Naina, Harris

7039 Background: Erythropoiesis-stimulating agents are known to increase the risk for VTE events, especially in patients with underlying malignancies. However, there is a paucity of information on other hematopoietic growth factors such as granulocyte colony-stimulating factor (GSCF) granulocyte-macrophage colony stimulating factor (GM-CSF) AMD 3001 and risk for VTE. Methods: Between January 2000 and October 2008, a total of 631 patients underwent peripheral blood stem cell mobilization (PBSCM) using either GCSF, GMCSF, cyclophosphamide, AMD 3100, or with any of the above combination. We included only patients with a diagnosis of AL amyloidosis (AL), multiple myeloma (MM) Hodgkin's lymphoma (HL) and non Hodgkin's lymphoma (NHL). Patients’ demographic details and diagnosis of VTE were collected from electronic medical records. Results: Of the 631 patients who underwent PBSCM the median age of the patients was 57 years (range 17–77). 448 patients (71%) received single agent GCSF, 82 (13%) received combination of GMCSF and cyclophosphamide, 52 (8%) received cyclophosphamide and GCSF, 30 patients received a combination of GMCSF and GCSF, 10 (1.5%) patients received GCSF and AMD 3100. Of the 631 patients, 278 (44%) MM, 209 (33%) NHL, 114 (18%) AL, and 20 (3%) had HL. We found 7 (1.1%) patients with symptomatic VTE occurring between administration of growth factors and stem cell transplant. The median duration from the administration of growth factors to detection of VTE was 5 days (range 1–30). Two AL,3 MM and 2 NHL. Of the 7 patients, 2 patients had pulmonary embolism and 1 patient developed deep vein thrombosis. Two patients with AL developed heparin induced thrombocytopenia (HIT). The remaining 4 patients developed symptomatic catheter related thrombosis. Only 1 patient had past history of VTE. Of the 7 patients, 5 received GCSF alone, 1 received GMCSF, and cyclophosphamide, 1 received GCSF and cyclophosphamide. Of the 4 patients who developed catheter related thrombosis, catheter was removed in 2 patients. None of the patients developed VTE related morality. Conclusions: The risk for symptomatic VTE during PBSCM is low. HIT should be considered as a possible cause for VTE in patients undergoing PBSCM. No significant financial relationships to disclose.

Abstract Background: Although thalidomide induced neuropathy has been described for decades, many features such as incidence, risk factors, severity and character of the neuropathy are not well defined. We retrospectively reviewed the incidence and clinical course of peripheral neuropathy in patients treated with thalidomide or thalidomide/dexamethasone (Thal/Dex) on a Phase II Mayo Clinic trial. Methods: Patients who participated in a Mayo Clinic Phase II trial of thalidomide in myeloma were studied. In this trial, patients with SMM and RMM received thalidomide 200 mg per day escalated as tolerated to a maximum of 800 mg/day. Patients with NMM received thalidomide 200 mg/day plus dexamethasone 40 mg/day orally on days 1–4, 9–12, 17–20 (odd cycles) and 40 mg/day days 1–4 (even cycles) repeated monthly. The incidence and clinical course of neuropathy was assessed by chart review. The study was approved by the Mayo Clinic Institutional Review Board. Results: All 113 patients (70 male, 43 female) treated on trial were studied; 31 patients with smoldering/indolent myeloma (SMM), 32 patients with relapsed/refractory myeloma (RMM) and 50 patients with newly diagnosed myeloma (NMM). Patients were accrued to the parent protocol from April 1999 through March 2002. The median age was 62 years (range, 36–78). The median duration of thalidomide therapy on protocol was 15 months in SMM, 6 months in RMM and 4 months in NMM. Overall, 63 patients (56 %) developed symptoms of peripheral neuropathy. The incidence of neuropathy was 77%, 50%, and 46% in patients with SMM, RMM, and NMM, respectively. Neuropathy worsened during the treatment phase with/without dose reduction or after cessation in 15%, remained stable in 52%, and improved in 27%. Overall grade of neuropathy was grade 1 in most pts; 11% of all patients had grade 2 neuropathy and 2% had grade 3 neuropathy. Predominant symptoms of neuropathy were tingling and numbness involving both upper limb and lower limbs. Small subsets of patients complained of hearing loss 6 patients), and erectile dysfunction (4 patients). Electromyographic studies and nerve conduction studies were performed in 11 patients; the most common finding was a length dependent axonal neuropathy. Conclusion: Peripheral neuropathy is an important and common adverse event with thalidomide therapy that often limits the dose and duration of treatment. Its incidence and severity are likely related to dose and duration of therapy.

