T- and B-cell immune reconstitution and clinical outcome in patients with multiple myeloma receiving T-cell-depleted, reduced-intensity allogeneic stem cell transplantation with an alemtuzumab-containing conditioning regimen followed by escalated donor lymphocyte infusions

Summary. Immune reconstitution after conventional allogeneic transplantation is a major determinant of survival. We conducted a detailed investigation of T‐ and B‐cell immune reconstitution and clinical outcome in 19 patients with multiple myeloma undergoing reduced‐intensity stem cell transplantation using in vivo T‐cell depletion with alemtuzumab. These patients experienced delayed T‐cell recovery, particularly in the naïve (CD45 RA⁺) CD4 compartment. T‐cell receptor spectratype analysis showed a reduced repertoire diversity, which improved rapidly after the administration of donor leucocyte infusions and subsequent conversion to full donor T‐cell chimaerism. Post‐transplant recovery of CD19⁺ B cells was also delayed for up to 18 months. Spectratype analysis of IgH CDR3 repertoire revealed a gradual normalization in IgM spectratype complexity by 6–12 months after transplant. There was a high incidence of viral infection, particularly cytomegalovirus reactivation, but the regimen‐related mortality was low, perhaps because of the very low incidence of acute graft‐versus‐host disease (GVHD; grade I‐II skin GVHD was seen in 5/19 patients). Over 80% of all patients have relapsed at a median of 283 (range 153–895) d after transplant, suggesting that the initially low rate of GVHD comes at a high price with regard to the desired graft‐versus‐myeloma effect.     

Limiting transplantation-related mortality following unrelated donor stem cell transplantation by using a nonmyeloablative conditioning regimen.

A nonmyeloablative conditioning regimen was investigated in 47 patients with hematological malignancy receiving allogeneic progenitor cells from matched, unrelated donors. The median patient age was 44 years. The majority of patients had high-risk features, including having failed a prior transplantation (29 individuals). Twenty of the transplants were mismatched for HLA class I and/or class II alleles. Recipient conditioning consisted of 20 mg CAMPATH-1H on days -8 to -4, 30 mg/m(2) fludarabine on days -7 to -3, and 140 mg/m(2) melphalan on day -2. Graft-versus-host disease (GVHD) prophylaxis was with cyclosporine A alone. Primary graft failure occurred in only 2 of 44 evaluable patients (4.5%). Chimerism studies in 34 patients indicated that the majority (85.3%) attained initial full donor chimerism. Only 3 patients developed grade III to IV acute GVHD, and no patients have yet developed chronic extensive GVHD. The estimated probability of nonrelapse mortality at day 100 was 14.9% (95% confidence interval [CI], 4.7%-25.1%). With a median follow-up of 344 days (range, 79-830), overall and progression-free survivals at 1 year were 75.5% (95% CI, 62.8%-88.2%) and 61.5% (95% CI, 46.1%-76.8%), respectively. In summary, a nonmyeloablative regimen incorporating in vivo CAMPATH-1H is effective in promoting durable engraftment in most patients and in reducing the risk of severe GVHD following matched unrelated donor transplantation.     

Reduced-intensity transplantation with in vivo T-cell depletion and adjuvant dose-escalating donor lymphocyte infusions for chemotherapy-sensitive myeloma: limited efficacy of graft-versus-tumor activity.

Reduced-intensity conditioning regimens allow application of allogeneic stem cell transplantation to greater numbers of patients with myeloma by reducing transplantation-related mortality. We prospectively evaluated the role of an approach incorporating in vivo T-cell depletion and subsequent adjuvant donor lymphocyte infusions (DLIs) as part of front-line therapy for chemotherapy-sensitive multiple myeloma. Twenty patients with HLA-matched related (n = 12) or unrelated (n = 8) donors entered the study. None had previously undergone autologous transplantation. Acute graft-versus-host disease (GVHD) following transplantation was minimal (3 grade II and no grade III or IV). Nonrelapse mortality rate was relatively low (15%) compared with conventional myeloablative allogeneic transplantation series, although it remained significantly higher than in the autologous setting. Disease responses by 6 months posttransplantation were modest (2 in complete remission, 4 in partial remission, 2 were minimally responsive, 6 had no change, 3 had progressive disease, and 3 were not evaluable). Fourteen patients received escalating-dose DLI for residual/progressive disease. Three developed acute GVHD and 2 developed limited chronic GVHD. Seven demonstrated further disease responses, which appeared to be more common in those developing GVHD (5 of 5 versus 2 of 9; P =.02). All responses were associated with conversion from mixed to full donor T-cell chimerism. Response durations were disappointing (5 <12 months) and progression often occurred despite persisting full donor chimerism. Two-year estimated overall survival and current progression-free survival rates (intention to treat with DLI from 6 months) were 71% and 30%, respectively. The current approach incorporating T-cell depletion appears excessively immunosuppressive despite attempts to restore immune function with DLI. Dose escalation failed to allow convincing dissociation of graft-versus-myeloma from GVHD. Attempts to hasten immune reconstitution and to focus and amplify appropriate components of allogeneic T-cell responses will be required to increase complete remission rates and response durations.     

Preoperative gefitinib versus gefitinib and anastrozole in postmenopausal patients with oestrogen-receptor positive and epidermal-growth-factor-receptor-positive primary breast cancer: a double-blind placebo-controlled phase II randomised trial

BACKGROUND: Some oestrogen-receptor (ER) positive breast cancers express epidermal growth factor receptor (EGFR), but whether inhibition of EGFR can suppress proliferation of breast cancer cells and ER function is not known. METHODS: In a double-blind, placebo-controlled randomised trial of 56 postmenopausal patients with ER-positive and EGFR-positive primary breast cancer, 27 women were randomly assigned to the tyrosine-kinase inhibitor of EGFR gefitinib (250 mg given orally once a day) and the aromatase inhibitor anastrozole (1 mg given orally once a day), and 29 women to gefitinib (250 mg given orally once a day) and placebo of identical appearance to anastrozole given orally once a day, all given for 4-6 weeks before surgery. Primary outcome was inhibition of tumour-cell proliferation, as measured by Ki67 antigen labelling index. Secondary outcomes were reduction in EGFR phosphorylation at Tyr 845, reduction in ER phosphorylation at Ser 118, tumour size, and toxic effects. Analyses were by intention to treat. FINDINGS: Patients assigned gefitinib and anastrozole had a greater reduction from pretreatment values in proliferation-related Ki67 labelling index than did those assigned gefitinib alone (mean % reduction 98.0 [95% CI 96.1-98.9] vs 92.4 [85.1-96.1]; difference between groups 5.6% [5.1-6.0], p=0.0054). Tumour size was reduced by 30-99% (partial response) in 14 of 28 patients assigned gefitinib and [corrected]in 12 of 22 assigned gefitinib, as assessed by ultrasonography. Reduction in phosphorylation of ER at Ser 118 was similar for both groups. Treatment was well tolerated and much the same for both groups. INTERPRETATION: Single-agent gefitinib and gefitinib combined with anastrozole are well-tolerated and effective treatments for reducing the size of breast tumours and levels of ER phosphorylation when given as neoadjuvant therapy.