Conditioning Regimens

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

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Summary:

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.

Main

Animal studies during the 1960s have shown that cyclophosphamide (Cy) can be used as a good immunosuppressive agent to facilitate durable and stable engraftment of allogeneic hematopoietic cells.1, 2, 3 These results led to the introduction of Cy into clinical practice for prevention of rejection of bone marrow allografts in the 1970s.4, 5 Use of high-dose Cy for the treatment of severe aplastic anemia (SAA), where myeloablation was not indicated, held great promise for hematopoietic reconstitution of patients with severe pancytopenia, but rejection remained a major obstacle in previously transfused recipients.6, 7 Storb and colleagues demonstrated that the use of antithymocyte globulin (ATG) in addition to Cy could be effective in overcoming pretransplant sensitization of patients with SAA.8, 9 However, the lymphoablative protocol, based on combining Cy and ATG, was considered effective exclusively for stem cell transplantation (SCT) of patients with severe marrow aplasia.10, 11, 12 Documentation of the role of donor lymphocyte infusion (DLI) in early 1987 by Slavin et al,13 by Kolb et al14 and subsequently by other investigators15, 16 suggested that once transplantation tolerance is accomplished by engraftment of donor stem cells, donor lymphocytes rather than myeloablative conditioning by chemoradiotherapy can play an important role in the elimination of malignant or otherwise abnormal host hematopoietic cells. It was reasoned that the use of nonmyeloablative conditioning for stem cell transplantation (NST) could reduce dramatically transplant-related toxicity and early mortality,17 thus possibly providing high-risk and heavily pretreated patients with cancer or life-threatening nonmalignant disorders with poor performance status a realistic chance to benefit from allogeneic cell-mediated immunotherapy subsequent to allogeneic SCT.17 Since Cy is a known antilymphocytic alkylating agent that could also be effective against lymphoma and rapidly proliferating cancer cells, it seemed reasonable and justified at the time, prior to the fludarabine era, to attempt induction of durable engraftment of donor stem cells with lymphoablative rather than myeloablative conditioning with different doses of Cy combined with ATG in eligible patients with no alternative modalities. In the present study, we report our first experience, applying ATG and different doses of Cy as the first attempt for intentional nonmyeloablative pretransplant reduced-intensity conditioning (RIC) in preparation for allogeneic SCT.

Patients and methods

In all, 15 patients were enrolled in this study. Indications for SCT and disease status are shown in Table 1. Patients were included if they had incurable metastatic solid tumor or resistant lymphoma as an indication for transplantation, yet their ability to survive the standard myeloablative protocol was judged to be low (Table 1), and if they agreed to participate in the clinical trial. There were five males and 10 females, ranging in age from 20 to 57 (median 49.5) years (Table 1). The mean Karnofsky performance status score was 90 (range 70–100). All patients were treated at the Department of Stem Cell Transplantation of the Hadassah University Hospital between July 1995 and August 1996. Each participant signed an approved informed consent form and the protocol was approved by an investigational review board. All patients were transplanted from fully matched HLA class I and II siblings. Pretransplant conditioning consisted of incremental doses of intravenous (i.v.) Cy 50 mg/kg/day (Table 2). Nine patients received four doses (days −8 to −5, total dose 200 mg/kg); one patient received three doses of Cy (days −7 to −5, total dose 150 mg/kg); three patients received two doses of Cy (days −6 and −5, total dose 100 mg/kg); and two patients received only one dose because of their poor medical condition and also in order to check if truly minimal dose of Cy with ATG will enable durable engraftment. All patients received i.v. ATG 10 mg/kg/day (on days −4 to −1, total dose 40 mg/kg). Donors were injected subcutaneously with granulocyte colony-stimulating factor (G-Neupogen©, 5 μg/kg twice daily for 5 days) and large inocula of mobilized peripheral blood stem cells were collected on days 5 and 6.

