Ester Pungolino

A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment)

Age older than 65 years, hemoglobin level lower than 100 g/L (10 g/dL), white blood cell count greater than 25 x 10(9)/L, peripheral blood blasts 1% or higher, and constitutional symptoms have been shown to predict poor survival in primary myelofibrosis (PMF) at diagnosis. To investigate whether the acquisition of these factors during follow-up predicts survival, we studied 525 PMF patients regularly followed. All 5 variables had a significant impact on survival when analyzed as time-dependent covariates in a multivariate Cox proportional hazard model and were included in 2 separate models, 1 for all patients (Dynamic International Prognostic Scoring System [DIPSS]) and 1 for patients younger than 65 years (age-adjusted DIPSS). Risk factors were assigned score values based on hazard ratios (HRs). Risk categories were low, intermediate-1, intermediate-2, and high in both models. Survival was estimated by the HR. When shifting to the next risk category, the HR was 4.13 for low risk, 4.61 for intermediate-1, and 2.54 for intermediate-2 according to DIPSS; 3.97 for low risk, 2.84 for intermediate-1, and 1.81 for intermediate-2 according to the age-adjusted DIPSS. The novelty of these models is the prognostic assessment of patients with PMF anytime during their clinical course, which may be useful for treatment decision-making.

Prognostic Factors for Malignant Transformation in Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma

PURPOSEnTo evaluate the natural history of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), identify early predictors of evolution, and assess whether associated conditions correlate with disease progression.nnnPATIENTS AND METHODSnA total of 1,231 consecutive patients with either MGUS (n = 1,104) or SMM (n = 127) diagnosed from July 1975 to March 1998 were included in the study. Cumulative survival probability and cumulative probability of transformation into lymphoproliferative disease were calculated by means of the Kaplan-Meier estimator. Univariate and multivariate Cox models were used to identify possible predictors of malignant evolution.nnnRESULTSnCumulative transformation probability at 10 and 15 years was 14% and 30%, respectively. At a median follow-up of 65 months (range, 12 to 239 months), 64 MGUS cases (5.8%) evolved to multiple myeloma (MM) (n = 43), extramedullary plasmacytoma (n = 1), primary amyloidosis (n = 1), Waldenströms macroglobulinemia (n = 12), non-Hodgkins lymphoma (n = 6), and B-chronic lymphocytic leukemia (n = 1). At a median follow-up of 72 months (range, 12 to 247 months), 25 SMMs (19.7%) evolved to overt MM. A lower evolution risk was observed in MGUS than in SMM (P <.0001). Greater than 5% marrow plasmacytosis, detectable Bence Jones proteinuria, polyclonal serum immunoglobulin reduction, and high erythrocyte sedimentation rate (ESR) were independent factors influencing MGUS transformation. SMM progression correlated with greater than 10% marrow plasma cells, detectable Bence Jones proteinuria, and immunoglobulin (Ig) A isotype. Neither concomitant diseases nor immunosuppression correlated with progression.nnnCONCLUSIONnCareful evaluation of marrow plasmacytosis, urinary paraprotein, background immunoglobulins, ESR, and paraprotein isotype might help identify at presentation patients with benign monoclonal gammopathies requiring stricter monitoring.

Long-term outcomes of 107 patients with myelofibrosis receiving JAK1/JAK2 inhibitor ruxolitinib: survival advantage in comparison to matched historical controls.

Ruxolitinib is JAK1/JAK2 inhibitor with established clinical benefit in myelofibrosis (MF). We analyzed long-term outcomes of 107 patients with intermediate-2 or high-risk MF receiving ruxolitinib at MD Anderson Cancer Center (MDACC) on phase 1/2 trial. After a median of 32 months of follow-up, 58 patients (54%) were still receiving ruxolitinib, with overall survival (OS) of 69%. The splenomegaly and symptom reductions achieved with ruxolitinib were sustained with long-term therapy. Therapy was well tolerated; discontinuation rates at 1, 2, and 3 years were 24%, 36%, and 46%, respectively. OS of 107 MDACC patients was significantly better (P = .005) than that of 310 matched (based on trial enrollment criteria) historical control patients, primarily because of highly significant difference in OS in the high-risk subgroup (P = .006). Furthermore, among MDACC patients, those with high-risk MF experienced the same OS as those with intermediate-2 risk. Patients with ≥ 50% reduction in splenomegaly had significantly prolonged survival versus those with < 25% reduction (P < .0001). Comparison of discontinuation rates and reasons for stopping the therapy to those reported for other 51 patients in the phase 1/2 trial, and 155 ruxolitinib-treated patients in phase 3 COMFORT-I study, suggest that continued therapy with ruxolitinib at optimal doses contributes to the benefits seen, including OS benefit.

Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up

The findings of this study suggest that imatinib mesylate at a daily dose of 600 mg is effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but does not significantly modify longer-term outcome of this condition. See related perspective article on page 1765. Background Imatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and Methods We conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. Results Ninety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. Conclusions Imatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: NCT00514969).

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR‐ABL1 by Q‐RT‐PCR does not equate to eradication of the disease. Digital‐PCR (dPCR), able to detect 1 BCR‐ABL1 positive cell out of 107, has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q‐RT‐PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q‐RT‐PCR for 36 months. Patients losing molecular remission (two consecutive positive Q‐RT‐PCR with at least 1 BCR‐ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow‐up of 21.6 months. Fifty‐two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not‐relapsed patients, 40 (37.0% of total) regained Q‐RT‐PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013–1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class ≥45 to <65 years and 33% of patients ≥65 years [P(χ2)u2009<u20090.0001]. Relapse rates ranged between 100% (<45 years, dPCR+) and 36% (>45 years, dPCR‐). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse. Am. J. Hematol. 90:910–914, 2015.

