Colistin is relatively safe in hematological malignancies and hematopoietic stem cell transplantation patients.

PURPOSE: Colistin is increasingly used as the last-resort treatment option against infections caused by multidrug-resistant (MDR) Gram-negative pathogens, but its nephrotoxicity is of concern, especially in severely ill patients. The aim of this study was to analyze the toxicity of colistin therapy in adults and children with hematological malignancies (HM) and hematopoietic stem cell transplantation (HSCT) recipients. METHODS: Data on HSCT recipients and HM patients, treated with intravenous colistin (2.5-5 mg/kg/day in children and 3-6 million international units (IU) in adults, adjusted to renal function) during the period 2008-2011 in our center, were retrospectively collected and analyzed. Nephrotoxicity was defined according to the RIFLE criteria (Risk, Injury, Failure, Loss, and End-stage kidney disease). RESULTS: Twenty-nine children and adults received 38 courses of intravenous colistin (2.5-5 mg/kg/day in children and 3-6 × 10(6) IU in adults, adjusted to renal function) [allogeneic HSCT (22 courses) and HM (16 courses)] for 3-28 days (median 10 days) for empirical therapy for nosocomial clinical sepsis (28) or local infection (6), and bacteremia with MDR Gram-negative rods (4). Nephrotoxicity was observed at the end of 4 (10.5%) courses. In 32 (84%) courses, nephrotoxic medications were concomitantly administered. Two patients had convulsions, probably unrelated to colistin. Seven patients (18%) died while on colistin therapy. No death was attributed to an adverse effect of colistin. CONCLUSIONS: Treatment with intravenous colistin, with dosage adjusted to renal function, was relatively safe for HM/HSCT patients, even with concomitantly administered nephrotoxic medications. Concern about nephrotoxicity should not justify a delay in initiating empirical colistin treatment in situations where infection with MDR Gram-negative rods is likely.

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 hematopoietic stem cell transplantation in the elderly.

The development of reduced intensity or non-myeloablative conditioning (NST) in preparation for allogeneic stem cell transplantation (SCT) revolutionized the field and led to reconsideration of the dogma of upper age limit that was set up by the transplant centers as an eligibility parameter. Analysis of the literature data showed that NST regimens are associated with decreased transplant related mortality, and graft-versus-host disease, in comparison with standard myeloablative conditioning, in patients above the age of 50-55 years, or in younger patients with significant comorbidities. However we have to mention, that our considerations are based on the retrospective analysis of the literature data, and that well controlled prospective randomized studies are needed in order to definitely assess the role of NST. Comorbidity indices might be proved as the most important parameters for the choice of the most proper regimen for each patient in need and should be included in future trials.

The effect of high-dose thiotepa, alone or in combination with other chemotherapeutic agents, on a murine B-cell leukemia model simulating autologous stem cell transplantation.

The use of thiotepa (TH) is increasing, especially in stem cell transplantation, mainly due to its safety and blood-brain barrier penetration. We evaluated the use of TH in a murine model simulating autologous stem cell transplantation, with or without additional agents. Between 1 and 11 days following inoculation of BALB/c mice with 10(5)-10(8) B-cell leukemia (BCL1) cells (simulating pre-transplant leukemia loads), each group received an 'induction-like' irradiation and/or cytotoxic regimen. Animals were either followed without treatment, or an adoptive transfer (AT) was performed to untreated BALB/c mice. Administered alone without AT, high-dose TH did not change the time to appearance of leukemia. Nevertheless, in the AT experiments, TH as a single agent showed better antileukemic activity than busulfan (BU). Cyclophosphamide (CY)-containing regimens were the most effective, and the TH-CY combination was as effective as the commonly used BU-CY combination, and more effective than the BU-TH combination. Moreover, a synergistic effect was seen in the TH-CY combination (none of the animals developed leukemia, whereas 4/10 animals in the CY-TBI group developed leukemia (P=0.029)). In conclusion, although TH produced only a moderate effect against BCL1 leukemia when used alone, its combination with CY is promising and should be tested further in allogeneic murine models and clinical studies.

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.

Treatment of post-hematopoietic stem cell transplantation hemorrhagic cystitis with intravesicular sodium hyaluronate.

Hemorrhagic cystitis (HC) is a well-known complication of HSCT. Its overall incidence has been reported to vary from 7-68%. The spectrum of clinical presentation varies from asymptomatic microhematuria to life-threatening bleeding. Sodium hyaluronate is a glycosaminoglycan present on the bladder mucosa, which serves as an important protective substance against uroepithelial damage. Preparations of this component have been shown to be effective in the treatment of interstitial cystitis. We report our experience in the treatment of post-transplant HC with intravesical instillation of sodium hyaluronate. Five out of the seven patients included in this study achieved complete response, while one patient had only partial response. Sodium hyaluronate administration was not associated with any local or systemic adverse effects. We consider that the results of our study are promising and the efficacy of sodium hyaluronate in the treatment of post-transplant HC should be tested in larger cohorts of patients.

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 and cell therapy for malignant and non-malignant diseases.

