysis of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cell (G-PBMC) products harvested from healthy donors indicates significant variability in both the absolute number and relative proportion of CD34, CD3, and CD14 cells obtained. This report examined whether variations in the cellular composition of G-PBMC products correlated with clinical outcomes after myeloablative allogeneic transplantation. The numbers of CD34, CD3, and CD14 cells infused into 181 human leukocyte antigen (HLA)-identical sibling recipients were analyzed with respect to tempo of engraftment, acute graft-versus-host-disease (GVHD), clinical extensive chronic GVHD, overall survival, and disease relapse. Neither acute GVHD, overall survival, nor disease relapse was statistically significantly associated with CD34, CD3, or CD14 cell doses or the CD14 to CD3 ratio. CD3 and CD14 cell doses and CD14 to CD3 ratios did not correlate with the tempo of neutrophil and platelet engraftment. However, increasing CD34 cell numbers were significantly associated with accelerated neutrophil (P =.03) and platelet (P =.01) engraftment. Higher doses of CD34 cells (> 8.0 x 10(6)/kg) were also associated with a significantly increased hazard of clinical extensive chronic GVHD (HR = 2.3, 95% confidence interval [CI] 1.4-3.7, P =.001), but neither CD3 nor CD14 doses were statistically significantly associated with chronic GVHD. It was concluded that CD34 cell dose in G-PBMC grafts appears to affect both the engraftment kinetics and the development of clinical extensive chronic GVHD in HLA-identical sibling recipients but without a demonstrable impact on survival, relapse, and acute GVHD. Given the morbidity associated with extensive chronic GVHD, efforts to further accelerate engraftment in HLA-matched sibling transplants by increasing CD34 cell number in G-PBMC products may be counterproductive.

Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects.

Toxicities have limited the use of allogeneic hematopoietic cell transplantation (HCT) to younger, medically fit patients. In a canine HCT model, a combination of postgrafting mycophenolate mofetil (MMF) and cyclosporine (CSP) allowed stable allogeneic engraftment after minimally toxic conditioning with low-dose (200 cGy) total-body irradiation (TBI). These findings, together with the known antitumor effects of donor leukocyte infusions (DLIs), led to the design of this trial. Forty-five patients (median age 56 years) with hematologic malignancies, HLA-identical sibling donors, and relative contraindications to conventional HCT were treated. Immunosuppression involved TBI of 200 cGy before and CSP/MMF after HCT. DLIs were given after HCT for persistent malignancy, mixed chimerism, or both. Regimen toxicities and myelosuppression were mild, allowing 53% of eligible patients to have entirely outpatient transplantations. Nonfatal graft rejection occurred in 20% of patients. Grades II to III acute graft-versus-host disease (GVHD) occurred in 47% of patients with sustained engraftment. With median follow-up of 417 days, survival was 66.7%, nonrelapse mortality 6.7%, and relapse mortality 26.7%. Fifty-three percent of patients with sustained engraftment were in complete remission, including 8 with molecular remissions. This novel allografting approach, based on the use of postgrafting immunosuppression to control graft rejection and GVHD, has dramatically reduced the acute toxicities of allografting. HCT with the induction of potent graft-versus-tumor effects can be performed in previously ineligible patients, largely in an outpatient setting. Future protocol modifications should reduce rejection and GVHD, thereby facilitating studies of allogeneic immunotherapy for a variety of malignancies. (Blood. 2001;97:3390-3400)

Relapse after allogeneic bone marrow transplantation for refractory anemia is increased by shielding lungs and liver during total body irradiation.

