Infusion Of Allogeneic Stem Cells Research Articles

Influence of Prophylactic Antibiotics Aiming at Gut Decontamination on Gastrointestinal Graft-Versus-Host Disease and Overall Survival Following Allogeneic Haematopoietic Stem Cell Transplantation

Introduction:The impact of commensal bacteria harbored in the gastrointestinal tract known as the microbiota has long been recognized as a pivotal factor in allogeneic hematopoietic stem cell transplantation (aHSCT). The microbiota is at the origin of acute graft-versus-host disease (aGVHD) and infections, two important lethal complications in aHSCT. High-dose conditioning chemotherapy prior aHSCT disrupts the gut epithelial barrier allowing bacterial by-products to translocate into the peripheral blood and modulates T cell response and pro-inflammatory cytokines. Such observation led to an effort by certain transplant centers to eliminate bacterial colonization prior to aHSCT to decrease the risk of gram-negative bacterial translocation. In this study, we assessed whether patients' gut decontamination prior to allogeneic stem cell infusion influenced the frequency of aGVHD, pneumomatosis coli (PC) a significant complication of gastrointestinal (GI) GVHD and overall survival.Methods:We retrospectively reviewed the charts of 543 patients who had undergone a single myeloablative or nonmyeloabaltive aHSCT for hematological malignancies from two academic hospitals in the province of Quebec, Canada between January 2005 and December 2012. Exclusion criteria included prior aHSCT, syngeneic and haploidentical aHSCT. Each university hospital has implemented a different pre-transplant antibioprophylaxis guideline. At HMR hospital, ciprofloxacin or moxifloxacine were started at initiation of the conditioning regimen for gut decontamination, but were omitted in patients with fluoroquinolone or penicillin allergy and during nosocomial infections outbreak. On the other hand, in the CHU de Quebec patients were not prescribed prophylactic antibiotics (ATB). In addition, ATB used to treat infections before the stem cells infusion were considered. To determine the impact of ATB, we performed multivariable analyses adjusting for the following confounding factors: age, gender, stem cell origin (source), donor type/match, and conditioning regimens to compare the frequency of aGVHD, PC, leucocytes recovery at day+14 and overall survival (OS) in patients receiving or not ATB.Results:500 patients were included and a total of 240 (48%) patients received ATB at the time of conditioning regimen. Demographics were similar in both groups with mean age of 48 years. Frequency of grade II-IV aGVHD was more elevated in patients receiving ATB compared to the no ATB group (42% vs 28% respectively with adjusted OR (aOR)=1.53 (p<0.05). The severity of the aGVHD in the ATB group was driven by the GI-GVHD with a higher level of grade II-IV (20.7%) compared to no ATB group (10.8%) with aOR=2.00 (p<0.01). Severity of skin and liver GVHD were similar in both groups. Among the 12 patients that developed PC diagnosed on CT-scan, all received ciprofloxacin during conditioning and PC was associated with 80% mortality. The difference of aGVH frequency may have translated into survival as the ATB group was associated to lower 1 year survival compared to no ATB group (74% vs 88%, OR=0.36 and aOR=0.38 (p<0.05). This significant survival difference at 1 year persisted over time and median OS was 4 and 5 years respectively (p<0.05). Taking into consideration the entire follow-up period of 10 years, the hazard rates associated with ATB were estimated at 1.61(p<0.06) and 1.43 (p<0.05) after adjusting for clinical parameters. Interestingly, post-hoc analysis revealed independent impact of the ATB on D+14 neutrophils. This was reflected by a lower neutrophil count in patients on ATB that received stem cells from a match-related donor compared to no ATB counterpart with a ratio of 0.38 (p<0.05).Discussion:This retrospective study indicated that ATB were associated to a more severe aGVHD driven by digestive manifestations of the GVHD and higher incidence of PC even after multivariable analysis. These life-threatening complications may impact on the 1-year and OS that were lower in the ATB group. Without undermining the role of ATB prophylaxis to prevent infection in aHSCT setting, treatment with ATB impact on the commensal microbiota and diminishes its diversity. This imbalance created by the ATB may have contributed to the pathophysiology of GI-GVHD. This ultimately highlights the importance to reconsider antibioprophylaxis to preserve an intact flora and its benefits in aHSCT. DisclosuresNo relevant conflicts of interest to declare.

