Germana Beltrami

Reduced intensity conditioning for allograft after cytoreductive autograft in metastatic breast cancer

The benefits of allografting noted in some malignant diseases might be safely extended to metastatic breast cancer by a combination of cytoreduction with high-dose chemotherapy (HDT) and autologous stem-cell transplant (ASCT) with graft-versus-tumour effect mediated by transplanted donor immune cells with nonmyeloablative allografting (reduced intensity conditioning transplantation, RICT). 17 patients with heavily pretreated disease were given tandem transplants. 13 patients sustained donor engraftment. Three had partial remission after HDT and ASCT and complete remission after RICT; they achieved full chimerism and all developed graft-versus-host disease (GVHD) before regression of cancer. Another patient did not respond to HDT and ASCT but had partial remission after RICT, giving an overall response rate of 24%. Five patients had grade II or higher acute GVHD and five had extensive chronic GVHD. No non-relapse-related deaths occurred during the first 100 days. Five patients (29%) were alive 90-2160 days (median 1320) after RICT. This two-step approach is feasible in patients with metastatic breast cancer.

First line Fludarabine treatment of symptomatic chronic lymphoproliferative diseases: clinical results and molecular analysis of minimal residual disease

Abstract: Fludarabine (25 mg/m2 for 5 d, every 4 wk, for 6 courses) was administered as first line therapy in 32 symptomatic chronic lymphoproliferative diseases. All CLL patients achieved at least partial response (5 CR, 2 nPR, 9 PR) but 44% of patients relapsed. In LG‐NHLs response and relapse rate were similar. Haematological toxicity was low. VDJ rearrangement PCR analysis was performed on marrow samples at diagnosis and at the time of response evaluation. In the 3 patients who underwent high dose therapy with peripheral blood progenitor cell rescue analysis was also performed on apheresis samples and on marrow samples at the end of the procedure. Clonal VDJ rearrangement was always evident after Fludarabine therapy even in those patients who achieved histological and immunophenotypic complete remission, whereas it disappeared in 2 of 3 patients who underwent HDT. Our data confirm that Fludarabine monotherapy can reduce the neoplastic mass to a subclinical level and suggest the possibility that high dose therapy might produce true complete remission.

WT1 overexpression at diagnosis may predict favorable outcome in patients with de novo non-M3 acute myeloid leukemia

Abstract We reviewed the frequency and prognostic significance of FLT3 (fms-like tyrosine kinase receptor-3) and NPM (nucleophosmin) gene mutations and WT1 (Wilms’ tumor) and BAALC (brain and acute leukemia, cytoplasmic) gene expression in 100 consecutive patients with intermediate and poor cytogenetic risk de novo acute myeloid leukemia (AML) receiving conventional anthracycline–AraC based therapy. We observed a strict relationship between unfavorable karyotype and BAALC >1000 (p = 0.0001). Multivariate analysis of 81 patients with intermediate karyotype revealed that younger age (p = 0.00009), NPM gene mutation (p = 0.002), and WT1 >75th percentile (>2365) (p = 0.003) were independent, positive factors for complete remission (CR). WT1 expression above 2365 was correlated also to longer event-free survival (EFS) and overall survival (OS) in the same subset of patients (p = 0.003 and p = 0.02, respectively); the same finding occurred in younger patients with AML with intermediate karyotype (p = 0.008 and p = 0.01, respectively). In patients with intermediate karyotype, FLT3 internal tandem duplication (ITD) negatively affected EFS (EFS at 30 months: 30% vs. 6% in FLT3-ITD negative and FLT3 positive patients, respectively; p = 0.01) and OS (OS at 30 months: 38% vs. 20%, p = 0.03). The positive prognostic value of high WT1 expression does not have a clear explanation; it may be implicated either with WT1 anti-oncogenic function, or with the stimulating effect of WT1 oncogene on the leukemic cellular cycle, possibly associated with an enhanced response to chemotherapy.

Combined use of autografting and non-myeloablative allografting for the treatment of hematologic malignancies and metastatic breast cancer.

