Yossi Cohen

Kidney involvement and renal manifestations in non-Hodgkin's lymphoma and lymphocytic leukemia: a retrospective study in 700 patients

Abstract: Renal involvement as part of systemic lymphoma (LY) is quite frequent, however, primary extranodal renal non‐Hodgkins lymphoma (NHL) is extremely rare, and only about 65 cases have been reported in the world literature. In a retrospective study of renal manifestations in 700 patients with documented LY and chronic lymphocytic leukemia (CLL) seen at our hospital during 1986–95, 83 patients had signs of acute renal failure. Only five of these had proven renal infiltration, but none of them satisfied the criteria for primary renal LY. Glomerulonephritis (GN) has also rarely been reported in association with LY and CLL, and only 37 glomerular lesions in NHL and 42 in CLL have been documented, respectively. GN may precede, coexist, or follow the diagnosis of LY by several years. Of the 42 cases of CLL reported worldwide, 36 had nephrotic syndrome. Renal failure was seen in about one third. The most common glomerular lesion reported is membranoproliferative GN, followed by membranous GN. In our study, we found only five biopsy‐proven cases with GN amongst the 700 patients seen. In this report we also briefly describe some rare interesting associated renal syndromes in CLL and NHL.

Umbilical cord blood transplantation – how, when and for whom?

In recent years, umbilical cord blood (UCB) has emerged as a feasible alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients who lack HLA-matched marrow donors. Since the first case reported in 1998, more than 3500 patients have received UCB transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20 kg; however, more than 500 UCB transplantations (UCBTs) have already been performed in adults. The naive nature of UCB lymphocytes also permits the use of HLA-mismatched grafts at 1-2 loci without higher risk for severe graft versus host disease (GvHD) relative to bone marrow transplantation (BMT) from a full matched unrelated donor. Furthermore, UCB is rich in primitive CD16(-)CD56++ NK cells, which possess impressive proliferative and cytotoxic capacities and can be induced to expand using IL-12 or IL-15, so as to mount a substantial graft versus leukemia (GvL) effect. The main disadvantage of UCB is the low stem cell yields, resulting in higher rates of graft failure as well as delayed time to engraftment compared to BMT. One rational approach to overcome this limitation involves ex vivo expansion of UCB derived hematopoietic precursors. In this review we tried to answer the question: UCBT how, when and for whom. This procedure is mostly applicable for children and especially those with indication for full allogeneic transplantation but who lack a matched sibling donor. Experimental approaches including ex vivo expansion of CB with cocktail of hematopoietic growth factors, with or without differentiation blocking agents, co-transplantation of haploidentical and CB cells or co-transfusion of CB and mesenchymal cells may enable successful UCBT in adults and probably will result in expanding the indication to solid tumors or autoimmune disorders.

Hematopoietic stem-cell transplantation using umbilical-cord blood

In the recent years, umbilical cord blood (UCB) has emerged as an alternative source of hematopoietic progenitors (CD34+) for allogeneic stem cell transplantation, mainly in patients lacking an HLA-matched marrow donor. Since 1998, about 2500 patients have received UCB transplants for a variety of malignant and non-malignant diseases. The vast majority of recipients were children with an average weight of 20kg, however, more than 500 UCB transplantations (UCBT) have already been performed in adults. The naive nature of UCB lymphocytes may explain the lower incidence and severity of graft vs. host disease (GvHD) encountered in UCBT compared to the allogeneic transplant setting. Furthermore, UCB is rich in primitive CD16-CD56++ NK cells, which possess significant proliferative and cytotoxic capacities and can be expanded using IL-12 or IL-15, so as to mount a substantial graft vs. leukemia (GvL) effect. The major disadvantage of UCB is the low yield of stem cells, resulting in higher rates of engraftment failure and slower time to engraftment compared to bone marrow transplantation (BMT). A rational approach thus involves ex vivo expansion of UCB derived hematopoietic precursors. All these issues are discussed in detail in this review.

Monotherapy with Rituximab Induces Rapid Remission of Recurrent Cold Agglutinin-Mediated Hemolytic Anemia in a Patient with Indolent Lympho-Plasmacytic Lymphoma

Cold agglutinin mediated immune hemolytic anemia secondary to lymphoproliferative disease (LPD), is primarily treated with measures directed to eliminate the malignant clone and as such, chemotherapy is usually given. The recent availability of monoclonal antibodies, has made it feasible to obtain both a clinical and molecular remission, as well as a remission on the functional level, such as elimination of secondary autoimmune phenomena. Recently we have administered a course of monotherapy with rituximab (4 weekly injections, × 375 mg/m2) to a patient with refractory and transfusion dependent cold agglutinin mediated hemolytic anemia secondary to indolent B-cell lymphoma. She achieved complete remission with a significant improvement in hemolysis and also became transfusion independent with a current follow-up of over one year. In individual cases, Rituximab has the potential of achieving not only a complete clinical remission (CR) but also a molecular CR, as well as a “functional” CR, by eliminating the clinical manifestations of autoimmunity; in this case, cold agglutinin mediated hemolytic anemia, secondary to NHL. Good results in autoimmunity secondary to lymphoma raises the possibility of future potential benefit of this agent in other primary autoimmune disorders.

Large-cell transformation of chronic lymphocytic leukemia and follicular lymphoma during or soon after treatment with fludarabine–rituximab-containing regimens: natural history- or therapy-related complication?