Graft-Failure After Allogeneic Stem Cell Transplantation. Outcome and Prognostic Factors in 80 Patients

Abstract 1936 Background and aims:Graft-failure (GF) is an infrequent and poor complication of allogeneic stem cell transplantation (SCT). Strategies for reversing GF will depend on the options available in each situation. Patients and Methods:A questionnaire about GF was sent to all centers of the Grupo Español de Trasplante Hematopoyético (GETH). Fourteen Spanish institutions reported their GF from January 2006 to October 2010. Primary GF was defined as ANC >0.5×109/L not reached for three consecutive days by day +28 after SCT from peripheral blood (PB) or bone marrow (BM) progenitors and by day +60 after SCT from unrelated cord blood (UCB) progenitors. Secondary GF was defined as a recurrent ANC <0.5×109/L for at least 7days. Results:Eighty patients with GF were reported (median age 34 yr. [range: 1–68]; 54M/26F). Basal diseases were AML 30 (38%), ALL 14 (17%), lymphoproliferative disorder 12 (15%), myelodysplastic syndromes 9 (11%), myeloproliferative syndromes 7 (9%), aplastic anemia 5 (6%), and congenital disorders 3 (4%). Status of the neoplastic disease was: 1st/2nd CR or 1st chronic phase in 50 (62%) patients and >2nd CR or active disease in 30 (38%) patients. Conditioning therapy for 1st SCT was myeloablative in 45 (56%) and non-myeloablative in 35 (44%) patients. Donors were related in 35 (44%) and unrelated in 45 (56%). Progenitors were from mobilized PB in 45 (56%), UCB in 26 (33%) and BM in 9 (11%). At the time of GF, chimerism status (n=75) was donor complete in 6 (8%), mixed in 28 (35%) and from the patient in 41 (55%) individuals. Forty-five (56%) and 35 (44%) patients presented primary and secondary GF.Seventy-one patients received a second SCT from the same donor (31 patients [44%]), from a different donor (35 patients [49%]) or an autologous back-up (5 patients [7%]). The most frequent conditioning regimens (n=65) in second allogeneic stem cell infusion were fludarabine+ thymoglobulin (ATG) (19 [29%]), anti-lymphocyte immunoglobulin alone (9 [14%]) and cyclophosphamide+ATG (6 [9%]). ATG or alemtuzumab were used in 52 patients (80%) as part of the preparative regimen. Progenitors were from mobilized PB in 52 (79%), UCB in 8 (12%) and BM in 6 (9%) patients. Eleven (20%) and 2 (4%) out of 55 evaluable patients presented again primary or secondary GF.The median survival time from GF was 12 months [range: 1–23].The 5-yr. probability of survival was 28% (95%CI: 14%–42%) with a median follow-up for alive patients of 27 months [range: 1–103]. The 5-yr. non-relapse mortality was 47% [35%–59%]. There was a trend for a better survival in patients under 18 years-old. No other factors such as graft source, in vivo T-cell depletion or the conditioning regimen influenced on patient’s survival. By competing risk estimation, the transplant-related mortality and the relapse probability at 5 years in the 66 patients that received a second transplant were 51% [95%CI: 38% – 63%] and 24% [95%CI: 10% – 41%]. Conclusions:The prognosis of GF after allogeneic SCT was poor, although some patients presented long survival if successful recovery of GF was obtained. The strategy adopted to treat GF has been heterogeneous. Younger age showed a trend for better survival in this series. Supported by grants P-EF/10 from FIJC and RD06/0020/1056 from RETICC. Disclosures:Sanz:Novartis: Speakers Bureau.