Abstract Background: Post-transplant lymphoproliferative disorder (PTLD) represents one of the most serious consequences of immunosuppression in patients with solid organ transplantation. The incidence of PTLD is related to the organ transplanted and is dependent on the duration of follow-up. In various publications, the incidence of PTLD in renal transplantation ranges between 0.8% to 1.2%. In a previous study, the development of monoclonal (M) protein following liver transplantation is associated with the development of PTLD. In this study, we investigate this relationship in the kidney transplant population. Methods: A total of 3518 patients underwent kidney transplantation between 1963 to March 2006. These patients were cross referenced with the Monoclonal Gammopathy of Undetermined Significance (MGUS) database. Results: We identified 97 patients who had a monoclonal gammopathy either before or after transplantation. Patients with amyloidosis, multiple myeloma, heavy and light chain deposition disease and multi-organ transplantation were excluded from the analysis. A total of 69 patients met the inclusion criteria. Ten of the 69 (14.5%) patients developed PTLD. Median follow-up was 14.8 years. Twenty three patients had pretransplant MGUS, 20 patients developed MGUS following the transplant, and the other 26 did not have a monoclonal protein study prior to the transplant. Of the 23 patients who had a positive MGUS prior to the transplant, 4 patients (17.3%) developed PTLD, 1 patient developed EBV positive diffuse large cell lymphoma (DLCL), 1 developed EBV negative DLCL, 1 developed Hodgkin’s lymphoma and 1 developed increased plasma cells in bone marrow (20%) with stable M protein with no evidence of progression to multiple myeloma. None of these patients had a quantifiable M-protein prior to transplantation. The mean duration from diagnosis of MGUS to PTLD was 8.2 years (range 3 to 14 years). Of the 20 patients with a negative pre-transplant study for para proteniemia, 2 (10%) developed PTLD (T cell lymphoproliferative disorder). Two patients developed MGUS after the transplant at 1 and 12 years post transplant. It took an average of 15 years to develop PTLD after the diagnosis of MGUS. Four of the 26 patients who did not have a pretransplant study for MGUS developed PTLD. These included an EBV positive gamma delta type T cell lymphoproliferative disorder, an EBV positive plasmablastic lymphoma, one multiple myeloma and a plasmacytoma. The latter two patients had M-protein > 3g/dL. It took an average of 14 years after their transplant for these patients to develop PTLD. Conclusion: Our study showed that the development of a monoclonal protein in patients undergoing kidney transplantation is a strong risk factor for PTLD. Monoclonal protein study should be performed pretransplant and monitored post transplant as a surveillance of PTLD. Those who are positive or convert should be monitored closely for development of lymphoproliferative disorder.