Abstract: Novel therapeutic regimens containing purine analogs and monoclonal antibodies have led to significant improvement in the course of indolent lymphoproliferative diseases (LPD). Complete clinical and even molecular remissions have been achieved in an increasing proportion of patients. In parallel to their tumor cytotoxic effect, these agents are inevitably associated with prolonged immunosuppression inherent to their mechanism of antilymphocytic activity. Until now, attention has been paid mainly to opportunistic infection occuring as a result of the above drug‐induced immunosuppression and less to other possible complications, such as malignancy or tumor progression in the immunocompromised host. Here we briefly report nine patients with previously treated indolent LPD in whom the onset of large‐cell transformation occured during or shortly after the initiation of regimens containing these agents before transformation occured. One patient had received rituximab alone, three fludarabine‐containing regimens and five received sequential regimens containing both agents. This ‘switch’ in the histopathology could merely reflect the natural course of progressive lymphoma and be unrelated to the therapy given. The onset of this complication during, or so soon after, administration of these regimens seems to us more than just a chance relationship in these cases; however, we have no conclusive evidence to prove this hypothesis definitively. We draw attention to this phenomenon.

Treatment of refractory autoimmune diseases with ablative immunotherapy

Immunological manipulations are the basis of modern therapy for refractory autoimmune diseases (AID). Ablative chemotherapy with stem cell support (autotransplant) as well as targeted immunotherapy using specific monoclonal antibodies, such as rituximab and campath 1-H have become acceptable second line therapy for severe refractory AID. Until now, more than 500 autotransplants have been performed worldwide for various autoimmune disorders, including multiple sclerosis (MS), systemic sclerosis (SSc), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA) with encouraging results, although transplant related mortality (TRM) in the range between 2 and 17% still remains one of the major limitations of the procedure. Immunotherapy is a relatively safe approach associating with sustained remissions in a considerable proportion of treated patients. Better selection of patients and earlier immunotherapy, preceded an irreversible organ damage might further improve the clinical outcome of patients with AID.

Treatment of Refractory Autoimmune Diseases with Ablative Immunotherapy Using Monoclonal Antibodies and / or High Dose Chemotherapy with Hematopoietic Stem Cell Support

Immunological manipulations are the basis for modern treatments of autoimmune diseases (AID). Targeted immune suppression with lymphopenic based chemotherapy, and monoclonal anti B or T lymphocytic antibodies, are integral part of the conditioning for stem cell transplantation (SCT). Immune manipulation by Cyclophosphamide (Cy), ATG, Campath and recently rituximab (RI), with or without stem cell support are the basis for emerging therapeutic modalities aiming to eradicate the autoreactive clone in various autoimmune disorders. Couple of hundreds of SCTs have been recently performed in various autoimmune disorders, mainly multiple sclerosis (MS), progressive systemic sclerosis (PSS), systemic lupus erythematosis (SLE) and rheumatoid arthritis (RA). Preliminary results are encouraging. Better selection of patients and earlier treatment, before irreversible organ failure develops will probably improve results. Current ongoing multicenter studies are evaluating the role of SCT in MS, RA, SLE, and PSS.

Primary ALK positive anaplastic large cell lymphoma of the pancreas

Here we present an unusual case of anaplastic lymphoma kinase positive anaplastic large cell lymphoma (ALCL), appearing as a primary tumor of the pancreas which invaded into the adjacent duodenal wall, causing upper gastrointestinal bleeding. After complete resection of the tumor (Whipples operation), the patient received 4 cycles of CHOP chemotherapy. Currently, 2 years after diagnosis the patient still remains lymphoma free. Primary ALCL of the pancreas is very rare and has only been reported on one previous occasion. Nevertheless, lymphoma should be considered in the differential diagnosis of pancreatic tumors and an attempt to obtain tissue diagnosis is always necessary before continuing with radical surgery, especially in young patients.

Large B-cell Lymphoma Manifesting as an Invasive Cardiac Mass: Sustained Local Remission after Combination of Methotrexate and Rituximab

Cardiac tumor is an infrequent but serious manifestation of lymphoma and optimal management has not been well defined in these rare cases. Here we describe a patient who after autologous transplant for large B-cell lymphoma, relapsed with an invasive cardiac tumor, infiltrating the full thickness of the right myocardial wall. During therapy, she developed hemodynamic collapse due to complex atrial arrhythmias and had to be treated and stabilized in the intensive cardiac care unit. Despite initial significant regression of the cardiac tumor, new extranodal sites of lymphoma soon appeared in the skin, stomach and nervous system. Because of poor compliance, she was given salvage therapy with weekly four I.V. infusions of methotrexate and rituximab followed by monthly four maintenance cycles of rituximab alone. This produced an unexpected prolonged complete remission lasting 12 months, but she then developed a fatal leukemic phase. The relapse spared the heart and no cardiac abnormality was evident clinically or by any imaging technique. To the best of our knowledge this case, unique in terms of tumor size and extent of invasion, represents the first report of the treatment of invasive cardiac lymphoma using a combination of modest chemotherapy and rituximab.

Development and rapid dissemination of Merkel-cell carcinomatosis following therapy with fludarabine and rituximab for relapsing follicular lymphoma

Abstract: This report deals with an unusual case of a patient with follicular small cleaved lymphocytic lymphoma who developed Merkel‐cell carcinoma soon after receiving chemoimmunotherapy with a fludarabine‐containing regimen and rituximab. The presentation of the Merkel‐cell carcinoma in this patient was atypical because of the absence of dermal involvement and the very rapid clinical progression. In the light of recent reports which suggest a possible link between the immunocompromised state and the development of Merkel‐cell carcinoma, the atypical presentation seen in this patient may indeed imply a possible link between the therapy given and the development of Merkel‐cell carcinoma. To the best of our knowledge, this is the first documentation of Merkel‐cell carcinoma appearing in a patient soon after treatment with fludarabine and/or rituximab.