Characterization of Bacterial Infections in Allogeneic Hematopoietic Stem Cell Transplant Recipients Who Received Prophylactic Levofloxacin With Either Penicillin or Doxycycline

To describe the effect of a combination prophylactic regimen of levofloxacin, a synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class, with either penicillin or doxycycline on the changing epidemiology of bacterial infections and antimicrobial resistance patterns of isolated organisms in the allogeneic hematopoietic stem cell transplant (HSCT) patient population. We conducted a single-center, retrospective cohort study of all allogeneic HSCT recipients from January 1, 2003, through August 31, 2008, who received prophylactic levofloxacin in combination with penicillin (or with doxycycline in penicillin-allergic patients) from allogeneic stem cell infusion until neutrophil engraftment. Of the 258 patients who underwent allogeneic HSCT during the study period, 231 received levofloxacin prophylaxis, 76 (33%) of whom developed an infection within 3 months after transplant. Over time, the ratio of gram-positive to gram-negative (GN) infections decreased from 2.11 in 2004, the first year that GN organisms were isolated, to 1.11 in 2008 (P=.20). Emergence of fluoroquinolone-resistant GN bacteria was observed (P=.02), whereas resistance to extended-spectrum beta-lactams did not change over time. Combined vancomycin-resistant enterococci colonization and infection rates increased during the study period (P=.04). Clostridium difficile colitis was uncommon. Levofloxacin with penicillin or doxycycline prophylaxis may contribute to the emergence of resistant GN infections in allogeneic HSCT recipients over time. Our findings provide additional support for the current standard of practice of administering empiric monotherapy with an antipseudomonal beta-lactam if these patients develop fever or are suspected to have an infection.

Short Progression Free Survival Post Non-Myeloablative Sibling Allogeneic Stem Cell Transplantion for Multiple Myeloma.

Abstract 4323 Introduction Allogeneic stem cell transplant has been considered the only potentially curative treatment for patients with myeloma. Due to the high treatment related mortality associated with myeloablative allogeneic stem cell transplantation, non-myeloablative allogeneic stem cell transplantion is being investigated. Methods Between May 2003 and June 2008, 23 patients received a non-myeloablative allogeneic stem cell transplant (NMT) using a fully matched sibling as the donor. All had received a previous autologous stem cell transplant (ASCT). 17 received the NMT as a part of a planned tandem transplant post ASCT. Six received the NMT after relapse post ASCT. Conditioning chemotherapy was a combination of cyclophosphamide 1000 mg/m2 daily x 2 days and Fludarabine 25mg/m2 daily for 5 days. Survival was measured from the date of allogeneic stem cell infusion. Results Median age at NMT was 52 years. Eight were female. Immunoglobulin isotype was 13 IgG; 5 IgA; 1 IgD; 4 light chain. ISS stage was 10 – stage 1; 8 – stage 2; 3- stage 3; 2 – insufficient information. 9/21 had del 13q; 3/9 t (4;14); 1/7 del 17p. Disease status at the time of NMT were 5 CR/nCR, 11 PR, 1 SD, 3 relapse chemo-sensitive, 3 relapse chemo-resistant. Median follow-up is 29 months (7 – 65 months). Median event free survival (EFS) for all patients is 17 months (95 % CI 8-26 months). Median EFS for the 17 patients who received NMT as a part of a planned tandem procedure was 18 months. Median overall survival (OS) for all patients is 29 months (95% CI unable to calculate). At the time of analysis 17 patients remain alive. Five patients are alive in continuous remission at a median of 40.9 months from NMT (13.5-47.6 months). Twelve patients have active disease requiring treatment. Three patients have died of myeloma, one of graft-versus-host-disease (GVHD) and two of other causes. Nineteen patients (83%) developed GVHD at some time post-transplant. Of 14 patients who have relapsed, eleven patients had GVHD at the time of relapse. Of the 6 patient who received the NMT after relapse post ASCT, 5 have relapsed post NMT and one died of GVHD within 9 months. Conclusion Non-myeloablative sibling allogeneic stem cell transplantation for myeloma produces short progression free survival in-spite of the presence of graft-versus-host-disease and only a limited number of patients benefit. Patient who receive this treatment after relapse from prior autologous stem cell transplant do particularly poorly. Improved overall survival is primary due to improvements in post-relapse myeloma therapy.

