The number of infused CD34+ cells does not influence the incidence of GVHD or the outcome of allogeneic PBSC transplantation, using reduced-intensity conditioning and antithymocyte globulin.

The influence of graft composition on the outcome of reduced-intensity (RIC) allogeneic PBSC transplantation (allo-PBSC) remains controversial. In this study, we analyzed the impact of CD34+ cell dose on the incidence of GVHD, and on the outcome after allo-PBSC, in 103 patients with hematological malignancies, using a uniform RIC regimen. The following variables were included in statistical analysis: (1) number of C34+ cells, (2) high-risk vs low-risk disease status, (3) matched related vs matched unrelated donor, (4) female donor to male recipient vs any other combination, (5) age of recipient (above vs below the median). Univariate and multivariate analysis did not reveal any association between CD34+ cell dose and acute grade-2 to grade-4, cGVHD, non-relapse mortality (NRM), relapse rate (RR) and OS. High-risk disease status was the only variable independently associated with increased NRM (P=0.001), increased RR (P=0.012) and decreased OS (P<0.001). The same results were obtained when analysis was restricted to a subgroup of 55 patients with myeloid neoplasms. The influence of graft composition on the outcome of RIC allo-PBSC should be further investigated via well-controlled randomized prospective studies.

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

Allogeneic stem cell transplantation from matched related and unrelated donors in thalassemia major patients using a reduced toxicity fludarabine-based regimen.

The only radical cure for thalassemia major patients today is the replacement of the defective hematopoietic system by allogeneic stem cell transplantation (allo-SCT). The major obstacles for the application of allo-SCT even from matched family members have been the transplant-related morbidity and mortality and graft failure that is usually associated with the recurrence of the thalassemia hematopoiesis. The outcome of allo-SCT from HLA-identical family donors is largely dependent on the age of the recipient as well as on pretransplant parameters reflecting the degree of organ damage from iron overload. In this study we report our experience of allo-SCT from matched related and unrelated donors, using a reduced toxicity conditioning consisting of fludarabine, busulfan or more recently busulfex and antithymocyte globulin, in a cohort of 20 patients with thalassemia major. The regimen-related toxicity was minimal, while the incidence of acute grade II-IV and chronic GVHD was 25 and 25%, respectively. With a median follow-up period of 39 months (range: 5-112 months) the overall survival was 100%, while thalassemia-free survival was 80%. Although the results of our study look promising, larger cohorts of patients and prospective clinical trials are required to confirm the benefits of our approach as a possible better alternative to the existing protocols.

A patient with progressive multiple myeloma treated successfully with arsenic trioxide after allogeneic bone marrow transplantation.

Multiple myeloma (MM) is an incurable progressive disease. Many therapeutic options are available to delay progression, including autologous and allogeneic bone marrow transplantation. At advanced stages, MM is often refractory to treatment. We report a heavily pretreated patient with graft-versus-host disease after bone marrow transplantations, treated at a terminal stage with a modified protocol for arsenic trioxide (ATO). This patient with poor clinical status tolerated the treatment very well. He had a remarkable clinical response and achieved complete remission. The mechanisms of ATO are presented and the potential role of ATO for MM is discussed.

Safety and efficacy of donor lymphocyte infusions following mismatched stem cell transplantation.