Patients with the refractory anemia (RA) subtype of myelodysplastic syndrome who undergo allogeneic bone marrow transplantation (BMT) have a low risk of relapse, but they have a high risk of nonrelapse mortality when prepared with conventional preparative regimens. To try to reduce nonrelapse mortality, we treated 14 RA patients with a modified approach to total body irradiation (TBI) followed by cyclophosphamide (CY) and HLA-identical sibling BMT. Median patient age was 44 years (range, 28 to 65 years). Patients received TBI with shielding of the right lobe of the liver and both lungs followed by electron beam boosts to shielded ribs. Total radiation exposure in nonshielded areas was 12 Gy (n = 10), 10 Gy (n = 3), or 6 Gy (n = 1). After TBI, patients received CY at 120 mg/kg over 2 days, followed by transplantation of unmanipulated bone marrow. All patients initially achieved engraftment with donor cells, although 2 patients had subsequent reemergence of host hematopoiesis without evidence of disease relapse. Five patients died of transplantation-related causes between 22 and 1262 days post-BMT. Four patients relapsed between 157 and 1096 days post-BMT. These 14 patients were compared with 46 historical controls with RA who received conventional CY/TBI or busulfan/CY preparative regimens. Patients in the experimental group had a similar nonrelapse mortality rate compared with the historical control group (29% versus 37%, respectively; P = .8), but a higher relapse rate (34% versus 2%, P = .0004) and a lower disease-free survival (38% versus 61%, P = .16). We conclude that this modified TBI approach is associated with an unacceptably high risk of relapse for patients with RA undergoing BMT.

Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.

BACKGROUND: In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS: Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS: The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS: In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.

Drug resistance mechanisms in acute leukemia.

Markers of anticancer drug resistance are predictive of treatment response and outcome in patients with acute myeloid leukemia. Immunologic detection of the drug efflux pumps, P-glycoprotein (Pgp) and multidrug resistance-associated protein 1 (MRP1), correlate with functional assays of drug resistance. These accumulation defects also appear operable in acute lymphoblastic leukemia. Many of the efflux pumps identified share significant structural homology with the large superfamily of ATP-binding cassette transporters. Other markers such as lung-resistance protein, bcl-2, and breast cancer-resistance protein, have been described in acute myeloid leukemia patients although their pathophysiology and clinical relevance are less clear and the methodology for their quantification are not well standardized. Preclinical studies have shown that small molecules capable of reversing efflux can restore drug sensitivity in resistant tumor models. Although initial clinical studies were limited by both potency and specificity of the reverser, later studies with more effective reversers have in many instances been limited by pharmacokinetic interactions exacerbating the clinical toxicities of chemotherapy. Although one large randomized study has demonstrated a proven survival advantage without increased toxicity using cyclosporine, the inconsistent results with other modulators raise doubt as to the utility and overall strategy of using drug efflux blockers in patients with established Pgp overexpression. Many of these patients have additional resistance mechanisms, and achieving meaningful clinical responses will likely require more complex clinical strategies. Preventing or delaying development of drug resistance in chemosensitive patients represents another therapeutic strategy to be tested.

Pilot trial of cytoprotection with amifostine given with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

In an attempt to limit toxicities associated with dose-intensive therapy used for transplant regimens, we performed a pilot study using amifostine with high-dose busulfan (12 mg/kg), melphalan (100 mg/m2), and thiotepa (500 mg/m2) in 21 patients with a variety of malignancies. After 3 days of oral busulfan, amifostine was given at 910 mg/m2 IV for 10 minutes, preceding the infusion of each of 2 doses of melphalan and thiotepa given for 4 days. Antiemetic premedication for amifostine was given to all patients. The median patient age was 50 years (range: 32-65 years). Twenty-one patients received 82 separate amifostine infusions. One patient discontinued amifostine after the second dose because of severe nausea and emesis, and two infusions were temporarily held secondary to hypotension. Of these 82 cycles, there was a total of 37 episodes of nausea/vomiting, 28 episodes of sneezing, 11 episodes of flushing, and 1 episode of oral paresthesia. Systolic blood pressure and mean arterial pressure decreased by a mean of 8.4 mm Hg and 5.0 mm Hg, respectively. In general, the infusion was well tolerated. Patients were observed until discharge home (N = 15), until initiation of an additional tandem transplant procedure (N = 4), or until death (N = 2). All twenty-one patients experienced nonhematologic toxicities grade II or greater. Grade II toxicities included mucositis (N = 21), gastrointestinal (N = 3), skin (N = 1), and liver (N = 1), and grade III toxicities included liver (N = 1). Mucositis was also scored according to a detailed toxicity assessment. Mucositis did not appear to be improved with amifostine when compared with a control group of patients not receiving amifostine. Renal dysfunction after transplantation was decreased in the amifostine group, whereas there was no significant effect on posttransplant hepatic dysfunction. Although these data demonstrate the feasibility of delivering parenteral amifostine in conjunction with dose-intensive chemotherapy and autologous peripheral blood stem cell transplantation, there was no evidence of a significant reduction in nonmarrow toxicities.