Safety Analysis of Ex Vivo -Expanded NK and NK-Like T Cells Administered to Cancer Patients: a Phase I Clinical Study

The chimeric state after allogeneic hematopoietic stem cell transplantation provides a platform for adoptive immunotherapy using donor-derived immune cells. The major risk with donor lymphocyte infusions (DLIs) is the development of graft-versus-host disease (GvHD). Development of new DLI products with antitumor reactivity and reduced GvHD risk represents a challenging task in cancer immunotherapy. Although natural killer (NK) and NK-like T cells are promising owing to their antitumor activity, their low concentrations in peripheral blood mononuclear cells reduces their utility in DLIs. We have recently developed a system that allows expansion of clinical-grade NK and NK-like T cells in large numbers. In this study, the safety of donor-derived long-term ex vivo-expanded human NK and NK-like T cells given as DLIs was investigated as immunotherapy for cancer in five patients following allogeneic stem cell infusion. Infusion of the cells was safe whether administered alone or with IL-2 subcutaneously. No signs of acute GvHD were observed. One patient with hepatocellular carcinoma showed markedly decreased serum alpha-fetoprotein levels following cell infusions. These findings suggest that the use of ex vivo-expanded NK and NK-like T cells is safe and appears an attractive approach for further clinical evaluation in cancer patients.

In Vivo Selection and Chemoprotection After Drug Resistance Gene Therapy in a Nonmyeloablative Allogeneic Transplantation Setting in Dogs

We have previously demonstrated successful in vivo selection, chemoprotection, and modulation of donor chimerism in dogs that received myeloablative allogeneic stem cell transplantation with cells expressing the P140K mutant of the DNA repair enzyme methylguanine methyltransferase (MGMTP140K). Here, we wished to investigate whether in vivo selection, chemoprotection, and modulation of donor chimerism could also be achieved after nonmyeloablative transplantation, which could allow for less toxic transplantation regimens for patients with malignant and genetic diseases. Three dogs received a nonmyeloablative conditioning regimen and infusion of allogeneic stem cells transduced with MGMTP140K. All three dogs had stable gene marking and donor chimerism before receiving a course of O(6) -benzylguanine (O(6) BG)/1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) between days 210 and 589 after transplantation. One to four doses led to a marked increase in gene marking in all dogs. Furthermore, the transduced cells conferred chemoprotection and prevented severe neutropenia. Our results suggest that drug resistance gene therapy is feasible and safe in the nonmyeloablative transplantation setting.

Delayed Infusion of Allogeneic Stem Cells (72 Hours) Does Not Reduce the Severity of Acute Graft Versus Host Disease in Patients with Chronic Myeloid Leukemia after Myeloablative Conditioning Regimen.

Background: Some animal studies suggested that severity of aGVHD after allogeneic myeloablative hematopoietic cell transplantation (HCT) was affected not only by the histoincompatibility between donor and recipient cells but also by the inflammatory cytokines released during the conditioning regimen. Furthermore it was also shown that delayed transplantation reduced acute GVHD mortality and increased overall survival in normal mice. Our own human studies indicated that delay in stem cells infusion to 72 hours increased the recovery of absolute neutrophil (ANC) and platelet (PLT) counts. Based on these data we hypothesized that delay infusion of stem cells might reduce the incidence and severity of aGVHD without extending the duration of pancytopenia, thus improving OS. Here we retrospectively compared the incidence of grade II-IV aGVHD, time to ANC>500/uL and PLT>50,000/uL recovery and 100-day survival in 65 chronic myeloid leukemia patients from our center1 who received infusion of stem cells 72 hours (Group-72) to 57 similar patients from the comparable center2 but receiving stem cells 24 hours after the end of conditioning regimen (Group-24). Both groups did not differ in the EBMT pre-transplant (Gratwohl) risk score, however more patients (77%) were transplanted with peripheral blood in Group-24 compared to Group-72 (15%). All patients were conditioned with standard dose of busulfan (16mg/kg) and cyclophosphamide 120mg/kg, and received for aGVHD prophylaxis a short course of methotrexate and cyclosporine.Results: The increase of ANC>500/uL occurred after a median 19 (10–92) days in Group-72 and 20 (13–80) days in Group-24, whereas PLT count> 50,000/uL was achieved at a median of 27 (10–129) days in Group-72 and 22 (12–284) days in Group-24. The probability of reaching ANC>500/ul was not statistically different between two groups (p=0.15) whereas the probability of reaching PLT>50,000/ul was suggestively greater in Group-24 compared to Group-72 (RR=1.44, 95%CI [0.98–2.13], p=0.06). Data of acute GVHD grade were missing in 9 patients from Group-72. Grade II-IV aGVHD was scored in 29 (51%) patients in Group-24 and in 24 (43%) patients in Group-72. The probability of developing grade II-IV aGVHD was similar in both groups (p=0.15). Before day 100, six patients (11%) died in Group-24 and 15 (23%) in Group-72. The probability of 100-day survival was statistically significantly higher in Group-24 (0,89± 0.12) compared to Group-72 (0.76± 0.12), p=0.02. The increased mortality in Group-72 mainly resulted from infectious complications.Conclusion: Delay in allogeneic transplantation did not decrease the incidence of grade II-IV aGVHD and did not improve overall survival, therefore should not be recommended for further clinical studies.