The use of a mismatched allograft necessitates T cell depletion for prevention of uncontrolled graft-versus-host disease (GVHD), thus impairing a graft-versus-leukemia effect. Data on donor lymphocyte infusion (DLI) after mismatched stem cell transplantation are lacking. Our experience with 28 patients (treated with 59 mismatched DLIs; range, 1-7) is described. The procedure was prophylactic in 6 patients (9 DLIs) and therapeutic in 22 (50 DLIs). DLI dose ranged from 10(2) to 1.5 x 10(9) T cells/kg. In the 6 patients receiving prophylactic DLI, complete remission was maintained in 5; however, 2 died from GVHD. Clinical response to therapeutic DLI was seen in 6 of 22 (27.3%) patients; a greater tumor burden produced a lower response. GVHD appeared in 13 of 28 patients. Surprisingly, a greater HLA mismatch was associated with a lower risk of GVHD, with 3 of 19 DLIs in 3/6 matching and 16 of 29 DLIs in 5/6 matching with similar follow-up. Nevertheless, no correlation between efficacy and HLA mismatching was noted. Death was frequent and usually related to the basic disease rather than to DLI complications. We conclude that mismatched DLI is feasible and may be effective, especially if given soon after transplantation. Future developments using cell therapy with selective or targeted anticancer activity are warranted, with special attention to prophylactic treatment of T cell depleted mismatched allografts recipients.

Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors.

Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia.

A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation.

The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45+/-1 in the HDC group and 1.21+/-1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7+/-3.6 and 2.33+/-2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.

Rapid response to alefacept given to patients with steroid resistant or steroid dependent acute graft-versus-host disease: a preliminary report.

We evaluated the effect of alefacept (Amevive), a novel dimeric fusion protein, in steroid resistant/dependent acute graft-versus-host-disease (aGVHD). Seven patients were treated in eight aGVHD episodes. GVHD grade at treatment initiation and at peak ranged 2-4 (median 2.5) and 2-4 (median 4), respectively. System involvement at GVHD peak included skin (n=7), gastrointestinal tract (n=5) and liver (n=3). All patients responded. However, one patient with skin GVHD and two with gastrointestinal GVHD featuring an early initial response (IR) exacerbated and CR was not achieved. Skin GVHD responded rapidly with a median of 1 day to IR and 7 days to CR. Intestinal response was slower with median 7.5 days to IR. Of the four patients that achieved IR, CR was achieved in only one (40 days to CR). None of the patients had significant hepatic GVHD before treatment so no hepatic effect of alefacept could be determined. No immediate alefacept-related side effects were observed. Late side effects included infections (aspergillus sinusitis, pneumonia, bacteremia, pharyngeal thrush), pancytopenia and hemorrhagic cystitis. Three patients had CMV reactivation while on alefacept. We conclude that alefacept may have a beneficial effect in controlling aGVHD. Further investigations in larger cohorts of patients and controlled studies are warranted.

Nonmyeloablative stem cell transplantation using lymphoablative rather than myeloablative conditioning in the prefludarabine era by ATG and limiting doses of cyclophosphamide.

The feasibility of using lymphoablative rather than myeloablative conditioning for durable engraftment of allogeneic stem cells and subsequent cell therapy with donor lymphocytes was pioneered in the prefludarabine era in patients with resistant lymphoma and metastatic solid tumors. Between July 1995 and August 1996, 15 patients, five males and 10 females, median age 50 (range 20-57) years, were enrolled in a protocol that consisted of different doses of cyclophosphamide (Cy), 50 mg/kg/day for 1, 2, 3 or 4 consecutive days in parallel with a fixed dose of rabbit antithymocyte globulin (ATG) (Fresenius) 10 mg/kg/day for 4 consecutive days. All patients, except one treated with a single dose of Cy, achieved full tri-lineage engraftment and no late graft failure was observed. Only three patients suffered from grade III-IV graft-versus-host disease (GVHD). Three patients out of the 15 survived long term (follow-up >93 to >96 months). We concluded that lymphoablative conditioning with ATG and intermediate-to-high-dose Cy is well tolerated and can result in durable engraftment with acceptable GVHD in heavily pretreated patients with advanced malignancies. Hence, induction of tolerance to donor alloantigens by lymphoablative conditioning while avoiding myeloablative chemotherapy or radiation therapy may serve as a platform for subsequent cell therapy with donor lymphocytes.

Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients.

