S. Elkins

A high LDH to AST ratio helps to differentiate pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from HELLP syndrome

Objective: Differentiating between pre-eclampsia/HELLP syndrome and pregnancy-associated thrombotic thrombocytopenic purpura (TTP) is difficult but important in order to undertake timely and potentially life-saving plasma exchange (PEX) therapy for TTP recovery. We review our institutional experience with pregnancy-associated TTP and determine if the ratio of LDH to AST reliably distinguishes patients with TTP from those with HELLP syndrome. Study design: This is a retrospective case control study of all pregnant/puerperal patients with TTP from a single tertiary care center during 1986–2006. Laboratory findings in patients with TTP were compared to patients who met all criteria for class 1 or 2 HELLP syndrome within the first 24 hours of hospital admission during 2000–2007. Results: Thirteen pregnant (n = 10) or puerperal (n = 3) patients with TTP were identified; 11 cases were primary, 2 were recurrent. TTP laboratory findings included LDH to AST ratios of 77 ± 42.17; Patients with HELLP syndrome (N = 83) had significantly lower LDH to AST ratios of 20.04 ± 2.13. Based on an ROC analysis, an LDH/AST ratio ≥22.12 discriminates well between TTP and antenatal HELLP subjects (AUC = 0.99). Conclusion: A high LDH to AST ratio >22.12 suggests that TTP is a more likely diagnosis than HELLP syndrome in the third trimester pregnant patient, presenting with findings that could be compatible with either diagnosis. In these circumstances, it is advisable to obtain hematology consultation and to consider PEX implementation.

Thrombotic thrombocytopenic purpura : Evolution across 15 years

Thrombotic thrombocytopenic purpura (TTP) was originally described 70 years ago. It is considered an uncommon disorder with a reported occurrence rate of one case per 1 million patients. Mortality has decreased from almost 100% early on to 30–50% with the advent of newer treatment methods. We reviewed 41 patients with a diagnosis of TTP spanning the years 1980 to mid 1994. We found a much higher case rate, one per 6000 hosptial admissions, and an overall death rate of 40%. However, isolating 5 year periods we noted a marked fall in mortality from 54% (1980–1984), 44% (1985–1989), to 18% (1990–1994). Previous reports describe relapsing TTP and report an incidence of 7–15% although very recent data suggests a higher incidence. In our study, we found an overall relapse rate of 25% and by 5 year periods 23% (1980–1984), 13% (1985–1989), and 46% (1990–1994). We suggest that the improvement in survival and the increase in relapse rate are related and reflect more effective therapy for this once almost always fatal disease. Patients now survive their initial episode and thus are at risk for recurrence. Identification of risk factors for relapse will require further study.

Thrombocytosis During Antifungal Therapy of Candidemia

BACKGROUND Secondary, “reactive,” thrombocytosis has been attributed to bacterial infection and treatment with multiple pharmaceuticals and may be associated with an increase in the incidence of gastrointestinal tract bleeding and thrombotic events (eg, stroke). OBJECTIVE To characterize the dynamics of thrombocytosis in patients with candidemia receiving antifungal therapy. METHODS We initiated a retrospective observational description of patients with candidemia who were treated with antifungal agents. A total of 108 patients diagnosed with candidemia between August 1995 and September 2003 at our teaching hospital were enrolled. Three groups (candidemia with antifungal therapy, candidemia without antifungal therapy, antifungal therapy without candidemia) of patients >18 years of age were evaluated for the resence of thrombocytosis. Platelet administration, pharmacologic or pathologic contributors to thrombocytosis, and other pertinent details related to an elevation of platelet counts were scrutinized. RESULTS Reactive thrombocytosis was observed in approximately 10% of treated patients with candidemia. Within the subgroup developing reactive thrombocytosis, life-threatening thrombotic complications were uncommon. Mean baseline platelet counts were 393 × 103/mm3, with a mean peak (695 × 103/mm3) occurring an average of 13 days after initiation of therapy. All patients had resolution within 7 days after therapy. The maximum peak (1056 × 103/mm3) was observed in a patient after 14 days of antifungal therapy. The onset of thrombocytosis in this patient was 4 days and lasted 4 days after therapy. CONCLUSIONS Reactive thrombocytosis occurs during treatment of candidemia. The causative agent (drug vs disease), the risk associated with this reaction, and evaluation of treatment need to be elucidated by a larger epidemiologic study or controlled, prospective clinical trial.