Abstract Background: Monoclonal gammopathy of undetermined significance (MGUS) is reported in 3 to 5 percent of population, with the prevalence increasing with advancing age. Patients with MGUS are at increased risk for progression to multiple myeloma or other plasma cell dyscrasias. There is a paucity of information on clinical outcomes of patients with MGUS undergoing renal transplantation. A retrospective study was performed to determine wether MGUS is a contraindication to renal transplantation. Methods: Data was collected from both the kidney transplant and MGUS database. The diagnosis of MGUS was made on the basis of either serum protein electrophoresis (SPEP) or immunofixation after excluding multiple myeloma, amyloidosis and monoclonal immunoglobulin deposition disease. Results: Between 1977 and 2004, 3518 patients underwent kidney transplantation of whom 23 patients had a preexisting monoclonal gammopathy of undetermined significance (MGUS). Fourteen (61%) of these patients were males. The median age at the time of transplant was 59 ±12 years. Ten patients (43.5%) had IgG Kappa (GK), 7 (30.4%) had IgG Lambda (GL), 2 (8.7%) had IgA Lambda (AL), 1 (4.3%) had IgA Kappa (AK), 2 (8.7%) had IgM Lambda (ML). One patient had a biclonal gammopathy GL and ML. Patients were monitored with either SPEP or immunofixation for median duration of 1542 days after transplantation. Thirteen patients had either no change or stable monoclonal protein, 6 had a decrease in their paraprotein level. Two patients had a mild increase in their paraprotein. Two patients with GK developed into biclonal gammopathy (GK and AK). The median follow up of this cohort after the renal transplant was 1783 days. Twelve (52%) patients remained alive at the time of the study. A patient with GK prior to the transplant who underwent kidney transplantation twice developed a biclonal gammopathy and was found to have increased plasma cells (20%) in bone marrow after 14 years. On follow up for 6 years, his M-protein remained stable. Another patient was found to have 17% plasma cells around the time of kidney transplantation. He had a stable M-protein at follow-up, but underwent a stem cell transplant for recurrent immunotactoid glomerulonephritis. Two (9%) patients developed more than 15% plasma cells in their bone marrow with a stable M-protein. None of the patients with a preexisting MGUS evolved into multiple myeloma. Conclusion: In this small study, the presence of MGUS prior to kidney transplantation did not appear to have increased the incidence of multiple myeloma post transplant. Therefore, MGUS by itself should not be considered as an absolute contraindication for renal transplantation.

Abstract Abstract 1178 Poster Board I-200 Background: High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) has been shown to be of value in selected patients with malignant lymphoma and multiple myeloma (MM). Both granulocyte macrophage colony stimulating factor (GMCSF) and granulocyte colony stimulating factor (GCSF) are widely used following stem cell transplantation to support accelerated myeloid recovery and potentially shorten hospital stay. In the recent years, PBSCT is increasingly done in an ambulatory care setting and it is not clear if routine growth factor use has any potential benefit. We undertook this study to compare engraftment kinetics, incidence of febrile episodes, hospitalization duration and other outcomes among transplants done with or without growth factor support Patients and Methods: We included adult patients undergoing PBSCT for myeloma and lymphoma between May 2007 and June 2009 in an ambulatory care setting. Prior to April 2008 (Group-1) all patients received GMCSF 500 mcg/ day starting on day 6 routinely. Since April 2008, there was a shift in clinical practice and routine use of GMCSF was discontinued due to lack of clear evidence regarding benefit. Patients transplanted between April 2008 and June 2009 did not routinely receive GMCSF (Group-2). Typical conditioning regimen for lymphoma was BEAM (BCNU, Etoposide, Cytosine Arabinose, Melphalan) and for multiple myeloma was melphalan 200mg/m2. Patients' demographics details, indication for PBSCT, duration of neutropenic fever, hospital stay, and neutrophil and platelet engraftment were collected from electronic medical records. Neutrophil engraftment is defined as the first day of 2 consecutive days when ANC was > 0.5 × 109/L and platelet engraftment is defined as first of 7 consecutive days on which patient's unsupported platelet count was greater than 20× 109/L. Results: A total of 309 were included in this study, 126 (40%) patients in group-1 (69 with MM, 57 with lymphoma) and 183 (60%) in group-2 (100 with MM, 83 with lymphoma). In group-1, 73 (58%) and in group-2 130 (71%) were male patients. Median age was 59 (29-74) years in group 1 and 58 (24-76) years in group-2. Patients in group 1 received a median of 3.65 (1.1-8.7) versus 4.37 (1.1-9.54) CD34+ x106/kg in group 2 (P =0.005). Median time to neutrophil engraftment was 12 (95% CI 12, 12) for group-1 and 14 (95% CI; 13-14) for group-2 (Kaplan Meier analysis; log rank P < 0.0001). Median estimated time to platelet engraftment was 14 days (95% CI; 13, 15) for group 1 and 13 days (95% CI; 13-13) for group 2 (Kaplan Meier analysis; log rank P 0.007). In group-1 98 (78%) patients developed febrile episodes compared to 117(64%) in group-2 (P = 0.009). Median duration of fever was 2 days (range, 1-8) in group-1 compared to 1 day (range, 1-8) in group-2 (P = 0.0003). The median (range) duration of hospital stay was 7 (1-40) days for group-1 compared to 8 (2-56) days for group-2 (P=NS). There was no significant difference in mortality between these two groups. Conclusion: Routine use of granulocyte growth factors is associated with a shorter time to neutrophil engraftment, but associated with a delay in platelet engraftment. The longer time to neutrophil engraftment without growth factor use does not translate into any increase in frequency of febrile episodes. On the contrary, higher number of febrile days is seen with use of growth factors, likely explained on the basis of drug fever. No difference in the frequency of engraftment syndrome or treatment related mortality was seen. Disclosures: No relevant conflicts of interest to declare.