Hepato‐splenic γδ T‐cell lymphoma: A rare entity mimicking the hemophagocytic syndrome

Hepatosplenic γδ T‐cell lymphoma is a rare histologic type of the peripheral T‐cell lymphomas, clinically characterized by predominant involvement of liver and spleen, no or little adenopathy, and an often aggressive course; it affects mainly adolescents and young adults, with a male predominance. Postthymic T‐cell malignancies are heterogeneous in their clinical and laboratory features. Among the γδ postthymic T‐cell lymphomas, two distinct entities (cutaneous and hepatosplenic, respectively) are reported in the literature. The former shows predominant multiple involvement of the skin and subcutaneous tissue; it occurs mostly in older patients and the phenotype is CD3−, CD4−, CD8−. Because of the small number of reports, the course of the disease was unknown. The latter shows a clinical picture characterized by hepatosplenomegaly, no or little adenopathy, and sometimes systemic symptoms (fever, cytopenias likely due to hypersplenism); it presents a peculiar sinusoidal involvement of liver and spleen. The bone marrow histologic feature often reveals a little infiltration, especially sinusoidal and easily underestimated phenotype: CD2+, CD3+, CD7+, CD5−, CD4−, CD8−, CD44+. Few cases of this lymphoma associated by hemophagocytic syndrome are described (Sun, 1990; Kadin, 1981; Jaffe, 1983). We report a case of a young man with a rapid and fatal course in which the more important clinical feature was hemophagocytosis. The diagnosis of lymphoma was very difficult because of paucity of histologic involvement, and only the rearrangement of TCR γ chain gene by polymerase chain reaction on paraffin sections confirmed a clonal T‐cell proliferation. Am. J. Hematol. 60:61–65, 1999.

Successful CD34+ cell mobilization by intermediate-dose Ara-C in chronic lymphocytic leukemia patients treated with sequential fludarabine and Campath-1H.

Chronic lymphocytic leukemia (CLL) cells could be undetectable by flow cytometry or polymerase chain reaction after sequential treatment with fludarabine and Campath-1H. Concern has been raised regarding the ability to mobilize sufficient peripheral blood progenitor cells (PBPCs) for autografting after purine analogues, and there are few data about PBPC collection after Campath-1H. In all, 16 CLL patients responding to sequential chemo-immunotherapy entered the study. In 10, mobilization regimen consisted of granulocyte colony-stimulating factor (G-CSF) 5–10u2009μg/kg/die. Patients failing mobilization or not achieving the target of 2.5 × 106 CD34+ cells/kg underwent a second attempt using intermediate-dose (ID) Ara-C, 800u2009mg/m2 every 12u2009h for six doses+G-CSF. PBPC collection after G-CSF alone was successful in two out of 10 patients. An adequate number of CD34+ cells were collected after ID Ara-C+G-CSF in eight patients failing the mobilization with G-CSF alone and in five out of six who did not receive G-CSF before. Greater yields of PBPCs were collected with Ara-C+G-CSF compared with G-CSF alone (13.8 vs 3.3). The extrahematologic toxicity was manageable. In conclusion, PBPC collection is feasible in CLL patients treated with sequential therapy including fludarabine and Campath-1H. Excellent yields were obtained in 92.8% of patients primed with ID Ara-C+G-CSF.

Effects and outcome of a policy of intermittent imatinib treatment in elderly patients with chronic myeloid leukemia

We report a study of an alternative treatment schedule of imatinib (IM) in chronic myeloid leukemia (CML). Seventy-six Philadelphia-positive (Ph+), BCR-ABL-positive patients aged 65 years or older who had been treated with IM for more than 2 years and who were in stable complete cytogenetic response (CCgR) and major molecular response (MMR) were enrolled in a single-arm study to test the effects of a policy of intermittent IM (INTERIM) therapy for 1 month on and 1 month off. With a minimum follow-up of 4 years, 13 patients (17%) lost CCgR and MMR and 14 (18%) lost MMR only. All these patients resumed continuous IM and all but one (lost to follow-up) regained CCgR and MMR. No patients progressed to accelerated or blastic phase or developed clonal chromosomal abnormalities in Ph+ cells or BCR-ABL mutations. In elderly Ph+ CML patients carefully selected for a stable CCgR (lasting >2 years), the policy of INTERIM treatment affected the markers of residual disease, but not the clinical outcomes (overall and progression-free survival). This trial was registered at www.clinicaltrials.gov as NCT 00858806.

Late Response to Cyclosporine in Refractory Thrombotic Thrombocytopenic Purpura

Plasma exchange (PEX) with fresh frozen plasma, usually in association with steroid therapy, has been shown to be the firstline treatment of thrombotic thrombocytopenic purpura. It works by removing ultralarge von Willebrand factor (vWF) multimers and inhibitory antibody and by supplying normal protease. For patients with disease refractory to PEX, there is no standardized treatment. Limited and sporadic success with different therapies (vincristine sulfate, prostacyclin, intravenous immunoglobulins, splenectomy) has been described. We report the case of a woman who developed refractory disease after an initial response to PEX and despite a very high number of PEX procedures performed. Low activity (<5%) of serum vWF-cleaving protease and a low level of protease inhibitor were documented. The patient had a slow but sustained response when oral cyclosporine was administered concomitantly with PEX, which was slowly tapered. The activity of serum vWF-cleaving protease normalized. At relapse, treatment with cyclosporine, added after the failure of steroids and PEX, led to a lasting response. It is possible that in some cases cyclosporine therapy must be of particularly long duration before being considered ineffective.Int J Hematol. 2002;76:284-286.

Splanchnic vein thrombosis in myeloproliferative neoplasms: Risk factors for recurrences in a cohort of 181 patients

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd–Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.