Modification of the Bu/Cy myeloablative regimen using daily parenteral busulfan: reduced toxicity without the need for pharmacokinetic monitoring

Pharmacokinetic and clinical outcome measures among three groups of patients undergoing hematopoietic transplant were assessed: group A: Parenteral busulfan (Bu) 3.2 mg/kg i.v. given qd, n=20; group B: parenteral Bu 0.8 mg/kg i.v. given every 6 h, n=11; group C: Bu 1 mg/kg p.o. given every 6 h, n=25. All groups received Bu over 4 days followed by Cy 60 mg/kg i.v. qd over 2 days; followed by an infusion of allogeneic stem cells. Median Bu clearance was 3.21 ml/min/kg and median daily AUC was 4071 micromol/min for the group A patients. The dosing formula for Bu i.v. qd was highly predictive of the AUC for patients whose mass < or =IBW+20%. For patients of greater mass, the dosing formula uniformly resulted in lower-than-predicted AUC. Neurologic toxicity, hepatic toxicity, hematologic engraftment, and relapse at 100 days were comparable across all three groups. Severe AGVHD was least among group A, followed by group B when compared with group C. Bu i.v. qd is a safe and effective regimen for allogeneic transplantation and is at least clinically equivalent to every 6 h dosing schemes using either oral or parenteral Bu.

Preliminary Results of Sibling Donor Immunization with Patient-Derived Id-KLH Vaccine Prior to Reduced-Intensity Allogeneic Stem Cell Transplantation for Multiple Myeloma.