Unusual skin lesions in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a relatively rare, heterogeneous syndrome classified as a myelodysplastic syndrome according to the French-American-British classification system. The patients presenting symptom was a pigmented skin nodule that, although common for cases of acute monoblastic leukemia, is peculiar for CMML. This case should increase awareness of the inclusion of CMML in the differential diagnosis of a discolored nodule and highlight the clinicopathologic considerations and therapeutic challenges consistent with the diagnosis of CMML.

An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma

&NA; The panobinostat expansion (PANEX) treatment protocol (n = 39) provided access to panobinostat and gathered additional efficacy and safety data on the panobinostat, bortezomib, dexamethasone regimen before commercial availability. The findings from the study supported those that led to regulatory approval of the regimen. Additionally, the use of subcutaneous bortezomib in the PANEX trial resulted in potential tolerability benefits, including a relatively low rate of peripheral neuropathy. Background: Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability. Patients and Methods: In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m2 twice weekly with dexamethasone 20 mg on the days of and after bortezomib treatment. Patients with no change or better in treatment phase 1 proceeded to treatment phase 2, when bortezomib was reduced to once weekly. Unlike in the phase III trial, PANORAMA‐1 (panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma), bortezomib could be administered either subcutaneously or intravenously. Results: Thirty‐nine patients with a median number of previous treatments of 4 (range, 1‐12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed. Conclusion: Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

135 A CASE REPORT OF SINONASAL UNDIFFERENTIATED CARCINOMA WITH SYNCHRONOUS BREAST CANCER.

Purpose To investigate the occurrence and clinical features of sinonasal undifferentiated carcinoma (SNUC). Patient Case A 61-year-old Philippine female was referred to Oncology for a palpable breast mass. The biopsy demonstrated an intermediate-grade infiltrating ductal carcinoma. Markers for estrogen receptor and Her2 /neu were positive. The patient also gave a history of recent-onset epistaxis and decreased hearing. Bilateral enlarged cervical nodes were readily apparent on examination. She reported these as enlarging for the last 6 months. CT scan of the neck was pertinent for a large nasopharyngeal mass at the level of the palatine tonsils with extensive bilateral upper cervical adenopathy (up to 3.8 cm). CT scans of the head, chest, abdomen, and pelvis plus a bone scan were negative for metastatic disease. She was seen in consultation by an ENT who biopsied the nasal mass, yielding the diagnosis of SNUC. The patient is now postmastectomy and is to begin weekly paclitaxel, cisplatin, trastuzumab, and cranial radiotherapy. Discussion SNUC is a rare malignancy arising from the schneiderian mucosa first described by Frierson in 1986. Aggressive growth, poor prognosis, and lack of optimal management guidelines characterize it. Men are affected more often than women, with an average age of 55. Regional nodal metastases are present at diagnosis in up to 50% of cases. Bone appears to be the most common site of distant metastasis. This case is more unusual in that the tumor developed in the nasopharynx rather than the typical sites of the ethmoid or sphenoid sinuses (which are lined by schneiderian mucosa). The differential diagnosis of nasopharyngeal masses includes nasopharyngeal cancer, lymphoma, plasmacytoma, or metastasis. SNUC must be differentiated from olfactory neuroblastoma, sinonasal endocrine carcinoma, and primary sinonasal nasopharyngeal-type undifferentiated carcinoma by microscopy and immunohistochemistry. Despite previous beliefs, SNUC is not associated with EBV infection. Optimal therapy should include an aggressive multimodality approach combining platinum-based chemotherapy with radiation and craniofacial resection. Small studies have demonstrated 2-year survival figures approaching 64% with current therapy.

