Emilio Montserrat

Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.

The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of ‘poor-risk CLL’ requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.

Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance

Summary. In 100 untreated patients with chronic lymphocytic leukaemia (CLL) lymphocyte doubling time (LDT) has been investigated in relationship with clinical stages, bone marrow histological patterns, treatment‐free period and survival. Although partially correlated with clinical stages and bone marrow patterns. LDT has a clear prognostic significance by itself: whereas a LDT of 12 or less months identifies a population of patients with poor prognosis, a LDT higher than 12 months is indicative of good prognosis as substantiated by a long treatment‐free period and survival. This simple parameter can be useful in the clinical management of CLL patients.

HLA-Identical Sibling Bone Marrow Transplantation in Younger Patients with Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) is considered a disease of the elderly, but it is being increasingly diagnosed in younger people. About 40% of patients with CLL are less than 60 years old [1]. The median survival is about 3 years for patients with Rai stage 3 or 4 disease [1]. Prognostic variables associated with reduced survival include high blood lymphocyte levels, short lymphocyte doubling time, chromosome abnormalities, and a diffuse pattern of bone marrow infiltration with leukemia cells [1-7]. The short median survival of patients with Rai stage 3 or 4 CLL and of those with additional adverse prognostic features has led to studies of intensive treatments [8-10]. Bone marrow transplants from HLA-identical siblings reportedly result in long-term survival in some patients [11]. We analyzed results of HLA-identical sibling bone marrow transplantation for CLL in 54 patients who were younger than 60 years old; these transplantations were done between 1984 and 1992 and reported to either the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry. We estimate that this analysis includes more than half of all HLA-identical sibling donor transplants for CLL done before 1993 [12]. Methods Patients Data on 54 patients receiving HLA-identical sibling bone marrow transplants for CLL were reported to the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry or both between 1984 and 1992. Patient and disease characteristics are described in Table 1. The median age of the 54 patients was 41 years (range, 21 to 58 years). The median interval from diagnosis to transplantation was 37 months (range, 5 to 130 months). Seventeen patients have been previously described [11]. Six transplantations were done in the first year after diagnosis; 17 were done 1 to 3 years after diagnosis; 19 were done 3 to 5 years after diagnosis; and 12 were done more than 5 years after diagnosis. Forty-seven patients had B-cell CLL, and the immunotype was unknown in 7 patients. Table 1. Characteristics and Transplant Outcomes for 54 Patients Receiving HLA-Identical Sibling Transplants for Chronic Lymphocytic Leukemia* The therapy administered before transplantation varied. Four patients received no treatment; 19 received chlorambucil alone or with prednisone; 5 received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and 21 received cyclophosphamide, vincristine, doxorubicin, bleomycin, and interferon, alone or in combination. No data on previous treatment were available in 5 patients. Two patients received local irradiation and 3 received total lymphoid irradiation and chemotherapy. Ten patients had a splenectomy. Of 47 evaluable patients, 7 were considered to have disease responsive to chemotherapy at the time of transplantation, 19 had stable disease, and 21 had progressive disease according to previously published criteria [13]. Patients were selected for transplantation according to criteria set at each transplantation center. Most received transplants for advanced (Rai stage 3 or 4) or longstanding disease. In patients with Rai stage 0 to 2 CLL whose disease had been diagnosed less than 3 years previously, indications varied from consolidation of a good response to chemotherapy, poor response to conventional-dose therapy, or young age. Donors Donors were HLA-identical siblings; 39 were men and 15 were women. The median age was 41 years (range, 21 to 55 years). Pretransplant Conditioning All patients received cyclophosphamide (median dose, 120 mg/kg body weight; range, 90 to 150 mg/kg). Fifty-one also received total body irradiation (median dose, 12 Gy [range, 8 to 14 Gy]; median fractions, 5 [range, 1 to 9 fractions]). Three patients received cyclophosphamide and busulfan (16 mg/kg) without irradiation. Nineteen patients received one or more additional drugs including etoposide (n = 13), cytarabine (n = 5), chlorambucil (n = 1), melphalan (n = 1), and daunorubicin (n = 1). Prophylaxis for Graft-versus-Host Disease All patients received prophylactic therapy for graft-versus-host disease. Two received methotrexate, 8 received cyclosporine, and 35 received both methotrexate and cyclosporine. Eight patients received a T-cell-depleted graft; 7 of these patients also received cyclosporine. One patient received a monoclonal anti-interleukin-2 receptor antibody and cyclosporine. Four patients had prednisone added to these regimens. Outcome Measures