Reduced-intensity allogeneic stem cell transplantation (RIST) results in significant reduction in treatment-related mortality for multiple myeloma (MM) patients (pts); however, success with RIST is limited by a significant risk of relapse. To reduce the risk of relapse, HLA-matched sibling donors were vaccinated with patient-derived idiotype (Id) conjugated to keyhole limpet hemocyanin (Id-KLH) prior to stem cell donation with the goal of transferring tumor antigen-specific immunity. MM pts with HLA-matched siblings underwent plasmapheresis prior to treatment to generate Id-KLH vaccine. After vaccine generation donors received 3 SQ injections of Id-KLH + GM-CSF at 10, 8, and 4 weeks before G-CSF mobilized blood stem cell collection. During vaccine generation and donor immunizaton, MM pts received an induction regimen of EPOCH-F (etoposide, prednisone, vincristine, cyclophosphamide, adriamycin, fludarabine) to achieve a minimal disease state and deplete host T cells in preparation for RIST. MM pts then received a reduced-intensity conditioning regimen consisting of fludarabine (30 mg/m2/d x 4d) and cyclophosphamide (1200 mg/m2/d IV x 4d) followed by allogeneic stem cell infusion. MM pts were then vaccinated with the Id-KLH+GM-CSF at 3, 4, and 6 months post-RIST. Both donors and MM pts were monitored for Id-specific humoral and cellular responses. Five MM pts (ages: 50–60 years; IgG = 4, IgA = 1) and their respective donors have been enrolled onto study. Vaccine was generated from all 5 MM pts. All 5 donors completed vaccinations without significant complications; there were no grade 3 or 4 toxicities. Most common toxicities experienced by donors were erythema, pain, induration and pruritus at sites of injection and diffuse arthralgias. Four MM pts have undergone RIST. There has been one treatment-related death (GVHD) at day +67. Two patients are in CR at 15 and 9 months post-RIST; the third patient is in a PR at 4 months post-RIST. KLH-specific immunity was induced in all of the first 3 donors tested, and Id-specific T cell immunity was induced in 2 of the first 3 donors. In donor-MM pt pair #2 there was evidence that Id-specific T cell immunity was induced in the donor (Figure 1) and passively transferred to the recipient with RIST (Figure 2). Id-specific T cell responses were blocked with HLA Class I and Class II antibodies. These preliminary data confirm that Id-KLH vaccines can be safely and effectively given to normal stem cell donors. More importantly, these data suggest that tumor specific immunity can be induced and passively transferred to the recipient after RIST. Vaccination of donors with tumor-specific antigen represents a tactic to potentially reduce relapse after RIST. [Display omitted] [Display omitted]

Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease

Reduced-intensity allogeneic transplantations for myelodysplastic syndrome (MDS) patients have been limited by significant graft-versus-host disease (GVHD), treatment-related mortality, and disease relapse. We treated 18 MDS patients ineligible for standard allogeneic transplantation with a preparative regimen of photopheresis day −7 and −6, pentostatin 4 mg/m 2 by continuous infusion day −5 and −4, and total body irradiation 600 cGy in 3 fractions day −3 and −2, followed by allogeneic stem cell infusion from 6/6 or 5/6 HLA-matched related donors or 6/6 HLA-matched unrelated donors. GVHD prophylaxis consisted of cyclosporin A and a short course of methotrexate. The median age was 54 years (range, 30–70 years). Diagnoses included refractory anemia (n = 2), refractory anemia with ringed sideroblasts (n = 2), refractory anemia with excess blasts (n = 10), refractory anemia with excess blasts in transformation (n = 3), and chronic myelomonocytic leukemia (n = 1). Sixteen of 18 patients developed full donor chimerism with no day +100 transplant-related mortality. Grade II to IV acute GVHD and extensive chronic GVHD developed in 19% and 18% of patients, respectively. Disease relapse occurred in 2 patients. At a median follow-up of 14 months (range, 1–35 months), the 1-year failure-free and overall survival were 64% and 65%, respectively. Our photopheresis and pentostatin-based reduced-intensity preparative regimen for allogeneic bone marrow transplantation in high-risk MDS patients achieves successful donor engraftment and disease remission with less transplant toxicity and grade II to IV acute GVHD.

Extracorporeal photopheresis in the treatment of graft-vs-host disease.

