Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma.

Grade 3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade 3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs autologous hematopoietic cell transplantation (auto-HCT) in the rituximab era. A total of 197 patients undergoing first reduced-intensity conditioning (RIC) allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naive patients were excluded. Allo-HCT recipients were younger, more heavily pretreated and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, PFS and overall survival (OS) for auto-HCT vs allo-HCT groups were 4% vs 27% (P<0.001), 61% vs 20% (P<0.001), 36% vs 51% (P=0.07) and 59% vs 54% (P=0.7), respectively. On multivariate analysis, auto-HCT was associated with reduced risk of NRM (relative risk (RR)=0.20; P=0.001). Within the first 11 months post HCT, auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11 months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; P=0.003) and inferior PFS (RR=3.2; P=0.005). In the first 24 months post HCT, auto-HCT was associated with improved OS (RR=0.42; P=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; P=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors.

Alternative donors extend transplantation for patients with lymphoma who lack an HLA matched donor.

Alternative donor transplantation is increasingly used for high-risk lymphoma patients. We analyzed 1593 transplant recipients (2000-2010) and compared transplant outcomes in recipients of 8/8 allele HLA-A, -B, -C and DRB1 matched unrelated donors (MUDs; n=1176), 7/8 allele HLA mismatched unrelated donors (MMUDs; n=275) and umbilical cord blood donors (1 or 2 units UCB; n=142). Adjusted 3-year non-relapse mortality of MMUD (44%) was higher as compared with MUD (35%; P=0.004), but similar to UCB recipients (37%; P=0.19), although UCB had lower rates of neutrophil and platelet recovery compared with unrelated donor groups. With a median follow-up of 55 months, 3-year adjusted cumulative incidence of relapse was lower after MMUD compared with MUD (25% vs 33%, P=0.003) but similar between UCB and MUD (30% vs 33%; P=0.48). In multivariate analysis, UCB recipients had lower risks of acute and chronic GVHD compared with adult donor groups (UCB vs MUD: hazard ratio (HR)=0.68, P=0.05; HR=0.35; P<0.001). Adjusted 3-year OS was comparable (43% MUD, 37% MMUD and 41% UCB). These data highlight the observation that patients with lymphoma have acceptable survival after alternative donor transplantation. MMUD and UCB can extend the curative potential of allotransplant to patients who lack suitable HLA matched sibling or MUD.

Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome.

We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.

Should persons with acute myeloid leukemia have a transplant in first remission?

Despite more than 40 years of extensive study, it remains uncertain which individuals, if any, with acute myelogenous leukemia (AML) in first remission should receive a blood cell or bone marrow transplant versus post-remission chemotherapy (or both). Nevertheless, there is a recent trend toward recommending more transplants in this setting. We consider four myths underlying this recommendation: (1) only individuals achieving second remission benefit from a transplant; (2) there is no effective therapy for relapse other than an allotransplant; (3) we can accurately predict which individuals with AML in first remission need a transplant; and (4) detection of minimal residual disease in first remission will resolve this controversy. We discuss these misconceptions and suggest approaches to resolve this issue.

Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research.

For adults with high-risk or recurrent ALL who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analysed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) CR. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five-year leukemia-free (37 vs 39%) and overall survival (OS) rates (38 vs 39%) were similar for Auto HSCT vs URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long-term follow-up in this analysis demonstrated that either Auto or URD HSCT could result in long-term leukaemia-free survival and OS for adult ALL patients. The optimal time (CR1 vs CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.

Metastatic solid-pseudopapillary tumour of the pancreas: clinico-biological correlates and management.