Historically, age >60 years was considered a contraindication for allogeneic stem cell transplantation (allo-SCT). In recent years, elderly (>60 years) patients have become eligible for allo-SCT due to the application of reduced intensity conditioning (RIC). The present report summarizes our cumulative experience in a cohort of 17 elderly patients (age 60-67, median 62.5 years) with hematological malignancies treated with 18 allo-SCT procedures, mostly nonmyeloablative. In all, 14 patients received fludarabine and busulfan/busulfex regimen, three patients were conditioned with the fludarabine and low-dose TBI and one patient received busulfan alone. All patients displayed tri-lineage engraftment. The time to recovery of absolute neutrophil count >/=0.5 x 10(9)/l was 9-27 days (median 14 days). The time interval to platelet recovery >/=20 x 10(9)/l was 3-96 days (median 11 days). Veno-occlusive disease occurred only in 3/18 procedures and subsided with conventional treatment. Nonfatal transplant-related complications occurred in 6/18 (33.3%) procedures including: renal failure, arrhythmia, CNS bleeding, cystitis, typhlitis and gastrointestinal bleeding. Transplant-related mortality occurred in 6/18 (33.3%) episodes. Of the 17 patients, 12 (12/18 episodes) were discharged. Five of 17 (29%) patients survived (median follow-up 11 m, range 8-53 m). Our data suggest that RIC-allo-SCT may be safely applied in the elderly, suggesting that allogeneic immunotherapy may become an important tool for treatment of hematological malignancies without an age limit.

Tube thoracostomy during allogeneic stem cell transplantation does not carry an increased risk for infections or bleeding.

BACKGROUND: Candidates for stem cell transplantation may occasionally suffer from massive pleural effusions related to their disease and require tube thoracostomy. The additional risk of this procedure during allogeneic transplantation procedure is not known. METHODS: Four high-risk patients transplanted in our institution during a 2-yr period had chest drainage by tube thoracostomy. The characteristics of the fluid, the clinical course, and the outcome were assessed. RESULTS: A total of nine chest drains were inserted (range 1-5). No bleeding complications related to the procedure were noted. None of the patients developed any clinical signs of local infection at the tube insertion site or within the pleural fluid. All cultures taken from the drained fluid or from the insertion wound were negative. CONCLUSIONS: Tube thoracostomy in itself does not seem to pose additional risks in the transplant procedure, despite all patients in this series being considered to be at high-risk for complications.

Rhinolalia as a presenting sign of pneumomediastinum complicating post peripheral blood stem cell transplantation bronchiolitis obliterans.

A 26-year-old male with graft vs. host disease (GVHD) presented with rhinolalia (a squeaky voice of nasal quality) as a presenting sign for pneumonasopharynx and pneumomediastinum secondary to bronchiolitis obliterans. The patient underwent HLA-identical related peripheral blood stem cells transplantation 8 months before the diagnosis. Three weeks after transplantation he began to suffer from GVHD Grade III that involved the gut, liver, and skin and later on the lungs. Due to severe obstructive bronchiolitis obliterans the patient developed intensive cough evolving into pneumomediastinum and pneumonasopharynx with rhinolalia. The patient was treated conservatively with complete resolution. Although rare, pneumomediastinum and pneumonasopharynx can be a life-threatening event, and one should be aware of the signs and symptoms on physical examination, which may be as subtle as rhinolalia alone.

A new minimally ablative stem cell transplantation procedure in high-risk patients not eligible for nonmyeloablative allogeneic bone marrow transplantation.

