Low-intensity conditioning and hematopoietic stem cell transplantation in patients with renal and colon carcinoma

Abstract

Summary:We have evaluated whether allogeneic hematopoietic stem cell transplantation (HSCT) could induce an antitumor effect in patients with metastatic solid tumors. A total of 12 HLA-identical siblings and 6 HLA-A-, -B-and -DRb1-compatible unrelated grafts were used. Diagnoses were adenocarcinoma of kidney (n ¼ 10), colon (n ¼ 6), breast (n ¼ 1) and cholangiocarcinoma (n ¼ 1). Conditioning was fludarabine 30 mg/m 2 /day for 3 days and 2 Gy of total body irradiation. Recipients of unrelated HSCT were also given thymoglobuline and two additional days of fludarabine. The median CD34+ cell dose was 7.5 Â 10 6 / kg. Immunosuppression was mycophenolate mofetil and cyclosporin. Among all, 12 patients became complete donor chimeras within a median of 28, 29 and 65 days for B, myeloid and T cells, respectively. Two patients rejected the grafts, one developed marrow aplasia and three were mixed chimeras. The probability of grades II-IV acute graft-versus-host-disease (GVHD) was 57%. Regression of all tumor metastases was seen in one patient with colon carcinoma. Another patient with colon and two with renal carcinoma had regression of lung metastases, but progression of metastases in the liver and/or bone. Necrosis of lung metastasis was found in one further patient with renal carcinoma who died of graft-versushost-disease (GVHD). In all, 10 patients died; four of transplant-related complications, one of trauma and five of progressive disease. Thus, progression was common after allogeneic HSCT in unselected patients with advanced solid tumors. However, the regression of some metastases associated with GVHD provides suggestive evidence that the GVHD effect may occur in renal and colon adenocarcinoma using reduced intensity conditioning. The immune system is known to induce tumor regression. 1 Following allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) has been found to contribute to an antileukemic effect. 2,3 An alloresponse of donor T lymphocytes is most probably the cause of GVHD and the graft-versus-leukemia (GVL) effect. 4 An allogeneic graft-versus-tumor (GVT) effect has also been reported in breast and renal metastatic carcinoma. [5][6][7][8][9] When performing HSCT, lethal myeloablative conditioning to eradicate leukemia and induce marked immunosuppression to pave the way for the donor immunohematopoietic system has been the routine for several decades 10À13 . However, this approach has been challenged by using lower doses and less toxic conditioning to induce immunosuppression and take advantage of the GVT effect later rather than the antitumor effect of chemoradiotherapy. [14][15][16][17][18][19]

Increased costs after allogeneic haematopoietic SCT are associated with major complications and re-transplantation

“…RIC is being increasingly used and enables transplantation of older patients and those with comorbidities. 14,15,24,25 In recent years, more unrelated donor transplants are being performed, most patients are receiving PBSCs as a source of stem cells as opposed to BM, and home care has also been introduced on a regular basis. Cord blood transplants are only used for patients for whom an HLA-identical donor is not available.…”

“…RIC, Fludarabine combined with BU, TBI (2 or 6Gy) or CY was administered to 122 (60%) of the patients. 14,15 Immunosuppression Pre-transplant thymoglobulin (ATG, Genzyme, Cambridge, MN, USA) was administered to recipients of unrelated or HLA-mismatched grafts and to all patients with non-malignant disorders, regardless of the type of donor (n ¼ 157, 78%). 16 As immunosuppression, the vast majority received CsA combined with four doses of MTX.…”

Long-term follow-up of nonmyeloablative allogeneic stem cell transplantation for renal cell carcinoma: The University of Chicago Experience

“…[8][9][10] Childs et al 8 pioneered NST for RCC reporting 10 responses among 19 patients. Response rates in subsequent series have generally been lower, varying from 0 to 50% [8][9][10][11][12][13][14] but averaging around 20-25%. There are limited data on response duration, progression after response, and even less insight into causes for the discrepant results.…”

Cyclosporine A (CsA) 2-h concentrations vary between patients without correlation to graft-versus-host disease after allogeneic haematopoietic stem cell transplantation

“…14 In 11 solid tumour patients, reduced-intensity conditioning was given using cyclophosphamide at 30 mg/kg BW/day for 2 days together with fludarabine at 30 mg/m 2 for 3 or 5 days in patients with Sib or MUD, respectively. 15 Antithymoglobulin (Thymoglobuline, Genzyme, Cambridge, MA, USA) was administered at 4-8 mg/kg depending on the disease type to all patients with MUD (n ¼ 42; Table 1). 16 All patients with myeloablative conditioning received initially CsA (Sandimmun, Novartis Pharma AG, Stein, Switzerland) 0.5 or 2.5 mg/kg intravenous (i.v.)…”