Solid-pseudopapillary tumour of the pancreas is a rare neoplasm of young women, currently categorised in the World Health Organization classification under exocrine pancreatic tumours. Increased awareness of this condition correlated recently with an apparent rise in incidence as well as recognition of more aggressive clinical courses. We describe two patients with solid-pseudopapillary tumour of the pancreas. A smaller, localised tumour in an unusually young white man was surgically excised with no evidence of recurrence after 2 years. The other case also had an uncommon presentation, with an aggressive course resulting in vascular encasement of the superior mesenteric bundle and aorta, and local involvement of the mesenteric lymph nodes. A literature review was carried out, and the main clinico-pathological features and strategies of treatment of solid-pseudopapillary tumour of the pancreas are presented. Pathological, genetic and molecular features distinguish solid-pseudopapillary tumours from pancreatic ductal adenocarcinoma. Furthermore, neuroendocrine differentiation can be found focally in occasional cases of solid-pseudopapillary tumour. Patients with localised disease are usually cured by surgery. Prolonged survival can be seen in the presence of distant metastasis, if such lesions are resected surgically. Chemotherapy and radiation therapy are used in rare cases when resection is not possible. No current chemotherapy regimens are considered standard in the treatment of this tumour. A rational chemotherapy protocol for such a rare tumour needs to consider its origin and clinical behaviour. However, the indolent clinical progression of solid-pseudopapillary tumours is similar to that of pancreatic neuroendocrine tumour.

Unusual cutaneous involvement during plasma cell leukaemia phase in a multiple myeloma patient after treatment with thalidomide: a case report and review of the literature.

We report the case of a 54-year-old African-American male with IgG multiple myeloma (MM) with disease resistant to multiple chemotherapy regimens and immunomodulatory treatment with thalidomide. In spite of achieving a partial remission of short duration, his disease accelerated to peripheral plasmacytosis and subsequent development of cutaneous plasmacytomas. The malignant plasma cells derived from the dermal lesions were CD45+, CD38+, CD138+ and matched the immunophenotype of the plasmacytes during the leukaemic phase. Occurrence of extramedullary lesions in the setting of MM treated with thalidomide is of concern, although currently there are very few reports describing this association. We discuss the possible relationship between the patient's unusual disease course and the administered chemo- and immunotherapy. The significance of the changes in adhesion molecules, especially CD138 and CD56, relevant to the development of cutaneous plasmacytomas is discussed.

Steroid-responsive inclusion body myositis associated with endometrial cancer.

Inclusion body myositis (IBM) is an uncommon chronic inflammatory myopathy. Although the association between other myopathies and cancer has been well established, the relationship between IBM and neoplasia is not completely understood. Unlike polymyositis (PM) or dermatomyositis (DM), IBM rarely responds to immunosuppressive treatment and the response is seldom long-lasting. We describe a case of IBM associated with endometrial carcinoma that also demonstrated a unique response to steroids alone which persisted despite cancer relapse. The factors that are associated with a response of IBM to steroids are discussed. An atypical, steroid-responsive form of the disease is delineated.

Chemotherapy-induced scleroderma: a pleiomorphic syndrome.

A scleroderma-like disease has recently been described in association with taxanes. We present the first case of diffuse scleroderma occurring in a woman treated with doxorubicin and cyclophosphamide for breast cancer. The clinical pattern of skin involvement and histological alterations were identical to those found in the classical form of scleroderma. Skin involvement progressed to affect 80% of total body area, and subsequently remained unchanged despite progression of the underlying cancer, making a paraneoplastic aetiology of the scleroderma unlikely. Specific chemotherapeutic agents might be directly responsible for the clinical manifestations and the parameters of progression. Analysis of all similar case reports defines the particular features and clinical course of this phenomenon.

Phase II study of theophylline in chronic lymphocytic leukemia: a study of the Eastern Cooperative Oncology Group (E4998).