Nonmyeloblative stem cell transplantation (NST, SCT) aims to induce host-versus-graft tolerance for subsequent immunotherapy of underlying disease with alloreactive donor lymphocytes, focusing on well-tolerated conditioning suitable for elderly individuals or for other risk factors. However, there is a subset of high-risk patients who cannot tolerate NST. A new protocol consisting of fludarabine 30 mg/m(2) x 6 days (days -8 to -2), very-low-dose busulfan (2 mg/kg x 2 days, days -6 to -5), without anti thymocyte globulin (ATG), was employed in 11 high-risk patients aged 26-58 years. Graft-versus-host-disease (GVHD) prophylaxis consisted of low-dose and short-course cyclosporine-A (CSA) alone. One patient died during the nadir due to pulmonary complications. Other patients showed rapid three-lineage engraftment, without complete aplasia; 6/10 patients did not require platelet transfusion and 8/10 had full donor chimerism without transient mixed chimerism. Owing to intentional selection of highly poor-risk patients, overall mortality was high and only one patient survived. Acute GVHD (>/=grade I) occurred in 8/10 evaluable patients, 5/8 while off CSA; 5/8 developed grade III-IV acute GVHD. It appears that our modified, minimally ablative stem cell transplantation (MST) may be used for high-risk patients in need of allo-SCT. Furthermore, although the MST conditioning is not myeloablative, it results in myeloablation of the host hematopoietic system, mediated by alloreactive lymphocytes.

Immunotherapy of relapsed resistant chronic myelogenous leukemia post allogeneic bone marrow transplantation with alloantigen pulsed donor lymphocytes.

Allogeneic cell-mediated immunotherapy with donor lymphocyte infusion (DLI) can successfully reverse chemoradiotherapy-resistant relapse in patients with chronic myeloid leukemia treated by allogeneic bone marrow transplantation (BMT). We describe the first successful attempt in 1992 to treat DLI-resistant relapse in a patient with CML in full hematologic relapse, using immunized donor lymphocytes. Donor lymphocytes were pulsed in vitro with a mixture of irradiated peripheral blood lymphocytes (PBL) obtained from both parents, in order to trigger alloactivation of donor lymphocytes against host alloantigens presented by parental cells, using as stimulating cells maternal PBL expressing the shared maternal haplotype and paternal PBL expressing the shared paternal haplotype of the patient. Full hematologic, cytogenetic and molecular remission was induced for the first time, independently of GVH, and has persisted for more than 9 years. To the best of our knowledge, this report represents the first successful immunotherapy with donor lymphocytes activated against host-type antigens. We suggest that immune donor PBL may be superior to DLI, possibly effective even when all other modalities fail, perhaps even independently of GVHD.

Adoptive immunotherapy with haploidentical allogeneic peripheral blood lymphocytes following autologous bone marrow transplantation.

Patients who undergo autologous bone marrow transplantation for acute leukemia are at high risk for relapse. We have evaluated the feasibility of administering cell-mediated immunotherapy with family-related haploidentical lymphocytes following autologous bone marrow transplantation in order to evoke a graft-vs-leukemia effect in the autologous setting.Twenty-six patients aged 1.5-48 years were enrolled in this study. Eighteen suffered from acute myeloid leukemia, seven from acute lymphoblastic leukemia, and one from myelodysplastic syndrome. Eleven patients were transplanted in first remission, six in second remission, one in fourth remission, and eight in relapse. Conditioning consisted of Busulfan/Cyclophosphamide or Busulfan/Thiotepa/Cyclophosphamide. Nineteen patients (Group A) were treated with gradual increments of haploidentical donor T cells, starting on day +1, with an additional course of T cells plus intravenous recombinant human interleukin-2 one month later if no signs of graft-vs-host disease developed in the interim. Seven patients (Group B) were treated with high-dose haploidentical T cells on day +1 in conjunction with intravenous recombinant human interleukin-2. Donor cells were detected in the peripheral blood of both groups 12-48 hours post-cell-mediated immunotherapy, peaking at 48 hours. Three patients in Group A developed transient Grade I graft-vs-host disease. One patient in Group B developed Grade I, and three Grade IV, graft-vs-host disease. Group A patients engrafted normally, but the Group B patients with Grade IV graft-vs-host disease showed no signs of engraftment. Our results show that it is feasible to induce graft-vs-host disease in the autologous stem cell transplantation setting. However, the high-dose regimen of haploidentical T cells in conjunction with interleukin-2 results in severe toxicity and nonengraftment.

