Donna E. Hogge

Lymphoproliferative disorders following allogeneic bone marrow transplantation : the Vancouver experience

Between June 1988 and May 1996, 428 patients underwent allogeneic BMT (288 related donor (RD) and 140 unrelated donor (UD)) at the Vancouver General Hospital. Eight patients (UD six and RD two) developed a post-transplant lymphoproliferative disorder (PTLD). Median age at BMT was 38 years (range 22–51). Five of the six UD allografts were T cell depleted. Cyclosporineu2009±u2009methotrexate was used for GVHD prophylaxis. All eight patients developed GVHD; in six this was refractory to treatment with corticosteroids. Rabbit antithymocyte globulin (ATG) or an anti-CD5-ricin A chain immunotoxin (Xomazyme) was used as second-line therapy for GVHD. Presentation with PTLD occurred at median day 90.5 (range 34–282) post BMT. Five of the eight patients had a rapidly progres- sive course characterized by fever, lymphadenopathy, lung and liver involvement and died within 3–8 days. PTLD was an incidental finding at post mortem examination in two patients. The remaining patient had localized disease and recovered. Pathological analysis revealed two morphological patterns; diffuse large B cell lymphoma (DLBC lymphoma, five patients) and polymorphous B cell hyperplasia (PBCH, three patients). EBV expression was positive in all eight cases and monoclonality was demonstrated in seven cases. In multivariate analysis, T cell depletion of the allograft (Pu2009=u20090.0001, relative risk (RR)u2009=u200930.5), anti-T cell therapy for GVHD (Pu2009=u20090.006, RRu2009=u200912.7) and acute GVHD grades 3–4 (Pu2009=u20090.04, RRu2009=u20097.7) were the significant factors for development of PTLD. In conclusion, we have identified two forms of PTLD after BMT: one is characterized by disseminated disease with a rapidly progres- sive and often fulminant course and the other by localized, relatively indolent disease. Morphology, EBV positivity and clonality do not appear to correlate with the clinical course. The major risk factors for development of PTLD after BMT are ex vivo T cell depletion of the allograft and in vivo anti-T cell therapy for GVHD.

Allogeneic bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia

Twenty-six patients with low-grade lymphoma (LGL) (nu2009=u200918) or chronic lymphocytic leukemia (CLL) (nu2009=u20098) received allogeneic BMTs between 1985 and 1998. Median age was 42 years, median interval from diagnosis to transplant 22u2009months and median number of prior treatments three. Twenty (77%) had stageu2009IV disease; 22 (85%) had never achieved CR. Donor source was HLA matched sibling (nu2009=u200919, 73%), matched unrelated (nu2009=u20096, 23%) or syngeneic (nu2009=u20091). Conditioning therapy included total body irradiation in 23 patients and busulphan in three. Twenty-five received GVHD prophylaxis with cyclosporine A; + methotrexate (nu2009=u200919), + methylprednisolone (nu2009=u20092) or + T cell depletion of allograftu2009±u2009methotrexate (nu2009=u20094). Sixteen patients are alive, a median of 2.4u2009years post BMT. Death occurred due to transplant complications (nu2009=u20097) or underlying disease (nu2009=u20093). Eighteen (12u2009LGL, six CLL) of 22 evaluable patients (82%) achieved CR post BMT. Cumulative incidence of refractory/recurrent disease was 18% (95% confidence interval (CI) 7–42%). Overall and event-free survivals were 58% (95% CI 35–75%) and 54% (95% CI 32–72%), respectively. Allogeneic BMT for young patients with advanced LGL or CLL is feasible and can result in long-term disease-free survival. Bone Marrow Transplantation (2000) 25, 605–612.

Treatment of Steroid-Resistant Acute Graft-Versus-Host Disease with Rabbit Antithymocyte Globulin