The Eastern Cooperative Oncology Group (ECOG) performed a phase 2 study in B-cell chronic lymphocytic leukemia (CLL) of oral theophylline, a methylxanthine that inhibits cyclic nucleotide phosphodiesterases, thereby inducing the intracellular accumulation of cyclic adenosine monophosphate (cAMP). In 25 patients with Rai stages 0-I, theophylline, 200 mg given orally every 12 h was well tolerated. There was one complete response after 22.5 months of treatment, which continues at 27+ months, and 18 other patients had stable disease. In vitro exposure of patients' lymphocytes to aminophylline (75-250 microg/ml), the soluble form of theophylline, resulted in dose- and time-dependent induction of apoptosis in 9/20 patients studied. Apoptosis was documented flow-cytometrically by monitoring the expression of bcl-2 and bax, forward light scatter, fluorescence intensity of binding of CD45 antibody, and the binding of annexin. Patients whose leukemic lymphocytes were susceptible to apoptosis induction by aminophylline in vitro experienced a significantly longer progression-free survival than patients whose cells were resistant to the drug in culture (P=0.025). This suggests that in a CLL population treated with theophylline, induction of an apoptotic response to the drug in vitro is prognostic for absence of clinical progression.

A surrogate marker profile for PML/RAR alpha expressing acute promyelocytic leukemia and the association of immunophenotypic markers with morphologic and molecular subtypes.

BACKGROUND: The availability of genotype-specific therapy for PML/RAR alpha(pos) acute promyelocytic leukemia (APL) requires that this disease be precisely diagnosed. Immunophenotypic characteristics heretofore proclaimed as reliably characterizing APL (HLA-DR(low), CD34(low), P-glycoprotein(low) myeloid phenotype) do not differentiate from APL-like immune profiles unassociated with the PML/RAR alpha fusion transcript. METHODS: To establish a surrogate marker profile for APL, we explored 19 potentially predictive markers compared with differentiated acute myeloid leukemia using the classification tree approach with recursive partitioning. RESULTS: In a test group of 58 APL patients, the most predictive immune profile was HLA-DR(low), CD11a(low) (alpha(L) subunit of the leukocyte integrin LFA-1), CD18(low) (beta(2) subunit of LFA-1). APL cells always expressed CD117 (c-kit) but lacked the progenitor antigen CD133 and the more mature myeloid antigen, CD11b (alpha(M) leukocyte integrin). This antigen pattern was validated in 90 additional APL patients. M3v APLs (n = 30) had more leukemic promyelocytes expressing the T-cell antigen, CD2 (P < 0.0001) or the stem cell marker, CD34 (P = 0.0003) and demonstrated higher fluorescence intensity for the binding of antibody to the common leukocyte antigen, CD45 (P = 0.0008) than M3 (n = 102). S-form APL (n = 45) had a higher percent of cells expressing CD2 or CD34 (P < 0.0001 for both) or the neural cell adhesion molecule CD56 (P = 0.001) than L-form APL (n = 66). CONCLUSIONS: PML/RAR alpha(pos) APL cells typically lack leukocyte integrins. HLA-DR(low), CD11a(low), CD18(low) is a reliable surrogate antigen expression profile for PML/RAR alpha(pos) APL, irrespective of morphology and transcript isoform.

Autologous stem cell transplantation in multiple myeloma patients <60 vs >/=60 years of age.

The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients >/=the age of 60 (median 63; range 60-73) years, undergoing AuSCT with that of 382 patients <60 (median 52; range 30-59) years. The two groups were similar except that older patients had a higher beta(2)-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4-9) and 1-year treatment-related mortality (TRM) was 9% (6-13) in patients <60 years, compared with 5% (2-10) and 8% (4-14), respectively, in patients >/=60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT >12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.

Low expression of the myeloid differentiation antigen CD65s, a feature of poorly differentiated AML in older adults: study of 711 patients enrolled in ECOG trials.