325 THROMBOEMBOLISM IN MULTIPLE MYELOMA PATIENTS RECEIVING THALIDOMIDE COMBINATION CHEMOTHERAPY.

Purpose To establish the incidence of thromboembolism (TBE) in multiple myeloma (MM) patients on thalidomide combination chemotherapy. Methods A retrospective review was performed on all multiple myeloma patients at our tertiary care facility from January 2000 to December 2006. Patients were assessed for baseline characteristics, including age, sex, and past medical and surgical histories. Risk factors for TBE were evaluated, including a documented hypercoagulable state, a history of prior TBE, comorbidities, cytogenetics, and concurrent medications. It was also noted whether a central venous catheter (CVC) was in place. TBE included deep vein thromboses (DVTs) and pulmonary embolism (PE). It was also noted if patients had arterial TBEs. Patient chemotherapy regimens with or without thalidomide were reviewed, and each patient was assessed for evidence of TBE. Furthermore, thalidomide doses and titration intervals were documented. If thalidomide was used, patients were evaluated for concurrent use of prophylactic anticoagulation. Types of anticoagulation included low-molecular-weight heparin, full-dose warfarin, low-dose warfarin (usually 1 mg), and aspirin. If the patient had documented TBE, the median time to TBE while on the thalidomide combination was noted. Patients on full anticoagulation following TBE were followed for continued thalidomide use and bleeding events. Results Of 118 eligible patients, there were 29 (24% of patients) occurrences of DVT or PE. Preliminary results show that 13 (11%) of the patients with TBE were on some thalidomide combination, whereas 15 (13%) were not. Seven of 13 patients with TBE on thalidomide were not on prophylactic anticoagulation. Three events occurred on low-dose warfarin, two on full-dose warfarin, and one on enoxaparin. Conclusions It has been previously reported that about 10% of MM patients develop DVT when treated with chemotherapy alone. DVT rates of 25 to 30% have been documented with the addition of thalidomide to conventional chemotherapy or dexamethasone, whereas it occurs in only 3% of those treated with dexamethasone alone. No randomized trials have been done to establish the most effective type of prophylactic anticoagulation in this patient population. We hope to identify those patients at highest risk for TBE in our population and the best regimen for TBE prophylaxis.

220 REDUCED-INTENSITY CONDITIONING USING ALEMTUZUMAB IN ALLOGENEIC HEMATOPOIETIC TRANSPLANTATION.

Purpose Allogeneic hematopoietic transplantation after a myeloablative conditioning regimen has been shown to be an effective and potentially curative treatment for many hematologic malignancies due to the graft-versus-malignancy (GVM) effect. However, significant toxicities of such regimens have limited their use to younger, otherwise healthy patients. Reduced-intensity conditioning (RIC) transplantation has broadened eligibility to include older patients and those with comorbid conditions. RIC regimens using fludarabine and melphalan have been associated with a high risk of graft-versus-host disease (GVHD). Our institution adopted a RIC protocol that added alemtuzumab, an anti-CD52 monoclonal antibody that decreases T cells in the transplant recipient, to melphalan and fludarabine in an attempt to reduce the risk of GVHD while maintaining the GVM effect. Methods From January 2005 to June 2006, 19 patients with hematologic malignancies received an allogeneic transplant using the RIC protocol. Median patient age was 52 years (34-66). Results Acute and chronic GVHD occurred in 6 of 19 (31%) and 5 of 19 (26%), respectively, with only 17% of each being > grade II. Cytomegalovirus (CMV) reactivation occurred in 13 of 19 (68%). Seven of 19 (37%) patients experienced disease relapse or progression. One hundred-day survival was 79%. Ten of 19 (53%) have died at the time of this report. CMV infection was the probable cause of death in 3 of 10 (30%) deaths, or 16% of patients overall. Only one death was attributable to GVHD. Conclusions RIC allogeneic transplant represents a reasonable treatment option for a variety of hematologic malignancies. There was a low incidence of severe GVHD and a 100-day survival of 79%. However, the mortality rate due to toxicity of this regimen was high at 37%. CMV infection represents a large proportion of this toxicity and provides an area to be improved upon in future RIC protocols, perhaps by using lower doses of alemtuzumab.

