Khaled M. Ramadan

Autologous and Allogeneic Stem-Cell Transplantation for Transformed Follicular Lymphoma: A Report of the Canadian Blood and Marrow Transplant Group

PURPOSE To determine whether autologous (auto) or allogeneic (allo) stem-cell transplantation (SCT) improves outcome in patients with transformed follicular lymphoma compared with rituximab-containing chemotherapy alone. PATIENTS AND METHODS This was a multicenter cohort study of patients with follicular lymphoma and subsequent biopsy-proven aggressive histology transformation. Patient, treatment, and outcome data were collected from each transplantation center and combined for analysis. A separate control group was composed of patients with transformation treated with rituximab-containing chemotherapy but not SCT. The primary end point was overall survival (OS) after transformation. RESULTS One hundred seventy-two patients were identified: 22 (13%) treated with alloSCT, 97 (56%) with autoSCT, and 53 (31%) with rituximab-containing chemotherapy. Five-year OS after transformation was 46% for patients treated with alloSCT, 65% with autoSCT, and 61% with rituximab-containing chemotherapy (P = .24). Five-year progression-free survival (PFS) after transformation was 46% for those treated with alloSCT, 55% with autoSCT, and 40% with rituximab-containing chemotherapy (P = .12). In multivariate analysis, patients treated with autoSCT had improved OS compared with those who received rituximab-containing chemotherapy (hazard ratio [HR], 0.13; 95% CI, 0.05 to 0.34; P < .001). On the other hand, there was no OS difference between those treated with alloSCT and rituximab-containing chemotherapy (HR, 0.44; 95% CI, 0.16 to 1.24; P = .12). OS and PFS after SCT were similar between those treated with autoSCT and alloSCT. Five-year transplantation-related mortality was 23% for those treated with alloSCT and 5% for autoSCT. CONCLUSION Patients undergoing autoSCT had better outcomes than those treated with rituximab-containing chemotherapy alone. AlloSCT did not improve outcome compared with rituximab-containing chemotherapy and was associated with clinically significant toxicity.

Improved survival in red blood cell transfusion dependent patients with primary myelofibrosis (PMF) receiving iron chelation therapy

Many patients with primary myelofibrosis (PMF) become red blood cell (RBC) transfusion dependent (TD), risking iron overload (IOL). Iron chelation therapy (ICT) may decrease the risk of haemosiderosis associated organ dysfunction, though its benefit in PMF is undefined. To assess the effect of TD and ICT on survival in PMF, we retrospectively reviewed 41 patients. Clinical data were collected from the database and by chart review. The median age at PMF diagnosis was 64 (range 43–86) years. Median white blood cell (WBC) count at diagnosis was 7.6 (range 1.2–70.9) × 109/L; haemoglobin 104 (62–145) G/L; platelets 300 (38–2088) × 109/L. Lille, Strasser, Mayo and International Prognostic System (IPS) scores were: low risk, n = 15, 8, 11, 3; intermediate, n = 15, 19, 9, 16; high, n = 5, 11, 5, 7; respectively. Primary PMF treatment was: supportive care, n = 23; hydroxyurea, n = 10; immunomodulatory, n = 4; splenectomy, n = 2. Sixteen patients were RBC transfusion independent (TI) and 25 TD; of these 10 received ICT for a median of 18.3 (0.1–117) months. Pre‐ICT ferritin levels were a median of 2318 (range 263–8400) and at follow up 1571 (1005–3211 µg/L (p = 0.01). In an analysis of TD patients, factors significant for overall survival (OS) were: WBC count at diagnosis (p = 0.002); monocyte count (p = 0.0001); Mayo score (p = 0.05); IPS (p = 0.02); number of RBC units (NRBCU) transfused (p = 0.02) and ICT (p = 0.003). In a multivariate analysis, significant factors were: NRBCU (p = 0.001) and ICT (p = 0.0001). Five year OS for TI, TD‐ICT and TD‐NO ICT were: 100, 89 and 34%, respectively (p = 0.003). The hazard ratio (HR) for receiving >20 RBCU was 7.6 (95% Confidence Intervals [CI] 1.2–49.3) and for ICT was 0.15 (0.03–0.77). In conclusion, 61% of PMF patients developed RBC‐TD which portended inferior OS; however patients receiving ICT had comparatively improved OS, suggesting a clinical benefit. Prospective studies of IOL and the impact of ICT in PMF are warranted. Copyright