Table 1 Characteristics of patients undergoing nonmyeloablative stem cell transplantation using CY-ATG as a conditioning protocol
Table 2 Characteristics of treatment, course and prognosis of patients who underwent SCT using CY-ATG as a conditioning protocol

Prior to transplantation, all patients received trimethoprim/sulfamethoxazole (10 mg/kg/day trimethoprim) on day −8 to −2, acyclovir (500 mg/m2 × 3/day) from day −8 until day +100 and allopurinol (300 mg/day) on day −8 to −1. Administration of trimethoprim/sulfamethoxazole (twice weekly) was reinstituted after recovery from neutropenia as a preventive measure against pneumocystis carinii infection. Documented cytomegalovirus (CMV) reactivation was treated with ganciclovir 10 mg/kg/day.

Graft-versus-host disease (GVHD) prophylaxis consisted of single-drug low-dose short-term cyclosporine (CSP) 3 mg/kg i.v. daily in two divided doses was started on day −1 in 10 of the patients. The other five patients did not get any GVHD prophylaxis (Table 2). The decision as to who will receive CSP was made according to the clinical status of the patient pretransplantation including treatment history, kidney dysfunction and general state. Those who were in bad clinical situation with border-line kidney function and/or were suspected of developing kidney dysfunction and/or other CSP-related toxicities did not get the medication. Once the patients were mobile, CSP was administered orally. CSP dosage was tapered during the second or third month post transplant, according to chimeric status and evidence of GVHD.

Neutropenic patients with culture-negative fever received a combination of gentamicin, cefazolin and mezlocillin, as a first-line antibiotic protocol. Persisting fever was treated with amikacin and ceftazidime as a second-line protocol, while meropenem and vancomycin were used as the third-line protocol. In cases of persistent fever not responding to antibiotic therapy within 5 days, amphotericin B (1 mg/kg every other day) was added until the neutropenia resolved.

Starting on day −8, a DNA-PCR test was carried out weekly to detect CMV. Two consecutive positive PCR results served as an indication for replacing acyclovir with ganciclovir until a minimum of two negative tests was obtained. Patients were treated in standard hospital rooms and received a normal diet. Additional supportive measures, such as parenteral nutrition and blood component transfusion, were administered as necessary.

Acute GVHD was graded according to the Glucksberg's criteria,18 and chronic GVHD graded according to the International Bone Marrow Transplant Registry (IBMTR) consensus criteria.19 Immediately upon the appearance of signs and symptoms of acute GVHD >grade I, methylprednisolone (2 mg/kg) and CSP were administered.

In order to confirm engraftment and assess the degree of chimerism, minimal residual disease and early relapse, patients were monitored at regular interval by cytogenetic analysis, and by donor and host-specific DNA markers, including male and female amelogenine gene PCR bands,20 and VNTR-PCR assay.21

Results

The protocol used for conditioning was well tolerated by all the patients. Two patients died during hospitalization (day +20 and day +25), after engraftment was confirmed on days +10 and +8, due to pulmonary dysfunction and disease progression, respectively. All other patients were fully mobile. Severe oral mucositis was absent in all of the patients, facilitating maintenance by normal oral intake. Moderate or severe hepatic veno-occlusive disease (VOD) did not occur in any of the patients, and only three patients suffered from mild symptoms of VOD (unique patient numbers (UPNs) 917, 932, 1056). Fever was noted in all patients (mean of febrile episodes 1.4, range 1–3) with mean 9 (range 1–19) febrile days.

The mean total nucleated cell count infused was 9.52 × 108 cells/kg (range 2.9–23.8 × 108 cells/kg). The mean CD34+ cell infused was 8.3 × 107 cells/kg with a range of 0.1–28.5 × 107 cells/kg. All patients except one (UPN 971) displayed evidence of tri-lineage engraftment shortly after transplant (Table 2) and none exhibited immune-mediated rejection. The patient who did not engraft, one of the two conditioned with a single dose of Cy, recovered her host white blood cell (WBC) counts spontaneously at day +12 post transplantation. She received her own stem cells, at day +82 post the allogeneic transplantation, as part of an autologous transplantation that was made due to disease progression. Short course of mixed chimerism was detected in all successfully engrafted patients during the immediate post transplant period, but this was spontaneously changed to full donor cell chimerism then after. The mean lowest WBC count was 0.3 × 109/l (range 0.1–1.6 × 109/l). Time to recovery of absolute neutrophil count (ANC) 0.5 × 109/l and 1.0 × 109/l was 0–26 (mean 12.1) days and 0–44 (mean 15.1) days, respectively. The time interval to platelet recovery 20 and 50 × 109/l ranged from 0 to 22 (mean 7.7) days and 0 to 28 (mean 10.9) days, respectively. Six patients did not drop their platelet counts below 30 × 109/l. In 9/15 of the patients, platelet support was not required. The mean lowest platelet count was 33 × 109/l (range 2–103 × 109/l). Of the 15 patients, 13 were discharged home for continuing outpatient treatment.