Abstract Inherited giant platelet disorders are a group of rare disorders characterized by thrombocytopenia, giant platelets and variable bleeding symptoms. Naina et al., described a new giant platelet disorder called Harris Platelet Syndrome (HPS), the most common inherited giant platelet disorder occurring in up to one third of blood donors from north eastern part of Indian subcontinent. HPS is characterized by an autosomal dominant mode of inheritance with normal to severe thrombocytopenia (less than 50x109/L), giant platelets (mean platelet volume more than 10fL) and absent bleeding symptoms with normal platelet aggregation studies. Occasionally abnormalities in red blood cell morphology have been associated with certain giant platelet disorders such as stomatocytosis in Mediterranean Macrothrmboctopenia, dyserythropoiesis in GATA 1 associated macrothrombocytopenia and thalassemia, in X Linked Thrombocytopenia Thalassemia (XLTT). This study was undertaken to analyze the platelet and red blood cell indices in blood donors with Harris Platelet syndrome. A total of 203 blood donors were included in this study, 101 blood donors from northeaster part of India with MPV more than 12fl (normal 7–10fl) and 102 blood donors from southern part of India. Before blood donation, all donors were questioned about a history of bleeding conditions, in either themselves or their relatives. Blood samples were collected in ethylenediaminetetraacetic acid (EDTA). Automated platelet counts were performed using a Coulter STKS (Coulter, Hialeah, Florida) within 2 hours of collection. Peripheral blood smears were examined to confirm thrombocytopenia, giant platelets and red blood cell morphology. There was a significant difference between platelet count (Mean ±SD) 136± 40 Vs 262 ± 53 in southern India (p<0.000). Thirty three donors with HPS had a normal platelet count with MPV more than 12fL. MPV was 13.6±0.13 (range 12 to21.9fL) in donors with HPS and 7.3 ±0.6 (range 6–9.2fl) in southern Indian blood donors. The platelet distribution width (PDW) was 17.4±0.8 in donors with HPS and was 16.38±0.5 in southern India blood donors(p<0.000). Though there was a significant difference between hemoglobin, 13.8 ± 1.0 vs and 14.7± 1.1 (P<0.00), there was no significant difference between RDW, MCV, MCH, MCHC. Peripheral blood smear did not show any obvious red blood cell abnormality, but showed giant platelets and thrombocytopenia. Harris platelet syndrome is associated with normal to severe thrombocytopenia, giant platelets and significant platelet anisocytosis. There was no associated red blood cell abnormalities observed with HPS.

Although rare, clinicians and patients must be aware that therapy related malignancies, specifically acute myeloid leukemia (AML), can occur as a complication of adjuvant chemotherapy for breast cancer. Vigilance for signs and symptoms is appropriate. AML with t (8;16) is a specific translocation leading to formation of a fusion protein ( MYST3/CREBBP ). The MYST3/CREBBP AML tends to develop within 2 years of adjuvant chemotherapy, especially for breast cancer, without preceding myelodysplasia. It usually presents with disseminated intravascular coagulation and osteolytic lesions and has a poor prognosis despite aggressive resuscitation and therapy. With the increasing use of adjuvant chemotherapy for breast cancer, we are seeing a definite increase in the incidence of therapy related myelodysplastic syndromes and AML. One must keep this complication in mind while counseling and following up breast cancer patients who have received adjuvant chemotherapy. New osteolytic bone lesions in a patient with history of breast cancer do not necessarily mean metastatic disease and should be fully evaluated.