Patients were considered evaluable for engraftment if they survived more than 30 days after transplantation. Those with engraftment who survived more than 21 days were considered at risk for acute graft-versus-host disease, and those with engraftment who survived more than 100 days were considered at risk for chronic graft-versus-host disease. Hematologic remission was defined as normalization of leukocyte counts, hemoglobin level, and platelet counts and absence of lymphadenopathy and hepatosplenomegaly. There was no requirement for bone marrow normalization. The focus of the study was hematologic remission and survival; we did not study leukemia-free survival because bone marrow examinations were not routinely done after transplantation and because leukemia-free survival is poorly defined in CLL. Data from immunologic and molecular tests were not used to define remission; tests for assessing clonality, such as immunoglobulin gene rearrangement and dual antibody-labeling flow cytometry, are not commonly done and are of unproven clinical significance. However, these data are reported when available. Kaplan-Meier survival estimates and CIs were calculated using BMDP software (BMDP Statistical Software, Los Angeles, California). Results Patient outcomes are shown in Table 1. Forty-five of 49 evaluable patients (92%) had stable engraftment, and 4 (8%) had graft failure. Acute (grade II-IV) graft-versus-host disease developed in 17 of 46 patients at risk (37%); 9 of these patients (53%) died. Chronic graft-versus-host disease developed in 17 of 35 patients at risk (49%) and was extensive in 6. Thirty-eight patients (70%) achieved hematologic remission. Twenty-four were alive at a median of 27 months (range, 5 to 80 months) after transplantation. Three-year survival probability was 46% (95% CI, 32% to 60%) (Figure 1). The 3 patients receiving transplants at Rai stage 0 were alive 21, 32, and 45 months after transplantation. Three-year survival probabilities were 68% (CI, 38% to 98%) in the 10 patients receiving transplants at Rai stage 1, 30% (CI, 2% to 58%) in the 10 patients receiving transplants at Rai stage 2, 57% (CI, 21% to 93%) in the 7 patients receiving transplants at Rai stage 3, and 34% (CI, 12% to 56%) in the 22 patients receiving transplants at Rai stage 4. Three-year survival probability was 86% (CI, 62% to 100%) in patients with disease responsive to pretransplant chemotherapy; 61% (CI, 38% to 84%) in those with stable disease; and 23% (CI, 2% to 44%) in those with progressive disease. Figure 1. Probability of survival among 54 patients after HLA-identical sibling bone marrow transplantation for chronic lymphocytic leukemia. Of the 24 transplant recipients who are alive, 23 (96%) are in hematologic remission. Ten of these 23 patients had immune phenotyping of the peripheral blood: Seven had a normal profile (patients 7, 10, 12, 21, 23, 27, and 42), whereas 3 (patients 3, 24, and 30) had an excess of cluster differentiation antigen 5 (CD5) expression, which is known to be associated with CLL. Four patients had molecular studies after transplantation; these studies did not show gene rearrangement that would suggest persistent leukemia (patients 12, 21, 27, and 49). Of the 30 patients who died, 5 died of disease and 25 died of treatment-related causes. Ten treatment-related deaths were from acute or chronic graft-versus-host disease; 4 from hepatic veno-occlusive disease; 2 each from graft failure, adult respiratory distress syndrome, interstitial pneumonitis, and bacterial infection; and 1 each from hemorrhage, fungal infection, and viral infection. Discussion The 54 patients we evaluated all had CLL, were less than 60 years of age, and received HLA-identical sibling transplants. About half of this patient group achieved hematologic remission. Although we studied data from more than half the transplant recipients for CLL worldwide, the small number of patients precluded adjustment for potential prognostic variables like interval from diagnosis to transplantation and response to conventional chemotherapy. Treatment-related mortality in this study was highnearly 50%a figure similar to that observed after allografts for adults with acute lymphoblastic leukemia in first remission, acute myelogenous leukemia in second remission, and Hodgkin disease [14-16]. It may result, in part, from effects of extensive previous treatment. The focus of this study was on hematologic remission and survival after transplantation. We did not consider leukemia-free survival, because this is poorly defined in CLL. We also did not use data from immunologic or molecular tests because these are not uniformly performed and are of unproven clinical import. Our study was not designed to evaluate the role of HLA-identical sibling bone marrow transplantation in the treatment of CLL. However, we believe that the results in 54 patients treated at different centers suggest that allogeneic transplantation is feasible in patients less than 60 years of age. These results must be compared with those for other therapies, such as traditional chemotherapy, fludarabine, 2-chlorodeoxyadenosine, and autotransplantation [17-20]. Appendix Other contributors to this manuscript were Mary M. Horowitz, MD, MS, John P. Klein, PhD, and Mortimer M. Bortin, MD (deceased), of the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; Kerry Atkinson, MD, of the Depar

