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Pulmonary alveolar proteinosis (PAP) developed in 5 patients with hematologic malignancy or lymphoma. Possible pathogenetic mechanisms which might predispose the patient to this association include the unavailability of competent alveolar phagocytes secondary to profound leukopenia, or inhibition of alveolar phagocytosis by elevated globulins. The spectrum of pulmonary abnormalities produced by PAP includes classical butterfly perihilar alveolar consolidation, lobar consolidation, parenchymal nodules, and hilar adenopathy. Four of the 5 cases had complicating infections, making the exact radiological correlation with PAP difficult.

Following the 53rd annual meeting of the American Society of Hematology (ASH) in San Diego in December 2011, a group of clinical and laboratory investigators convened for the 6th Post-ASH International Workshop on Chronic Myeloid Leukemia (CML) and Myeloproliferative Neoplasms (MPN). The Workshop took place on 13-14 December at the Estancia, La Jolla, California, USA. This report summarizes the most recent advances in the biology and therapy of CML that were presented at the ASH meeting and discussed at the Workshop. Preclinical studies focused on the CML stem cell and its niche, and on early results of deep sequencing of CML genomes. Clinical advances include updates on second- and third-generation tyrosine kinase inhibitors (TKIs), molecular monitoring, TKI discontinuation studies and new therapeutic agents. A report summarizing the pertinent advances in MPN has been published separately.

Objective: To compare outcomes of identical-twin with HLA-identical sibling bone marrow transplants for leukemia.Design: Matched-pair analysis comparing relapse, treatment-related mortality, and leukemia-free survival in cohorts matched for disease and variables correlated with transplant outcome, with and without adjustment for graft-versus-host disease.Setting: 163 institutions worldwide between 1978 and 1990, reporting to the International Bone Marrow Transplant Registry.Participants: 103 identical-twin transplants: 24 for acute lymphoblastic leukemia (ALL) in first remission, 45 for acute myelogenous leukemia (AML) in first remission, and 34 for chronic myelogenous leukemia (CML) in first chronic phase. Results were compared with those in 1030 concurrent HLA-identical sibling transplants matched for prognostic factors.Results: Three-year probabilities of relapse after identical-twin compared with HLA-identical sibling transplants were as follows: ALL, 36% (95% CI, 17% to 55%) compared with 26% (CI, 20% to 32%); AML, 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%); and CML, 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%). Increased relapse risks in AML and CML persisted after adjusting for graft-versus-host disease (relative risk, 3.1 [CI, 1.9 to 5.1] and 5.5 [CI, 2.8 to 11.0], respectively). Although twins had less treatment-related mortality than HLA-identical siblings, leukemia-free survival was similar. Three-year leukemia-free survival probabilities after twin compared with HLA-identical sibling transplants were as follows: ALL, 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%); AML, 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%); and CML, 59% (CI, 42% to 76%) compared with 61% (CI, 56% to 66%).Conclusions: Identical-twin transplants in AML and CML are associated with increased relapse risk compared with HLA-identical sibling transplants. A similar trend was observed in ALL but was not statistically significant. Increased relapse in twin transplants is not explained by lack of graft-versus-host disease. Leukemia-free survival after twin and HLA-identical sibling transplants is similar because increased relapse in twins is offset by decreased treatment-related mortality. [ABSTRACT FROM AUTHOR]

We have identified two novel ABL1 fusion genes in two patients with B-cell acute lymphoblastic leukaemia (ALL) associated with a t(3;9)(p12;q34) and a t(5;9)(q23;q34), respectively. Molecular analysis revealed a FOXP1-ABL1 fusion for the t(3;9) and a SNX2-ABL1 fusion for the t(5;9). The fusions were confirmed by specific amplification of the genomic breakpoints using reverse transcription polymerase chain reaction. The identification of ALL with rare ABL1 fusion partners is important because the leukaemia may respond to tyrosine kinase inhibitors in the same way as ALL patients with a classical BCR-ABL1 fusion gene. [ABSTRACT FROM AUTHOR]

Disease stage and recipient/donor human leukocyte antigen (HLA) matching are important determinants of outcome in transplantation using volunteer-unrelated donors (VUD). Matching for HLA-A, -B, -C, -DRB1, -DQB1 is beneficial, whereas the importance of DPB1 matching is more controversial. The impact of HLA matching status may differ dependent on disease stage. We investigated the outcome according to the degree of HLA matching at 6 loci, in 488 recipients of predominantly T-cell depleted bone marrow VUD transplants for leukaemia. Survival was significantly better in 12/12-matched transplants in those with early leukaemia (5 years: 63 versus 41% in 10/10 matched, P=0.006), but not late stage disease. Conversely, within the HLA-mismatched group (< or =9/10), there was a significant survival advantage to DPB1 mismatching (5 years: 39 versus 21% in DPB1 matched, P=0.008), particularly in late leukaemia (P=0.01), persisting in multivariate analysis (odds ratio 0.478; 95% confidence interval 0.30, 0.75; P=0.001). These novel findings suggest that the best outcome for patients with early leukaemia, with a 10/10-matched donor, is achieved by matching for DPB1. Conversely, our results suggest that in patients receiving an HLA-mismatched graft, the outcome is significantly better if they are also mismatched for DPB1. We recommend validation of these results in independent datasets. [ABSTRACT FROM AUTHOR]

