Blood Stem Cell Transplantation Research Articles

Concise Review: Sowing the Seeds of a Fruitful Harvest: Hematopoietic Stem Cell Mobilization

Abstract Hematopoietic stem cell transplantation is the only curative option for a number of malignant and nonmalignant diseases. As the use of hematopoietic transplant has expanded, so too has the source of stem and progenitor cells. The predominate source of stem and progenitors today, particularly in settings of autologous transplantation, is mobilized peripheral blood. This review will highlight the historical advances which led to the widespread use of peripheral blood stem cells for transplantation, with a look toward future enhancements to mobilization strategies. Stem Cells 2013;31:2599–2606

Impact of Macrophage Activation on Delayed Engraftment Following Allogeneic Hematopoietic Stem Cell Transplantation: Mac Ratio, a New Predictive Index

Introduction Delayed engraftment and subsequent engraftment failure cause fatal complications including severe infection and lead to poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-SCT). We have previously reported that hemophagocytic syndrome (HPS) induced by uncontrolled macrophage activation in bone marrow had high mortality due to engraftment failure (BMT.2012;47:387–394). Macrophages are phagocytic cells with abilities of phagocytosis, antigen-presenting, and secretion of cytokines. Although phagocytosis reflects only a part of their activation, their morphological changes or increased cell counts can be used for evaluating their activation. Our hypothesis was that macrophage activation would have intrinsic value whether it would meet diagnostic criteria for HPS or not. In this study, we analyzed the clinical impact of activated macrophages in bone marrow during the peri-enrgaftment period in patients with delayed engraftment and engraftment failure. Patients and Methods We retrospectively reviewed 212 adult patients who received a first allo-SCT for hematological diseases from January 2006 to December 2011 in our institution. Delayed engraftment was defined that neutrophil engraftment was achieved later than day 15, 20 and 27 post peripheral blood stem cell, bone marrow and cord blood transplantation, respectively, whereas engraftment failure was defined that engraftment was never observed including those who received second allo-SCT. Bone marrow clot sections of day 14±7 and day 28±7 post allo-SCT were analyzed by staining macrophages with anti-CD163 monoclonal antibody. CD163 is a member of the scavenger receptor cystein-rich superfamily and is an exclusive marker for macrophages, playing a major role in the scavenging components of damaged cells. Recently macrophages with an unrestrained proinflammatory activation state along with highly expressed CD163 were reported (JCI.2011;121:985–97). Therefore, the total number of CD163 positive-macrophages was counted in three fields at a 200-fold magnification. We calculated the ratio of macrophages (mac ratio), dividing the number of macrophages by the total cell counts per field. Total area of CD163 positive-macrophages was measured with a digital microscope (BZ-9000, Keyence, Japan). The size of a macrophage was estimated total area of CD163+/ number of CD163 positive-macrophages. Results Delayed engraftment and engraftment failure were observed in 17 (8.0%) and 7 (3.3%) out of 212 patients, respectively. Median mac ratio of day 14 marrow was 0.09 (0.03-0.28), 0.54 (0.15-0.82) and 0.57 (0.46-0.65), whereas that of day 28 marrow was 0.05 (0.02-0.08), 0.25 (0.14-0.70) and 0.53 (0.33-0.82) in normal engraftment, delayed engraftment and engraftment failure groups, respectively. Both delayed engraftment and engraftment failure groups had significantly higher mac ratio in both day 14 and 28 than normal engraftment group (p=0.0002, 0.002 at day 14, p=0.0000, 0.0004 at day 28, respectively). Between delayed engraftment and engraftment failure groups, mac ratio was significantly higher in engraftment failure group in day 28 marrow (p=0.04), while no difference was observed in day 14 marrow (p=0.64). Higher mac ratio than 0.5 could predict delayed engraftment or engraftment failure in day14 marrow (p=0.002), and engraftment failure in day 28 marrow (p=0.000). Only 1 patient of 7 engraftment failure patients (14%) met the criteria of HPS, while mac ratio of 5 patients (71%) was >0.5 at day14. The size of macrophages at day 14 was significantly larger in delayed engraftment and engraftment failure groups than normal engraftment group (p=0.03; 1682.2 μm2 in engraftment failure, 1537.1 μm2 in delayed engraftment and 1054.3 μm2 in normal engraftment, respectively), which indicated the activation of macrophages. Conclusion Increased number of activated macrophages in bone marrow during the peri-engraftment period post allo-SCT was associated with subsequent delayed engraftment and engraftment failure. Our data also suggest that delayed engraftment and engraftment failure could be predicted by the mac ratio of day 14 and 28 marrow, which could be more sensitive marker than the criteria of HPS. This study suggests rationale for macrophage-targeted therapy among patients with the proliferation of activated macrophages in their bone marrow to prevent engraftment failure. Disclosures: No relevant conflicts of interest to declare.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Brentuximab vedotin (SGN-35) in Hodgkin lymphoma patients with relapsed after autologous peripheral blood stem-cell transplantation

Background: Approximately 15 to 30% of patients with Hodgkin's lymphoma (HL) do not have a long-term remission with conventional therapy. Autologous peripheral blood stem-cell transplantation (APBSCT) represents a potentially curative treatment for some patients with recurrent or progressive HL after failure of initial combination chemotherapy. Unfortunately, APBSCT is only effective in approximately 50% of such patients. Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a plasma-stable linker to the potential microtubule agent, monomethyl auristatin.