Granulocyte colony-stimulating factor given to donors before apheresis does not prevent aplasia in patients treated with donor leukocyte infusion for recurrent chronic myeloid leukemia after bone marrow transplantation.

We conducted 2 sequential studies of donor leukocyte infusion (DLI) in 26 patients with chronic myeloid leukemia in hematologic relapse after unmodified allogeneic bone marrow transplantation. In the first study, cells for DLI were collected from 13 donors who were not treated with granulocyte colony-stimulating factor (G-CSF) (group 1). In the second study, cells were collected from 13 donors who received G-CSF before apheresis (group 2) in an attempt to avoid aplasia after DLI. Patients in group 2 received 550-fold more CD34+ cells than those in group 1. We found no significant difference in the incidence (31% versus 22%), onset time (41 vs. 48 days), or duration (15 vs. 14 days) of cytopenia after DLI in the 2 groups. G-CSF given to donors before collection of cells did not prevent aplasia. These findings support the hypothesis that the pathogenesis of aplasia after DLI is not restricted to the destruction of recipient hematopoietic cells but also involves failure of donor hematopoiesis by undefined mechanisms.

Bile duct apoptosis and cholestasis resembling acute graft-versus-host disease after autologous hematopoietic cell transplantation.

BACKGROUND: Acute graft-versus-host disease (GVHD) of the liver is a frequent complication of allogeneic hematopoietic cell transplantation. This report describes hepatic GVHD following autologous transplantation. METHODS: We reviewed 116 consecutive autologous transplant recipients. A diagnosis of GVHD was based on histology (segmental to subtotal destruction of bile ductal epithelial cells with apoptosis and lymphocytic infiltrates), clinical criteria (elevated serum alkaline phosphatase), a response to immunosuppressive therapy, and finding no other cause for cholestatic liver disease. RESULTS: Two patients developed cholestatic liver disease (alkaline phosphatase levels over five times the normal upper limit) and had liver biopsies showing apoptotic and dysmorphic ductular epithelial cells typical of GVHD. Three additional patients developed cholestasis and intestinal symptoms but had gastric biopsies only, showing apoptotic crypt epithelial cells and crypt cell drop-out typical of GVHD. CONCLUSION: Two recipients of autologous hematopoietic cells developed histologic abnormalities of small bile ducts and cholestatic liver disease resembling GVHD of the liver after allogeneic transplant. The mechanisms of bile duct damage in this setting may involve immune dysregulation related to reconstitution of immunity with peripheral blood stem cells.

A phase I study of induction chemotherapy for older patients with newly diagnosed acute myeloid leukemia (AML) using mitoxantrone, etoposide, and the MDR modulator PSC 833: a southwest oncology group study 9617.

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

Radiation myelitis following allogeneic stem cell transplantation and consolidation radiotherapy for non-Hodgkin's lymphoma.