CD65s appears when the progenitor antigen CD34 disappears, suggesting that this sialylated carbohydrate antigen marks a turning point in normal myeloid differentiation. We characterized acute myeloid leukemia (AML) with low CD65s expression (CD65s(low) AML) in 711 patients entered on seven Eastern Cooperative Oncology Group AML treatment trials (1986-1999). Of those, 198 (28%) qualified as having CD65s(low) AML. Morphologically, CD65s(low) AML was more common in FAB subgroups with minimal differentiation, M0/M1 (P=<0.0001). Early precursor antigens CD34, CD117 and terminal transferase were more frequent in CD65s(low) than CD65s(high) AML (P=<0.0001). Myeloperoxidase was present in fewer CD65s(low) myeloblasts, and the more mature myeloid antigens, CD15 and CD11b, were rarely detected (P=<0.0001). Yet, the two diagnoses did not differ in the distribution of cytogenetic prognostic groups or the occurrence of the multidrug-resistance mediator, P-glycoprotein. CD65s(low) AML patients were significantly older than CD65s(high) cases (P<0.0001). Furthermore, the incidence of CD65s(low) cases increased with age, from 20% in patients under the age of 50 years to 67% in patients older than 80 years (P<0.0001). Overall, complete remission (CR) rate and overall survival were comparable in CD65s(low) and CD65s(high) AML. However, among patients >55 years of age, CD65s(low) AML had a decreased CR rate of 33 vs 44% in CD65s(high) AML (P=0.055). Thus, CD65s(low) AML represents immunophenotypically undifferentiated disease and occurs predominantly in older adults. Although not statistically significant, the observed association between low CD65s expression and decreased CR rate only in patients over the age of 55 is intriguing.

Hairy cell leukemia in first cousins and review of the literature.

Familial hairy cell leukemia (HCL) occurs rarely. So far, 26 familial instances of HCL (in 12 families) have been reported in the literature. The consistent human leukocyte antigen (HLA) linkage could not be established in most cases of familial HCL. History of exposure to organic chemicals or employment in woodworking or farming was noted in only two out of 11 affected families. We present two familial cases of HCL as well as a thorough literature review. An influence of HLA or farming themselves on a predisposition to HCL remains unproven but does not rule out an HLA-linked and as yet unidentified gene responsible for increased disease susceptibility. HCL in families is unlikely to be due to random patterning, but there are insufficient data so far to decisively incriminate either HLA-related or environmental causative factors.

Treatment of human immunodeficiency virus-related lymphoma.

In newly diagnosed human immunodeficiency virus (HIV)-positive patients with non-Hodgkin's lymphoma (NHL), standard lymphoma regimens yield approximately a 50% complete response (CR) rate and an overall median survival of < or = 9 months. Treatment results of relapsed patients are extremely poor. Regimens that appear more effective than standard therapy have usually been investigated only in patients with relatively high CD4 counts. An exception is a regimen consisting of a continuous 96-hour infusion of cyclophosphamide, doxorubicin, and etoposide (CDE). A 62% CR rate was achieved in 21 patients with a median CD4 count of 87/microL, and the median overall survival was 18 months. In another study of 25 patients, didanosine (ddI) was added to CDE and was shown to cause less myelosuppression without compromising efficacy. Other studies suggest that highly active antiretroviral therapy (HAART) can be combined with intensive chemotherapy regimens, with improved efficacy attributed to less frequent dosage reduction of chemotherapeutic agents. More recently, autologous and syngeneic bone marrow transplantation have been explored in a handful of patients with acquired immunodeficiency syndrome (AIDS)-related NHL with promising results. Data on whether widespread use of HAART decreases the incidence of HIV-positive NHL are conflicting. Some clues from recent studies suggest we are close to an answer: (1) protease inhibitors significantly improve survival of HIV-positive patients with NHL; (2) only one of eight recent cases of HIV-positive men with NHL received HAART compared with greater than 70% of HIV-positive men free of NHL; and (3) no prior HAART independently predicted for AIDS-related NHL development. On the other hand, Hodgkin's disease may be increasing in frequency in HIV-positive patients as the incidence of NHL declines. It is hypothesized that more effective reconstitution of the immune system with HAART may facilitate the inversion of these incidences. Future prospective studies will hopefully answer these questions.