Graft-vs-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic stem cell transplantation. GVHD was first described by Barnes and Mole as a fatal disease manifest by skin changes, diarrhea, and runting in irradiated mice given allogeneic spleen cells. Early human allogeneic bone marrow transplant patients were noted to manifest a similar syndrome of dermatitis, hepatitis, and enteritis occurring within the first 100 days after infusion of allogeneic stem cells. The etiology of GVHD is related to alloreactivity between immunocompetent donor lymphocytes and transplantation alloantigens on host tissues. The incidence of acute GVHD (aGVHD) ranges from 27% to 50% after sibling-matched related donors and from 42% to 72% after unrelated donor bone marrow or peripheral blood stem cell transplants. Despite aggressive immunosuppressive therapies, including high-dose corticosteroids, cyclosporine A, antithymocyte globulin, tacrolimus, and mycophenolate mofetil, the mortality from acute GVHD remains high. Chronic GVHD (cGVHD) is a syndrome of immune dysregulation whose onset has been arbitrarily defined as occurring at least 100 days after allogeneic stem cell infusion. Clinical features of cGVHD are distinguished from aGVHD in that they more closely resemble autoimmune disorders. Histopathologic changes include sclerodermatous skin changes from collagen deposition, pulmonary fibrosis, esophageal dysfunction, dry mouth or mucocutaneous ulcerations, cholestasis, and myositis or fasciitis and are thought to be initiated, in part, by autoantibodies to cell surface and intracellular proteins. The incidence of cGVHD ranges from 30% in siblingmatched donors to over 70% in matched unrelated donor transplants. Factors associated with cGVHD include increased donor and recipient age, prior aGVHD, and the use of alloimmune female donors. Conventional therapeutic approaches for cGVHD, including corticosteroids and immunosuppressive agents, have demonstrated limited efficacy in patients with extensive disease. Oral methoxsalen followed by ultraviolet A therapy (PUVA), while effective in alleviating the symptoms of chronic skin GVHD, has had no impact on visceral involvement. Novel agents demonstrating activity include T-cell directed therapies, such as humanized anti-CD25 antibody (dacluzimab) and pentostatin, as well as anti-TNF-a antibody (infliximab) and thalidomide. While aGVHD is understood as a disease of acute alloreactivity, the etiology of cGVHD is controversial and is believed to be either an extension of aGVHD and/ or a result of dysfunctional immune reconstitution with generation of autoantibodies and tissue autoreactive Tcell clones. Acute GVHD is believed to be a Th1-driven disease wherein inflammatory cytokines, such as IL-2 and IFN-c as well as the monokines IL-1 and TNF-a, contribute to tissue damage. In murine models, donor CD4-enriched cells of Th2 phenotype have been shown to prevent aGVHD without affecting engraftment, suggesting that they play a role in downregulating the Th1 response, and, in other studies, administration of a Th1 inhibitor (TAK-603) markedly reduced the mortality associated with aGVHD. Chronic GVHD has been proposed by others to be a Th2-mediated disease, but recent studies demonstrating upregulation of Th1 cytokines IFN-c and IL-12 in peripheral blood mononuclear cells implicate, in part, a Th1-derived mechanism similar to that seen in acute alloreactivity.

Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies.

To investigate the use of a nonmyeloablative fludarabine-based preparative regimen to produce sufficient immunosuppression to allow engraftment of allogeneic stem cells and induction of graft-versus-leukemia/lymphoma (GVL) as the primary treatment modality for patients with chronic lymphocytic leukemia (CLL) and lymphoma. Fifteen patients were studied. Six patients were in advanced refractory relapse, and induction therapy had failed in two patients. Patients with CLL or low-grade lymphoma received fludarabine 90 to 150 mg/m2 and cyclophosphamide 900 to 2,000 mg/m2. Patients with intermediate-grade lymphoma or in Richter's transformation received cisplatin 25 mg/m2 daily for 4 days; fludarabine 30 mg/m2; and cytarabine 500 mg/m2 daily for 2 days. Chemotherapy was followed by allogeneic stem-cell infusion from HLA-identical siblings. Patients with residual malignant cells or mixed chimerism could receive a donor lymphocyte infusion of 0.5 to 2 x 10(8) mononuclear cells/kg 2 to 3 months posttransplantation if graft-versus-host disease (GVHD) was not present. Eleven patients had engraftment of donor cells, and the remaining four patients promptly recovered autologous hematopoiesis. Eight of 11 patients achieved a complete response (CR). Five of six patients (83.3%) with chemosensitive disease continue to be alive compared with two of nine patients (22.2%) who had refractory or untested disease at the time of study entry (P = .04). These findings indicate the feasibility of allogeneic hematopoietic transplantation with a nonablative preparative regimen to produce engraftment and GVL against lymphoid malignancies. The ability to induce remissions with donor lymphocyte infusion in patients with CLL, Richter's, and low-grade and intermediate-grade lymphoma is direct evidence of GVL activity against these diseases. This approach appears to be most promising in patients with chemotherapy-responsive disease and low tumor burden.