Multidisciplinary Collaborative Therapy for 30 Children with Orbital Rhabdomyosarcoma

To explore clinical experience and propose new ideas for treating children diagnosed with orbital rhabdomyosarcoma (RMS). We retrospectively analyzed the clinical data for30 patients (16 males and 14 females, with a median age of 6.2 years) with primary orbital RMS who were enrolled in the Department of Eye Oncology and Pediatrics of our hospital from November 2004 to December 2012. International Rhabdomyosarcoma Organization Staging Standards indicated that among the 30 patients, 4 cases were in phase II, 20 were in phase III, and 6 were in phase IV. All patients underwent a multidisciplinary collaborative model of comprehensive treatment (surgery, chemotherapy, external radiotherapy, 125I radioactive particle implantation, and autologous peripheral blood stem-cell transplantation). Follow-up was conducted until March 2013, with a median follow-up time of 47.2 months (5 to 95 months), and 7 deaths occurred. The 2-year estimated survival rate reached 86.1%, the ≥3-year estimated survival rate was 77%, and the 5-year estimated survival rate was 70.6%. The multidisciplinary collaborative model can be a safe and effective approach to the comprehensive treatment of children with orbital RMS. It has clinical significance in improving the tumor remission rate.

Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial

Myeloablative chemoradiotherapy and immunomagnetically purged autologous bone marrow transplantation has been shown to improve outcome for patients with high-risk neuroblastoma. Currently, peripheral blood stem cells (PBSC) are infused after myeloablative therapy, but the effect of purging is unknown. We did a randomised study of tumour-selective PBSC purging in stem-cell transplantation for patients with high-risk neuroblastoma. Between March 16, 2001, and Feb 24, 2006, children and young adults (<30 years) with high-risk neuroblastoma were randomly assigned at diagnosis by a web-based system (in a 1:1 ratio) to receive either non-purged or immunomagnetically purged PBSC. Randomisation was done in blocks stratified by International Neuroblastoma Staging System stage, age, MYCN status, and International Neuroblastoma Pathology classification. Patients and treating physicians were not masked to treatment assignment. All patients were treated with six cycles of induction chemotherapy, myeloablative consolidation, and radiation therapy to the primary tumour site plus meta-iodobenzylguanidine avid metastases present before myeloablative therapy, followed by oral isotretinoin. PBSC collection was done after two induction cycles. For purging, PBSC were mixed with carbonyl iron and phagocytic cells removed with samarium cobalt magnets. Remaining cells were mixed with immunomagnetic beads prepared with five monoclonal antibodies targeting neuroblastoma cell surface antigens and attached cells were removed using samarium cobalt magnets. Patients underwent autologous stem-cell transplantation with PBSC as randomly assigned after six cycles of induction therapy. The primary endpoint was event-free survival and was analysed by intention-to-treat. The trial is registered with ClinicalTrials.gov, number NCT00004188. 495 patients were enrolled, of whom 486 were randomly assigned to treatment: 243 patients to receive non-purged PBSC and 243 to received purged PBSC. PBSC were collected from 229 patients from the purged group and 236 patients from the non-purged group, and 180 patients from the purged group and 192 from the non-purged group received transplant. 5-year event-free survival was 40% (95% CI 33-46) in the purged group versus 36% (30-42) in the non-purged group (p=0·77); 5-year overall survival was 50% (95% CI 43-56) in the purged group compared with 51% (44-57) in the non-purged group (p=0·81). Toxic deaths occurred in 15 patients during induction (eight in the purged group and seven in the non-purged group) and 12 during consolidation (eight in the purged group and four in the non-purged group). The most common adverse event reported was grade 3 or worse stomatitis during both induction (87 of 242 patients in the purged group and 93 of 243 patients in the non-purged group) and consolidation (131 of 177 in the purged group vs 145 of 191 in the non-purged group). Serious adverse events during induction were grade 3 or higher decreased cardiac function (four of 242 in the purged group and five of 243 in the non-purged group) and elevated creatinine (five of 242 in the purged group and six of 243 non-purged group) and during consolidation were sinusoidal obstructive syndrome (12 of 177 in the purged group and 17 of 191 in the non-purged group), acute vascular leak (11 of 177 in the purged group and nine of 191 in the non-purged group), and decreased cardiac function (one of 177 in the purged group and four of 191 in the non-purged group). Immunomagnetic purging of PBSC for autologous stem-cell transplantation did not improve outcome, perhaps because of incomplete purging or residual tumour in patients. Non-purged PBSC are acceptable for support of myeloablative therapy of high-risk neuroblastoma.