ALEMTUZUMAB DOSING BY RECIPIENT WEIGHT IS IMPORTANT FOR REDUCED-INTENSITY CONDITIONING FOR ALLOGENEIC TRANSPLANTATION.: 329

From June 2002, to August 2006, our institution used reduced-intensity conditioning (RIC) regimens for allogeneic transplantation of 40 adult at-risk older patients or patients with comorbid conditions. Malignancies included multiple myeloma, AML, CML, NHL, MDS, CLL, and one renal cell carcinoma. Thirteen (32%) were in CR at time of transplant, whereas 27 (68%) had relapsed or refractory disease. Median age was 50 years (range 24-66) and median follow-up was 8 months (1-36 months). Degree of HLA match at A, B, and DR was 6/6 or better for 31 patients and either single antigen or allele mismatches for the others. Three RIC regimens consisted of intravenous infusions of: fludarabine 30 mg/m2 × 5 days and melphalan 140 mg/m2 × 1 day in all groups, and of Alemtuzumab 20 mg/d × 5 days (protocol 1), × 3 days (protocol 2), and × 2 days (protocol 3). Twenty-three patients received MUD products and 17 received MRD products; cell source was bone marrow (17), PBSC (19), cord blood (1), and combination products (3). All patients received an adequate CD34+ cell dose or TNC dose (cord blood transplant). GVHD prophylaxis was tacrolimus tapering after day +100 and mycophenolate mofetil tapering after day +30. Determination of the optimal dose of alemtuzumab was a goal of this study. All patients except one achieved a WBC graft. Relapse or disease progression occurred in only 37% of protocol 3, 40% of protocol 2, and 67% of protocol 1. Although alemtuzumab doses were given in a standard fashion not adjusted for body weight or surface area, it was found that a lack of consideration of patient size did not represent the intent of the given protocols. Weight-based alemtuzumab dose adjustment showed that a much broader dose range than expected had occurred. Those receiving protocol 1 were in a dose range of 1.01 to 1.90 mg/kg; for protocol 2, the range was 0.36 to 1.08 mg/kg; for protocol 3, the range was 0.36 to 0.70. The median dose of alemtuzumab for the cohort was 0.68 mg/kg. A clustering of acute GVHD grades I to II appeared below the median dose at approximately 0.55 mg/kg; only one patient had grade IV GVHD. In summary, these data indicate that using the patient9s body weight in the determination of an optimal alemtuzumab dose is a more reasonable approach to developing and standardizing RIC protocols with this drug.

103 A CASE REPORT OF OPHTHALMIC AND CUTANEOUS SECONDARY PLASMACYTOMAS IN A PATIENT WITH MULTIPLE MYELOMA.

Purpose To report an unusual presentation of ophthalmic and cutaneous plasmacytomas in a patient with relapsed multiple myeloma. Methods A 57-year-old Hispanic female with IgG lambda multiple myeloma (MM) diagnosed in 2001 was treated with cytotoxic chemotherapy. She obtained a complete response lasting for 2 years before presenting with complaints of headache and right-sided blurred vision. Furthermore, she was found to have worsening fatigue and increasing bony pain. Upon physical exam, she was found to have two new small nodules on her right anterior chest wall and one new nodule on her right anterior abdominal wall. During examination of her right eye, a lesion was found in her conjunctiva and another in the right lateral rectus muscle insertion. All lesions were biopsied. Results Histopathologic examination of all five lesions was consistent with plasmacytomas. She was treated with bortezomib and obtained a partial response by decreased quantitative immunoglobulins. Due to intolerability, she was switched to thalidomide. Thalidomide was quickly discontinued due to rash, and she was referred to our tertiary care center for evaluation for autologous bone marrow transplantation. Conclusions Ophthalmic presentations of MM are rare. Those patients who present with primary ocular or orbital plasmacytomas are considered to have localized disease and have a median survival of 8.3 years. On the other hand, our patient had secondary plasmacytomas of the eye with relapsed systemic disease. These patients tend to do poorly, with a median survival of approximately 20 months. Our patient provides a good example of the rare presentation of ophthalmic plasmacytoma with MM.