Myelofibrosis with myeloid metaplasia in young indidviduals: disease characteristics, prognostic factors and identification of risk groups

Myelofibrosis with myeloid metaplasia (MMM) is an uncommon disorder in young individuals, for whom haemopoietic stem cell transplantation offers the only possibility of cure. However, although the latter procedure is associated with significant morbidity and mortality, the clinical course of MMM is variable, with some patients surviving for less than a year and others showing an indolent course. Selection of young MMM patients for transplantation or other newer therapies is currently difficult since no prognostic data exists for this subgroup. In the present collaborative study a number of initial clinical and laboratory parameters have been evaluated for prognosis in 121 MMM patients aged 55 years or less. Median survival of the series was 128 months (95% CI 90–172). In the Cox proportional hazard regression model three initial variables were independently associated with shorter survival: Hb <10 g/dl (P < 0.0001), the presence of constitutional symptoms (fever, sweats, weight loss) (P = 0.001), and circulating blasts ≥ 1% (P = 0.003). Based on the above three criteria, of the 116 patients with complete data, two groups were identified: a ‘low‐risk’ group, characterized by 88 patients with up to one adverse prognostic factor, in whom MMM had an indolent course (median survival 176 months, 95% CI 130–188), and a ‘high‐risk’ group, including 28 patients with two or three factors, who had a more aggressive disease (median survival 33 months, 95% CI 20–42). The above prognostic scoring system showed a high positive predictive value, sensitivity and specificity to predict survival in the series, and could be of help in making treatment decisions in young patients with MMM.

Applicability of the International Index for aggressive lymphomas to patients with low-grade lymphoma.

PURPOSE Variables used to build up the International Index for aggressive lymphomas (age, performance status, stage, extranodal involvement, and lactic dehydrogenase [LDH]) are also important in low-grade lymphoma. To assess the prognostic value of this index in low-grade lymphoma, we have applied it to a series of 125 patients. PATIENTS AND METHODS One hundred twenty-five patients with low-grade lymphoma who were diagnosed at a single institution over a 20-year period and treated with standard chemotherapy were studied. End points of the study were response to therapy and survival according to the International Index. In addition to the International Index, main initial and evolutive variables were evaluated. Univariate and multivariate methods were used. RESULTS After applying the International Index, the patients divided into four risk groups: low (36% of cases), low-intermediate (32%), high-intermediate (20.8%), and high (11.2%), with complete response (CR) rates in the four groups being 60%, 35%, 23%, and 21%, respectively. Ten-year overall survival rates for the risk groups were as follows: low, 73.6%; low-intermediate, 45.2%; high-intermediate, 53.5%; and high, 0% (P < .001). When the International Index was included in a multivariate analysis, along with the main initial variables, International Index (P < .001) and sex (male, worse) (P = .038) were the only parameters related to survival. When response to therapy was also included, achievement of CR (P < .0001) and International Index (P < .001) were the most important factors. In patients who achieved a CR, the International Index was the only parameter related to survival (P = .051). The results were the same when the International Index was applied to the subset of 107 patients with follicular lymphoma. CONCLUSION In this study, the International Index has been found to be an important prognostic tool in low-grade lymphomas. Such an index could be used to predict prognosis not only in aggressive, but also in low-grade lymphomas.