Amplification of immunological functions by subcutaneous injection of intermediate-high dose interleukin-2 for 2 years after autologous stem cell transplantation in children with stage IV neuroblastoma.

BACKGROUND: Immunotherapy given post-autologous stem cell transplantation may eliminate residual tumor cells escaping the conditioning protocol. METHODS: Five children suffering from stage IV neuroblastoma were treated by recombinant interleukin-2 (IL-2) post-autologous peripheral blood stem cell transplantation. The patients' peripheral mononuclear cells were monitored for CD3+ and CD56+ levels, their proliferative response and killing of various cell lines targets. RESULTS: An increase in the level of total lymphocytes, mainly due to expansion of T cells, and enhanced proliferative response to phytohemaglutinin were observed. Elevated cytotoxicity against K562 and neuroblastoma target cells was detected in four patients and against K562 targets in one patient. Toxicity included mild thrombocytopenia, and fever in four patients and mild to moderate encephalopathy which necessitated withdrawing one patient from the protocol. Three of five patients studied are alive today, one of them whose IL-2 was stopped, is in relapse. Two patients have died. CONCLUSIONS: Immunotherapy with s.c. intermediate-high dose IL-2 is feasible and results in expansion of T cells and in stimulation of killing activity against several targets including in some cases, neuroblastoma tumor cells.

Donor lymphocyte infusion post-non-myeloablative allogeneic peripheral blood stem cell transplantation for chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease symptomized by failure to generate superoxide and recurrent bacterial and fungal infections. Allogeneic bone marrow transplantation (BMT) is one of the therapeutic options available. However, it presents considerable risk to the recipient, especially if the patient is already at an advanced stage of disease, after repeated bacterial and fungal infections and organ damage. We present a case report of a 6-year-old child with long-standing CGD, severe clubbing, and jeopardized pulmonary function after multiple bacterial pulmonary infectious episodes, who had failed treatment with sulphamethazole trimethoprim, multiple antibiotic courses, itraconazole, as well as steroid and interferon-y therapy. He underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from his HLA-matched MLC non-reactive sister following non-myeloablative conditioning. His ANC did not fall below 0.2 x 10(9)/l, his lowest WBC was 0.6 x 10(9)/l, and his platelets did not fall below 28 x 10(9)/l. He had normal engraftment, with no mucositis or organ toxicity. Neither parenteral nutrition nor platelet infusions were necessary. Partial donor chimerism following alloPBSCT was converted to full donor chimerism and superoxide production reverted to normal after donor lymphocyte infusions (DLI) from his HLA-matched sister. Twenty four months post transplant the patient is well, with stable and durable engraftment, 100% donor chimerism, normal superoxide production, no GVHD, and stabilization of his pulmonary condition. We suggest that alloPBSCT preceded by non-myeloablative conditioning and followed by DLI may constitute a successful mode of therapy for patients suffering from advanced CGD with recurrent infectious episodes resulting in organ dysfunction, enabling them to achieve full donor chimerism and normal superoxide production with minimal risk of transplant-related toxicity and GVHD.

Allogeneic cell-mediated immunotherapy for eradication of minimal residual disease: comparison of T-cell and IL-2 activated killer (LAK) cell-mediated adoptive immunotherapy in murine models.