Although all patients had resistant, advanced disease, three of 15 patients survived long term (follow-up >93 to >96 months). One of those patients (UPN 1050) received DLI but did not develop any clinical signs of GVHD. Follow-up of those three patients at 100 days, 1 year and 5 years post transplantation revealed all the patients in a very good health status and with good complete blood counts (Table 3). Causes of death included basic disease progression (7/15 patients, mean time to death 385 (range 25–1,073) days). Two patients died from late sepsis (days +167 and +194); one died from the combination of basic disease progression and sepsis (day +68); one died from pulmonary insufficiency (day +20); and one from acute GVHD (day +53) (Table 2).

Table 3 Follow-up for the three patients who survived long terma

Acute GVHD (grade I) occurred in 9/15 patients, but only three patients developed GVHD grade III–IV (Table 2). All patients except one received CSP either for prevention of GVHD or after the onset of signs and symptoms of GVHD. Only three patients progressed to chronic GVHD and only one patient died of GVHD as a single cause of death.

Discussion

Our data based on a small cohort of 15 heavily pretreated patients suggest that durable engraftment of fully matched related allografts may be accomplished with a minimal yet effective lymphoablative rather than myeloablative conditioning. Evaluation of larger cohorts of patients is needed in order to confirm our results. Interestingly, engraftment was accomplished in all patients receiving Cy 100 mg/kg, and even in one of two patients receiving one dose of Cy 50 mg/kg only. The only patient not showing consistent engraftment was the one receiving only one dose of Cy. This patient was heavily pretreated and received good dose of stem cells (10.6 × 107 cells/kg), but still did not engraft. In a study published by Porter et al,22 engraftment of donor alloreactive lymphocytes was achieved in 4/18 patients, none of them suffering from solid tumors, after priming with only interferon-α-2b. Moreover, low-dose TBI (100 cGy) followed by DLI showed donor chimerism in 4/11 hematological malignancies treated. Again, none of the solid tumor patients enrolled in that study developed evidence of mixed chimerism.23 In comparison, stem cells rather than lymphocytes that were given by us showed evidence of donor chimerism in all but one patient, among them solid tumor patients, suggesting the fundamental role of stem cells in engraftment. On the other hand, all three trials were carried out in heavily pretreated patients, suggesting the degree of host immunosuppression pretransplantation as a key determinant in ensuring engraftment. In which case, such conditioning may not be sufficient for engraftment for patients treated at an earlier stage of their disease. In this regard, it should be noted that whereas engraftment following NST or any variation of RIC seems to be consistent in patients with hematologic malignancies, previously untreated patients with genetic disorders (eg severe beta thalassemia major; metachromatic leukoencephalopathy and Gaucher's disease) may require more intensive conditioning including busulfan, due to considerations associated with the need for successful hematopoietic competition (S Slavin, unpublished observations). Indeed, engraftment following the use of Cy and ATG seems to be consistent in patients with SAA, where no effective hematopoietic competition exists.10 However, whereas in SAA engraftment without any GVHD is the goal, in treating hematologic malignancies and especially metastatic solid tumors, the goal of the procedure is induction of graft-versus-tumor (GVT) effects, which depend on full reactivity of donor T-lymphocytes (not excluding some role for natural killer cells), which must be accompanied by some degree of GVHD in nearly all cases.24 Therefore, whereas optimal post transplant immunosuppression is indicated in patients with SAA following successful engraftment of donor stem cells, only suboptimal or no post transplant immunosuppression may be indicated for the treatment of resistant cancer, or at least, additional treatment with DLI, preferably with activated17 or immune donor lymphocytes25 following discontinuation of post transplant anti-GVHD prophylaxis seems to be desirable. However, the feasibility of relatively easy engraftment following lymphoablative conditioning may offer future opportunities for advanced and more effective cell therapy in patients incurable with any chemotherapy using activated or specifically immune donor lymphocytes, as has been already documented in preclinical animal models26, 27, 28 and piloted in clinical practice in patients with hematologic malignancies.17, 24 Durable engraftment of donor stem cells leading to induction of unresponsiveness to donor alloantigens and persistence of immunocompetent donor cells may also allow donor cell immunization in vivo following transplantation, thus providing new therapeutic opportunities for otherwise incurable, chemotherapy-resistant patients.