Ph-positive chronic myeloid leukemia (CML) and Ph-negative chronic myeloproliferative diseases (MPDs), characterized in many cases by the presence of the JAK2V617F mutation, have many features in common and yet also show fundamental differences. In this review, we pose five discrete and related questions relevant to both categories of hematological malignancy, namely: What are the mechanisms that underlie disease progression from a relatively benign or chronic phase? By what therapeutic methods might one target residual leukemia stem cells in CML? Is JAK2V617F the original molecular event in MPD? What epigenetic events must have a role in dictating disease phenotype in MPDs? And finally, Will the benefits conferred by current or future JAK2V617F inhibitors equal or even surpass the clinical success that has resulted from the use of tyrosine kinase inhibitors in CML? These and others questions must be addressed and in some cases should be answered in the foreseeable future. [ABSTRACT FROM AUTHOR]

Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3+ cell dose 107/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility.Leukemia (2007) 21, 943–948. doi:10.1038/sj.leu.2404641; published online 15 March 2007 [ABSTRACT FROM AUTHOR]

We monitored BCR-ABL transcript levels by quantitative real-time PCR in 103 patients treated with imatinib for chronic myeloid leukaemia in chronic phase for a median of 30.3 months (range 5.5-49.9) after they achieved complete cytogenetic remission (CCyR). The patients could be divided into three groups: (1) in 32 patients transcript levels continued to decline during the period of observation (nadir BCR-ABL/ABL ratio 0.015%); in five of these patients BCR-ABL transcripts became undetectable on repeated testing, (2) in 42 patients the transcript levels reached a plateau and (3) in 26 patients transcript numbers increased and the initial CCyR was lost. Three patients were not evaluable. Patients who remained in CCyR for at least 24 months appeared to have a low risk of subsequent cytogenetic relapse. We conclude that the pattern of‘residual’disease after achieving CCyR on imatinib is variable: some patients in CCyR show a progressive reduction in the level of residual disease, some reach a plateau where transcript numbers are relatively stable and others relapse with Ph-positive metaphases.Leukemia (2005) 19, 507-512. doi:10.1038/sj.leu.2403664 Published online 10 February 2005 [ABSTRACT FROM AUTHOR]

The study of chronic myeloid leukemia has yielded many insights, especially after the discovery of the Ph chromosome, into the pathogenesis of leukemia and other forms of malignant disease. Most recently, knowledge of the central function of the BCR-ABL fusion gene led to the development of a small molecule, imatinib, that has proved remarkably effective at reducing the number of leukemia cells in individual CML patients and promises to prolong life substantially in comparison with earlier treatments. However, many questions relating to this exciting new agent remain unanswered, for example, how exactly it works, how patients develop resistance and what can be done to prevent or delay its onset, and whether any patient can really be “cured” by its use. [Copyright &y& Elsevier]

Focuses on a number of tools to circumvent or reverse some of the disadvantages of allogeneic bone marrow transplantation. Reconstitution of viral-specific immunity; Immunotherapy of relapsed leukemias; Factors influencing the time to achieve molecular remission following donor lymphocyte infusions in patients who relapse with chronic myeloid leukemia.