Infection profile in patients developing febrile neutropenia after high-dose chemotherapy and stem cell transplantation.

e18016 Background: Febril neutropenia is absorved in all patients after stem cell transplantation (SCT) antibiotic and antifungal prophlaxis is recommended to patients after the transplantation. The aim of this study was to evaluate the infection agents in patients developing febrile neutropenia after high dose chemotherapy (HDC) and SCT. Methods: Patients who underwent HDC and auto- and allogenic SCT between 2003-2012 in the GATA medical oncology department were investigated for infection agents. After the development of fever in the neutropenic period of SCT blood and urine cultures were taken and antibiotics was started. Data of 278 patients were reached who were eligible for evaluation. Of these 67 patients cultural examination were positive. 8 allogeneic SCT, 59 autologous SCT patients consisted of NHL (n=20), testicular cancer (n=11), multiple myeloma (n=10), Hodgkin Lymphoma (n=9), AML (n=4), ALL (n=2) and other diognosis (n=11). Results: When the agents identified according to standart blood culture examinations 44.5 % were coagulase neg. staph, 24% were gram neg. bacils and 15% consisted of candidas. When the results of urine culture was observed: 66.8% were gram neg. bacils, 11.1% were coagulase neg. Staph and 5.5% consisted of candidas. Gram neg. bacilli growth was present in 80% of the blood cultures of Hodgkin’s Lymphoma patients and coagulase neg. Staph growth were observed in 20% of the patients. Coagulase neg. Staph consisted 66.8% of the catheter culture results, 13.2% consisted of Acinetobacter beumonii and 6.6% consisted of enterococci. Conclusions: Physicians who are working in SCT area should be aware of different kind of infections, which is reported in this study. [Table: see text]

Effects of platelet concentrate storage time reduction in patients after blood stem cell transplantation

To evaluate the clinical effect of platelet concentrate (PC) transfusions after PC storage time reduction to 4days. This was a single-centre cohort study comparing two 3-month periods of time, before and after the reduction of PC storage time from 5 to 4days. Seventy-seven consecutive patients with PC transfusions were enrolled after blood stem cell transplantation. Corrected platelet count increment (CCI) on the morning after transfusion, time to next platelet transfusion, need for red blood cell (RBC) transfusion and clinical bleeding symptoms were compared. Platelet concentrate storage time was reduced between period 1 (storage for up to 5days, median storage time 78h, range 11-136h) and period 2 (storage for up to 4days, median storage time 53h, range 11-112h). Patients were comparable for age, weight, body surface area, underlying disorder, type of transplantation and transfused platelet dose. The CCI increased from a median of 4 (range 0-20) to 8 (0-68)×10(9) /l per 10(11) platelets/m(2) (P<0·0001). Time to next PC transfusion increased from 1·1 to 2·0days (P<0·0001). Any bleeding symptom was noted in 20 of 36 patients (56%) vs. 9/41 patients (22%, P<0·01). Nose bleeds, haematuria and bleeding at more than one site were significantly reduced. Frequency of RBC transfusion within 5days after PC transfusion was reduced from 74 to 58% (P<0·0001). Platelet concentrate storage time shortening was associated with highly significant CCI increase, reduced RC needs and lower patient numbers with bleeding events.

Total Lymphoid Irradiation and High-Dose Chemotherapy with Autologous Blood Stem-Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma: Excellent Disease Control and Long-Term Survival Rates