Improved survival with iron chelation therapy for red blood cell transfusion dependent lower IPSS risk MDS may be more significant in patients with a non-RARS diagnosis

Retrospective analyses suggest iron overload is associated with inferior survival (OS) in lower risk MDS and iron chelation therapy (ICT) with improvement. However, an analysis of RARS patients found no such association. We analyzed subtypes of lower risk MDS. Median OS for non-RARS without and with ICT was 44 months and not reached (P<0.001), and for RARS 99 and 134.4 months (P=NS); in red blood cell (RBC) transfusion dependent RARS patients not receiving ICT, median OS was 73.8 months (P=0.025). These results suggest a stronger association between ICT and OS in non-RARS MDS than in RARS, with significantly superior OS in transfusion dependent patients receiving ICT.

Oral fludarabine and rituximab as initial therapy for chronic lymphocytic leukemia or small lymphocytic lymphoma: population-based experience matches clinical trials.

Abstract Clinical trials report that fludarabine and rituximab (FR) as initial therapy for chronic lymphocytic leukemia (CLL) improves progression-free and overall survival (OS) when compared historically to fludarabine alone. To determine whether similar results are achievable with oral FR in a community-based setting, we conducted a population-based analysis of patients treated for CLL or small lymphocytic lymphoma (SLL) in British Columbia, where FR is standard initial therapy. Ninety-eight patients received FR for CLL/SLL from 2004 to 2009. Two- and 4-year OS was 90% and 73%, respectively (median not reached); 2- and 4-year treatment-free survival (TFS) was 69% and 54% (median 4.0 years). Age ≥ 60 years or ≥ 70 years had no effect on OS or TFS. Toxicity led to treatment discontinuation in 13%. FR with oral fludarabine was safely, conveniently and successfully given to community-based patients, irrespective of age, for first-line therapy for CLL/SLL, achieving OS and TFS similar to those in clinical trials.

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.

Preservation of lower incidence of chronic lymphocytic leukemia in Chinese residents in British Columbia: a 26-year survey from 1983 to 2008

Abstract The incidence of chronic lymphocytic leukemia (CLL) in the Asian population is up to 10 times lower than that in Caucasians. Studies on CLL in Asian residents in North America may help to determine the relative genetic and environmental causes of such a difference. Computerized records of CLL incidence from the combined British Columbia (BC) databases (n = 2736) and the Hong Kong Cancer Registry (HKCR, n = 572) were traced. Ethnic Chinese cases of CLL in BC were identified (n = 35). The world age standardized rates (WASRs) of CLL (per 100 000) were calculated in BC (1.71), HK (0.28) and BC Chinese (0.4), respectively. Using standard incidence ratios (SIRs), the observed BC Chinese case number was comparable to the figure projected from HK rates (SIR 1.3, p = 0.1) but significantly lower than the figure following BC rates (SIR 0.22, p < 0.0001). The difference was maintained over both genders, in all age groups and through the years. Our data over three decades suggest that genetic factors outplay environmental factors to give lower CLL rates in Chinese.

Acute intestinal obstruction due to intramural haemorrhage in small intestine in a patient with severe haemophilia A and inhibitor.