Myelitis is a rare but well documented complication of therapeutic radiation exposure to the spinal cord and is characterized by delayed development of paresthesias, sensory changes and, in severe cases, progressive paresis and paralysis. Although accepted radiation tolerance limits for the spinal cord have successfully limited the incidence of this problem (45-50 Gy, in daily 1.8-2 Gy fractions), aggressive systemic therapy may render patients more susceptible to radiation-related neurotoxicity. We describe the case of a 38-year-old man with refractory non-Hodgkin's lymphoma who underwent matched sibling peripheral blood stem cell transplant following a conditioning regimen of cyclophosphamide (60 mg/kg x 2) and total body irradiation (120 cGy x 11). This was followed by delivery of 30.6 Gy involved-field radiation at 1.8 Gy/day to the mediastinum and left supraclavicular fossa for bulky residual tumor. Although maximum cumulative radiation dose to the spinal cord was less than 45 Gy, the patient subsequently developed progressive lower extremity weakness and MRI abnormalities of the spinal cord limited to the radiation field. This represents the second report in the literature of this unexpected complication, prompting a need to re-examine current guidelines for radiotherapy in the context of high-dose systemic treatment.

Chemotherapy resistance in Acute Leukemia.

Drug resistance markers are often predictive of treatment response and outcome in patients with acute myeloid leukemia. The immunologic detection of drug efflux pumps such as P-glycoprotein (Pgp) and multidrug resistance associated protein 1 (MRP1) rrelate with functional assays of drug resistance and these drug accumulation defects also appear operable in ALL. Other markers such as LRP, bcl- 2, and BRCP, have been described in patients with AML although their pathophysiology and clinical relevance is less clear and methodology for their quantification not well standardized. Preclinical tudies have shown that small molecules capable of reversing efflux can restore drug sensitivity in resistant tumor models. While initial clinical studies were limited by both potency and specificity of the reverser, later studies with more effective reversers have in many instances been limited by pharmacokinetic interactions exacerbating the clinical toxicities of chemotherapy. Nonetheless, one large randomized study using cyclosporine has demonstrated a proven survival advantage without increased toxicity, although the inconsistent results with other modulators raises doubt as to the utility and overall strategy of using drug efflux blockers in patients with established Pgp overexpression. Most of these patients have additional mechanisms of resistance and achieving meaningful clinical responses will likely require more complex clinical strategies. Preventing or delaying development of drug resistance in chemosensitive patientsrepresents another therapeutic strategy to be tested.

A phase I-II clinical trial to evaluate removal of CD4 cells and partial depletion of CD8 cells from donor marrow for HLA-mismatched unrelated recipients.

We conducted a phase I-II clinical trial to test the hypothesis that removal of CD4 cells from an HLA-mismatched unrelated marrow graft would substantially reduce the risk of grades III-IV graft-versus-host disease (GVHD) and that retention of a specified number of CD8 cells in the graft would be sufficient to prevent rejection. Patients were eligible for this study when an HLA-A, -B, or -DRB1-matched unrelated donor could not be identified. HLA matching of the donor and recipient was based on typing of HLA-A and -B antigens by serologic methods and by typing of HLA-DRB1 alleles by molecular methods, and donors were selected when disparity was limited to a single HLA-DRB1 allele or a single HLA-A or -B antigen. Twenty-seven patients with hematologic malignancy or aplastic anemia were prepared to receive a transplant with conventional regimens of cyclophosphamide and fractionated total body irradiation, and a standard regimen of methotrexate and cyclosporine was given for GVHD prophylaxis. CD4 cells were removed from the donor marrow, and the numbers of CD8 cells were adjusted systematically in graded steps for successive patients, depending on the occurrence of grades III-IV GVHD or graft failure in previously enrolled patients. Removal of CD4 cells did not cause graft rejection or appreciably decrease the risk of grades III-IV GVHD. Depletion of CD8 cells was associated with an increased risk of rejection with either HLA-DRB1 disparity or with HLA-A or -B disparity. With either type of disparity, the risk of grades III-IV GVHD is likely to be higher than 15% at any dose of CD8 cells associated with less than 5% risk of graft failure. The absence of graft failure associated with CD4 depletion supports the hypothesis that donor CD4 cells are not essential for preventing marrow graft rejection in humans. The correlation between graft failure and the number of CD8 cells in the donor marrow supports the hypothesis that donor CD8 cells help to prevent marrow graft rejection.