AbstractAbstract 2024 Background:For patients with relapsed or refractory HL, salvage chemotherapy followed by aHSCT is the standard of care. Our group previously reported excellent clinical outcomes with accelerated hyperfractionated TLI followed by high-dose chemotherapy and aHSCT (Ann of Oncol. 16:679, 2007). This strategy has been adopted as the standard at our institution for eligible individuals and we now report long-term outcomes of patients previously reported on the phase I/II clinical trial in addition to those who were subsequently treated as standard of care. Patients and methods:Patients with biopsy confirmed relapsed/refractory classical HL who previously received no more than 20 Gy were eligible. Salvage chemotherapy was chosen by the patient’s treating physician. All patients received accelerated hyperfractionated TLI prior to transplantation administered twice daily at 150 cGy, five days/week for 10 days. The morning dose was delivered to all nodal sites including the spleen, and the afternoon dose was delivered to all sites of previous and current disease. The goal was to treat uninvolved nodal sites and spleen to 1500 cGy and sites of current and previous disease to 3000 cGy. Conditioning chemotherapy consisted of high-dose carboplatin, cyclophosphamide, and etoposide. All patients received carboplatin 450 mg/m2 by continuous intravenous infusion (CIV) on days –6 to –4 (total dose = 1350 mg/m2) and cyclophosphamide 60 mg/kg/day over 1 h on days –3 and –2 (total dose = 120 mg/kg). Patients on the phase I portion of the trial received escalating doses of etoposide by CIV from days –6 to –4. Initial dosing levels were 400 mg/m2/day, 450 mg/m2/day, 500 mg/m2/day, 600 mg/m2/day and 700 mg/m2/day. Those treated on the phase II portion of the clinical trial or subsequent to the closing of the trial were treated with etoposide 700 mg/m2/day for a total of 2100 mg/m2. Results:52 patients with relapsed/refractory HL at Northwestern University were treated with TLI and aHSCT from 1993 to January 2011. One patient was lost to follow-up immediately post-transplant. 51 patients were included in this analysis and had a median follow-up of 47 months (range: 0.07–204 months). Thirty patients were treated on a previously reported prospective phase I/II clinical trial. Most patients had nodular sclerosis histology (n=39, 76%) and more than half had primary induction failure (PIF; n=29). Among patients who achieved a CR with induction, 62% relapsed within one year. The most common salvage regimens were ESHAP and ICE chemotherapy and most had received two lines of chemotherapy prior to aHSCT. Only 21 patients (41%) achieved a complete response (CR) with salvage therapy and in most cases (n=31, 61%), response was determined by functional imaging prior to aHSCT. The 10-year PFS and OS for all patients were 56% and 54%, respectively. Ten-year PFS and OS for patients with PIF was 53%, compared with 63% and 59%, respectively, for those with relapsed disease (p=0.13 and p=0.20, respectively). Patients who had incomplete responses to salvage therapy had a 10-year PFS and OS of 41% and 39%, respectively, compared to 76% and 81%, respectively, for those who achieved a CR (p=0.1 and p=0.056, respectively). Treatment-related mortality within the first 100 days was observed in one patient. Five patients (10%) developed secondary malignancies; three developed MDS (one who had received MOPP induction died with MDS; one had relapsed HL post-aHSCT and died of AML and one is alive with MDS 3+ yrs post-diagnosis). There was one case each of T-cell lymphoma (7 months post-aHSCT) and melanoma. Conclusions:Sequential TLI/chemotherapy conditioning for relapsed/refractory HL for patients with limited or no prior radiotherapy continues to be associated with excellent disease control and long-term survival rates including high-risk populations such as PIF and chemotherapy-resistant disease. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Passenger lymphocyte syndrome with hemophagocytic syndrome after peripheral blood stem-cell transplantation from an HLA-matched full biological sibling: Case report

Massive hemolysis due to passenger lymphocyte syndrome (PLS) is rare after peripheral blood stem-cell (PBSC) transplantation with a minor ABO mismatch. We present, in a 16-year-old boy (group A Rh+), PLS with hemophagocytic syndrome (HPS) after PBSC transplantation from his HLA (human leukocyte antigens)-matched biological sister (group O Rh+). Mild-to-moderate hemolysis was evident from day +11 to day +15 after transplantation. HPS was diagnosed by bone marrow examination on day +16, while antibodies against the recipient’s red blood cell antigens were detected on days +15 and +27. This hemolysis may have been due to PLS with HPS. Therefore, measurement of antibodies may provide a useful hallmark of immune hemolysis.

Long-term follow-up of high-dose chemotherapy with autologous stem-cell transplantation and response-adapted whole-brain radiotherapy for newly diagnosed primary CNS lymphoma: results of the multicenter Ostdeutsche Studiengruppe Hämatologie und Onkologie OSHO-53 phase II study

We previously reported the results of a phase II study for patients with newly diagnosed primary central nervous system lymphoma treated with autologous peripheral blood stem-cell transplantation (aPBSCT) and response-adapted whole-brain radiotherapy (WBRT). Now, we update the initial results. From 1999 to 2004, 23 patients received high-dose methotrexate. In case of at least partial remission, high-dose busulfan/thiotepa (HD-BuTT) followed by aPBSCT was carried out. Patients refractory to induction or without complete remission after HD-BuTT received WBRT. Eight patients still alive in 2011 were contacted and Mini-Mental State Examination (MMSE) and the European Organisation for Research and Treatment of Cancer quality-of-life questionnaire (QLQ)-C30 were carried out. Of eight patients still alive, median follow-up is 116.9 months. Only one of nine irradiated patients is still alive with a severe neurologic deficit. In seven of eight patients treated with HD-BuTT, health condition and quality of life are excellent. MMSE and QLQ-C30 showed remarkably good results in patients who did not receive WBRT. All of them have a Karnofsky score of 90%-100%. Follow-up shows an overall survival of 35%. In six of seven patients where WBRT could be avoided, no long-term neurotoxicity has been observed and all patients have an excellent quality of life.