Abstract:  Patients with severe haemophilia A usually present with joint, gastrointestinal and urinary tract haemorrhage. Bleeding elsewhere is often precipitated by pre‐existing pathology or trauma. We report a patient with severe haemophilia A, who presented with symptoms of acute intestinal obstruction. He has a factor VIII inhibitor and receives recombinant factor VIIa on demand at home. The CT scan of abdomen showed dilated small intestine with fluid filled loops and a long segment in the jejunum with marked transmural thickening. There was no other pathology in the small intestine. These appearances were consistent with intramural haemorrhage in the small intestine as the cause of acute obstruction. He was managed conservatively with recombinant factor VIIa and this resulted in resolution of his symptoms. This case highlights an unusual presentation of bleeding in a haemophilia patient. Intestinal obstruction due to haemorrhage in the small intestinal wall is extremely rare and only previously reported in a few haemophilia patients. It also highlights the effectiveness of conservative management with recombinant factor VIIa as opposed to immediate exploratory surgery.

Clinical response of cutaneous squamous-cell carcinoma to bortezomib given for myeloma

A 54-year-old man presented with nephrotic syndrome in October, 2000. Renal biopsy showed minimal-change glomerulonephritis and the disease was responsive to steroids. 1 year later he was referred to a haematology department with hypogammaglobulinaemia and vertebral collapse. Blood investigations showed the IgG concentration to be 5·7 g/L (range 7·0–14·0), IgA 0·23 g/L (0·8–4·0), and IgM 0·3 g/L (0·45–2·0). Protein electrophoresis showed a decrease in γ globulin concentration and urinary analyis showed a Bence Jones protein type λ concentration of 0·22 g in a 24 h sample. Further investigations showed β2 microglobulin of 2 mg/L (1·2–2·4) and C-reactive protein of 2 mg/L. Full blood count showed a haemoglobin concentration of 140 g/L, platelets of 194×10/L, leucocytes of 3·1×10/L, and neutrophils of 1·85×10/L. His erythrocyte sedimentation rate was 3 mm/h and he had normal concentrations of urea, creatinine, electrolytes, aminotransferases, bilirubin, and lactate dehydrogenase. Bone-marrow aspirate showed an increase in λ-restricted plasma cells consistent with the diagnosis of myeloma. He was treated with six courses of idarubicin and dexamethasone chemotherapy, which began in July, 2001, and ended in November, 2001, followed by high-dose melphalan with stem-cell support in February, 2002. He received monthly infusions of 90 mg pamidronic acid from April, 2001, until October, 2002, which were then switched to monthly intravenous 4 mg zoledronic acid. In July, 2003, Bence Jones protein increased rapidly to 5·8 g in a 24 h urine collection. His nephrotic syndrome relapsed and he was started on high-dose prednisolone followed by clarithromycin, dexamethasone, and thalidomide treatment. He responded well to this treatment, but because of neurological side-eff ects, thalidomide was stopped in October, 2003. In July, 2004, he developed a skin lesion on his left temple measuring 2×3 cm with no evidence of parotid or cervical node enlargement. Punch biopsy from the lesion showed moderately diff erentiated squamous-cell carcinoma (fi gure 1). The lesion extended the full depth of the 2·5 mm biopsy, which showed no perineural or lymphovascular invasion. Because the patient’s myeloma was progressing he was started on bortezomib (1·3 mg/m intravenously on days 1, 4, 8, and 11) in August, 2004, with a view to improving his haematological status before proceeding to surgery. The myeloma stabilised with bortezomib but, unexpectedly, the cutaneous squamouscell carcinoma on his temple regressed and eventually disappeared (fi gure 2), with complete healing of the skin occurring several months after discontinuation of bortezomib in December, 2004. Subsequently, his myeloma progressed and, despite further dexamethasone treatment, he died in June, 2005, with progressive and refractory myeloma, but with no evidence of recurrence of his cutaneous squamous-cell carcinoma. Squamous-cell carcinomas are the second most common non-melanoma skin cancer. Cutaneous squamous-cell carcinoma of the head and neck is usually a localised disease amenable to local treatment, with fewer than 5% of immunocompetent patients having metastasis at presentation. Patients presenting with unfavourable primary features, such as thick (>4 – 5 mm), large (>2 cm), or recurrent lesions, certain high-risk sites (dorsal hands, lip, ear, scalp, or penis), poorly diff erentiated tumours with specifi c pathological features, or tumours arising in areas of chronic ulceration—eg, sinus tracts and chronic osteomyelitis— have an increased rate of metastases. With optimum treatment—ie, surgery and adjuvant radiotherapy—cure rates in this poor-outlook group have improved, with up to 75% 5-year disease-free survival. For patients with metastatic cutaneous squamous-cell carcinoma there is no standard care; chemotherapy options for head and neck squamous carcinoma include cisplatin with fl uorouracil or taxanes, with an expected complete remission rate of about 30%, but little improvement in overall survival. At present, neoadjuvant or concurrent chemotherapy does not have a role in the curative setting of surgery and adjuvant radiotherapy. A substantial proportion of patients will die from progressive disseminated disease; in a few patients (around 5%) this recurrence, often in the lung, might be the only site of fi rst recurrence or might occur in conjunction with locoregional failure. Lancet Oncol 2006; 7: 958–59