The conditioning prior to allogeneic stem cell transplantation was originally designed as a myeloablative conditioning, designed to eliminate malignant or genetically abnormal cells and then use the transplant procedure for rescue of the patients or to replace missing bone marrow products. However, allografts can induce effective graft vs. malignancy effects and can also eliminate undesirable hematopoietic stem cells in patients with genetic disorders and autoimmune diseases, thus documenting that alloreactive effects mediated by donor lymphocytes post-grafting can play a major role in eliminating hematopoietic cell of host origin, as well as provide effective immunotherapy for the treatment of disease recurrence. The efficacy of donor lymphocyte infusion (DLI) could be improved by activation with rIL-2 or by donor immunization. The cumulative experience over the years suggesting that alloreactive donor lymphocytes were most effective in eliminating tumor cells of host origin resulted in an attempt to reduce the intensity of the conditioning in preparation for the transplant procedure used for the treatment of hematological and other malignancies as well as life-threatening non-malignant disorders for which allogeneic stem cell transplantation may be indicated. Our working hypothesis proposed that the myeloablative conditioning which is hazardous and may be associated with early and late side effects, may not be required for treatment of patients with any indication for allogeneic stem cell transplantation. Instead, nonmyeloablative conditioning based on the use of reduced intensive preparatory regimen, also known as nonmyeloablative stem cell transplantation, may be sufficient for engraftment of donor stem cells while avoiding procedure-related toxicity and mortality, followed by elimination of undesirable cells of host origin by post-transplant effects mediated by alloreactive donor lymphocytes infused along with donor stem cells or administered subsequently as DLI. Improvement of the immediate outcome of stem cell transplantation using NST due to a significant decrease in transplant related mortality has broadened the spectrum of patients eligible for allogeneic stem cell transplantation, including elderly patients and other patients with less than optimal performance status. Likewise, the safer use of stem cell transplantation prompted expanding the scope of potential indications for allogeneic stem cell transplantation, such as metastatic solid tumors and autoimmune disorders, which now are slowly becoming much more acceptable. Current strategies focus on the need to improve the capacity of donor lymphocytes to eliminate undesirable malignant and non-malignant hematopoietic cells of host origin, replacing abnormal or malignant stem cells or their products with normal hematopoietic stem cells of donor origin, while minimizing procedure-related toxicity and mortality and improving the quality of life by reducing the incidence and severity of hazardous acute and chronic GVHD.

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.

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.

Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.

The incidence and outcome of moderate-to-severe veno-occlusive (VOD) disease was analyzed in 271 consecutive patients with hematological malignancies who underwent allogeneic SCT (allo-SCT) using the same reduced intensity regimen (RIC). RIC consisted of fludarabine, BU and antithymocyte globulin (ATG). Twenty-four out of 271 patients (8.8%) developed VOD, which was severe in only 4 (1.4%) out of 24 cases. All four patients with severe VOD finally succumbed to their disease. In multivariate analysis, i.v. administration of BU was associated with significant reduced incidence of VOD as compared with per os administration. In conclusion, VOD remains a serious complication of allo-SCT using RIC regimens containing BU. Although the incidence of severe VOD is very low, the overall mortality rate in the group of patients with severe VOD remains extremely high and therefore novel treatment approaches are needed.

Assessment of CD4 T-lymphocyte reactivity by the Cylex ImmuKnow assay in patients following allogeneic hematopoietic SCT.

After allogeneic hematopoietic SCT (alloHSCT), immunosuppressed patients are susceptible to opportunistic infections, and uncontrolled function of the graft can result in GVHD. Accurate immune monitoring may help early detection and treatment of these severe complications. Between October 2005 and November 2007, a total of 170 blood samples were collected from 40 patients after alloHSCT in the Hadassah Hebrew University Medical Center and from 13 healthy controls. We utilized the Cylex ImmuKnow assay for CD4 ATP levels to compare known clinically immunocompromised vs immunocompetent patients after alloHSCT. We also compared the reconstitution of WBC count to the ImmuKnow results and clinical status. The patients' clinical course correlated with the stratification of immune response established by the ImmuKnow assay for solid organ transplantation (immunocompetent vs immunocompromised), and this often differed from their WBC count. On the basis of our observations, we conclude that the ImmuKnow assay is a simple and fast immune-monitoring technique for patients undergoing alloHSCT, with potential to predict clinical course and facilitate prompt management of post-HSCT complications. The assay should be evaluated prospectively in clinical trials.

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.

Alefacept treatment for refractory chronic extensive GVHD.

Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that is used for psoriasis control. We recently showed its effect in acute steroid-resistant/dependent GVHD. In this study, we describe the effect of alefacept treatment on chronic extensive GVHD (cGVHD). Twelve patients were included in this study; of these 8 (9 of 13 episodes) showed response. The median time to initial response was 2.25 weeks and the response was marked (n=3), moderate (n=2) or minimal (n=4). In two responding patients, the response was only temporary. Complications that appeared during treatment included infection, pericarditis and squamous cell carcinoma of the lip. All these events may be related to other drugs given simultaneously. With a 30-month median follow-up, 6 of 12 patients are alive, with all but one with stable or improved cGVHD. Six patients died because of GVHD progression, whereas none of the patients experienced relapse of the disease for which the transplantation was done. As reported earlier in psoriatic patients treated with alefacept, we found a consistent increase in the percentage of naive T cells as a consequence of treatment. In conclusion, alefacept is effective for the treatment of cGVHD, and dose and time intervals of treatment should be explored further.

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.

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.

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.

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.