Chronic myeloid leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

In most cases, diagnosis is based on blood counts (leukocytosisand frequently also thrombocytosis) and differential (immaturegranulocytes, from the metamyelocyte to the myeloblast, andbasophilia). Splenomegaly is present in >50% of cases of CMLin the initial chronic phase (CP), but 50% of patients areasymptomatic.Proof of diagnosis is attained by demonstration of thePhiladelphia (Ph) chromosome (22q-) resulting from thebalanced translocation t(9;22) (q34;q11), and/or the BCR-ABLrearrangement in peripheral blood or bone marrow cells. Insome cases ( 5%) a Ph chromosome cannot be detected, andconfirmation of diagnosis rests on molecular genetic methods,e.g. fluorescent in situ hybridization (FISH), or reversetranscriptase–polymerase chain reaction (RT–PCR).

Chronic Lymphocytic Leukaemia: Proposals for a Revised Prognostic Staging System

In the past the clinical course of chronic lymphocytic leukaemia (CLL) has been considered to be highly variable primarily due to a lack of understanding of prognostic factors. In the mid-1’370s Rai et al (1975) developed a simple staging system based on easily obtainable clinical and haematological data. The validity of the Rai clinical staging classification to predict the expected duration of survival of CLL patients has been confirmed by a number of subsequent publications (Phillips et al, 1977; Binet et al, 1977; Dighiero et al, 1979; Santoro et al, 1979; Rundles & Moore, 1978; Montserrat et al, 1977). This staging system brought a new perspective to clinical investigations in CLL by allowing the study of groups of patients of similar life expectancy in more comparable therapeutic trials. With use, certain limitations of the staging system have been recognized. The major inadequacies that have emerged requiring a revision of the system include: (1) the use of too many clinical groups (stages) making the design of useful therapeutic trials more difficult; and (2) a lack of consideration for the role of isolated organomegaly (e.g. splenomegaly or hepatomegaly) without lymphadenopathy in estimating the clinical prognosis of patients. An international workshop on CLL met in Paris in November 1979 and data on 295 patients were presented (Binet et al, 1981). In a second meeting in Montreal in August 1980 data on a larger number of patients were pooled. The outcome of a multivariatc analysis of more than 900 patients demonstrated three patterns of survival curves and the analysis resulted in a proposal for a new staging classification of CLL. Patients with anaemia (Hb < 10 g/dl) and/or thrombocytopenia ( < 100 x 10y/l) were found to have the poorest prognosis and were to be called group C. The prognosis of the remaining patients (approximately 80% of all the patients) was found to depend on the number of clinically relevant areas involved. Clinical enlargement of the spleen, the liver, and of lymph nodes in the cervical, axillary and inguinal regions constituted * Sponsored by the French National Cancer League and the National Leukemia Association, Inc. (U.S.A.). Participants: A. AUQUIER, Paris, France; J. BENNETT, Rochester, New York, U.S.A.; J.-L. BINET, Paris, France; K. BREMER, Essen, Germany; D. CATOVSKY, London, England; P. CHANDRA, Upton, New York, U.S.A.; C. CHASTANG, Paris, France; E. P. CRONKITE, Upton, New York, U.S.A.; G. DIGHIERO, Paris, France; D. A. G. GALTON, London, England; M. M. HANSEN, Copenhagen, Denmark; A. HUANG, Durham, N. Carolina, U.S.A.; C. JACQUILLAT, Paris, France; E. MONTSERRAT, Barcelona, Spain; H. PIGUET, Rouen, France; K. R . RAI, New Hyde Park, New York, U.S.A.; C. ROZMAN, Barcelona, Spain; W. RUNDLES, Durham, N. Carolina, U.S.A.; A. SAWITSKY, New Hyde Park, New York, U.S.A.; P. STRYCKMANS, Brussells, Belgium; C. SULTAN, Paris, France; M. WEIL, Paris, France. Correspondence: Dr A. Sawitsky, Long Island Jewish-Hillside Medical Center,. New Hyde Park, New York 11042, U.S.A.

Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk

To identify new risk variants for chronic lymphocytic leukemia (CLL), we conducted a genome-wide association study of 299,983 tagging SNPs, with validation in four additional series totaling 2,503 cases and 5,789 controls. We identified four new risk loci for CLL at 2q37.3 (rs757978, FARP2; odds ratio (OR) = 1.39; P = 2.11 × 10−9), 8q24.21 (rs2456449; OR = 1.26; P = 7.84 × 10−10), 15q21.3 (rs7169431; OR = 1.36; P = 4.74 × 10−7) and 16q24.1 (rs305061; OR = 1.22; P = 3.60 × 10−7). We also found evidence for risk loci at 15q25.2 (rs783540, CPEB1; OR = 1.18; P = 3.67 × 10−6) and 18q21.1 (rs1036935; OR = 1.22; P = 2.28 × 10−6). These data provide further evidence for genetic susceptibility to this B-cell hematological malignancy.

Major vascular complications in essential thrombocythemia: a study of the predictive factors in a series of 148 patients.

To determine the clinicohematological factors predictive for the appearance of major vascular complications (MVC) in patients with essential thrombocythemia (ET), 148 consecutive such patients were retrospectively assessed for the development of MVC during a median follow-up of 58.5 months. Seventy-seven patients had vascular risk factors, and 37 a history of MVC at ET diagnosis. Forty-nine MVC were registered in 33 patients during the follow-up period. The actuarial probability of MVC was 27% at 6 years in the whole series, 35.6% for patients above 60 years, and 21.4% for patients younger than 60 years, whereas only one of the 36 patients younger than 45 years had MVC. At multivariate analysis, age >60 years, history of major ischemia and hypercholesterolemia were the variables associated with an increased MVC risk. These results suggest that all ET patients above 60 years should be treated, whereas in younger patients treatment decisions should be primarily based on the existence of risk factors for MVC.

Identification of ‘short-lived’ and ‘long-lived’ patients at presentation of idiopathic myelofibrosis

To contribute to a better knowledge of the prognosis of idiopathic myelofibrosis (IM), the prognostic value of the presenting features in 106 patients diagnosed with IM at a single institution during a 21‐year period was retrospectively analysed. Median survival was 59.4 months (95% CI 40.7–75.4). Using univariate analysis, age < 64 years, constitutional symptoms (fever, night sweats, weight loss), Hb < 10 g/dl, circulating blasts (≫1%), and serum LDH > 3 times upper normal level were associated with a significantly shorter survival; male sex, platelet count <100×109/l, blood percentage of immature granulocytes (excluding blasts), low cholesterol levels and advanced marrow histological stage had borderline significance. Using multivariate study, only age > 64 years, constitutional symptoms, Hb < 10 g/dl, and circulating blasts retained their prognostic relevance. The latter three variables confirmed their predictive value in patients above and below the series median age, and were able to identify two groups of patients: a low‐risk group of 67 patients with none or one bad prognostic factor, in whom IM had an indolent course (median survival 98.8 months, 95% CI 68.7–127.6), and a high‐risk group, including 39 patients with two or three factors, with a more aggressive disease (median survival 20.6 months, 95% CI 10–28.2). Finally, the application of two recently proposed scoring systems (in which three prognostic groups are considered) was unable to separate intermediate‐ from high‐risk patients.