Efficacy of lenalidomide plus dexamethasone for POEMS syndrome relapsed after autologous peripheral stem‐cell transplantation

POEMS syndrome is a rare paraneoplastic condition associated to an underlying plasmacellular dyscrasia. The pathogenesis of POEMS is poorly understood, but overproduction of VEGF, probably secreted by clonal plasma cells, is thought to be responsible for the signs and symptoms of the syndrome, and it seems to be useful for the monitoring of the response to therapy. At present, an effective therapeutic option for the patients is represented by autologous peripheral blood stem-cell transplantation (aPBSCT), although relapses have been described, and there is an important morbidity associated with this procedure. Before the implementation of aPBSCT, the clinical course of POEMS syndrome was characterized by progressive polyneuropathy potentially leading to death for respiratory failure. Given the high serum and plasma levels of VEGF observed in POEMS patients, the use of anti-angiogenetic drugs such as thalidomide and lenalidomide and other drugs with anti-VEGF and anti-TNF effect such as bortezomib have been considered to treat this syndrome. There are evidences of lenalidomide benefit in both front-line and previously treated patients, but scanty data are available about its use for relapse after aPBSCT. Here, we report the successful use of lenalidomide in a patient who relapsed after aPBSCT.

Karpaltunnelsyndrom bei Kindern mit Mukopolysaccharidose Typ 1H. Diagnostik und Therapie im Rahmen eines interdisziplinären Zentrums

Carpal tunnel syndrome is common in children with mucopolysaccharidosis type 1H (MPS type 1H). Clinical signs of carpal tunnel syndrome are frequently absent in these children and it is often very difficult to perform and interpret neurophysiological investigations. In this article we wish to present our experience and results regarding the diagnosis and postoperative results after decompression of the median nerve.In an interdisciplinary set-up we are currently treating 11 MPS type 1H children following blood stem cell transplantation. 7 patients were operated 12 times (5 bilateral operations) because of a carpal tunnel syndrome (age at the time of operation 83,3 months, (43-143 months), 2 male, 5 female). 6 patients had a follow up after 23,7 months (9-59 months). 6 patients had a histological analysis of the flexor retinaculum. Three patients had a postoperative neurophysiological investigation.Each of the operated patients had at least 1 preoperative clinical sign of a carpal tunnel syndrome. We found at least 1 pathological finding in motor and sensory nerve conduction studies in each patient. 6 of the 7 children operated on were symptom-free at postoperative follow-up. 1 of the 3 patients with a postoperative neurophysiological follow up showed a deterioration of the nerve conduction studies. This patient was free of symptoms postoperatively. Biopsy of the flexor retinaculum confirmed abundant proteoglycan deposition. We had neither postoperative complications nor were revisional operations necessary.The Diagnosis of a carpal tunnel syndrome in children with MPS Typ 1H needs a thorough medical history, the correct interpretation of the clinical symptoms and sophisticated nerve conduction studies. Wether the improvement of the postoperative clinical situation lasts has to be evaluated in a long term investigation especially because in one patient in our group we saw a deterioration of the nerve conduction studies postoperatively.

Everolimus Associated with Activated Vitamin D for Post-Transplant Increase Epstein-Barr-Virus Load Treatment. Two Case Reports

Post-transplant lymphoproliferative disease (PTLD) is an uncommon but life-threatening complication of solid-organ and blood stem-cell transplants. It is caused by an uncontrolled expansion of B lymphocytes infected with Epstein-Barr virus (EBV). It responds poorly to therapy, including reduction of immunosuppression, interferon, antivirals or chemotherapy. Therefore the optimal strategy for management is currently focused on prevention. Some centers have already introduced chemoprophylaxis and/or preemptive strategies using EBV viral load as a surveillance. Some experimental studies suggest that mTOR inhibitors inhibits growth of human EBV-transformed B lymphocytes and vitamin D had an immune response to EBV. We report two cases of an increased of blood BKV viral load after renal transplantation that were successfully treated with everolimus in association with calcitriol. This report suggests that everolimus associated with calcitriol could be an effective and safe treatment for the prevention of PTLD in transplant recipients.

Interstitial pneumonitis associated with the immunomodulatory drugs thalidomide and lenalidomide

The immunomodulatory drugs (IMiDs), thalidomide andlenalidomide, and the proteasome inhibitor bortezomibhave recently been indicated for multiple myeloma treat-ment. Although pulmonary complications associated withbortezomib are widely known [1], those of IMiDs arethought to be rare. We present a multiple myeloma patienttreated with bortezomib, who subsequently developedinterstitial pneumonitis (IP) after treatments with boththalidomide and lenalidomide.A 51-year-old Japanese man was diagnosed with multi-ple myeloma (IgG-lambda type), Durie–Salmon stage IIand International Staging System stage II in 2005. Afterinduction therapy with vincristine, doxorubicin, and dexa-methasone (VAD, 3 courses), he underwent tandem auto-logous peripheral blood stem-cell transplantation andachieved complete remission. However, in April 2008, herelapsed with complaints of rib pain and hypercalcemia.The recurrent multiple myeloma was a more immature non-secretory type. We immediately administered bortezomiband dexamethasone (two courses), but without effect. We,therefore, started thalidomide (100 mg, daily) in August2009. This therapy achieved immediate symptom relief anda 5-month remission. In February 2010, he experienceddyspnea and dry cough, and visited our clinic. On admis-sion, his temperature was 36.6 C, oxygen saturation (pulse-oximetry, room air) 86%. Laboratory work-up showed awhite blood cell (WBC) count of 3.2 9 10