In the course of allogeneic bone marrow transplantation (BMT), avoiding graft-versus-host disease (GVHD) while retaining the antileukemic effects of the T cells remains a major challenge. T-cell depletion (TCD) reduces the incidence of GVHD but increases the relapse rate after allogeneic BMT. We attempted to develop a regimen that would retain or increase the graft-versus-leukemia effect induced by donor T cells while preventing GVHD. Immunosuppressed mice were given immunocompetent donor cells, i.e., fresh lymphocytes or lymphokine-activated killer (LAK) cells differing from the host in major (MHC) or minor (MiHC) histocompatibility antigens. Engraftment of donor cells was documented by polymerase chain reaction analysis. Administration of MHC- and MiHC-incompatible allogeneic LAK cells, especially in conjunction with recombinant interleukin-2 (rIL-2), increased disease manifestations and mortality associated with GVHD. On the other hand, irradiated LAK cells or TCD-LAK cells prevented GVHD in both mice models studied. Phenotypic analysis of LAK cells demonstrated that CD8(+)-equivalent (Lyt-2) T cells are of significance in aggravation of GVHD. The in vitro cytotoxic capacity of LAK cells against MHC-nonrestricted target cells was not reduced by either irradiation or TCD. These results provide the background for designing improved protocols for immunotherapy of residual disease after BMT. In addition, the data imply that antitumor effects may be retained by irradiated rIL-2-activated allogeneic cells without causing GVHD. Whereas unmodified allogeneic LAK cells can induce more effective graft-versus-leukemia effects at the cost of GVHD, irradiated allogeneic donor LAK cells might play some role in eradication of minimal residual disease following autologous or allogeneic BMT without causing GVHD.

Allogeneic cell-mediated and cytokine-activated immunotherapy for malignant lymphoma at the stage of minimal residual disease after autologous stem cell transplantation.

Immunocompetent donor-derived T lymphocytes play a crucial role in the elimination of residual leukemic cells post allogeneic bone marrow transplantation. Because this graft versus leukemia (GVL) effects is absent after autologous stem cell transplantation (ASCT), a high rate of relapse ensues. We introduced cell-mediated immunotherapy at the stage of minimal residual disease in lymphoma patients to help effect a GVL-like reaction by adoptive transfer of immunocompetent human leukocyte antigen-matched donor peripheral blood lymphocytes (PBL). Thirteen consecutive patients with high-risk lymphoma were treated with allogeneic cell therapy (AlloCT) after having undergone ASCT. In the absence of graft-versus-host disease, cell therapy-induced graft-versus-lymphoma reaction was amplified by human recombinant interleukin 2 (rIL-2) during 3 days to activate donor PBL in vivo, followed by infusion of in vitro rIL-2 activated donor lymphocytes combined with 3-day rIL-2 therapy. Nine of the patients underwent the treatment protocol well. In the four other patients, in whom the AlloCT resulted in marrow aplasia due to elimination of host hematopoietic cells, treatment with donor marrow cell infusion without further conditioning was performed. Adoptive cell therapy in the form of AlloCT may turn out to be an effective therapeutic modality for the treatment of resistant residual disease in lymphoma patients.

Continuous interleukin-2 infusion combined with cyclophosphamide- based combination chemotherapy in the treatment of hemato-oncological malignancies. Results of a phase I-II study.

The combination of a cyclophosphamide (CTX)-based chemotherapy regimen and interleukin-2 (IL-2) has been shown to provide synergistic effects against malignancy in animal models. We therefore conducted a phase I-II trial combining CTX-based combination chemotherapy or CTX alone with high-dose IL-2 in patients with advanced and refractory malignant disease. Fifteen patients with hemato-oncological malignancies (malignant lymphoma 8, multiple myeloma 3, solid tumor 2, leukemia 2) were enrolled in the study. Continuous high-dose IL-2 infusion was shown to be safely administered, starting as soon as recovery of white blood cell count. All patients developed rebound lymphocytosis 24-48 h after termination of IL-2 infusion. Although grade IV toxicity was observed in 5 patients (7 episodes), all side effects completely subsided. Triple chemotherapy (CTX, etoposide and Ara-C) seemed rather toxic (in this group of heavily treated patients) while CTX alone was well tolerated. Four out of 13 (31%) evaluable patients had partial response and another patient (7%) had stabilization of disease progression lasting 2-8 months. Our conclusion is that the combination of CTX and continuous infusion of IL-2 is feasible and should be investigated in patients with various malignant neoplasms.