Acute graft-versus-host disease (A-GVHD) is a life-threatening complication of allogeneic stem cell transplantation (SCT), and primary therapy consists of high-dose corticosteroids. Patients who fail to respond adequately to corticosteroids require salvage treatment, with anti-T cell antibodies being the most commonly utilized group of agents. We report our institutions experience treating steroid-resistant GVHD in 36 adult patients (median age 39 years, range 24-55) with a rabbit antithymocyte globulin product (thymoglobulin). Eleven patients had undergone sibling SCT (10 histocompatible, 1 one-antigen mismatched) and 25 patients had received unrelated donor bone marrow (17 matched, 8 one-antigen mismatched); 32 patients (89%) had grade III or IV A-GVHD. Thymoglobulin was administered in two different regimens; group 1 patients (n = 13) received 2.5 mg/kg/day x 4-6 consecutive days with maintenance of all other immunosuppressives. Group 2 patients (n = 21) were given the same dose of thymoglobulin on days 1, 3, 5, and 7 with discontinuation of cyclosporine for 14 days, during which the corticosteroid dose was held at 2-3 mg/kg/day. Two patients had severe adverse reactions to thymoglobulin (hypoxemia and hypotension) and could not complete treatment, however, in the other patients, aside from transient leukopenia (25%) and and hepatic dysfunction (25%), the antibody preparation was well tolerated. Of the 34 evaluable patients, 13 patients had a complete response (38%) and 7 patients (21%) had a partial response, for an overall response rate of 59%. Response rate was higher in group 1 patients (77%) compared to group 2 patients (48%), (p = 0.15); skin GVHD was more responsive (96% of patients) than gut GVHD (46% of patients) or hepatic GHVD (36% of patients). Opportunistic infections were a significant complication, with 11 patients developing systemic fungal infections and 9 patients serious viral infections; there were seven episodes of bacteremia following thymoglobulin treatment and one fatal protozoal infection. There were 9 patients (25%) who developed post-SCT lymphoproliferative disorder (PTLD) and 4 patients who had a relapse of underlying primary malignancy; none of these patients survived. Of the 36 patients entered on the study, only 2 patients (6%) survive, at 15+ and 34+ months post-unrelated donor SCT. Although thymoglobulin is associated with an impressive response rate when administered for advanced steroid-resistant GVHD, long-term survival is uncommon, even in responders, primarily due to the high risk of developing either an opportunistic infection or a PTLD.

High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

While allogeneic stem cell transplantation (SCT) is curative for a significant number of patients with AML, relapse of disease within the bone marrow and/or extramedullary (EM) sites following high-dose therapy continues to limit the success of this treatment. Between October 1985 and December 1996, 81 adults underwent allogeneic SCT for de novo AML at our centre. Forty-two patients remain alive and free of leukaemia with a median follow-up of 50 months. The 5-year actuarial event-free survivals (EFS) for all patients and for those undergoing SCT in CR1 or with advanced disease were 46% (95% confidence interval (CI) 34–58%), 63% (CI 46–76%), and 19% (CI 7–36%), respectively. Twenty-two patients relapsed at a median of 8 (range 1.6–54.5) months with the actuarial risk of relapse for all, CR1 and advanced disease patients being 38%, (CI 27–52%), 23% (CI 13–40%) and 68% (CI 46–88%), respectively. Ten patients relapsed at EM sites; six of these (27% of relapses) had an isolated EM relapse at a median of 31 (range 8.5–54) months. Three of the patients with isolated EM relapse survived ⩾24 months following relapse and two patients remain disease-free at 29+ and 33+ months. BuCy conditioning followed by allogeneic SCT in AML results in satisfactory EFS although there is a significant risk of late isolated EM relapse.

Allogeneic SCT for relapsed composite and transformed lymphoma using related and unrelated donors: long-term results

Outcome is poor with conventional therapy for relapsed transformed non-Hodgkins lymphoma (NHL). Autologous SCT has been successfully employed; however the impact of allogeneic SCT has not been well defined. We therefore studied 40 consecutive patients who received allogeneic SCT for relapsed composite and transformed NHL (25 transformed, 8 composite (same site) and 7 discordant (different sites)) with related (n=25) and unrelated donors (n=15) to evaluate long-term outcome. Conditioning was myeloablative in the majority (39 of 40). Of 40 patients, 11 survive with median follow-up of 25 months. Death occurred in similar proportions due to relapsed NHL (n=14) or treatment-related complications (transplant-related mortality, TRM; n=15). The cumulative incidence of TRM was 36% at 3 years and disease relapse was 42% at 5 years. Probability of 2- and 5-year event-free survival is 36 and 23% with overall survival 39 and 23%. Performance of SCT within 1 year of NHL diagnosis predicted improved outcome. Relapse and TRM remain significant problems in this setting, indicating the need for strategies whereby patients at high risk of transformation should be selected for early SCT, ideally before their actual transformation.

Quantitation of primitive and lineage-committed progenitors in mobilized peripheral blood for prediction of platelet recovery post autologous transplant.