Population-based characterization of the genetic landscape of chronic lymphocytic leukemia patients referred for cytogenetic testing in British Columbia, Canada: the role of provincial laboratory standardization

Detection of recurrent chromosome abnormalities by fluorescence in situ hybridization (FISH) is an essential component of care in chronic lymphocytic leukemia (CLL) patients. In the province of British Columbia (BC), Canada, population 4.6 million, CLL patients receive uniform evaluation and therapy with FISH testing performed in three jurisdictions. The aims of this study were to (i) validate CLL-FISH testing among the BC cytogenetic laboratories to ensure standardization of results and (ii) characterize population-level CLL-FISH abnormalities by pooling provincial data. From 2004 to 2011, 585 consecutive patients underwent pretreatment CLL-FISH testing at laboratory A (50.1%), laboratory B (32.3%), or laboratory C (17.6%). For validation purposes, 26 CLL-FISH abnormalities were tested by each laboratorys protocol, with 91% result concordance. Discordant results involved percent abnormalities at or near cutoff values; therefore, a 10% universal cutoff was established when pooling results. Applying the universal cutoff to the provincial cohort, CLL-FISH abnormalities were detected in 74.9%: 54.9% 13q-, 18.8% +12, 8.5% 11q-, and 7.7% 17p-. In this large population-based cohort of patients referred for CLL-FISH testing, frequencies of abnormalities detected by FISH analysis were highly consistent with those reported in single-institution and clinical trial populations. Provinces or districts that work together to care for CLL patients can effectively pool data with appropriate laboratory validation to ensure standardization of results.

Immunoglobulin heavy chain (IGH@) translocations negatively impact treatment-free survival for chronic lymphocytic leukemia patients who have an isolated deletion 13q abnormality.

Immunoglobulin heavy chain translocations (t(IGH@)) are suggested to portend a poor prognosis in chronic lymphocytic leukemia (CLL). To determine the clinical significance of a t(IGH@) on CLL-specific cytogenetic abnormalities, we analyzed the outcomes of 142 CLL patients referred for fluorescence in situ hybridization (FISH) analysis with our standard FISH panel, which includes testing for a t(IGH@). Whereas patients with unfavorable (deletion 17p, deletion 11q) and intermediate (trisomy 12, normal FISH) cytogenetics with concomitant t(IGH@) had similar median treatment-free survival (TFS) as those without a t(IGH@), patients with deletion 13q (del13q) and a t(IGH@) had significantly worse TFS than those without a t(IGH@): median TFS 4.7 versus 8.0 years, P = 0.03 (hazard ratio 4.21, 95% confidence interval 1.06-16.69 y, P = 0.04 in multivariate analysis after adjusting for age, sex, Rai stage, and white blood cell count). The presence of a t(IGH@) further stratified patients with del13q into two prognostic entities, whereby outcomes of those with coexistent del13q and a t(IGH@) were similar to outcomes of those with high risk cytogenetics. Knowledge of the t(IGH@) status in CLL is therefore of clinical importance, as del13q patients with concomitant t(IGH@) may not retain the previously expected favorable outcome.