To determine the source of residual disease detected in patients with chronic myeloid leukaemia (CML) in complete cytogenetic remission (n = 8) after treatment with interferon-α (IFN-α), we have tested CFU-GM colonies grown from bone marrow mononuclear cells or from plastic-adherent (PΔ) cells for BCR-ABL mRNA using a nested multiplex RT-PCR. We compared our results with those obtained by analysis of colonies from newly diagnosed patients (n = 4) and patients achieving no cytogenetic response (n = 1) or incomplete cytogenetic response to treatment with IFN-α (n = 5). A total of 1239 informative colonies were analysed. A small proportion of BCR-ABL-positive colonies was detected in all eight patients in complete cytogenetic remission, suggesting the persistence of leukaemia that could potentially lead to relapse. The overall proportion of BCR-ABL-positive colonies in patients achieving a cytogenetic response to IFN-α correlated with the levels of BCR-ABL transcripts detected in the peripheral blood by competitive RT-PCR (P = 0.004). We conclude that residual disease detected in the peripheral blood of complete cytogenetic responders to IFN-α is at least partly derived from clonogenic myeloid cells. It is probable that the leukaemia clone in CML is only very rarely or never entirely eradicated by treatment with IFN-α. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome-positive (Ph+) hemopoietic cells predominate in patients with chronic myeloid leukemia (CML) in chronic phase, but some Ph presumably normal stem cells persist in most patients. Ph cells are relatively frequent, compared to mature cell populations, in primitive hemopoietic cell populations from CML patients. We have purified CD34+ cells from chronic phase CML blood and separated them into two fractions on the basis of adherence or non-adherence to tissue culture plastic. We also separated CD34+ CML cell populations into HLA-DR(hi) and HLA-DR(lo) fractions and CD38(hi) and CD38(lo) fractions by flow cytometry. The CD34+ cells that adhered to plastic were predominantly CD33-, CD38- and HLA(-)-DR; cells with these phenotypic properties were significantly rarer in the CD34+ non-adherent cell population (P = 0.008-0.02). Expression of p210 BCR/ABL mRNA by adherent, non-adherent, HLA-DR(hi) and HLA-DR(lo)CD34+ cell subpopulations was demonstrated by RT-PCR. Using fluorescence in situ hybridization (FISH) in conjunction with BCR and ABL probes we detected Ph+ and Ph- cells in both adherent and non-adherent CD34+ cell fractions of 15/15 patients studied and in the HLA-DR(lo) or CD38(lo) sorted CD34+ cell fractions. The concentration of Ph- cells in the adherent CD34+ cell fraction was three-fold higher than in the non-adherent fraction (P = 0.001). Ph- adherent cells were detected in untreated CML patients and as late as 6 years after diagnosis of CML in patients treated with hydroxyurea (HU) or interferon-alpha (IFN-alpha). We conclude that whilst appreciable numbers of Ph- primitive hemopoietic progenitors are present in the circulation in untreated patients and also in treated patients in late chronic phase, the majority of cells expressing CD34 but not CD33, CD38 or HLA-DR antigens, are part of the CML clone. [ABSTRACT FROM AUTHOR]

The author reflects on the chronic myeloid leukemia (CML) which is assumed to be one of the major forms of cancer in India. Topics include clinical results of using Imatinib, a drug, in large numbers of patients, best methodology for diagnosing CML and monitoring response to therapy, and the Glivec International Patient Assistance Program (GIPAP). Other topics include Indian patients.

The article discusses reports published within the issue including one about cases of leukemia occurring in individuals who had received hematopoietic growth factors and another about abnormalities in lymphocytes in normal people who had received granulocyte colony-stimulating factors.

Reports that single immunodominant minor H antigen is responsible for the beneficial effects of donor T lymphocytes against host leukemia. Infusion of T cells directed against multiple minor H antigen differences; Assessment of the numbers of antigen-specific T cells directed against a particular minor H epitope.

The article offers information on the term minimal residual disease (MRD) which is used in the past years when techniques to measure residual leukemia were rather insensitive by modern's standards.

Increasing numbers of allogeneic hematopoietic stem cell transplantation (allo-SCT) are being performed for patients who have failed a previous allogeneic or autologous SCT. We investigated whether the EBMT risk score could predict outcome after a subsequent allo-SCT. We analyzed prognostic factors in 124 consecutive patients who underwent a second transplantation using an allogeneic donor at our institution. Patients with either a first autologous (N = 64) or first allogeneic (N = 60) SCT were included. Age, disease stage, time interval from diagnosis to transplantation, donor type, and donor–recipient sex combination were used to establish a score from 0 to 7 points, from which 3 groups were identified. The 5-year survival probability decreased from 51.7% for risk scores 0-3 (low, n = 25), to 29.3% for risk score 4 (intermediate, n = 42), and only 10.4% for risk scores 5-7 (high, n = 57), P = .001. We propose that the EBMT risk score can identify patients most likely to benefit from a second transplantation. [ABSTRACT FROM AUTHOR]

Until the recent introduction of imatinib, interferon alfa was the standard treatment for patients in the chronic phase of chronic myeloid leukaemia. We compared survival of 143 such patients, who did not respond to interferon alfa and were treated with imatinib, with that of 246 historical controls who received conventional treatment. Patients on imatinib showed an overall survival advantage (relative risk 0.54, 95% CI 0.31-0.93). However, although patients on imatinib who achieved at least some degree of cytogenetic response after 6 months had better survival than controls (0.13, 0.05-0.39), those with no cytogenetic response to imatinib had significantly worse survival (1.69, 1.09--2.64). Our findings suggest that cytogenetic responders obtain benefit from imatinib but patients who show no cytogenetic response should be given alternative treatment without delay. We confirmed these results in a case-matched analysis. [ABSTRACT FROM AUTHOR]