Allogeneic Hematopoietic Peripheral Blood Stem-Cell Transplantation From HLA-Identical Siblings Versus Allelic-Matched Unrelated Donors (10/10 high resolution) in Patients with Acute Myeloid Leukemia and Myelodyplasic Syndrome After Reduced Intensity Conditioning,

Abstract 4132 Introduction:Although precise matching of the donor/recipient pairs has been made easier by HLA typing at the allelic level, several issues with respect to unrelated transplantation remain to be addressed. In particular, the impacts of allelic HLA matching in patients with Acute Myeloid Leukemia (AML) and myelodysplasic syndrome (MDS) who receive allogeneic Peripheral Blood Stem cells (PBSC) after a reduced intensity conditioning (RIC) regimen is still unclear. In the present study, we aim to compare the impact of the donor type in this setting: HLA identical sibling versus HLA matched 10/10 (high resolution) unrelated donor (MUD). Method and transplantation characteristics:From 01/2001 to 12/2010, 108 consecutive patients with AML (n=63) and MDS (n=45) received PBSC after RIC in our center, either from HLA identical sibling (n=69) or MUD (n=39). Conditioning regimen was fludarabine based in 95% of patients and GvHD prophylaxis consisted in cyclosporine plus mycophenolate in 79% of patients. Engraftment, acute and chronic graft-versus-host disease (GvHD), transplantation-related mortality (TRM), relapse rate and overall survival (OS) at 3 years were compared according to type of donor: HLA identical sibling donor and MUD. Disease characteristics:WHO classification for MDS at time of hematopoietic stem cell transplantation (HSCT) was RAEB1 (24%), RAEB2 (36%), MDS transformed into secondary AML (20%), CMML2 (9%), RA (4%), or other (7%). Disease risk was assumed by cytogenetic (MRC for AML, IPSS for MDS) and EBMT score (good risk: CR1 for AML or MDS or untreated MDS, intermediate risk: CR2 for AML, CR2 or partial remission for MDS, poor risk: all other status). Cytogenetic (no missing data) was poor, intermediate or good for 21, 74 and 5% of AML and 24, 36 and 40% of MDS, respectively. EBMT score at time of HSCT was poor, intermediate or good for 29, 7, 64% of MDS and 11, 21, 68% of AML, respectively. Results of the comparison:Patients characteristics according to type of donor were similar for age (median 57 years), gender and disease distribution. Particularly, disease risks were comparable in 2 groups. Conversely, conditioning regimen (more ATG in MUD: 69 vs. 43%, p=0.016), donor age (younger for MUD: 30 vs. 52 years, p<0.0001) and number of CD34+ cells infused (higher in MUD: 7 vs. 6.5 × 106/kg, p=0.022) were different. The median follow-up was 36 months (range 2 to 72). All patients engrafted. The cumulative incidence of acute GvHD was 40% with HLA matched sibling donor and 44% for MUD (p=0.58). The cumulative incidence of chronic GvHD at 3 years was 49% with HLA matched sibling donor and 45% with MUD (p=0.66). No risk factor was associated with acute GvHD but chronic GvHD was less frequent in patients with AML vs. MDS (41% vs. 59%, p=0.077) and in those patients who received ATG in conditioning regimen (54% vs. 43%, p=0.067). During follow-up, 47 patients died. The 3-year cumulative incidence of TRM was 17% and 22% with HLA matched sibling donor and MUD, respectively (p=0.55). Adjusting for age, MDS was the only factor increasing TRM (HR 3.4; 95% CI 1.2 to 9.5; p=0.02). The 3-year cumulative incidence of relapse was 46% with HLA matched sibling donor and 30% with MUD (p=0.28) knowing that there was no difference between both groups regarding disease risk (cytogenetic and EBMT score). The 3-year OS was 44% with HLA matched sibling donor (95%CI: 33–61) and 50% with MUD (95%CI: 35–71) (Figure 1). [Display omitted] Disclosures:Fenaux:Celgene: Honoraria, Research Funding. Peffault de Latour:Alexion: Consultancy, Research Funding.

The treatment of chronic graft-versus-host disease: consensus recommendations of experts from Germany, Austria, and Switzerland.

