Serum Thymus and Activation-Regulated Chemokine Level Monitoring May Predict Disease Relapse Detected by PET Scan after Reduced-Intensity Allogeneic Stem Cell Transplantation in Patients with Hodgkin Lymphoma

Abstract There are few treatment options for pts with multiply relapsed or refractory lymphoma. Allogeneic stem cell transplantation has historically been limited in this group by high transplant-related mortality (TRM) rates, and evidence for a clinically relevant graft-versus-lymphoma (GvL) effect has been limited. We evaluated reduced-intensity transplantation (RIT) in these pts with the aim of reducing TRM while exploiting the GvL effect. Between 12/00 and 02/05, 31 pts with an HLA-identical sibling were enrolled, 18 with non-Hodgkin (NHL) and 13 with Hodgkin (HL) lymphoma. Main characteristics were: median age = 33 years (range, 17–60); male gender = 20; histology = diffuse large B cell (9), T-cell anaplastic large cell (2), transformed-large cell (2), mantle cell, lymphoplasmacytic, T-peripheral, diffuse mixed large and small cell (1 each), and Hodgkin lymphoma (13). At study entry, 19 pts (36% NHL, 92% HL) had previously failed autologous transplantation (AT) and even patients who had not received high-dose chemotherapy had failed a median of 4+ lines of therapy. Five patients were in partial remission, 2 in untreated relapse post-AT and 24 had chemorefractory disease. Conditioning consisted of fludarabine (25 mg/m2 x 5 d) and cyclophosphamide (60 mg/kg x 2 d). Twenty nine pts received peripheral blood and 2 received marrow stem cells. GVHD prophylaxis comprised cyclosporin and mini-methotrexate. Early death occurred in 3 pts from aspergillosis, pulmonary fibrosis and cardiac failure. All other patients engrafted, 1 with a progressively autologous pattern of chimerism. The overall incidende of grades II, III and IV acute GVHD was 50%, 10% and 7%, respectively. Chronic extensive GVHD occurred in 7/23 (30%) of evaluable pts. Eight pts (25%) died of progressive disease and 9 (29%) of non-relapse causes at a median of 2.5 (range, 1–12) months. Median overall and disease-free survival for all pts is 15.3 months and 7.9 months, respectively. Differences in overall and disease-free survival were not statistically significant between pts with NHL and HL (15.3 vs 25.2 months, p = 0.7; 5.9 vs 8.1, p = 0.44; respectively). Seven pts remain alive and disease-free (HL = 2/13 [15%]; NHL = 5/18 [27%]; p = 0.66) at median follow-up of 33.7 (range, 13.2 – 54.5) months. Allogeneic RIT is a reasonable therapeutic alternative for pts with relapsed NHL or HL, even those who have relapsed after AT. Mortality rates were acceptable for this heavily pretreated group of patients.

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Allogeneic Stem Cell Transplantation Conditioning for MDS and AML with Clofarabine, Cytarabine and ATG

Blood ◽

10.1182/blood.v112.11.4427.4427 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4427-4427

Author(s):

Michael G. Martin ◽

Geoffrey L. Uy ◽

Elizabeth Procknow ◽

Keith Stockerl-Goldstein ◽

Amanda F. Cashen ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Median Duration ◽

Allogeneic Stem Cell Transplantation ◽

Morbidity And Mortality ◽

Disease Relapse ◽

Grade 3 ◽

Reduced Intensity

Abstract Myeloablative allogeneic stem cell transplantation, though, potentially curative for patients with MDS and AML, is limited by its associated morbidity and mortality. Reduced-intensity conditioning (RIC) regimens attempt to diminish the morbidity and mortality of the conditioning regimen but are associated with a higher risk of disease relapse. Given the evidence of activity of the combination of clofarabine and cytarabine in MDS/AML, we explored a novel RIC regimen in patients with MDS/AML in complete remission with the intention to capitalize on the benefits of a RIC regimen while potentially decreasing the risk of relapse. Patients received clofarabine 40mg/m2 IV days -6 thru -2, cytarabine 1gm/m2 IV days -6 thru -2 and ATG 1mg/kg on day -4 and 2.5mg/kg x2 days on Days -3 and -2. All patients also received GVHD prophylaxis with methotrexate and tacrolimus as well as herpes simplex, PCP and fungal prophylaxis. Seven of a planned 20 patients were enrolled. The median age was 54 years (range= 24 – 68). 3 of 7 patients had MDS (WHO classifications RAEB, RAEB-2 and RCMD-RS; all 3 had received 3 cycles of decitabine and achieved stable disease prior to transplant) and 4 patients had AML (FAB classifications M1, M0, M5b and M1; 3 were in CR1 after standard induction and up to 2 cycles of consolidation and 1 was in CR3 and had received a prior allogeneic transplantation). Source of stem cells was matched unrelated donors in 4 patients and matched sibling donors in 3 patients. All patients received G-CSF mobilized peripheral blood CD34+ cells. Median number of CD34+ stem cells infused was 5.75×106 cells (range = 2.2 ×106 – 11.35 ×106 cells/kg). The median duration of neutropenia (ANC<500) was 14 days (range = 12 – 16) with 2 patients expiring before ANC recovery. The median duration of thrombocytopenia (Plts<50,000) was 22 days (range = 10 – 33) with 3 patients expiring before platelet recovery. 43% (3/7) of patients had grade 3/4 anemia; 71% (5/7) of patients had grade 3/4 neutropenia and 57% (4/7) of patients had grade 3/4 thrombocytopenia. All patients experienced neutropenic fevers. 86% (6/7) of patients had a documented infection (1 with CMV, 1 with C. difficile colitis and 4 with bacteremia). Other toxicities included grade 2 hand-foot syndrome (57%), grade 3 dyspnea (71%), diarrhea (all grade 100%; 29% grade 3), mucositis (all grade 100%), elevated ALT (all grade 100%; 57% grade 3), elevated AST (all grade 100%; 86% grade 3), and hyperbilirubinemia (all grade 86%; 29% grade 3–5). No acute GVHD was observed. However, enrollment to the trial was halted after 3 of the first 7 patients (1 with MDS and 2 with AML) expired on days +15, +26 and +32. Cause of death was sepsis in 2 patients and VOD in 1 patient. The patient who died of VOD had no history of liver disease and had not previously received gemtuzumab but had been on prolonged azole therapy for an invasive fungal infection. Day +40–60 chimerism studies on the 4 evaluable patients showed 60% (PB), 100% (PB), 70% (BM) and 75% (BM) donor chimerism. Follow-up studies at day +80–90 showed a decline in donor chimerism in three patients from 60% to 0%; 70% to 33%; 75% to 67%. The patient with 100% donor has maintained full engraftment. Overt disease relapse has not occurred in any patients. CONCLUSION: This regimen of clofarabine/cytarabine/ATG was not sufficiently immunosuppressive to ensure engraftment and was associated with substantial morbidity and mortality. Other transplant regimens, both reduced intensity and myeloablative, incorporating clofarabine are currently being investigated.

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