A study of the pharmacokinetics, antiviral activity, and tolerability of oral ganciclovir for CMV prophylaxis in marrow transplantation.

Oral ganciclovir is effective in preventing cytomegalovirus (CMV) disease in HIV-infected patients despite a bioavailability of only 6-9%. To determine safety, pharmacokinetics, and the influence of acute gastrointestinal graft-vs.-host disease (GI-GVHD) on the bioavailability and antiviral effect of oral ganciclovir after marrow transplantation, CMV seropositive patients received oral ganciclovir (1000 mg 3 times per day) from day 35 (+/- 7 days) until day 100 after transplantation. Single-dose (intravenous and oral) and steady-state oral pharmacokinetic profiles and weekly trough levels were performed. Twenty-one patients received oral ganciclovir (seven with GI-GVHD, 14 without); 17 had steady-state pharmacokinetic profiles and seven had single-dose profiles. The absolute bioavailability was similar in patients with or without acute GI-GVHD (7.2 vs. 6.9%). At steady state, the extent and rate of absorption of oral ganciclovir were comparable in these same patient subgroups (area under the curve [AUC] = 13.5 and 10.2 mg x hours/L, respectively; time to peak serum ganciclovir concentrations = 5.5 and 3.8 hours, respectively). Breakthrough CMV antigenemia, viremia, or plasma polymerase chain reaction positivity occurred in eight of 21 (38%) patients (four of seven with GVHD and four of 14 without). Drug discontinuation because of GI adverse effects was required in six of 21 (29%) patients. Neutropenia occurred in two of 15 (13%) patients who had received oral ganciclovir for more than 10 days. In conclusion, the bioavailability of oral ganciclovir seems similar to that reported in other settings. The presence of acute GVHD of the GI tract did not appear to adversely affect absorption of oral ganciclovir. The use of oral ganciclovir was limited by the presence of GI intolerance in the early posttransplant period. The efficacy of oral ganciclovir in preventing CMV infection in marrow transplant recipients is being assessed in a separate randomized controlled trial.

Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia.

BACKGROUND: Chronic myeloid leukemia can be cured by marrow transplantation from an HLA-identical sibling donor. The use of transplants from unrelated donors is an option for the 70 percent of patients without an HLA-identical sibling, but the morbidity and mortality associated with such transplants have been cause for concern. We analyzed the safety and efficacy of transplants from unrelated donors for the treatment of chronic myeloid leukemia and identified variables that predict a favorable outcome. METHODS: Between May 1985 and December 1994, 196 patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase received marrow transplants from unrelated donors. RESULTS: The median follow-up was 5 years (range, 1.2 to 10.1). Graft failure occurred in 5 percent of patients who could be evaluated. Acute graft-versus-host disease of grade III or IV severity was observed in 35 percent of patients who received HLA-matched transplants, and the estimated cumulative incidence of relapse at five years was 10 percent. The Kaplan-Meier estimate of survival at five years was 57 percent. Survival was adversely affected by an interval from diagnosis to transplantation of one year or more, an HLA-DRB1 mismatch, a high body-weight index, and an age of more than 50 years. Survival was improved by the prophylactic use of fluconazole and ganciclovir. The Kaplan-Meier estimate of survival at five years was 74 percent (95 percent confidence interval, 62 to 86 percent) for patients who were 50 years of age or younger who received a transplant from an HLA-matched donor within one year after diagnosis. CONCLUSIONS: Transplantation of marrow from an HLA-matched, unrelated donor is safe and effective therapy for selected patients with chronic myeloid leukemia.