Leukapheresis collections obtained following one of four mobilization regimens from 90 cancer patients were analyzed for their content of various progenitor cell types including erythroid and granulopoietic colony-forming cells in methylcellulose (total CFC), CFC-megakaryocyte (CFC-Mk), CFC detected after 10, 35 and 56 days in long-term culture (LTC), and total CD34+ cells. The number of each of these progenitor cell types collected from individual patients varied over 1000-fold. Nevertheless, within an individual leukapheresis, there was a significant correlation between the number of CD34+ cells and each progenitor type (except day 56 LTC CFC) suggesting that all of them are mobilized by a common mechanism. Patients who had previously received extensive chemotherapy and/or radiotherapy mobilized fewer of all these cell types than those who had not. For the 65 patients who proceeded to autologous transplantation, the median times to an absolute neutrophil count (ANC) of ⩾0.5u2009×u2009109/l and the last platelet transfusion post transplant were 13 and 11 days, respectively, with 14 (22%) of patients having platelet recovery delayed beyond day 21. There was no significant difference between patients who had or had not received extensive chemo/radiotherapy or among the different mobilization regimens for time to neutrophil or platelet recovery or the number of platelet or red blood cell transfusions received post transplant. Threshold doses of the different cell types transplanted (per kg of patient weight) which predicted rapid platelet recovery were 2u2009×u2009106 CD34+ cells, 5u2009×u2009105 total CFC and 2.5u2009×u2009104CFC-Mk. Corresponding thresholds for progenitor activity measured in LTC could not be established. These results further support the view that standard mobilization regimens yield progenitor numbers that are, in most cases, nonlimiting for generating neutrophil and platelet recoveries within 2 to 3 weeks after myeloablative therapy. Assessment of the CD34+ cell and/or CFC content of leukapheresis collections may identify patients in whom platelet recovery is likely to be significantly delayed although CFC-Mk enumeration does not appear to offer any unique predictive advantage. Bone Marrow Transplantation (2000) 25, 589–598.

Development of a Biologically Distinct EBV-Related Lymphoproliferative Disorder Following Autologous Bone Marrow Transplantation for an EBV-Negative Post-Renal Allograft Burkitt's Lymphoma

Post-transplant lymphoproliferative disorder (PTLD) is a known complication of both solid organ transplantation and allogeneic bone marrow transplantation (BMT) but is rarely seen following autologous BMT. We report the case of a 45 year-old female who developed Burkitts lymphoma eight years after a renal allograft. This PTLD was found to have lambda light chain restriction, contained del(8)(q24) and add(14)(q32), and was negative for EBV on immunohistochemical and DNA-based PCR analyses. Immunoglobulin heavy chain (IgH) PCR studies revealed a prominent clonal rearrangement. She responded to intravenous cyclophosphamide and proceeded to high-dose chemoradiotherapy and mafosfamide-purged autologous BMT. Thirty-nine days post-BMT she presented with cough and fever and developed hepatic dysfunction; abnormal lymphoplasmacytoid cells were noted in the peripheral blood. Investigations revealed kappa light chain restriction, an oligoclonal IgH rearrangement, a normal karyotype and PCR studies for EBV were positive, consistent with a clinically and biologically distinct PTLD. She initially improved following discontinuation of immunosuppression, but then deteriorated abruptly and died 58 days post-BMT. It is likely that the two separate episodes of PTLD in this patient, one of which was atypical, arose as a result of both the chronic use of cyclosporine and the impairment of cell-mediated immunity associated with autologous BMT. The sequence of events in this patient should contribute to a better understanding of late-onset, EB V-negative PTLD.

Phase 1 trial of linifanib (ABT-869) in patients with refractory or relapsed acute myeloid leukemia

Abstract Linifanib, a potent oral inhibitor of fms-like tyrosine kinase 3 (FLT3) and vascular endothelial growth factor receptor tyrosine kinases, has demonstrated promising preclinical single-agent and synergistic anti-leukemic activity in combination with cytarabine. In this phase 1, multicenter, open-label, dose-escalation study, 45 adults with relapsed/refractory acute myeloid leukemia (AML) received linifanib alone in arm A (n =u200929) and linifanib plus intermediate-dose cytarabine in arm B (n =u200916). Median treatment duration was 21 days (range 5–110). Linifanib was well tolerated overall. The most common grade 3/4 events were fatigue (arm A) and febrile neutropenia (arm B). The recommended phase 2 dose was 15 mg (alone), and 10 mg (with cytarabine). Evidence of on-target kinase inhibition in patients with FLT3-mutant and wild-type AML was seen. Decreased phosphorylated FLT3 was seen in 3/3 patients with FLT3-internal tandem duplication (ITD) with peripheral blast reductions and in 8/24 (33%) patients with wild-type, D835 or unknown FLT3 mutation. Eight/29 (28%) patients had decreased phosphorylated extracellular signal-regulated kinase (ERK).