Durable engraftment can result in effective GVT effects,29 similarly to induction of graft-versus-leukemia (GVL) effects. As featured in our small study, immunotherapy mediated by donor lymphocytes during and following the transplant procedure can result in durable disease-free survival even in heavily pretreated patients with otherwise resistant disease. Although the success rate was rather low in this cohort of patients, it seems rather satisfactory when taking into consideration the disease status and performance status of the patients considered eligible for the new protocol, which was designed to answer the question whether engraftment could be accomplished by induction of a window of immunosuppressive treatment while avoiding myeloablative conditioning.

Whereas patients with resistant metastatic disease as well as patients with lymphoma failing all conventional modalities represent a subset of patients suitable for experimental approaches such as cell-mediated immunotherapy, it should be remembered that treatment of bulky disease is unlikely to be highly effective. Therefore, once a proof of concept is available, additional clinical trials may be justified in better cohorts of patients with resistant, yet less advanced disease, in order to investigate whether immunotherapy of minimal residual disease can result in long-term survival and possibly cure. GVT as well as GVL effects are time-consuming slow processes,29, 30 and rapid tumor growth may easily overcome the slow piecemeal process of GVL and especially GVT. In addition, large tumor bulks may be much more effective in the downregulation of the function of alloreactive donor lymphocytes. First, it has been shown that induction of host-versus-tumor tolerance under condition of large antigenic excess may impair induction of GVL effects.31 Second, it has been shown that some tumors can evade the immune system by direct downregulation of T-cell function or even through induction of apoptosis of T cells by Fas–Fas-ligand-dependent mechanisms.32

In order to try and exploit the use of allogeneic cell-mediated immunotherapy for the treatment of patients at an earlier stage of their disease, it seems important to be able to offer a truly safe, RIC. Therefore, theoretically, low or acceptable doses of Cy in combination with nontoxic lymphoablative agents such as ATG, or nowadays, based on a much broader experience with NST protocols, using fludarabine instead of Cy, seems to be an attractive conditioning for patients in need of allogeneic cell therapy.2 Moreover, at the time, Cy seemed a better choice than regimens based on total body irradiation since it promised a lesser early procedure-related risk of marrow ablation as well as lack of infertility, growth retardation, cataract formation and carcinogenicity in the future.33, 34 Adding ATG to the protocol may explain, at least partially, consistent engraftment in 14/15 patients and the low incidence of severe acute GVHD in our patients. In vivo depletion of residual T cells of the recipient may facilitate engraftment, whereas due to anticipated 2–3 weeks half-life time of ATG circulating in vivo may explain relatively low incidence of severe GVHD, due to partial depletion of donor T cells in vivo through antibody-dependent cell-mediated cytotoxicity.35

Overall, it seems that the data summarizing our pilot experience in clinical application of NST clearly suggest that induction of a window of immunosuppression by strictly lymphoablative conditioning without accompanying myeloablation may enable engraftment of donor stem cells, thereby leading to induction of host-versus-graft unresponsiveness. Once a state of host-versus-graft tolerance develops, persistence of alloreactive donor lymphocytes may result in the elimination of residual hematopoietic cells of host origin and possibly some metastatic solid tumors as well, in parallel with reversal of the host to donor immunohematopoietic system.

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Bitan, M., Or, R., Shapira, M. et al. Nonmyeloablative stem cell transplantation using lymphoablative rather than myeloablative conditioning in the prefludarabine era by ATG and limiting doses of cyclophosphamide. Bone Marrow Transplant 35, 953–958 (2005) doi:10.1038/sj.bmt.1704936

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Keywords

  • stem cell transplantation
  • cyclophosphamide
  • antithymocyte globulin
  • reduced-intensity conditioning
  • nonmyeloablative stem cell transplantation
  • graft-versus-tumor effects