Chronic graft-versus-host disease (cGVHD) is the commonest complication of allogeneic bone marrow and blood stem-cell transplantation, occurring in 50% of all cases and causing late mortality in as many as 25%. There are now about 10 000 patients with cGVHD in Germany, and their number is growing by about 500 each year. cGVHD is a chronic multisystem disease due to impaired tolerance mechanisms. It affects many organs in variable ways, impairing organ function and lowering quality of life. We present consensus recommendations on the treatment of cGVHD that were developed jointly by the German Working Group on Bone Marrow and Blood Stem-Cell Transplantation, the German and Austrian Societies of Hematology and Oncology, the Swiss Blood Stem-Cell Transplantation Group, and the German-Austrian Working Group on Pediatric Stem-Cell Transplantation. All of the recommendations are based on an evaluation of selected publications. Recommendations are given regarding the diagnostic evaluation of cGVHD, first-line treatment (which has a response rate of 30% to 50%), second-line treatment, and topical immunosuppression. Patients with cGVHD should also receive supportive care including anti-infective prophylaxis, vaccinations, hormone replacement, prevention and treatment of osteoporosis, physiotherapy, rehabilitation, and psychosocial assistance. Patients with cGVHD need multidisciplinary care under the guidance of the transplantation center. The aim of these recommendations is to standardize the treatment of cGVHD and thereby improve patient care.

Radiation Bone Marrow Stromal Injury Affects Stem Cell Engraftment in Patients Undergoing Peripheral Blood Stem Cell (PBSC) Transplantation

Radiation Bone Marrow Stromal Injury Affects Stem Cell Engraftment in Patients Undergoing Peripheral Blood Stem Cell (PBSC) Transplantation

A composite small lymphocytic lymphoma and Hodgkin transformation presenting as acute appendicitis

Dear Editor, Richter's transformation occurs in 2–8% of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and usually involves transformation to diffuse large B-cell lymphoma (DLBCL) or rarely (0.4% of cases) Hodgkin lymphoma [1]. Both transformations may involve nodal or extranodal sites and both could locate in separate or in the same tissue (composite lymphoma). Molecular and immunophenotypic evidence indicates that the transformed cells usually, but not always, derive from the same clone as the original CLL/SLL [1, 2]. The vermiform appendix, naturally rich in gut-associated lymphatic tissue, is often involved in patients with nonHodgkin lymphoma. However, there have been only 13 cases of classical Hodgkin lymphoma and 1 of nodular lymphocyte-predominant Hodgkin lymphoma reported in the appendix [3–5]. To our knowledge, a composite CLL/ SLL with Hodgkin transformation heralded by acute appendicitis has not been reported. Here, we document this rare case below. A 64-year-old woman presented to our facility with bilateral axillary adenopathy and splenomegaly and was subsequently diagnosed with CLL/SLL. Sixteen months after this initial diagnosis, she presented with acute appendicitis. The appendectomy specimen showed acute serositis associated with two zonal atypical lymphoid infiltrates composed of: (1) a monotonous population of small, mature lymphoid cells with clumped nuclei and scant cytoplasm that expanded the lamina propria (Fig. 1a 1 and 2) and (2) multiple nodular proliferations consisting of numerous Reed-Sternberg (RS)like cells or Hodgkin cell variants in a matrix of polymorphous inflammatory cells, including predominantly histiocytes, small lymphocytes, and few granulocytes throughout the wall of the appendix (Fig. 1c 1 and 2). Immunohistochemical stains and in situ hybridization demonstrated two distinct phenotypic features: (1) PAX5+/CD5+/ CD23+/cyclin D1-neoplastic B cells, compatible with SLL (Fig. 1b 1 and 2) and (2) CD30+/CD15+/CD45-/ EBER+atypical large cells, compatible with classical Hodgkin lymphoma (Fig. 1d 1 and 2). Immunostains also confirmed that the small lymphocytes surrounding the RSlike cells were T cells. According to the literature, the infiltrate distribution is consistent with so-called type 2 transformation, where the RS-like cells are found in a polymorphous inflammatory background, characteristic of primary classical Hodgkin lymphoma, and separate from SLL cells. In contrast, in type 1 transformation, the RSlike cells are distributed among clonal B cells, that is, SLL cells [1]. The patient received a matched related peripheral blood stem-cell transplant 21 months after her initial diagnosis. Although Hodgkin lymphoma is among the most common malignancies to secondarily involve patients with CLL/SLL [6], Hodgkin transformation of CLL/SLL is a B. Quigley (*) Department of Pathology and Cell Biology, University of South Florida College of Medicine, 4105 W Coachman Ave, Tampa, FL 33611, USA e-mail: bquigley@health.usf.edu