N-Methylformamide in advanced squamous cancer of the uterine cervix: an Eastern Cooperative Oncology Group phase II trial.

PURPOSE: Preclinical and clinical data support the study of polar-planar compounds such as N-Methylformamide (NMF) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II trial sought to determine the efficacy and toxicities of NMF in patients with advanced SCC. PATIENTS AND METHODS: Eligibility for this trial required bidimensionally measurable squamous or adenosquamous cell cancer of the uterine cervix incurable by surgery or radiation therapy, ECOG performance status of < or = 2, no prior NMF and no more than one prior chemotherapy regimen. Patients received NMF at 2000 mg/m2 intravenously over 15-30 minutes days 1, 8 and 15. The cycle was repeated every 42 days. A single dose escalation of 25%, 500 mg/m2 was made after the first cycle if the toxicities did not exceed grade I for hepatic toxicity and grade II for nausea and vomiting. RESULTS: From July 1987 through September 1998, 21 patients with advanced squamous cell carcinoma of the uterine cervix were entered on study. Two patients were ineligible because there was no pretreatment SGOT on one and the other deteriorated prior to drug approval. Therefore, 19 patients were include in the analysis of response and survival. Four were inevaluable, three due to inappropriate tumor evaluation and one secondary to grade III vomiting, who went off study. These patients were included in the denominator while computing the results. There were 2 deaths, one due to pulmonary hemorrhage from perforation during central venous insertion and one due to disease. 30% (6/19) patients had toxicities, Eastern Cooperative Oncology Group (ECOG) grade III or higher and 2 of these patients suffered multiple grade III toxicities. There were no complete or partial responses. CONCLUSION: In this population, NMF in the dose and schedule employed exhibited no clinical activity.

Bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone (BLEO-CCVPP) in patients with Hodgkin's disease who relapsed after radiotherapy alone: a long-term follow-up study of the Eastern Cooperative Oncology Group (E3481).

Thirty-three evaluable patients with Hodgkin's disease who failed radiotherapy were treated on this phase II study with bleomycin, lomustine, cyclophosphamide, vincristine, procarbazine and prednisone given every 28 days for a minimum of eight courses. Twenty-five patients (76%; 95% CI=55.6-87.1%) achieved a complete remission, the median duration of which cannot yet be determined, but the probability of remaining in continuous complete remission at 10 years is.64. The median survival from entry on this study for all evaluable patients is 10 years, and 12 patients were alive at the time of this analysis with a median follow-up for them of 15.5 years. Of the 22 patients who died, 11 died of progressive or recurrent Hodgkin's disease and 11 died of other causes including 7 second primary neoplasms and at least one myocardial infarction. Both are now well known late complications of Hodgkin's disease treatment.

Anticipation in familial chronic lymphocytic leukaemia.

Anticipation, a phenomenon in which an inherited disease is diagnosed at an earlier age in each successive generation of a family, has been demonstrated in certain heritable neurological disorders and in multiple myeloma, non-Hodgkin's lymphoma and other haematological neoplasms. The present study was conducted to determine whether anticipation occurs in familial chronic lymphocytic leukaemia (CLL). Fourteen published reports of multigenerational familial CLL were analysed for anticipation, together with 10 previously unreported families with familial CLL, and the difference in disease-free survival between generations was determined. The difference between age at onset for each affected parent-child pair was tested against the null hypothesis that there was no difference in age at onset. The age at onset of the studied cases was also compared with that of the Surveillance Epidemiology and End Results (SEER) Program of the U.S. National Cancer Institute. The median ages at onset in the child and parent generations of all families (51.0 and 72.0 years respectively) were significantly different (P < 0.000001), and the null hypothesis was rejected (P < 0.000001). A significant difference was observed between the ages of onset of the child generation and the SEER population (P < 0.00001), but not between the parent generation and the SEER population. Anticipation characterizes familial CLL.