Conventional allografting has relied on a combination of myeloablative and immunosuppressive therapies, which results in substantial morbidity and mortality. To circumvent the problems inherent to the toxicity and treatment related deaths associated with allografting, it has been recently assessed that it is possible to achieve engraftment of donor hematopoietic stem cells (HSC) after immunosuppressive therapy combined or not with myelosuppressive but nonmyeloablative therapy.1-5The basic observation which serves as the rationale for non-myeloablative hematopoietic stem cell transplantation (NST) originates from the documented therapeutic potential of adoptive transfer of alloreactive donor lymphocytes to eradicate resistant malignant host cells escaping maximally tolerated doses of chemoradiotherapy. This is an observation that has provided an option for cure of patients with a large variety of hematologic malignancies,6-8especially chronic myeloid leukemia (CML).7-14

Management of early stage chronic myeloid leukemia: state-of-the-art approach and future perspectives.

Tyrosin kinase inhibitors (TKI), have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to an impressive increase in overall survival rates and allowing many CML patients to achieve a close-to-normal life expectancy. Unfortunately, there is growing evidence that these drugs are not curative, about 30-35% of the patients who receive imatinib become resistant or discontinue the drug because of side effects; moreover, 15% of all patients become resistant to all TKIs, a condition which represents the biggest challenge in CML treatment. Recent progresses in CML stem cell biology have identified new agents and therapeutic strategies that can be used to target the CML stem cell compartment. These studies have opened new perspectives and have highlighted key strategies for treating, and possibly curing, CML in the upcoming years.

Chronic Myeloid Leukaemia - The Choice of Therapy and Future Perspectives

Recently, the advent of imatinib has opened a new era in the treatment of chronic myeloid leukaemia (CML), leading to an impressive increase in overall survival rates. Today, many CML patients can expect to survive, if properly managed, likely similar to the general population. Recent progresses in CML stem cell biology have identified new leukogenetic pathways and therapeutic strategies that can be used to target the CML stem cell compartment. These studies have opened new perspectives in CML therapy and have highlighted major strategies for treating, and possibly eradicating, CML in the upcoming years.

Haploidentical bone marrow transplantation in patients with advanced myelodysplastic syndrome

In 1992, my coworkers and I published a paper in the American Journal of Hematology entitled “On the laboratory problems of diagnosing mild von Willebrand’s disease” and elsewhere another report “On the intraindividual and gender variability of hemostatic components.” Data in both papers were based on fifteen young healthy women, sampled 10-16 times during one month (one menstrual cycle) and on six young men sampled six times during one month. Considerable variations were found in the values of FVIII activity (FVIIIc), VWF:Ag, and VWF ristocetin cofactor (VWF:Rcof) activity, in both genders. In 3 of the 15 female volunteers, the VWF Ag values on some samples were so low that they could be suspected to have a mild form of von Willebrand’s disease (VWD) although they had no history of bleeding; this was associated with high individual variability in VWF:Ag. In one of these females, VWF:Ag varied from a low of 0.25 IU/mL to a high of 1.4 IU/mL (see Fig 1 in reference # 1). In 2001 € Onundarsson et al. investigated VWF activity ((Rcof), VWFAg, and FVIIIc during one menstrual cycle (early, middle, and late phase), in 95 young healthy women but found no comparable variation of these three parameters. Subsequently, we learned that the subjects with the highest VWF variability had run before the blood sampling took place. In our 1992 study, we failed to inform the volunteers that physical and mental stress could influence the results. In 2002 Miller et al. studied 175 women sampled during one cycle and found lowest levels of all three parameters VWF:Ag, VWF:Rcof, and FVIIIc during days 1-4 and highest during days 5-11. In 2007 we and others on behalf of ISTH/SSC summarized key preanalytical requirements such as abstain from physical exercise for at least 24 h; abstain from fatty food and smoking before sampling; take samples in morning hours after sitting in a relaxed position and environment for 20-30 min for equilibration of the hydrostatic pressure. In addition, for the diagnosis of VWD in fertile women, samples should be obtained on cycle days 1-4. Thus, I feel that the limitations of our 1992 study provide an explanation for its discrepant values, and I welcome the opportunity to correct the records.