Michael Y. Shapira

Allogeneic stem cell transplantation for severe acquired aplastic anaemia using a fludarabine-based preparative regimen.

We reviewed our experience in the treatment of 13 patients with severe acquired aplastic anaemia, using a newly developed non‐myeloablative regimen consisting of fludarabine (total dose 180 mg/m2), cyclophosphamide (total dose 120 mg/kg), and antithymocyte globulin (total dose 40 mg/kg). All except one patient received multiple transfusions and had failed prior immunosuppressive treatment. Twelve out of 13 patients achieved sustained engraftment. One patient was not evaluable for engraftment because of early death on day +10. None of the patients developed graft failure. Mucositis of mild‐to‐moderate severity was the only observed regimen‐related toxicity. The cumulative incidence of acute graft‐versus‐host disease (GvHD) grade II–IV and III–IV was 8·3% and 0%, respectively. With a median follow‐up period of 45 months, the 5‐year overall survival probability was 84%. Eight out of 11 surviving patients have been followed for more than 1 year and only one developed limited chronic GvHD. All patients enjoy a normal life style, with a Karnofsky score of 100%, and all except three, followed for 3, 5 and 6 months respectively, are free of any immunosuppressive medication. The results of this study look promising, while prospective clinical trials may be required to confirm the benefits of this regimen as an alternative to 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.

Summary: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.

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

Summary: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 × 109/l was 9–27 days (median 14 days). The time interval to platelet recovery ⩾20 × 109/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.

Intra-arterial catheter directed therapy for severe graft-versus-host disease

Summary. Graft‐versus‐host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), resulting in death in the majority of steroid‐resistant patients. We assessed the efficacy of regional intra‐arterial treatment in patients with resistant hepatic and/or gastrointestinal (GI) GVHD. In total, 15 patients with steroid resistant grade 3–4 hepatic (n = 4), gastrointestinal (GI) (n = 8) GVHD or both (n = 3) were given intra‐arterial treatment. Patients with hepatic GVHD received methotrexate and methylprednisolone into the hepatic artery. Patients with GI GVHD were treated with infusions of methylprednisolone into the superior and inferior mesenteric arteries. Two patients with pronounced upper GI symptoms also received upper GI treatment. In total, 25 procedures were carried out (range 1–3 per patient). Hepatic response was observed in four out of seven (57%) patients with hepatic GVHD, three (43%) featuring good response. Complete responses were observed in nine (82%) GI GVHD patients, with median time to initial and complete response of 3 d (range 1–7) and 15·8 d (range 4–33) respectively. Regional treatment of severe GVHD with intra‐arterial treatment appears to be effective and safe. GI treatment maybe more effective than intrahepatic treatment. Early administration of isolated intra‐arterial therapy in high‐risk patients may further improve the outcome and reduce untoward effects of systemic immunosuppressive treatment.

The role of natural killer cells in hematopoietic stem cell transplantation

Abstract Natural killer (NK) cells are important elements of innate immunity, and a large body of evidence supports the significant role of NK in immune surveillance against infections and tumors. Regulation of cytotoxic activity is mediated through activating and inhibitory receptors expressed on the cell surface. NK cells are key players of allogeneic hematopoietic stem cell transplantation (allo-SCT), and previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. Biology of human NK cells is an area of active research. Exploitation of the molecular mechanisms regulating NK maturation, tolerance to self, and NK-mediated cytotoxicity will help in the development of innovative NK cell immunotherapy methods.

Immunotherapy of hematologic malignancies and metastatic solid tumors in experimental animals and man

Following engraftment of donor hematopoietic cells and induction of host-versus-graft tolerance, immunocompetent lymphocytes of donor origin can induce graft-versus-leukemia (GVL) and graft-versus-tumor (GVT) effects. Engraftment of allogeneic bone marrow cells can be accomplished following non-myeloablative conditioning while possibly controlling graft-versus-host disease (GVHD). GVL and GVT effects may thus be successfully accomplished following non-myeloablative stem cell transplantation (NST) as shown by data derived from experimental animals and man. Bone Marrow Transplantation (2000) 25, Suppl. 25, S54–S57.

Indolent aspergillus arthritis complicating fludarabine-based non-myeloablative stem cell transplantation.

Fungal arthritis and osteomyelitis are rare and documented mainly in immunocompromised or neutropenic patients. Patients receiving therapeutic immunosuppression for organ transplants have also reported to suffer from aspergillus osteoarthritis. We describe two patients with aspergillus arthritis of the knee joint following fludarabine-based non-myeloablative stem cell transplantation. Both were suffering from acute and chronic GVHD and treated with heavy immunosuppression including steroids and cyclosporine. Interestingly in one of our patients, the arthritis was almost asymptomatic and did not spread to other organs. Heavy pre- and post-transplant immunosuppression is a major risk factor for invasive fungal infection, which can involve remote organs and manifest in an indolent and atypical manner. Bone Marrow Transplantation (2001) 27, 659–661.

Allogeneic haematopoietic cell transplantation for extranodal natural killer/T‐cell lymphoma, nasal type: a CIBMTR analysis

Author(s): Kanate, Abraham S; DiGilio, Alyssa; Ahn, Kwang W; Al Malki, Monzr; Jacobsen, Eric; Steinberg, Amir; Hamerschlak, Nelson; Kharfan-Dabaja, Mohamed; Salit, Rachel; Ball, Edward; Bashir, Qaiser; Cashen, Amanda; Couriel, Daniel; Diez-Martin, Jose; Katsanis, Emmanuel; Linhares, Yulia; Mori, Shahram; Nash, Richard; Pawarode, Attaphol; Perales, Miguel-Angel; Phipps, Colin D; Richman, Carol; Savani, Bipin N; Shapira, Michael Y; Stiff, Patrick; Strair, Roger; Fenske, Timothy S; Smith, Sonali M; Sureda, Anna; Olteanu, Horatiu; Hamadani, Mehdi

Spinal epidural lipomatosis following haploidentical allogeneic bone marrow transplantation for non‐Hodgkin lymphoma

Abstract:  Objectives:  Spinal epidural lipomatosis, is a very rare condition, usually seen as an uncommon complication of Cushings syndrome secondary to chronic steroid therapy leading to increased fat deposits in the epidural space.