294 Prognostic significance of beta 2 microglobulin in survival and transformation to acute myelogenous leukemia in patients with myelodysplastic syndrome

s of the 11th International Symposium on Myelodysplastic Syndromes (MDS) 18 May 2011 21 May 2011 S116 Posters / Leukemia Research 35 (2011) S27–S142 294 Prognostic significance of beta 2 microglobulin in survival and transformation to acute myelogenous leukemia in patients with myelodysplastic syndrome A. Galanopoulos, A. Aggelidis, D. Gogos, A. Megalakaki, I. Kotsianidis, M. Dimou, P. Panagiotidis, N. Zoumbos, N.I. Anagnostopoulos, M. Voulgarelis, H. Papadaki, A. Symeonidis. Clinical Hematology, G. Gennimatas General Hospital, Athens, Clinical Hematology, Metaxas Hospital, Piraeus, Clinical Hematology, Dimokritio University of Thraki, Alexandroupolis, Clinical Hematology, Laikon General Hospital/National and Kapodistrian University of Athens, Athens, Clinical Hematology, University of Patras, Medical School, Patras, Clinical Hematology, University of Crete School of Medicine, Heraklion, Greece Background: Beta 2 microglobulin (b2M) is a 12 kDa light chain protein that binds to the a chain of class I MHC (MHC1) molecule. Serum b2M levels are known to reflect renal function and membrane turnover, which is associated with tumor mass and growth rate. Elevated serum levels of b2M are reported to predict poor survival in several hematologic malignancies. Purpose: To investigate the prognostic relevance of b2M with regard to survival and the risk of transformation into acute myelogenous leukemia (AML) in patients with myelodysplastic syndrome (MDS). Material and Methods: We evaluated serum b2M levels in 407 MDS patients from the Hellenic MDS Study Group. From these 152 patients were excluded from further analysis for various reasons such as serum creatinine levels greater than 1.5mg/dl, treatment with intensive therapy and blood stem cell transplantation or insufficient data. B2M and karyotype were recorded along with other hematologic, biochemical and clinical covariates. Serum b2M levels were quantified by a radioimmunoassay. The log rank test was used to compare overall survival and AML transformation. Multivariate analysis was conducted utilizing the Cox proportional hazards regression model with a stepwise backward selection. Results: Thirty patients had refractory anemia (RA), 64 refractroy anemia with excess of blasts-1(RAEB-1), 34 refractory anemia-2 (RAEB-2), 24 refractory anemia with ringed sideroblasts (RARS), 69 refractory cytopenia with multilineage dysplasia (RCMD), 13 refractory cytopenia with multilineage dysplasia with ringed sideroblasts (RCMD-RS) and 11 5q− syndrome. The median value for b2M was 2.67(±1.53). The univariate analysis revealed that patients with b2M below 3mg/dl had a higher overall survival compared to patients with b2M above 3mg/dl (log-rank=7.42; p = 0.006). Other factors that exerted a statistically significant effect on overall survival were the medullary blasts (log-rank =13.5; p 15%. MDS with del(5q) was identified in 135 (6.6%) of the cases, RARS-T in 76 patients (3.7%). There were 122 (6%) cases with MDS unclassifiable, including 95 (4.7%) with 1% peripheral blasts, 26 (1.3%) with pancytopenia, and only one patient without signs of dysplasia despite chromosomal abnormalities. Survival data (months) and AML progression rates (%) at 2 and 5 years are shown in the tables. Types with unilineage Dysplasia WHO 2008 Hb g/dl PLT/ nl ANC/ ml Abnormal karyotype in % Complex karyotype in % IPSS low/ int 1/int 2 median survival in month AML progression in % after 2 years AML progression in % after 5 years RCUDbi 10.3 116 2000 50 19 30/57/13 64 9 14 RA 8.5 248 3900 40 14 91/9/0 48 2 2 RT 11.7 56 2650 57 0 80/20/0 not reached 0 11 RN 11.9 137 1300 8 0 92/8/0 141 10 10 RARS 9.5 267 3150 28 6 73/24/2 63 4 4 MDS-U-PAN 8.5 44 750 33 0 0/100/0 30 0 18 Types with multilineage Dysplasia WHO 2008 HB g/dl PLT/ nl ANC/ ml Abnormal karyotype in % Complex karyotype in % IPSS low/ int 1/ int 2 median survival in month AML progression in % after 2 years AML progression in % after 5 years RCMD 9.3 134 2030 49 19 40/51/9 36 11 17 RCMD-RS 8.8 185 2200 55 24 45/41/14 31 10 17 RARS-T 9.1 584 4750 41 18 67/33/0 55 3 8 MDS del (5q) 9.3 255 2300 100 0 73/27/0 91 4 14 MDS-U-PB 9.4 118 2300 47 20 41/52/7 35 10 13 Conclusions: 1. While RCUD carries a relatively good prognosis, pancytopenic patients (MDS-U-Pan) have a shorter survival, similar to RCMD. The separation of MDS-U-Pan therefore seems to be is justified. 2. RCUD with bicytopenia accounts for a considerable fraction (52.3%) of RCUD. The prognosis of RCUDbi is intermediate between RCUD with unilineage cytopenia and MDS-U-Pan. 3. The prognostic impact of blast cells in the peripheral blood is similar to that of pancytopenia. 4. Survival rates are not substantially different for RCMD and RCMDRS. 5. RARS-T and MDS with del5q usually present with multilineage dysplasia. From a prognostic point of view, they are similar to RCUD, but their specific pathogenetic features justify their existence as distinct subtypes in the WHO classification.